JCS 2017 Guideline on Management of Vasculitis Syndrome　― Digest Version ―

Abbreviations

AAV	ANCA-associated vasculitis
ACR	American College of Rheumatology
ADA	adalimumab
ANCA	anti-neutrophil cytoplasmic antibody
AZA	azathioprine
bDMARDs	biologic disease-modifying anti-rheumatic drugs
c-ANCA	cytoplasmic ANCA
CG	cryoglobulin
CHCC	Chapel Hill Consensus Conference
Cr	creatinine
CT	computed tomography
CRP	C-reactive protein
CyA	cyclosporine
CV	cryoglobulinemic vasculitis
CY	cyclophosphamide
DMARDs	disease-modifying anti-rheumatic drugs
eGFR	estimated glomerular filtration rate
EGPA	eosinophilic granulomatosis with polyangiitis
ESR	erythrocyte sedimentation rate
ETN	etanercept
EULAR	European League Against Rheumatism
EVG	Elastica van Gieson
FDG	fluorodeoxyglucose
GC	glucocorticoid
GCA	giant cell arteritis
GBM	glomerular basement membrane
GPA	granulomatosis with polyangiitis
GRADE	Grading of Recommendations, Assessment, Development and Evaluation
GWAS	genome-wide association study
HBV	hepatitis B virus
HCV	hepatitis C virus
HE	hematoxylin and eosin
HLA	human leukocyte antigen
HUV	hypocomplementemic urticarial vasculitis
HUVS	hypocomplementemic urticarial vasculitis syndrome
IFX	infliximab
IL	interleukin
IVCY	intravenous cyclophosphamide
IVIG	intravenous high-dose immunoglobulin
LV-GCA	large-vessel giant cell arteritis
MMF	mycophenolate mofetil
MPA	microscopic polyangiitis
MPO	myeloperoxidase
mPSL	methylprednisolone
MRA	malignant rheumatoid arthritis
MHLW	Ministry of Health, Labour and Welfare
MRI	magnetic resonance imaging
MTX	methotrexate
PAN	polyarteritis nodosa
p-ANCA	perinuclear ANCA
PET	positron emission tomography
PMR	polymyalgia rheumatica
PR3	proteinase 3
PSL	prednisolone/prednisone
RA	rheumatoid arthritis
RF	rheumatoid factor
RPGN	rapidly progressive glomerulonephritis
RTX	rituximab
RV	rheumatoid vasculitis
SLE	systemic lupus erythematosus
SNP	single nucleotide polymorphism
TCZ	tocilizumab
TNF	tumor necrosis factor

I. Notes on the Revision

1. Background of the Guidelines

Vasculitis is a general term for diseases that cause inflammation in the blood vessels themselves. Table 1 shows the 2012 revised version of Chapel Hill Consensus Conference (CHCC) classification (CHCC2012).¹ In 2007, the Guidelines for Management of Vasculitis Syndrome were published by a joint working group staffed primarily by the Japanese Circulation Society and the Research Committee on Intractable Vasculitis of the MHLW of Japan.² This time, based on the subsequent development of basic and clinical research, the 2017 totally revised version of the Guidelines for Management of Vasculitis Syndrome and the digest version is published 9 years after the publication of its first version. This digest version plainly describes important points and is compiled for quick reference in daily clinical practice. We hope that it is of use in clinics.

Table 1. Categories and Diseases of Vasculitis Adopted by CHCC2012¹

Large vessel vasculitis, LVV

Takayasu arteritis, TAK*

Giant cell arteritis, GCA*

Medium vessel vasculitis, MVV

Polyarteritis nodosa, PAN*

Kawasaki disease, KD

Small vessel vasculitis, SVV

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, AAV

Microscopic polyangiitis, MPA*

Granulomatosis with polyangiitis (Wegener’s), GPA*

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss), EGPA*

Immune complex SVV

Anti-glomerular basement membrane (anti-GBM) disease*

Cryoglobulinemic vasculitis, CV*

IgA vasculitis (Henoch-Schönlein), IgAV*

Hypocomplementemic urticarial vasculitis, HUV (anti-C1q vasculitis)*

Variable vessel vasculitis, VVV

Behçet’s disease, BD*

Cogan’s syndrome, CS

Single-organ vasculitis, SOV

Cutaneous leukocytoclastic angiitis

Cutaneous arteritis

Primary central nervous system vasculitis

Isolated aortitis

Others

Vasculitis associated with systemic disease

Lupus vasculitis

Rheumatoid vasculitis*

Sarcoid vasculitis

Others

Vasculitis associated with probable etiology

Hepatitis C virus-associated cryoglobulinemic vasculitis*

Hepatitis B virus-associated vasculitis

Syphilis-associated aortitis

Drug-associated immune complex vasculitis

Drug-associated ANCA-associated vasculitis

Cancer-associated vasculitis

Others

(Jennette JC, Falk RJ, Bacon PA, et al., Arthritis Rheum 2013,¹ John Wiley and Sons. (c) 2013, American College of Rheumatology.) *Diseases covered by the present guidelines.

2. Basic Principles for Preparation of the Guidelines

2.1 Target Diseases

Vasculitis is commonly referred to CHCC2012 (Table 1),¹ and is classified into large, medium, and small vessel vasculitides based on the size of the affected blood vessel. The present guidelines cover large vessel vasculitis (Takayasu arteritis and giant cell arteritis), Buerger disease, a medium-vessel vasculitis (polyarteritis nodosa) and small vessel vasculitides [anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis {microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA)}, immune complex small vessel vasculitis (anti-GBM disease, cryoglobulinemic vasculitis, IgA vasculitis and hypocomplementemic urticarial vasculitis)].¹ Kawasaki disease, which is a medium vessel vasculitis, was excluded from target diseases in consideration of the clinical fields of the guidelines users. CHCC2012 covers variable vessel vasculitis, single-organ vasculitis, vasculitis associated with systemic disease, and vasculitis associated with probable etiology in addition to the above vasculitides.¹ Behçet’s disease and rheumatoid vasculitis were selected from them as target diseases in consideration of the frequency of encounters in clinical settings in Japan and diagnostic importance.

2.2 Common Procedures for the Development of Clinical Practice Guidelines

The definition of clinical practice guidelines and the procedure for their preparation change with time. The World Health Organization (WHO) defines clinical practice guidelines as “any document developed by the World Health Organization containing recommendations for clinical practice or public health policy”³ and adopts the GRADE system for their preparation. The Minds Guidelines Center of Japan defines clinical practice guidelines as “a document that presents appropriate recommendations to assist patients and practitioners in making decisions regarding clinical practice of high importance, based on the body of evidence evaluated and integrated by systematic reviews and the balance between benefits and harms”.⁴

2.3 Methods for the Development of the Present Guidelines

Although clinical practice guidelines are recommended to be developed using the GRADE or Minds system, it is extremely difficult to completely apply these methods to each of rare vasculitides. For these reasons, recommendations for the treatment of MPA and GPA were developed using the GRADE system, but the conventional review style was adopted for the other target diseases. The classification of recommendation and level of evidence for other target diseases were determined using the criteria shown in Tables 2 and 3.

Table 2. Classification of Recommendations

Class I	Treatment should be administered
Class IIa	It is reasonable to administer treatment
Class IIb	Treatment may be considered
Class III	Treatment should not be administered since it is not helpful and may be harmful

Table 3. Levels of Evidence

Level A	Data derived from multiple randomized clinical trials or meta-analyses
Level B	Data derived from a single randomized trial or nonrandomized studies
Level C	Only consensus opinion of experts

II. Takayasu Arteritis

1. Definition/Epidemiology/Subclassification

1.1 Definition

Takayasu arteritis is a large vessel vasculitis that affects the aorta and its primary branches, coronary arteries, and pulmonary arteries. Its principal manifestations are systemic inflammation, pain due to vasculitis, and vascular stenosis, occlusion, and dilatation, and poses problems including disorders of various organs due to disturbance of the blood flow and aneurysms even after remission of inflammation. Its symptoms are diverse and non-specific, but its early diagnosis has become possible, and the prognosis has been improved.^5,6

1.2 History

In 1908, Mikito Takayasu reported a 22-year-old woman as a case of “Peculiar changes of the central retinal vessels” (Figure 1).⁷ Absence of the pulses of the radial artery was pointed out. In 1951, Kentaro Shimizu, et al., amassed 25 cases and reported them under the name of “pulseless disease”.⁸ Hideo Ueda, et al., renamed the disease “aortitis syndrome.^9,10

Figure 1.

Dr. Mikito Takayasu (Left) and funduscopic image of a patient (Right). Wreath-like vascular anastomosis is surrounding the optic disc. (Mikito Takayasu, 1908⁷)

1.3 Epidemiology

1.3.1 Incidence by Age and Sex

In Japan, more than 6,000 patients with this disease have been registered, and about 300 new patients are counted annually (Figure 2).¹¹ The male/female ratio is about 1:9, and the age of onset in women peaks around 20 years. The symptoms are not only diverse but also often non-specific, and many cases are still considered to be left undiagnosed.

Figure 2.

Changes in the number of certificates of receipt of care for specified disease issued for Takayasu arteritis. (Data by the Japan Intractable Diseases Information Center¹¹)

1.3.2 Geographic Differences

Takayasu arteritis is prevalent in Asia and Middle East, and females tend to be more often affected in both regions. While carotid artery lesions are characteristic in Japan and South America, hypertension due to lesions primarily affecting the abdominal aorta is frequently observed in Asian countries.

1.4 Classification

The classification based on the distribution of vascular lesions proposed by Numano et al. is used (Figure 3).^12–14 The cases are divided into those with lesions in the 3 branches of the aortic arch and those with lesions also below the diaphragm. This classification is based on angiographic findings, but it should be noted that inflammatory thickening is diffusely observed also in regions with no marked changes in the vascular lumen.¹⁵

Figure 3.

Types of Takayasu arteritis based on the distribution of vascular lesions and their frequencies (Cited from Hata A, et al. 1996,¹³ Mitsuaki Isobe, 2014,¹⁴ Watanabe Y, et al. 2015¹²). Classification based on angiographic findings by Numano et al.¹³ Type I: Branches of the aortic arch. Type IIa: Ascending aorta, aortic arch and its branches. Type IIb: IIa lesions+thoracic descending aorta. Type III: Thoracic descending aorta, abdominal aorta, and/or renal arteries. Type IV: Abdominal aorta and/or renal arteries. Type V: Type IIb+IV (ascending aorta, aortic arch and its branches, and thoracic descending aorta as well as abdominal aorta and/or renal arteries). The presence of coronary artery lesions and pulmonary artery lesions is indicated by C(+) and P(+), respectively.

2. Pathogenesis

Takayasu arteritis is estimated to be caused by destruction of elastic arteries, particularly, the aorta, by autoimmune mechanisms triggered by environmental factors including infection based on genetic factors.

2.1 Genetic Factors

HLA-B*52 has been reported to be related to the pathogenesis of this disease.^16,17 In addition, SNP of the IL12B gene has recently been identified as a susceptibility factor.¹⁸

2.2 Environmental Factors

Although an involvement of viral infection is suspected, viruses that may induce Takayasu arteritis have not been identified.

2.3 Mechanism of Vascular Damage

Cells including T cells, macrophages, and NK cells along with cytokine abnormalities are considered to damage the vascular wall, but detailed mechanism has not been elucidated.

3. Pathological Findings

Takayasu arteritis, which is classified as a large vessel vasculitis, often affects the aorta and its primary branches. Macroscopically, all layers of the vascular wall are thickened in the affected arteries, and the luminal surfaces of the lesions show irregularities and macular or granular changes. Normal areas are often present between lesions (Figure 4). In the adventitia, vaguely circumscribed fibrotic thickening is notable. In the scar stage, the arterial wall develops plate-like calcification and presents a lead-pipe-like appearance (Figure 5).^19,20

Figure 4.

Gross appearance of the aorta with Takayasu arteritis 1. Brownish lesions showing coarse luminal surface are observed in the aortic arch and abdominal aorta. Skip lesions are formed as normal areas interpose between lesions. A teenage male.

Figure 5.

Gross appearance of the aorta with Takayasu arteritis 2. The aorta shows a bark-like luminal surface and marked fibrotic thickening accompanied by calcification. A female in her 50 s.

Histologically, in an early stage, adventitial mononuclear cell infiltration accompanied by inflammatory cell infiltration to areas around the vasa vasorum is observed, and the media exhibits infarct lesions and granulomatous arteritis mixed with multinucleated giant cells that have phagocytosed fragmented elastic fibers (Figure 6).^19–22 As a result of inflammation occurring on the adventitial side of the tunica media, elastic fibers of the media are lost in a moth-eaten pattern. While diffuse fibrosis is caused in the media and adventitia, the intima also develops marked thickening due to cell fibrosis, resulting in luminal stenosis (Figure 7).^19,20

Figure 6.

Histological findings of the aorta in Takayasu arteritis. Along with diffuse fibrosis of the adventitia, the outer side of the media is invaded by inflammation from the adventitia, resulting in scattered infarct foci in the media (outlined arrow). In the lesions, multinucleated giant cells appear in addition to histiocytes and lymphocytes, presenting an image of granulomatous inflammation. Giant cells phagocytose elastic fibers (filled arrow). (Left: HE staining, Right: anti-elastin antibody staining)

Figure 7.

Histological findings of Takayasu arteritis. Histological findings of the aorta (Left) and brachiocephalic artery (Right). Along with diffuse fibrosis of the adventitia, moth-eaten loss of elastic fibers primarily on the outer side of the media is observed due to inflammation from the adventitia. Intimal thickening is localized at the sites of medial damage and not observed in areas where elastic fibers are intact. (EVG staining)

In the scar stage, the adventitia is thickened due to marked fibrosis, and vasa vasorum with thickened wall is often observed. The arterial intima shows progressive fibrotic thickening, and major branches of the aorta often develop luminal stenosis. In addition, despite the presence of marked fibrotic lesions, active inflammation accompanied by multinucleated giant cells is often observed in the peripheries of the lesions.¹⁹ With the recent increases in long-time survivors due to early detection and improvements in treatments, cases of Takayasu arteritis accompanied by atherosclerosis, aortic aneurysm, or aortic insufficiency are increasing.

4. Symptoms

Initial signs and symptoms include FUO, malaise, neck pain, pain in various regions, and dizziness, which resemble those of upper airway inflammation (Table 4).¹² They are followed by signs and symptoms caused by vascular lesions.

Table 4. Chief Complaints of Takayasu Arteritis at Onset

Head and neck	365 (26.6)
Dizziness/vertigo	129 (9.4)
Headache	113 (8.2)
Syncope	36 (2.6)
Masseter claudication	5 (0.4)
Neck pain	133 (9.7)
Eyes	45 (3.3)
Sight loss	2 (0.1)
Visual disorder	37 (2.7)
Upper limbs	238 (17.3)
Pulselessness	67 (4.9)
Systolic blood pressure difference (≥10 mmHg)	53 (3.9)
Fatigue	63 (4.6)
Coldness	23 (1.7)
Numbness	49 (3.6)
Heart	153 (11.1)
Breathlessness	61 (4.4)
Palpitation	29 (2.1)
Feeling of chest tightness	21 (1.5)
Lung	92 (6.7)
Hemosputum	11 (0.8)
Sensation of dyspnea	61 (4.4)
Hypertension	54 (4.0)
Lower limbs#	49 (3.6)
Body pain*	218 (15.9)
Systemic manifestation	562 (41.0)
Fever	476 (34.7)
Malaise	166 (12.1)
Fatigue	23 (1.7)

Data are expressed as n (% of 1,372 patients). ^#Leg claudication, fatigue, coldness, numbness, or pain. *Chest, back, or abdominal pain. (Cited from Watanabe Y, et al. Circulation. 2015,¹² (c) 2015 by American Heart Association, Inc.)

When objective findings are included, signs of ischemia of the upper limbs such as a difference in blood pressure between the left and right arms and the absence of pulses in the upper limb are observed most frequently in about 66% of the patients, followed by dizziness and headache observed in about 48%. About 14% of the patients had visual disorders, and about 40% of the patients were hypertensive (Table 5).¹² In Takayasu arteritis, many skin lesions (erythema nodosum) are often noted in the lower limbs, particularly, on the anterior aspect of the tibial region (Figure 8).

Table 5. Clinical Features of Takayasu Arteritis

	Prevalence (%)
Head and neck	47.5
Eyes	14.3
Upper limbs	66.4
Heart	37.8
Lung	10.8
Hypertension	38.0
Intermittent claudication in the legs	9.5
Systemic manifestation	74.9

Data are expressed as % of 1,372 patients.

Head and neck ................ Dizziness/vertigo, Headache, Syncope, Hemiplegia, Masseter claudication

Eyes ................................ Sight loss, Visual disorder, Aphose

Upper limbs ..................... Pulselessness, systolic blood pressure difference (≥10 mmHg), Fatigue, Coldness, Numbness

Heart ............................... Breathlessness, Palpitation, Feeling of chest tightness

Lung ................................Hemosputum, Cough, Sensation of dyspnea

Systemic manifestation ... Fever, Malaise, Fatigue

(Excerpts from Watanabe Y, et al. 2015¹²)

Figure 8.

Skin lesions observed in Takayasu arteritis (erythema nodosum). Skin lesions (erythema nodosum) often occurs in large numbers in the lower limbs, particularly, on the anterior aspect of the tibial region.

Complications include aortic insufficiency, aortic aneurysm, aortic dissection, ischemic attacks of the brain, pulmonary infarction, angina pectoris, subclavian steal syndrome, atypical coarctation of the aorta, and renovascular hypertension (Table 6).¹² As observed in Table 6, complications vary widely including those caused by stenotic lesions and dilated lesions and tend to occur in large numbers. Symptoms are also diverse with some patients remaining asymptomatic and others developing various symptoms in an early stage. Moreover, Takayasu arteritis may be complicated by symptoms of autoimmune diseases such as inflammatory bowel disease, erythema nodosum, and arthritis.

Table 6. Complications of Takayasu Arteritis

	Prevalence (%)
Aortic valve regurgitation	33.2
Grade I*	14.1
Grade II*	8.6
Grade III*	9.8
Grade IV*	6.2
Ischemic heart disease	10.6
Eyes	14.0
Cataract	7.6
Funduscopic findings	8.7
Aortic aneurysm	15.0
Aortic dissection	1.9
Renal disorder	11.2
Hypertension	39.4
Renal artery stenosis	13.1
Brain ischemia	13.2
Thrombosis	3.7
Hemorrhage	0.9

Data are expressed as % of 1,372 patients. *Regurgitation grade measured by color Doppler ultrasound. (Excerpts from Watanabe Y, et al. 2015¹²)

5. Laboratory and Imaging Findings

5.1 Laboratory Findings

Currently, there are no specific findings on blood or biological tests for the diagnosis of Takayasu arteritis. Therefore, non-specific indices of inflammation including CRP and ESR are used as the biomarkers for the diagnosis of Takayasu arteritis. Increasing lines of evidence suggest that the presence of specific human leucocyte antigen (HLA) class I molecules, such as HLA-B*52 and HLA-B*67,^23,24 are related to clinical manifestations and genetic predisposition of Takayasu arteritis. Thus, the presence of HLA-B*52 and HLA-B*67 are useful as adjunct to the diagnosis of Takayasu arteritis.

Laboratory findings useful for the evaluation of the activity of Takayasu arteritis include an increase in the number of leukocytes, exacerbation of anemia, and abnormalities of immunological indices such as immunoglobulin and complement levels as well as the elevation of CRP and ESR. Particularly, CRP is useful for the follow-up of patients who have received GC therapy,^25,26 but it should be noted that CRP cannot be used for the evaluation of the activity of Takayasu arteritis in patients administered TCZ, a humanized antihuman IL-6 receptor monoclonal antibody.

Although serum amyloid A,²⁷ Pentraxin-3,^28–30 IL-6,³¹ IL-18,³² sRAGE,³³ soluble ICAM-1,³⁴ and matrix metaprotease³⁵ have also been reported to be useful for the evaluation of the activity of Takayasu arteritis, these biomarkers have not been used for the actual clinical diagnosis of Takayasu arteritis and are not covered by health insurance in Japan as of 2018.

5.2 Imaging Findings

CT and MRI are recommended imaging modalities for the initial work-up of Takayasu arteritis (Figure 9).

Figure 9.

Imaging findings of Takayasu arteritis. (A) Irregular contour of the descending aorta on chest plain radiography. (B) Calcification of the aortic wall on CT angiography (maximum intensity projection image). (C) Diffuse/circumferential thickening of the intima-media complex on carotid artery ultrasonography.

5.2.1 Chest Radiography

Irregular contour of the descending aorta is noted in the margin of the descending aorta (Figure 9A, arrows).³⁶

5.2.2 CT

By CT, large vessels, coronary arteries, and various organs are evaluated (Figure 9B).

Dynamic CT angiography protocol consisted of a set of non-contrast, arterial-phase and late-phase scans is recommended for the initial examination, but a reduction of radiation exposure must be considered on follow-up examinations. On non-contrast images, the density of the arterial wall appears higher than the lumen (Figure 10A).³⁷ Arterial phase images demonstrates clear contrast between the lumen and wall (Figure 10B). In the late-phase images, the “double ring-like pattern” is observed in the aortic wall in the early stage of Takayasu arteritis (Figure 10C).

Figure 10.

Dynamic CT images of Takayasu arteritis. (A) Non-contrast image. (B) Arterial-phase image. (C) Late-phase image.

In the chronic stage, stenosis or dilatation of the lumen, circumferential calcification of the wall (Figure 9B), and development of collaterals are noted.^36,38

5.2.3 MRI

By contrast-enhanced MR angiography, the vascular lumen, wall thickening, and contrast enhancement of the wall are evaluated (Figures 11 and 12).^15,39,40 Morphological information of large vessels is also available by non-contrast MR angiography. For long-term follow-up, MRI is recommended because of no risk for radiation exposure.⁴¹

Figure 11.

Gadolinium-contrast-enhanced MRA. Mild dilatation of the ascending aorta and occlusion of the brachiocephalic artery as well as proximal segments of the left common carotid and subclavian arteries are observed.

Figure 12.

MR images of Takayasu arteritis. (A) Non-contrast T1-weighted image. (B) Gadolinium-contrast-enhanced T1-weighted image. Wall thickening with contrast enhancement are appreciated in the left common carotid artery.

5.2.4 Angiography

Angiography is indicated for endovascular treatment and evaluation of coronary and small arteries.⁴²

5.2.5 Ultrasonography

In Takayasu arteritis, a hyperechoic area is observed in the thickened wall of the common carotid artery (macaroni sign) (Figure 9C).^43,44

5.2.6 ¹⁸F-FDG PET/PET-CT

Accumulation of ¹⁸F-FDG in the wall of large vessels is a finding useful for the diagnosis of Takayasu arteritis (Figure 13).⁴⁵ Since April 2018, it has become possible to perform ¹⁸F-FDG PET/PET-CT under health insurance at some PET facilities in Japan for patients with large vessel vasculitis when the localization or activity of the lesion is difficult to determine by other examinations.

Figure 13.

¹⁸F-FDG PET-CT fusion images of Takayasu arteritis. Accumulation is noted in the thoracic aorta and the branches of the aortic arch.

5.3 Ophthalmological Examinations

5.3.1 Manifestations Related to Ocular Ischemia

18–30% of patients with Takayasu arteritis have ocular symptoms such as blurred vision, transient visual loss, and eye pain,^46,47 and most of these symptoms come from circulatory disturbance to the eye. Ophthalmological examinations can reveal manifestations related to ocular ischemia including Takayasu retinopathy (hypoperfusion retinopathy), ischemic optic neuropathy, and rubeosis iridis caused by type I, II, and V Takayasu arteritis (Numano’s classification by angiography)¹³ (Figure 3).^12–14 In Takayasu retinopathy, tortuosity of retinal vessels, dilated retinal veins, retinal microaneurysms, hemorrhage, and cotton-wool spots can be seen in the fundus (Figure 14). Multiple microaneurysms scattered in the retina and wreath-like vascular anastomoses around the optic disc indicating prolonged retinal ischemia are characteristic findings (Figure 1).⁷ On fluorescein fundus angiography, prolonged arm-to-retina circulation time, occlusion of capillaries, microaneurysms, and arteriovenous anastomoses can be observed, and neovascularization in the retina and optic disc can be seen in the severe cases (Figure 15).

Figure 14.

Funduscopic findings in Takayasu arteritis. The retinal veins are markedly dilated, and retinal hemorrhage and soft exudates are observed.

Figure 15.

Fluorescein fundus angiography findings in Takayasu arteritis. Dilatation and caliber variation of the retinal veins and microaneurysms are observed. Retinal neovascularization occurs in the upper peripheral areas.

5.3.2 Ocular Manifestations Due to Systemic Hypertension

In Type III, IV, or V Takayasu arteritis, which may be complicated by hypertension due to abdominal aorta/renal artery stenosis, hypertensive retinopathy may be observed. In this condition, narrowing of the retinal artery, retinal edema, white spots, hemorrhage, and optic disc edema develop. Although reports are few, hypertensive choroidopathy may also develop.

6. Diagnostic Methods and Criteria

6.1 Diagnostic Criteria

For the present revision of the guidelines, the Subcommittee of Large Vessel Vasculitis of the MHLW Research Committee for Intractable Vasculitis prepared new diagnostic criteria for Takayasu arteritis with partial modifications of those in the Guidelines 2008 reflecting progress in medicine without changing their basic principles (Table 7). The diagnosis is made primarily by imaging (CT, MRI, ultrasonography, PET-CT, chest radiography, and angiography). According to the diagnostic criteria in Table 7, Takayasu arteritis is diagnosed when there is 1 or more of the symptoms listed in A), when there are either multiple or diffuse hypertrophic lesions, stenotic lesions (including occlusions), or dilated lesions (including aneurysms) in the aorta or its primary branches or both as in B), and when the differential diagnoses shown in C) can be excluded.

Table 7. Diagnostic Criteria for Takayasu Arteritis

A. Signs and symptoms

1. Systemic signs and symptoms: Fever, generalized malaise, easy fatigability, lymphadenopathy (cervical), hypertension in younger patients (≥140/90 mmHg)

2. Pain: Carotidynia, chest pain, back pain, lower back pain, shoulder pain, upper limb pain, lower limb pain

3. Visual signs and symptoms: Transient or persistent visual impairment, preocular bright or dark sensation, loss of vision, fundus changes (hypotensive changes, hypertensive changes)

4. Head and neck signs and symptoms: Headache, toothache, jaw claudication,*a dizziness, hearing impairment, tinnitus, syncope, cervical vascular murmurs, hemiplegia

5. Upper limb signs and symptoms: Numbness, cold sensation, difficulty in arm raising, claudication,*b abnormal pulse and blood pressure (weakness or loss of radial artery pulse or left-right difference of ≥10 mmHg), increased pulse pressure (related to aortic insufficiency)

6. Lower limb signs and symptoms: Numbness, cold sensation, weakness, claudication, abnormal pulse and blood pressure (augmented or weakened pulse of lower limb arteries, reduced blood pressure, blood pressure difference between upper and lower limbs*c)

7. Chest symptoms: Shortness of breath, palpitation, dyspnea, bloody sputum, sensation of chest compression, anginal symptoms, arrhythmia, cardiac murmur, back vascular murmur

8. Abdominal signs and symptoms: Abdominal vascular murmur, complication by ulcerative colitis

9. Skin signs and symptoms: Erythema nodosum

*a Intermittent mastication due to pain caused by mastication

*b Intermittent exertion of the upper limbs due to pain and weakness caused by exertion

*c Instances other than “10–30 mmHg higher in the lower limb than upper limb”

B. Examination findings

Imaging examination findings: In the aorta or its primary branches*a or both, multiple*b or diffuse hypertrophic lesions,*c stenotic lesions (including occlusions),*d or dilated lesions (including aneurysms)*d detected.

*a The aorta and its primary branches corresond to the aorta (ascending, arch, thoracic descending, abdominal descending), primary branches of the aorta (including the coronary artery), and pulmonary artery.

*b Multiple lesions are defined as those that involve two or more of the above arteries or sites or two or more segments of the aorta.

*c Hypertrophic lesions are detected by ultrasonography (macaroni sign of the common carotid artery), contrast-enhanced CT, contrast- enhanced MRI (circumferential contrast enhancement of the arterial wall), and PET-CT (circumferential FDG uptake of the arterial wall).

*d Stenotic lesions and dilated lesions are detected by chest radiography (wave-like deformation of the descending aorta), CT angiography, MR angiography, echocardiography (aortic insufficiency), and angiography. They are accompanied by dilatation of the ascending aorta and frequently also by aortic insufficiency. In the chronic stage, circumferential calcification of the arterial wall is visualized by CT, and the development of collateral circulation is detected by CT angiography and MR angiography

Points of attention in imaging diagnosis: Contrast-enhanced CT is performed in the late phase of contrast enhancement. CT angiography is performed in the early phase of contrast enhancement with 3-dimensional image processing. Angiography is usually performed when other procedures such as endovascular treatment and coronary artery angiography or left ventriculography are simultaneously intended.

C. Conditions to be included in the differential diagnoses of Takayasu arteritis

Arteriosclerosis, congenital vascular anomaly, inflammatory abdominal aortic aneurysm, infectious aneurysm, syphilitic mesaortitis, giant cell arteritis (temporal arteritis), vascular Behçet’s disease, IgG4-related diseases.

<Diagnostic categories>

Definite: At least 1 of the items in A + any of the conditions in B are observed, and conditions in C can be excluded.

(Suggestive findings)

1. Hematological/biological findings: Increased ESR or CRP, leukocytosis, anemia

2. Genetic examinations: Presence of HLA-B*52 or HLA-B*67

Since findings suggestive of inflammation are exacerbated on blood tests in most patients with active Takayasu arteritis, they are useful as references for the diagnosis. However, inflammatory signs are negative in some patients at the initial examination, and it must be noted that there are usually no signs of inflammation in patients with inactive Takayasu arteritis. Epidemiological characteristics (a predilection for young women and symptoms usually occur at ages under 40 years) and presence of HLA-B*52 or HLA-B*67 are suggestive findings.

Since April 2018, ¹⁸F-FDG PET has begun to be performed under health insurance at some PET facilities in Japan for patients with large vessel vasculitis in which the localization or activity of the lesions is difficult to determine by other examinations.

6.2 Differential Diagnosis

Takayasu arteritis should be differentially diagnosed from (1) arteriosclerosis, (2) congenital vascular anomalies, (3) inflammatory abdominal aortic aneurysm, (4) infectious aneurysm, (5) syphilitic mesaortitis, (6) giant cell arteritis (temporal arteritis), (7) vascular Behçet’s disease, and (8) IgG4-related periaortitis. It can be differentiated from arteriosclerosis to an extent by the age of onset and distribution of the affected vessels. Mid-aortic syndrome is a possible congenital vascular anomaly that can be mistaken for Takayasu arteritis, but it can be differentiated, because the aortic wall is smooth despite stenosis. Inflammatory abdominal aortic aneurysm shows signs of inflammation, is often accompanied by hydronephrosis, and exhibits the characteristic mantle sign on CT. Infectious aneurysm often presents as a saccular aneurysm, can be multiple, but lacks other lesions, and it can be differentiated by checking other findings. Syphilitic mesaortitis is rarely encountered recently and is differentiated serologically and bacteriologically. GCA frequently affects older individuals and is often complicated by myalgia (polymyalgia rheumatica). Vascular Behçet’s disease occasionally presents with saccular aneurysms but can be differentiated by checking other findings. IgG4-related periaortitis can be differentiated by the serum IgG4 concentration and IgG4-related lesions in other organs.

7. Policies and Guidelines of Treatment

Table 8 shows recommendations about treatment for Takayasu arteritis, and Figure 16 shows a flow chart of treatment for Takayasu arteritis.

Table 8. Recommendations and Levels of Evidence About Treatments for Takayasu Arteritis

	Recommendations	Levels of evidence
Glucocorticoid (GC)	I	B
Steroid pulse therapy	IIb	C
Methotrexate (MTX)*	IIa	B
Azathioprine (AZA)	IIa	B
Cyclophosphamide (CY)	IIb	B
Mycophenolate mofetil (MMF)*	IIb	B
Tacrolimus (TAC)*	IIb	C
Cyclosporine (CyA)*	IIb	C
Tocilizumab (TCZ)	I	B
TNF-inhibitors*	IIa	B
Antiplatelet drugs	IIa	B
Vascular bypass surgery	IIa	C
Endovascular treatment	IIb	C

*Uncovered by health insurance in Japan.

Figure 16.

Flow chart of treatments for Takayasu arteritis.

7.1 Glucocorticoid/Immunosuppressant

7.1.1 Glucocorticoid

a. Indications

In previous cohort analyses, PSL was administered to 79–94% of the patients^6,48–50 based on the disease activity (judged according to Kerr’s criteria^50a).

b. Initial Dose and Period of Its Continuation

According to overseas reports, regimens such as PSL at 1 mg/kg/day×1 month^48,50–52 have been used. The Guidelines 2008 recommend a low dose regimen of PSL 20–30 mg/day×2 weeks but has the additional statement, “increased to a maximum of 60 mg/day depending on the case”, and the efficacy rate of PSL alone by this regimen was about 50%.⁵³ In a Japanese retrospective cohort of 106 cases,⁶ the initial dose of PSL was 38.9±14.6 mg/day and approximately corresponded to 0.5–1 mg/kg/day.

c. Steroid Pulse Therapy (recommendation class IIb, evidence level C)

This regimen is performed in emergent cases and at relapse of refractory cases.^52,54,55

d. Dose-Reduction Rate and Maintenance Dose

The dose of PSL should be reduced by confirming remission according to (1) symptoms, (2) blood inflammation markers, and (3) imaging findings. In a Japanese retrospective cohort study of 106 cases,⁴⁹ the PSL dose-reduction speed was the most important factor that contributed to relapse, and the relapse rate differed significantly between dose-reduction speeds faster and slower than 1.2 mg/month. By the protocol of the Guidelines 2008,⁵⁶ the dose was reduced by 5 mg every 2 weeks to 10 mg/day and by 2.5 mg every 2 weeks thereafter to the maintenance dose. However, considering that the PSL dose at relapse was 13.3±7.5 mg/day in the Japanese cohort,⁶ the dose should be reduced very carefully after it has been reduced to less than 20 mg/day. The maintenance dose is PSL 5–10 mg/day in many protocols.^49,52,57

e. GC-Free Remission

GC-free remission was maintained in 5 (17%) of the 30 patients by a protocol of the United States aimed to discontinue PSL.⁵¹ According to the surveillance of 150 cases in Japan reported in 1975, the GC discontinuation rate was 37.4%.⁵⁶

f. Dose Increase at Relapse

Whether the remission-inducing therapy is repeated or minor dose increases are attempted should be judged according to the severity.

7.1.2 Immunosuppressants

a. MTX (recommendation class IIa, evidence level B) (Uncovered by Insurance in Japan)

In a single-arm study in the United States, MTX (gradually increased from 0.3 mg/kg/week) and PSL (gradually reduced from 1 mg/kg/day) were administered to those in whom the effectiveness of PSL alone was insufficient or relapse was observed, resulting in remission attained in 81% and remission maintained after 7–18 months in 50%.⁵⁸ MTX is the immunosuppressant that has been used most frequently for Takayasu arteritis. However, its problems are that the progression of vascular lesions may not be prevented and that it is often discontinued due to the lack of effect or adverse effects.^6,50,59

b. AZA (recommendation class IIa, evidence level B) (Covered by Health Insurance in Japan Since February 23, 2011)

In a single-arm study in India, AZA (2 mg/kg/day) and PSL (gradually reduced from 1 mg/kg/day) were administered to newly-onset patients. While remission was attained and maintained until after 12 months in all patients, CRP or ESR rose after 12 months in 40%, and progression of vascular lesions was observed in some.⁵⁷ AZA is highly evaluated in protocols of various countries and is often administered to patients not responding to MTX.

c. CY (recommendation class IIb, evidence level B) (Covered by Health Insurance in Japan Since February 23, 2011)

In a prospective cohort of 20 cases in the United States, CY was added at 2 mg/kg/day (dose was modified to adjust the WBC to >3,000/μL) to 7 patients who responded insufficiently to PSL alone. The PSL dose-reduction effect was observed in all patients, and further progression was prevented in 4 of the 6 patients who had shown progression of vascular lesions.⁴⁸ In many protocols, CY is substituted for MTX or AZA after 3 months in consideration of the possibility of adverse effects.

d. MMF (recommendation class IIb, evidence level B) (Uncovered by Health Insurance in Japan)

According to reports of 21 cases from India⁵⁵ and 10 cases from Brazil,⁶⁰ MMF (2 g/day) was administered to patients first treated for Takayasu arteritis or those who showed poor treatment responses, and reduced disease activity, decreases in CRP/ESR, and PSL-reducing effect were observed in most cases.

e. Calcineurin inhibitors (recommendation class IIb, evidence level C) (Uncovered by Health Insurance in Japan)

There have been case reports using tacrolimus at 1.5–4 mg/day^61,62 and CyA at 150 mg/day or 4.3 mg/kg/day.^63,64

7.2 Biological Agents, Antiplatelets

7.2.1 Biological Agents

The efficacy of biological agents for Takayasu arteritis has been evaluated primarily regarding two groups of biological agents, namely, TNF inhibitors and anti-IL-6 receptor antibody.

a. TCZ (recommendation class I, evidence level B) (Covered by Health Insurance in Japan Since August 25, 2017)

In the serum of patients with Takayasu arteritis, the IL-6 concentration has been reported to increase in association with the disease activity.^31,32 Since Nishimoto et al. first reported TCZ treatment for patients with refractory Takayasu arteritis,⁶⁵ similar reports have appeared in Japan, Europe, and the United States suggesting the efficacy of TCZ against Takayasu arteritis.^66–70

In a retrospective registry study of biological agents (TNF inhibitors and TCZ) in France, 49 patients with Takayasu arteritis were treated with biological agents (35 with a TNF-inhibitor, 14 with TCZ) with remission rates after 6 and 12 months of 75 and 83%, respectively. The 3-year relapse-free rate was 90.9% in those treated with biological agents and 58.7% in those treated with conventional synthetic DMARDs, showing a significant difference (P=0.0025).⁷¹

In Japan, a clinical trial of TCZ was carried out in patients with refractory Takayasu arteritis (TAKT study).⁷² By the double-blind design, GC was forcedly tapered, and the time until relapse was evaluated as a primary endpoint. The hazard ratio in the TCZ group relative to the placebo group was 0.41 (decrease rate of relative risk: 59%) (P=0.0596).

b. TNF Inhibitors (recommendation class IIa, evidence level B) (Uncovered by Health Insurance in Japan)

Hoffman et al. reported that TNF inhibitor therapy was effective for Takayasu arteritis resisting GC therapy.⁷³ However, according to the report by Schmidt et al. in 20 patients with refractory Takayasu arteritis, the remission induction rate was also satisfactory, but relapse was noted in 33% while TNF inhibitor therapy was continued, and the administration was discontinued due to adverse effects in 20%.⁷⁴ No clear conclusion has been reached regarding the efficacy of TNF inhibitor therapy against Takayasu arteritis.

7.2.2 Antiplatelets (recommendation class IIa, evidence level B)

In patients with Takayasu arteritis, the occurrence of acute ischemic events such as acute myocardial infarction, unstable angina, transient ischemic attacks, stroke, acute lower limb ischemia, and acute intestinal ischemia has been reported to be significantly suppressed by oral administration of an antiplatelet (aspirin).⁷⁵

7.3 Surgical Treatment (Open Surgery and Endovascular Treatment)

7.3.1 Principles of Surgical Treatment

In both open surgery and endovascular treatment (EVT) for patients with Takayasu arteritis, pre- and post-operative medical management of disease activity is crucial to obtain good surgical outcomes. The evaluation of indications for surgery, selection of strategies and the procedures, and postoperative management should be conducted by a multidisciplinary team. As for occlusive lesions, vascular restenosis occurs more frequently after EVT than after bypass surgery. Therefore, careful consideration is required to select EVT as the first-line treatment. After surgical treatment, all patients should have lifelong follow-up care.

7.3.2 Disease Activity and Surgical Outcomes

The purpose of surgical treatment is to improve organ blood flow or to prevent rupture of aneurysms. Surgical treatment is best performed during a period of remission (non-active period) in which the patient needs neither GC nor immunosuppressants for maintaining the condition, if possible. However, even in patients in active phase, urgent surgery is often unavoidable to prevent aneurysm rupture or permanent ischemic organ damage, and performed under every effort to manage the inflammation.^76–79 After surgery, maintaining remission leads to favorable long-term outcomes.^76,79,80

The selection of surgical treatment strategy, open surgery or EVT, is still based on experts’ experiences. The strategy should be selected considering the long-term prognosis of the patient, since many patients with Takayasu arteritis have a potential of favorable life prognosis.

7.3.3 Postoperative Management

If GC has been used preoperatively, GC therapy should be resumed immediately after surgery. Even in patients in remission phase, low dose GC therapy is recommended.⁷⁶ The operated sites and residual lesions should be followed up routinely to prevent late complications including pseudoaneurysm at the anastomosis.

7.3.4 Treatment for Vascular Lesions

a. Surgical Revascularization

While Numano’s angiographic classification (Figure 3)¹³ is appropriate for representing epidemiological case profiles, the following Ueno’s clinical classification is useful to consider the target lesions of surgical treatment.⁸¹

i. Treatment for Type I Lesions (Occlusive Lesions of Aortic Arch Branches)

The patient can be treated conservatively if they have few problems in their daily life. Concerning visual impairment, stage 2 and early stage 3 by Uyama’s classification⁸² or a fundus blood pressure of around 50 mmHg are considered to be indications for revascularization.⁸³ Bypass surgery is often selected.^51,84 If there are severely diseased lesions in the bilateral carotid arteries, unilateral revascularization is recommended to avoid cerebral hyperperfusion syndrome.^83–85

ii. Treatment for Type II Lesions (Occlusive Lesions of Thoracoabdominal Aorta)

If the lesion does not involve the orifice of major branches of abdominal organs, extra-anatomical bypass surgeries such as aorto-aortic bypass grafting or replacement of the diseased aorta can be indicated. If there are symptoms of organ ischemia, surgical treatment is indispensable. Particularly the refractory renovascular hypertension should be managed for improving life prognosis by adopting renal artery bypass surgery, autologous renal transplantation, or even nephrectomy.⁸⁶ For the patients with abdominal angina, mesenteric artery revascularization should be considered.

iii. Treatment for Type III Lesions (Extensive Occlusive Lesions; Type I+Type II)

In patients with both severe brain ischemia and severe hypertension, to prevent the brain from being exposed to high blood pressure after cerebral arterial reconstruction, simultaneous surgical treatment for renovascular hypertension should be considered. If brain ischemia is not severe, the initial target for surgery should be renovascular hypertension. Then, if hypoperfusion-associated brain disorders appear due to normalized blood pressure, carotid revascularization is performed in the second stage.⁸³

iv. Treatment for Type IV Lesions (Aneurysmal Lesions)

True aneurysms are the majority of the aneurysm. The Surgical indications for aneurysms in Takayasu arteritis are similar to those for common degenerative aortic and peripheral artery aneurysms.

Vascular occlusion and restenosis are may occur frequently after surgical revascularization. On the contrary, there is a report that the long-term patency and survival in Japan are relatively satisfactory.⁸⁷

b. EVT

i. EVT for Occlusive Lesions

Even though EVT is usually selected restrictively for localized lesions,^80,88,89 restenosis occurs more frequently after EVT than after bypass surgery.^{51,79,80,88–90} Since the target artery wall is occasionally scarred and fibrosed in the whole layers, a deliberate decision should be made to select EVT as the first-line treatment. The effect of stenting on the patency remains unknown.

ii. Stent-Graft Implantation for Dilated Lesions

Long-term outcomes have not been revealed yet.

7.3.5 Treatments for Cardiac Lesions

a. Aortic Insufficiency

Indications for aortic valve replacement should be evaluated based on patient’s condition and left ventricular function.^91,92 Biological valves are used for elderly patients and women who wish pregnancy. Reports that positively recommend aortic root replacement (Bentall procedure) have increased. In addition, if the patient seems difficult to achieve remission of the inflammation even after long-term medical treatment, aortic root replacement is recommended even without aortic root dilatation.^93–95

b. Aortic Root Dilatation

Composite graft replacement of aortic valve, aortic root, and ascending aorta, combined with re-implantation of the coronary arteries into the graft (Bentall procedure) is the most common procedure. Valve-sparing aortic root replacement is not recommended as the aortic valve tends to degenerate in many patients in a long period after surgery.⁹⁶ The suture usually needs additional reinforcements in the surgical procedures.⁹⁷

c. Coronary Artery Stenosis

In coronary artery bypass surgery, appropriate graft selection is essential. If there are lesions in the aortic arch branches, the internal thoracic artery graft is inappropriate. The proximal end of a free graft should not be anastomosed to the diseased aorta. If coronary artery bypass grafting is performed simultaneously with procedures such as ascending aortic replacement, the proximal anastomosis should be made at the prosthetic aortic graft. Ostial endarterectomy and ostial patch angioplasty are effective in some patients.⁹⁸

7.3.6 Treatment for Pulmonary Artery Lesions

A pressure overload of the right ventricle due to pulmonary hypertension is an indication for surgery and is treated by patch angioplasty using the pericardium or prosthetic graft replacement of the pulmonary artery. Favorable results of plain old balloon angioplasty (POBA) have also been reported.⁹⁹

8. Prognosis

The 15-year survival rate of patients with Takayasu arteritis has been reported to be around 80%,^100,101 but it can be modified by some poor prognostic factors, which include retinopathy, hypertension, aortic insufficiency, aortic aneurysm, progressive course, onset at a young age, and increased ESR.¹⁰⁰ The disease activity may temporarily subside, but there have been many reports of high relapse rates.

The percentage of patients who require surgical treatment varies from 12 to 50%, but the percentage of those who receive early surgical intervention including percutaneous procedures is increasing.⁹⁶ Heart failure is a more frequent cause of death than anastomotic complications, and heart failure is caused by aortic valve disease or ischemic heart disease.⁸⁷ Late detachment of the aortic prosthetic valve and coronary bypass graft insufficiency are observed in about 10% of the patients who have undergone surgery,⁹⁷ and the incidence of surgery-related late complication in Takayasu arteritis is high.

For the future, the cure rate is expected to be improved by the development of diagnostic techniques, particularly imaging modalities such as PET and MRI, and the use of biological agents.

9. Takayasu Arteritis in Children

According to the database for national research of intractable diseases run by the MHLW of Japan, there were 140 patients with childhood-onset Takayasu arteritis in Japan in 2016. The list included patients who had survived to adulthood as well as 70 children who were <16 years of age. The male/female ratio was 1:7, and the median age at the onset was 10–11 years.

The initial symptoms of Takayasu arteritis are fever, malaise, abdominal pain, chest pain, arthralgia, and lymph node enlargement, with fever noted in about 80% of the patients.^102,103 Children are now increasingly being diagnosed at an early stage of the disease because of improved diagnostic techniques and the spread of knowledge about Takayasu arteritis. In more than half the patients with childhood-onset Takayasu arteritis, the lesions are first seen in the abdominal aorta and its branches. In adult patients, the lesions occur most frequently in the head and neck arteries, ascending aorta, and aortic arch.^102,103

As there are no diagnostic criteria for childhood-onset Takayasu arteritis, the diagnosis depends on the criteria established for adults. Nevertheless, specific diagnostic criteria have been established for those applying for medical fee subsidies for children with specific chronic diseases.¹⁰⁴ In such cases, inflammatory markers such as CRP and the ESR are generally elevated during the acute period. Imaging modalities, including ultrasonography, contrast-enhanced CT, CT angiography, MRI, and positron emission tomography (PET)-CT, are used for diagnosis. In addition, as lesions in children with Takayasu arteritis are more often located in the abdominal aorta and its branches than in adults, ultrasonography is a useful, convenient, non-invasive tool for diagnosis and follow-up. PET-CT is also a powerful emerging modality not only for the early diagnosis but for evaluating the distribution of lesions and monitoring disease activity. Since April 2018, PET-CT has become available under health insurance coverage at some PET facilities in Japan for patients with large-vessel vasculitis in whom the localization or activity of the lesions is difficult to determine by other modalities.

Treatment for children with Takayasu arteritis is commonly initiated with two to three courses of steroid pulse therapy followed by daily PSL (0.8–1.0 mg/kg). MTX (not covered by insurance in Japan) or AZA is generally used to prevent relapse and to accelerate GC tapering from the onset.⁵⁸ IVCY and TCZ could be considered for those who have severe visceral lesions, who resist the initial treatment, who face difficulty reducing their GC dose, and/or who have repeated relapse. As children are less likely than adults to develop gonadal dysfunction from the CY, early treatment with IVCY may be positively considered.¹⁰⁵ Because GCs — including pulsed therapy for patients whose status is complicated with renovascular hypertension — could increase the risk of reversible posterior leukoencephalopathy and hypertensive brain hemorrhage, the blood pressure should be tightly controlled according to the age-matched standard value. Growth impairment is also a serious adverse effect of GC in children. Therefore, if inflammatory markers have been negative for 6–12 months, the PSL dose should be reduced to a level that does not affect growth. As CY has exhibited both carcinogenicity and gonadal toxicity, excessive use should be avoided. Intravenous TCZ therapy has been reported effective for treating childhood-onset Takayasu arteritis. The reports regarding subcutaneous TCZ therapy are limited, however, and future evaluation is awaited. Antiplatelets and anticoagulants are administered to patients who have vascular stenosis or marked vascular dilatation and are at high risk of thrombosis. More than half the children with Takayasu arteritis experience relapse and require treatment over a long period, although some can eventually discontinue all treatment.

III. Giant Cell Arteritis

1. Definition/Epidemiology/Subclassification

1.1 Definition

Giant cell arteritis (GCA) was defined by the 2012 CHCC as “arteritis, often granulomatous, usually affecting the aorta and/or its major branches, with a predilection for the branches of the carotid and vertebral arteries. Often involves the temporal artery. Onset usually in patients older than 50 years and often associated with polymyalgia rheumatica.”¹ Since the temporal artery is not affected in all patients with GCA, and since temporal artery may be affected in other vasculitides, the term “giant cell arteritis” was adopted.¹

1.2 Epidemiology

The age at onset is usually 50 years or above, and the disease has a slight predilection for females. According to the nationwide epidemiological survey by the Ministry of Health and Welfare of Japan, the estimated number of treated patients was about 690 (0.65/100,000 persons), and the mean age at onset was 71.5 years.¹⁰⁶

1.3 Subclassification

GCA is subclassified into cranial GCA (C-GCA) localized in intracranial arteries and large-vessel GCA (LV-GCA), arteritis not localized intracranially but is present extracranially. However, the definition or clinical significance of LV-GCA has not been fully established.

2. Pathogenic Mechanism

Although the etiology of GCA is still unclear, it is known to be correlated with HLA-DRB1*0401, HLA-DRB1*0404, HLA-DQA1*0301, and HLA-DQB1*0302 as genetic factors.^107,108 In addition, infection by microorganisms such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and parvovirus 19 and environmental factors including smoking have been also reported to be involved in its pathogenesis.¹⁰⁹

In GCA, inflammatory cell infiltration in all layers is observed as in Takayasu arteritis. Especially, giant cells in the media and intima and occlusion of vascular lumen due to intimal thickening are characterized. CD83-positive dendritic cells and CD4-positive T cells in the adventitia play an important role for this process. Immature dendritic cells in the adventitia are matured through Toll-like receptor (TLR) and their matured dendritic cells activate CD4-positive T cells. Moreover, cytokines secreted by these cells, IFN-α and IL-17, contribute to activation of macrophages and formation of giant cells. These macrophages and giant cells infiltrate into the intima, and secrete vascular endothelial growth factor, resulting in proliferation of vascular smooth muscle cells and remodeling of the vascular wall.

3. Pathological Findings

3.1 Affected Vessels

In GCA, middle-sized muscular arteries, particularly branches of the carotid artery and vertebral artery, are likely to be affected. Also, large elastic arteries such as the aorta, subclavian artery, and common iliac artery are often affected. Because the lesions are localized and occasionally segmented, temporal artery should be sampled over 2–4 cm and examined carefully.

3.2 Histological Findings

In muscular arteries such as the temporal artery, the lesions are formed primarily around the internal elastic lamina and the intimal side of the media (Figure 17).¹¹⁰ Inflammation is granulomatous; histiocyte proliferation, lymphocyte, plasma cell, and macrophage infiltration, and Langhans and foreign body giant cells are observed (Figure 18).¹¹⁰ The internal elastic lamina is ruptured and lost, multinucleated giant cells are likely to appear near it, and they occasionally seen to phagocytose the elastic lamina. Fibrinoid necrosis or neutrophil infiltration is rarely observed. The intima shows non-specific fibrotic thickening and may cause stenosis, but it is considered a secondary change associated with inflammation of the media.

Figure 17.

Pathological image of the temporal artery 1. (Cited from the web edition of the Vasculitis Pathology Atlas¹¹⁰) Rupture of the internal elastic lamina, granulomatous inflammation in the media including giant cells, marked fibrotic thickening of the intima, stenosis of the lumen, and fibrosis of the adventitia are noted. (EVG stain) I, intima; M, media; A, adventitia; IEL, internal elastic lamina.

Figure 18.

Pathological image of the temporal artery 2. (Cited from the web edition of the Vasculitis Pathology Atlas¹¹⁰) Calcification and rupture of the internal elastic lamina and granulomatous inflammation due to histiocyte proliferation is observed around the calcified and ruptured internal elastic lamina, particular on the inner side of the media. Many Langhans and foreign body giant cells are also observed, and some of them are seen to phagocytose the internal elastic lamina (insert). Moreover, infiltration of lymphocytes and macrophages is also noted. In this case, smooth muscle cells persist on the outer side of the media. (HE stain) (insert: EVG stain) IEL, internal elastic lamina; C, calcification; SMC, smooth muscle cells on the outer side of the media.

In the aorta (elastic artery), granulomatous inflammation is formed primarily in the middle layer of the media. Elastic fibers are lost locally in a moth-eaten pattern (Figure 19),¹¹⁰ and histiocyte and lymphocyte infiltration and multinucleated giant cells are observed at such sites (Figure 20).¹¹⁰ Inflammation is also observed along the vasa vasorum that enters from the adventitia. In addition, loss of smooth muscle cells considered an ischemic change may develop at sites not affected by granulomatous inflammation, but elastic fibers remain at such sites. Thus, many infiltrating cells are observed with loss of elastic fibers at inflamed areas, whereas elastic fibers are observed without inflammatory cells at non-inflamed areas; these contrasting observations are mixed (Figure 19, inserted figure).¹¹⁰

Figure 19.

Pathological image of the aorta 1. (Cited from the web edition of the Vasculitis Pathology Atlas¹¹⁰) In the middle layer of the media, moth-eaten loss of elastic fibers is diffusely observed. The insert shown in the upper left is an HE-stained image of the area in the square. Infiltration of mononuclear cells including multinucleated giant cells is observed in the areas where elastic fibers are lost, whereas smooth muscle cells are lost in the areas where elastic fibers persist. (EVG stain) (insert: HE stain)

Figure 20.

Pathological image of the aorta 2. (Cited from the web edition of the Vasculitis Pathology Atlas¹¹⁰) Granulomatous inflammation with infiltration of primarily histiocyte and multinucleated giant cells is observed in the severely inflamed area. Infiltration of lymphocytes and macrophages is also noted. (HE stain)

3.3 Differential Diagnoses and Similar Diseases

Takayasu arteritis: Since the frequent age at onset and sex difference in prevalence differ, age and sex are important information. In fact, differential diagnosis of GCA from Takayasu arteritis is considered difficult by pathological findings alone. However, inflammation occurs primarily in the inner and middle layers of the media in GCA, but the outer layer of the media to the adventitia are affected in Takayasu arteritis. Giant cells and granulomatous change are more notable in GCA than in Takayasu arteritis.

Buerger disease-like arteritis: Cases in which marked intimal thickening is observed in the temporal artery not accompanied by destruction of the internal elastic lamina or the media have been reported as Buerger disease.

Localized GCA: Granulomatous arteritis with giant cell infiltration occasionally occurs locally in small arteries of the urogenital organs including the uterus, ovary, and ureter and mammary glands, but their sites and the size of the affected arteries differ from those in GCA.

4. Symptoms

Generalized symptoms of GCA include fever associated with inflammation (often mild fever, occasionally remittent fever), malaise, easy fatigability, body weight loss, polymyalgia, and polyarthralgia. Local symptoms vary according to the site of the affected vessel. In the nationwide survey of 66 cases of GCA in Japan, symptoms including headache of the temporal region (80.3%), scalp pain (63.3%), tenderness of the temporal artery (52.6%), weakened pulse of the temporal artery (40.0%), visual impairment (43.9%), and ischemic optic neuropathy (21.2%).¹⁰⁶

External carotid artery lesions may cause temporal pain, swelling/tenderness of the temporal artery, jaw claudication, tongue claudication, and mandibular pain occur. These symptoms may occur both bilaterally and unilaterally. Scalp pain is often complained of when the patient combs or brushes hair, and jaw claudication is characterized by jaw pain during mastication.

If the ophthalmic artery is affected, symptoms including impairment of visual acuity, loss of vision, misty vision, and diplopia may occur. Abnormalities of visual acuity/visual field appear early after the onset, and caution is necessary, because about 23–44% of the patients show reduced visual acuity, and 4.4–6.5% show complete loss of vision.^106,111 Sudden loss of vision is often first noted on awakening in the morning.

As mentioned in the definition of CHCC2012, lesions of GCA appear in the aorta and/or its major branches. The presence of subclavian artery lesions is considered a characteristic of LV-GCA.¹¹² Common carotid artery lesions cause headache, dizziness, syncopal attacks, and hemiplegia. Subclavian artery lesions cause pain, cold sensation, and easy fatigability of the upper extremities and present attenuation or loss of the pulse of the radial artery and a difference in the blood pressure between the left and right limbs (≥10 mmHg). Aortic lesions cause disorders including chest pain, back pain, aortic aneurysm/dissecting aortic aneurysm, and aortic insufficiency.

Caution is needed as polymyalgia rheumatic (PMR) is observed in 30–60% of the patients with GCA, and as PMR is complicated by GCA in 16–21% of the patients.^106,113

5. Laboratory/Imaging Findings

5.1 Laboratory Findings

There are no laboratory findings specific to GCA. On blood tests, high ESR, increased CRP, chronic inflammatory anemia, and hypoalbuminemia are observed. An ESR of ≥50 mm/h is included in criteria for the classification of GCA, and GCA with normal CRP and ESR is rare. CRP and ESR are also used as markers of the flare of disease activity, and elevations of CRP and ESR may be the only findings at the relapse.^114–116 The IL-6 concentration in peripheral blood (uninsured) has been reported to change with the disease activity.^117,118

5.2 Imaging Findings

Diagnostic imaging modalities for GCA include CT, MRI, ultrasonography, and FDG-PET.

On MRI, thickening of the vascular wall and contrast enhancement by contrast agents are observed in 81% of the patients. MRI is also useful for the evaluation of extracranial and intracranial arteries (Figure 21).¹¹⁹

Figure 21.

MRI findings of GCA. MRI findings. On contrast-enhanced MRI of the head (fat-suppressed T1-weighted imaging) (A), thickening and contrast enhancement of the wall of the superficial temporal artery (arrow), which are findings specific to active GCA. In the neck (B) and chest (C), thickening of the bilateral internal carotid artery and aorta, suggestive of active GCA, is observed (arrow).

On CT, wall thickening and contrast enhancement are observed in 45% of the patients,¹¹⁹ and the modality is superior to MRI in that a broader area can be imaged more quickly and that image quality is relatively high.

On ultrasonography, the “dark halo” is detected around the superficial temporal artery due to edema of the arterial wall (Figure 22).¹²⁰ It may not be observed early after the onset, and the sensitivity is reported to be about 40%.¹²¹

Figure 22.

Ultrasound findings of the superficial temporal artery in GCA. A dark halo is observed around the superficial temporal artery.

The diagnostic ability of FDG-PET is high as abnormal accumulation has been reported to be observed in the blood vessel in 80% of the patients.^119,122 It has become possible to perform FDG-PET under health insurance at some PET facilities in Japan for patients with large vessel arteritis in whom the localization or activity of lesions is difficult to determine by other examinations since April 2018. However, there are limitations such as that it is expensive and that it can be performed at relatively few facilities.

5.3 Ophthalmological Examinations

20–30% of the GCA patients have blurred vision or visual deterioration,^111,123,124 and some patients with GCA have diplopia, transient visual impairment, and the visual field defects. Blurred vision, visual deterioration and visual field defects can be caused by anterior ischemic optic neuropathy, occlusion of the central retinal artery, or occlusion of the cilioretinal artery,^111,125 and they can be revealed by fundus examination. Diplopia is caused by restriction of ocular movements associated with ischemic external ophthalmoplegia. In anterior ischemic ocular neuropathy, which is the most frequent cause of visual impairment in GCA, pale edema of the optic disc is observed (Figure 23).¹²⁶

Figure 23.

Anterior ischemic optic neuropathy observed in GCA. (Cited from Tanano I, et al. 2011¹²⁶) Pale edema of the optic disc is observed.

In silent GCA, which presents with systemic symptoms such as fever, easy fatigability, and loss of body weight rather than conventionally known symptoms (headache, tenderness of the temporal artery, weakened pulse, blindness), visual disorders are rare, but fundus lesions such as cotton-wool spots may be observed.^124,127,128

6. Diagnostic Methods and Criteria

6.1 Diagnostic Criteria

The classification criteria by ACR of 1990 (Table 9),¹²⁹ which are widely used for the diagnosis of GCA, are also adopted as the criteria of the MHLW of Japan. Tenderness or reduced pulse along the temporal artery is evaluated by palpation. While conditions can be classified as GCA even without pathological demonstration of GCA, biopsy of the unilateral temporal artery is recommended for the diagnosis. Vascular ultrasonography for wall thickening of the temporal artery is useful as an adjuvant diagnostic method.^130,131

Table 9. ACR Criteria for the Classification of Giant Cell Arteritis (Proposed by the ACR in 1990)

Criterion	Definition
1. Age at disease onset ≥50 years	Development of initial symptoms or findings beginning at age 50 or older
2. New headache	New onset of, or new type of, localized headache
3. Temporal artery abnormality	Tenderness to palpation or decreased pulsation of temporal artery, un-related to arteriosclerosis of cervical arteries
4. Elevated erythrocyte sedimentation rate	Elevated ESR: ESR ≥50 mm/hr by Westergren method
5. Abnormal artery biopsy	Biopsy specimen of artery revealing vasculitis characterized by predominant mononuclear or granulomatous inflammation with multinucleated giant cells

(From Hunder GG, Bloch DA, Michel BA, et al., Arthritis Rheum 1990,¹²⁹ John Wiley and Sons. (c) 1990, American College of Rheumatology.) GCA is diagnosed if at least 3 of these 5 criteria are present (sensitivity: 93.5%, specificity: 91.2%)

Jaw claudication has low diagnostic sensitivity but is a clinical feature highly suggestive of vasculitis, which can be confirmed by temporal artery biopsy.¹³² Ischemic optic neuropathy is poorly sensitive but highly specific to GCA,¹²⁹ and prompt diagnosis in cooperation with an ophthalmologist is recommended if the patient is aware of reduced visual acuity.

6.2 Points of Attention in Diagnosing GCA

Since the 1990 ACR classification criteria are not prepared as diagnostic criteria, diagnosis by exclusion is necessary concerning unidentified fever, chronic inflammatory disease, and headache. Special attention to differential diagnoses must be paid if GCA cannot be pathologically demonstrated.^133,134 Temporal artery lesions may be observed in ANCA-associated vasculitis,^129,135 PAN,^129,136 and systemic amyloidosis.¹³⁷ Patients in whom both CRP and ESR are normal are rare.^138,139

In patients who have developed ophthalmic lesions and show reduced visual acuity, treatment must be initiated before biopsy because of the risk of blindness as delay of treatment may result in irreversible loss of vision. It is recommended to perform biopsy of the temporal artery within 1–2 weeks after the initiation of GC therapy.^140,141

6.3 Evaluation of Aortic Lesions

Aortic lesions are considered to complicate GCA in about 20–30% of the patients. Aortic lesions such as stenosis of branches of the aorta and aortic aneurysm appear at the diagnosis of GCA in some patients, but they appear 5 or more years after the diagnosis in others.^142–144 The relationship between aortic lesions and disease activity is unclear, but, epidemiologically, the risk of the occurrence of aortic aneurysm is higher than in those with non-GCA,¹⁴⁵ and aortic lesions are related to the prognosis of GCA.¹⁴⁶ Therefore, aortic lesions should be evaluated at the diagnosis or relapse of GCA by the same method as in Takayasu arteritis. FDG-PET is useful (it has become possible to perform the examination under health insurance at some PET facilities in Japan since April 2018 for patients with large vessel arteritis in which the localization or activity of the lesion is difficult to determine by other examinations).

7. Policies of Treatment

Recommendation classes and evidence levels of treatments for GCA are shown in Table 10. Figure 24 shows a flow chart of treatments for GCA.

Table 10. Recommendations and Evidence Level of Treatments for GCA

	Recommendations	Levels of evidence
Glucocorticoid (GC)	I	B
Steroid pulse therapy	I	B
Methotrexate (MTX)*	IIa	A
Cyclophosphamide (CY)	IIb	B
Azathioprine (AZA)	IIb	B
Cyclosporine (CyA)*	III	B
Tocilizumab (TCZ)	I	A
Infliximab (IFX)*	III	B
Adalimumab (ADA)*	III	B
Etanercept (ETN)*	IIb	B
Antiplatelets	IIa	B

*Uninsured in Japan.

Figure 24.

Flow chart of treatments for GCA.

7.1 Glucocorticoid/Immunosuppressants

7.1.1 Glucocorticoid

GC is effective and is the first-line treatment for GCA (recommendation class: I, evidence level: B). Since a delay in the initiation of treatment increases the risk of blindness and irreversible neurological damage, a high dose of GC should be initiated promptly if GCA is suspected.

a. Initial Treatment

1) In patients without ophthalmic or neurological symptoms, PSL at 0.5–1 mg/kg/day (60 mg/day at the maximum) is recommended (recommendation class: I, evidence level: B).

2) In patients with rapidly developed ophthalmic or neurological symptoms, steroid pulse therapy (mPSL at 0.5–1 g/day, 3 days) is recommended to be initiated and followed by PSL at 1 mg/kg/day (60 mg/day at the maximum) (recommendation class: I, evidence level: B).

GC reduction should be considered only in the absence of clinical symptoms and normalized inflammatory markers such as CRP and ESR after sustaining the initial dose for 2–4 weeks. Most patients can be weaned from GC in 1–2 years, but GCA recurs in about half the patients.^147,148

b. Treatment of Relapse

1) An increase of 5–10 mg/day of PSL is usually sufficient to treat a relapse in the absence of ophthalmic or neurological symptoms.

2) An increase to the initial dose of PSL should be considered in the presence of ophthalmic or neurological symptoms.

7.1.2 Immunosuppressants

Immunosuppressants are administered with GC to those who resist GC, those who have developed relapse with gradual reduction of GC, and those in whom rapid reductions of GC are needed due to adverse reactions. However, the therapeutic effect of the concomitant use of immunosuppressants on GCA is considered limited.¹⁴⁹ GCA is not treated with immunosuppressants alone. MTX (uninsured)¹¹⁶ (recommendation class: IIa, evidence level: A), CY^150–153 (recommendation class: IIb, evidence level: B), and AZA^154,155 (recommendation class: IIb, evidence level: B) have been reported to be effective as concomitant immunosuppressants.

7.2 Biological Preparations/Antiplatelets

7.2.1 Biological Preparations

GCA responds well to moderate or high dose of GC therapy. While early tapering of its dosage is necessary to reduce adverse events, GCA often relapses during tapering. To examine whether the concomitant use of biologics prevents flare-up of the disease, and reduce cumulative dose of GC, RCTs concerning the efficacy of the concomitant use of TCZ, ADA, or IFX were carried out in Europe and the United States.^115,156,157

7.2.2 TCZ

The efficacy of a protocol of initiating the administration of TCZ, which is an anti-IL-6 receptor antibody, with GC therapy has been confirmed by phase II and phase III trials. The phase II trial showed that the remission rate at week 12 was significantly higher, and the relapse rate until after week 52 was significantly lower, when TCZ was used concomitantly with early tapering schedule of PSL.¹⁵⁷ In the phase III trial, the remission maintenance rates at weeks 12–52 were significantly higher in the TCZ group even when PSL was discontinued at week 26, and cumulative dose of GC was significantly decreased in the TCZ group.¹⁵⁸ Concerning refractory cases with a history of treatment using immunosuppressants and TNF inhibitors, there have been case reports and small case series reporting that PSL could be reduced to a low dose or discontinued by the concomitant use of TCZ.^{67,69,159,160} The evidence level of TCZ is higher than those of immunosuppressants or TNF inhibitors. It should be administered to cases that flare during tapering of GCs or require early tapering of GC, with attention to the safety and in consideration of the risk-benefit balance (recommendation class: I, evidence level: A, covered by health insurance in Japan).

7.2.3 TNF Inhibitors

Since the efficacy of ADA and IFX, among the TNF inhibitors (uncovered by health insurance in Japan), has not been demonstrated by the results of clinical trials,^115,156 the concomitant use of TNF inhibitors with GC from an early stage of treatment is not recommended (recommendation class: III, evidence level: B) despite the problem that the evaluation method for the activity of GCA has not been sufficiently established. The efficacy of TNF inhibitors against relapse during GC therapy or the use of immunosuppressants is unclear. Etanercept (ETN) is expected to have a GC-sparing effect, and its reevaluation is awaited (recommendation class: IIb, evidence level: B).

7.2.4 Antiplatelets (recommendation class: IIa, evidence level: B)

GCA is occasionally complicated by cerebrovascular disorders and cardiovascular events, although vasculitis rarely develops in intracranial arteries except for the ophthalmic artery.¹⁶¹ The concomitant use of low-dose aspirin (81–100 mg/day) has been reported to reduce the risk of cerebrovascular disorders by retrospective observational studies,^162–164 and EULAR recommends the concomitant use of a small dose of aspirin without contraindications.¹⁴⁰

7.3 Invasive Treatments

The evidence concerning surgical/endovascular treatments for large vessel lesions associated with GCA is meager. Please refer to Chapter II 7-3 (Invasive Treatments for Takayasu Arteritis).

8. Prognosis

Factors that affect the prognosis include (1) sequelae of vascular ischemia (blindness, cerebral infarction, myocardial infarction), (2) aneurysm (dissecting/ruptured), and (3) treatment-related complications (infections, and morbid fracture due to immunosuppressive therapy such as long-term GC therapy). According to the national epidemiological survey by the Ministry of Health and Welfare of Japan in 1998, cure/recovery was reported in 81.8%, cerebral infarction in 12.1%, blindness in 6.5%, and death in 4.5% as short-term outcomes.¹⁰⁶ GCA as well as PMR is a disease that recurs repeatedly, and GC therapy was continued in 43% and 25% of the patients 5 and 9 years, respectively, after its initiation according to a report from Sweden.¹²²

Analysis of causes of death in a cohort study in Minnesota showed that the mortality rate due to ischemic enteritis was 4.9 times higher in patients with GCA, and 5.1 times higher in those with GCA complicated by aortic aneurysm or dissection, compared with the general population.¹⁴³ In a single facility cohort in northwestern Spain, aortic aneurysm occurred secondarily in 9.5% of the patients with GCA, and hypertension and marked acute inflammatory reaction at the time of first diagnosis were risk factors.¹⁶⁵

IV. Buerger Disease

1. Definition and Epidemiology

1.1 Definition

Buerger disease causes segmental lesions in arteries and veins of the extremities and is frequently observed in males in their 20–40 s. It is closely related to smoking and is occasionally complicated by migrating thrombophlebitis. Lesions mainly affect the arteries of the forearm to the hand and the infrapopliteal artery to arteries of the foot.

The life prognosis is favorable, but the quality of life (QOL) is sometimes impaired by ischemic pain at rest or ulcer/gangrene which leads to minor limb amputation. The incidence of major amputation increases if the patient fails to stop smoking.

1.2 Epidemiology

As of 2014, about 7,000 patients were certified to have Buerger disease, one of the specific diseases (Figure 25).¹¹ Recently, the number of female patients has been increased to 11–23% of the whole patients, presumably due to an increase in smoking rates in female.^166–169 In Japan, the majority of patients are elderly patients who have been grown old after the onset in young age.

Figure 25.

Annual changes in the numbers of patients with refractory vasculitides estimated from the numbers of certificates of patients with specific diseases issued. (Cited from the Japan Intractable Diseases Information Center¹¹)

The disease is prevalent in South Asia, Ease Asia, and Turkey. In Japan, Buerger disease used to be reported to account for 16% of patients treated for occlusive arterial disease¹⁷⁰ but is presently estimated to account for 1% or less due to the decrease in the number of patients with this disease and the increase in that with atherosclerotic diseases.

2. Pathogenesis

It has been suggested that pathogenesis of Buerger disease are related to smoking, infection, activated condition of vascular endothelial cells,^171–174 and the occurrence of microcirculation disorder.^175,176 The involvement of racial/ethnic factors has also been suspected.¹⁷⁶

Many of the patients are heavy smokers.^167,177 The disease has been reported to be induced by exposure to cold, trauma, and sympathetic nerve stimulating drugs,¹⁷⁸ but patients are considered to have some history of smoking including passive smoking. Many patients have dental root inflammation,¹⁷⁹ and the same periodontal pathogens have been detected in the arterial wall and oral cavity.¹⁸⁰

Attenuation of electric signals of the sympathetic nerve to the muscles and skin,¹⁸¹ reduced blood catecholamine level due to change in peripheral sympathetic nerve responses to smoking,¹⁸² impairment of endothelium-dependent vasodilatation of peripheral arteries, and increased expression of adhesion factors in endothelial cells and inflammatory cells¹⁸³ have been reported, and activation of platelets via serotonin receptors is speculated.¹⁸⁴

3. Pathological Findings

Figure 26 shows pathological images, and Figure 27 shows a diagram of characteristic features of Buerger disease. In Buerger disease, middle-sized vessels of the lower or upper extremities are affected, and as thrombi cause segmental occlusion of arteries, gangrene is observed in peripheries. The following pathogenic features characteristic of occluded arteries are observed: (1) In the acute period, microabscesses in which neutrophils aggregate and multinucleated giant cells are occasionally observed in the vascular wall, particularly, intima.^172,185 (2) The internal elastic lamina is not displaced, remains flexed, and may even be overflexed.¹⁸⁶ This contrasts with displacement of the internal elastic lamina by the intima observed in occlusive atherosclerosis and thrombosis, which are major differential diagnoses. (3) Fibrosis of the adventitia with no fibrosis of the media,¹⁸⁷ (4) edema immediately inside the external elastic lamina,¹⁸⁷ (5) onion-like multi-layering of endothelial cells of recanalized vessels,¹⁸⁷ and (6) thickening of the endothelial cells of vasa vasorum¹⁸⁷ are also observed frequently. These are features caused by inflammation within the vascular wall or from outside the blood vessel and impairment of microvessels. (7) Immunohistochemically, macrophage/lymphocyte infiltration tightly attached to the internal elastic lamina may be demonstrated.¹⁸⁸

Figure 26.

Pathological features of Buerger disease. (A) Microabscesses (arrowheads) containing multinucleated giant cells (arrow) observed in the intima of blood vessels that are considered characteristic of Buerger disease in the acute period. (HE staining). (B) The internal elastic lamina remains flexed (arrowheads) and is partly overflexed (arrow). Fibrosis of the adventitia is notable (EVG staining). (C) In the intima of the recanalized vessels, endothelial cells and perithelia show onion-like multi-layering (upward arrow). Vasa vasorum endothelial cells of the adventitia and media are thickened (downward arrow). Edema is observed immediately below the external elastic lamina (arrow pointing to the left). The arrowheads indicate the internal elastic lamina. (Azan staining) (D) CD4-positive T lymphocytes infiltrate the area around vasa vasorum (arrow) and are aligned in close contact with the internal elastic lamina (arrowheads). Immunohistochemical examination using anti-CD4-antibody.

Figure 27.

Pathological features characteristic of occluded vessels in Buerger disease.

4. Symptoms

4.1 Ischemic Signs/Symptoms in the Upper and Lower Limbs

4.1.1 Ischemic Signs/Symptoms in the Lower Limbs

a. Coldness

Patients feel coldness mainly in their toes.

b. Paresthesia

Numbness often occurs commonly in the fingers, toes, feet, and hands, particularly after exercising or walking.

c. Skin Color Change

The skin color of affected digits turns red (rubor) even when the limbs are located at the same level with the heart. Cyanosis indicates critical digit ischemia.

d. Intermittent Claudication

Ischemic intermittent claudication develops in the foot in an early stage, in the calf when the above-knee arteries are involved, and in the thigh and buttock when the iliac arteries are involved.

e. Rest Pain

Severe and stinging rest pain often disturbs patient’s sleep.

f. Ulcer/Gangrene

Ulcer and gangrene often occur in the fingers and toes, particularly around the nails. Ulcer and gangrene can develop beginning from small injury and extend rapidly.

4.1.2 Ischemic Signs/Symptoms in the Upper Limbs

Ischemic signs/symptoms in the upper limbs are milder than those in the lower limbs and are reported to be primary chief complaints in about 5–14% of the patients.^189,190

4.2 Involvement of Visceral Arteries

Although rare, lesions in the cerebral artery,¹⁹¹ coronary artery,^192,193 renal artery,¹⁹⁴ mesenteric artery,^195,196 and internal thoracic artery¹⁹³ have been reported.

4.3 Migratory Superficial Thrombophlebitis

Recurrent and migratory superficial thrombophlebitis (phlebitis migrans/migrating thrombophlebitis) occurs in the limbs.

4.4 Incidences of Signs/Symptoms

According to a survey in Japan in 1993, signs/symptoms were observed in the upper limbs alone in 5.1% of patients, lower limbs alone in 74.7%, and both upper and lower limbs in 20.2%. The affected arteries were the anterior tibial artery in 41.4%, posterior tibial artery in 40.4%, and ulnar artery in 11.5%.¹⁹⁷

According to the analysis conducted at the Department of Vascular Surgery of Nagoya University from 1977 to 1988, the initial symptoms were paresthesia, coldness, and cyanosis in 37% of patients, foot or calf claudication in about 30%, and severe ischemic symptoms such as rest pain and ulcer/gangrene in about 30%. Through the entire course, ulcer/gangrene was observed in 72%, migratory phlebitis in 43%, and upper limb lesions in 90%.¹⁸⁹

5. Clinical Features and Laboratory Findings

5.1 Physical Findings (Table 11)

Table 11. Physical Findings of Buerger Disease

(1) Appearance: Atrophy of the fingers and toes, underdeveloped nails, difference in hair growth between the right and left extremities, and migratory superficial thrombophlebitis

(2) Auscultation: Iliac artery, femoral artery, and popliteal artery

(3) Palpation: Decreased skin temperature in the extremities, fingers, and toes, and decrease or loss of pulse in peripheral arteries

(4) Provocation tests: Negative Allen’s test (abnormal), positive straight leg raising test

5.2 Examination Items (Table 12)

Table 12. Noninvasive Testing for Buerger Disease

A. Functional diagnosis

(1) Blood pressure (upper arm, fingers, ankle, toes): Doppler method, pulse wave method

(2) Skin perfusion pressure (SPP): Laser Doppler method

(3) Skin oxygen saturation: Transcutaneous oxygen tension (tcPO2) measurement

(4) Skin temperature: Thermography

(5) Skin blood flow: Laser Doppler method

(6) Muscle oxygen saturation: Near-infrared spectroscopy (uninsured)

(7) Blood flow: Air plethysmography

B. Diagnostic imaging

(1) Magnetic resonance angiography

(2) Contrast three-dimensional computed tomography (3D-CT)

(3) Angiography

Thermographic evaluation with cold-water stress is useful for the diagnosis of Raynaud’s phenomenon. For patients with intermittent claudication, maximum walking distance as well as recovery time of the ankle-brachial index, which is reduced after walking, can evaluate circulatory reserve of the lower limb. Angiography is indispensable in patients considered to have indication for bypass surgery of the lower leg.

5.3 Findings of Vascular Imaging (Table 13,¹⁹⁸ Figures 28–30^198–200)

Table 13. Arteriographic Findings of Buerger Disease

(1) Arterial occlusive lesions of infrapopliteal or below-elbow segments

(2) Chronic arterial occlusion secondary to the extension or thrombus

(3) Smooth arterial wall with no evidence for arteriosclerosis such as a moth-eaten appearance and calcification

(4) Abrupt or tapering occlusion of affected arteries

(5) Collateral arteries with corkscrew, tree-root, or bridging appearance

(Prepared from the 1976 report by a subgroup of the Study Group on Systemic Vascular Lesions as Specific Diseases of the Ministry of Health and Welfare of Japan, 1977¹⁹⁸)

Figure 28.

Arteriographic findings of Buerger disease. Arteriographic findings of Buerger disease in the lower (A) and upper (B) limbs. Occlusive lesions are present distally to the knee or elbow joint level. The arterial lumen near the lesions appear smooth without arteriosclerotic changes such as moth-eaten appearance and calcification. (A) (Cited from Shionoya S, Hirai M, Kawai S, Seko T, Ban I. Angiology. 1982.¹⁹⁹ Copyright (c) 1982 by SAGE Publications. Reprinted by Permission of SAGE Publications, Ltd.) (B) (Cited from S. Shionoya, 1990²⁰⁰)

Figure 29.

Images of arterial occlusion and collateral vessels in Buerger disease (lower limb arteriography) (From S. Shionoya, 1990²⁰⁰) Abrupt and tapering arterial occlusions with corkscrew and bridging type collateral developments are observed.

Figure 30.

Patterns of arterial occlusion and collateral vessels in Buerger disease. (Prepared from the 1976 report by a subgroup of the Study Group on Systemic Vascular Lesions as Specific Diseases of the Ministry of Health and Welfare of Japan, 1977¹⁹⁸) ①Abrupt occlusion, ②localized stenosis, ③moth-eaten, ④irregularity, ⑤bridging collaterals, ⑥cork screw collaterals, ⑦tree root collaterals, ⑧dilatation, ⑨early venous filling.

Differentiation from collagen diseases such as SLE, scleroderma, and vascular Behçet’s disease is particularly important. However, the differentiation is difficult by imaging findings alone.^201,202

5.4 Hematological Examinations

There is no specific hematological abnormality. ESR and CRP values are usually normal.

6. Diagnostic Methods and Criteria

6.1 Diagnosis

There are various diagnostic criteria.^203–205 When patients fulfill all of the 5 criteria of Shionoya’s clinical diagnostic criteria (Table 14),²⁰⁶ the clinical features are typical. However, even without fulfillment of all criteria, Buerger disease can be diagnosed if clinical findings including vascular images or pathological findings are consistent, and differential diagnoses can be excluded. Since young people with hypertension or dyslipidemia have increased, the careful diagnosis based on imaging and histological examinations is necessary, including differentiation from arteriosclerosis obliterans.

Table 14. Shionoya’s Clinical Diagnostic Criteria for Buerger Disease

(1) Onset before the age of 50 years

(2) History of smoking (including passive smoking)

(3) Infrapopliteal arterial occlusive lesions

(4) Either upper limb involvement or migratory thrombophlebitis

(5) Absence of atherosclerotic risk factors other than smoking

Buerger disease can be diagnosed without fulfillment of all diagnostic criteria if imaging and pathological findings are consistent, and other diseases can be excluded. See the text. (Prepared as a table from Shionoya S. 1993²⁰⁶)

6.2 Conditions to Be Differentiated From Buerger Disease

Conditions to be differentiated from Buerger disease include arteriosclerosis obliterans, traumatic arterial thrombosis, popliteal artery entrapment syndrome, popliteal artery adventitial cyst, SLE, scleroderma, vascular Behçet’s disease, thoracic outlet syndrome, and atrial fibrillation.

7. Policies and Guidelines of Treatment

Table 15 shows recommendations about treatment for Buerger disease.

Table 15. Recommendations and Evidence Levels of Treatments for Buerger Disease

	Recommendations	Levels of evidence
Smoking cessation	I	C
Antiplatelets	I	C
PGE1-CD, lipoPGE1	IIa	C
Exercise therapy	IIa	C
Pain control	I	C
Sympathetic nerve block	IIb	C
Sympathectomy	IIb	C
Vascular bypass surgery	IIa	C
Endovascular treatment	III	C

7.1 Conservative Treatment

7.1.1 Smoking Cessation/Lifestyle Guidance

Patients should avoid even passive smoking, keep the affected limbs warm and clean, and avoid injury.²⁰⁷ Smoking after the initial visit correlates with increased limb amputation rate.²⁰⁸ Symptoms can be resolved in many patients by conservative therapy centering on smoking cessation.

7.1.2 Drug Treatment

For coldness and numbness, drug treatment should be attempted first. As oral antiplatelet agents, Cilostazol, beraprost, sarpogrelate, limaprost alfadex, ticlopidine, and clopidogrel are used. Alprostadil (a complex of prostaglandin E₁ [PGE₁]-α-cyclodextrin [CD] complex, lipo-PGE₁) is an injection drug used for the treatment.

7.1.3 Exercise Therapy

Supervised exercise therapy is useful for the treatment of intermittent claudication.²⁰⁹ The effects should be evaluated after the program has been carried out for 3–6 months.

7.1.4 Pain Control

In addition to oral medications, fentanyl tape is also available. Continuous epidural anesthesia or toe amputation can be an option.

7.2 Surgical Treatment

7.2.1 Revascularization

Revascularization is indicated particularly in patients with rest pain or ulcer when no improvement has been observed in symptoms by conservative treatment. Using autogenous vein grafts is recommended for bypass surgery. The patency of infrapopliteal bypass in Buerger disease is generally lower than that in arteriosclerosis obliterans. However, major amputation is required in only small number of patients even if the graft occlusion has occurred.

7.2.2 Sympathectomy

Sympathectomy should be considered for painful ulcers of the toes and fingers when revascularization is impossible. Pharmacological sympathetic blockade can also be a choice.

7.2.3 Others

Angiogenesis therapy (gene therapy, autologous bone marrow (monocyte) transplantation,^210,211 peripheral blood monocyte transplantation²¹²), remains in the experimental stage.

8. Prognosis

8.1 Prognosis of Ischemic Limbs

It is estimated that 70% of the patient will experience ischemic ulcer or necrosis at least once during the course. Patients tend to repeat exacerbation and remission of symptoms, therefore, not all the patients with Fontaine stage III/IV disease need limb amputation.

On long-term follow-up studies, major limb amputation was performed in 2.7–10.5% of the patients.^200,213 According to questionnaire surveys by the MHLW Group Conference, 8.8% resulted in major limb amputation, and 16.7–20.5% of the patients required toe amputation.^208,214

Patients who need revascularization of the upper limb are few. While some patients require finger amputation, very few patients need major amputation of the upper limb.

8.2 Factors Contributing to Exacerbation and Improvement

Smoking is considered to shorten the remission period and invite exacerbation. Patients who continue smoking after the appearance of symptoms resist various treatments and often come to need major amputation consequently.²⁰⁸ If patients can avoid foot injury by hospitalization, their symptoms may be alleviated. Hospitalization also leads patients to strict smoking cessation.

8.3 Prognosis of Non-Critical Ischemic Limbs

Almost all patients have two or more affected limbs.²⁰⁰ The disease rarely progresses in non-critical or non-dominant ischemic limbs if patients can continue smoking cessation but may progress if patients continue smoking.

8.4 Concomitant Diseases and Life Prognosis

The life expectancy of patients is considered favorable. The most common cause of death is malignant neoplasm, followed by heart failure, cerebral infarction, and liver cirrhosis.²¹³ Concomitant diseases include diabetes, hypertension, dyslipidemia, cerebrovascular disorders, ischemic heart disease, and arteriosclerosis obliterans.²⁰⁸ Therefore, the disease management including atherosclerotic risk factors is required according to the patients’ age.

V. Polyarteritis Nodosa

1. Definition and Epidemiology

Polyarteritis nodosa (PAN) is defined as “Necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules, and not associated with ANCAs”.¹ Presently, the number of patients is estimated to be about 600, but 3,442 patients held certificates for medical benefits for specific diseases in 2015. The male/female ratio of the patients is 1:1 to 1:2, and the average age at onset is 55 years.²¹⁵

2. Pathogenic Mechanism

The etiology is unknown, but secondary PAN that follows HBV infection has been recognized.

3. Pathological Findings

In the acute period, severe inflammation and necrosis are observed in the vascular wall of muscular arteries, and lesions are present as segments.²¹⁶ In the affected blood vessels, fibrinoid necrosis and rupture of the internal/external elastic laminae are observed, often causing aneurysms (Figure 31).

Figure 31.

Necrotizing arteritis in the bladder muscle layer. Fibrinoid necrosis of the arterial wall and inflammatory cell infiltration to the arterial wall and surrounding tissue are observed. (HE stain) (Provided by Prof. Akihiro Ishizu, Hokkaido University)

4. Symptoms

Patients with PAN present systemic symptoms and organ symptoms due to ischemia (Table 16).²¹⁷ PAN in which lesions are localized in the skin is called cutaneous PAN²¹⁸ or cutaneous arteritis.¹

Table 16. Clinical Symptoms of Polyarteritis Nodosa

Clinical signs/symptoms		Prevalence (%)
General symptoms	Fever, Malaise, Weight loss	80
Neurologic manifestations	Mononeuritis multiplex, Polyneuropathy	75
Arthralgia, Myalgia	Joint pain or diffuse pain of the limbs	60
Cutaneous signs/symptoms	Livedo reticularis, Purpura, Ulcer	50
Renal manifestations	Increased creatinine, Hematuria, Glomerulonephritis	50
Gastrointestinal manifestations	Abdominal pain, Rectal bleeding	40
Hypertension	New onset	35
Pulmonary manifestations	Lung infiltrates, Nodular shadow, Cavity	25
Central nervous system manifestations	Stroke, Confusion	20
Testicular manifestations	Orchitis or testicular tenderness	20
Cardiac manifestations	Myocarditis, Pericarditis	10
Peripheral vascular manifestations	Claudication, Ischemia, Necrosis	10

(Reproduced with modification from Pagnoux C, et al. 2010²¹⁷)

5. Laboratory and Imaging Findings

There is no laboratory finding specific to PAN. ANCA must be confirmed to be negative. Examinations including skin biopsy, angiography, and sural nerve biopsy are performed.

6. Diagnosis and Diagnostic Criteria

Table 17 shows the diagnostic criteria for PAN by the MHLW of Japan.²¹⁹

Table 17. MHLW Diagnostic Criteria for Polyarteritis Nodosa

For Definite and Probable Diagnoses
[Diagnostic features]
(1) Major clinical findings
1) Fever (≥38℃ continued ≥2 weeks) and weight loss (≥6 kg over ≤6 months)
2) Hypertension
3) Rapidly progressive renal failure, renal infarction
4) Cerebral hemorrhage, cerebral infarction
5) Myocardial infarction, ischemic heart disease, pericarditis, heart failure
6) Pleurisy
7) Gastrointestinal hemorrhage, intestinal obstruction
8) Mononeuritis multiplex
9) Subcutaneous nodule, skin ulcer, gangrene, purpura
10) Polyarthralgia (polyarthritis), myalgia (myositis), muscular weakness
(2) Histological finding
Fibrinoid necrosis in medium- and small-sized arteries
(3) Angiographic findings
Multiple microaneurysms, stenoses, and occlusions in branches of the abdominal aorta (characteristically in renal arterioles)
(4) Diagnosis
1) Definite
Patients with ≥2 major clinical findings and the histological finding
2) Probable
(a) Patients with ≥2 major clinical findings and the angiographic findings
(b) Patients with ≥6 major clinical findings including item 1)
(5) Suggestive laboratory findings
1) Leukocytosis (≥10,000/μL)
2) Thrombocytosis (≥400,000/μL)
3) Elevated sedimentation rate
4) Strongly positive CRP
(6) Differential diagnosis
1) Microscopic polyangiitis
2) Granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis)
3) Eosinophilic granulomatosis with polyangiitis (formerly known as allergic granulomatous angiitis)
4) Kawasaki disease
5) Connective tissue disease (SLE, RA)
6) IgA vasculitis (formerly known as Henoch Schönlein purpura)
[Notes]
(1) Histologically, polyarteritis nodosa has been classified into Stage I (degenerative stage), Stage II (inflammatory stage), Stage III (granulation tissue stage), and Stage IV (scar tissue stage).
(2) Clinically, patients in Stages I and II exhibit signs and symptoms of severe inflammation of systemic vessels, while patients in Stages III and IV exhibit signs and symptoms of ischemia of affected organs.
(3) The diseases to be differentiated from polyarteritis nodosa also demonstrate necrotic vasculitis, but may be clearly differentiated from it on the basis of characteristic findings and laboratory results.

(Report of the Intractable Vasculitis Study Group of the MHLW, 2005 Revised²¹⁹)

7. Policies and Guidelines of Treatment

Table 18 shows recommendations about treatments for PAN.

Table 18. Recommendations and Evidence Levels Concerning Treatments for PAN

	Recommendations	Levels of evidence
Glucocorticoid (GC)	I	B
Steroid pulse therapy	IIa	C
Cyclophosphamide (CY)	IIa	A
Methotrexate (MTX)*	IIb	B
Azathioprine (AZA)	IIb	B
Plasma exchange therapy*	IIb	C

*Uncovered by medical insurance in Japan.

7.1 Remission Induction Therapy

7.1.1 Moderate/Severe PAN With Lesions in Vital Organs

Four-week initial treatment is performed using PSL at 1 mg/kg/day with IVCY or daily oral CY administration from the beginning of treatment²²⁰ (recommendation class: I, evidence level: B). If symptoms are extremely severe, steroid pulse therapy is performed simultaneously (recommendation class: IIa, evidence level: C). If severe renal disorder is noted, plasma exchange (uninsured)²²¹ should also be considered (recommendation class: IIb, evidence level: C).

7.1.2 Mild PAN Not Accompanied by Vital Organ Lesions

Treatment is initiated with PSL alone (0.5–1.0 mg/kg/day)²²² (recommendation level: I, evidence level: B). If symptoms are not improved, CY or MTX is used concomitantly.

7.1.3 Symptomatic Treatments/Management of Adverse Reactions

Antihypertensive drugs, circulation improving medications, and treatments for neurological disorders should be used in combination with prophylaxis for infection.

7.2 Remission Maintenance Therapy

PSL is reduced and continued at a maintenance dose of 5–10 mg/day. CY is replaced with AZA at 1–2 mg/kg/day or MTX at 7.5–15 mg/week (uninsured) (recommendation class: IIb, evidence level: B).

8. Prognosis

The 5-year survival rate of patients with PAN is 75–93%.^223,224 As prognostic factors, proteinuria of ≥1 g/day, renal insufficiency, cardiomyopathy, severe gastrointestinal manifestation and central nervous system involvement were extracted in 1996,²²⁵ and an age of ≥65 years, cardiac symptoms, renal insufficiency, and gastrointestinal involvement were reported in 2011.²²⁶

VI. Microscopic Polyangiitis

1. Definition and Epidemiology

1.1 Definition

Microscopic polyangiitis (MPA) is classified as small-vessel angiitis related to ANCA and defined as “a necrotizing vasculitis that primarily affects small vessels (capillaries, venules, arterioles) and shows only little or no immune deposits. Necrotizing arteritis may affect not only small vessels but also middle-sized vessel. Necrotizing glomerulonephritis is observed in most patients, pulmonary capillary angiitis is often observed, and granulomatous inflammation is not observed.”¹

1.2 Epidemiology

According to the summary of the number of certificates for recipients of medical care for specific diseases issued at the end of the fiscal year 2015, the number of MPA patients was 8,511 (Figure 25).¹¹ The male/female ratio is 1:1.1 slightly in favor of women, and the mean age of the patients was 70.5 years.²²⁷ The annual incidence of MPA per 1 million people has been reported to be 18 in Japan,²²⁸ 7 in the UK, 8 in Spain, and 3 in Germany.²²⁹ Among subtypes of ANCA, myeloperoxidase (MPO) ANCA (MPO-ANCA) is predominant in Japan, accounting for 97.4%, and proteinase 3 (PR3) ANCA (PR3-ANCA) accounts for 2.6%.²²⁷ In Western countries, MPO-ANCA and PR3-ANCA occupy 40–58% and 26–50%, respectively, and the PR3-ANCA is more prevalent than in Japan. Also, interstitial pneumonia is prevalent at 45% in Japan.²²⁷

2. Pathogenic Mechanism

An autoimmune mechanism, i.e., genetic and environmental factors interact to produce ANCA, which is an autoantibody, and it induces vascular endothelial damage, is suspected to be involved.

2.1 Genetic Factors

HLA haplotype analysis: In Japanese patients with MPA, 50% are reported to be positive for HLA-DRB1*0901, and the percentage is significantly higher than in healthy controls.²³⁰ According to the results of GWAS (comprehensive analysis of genetic polymorphisms in whole genome) concerning ANCA-associated vasculitis based on multicenter collaborative research in Europe, MPA and ANCA-associated vasculitis positive for MPO-ANCA were suggested to be significantly related to SNP in the HLA-DQ region.²³¹ In addition, gene polymorphism of ANCA-associated vasculitis is estimated to be more closely related to the specificity of ANCA such as MPO-ANCA and PR3-ANCA than clinical classification of MPA and GPA.²³¹

2.2 Environmental Factors

Agents including silica, drugs, and infection (viruses, Gram-negative rods) are suspected to be involved in MPA. Among drugs, propylthiouracil (anti-thyroid drug) has been reported most frequently, and minocycline (antibiotic) and hydralazine (antihypertensive) have also been reported.

2.3 Pathology

Inflammatory cytokines such as TNF-α, ANCA, MPO, and neutrophil activation have been suggested to be involved (ANCA-cytokine sequence theory). ANCA produced by an autoimmune mechanism excessively activates neutrophils alone with inflammatory cytokines is estimated to release a network of fine fibers (chromatin fibers) called neutrophil extra-cellular traps and damage the vascular endothelium.^232–234

3. Pathological Findings

In MPA, necrotizing vasculitis is observed primarily in small vessels (capillaries, venules, arterioles) distributed to various organs including the kidney, lung, skin, and nervous system (Figure 32).²³⁵ On immunoglobulin staining by the fluorescent antibody method, little or no immune deposits are observed (pauci-immune).

Figure 32.

Histopathological findings of MPA. (A) Necrotizing crescentic glomerulonephritis (PASM-HE stain). Rupture of the basement membrane, fibrin in Bowman’s space, and extracapillary cell proliferation are observed. (From Yoshihiro Arimura. Tell Us About Characteristics and Classification of Kidney Tissue Findings in RPGN. Guidelines for Clinical Management of RPGN Q&A Revised 2nd Edition. p.7. Shindan To Chiryo sha. 2015²³⁵) (B) Necrotizing vasculitis with fibrinoid necrosis of the interlobular artery (PASM-HE stain)

Typical small-vessel vasculitides due to MPA are focal/segmented necrotizing glomerulonephritis and crescentic glomerulonephritis in the kidney and alveolar hemorrhage due to pulmonary capillaritis in the lungs.

4. Signs and Symptoms

As systemic symptoms, there are fever, malaise, anorexia, and body weight loss. As local lesions/symptoms, there are a wide variety of symptoms due to organ disorders shown below.

Kidney symptoms: Various symptoms due to necrotizing glomerulonephritis (edema, glomerular hematuria, RPGN).

Lung lesions: Bloody sputum, hemoptysis, melanoptysis, cough, and dyspnea due to alveolar hemorrhage and dry cough and dyspnea due to interstitial pneumonia.

Skin symptoms: Purpura, livedo reticularis, subcutaneous nodules

Ophthalmic lesions: Conjunctival congestion, diplopia, reduced visual acuity, ophthalmalgia.

ENT symptoms: Hearing impairment due to otitis media

Peripheral nerve lesions: Paresthesia of the limbs, motor disorders

Central nervous system disorders: Symptoms due to lesions of the Hemiplegia, headache, and disturbance of consciousness due to cerebral infarction or cerebral hemorrhage, symptoms due to lesions of the cranial nerves such as facial nerve palsy, and headache and disturbance of consciousness due to hypertrophic pachymeningitis.

Gastrointestinal lesions: Abdominal pain, melena

5. Laboratory and Imaging Findings

As findings indicating inflammatory reaction, there are increases in CRP/gammaglobulin, ESR, peripheral blood leukocyte count, and platelet count. Laboratory/imaging findings in typical organ disorders are presented.

In patients with kidney lesions, abnormal urinalysis findings (proteinuria, glomerular hematuria, red blood cell cast, and granular cast) indicating nephritis and a decrease in eGFR or increase in BUN/serum creatinine indicating the reduction of renal function may be observed. RPGN is often noted, and serial measurements of eGFR are important.

Concerning lung lesions, non-segmental infiltrative shadow indicating alveolar hemorrhage is a typical finding. Interstitial pneumonia often presents reticular or annular shadows primarily in the bilateral lower lung fields on chest radiography and reticular shadow, honeycomb lung, and infiltrative shadow immediately below the pleura on CT, showing a usual interstitial pneumonia (UIP) pattern.

Ophthalmic lesions (episcleritis) and ENT lesions (neural deafness) are observed, and there are peripheral nerve lesions (findings of mononeuropathy multiplex), central nervous system disorders (headache, disturbance of consciousness due to cerebral infarction, cerebral hemorrhage, or hypertrophic pachymeningitis), and gastrointestinal lesions (abdominal pain, melena).

6. Diagnosis/Diagnostic Criteria

6.1 Diagnosis

Table 19 shows the diagnostic criteria for MPA by the MHLW Research Committee of Intractable Vasculitis.²³⁶

Table 19. Diagnostic Criteria for Microscopic Polyangiitis

<Diagnostic Criteria> For definite and probable diagnoses
[Major items]
(1) Major clinical findings
1. Rapidly progressive glomerulonephritis
2. Pulmonary hemorrhage or interstitial pneumonia
3. Visceral signs/symptoms other than renal/pulmonary manifestations: purpura, subcutaneous hemorrhage, gastrointestinal hemorrhage, mononeuritis multiplex, etc.
(2) Major histological findings
Necrosis of arterioles, capillaries and postcapillary venules, and infiltration of inflammatory cells into tissues surrounding vessels
(3) Major laboratory findings
1. Positive MPO-ANCA
2. Positive CRP
3. Proteinuria, hematuria, elevation in BUN, elevation in serum creatinine
4. Chest X-ray findings: Infiltrations (alveolar hemorrhage), interstitial pneumonia
(4) Diagnosis
1. Definite
(a) Patients with ≥2 major clinical findings and positive histological finding
(b) Patients with ≥2 major clinical findings including Items 1and 2 and positive MPO-ANCA
2. Probable
(a) Patients with 3 major clinical findings
(b) Patients with one major clinical finding and positive MPO-ANCA
(5) Differential diagnosis
1. Polyarteritis nodosa
2. Granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis)
3. Eosinophilic granulomatosis with polyangiitis (formerly known as allergic granulomatous angiitis/Churg Strauss syndrome)
4. Arteritis of Kawasaki disease
5. Collagen disease (SLE, RA, etc.)
6. IgA vasculitis (formerly known as Henoch Schönlein purpura)
[Notes]
1. In many patients, infection (mainly upper respiratory infection) develops one or two weeks prior to manifestation of major clinical findings.
2. Items 1 and 2 of the major clinical findings develop simultaneously in about half of patients, and either of the two develops first in the remaining patients.
3. In many patients, MPO-ANCA titer is related to disease activity.
4. Early discontinuation of treatment may be associated with relapse of disease
5. Various diseases to be differentiated exhibit necrotizing vasculitis but can be differentiated according to characteristic signs and symptoms and laboratory findings.

(Report of the Intractable Vasculitis Study Group of the MHLW²³⁶)

6.2 Procedure of Differential Diagnosis

First, vasculitides due to infection, malignant neoplasm, drugs, and other collagen diseases must be excluded. ANCA may also be positive in infectious endocarditis and collagen diseases such as SLE. For the differentiation of MPA from infectious endocarditis, the history of dental treatment, blood culturing, and echocardiography findings are important.

After the above condition have been excluded, and primary middle-sized/small-vessel vasculitis is considered possible, ANCA-associated vasculitides are classified by following the 3 steps shown in Figure 33.²³⁷ EGPA is excluded first, and GPA is excluded next. If these two diseases have been excluded, urinalysis findings characteristic of glomerulonephritis and findings of small-vessel vasculitis such as purpura are present, and ANCA is positive, the possibility of MPA is high. Even if MPA is initially diagnosed, the diagnosis is changed if lesions due to granulomatous inflammation such as pulmonary nodules are confirmed during the course, and the diagnosis of GPA or EGPA are fulfilled.

Figure 33.

Classification by Watts. (Please attach * to MPA, as MPA*) Reproduced from Ann Rheum Dis Watts R, Lane S, Hanslik T, et al. 2007,²³⁷ with permission from BMJ Publishing Group Ltd. *MPA includes renal-limited type and lung-limited type. Lung-limited MPA is not mentioned in Watts R, et al. 2007²³⁷ and was defined in Sada KE, et al. 2014.²²⁷ PSV, primary systemic vasculitis. CSS=EGPA, WG=GPA, cPAN=PAN.

In MPA, caution is necessary as impairment of only one organ may be observed at the facility that diagnoses the disease initially, but disorders of various organs may appear successively.

7. Policies and Guidelines of Treatment

The basic treatments for MPA are GC and immunosuppressants (including RTX) (Figure 34).^238,239 Plasma exchange therapy may also be included (uncovered by insurance in Japan).

Figure 34.

Selection of treatment regimens by the Guidelines for the Management of ANCA-associated Vaculitides 2017 (From the Guidelines for the Management of ANCA-associated Vasculitides 2017²³⁸)

By the Guidelines for the Management of ANCA-associated vasculitis 2017 (jointly prepared by the MHLW Study Groups on Intractable Vasculitides, Intractable Kidney Diseases, and Diffuse Lung Diseases), the following treatments are recommended (the strength of recommendation and reliability of the evidence are presented according to the GRADE system).²³⁸ See the recommendations and comments in Part 1 of the same Guidelines. See the section, VIII Treatments in Part 2 of the same Guidelines for the dosage and dose regimen of each drug.

7.1 Remission Induction Therapy

The following CQs and the answers to them are the same for MPA and GPA.

CQ1

What regimens are effective as remission induction therapies for ANCA-associated vasculitis?

(1)-(i) As a remission induction therapy for ANCA-associated vasculitis, GC+IVCY or oral CY is proposed instead of GC alone.

Strength of recommendation: Weak

Reliability of evidence: Very low

(1)-(ii) As a remission induction therapy for ANCA-associated vasculitis, GC+IVCY is proposed instead of GC+oral CY.

Strength of recommendation: Weak

Reliability of evidence: Very low

Oral CY may be used as an alternative for IVCY.

(2) As a remission induction therapy for ANCA-associated vasculitis, GC+CY is proposed instead of GC+RTX.

Strength of recommendation: Weak

Reliability of evidence: Very low*/low**

For patients in whom the use of RTX is judged to be appropriate, GC+RTX may be used as an alternative of GC+CY by a physician with sufficient knowledge and experience in the treatment for ANCA-associated vasculitis.

*Compared with IVCY, **Compared with oral CY

(3) When neither CY nor RTX can be used, GC+MTX* is proposed as a remission induction therapy for patients with ANCA-associated vasculitis with no severe organ disorders and mild impairment of renal function.

Strength of recommendation: Weak

Reliability of evidence: Very low

*Uncovered by insurance in Japan

(4) GC+MMF* is proposed when neither CY nor RTX can be used and when the above recommendation (3) is inappropriate.

Strength of recommendation: Weak

Reliability of evidence: Very low

*Uncovered by insurance in Japan

CQ2

Is plasma exchange useful as a remission induction therapy for ANCA-associated vasculitis with severe kidney disorder?

(1)-(i) As a remission induction therapy for ANCA-associated vasculitis with severe kidney disorder, GC+oral CY+plasma exchange* is proposed instead of GC+oral CY+steroid pulse therapy.

Strength of recommendation: Weak

Reliability of evidence: Very low

(1)-(ii) As a remission induction therapy for ANCA-associated vasculitis with severe kidney disorder, GC+oral CY+plasma exchange* is proposed instead of GC+oral CY.

Strength of recommendation: Weak

Reliability of evidence: Very low

*Covered by insurance in Japan from April 2018

Concerning the recommendations in CQ1 and CQ2, there are the following points of attention. Drugs/treatments indicated by * cannot be recommended in general, because they are uncovered by insurance in Japan. Consultation with nephrologists is recommended concerning patients with severe kidney disorders including RPGN. Plasma exchange should be performed by a physician with sufficient experience.

7.2 Remission Maintenance Therapies

CQ3

What regimens are useful as remission maintenance therapies for ANCA-associated vasculitis?

As a remission maintenance therapy for ANCA-associated vasculitis, the concomitant use of AZA in addition to GC is proposed.

Strength of recommendation: Weak

Reliability of evidence: Very low

RTX, MTX*, and MMF* can be alternative drugs to be used for remission maintenance therapy.

The drugs/treatments indicated by * cannot be recommended in general, because they are uncovered by insurance in Japan.

8. Prognosis

The prognosis of MPA has been markedly improved due to early detection as a result of the increased prevalence of ANCA measurement and knowledge about the disease, modifications of immunosuppressive therapy, improvements in anti-infection measures.

In 2008, EULAR reported that the remission rate of MPA except the renal-limited type was 81–91% and that the 5-year survival rate was 45–76%.²⁴⁰ However, in 2011, the European Vasculitis Study Group evaluated the long-term survival rate of patients with ANCA-associated vasculitis including MPA (mean follow-up period: 5.2 years) and reported a mortality rate of 25%.²⁴¹ The report mentioned a eGFR of <15 mL/min/1.73 m², old age, and high disease activity (BVAS) as factors that increased the mortality rate.

According to the Prospective Study of the Severity-Based Treatment Protocol for Japanese Patients with MPO-ANCA-associated Vasculitis (JMAAV), a prospective clinical study to clarify the usefulness of severity-based treatment protocols for MPO-ANCA-associated vasculitis carried out in Japan, the remission induction rate was 89.4%, mortality rate was 10.6%, rate of progression to end-stage renal disease was 2.1%, and relapse rate was 19.0%.²⁴² The mortality rate by the severity of the disease was 50% for severest, 13% for severe, and 4% for mild cases, and the causes of death included vasculitis and infection.

The RemiT-JAV-RPGN, a prospective study of 321 cases of ANCA-associated vasculitis by the Study Group on Intractable Vasculitis and Study Group on Progressive Kidney Diseases of the MHLW of Japan, which included 197 cases of MPA, reported that the survival rate was 92.5%, and the remission induction rate was 76%, half a year after the initiation of remission induction therapy.²²⁷ In addition, the condition progressed to end-stage renal disease in 12.7% during the observation period.

VII. Granulomatosis With Polyangiitis

1. Disease Concept, Definition, and Epidemiology

Granulomatosis with polyangiitis (GPA), first reported in 1939 by Wegener, a German pathologist,²⁴³ is an intractable vasculitis with the following 3 clinicopathological characteristics: (1) Necrotizing granulomatous inflammation in the upper airway (E; ear and nose) and the lung (L; lung), (2) focal segmental necrotizing glomerulonephritis in the kidney (K; kidney), and (3) generalized necrotizing vasculitis of middle-sized/small vessels. According to a recent clinical research, the disease has a slight predilection to women, and often affects people in their 40 s–60 s, but may also occur in children and older people.²⁴⁴

2. Pathogenic Mechanism

Concerning the action mechanism of ANCA in GPA, the ANCA-cytokine sequence theory was proposed,²⁴⁵ neutrophil extracellular traps released by neutrophils at cell death are considered to be involved in the formation of pathological features.²⁴⁶

3. Pathological Findings

In E and L, parenchymal necrosis and granulomatous inflammation are noted (Figure 35), and necrotizing vasculitis is observed from middle-sized to small arteries, veins and capillaries. Histological findings in K are consistent with focal segmental or crescentic nephritis and are pauci-immune.²⁴⁵

Figure 35.

Pathological images of granulomatosis with polyangiitis. Necrotizing vasculitis is observed in a small vessel of the lung by HE stain (A). The elastic lamina of the same vessel is found to be ruptured by EVG stain (B), suggesting disruption of the vascular wall due to vasculitis.

4. Signs and Symptoms

In addition to systemic symptoms such as fever and body weight loss, (1) symptoms of E (purulent rhinorrhea, nasal bleeding, saddle nose, otitis media, reduced visual acuity, laryngopharyngeal ulcer, hoarseness), (2) symptoms of L (bloody sputum, dyspnea, lung infiltration), (3) symptoms of K (hematuria, oliguria, RPGN), and (4) other symptoms of vasculitis (purpura, polyarthralgia, polyneuritis). They often occur in the order of (1)→(2)→(3).

5. Laboratory and Imaging Findings

Typical chest radiography findings are nodular lesions accompanied by multiple or single cavities (Figure 36), and differentiation from malignant neoplasm and tuberculosis is necessary. In Western countries, cytoplasmic ANCA (c-ANCA) (PR3-ANCA) is positive in 80–96% of the patients with previously untreated active GPA, but patients positive for perinuclear ANCA (p-ANCA) (MPO-ANCA) and those positive for c-ANCA (PR3-ANCA) are observed at a ratio of approximately 1:1 in Japan.²²⁷

Figure 36.

Chest CT findings in granulomatosis with polyangiitis. Nodular lesions with multiple cavities are observed.

6. Diagnosis and Diagnostic Criteria

A revised version of the diagnostic criteria proposed by the MHLW study group in 1998 is used for the diagnosis of GPA (Table 20).²⁴⁷

Table 20. Diagnostic Criteria for Granulomatosis With Polyangiitis (Formerly, Wegener’s Granulomatosis)

Criteria for diagnosis	1. Upper respiratory tract (E) signs/symptoms
	Nose (Purulent rhinorrhea, bleeding, saddle nose), eyes (eye pain, reduced visual acuity, exophthalmos), ears (otitis media), oropharyngeal pain (ulcer, hoarse voice, airway obstruction)
	2. Pulmonary (L) signs/symptoms
	Bloody sputum, cough, dyspnea
	3. Renal (K) signs/symptoms
	Hematuria, proteinuria, rapidly progressive renal failure, swelling, hypertension
	4. Signs/symptoms of vasculitis
	(a) Systemic findings: Fever (≥38℃ for ≥2 weeks) and weight loss (≥6 kg in ≤6 months)
	(b) Visceral findings: Purpura, polyarthritis (polyarthralgia), episcleritis, mononeuritis multiplex, ischemic heart disease (angina pectoris, myocardial infarction), gastrointestinal hemorrhage (hematemesis, melena), pleuritis, etc.
Major histological findings	1. Necrotizing granulomatous inflammation with infiltration of giant cells in E, L, K lesions
	2. Necrotizing crescentic glomerulonephritis without immunoglobulin deposits
	3. Necrotizing granulomatous vasculitis in small-sized arteries and arterioles
Major laboratory findings	Positive for PR3-ANCA (c-ANCA using the fluorescent antibody technique)
Diagnosis	1. Definite
	(a) Patients with ≥3 major clinical findings in E, L, K including visceral findings of E, L, and K
	(b) Patients with ≥2 major clinical findings in E, L, K or vasculitis and at least one of the major histological findings (1) to (3)
	(c) Patients with ≥1 major clinical findings in E, L, K or vasculitis and at least one of the major histological findings (1) to (3) and positive c (PR3)-ANCA
	2. Probable
	(a) Patients with ≥2 major clinical findings in E, L, K or vasculitis
	(b) Patients with ≥1 major clinical findings in E, L, K or vasculitis and one of the major histological findings (1) to (3)
	(c) Patients with 1 major clinical finding in E, L, K or vasculitis and positive c(PR3)-ANCA
Supportive laboratory findings	1. Leukocyte count, elevation in CRP
	2. Elevation in BUN and serum creatinine
Differential diagnosis	1. Granulomatous disorder in E and L due to other causes (such as sarcoidosis)
	2. Other vasculitis syndromes (microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis [Churg- Strauss syndrome], polyarteritis nodosa, etc.)
Notes	1. Wegener’s granulomatosis with visceral findings for E, L, K organs is referred to as systemic Wegener’s granulomatosis, while that with findings of one or two of E, L is referred to as localized Wegener’s granulomatosis.
	2. Signs and symptoms of systemic Wegener’s granulomatosis often develop in the order of E, L, then K.
	3. Shortly after onset, infection mainly with Staphylococcus aureus often occurs in E and L lesions.
	4. CT, MRI, and scintigraphy are useful in diagnosing space-occupying lesions due to granuloma formation in E and L.
	5. PR3-ANCA titer is often correlated with disease activity. There are some patients with positive MPO-ANCA.

(Cited with modification from the Study Group on Specific Diseases Systematic Vascular Disorders. 1998²⁴⁷)

7. Policies and Guidelines of Treatment

Treatments for GPA can be divided into remission induction therapy and remission maintenance therapy. The Guidelines for the Management of ANCA-associated vasculitis 2017 recommends the following based on the GRADE system.²³⁸

In ANCA-associated vasculitis, it is difficult to induce remission by inadequate immunosuppressive therapy, and the exacerbation rate is high even if remission has been achieved. However, excessive immunosuppressive therapy increases the risk of severe infection, and treatments dependent on GC is likely to induce complications such as osteoporosis and diabetes, which affects the patient QOL.

The following CQs and related recommendations apply both to MPA (Chapter VI) and GPA. (See Figure 34 in Chapter VI.)

7.1 Remission Induction Therapy

CQ1

What regimens are useful for remission induction therapy for ANCA-associated vasculitis?

(1)-(i) As a remission induction therapy for ANCA-associated vasculitis, GC+IVCY or oral CY is proposed instead of GC alone.

Strength of recommendation: Weak

Reliability of evidence: Very low

(1)-(ii) As a remission induction therapy for ANCA-associated vasculitis, GC+IVCY is proposed instead of GC+oral CY.

Strength of recommendation: Weak

Reliability of evidence: Very low

Oral CY may be used as an alternative of IVCY.

(2) As a remission induction therapy for ANCA-associated vasculitis, GC+CY is proposed instead of GC+RTX.

Strength of recommendation: Weak

Reliability of evidence: Very low*/low**

For patients in whom the use of RTX is judged to be appropriate, GC+RTX may be used as an alternative of GC+CY by a physician with sufficient knowledge and experience in the treatment for ANCA-associated vasculitis.

*Comparison with IVCY, **Comparison with oral CY

(3) If neither CY nor RTX can be used, GC+MTX* is proposed as a remission induction therapy for patients with ANCA-associated vasculitis with no severe organ disorders and mild impairment of renal function.

Strength of recommendation: Weak

Reliability of evidence: Very low

*Uncovered by insurance in Japan

(4) If neither CY nor RTX can be used, GC+MMF* is proposed when the above recommendation (3) cannot be applied.

Strength of recommendation: Weak

Reliability of evidence: Very low

*Uncovered by insurance in Japan

CQ2

Is plasma exchange useful in remission induction therapy for ANCA-associated vasculitis with severe renal disorder?

(1)-(i) GC+oral CY+plasma exchange* is proposed instead of GC+oral CY+steroid pulse therapy for remission induction therapy for ANCA-associated vasculitis with severe renal disorder.

Strength of recommendation: Weak

Reliability of evidence: Very low

(1)-(ii) GC+oral CY+plasma exchange is proposed instead of GC+oral CY for remission induction therapy for ANCA-associated vasculitis with severe renal disorder.

Strength of recommendation: Weak

Reliability of evidence: Very low

*Covered by insurance in Japan from April 2018

Points of attention concerning the recommendations for CQ1 and CQ2 are as follows: Since the drugs/treatments indicated by * are uncovered by health insurance in Japan, they cannot be recommended in general. It is recommended to consult a nephrologist concerning patients with severe renal disorders including RPGN. Plasma exchange should be performed by a physician with sufficient experience.

7.2 Remission Maintenance Therapy

CQ3

What regimens are useful as remission maintenance therapy for ANCA-associated vasculitis?

The concomitant use of AZA in addition to GC is proposed in remission maintenance therapy for ANCA-associated vasculitis

Strength of recommendation: Weak

Reliability of evidence: Very low

RTX, MTX*, and MMF* can be alternative drugs to be used in maintenance remission therapy.

*Since the drugs/treatments indicated by * are uncovered by health insurance in Japan, they cannot be recommended in general.

8. Prognosis

In GPA, induction of remission has become possible in many patients by GC+CY therapy. However, relapse during maintenance therapy is often observed. In addition, severe infection is the most frequent cause of death. The prognosis of GPA is expected to be improved by measures to prevent complications including infection and the development of new maintenance therapies.

VIII. Eosinophilic Granulomatosis With Polyangiitis

1. Definition and Epidemiology

Eosinophilic granulomatosis with polyangiitis (EGPA) is a disease separated from polyarteritis nodosa (conventionally periarteritis nodosa) due to 3 characteristics: (1) Bronchial asthma, (2) peripheral blood eosinophilia, and (3) histological findings of eosinophil infiltration around middle/small-sized vessels (primarily arterioles) and necrotizing and/or necrotizing granulomatous vasculitis or the presence of extravascular granuloma. The disease used to be called Churg-Strauss syndrome,²⁴⁸ but was renamed to EGPA in 2012 and defined as “Eosinophil-rich and necrotizing granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium vessels, and clinically associated with asthma and eosinophilia.”¹ The number of patients being treated is estimated to be about 1,900, the mean age at onset is about 55 years, and the male/female ratio is 1:1.7 slightly in favor of females.²⁴⁹ In Europe, 0.5–6.8 new patients/year/1 million people contract the disease, and the prevalence is reported to be 10.7–13/1 million people.²⁵⁰

2. Pathogenesis

The cause of the disease is unknown. Its relationship with the leukotriene receptor antagonist (LTRA) is dubious,²⁵¹ and a reduction in GC after the use of LTRA has been suggested to be a possible cause.²⁵² Genetically, relationships with HLA-DRB1*04, *07, and HLA-DRB4 have been reported.²⁵² The pathological features include tissue damage due to eosinophil infiltration and immunological mechanisms such as IL-4, IL-5, and IL-13.²⁵² Recently, a relationship with IgG4-related disease has also been suggested.²⁵³

3. Pathological Findings

Major histopathological findings of EGPA are infiltration of cells primarily eosinophils around middle/small vessels, fibrinoid necrosis, and the presence of extravascular granuloma.^248,252

4. Signs and Symptoms

Typically, bronchial asthma occurs first, and after repeated relapses of asthma attack, eosinophilia, systemic signs and symptoms such as fever, and vasculitic lesions such as mononeuritis multiplex, ischemic enteritis, cutaneous vasculitis appear (Figure 37).^252,254,255 Vasculitis often develops within 3 years after the onset of bronchial asthma. Mononeuritis multiplex is observed in more than 90% of the patients.²⁴⁹

Figure 37.

Typical clinical course of EGPA. (Prepared from the report by the Systematic Vascular Injury Study Group, Ministry of Health and Welfare of Japan. 1988²⁵⁵) Based on analysis of 74 cases by the Vascular Injury Study Group in 1987.

5. Laboratory and Imaging Findings

Eosinophilia should be more than 10% of leukocytes or 1,500/μL. The percentage of patients positive for MPO-ANCA is about 40–50%,²⁴⁹ and PR3-ANCA (c-ANCA) is rare. Chest radiography often presents bilateral infiltrative shadows with non-segmental distribution, occasionally exhibits ground-glass appearance, and may show thickening of the bronchial wall or interlobular septa.²⁵⁶

6. Diagnosis and Diagnostic Criteria

Patients are classified as EGPA by Lanham’s criteria (Table 21)²⁵⁷ or ACR criteria (Table 22).²⁵⁸ However, in Japan, the diagnostic criteria by the Ministry of Health and Welfare of Japan proposed in 1998 are used. (Table 23).²⁵⁹

Table 21. Lanham’s Criteria for Classification of Eosinophilic Granulomatosis With Polyangiitis

1. Asthma

2. Peak peripheral blood eosinophil counts in excess of 1.5×109/L.

3. Systemic vasculitis involving two or more extra-pulmonary organs.

(From Lanham JG, et al. 1984²⁵⁷)

Table 22. ACR Classification Criteria for Eosinophilic Granulomatosis With Polyangiitis

Criterion	Definition
1. Asthma	Wheezing or diffuse high pitched rales on expiration
2. Eosinophilia	Eosinophilia >10% on white blood cell differential count
3. Mononeuropathy or polyneuropathy	Development of mononeuropathy, multiple mononeuropathies, or polyneuropathy (i.e., glove/socking distribution) attributable to a systemic vasculitis
4. Pulmonary infiltrates, non-fixed	Migratory or transitory pulmonary infiltrates on radiographs (not including fixed infiltrates) attributable to a systemic vasculitis
5. Paranasal sinus abnormality	History of acute or chronic paranasal sinus pain or tenderness or radiographic opacification of the paranasal sinuses
6. Extravascular eosinophils	Biopsy including artery, arteriole, or venule, showing accumulations of eosinophils in extravascular areas

(From Masi AT, Hunder GG, Lie JT, et al., Arthritis Rheum 1990,²⁵⁸ John Wiley and Sons. (c) 1990, American College of Rheumatology.) The condition is classified as Churg-Strauss syndrome (presently EGPA) when 4 or more of the above criteria are met.

Table 23. Criteria for Classification of Allergic Granulomatous Angiitis (Presently EGPA) by the Ministry of Health and Welfare of Japan, 1998

1. Major clinical findings

1) Bronchial asthma or allergic rhinitis

2) Eosinophilia

3) Signs/symptoms of vasculitis:

Fever ≥38℃ for ≥2 weeks)

Weight loss (6 kg in ≤6 months)

Mononeuritis multiplex

Gastrointestinal hemorrhage

Purpura

Polyarthralgia (polyarthritis)

Myalgia, and muscular weakness

2. Typical clinical course

Major clinical findings 1) and 2) develop first, followed by major clinical finding 3)

3. Major histological findings

1) Presence of granulomatous or fibrinoid necrotizing vasculitis in small vessels associated with significant infiltration of eosinophils in the surrounding tissues

2) Presence of extravascular granuloma

4. Diagnosis

1) Definite

(a) Patients with ≥1 major clinical findings of 1), 2), and 3) and with ≥1 major histological findings

(b) Patients with 3 major clinical findings and a typical clinical course

2) Probable

(a) Patient with 1 major clinical finding and 1 major histological finding

(b) Patients with 3 major clinical findings without typical clinical course

1. Supporting laboratory findings

1) Leukocytosis (≥10,000/μL)

2) Thrombocytosis (≥400,000/μL)

3) Elevated serum IgE (≥600 U/mL)

4) Positive MPO-ANCA

5) Positive rheumatoid factor

6) Pulmonary infiltration shadows on X-ray

(From Sectional Meeting on Intractable Vasculitides, Specific Immune Disease Study Group, Ministry of Health and Welfare of Japan, 1999²⁵⁹)

7. Policies and Guidelines of Treatment

Table 24 shows recommendations concerning treatments for EGPA. Treatments for ANCA-associated vasculitides vary with the severity and disease type.

Table 24. Recommendations and Evidence Levels of Treatments for EGPA

	Recommendations	Levels of evidence
Glucocorticoid (GC)	I	B
Steroid pulse therapy	IIa	C
Cyclophosphamide (CY)	IIa	B
Azathioprine (AZA)	IIa	C
Methotrexate (MTX)*	IIa	C
High-dose immunoglobulin therapy	IIa	B
Rituximab (RTX)*	IIb	B
Anti-IL5 therapy	IIb	B
Anti-IgE therapy*	IIb	B
Plasma exchange therapy*	III	B

*Uncovered by health insurance in Japan.

7.1 Acute Phase

For patients with mild EGPA, oral PSL at 0.3–0.6 mg/kg/day (15–30 CY (1–2 mg/kg/day) or oral AZA (0.5–1.5 mg/kg/day) is used concomitantly as appropriate (recommendation class: IIa, evidence level: C). For patients with severe EGPA, oral PSL at 0.6–1.0 mg/kg/day (40–60 mg/day) or steroid pulse therapy is administered with concomitant administration of CY within 4 weeks²⁶⁰ (recommendation class: IIa, evidence level: B). CY is administered orally (2 mg/kg/day) or intravenously (0.5–0.75 g/m²/3–4 weeks, total of 3–6 times). For patients with severest EGPA showing conditions such as diffuse alveolar hemorrhage, plasma exchange (2.0–3.0 L for 3 days) should be performed simultaneously.^254,260 Overseas, RTX, an anti-CD20 antibody preparation, is used for patients with ANCA-positive treatment-resistant cases²⁶⁰ (recommendation class: IIb, evidence level: B).

7.2 Chronic Phase

After induction of remission, PSL is reduced gradually to 10 mg/day or less in 6–18 months.²⁶¹ High-dose intravenous γ-globulin (IVIG) therapy for residual peripheral neuropathy has been covered by health insurance in Japan from January 2010 (recommendation class: IIa, evidence level: B).

7.3 Remission Phase

PSL is maintained at 5–10 mg/day. CY should be discontinued after about 6 months and replaced by drugs such as MTX or AZA (recommendation class: IIa, evidence level: C).²⁶⁰

7.4 Exacerbation Phase (at the Time of Relapse)

In principle, treatments should be similar to those in the acute phase. A total dose of CY must be no more than 10–15 g by checking the past doses.²⁵⁰ Biological agents such as anti-IL-5 antibody mepolizumab and anti-IgE antibody omalizumab (omalizumab is uncovered by health insurance in Japan).²⁵²

8. Prognosis

By the above treatments, remission can be achieved within 6 months in 90% or more patients, and the 5-year survival rate is 97%.²⁵² In rare instances, intestinal perforation, heart failure, renal dysfunction, cerebrovascular disorders may occur. Dysesthesia due to mononeuritis multiplex often persists and irreversible impairment remains in about two-thirds of the patients.

IX. Anti-Glomerular Basement Membrane Disease

1. Definitions and Epidemiology

Anti-glomerular basement membrane disease means poor-prognosis kidney/lung lesions caused by antibody to glomerular basement membrane (GBM). By the CHCC classification revised in 2012, it is classified as an immune complex small vessel vasculitis and is subclassified into 3 disease types: (1) renal-limited anti-GBM antibody nephritis, (2) Lung-limited anti-GBM antibody alveolar hemorrhage, and (3) the type with both kidney and lung involvements.¹

Of these disease types, anti-GBM antibody glomerulonephritis is a disease with poor prognosis that clinically develops RPGN or, occasionally, acute kidney injury and histologically exhibits crescentic necrotizing glomerulonephritis and linear IgG staining (linear pattern) in the loop wall by immunofluorescence study. If complicated by lung hemorrhage, it is called Goodpasture’s disease.

It is a relatively rare disease with a reported incidence of 0.5–1.0 persons/year/1 million people. According to the survey by the MHLW of Japan, of the 1,772 patients with RPGN accumulated until 2006, 81 (4.6%) had anti-GBM antibody nephritis, 27 (1.5%) had Goodpasture’s disease with lung hemorrhage, and a total of 6.1% had anti-GBM disease.²⁶² The mean ages of the patients with anti-GBM nephritis and Goodpasture’s disease, which used to be observed frequently in middle-aged individuals, are 61.6 (11–77) and 70.9 (57–93) years, respectively, indicating advanced aging of the patients.

2. Pathogenesis

The antigen for anti-GBM antibody is present in the noncollagenous domain 1 (NC1 domain) in the C-terminal of the α3 chain of type IV collagen distributed in the glomerular and pulmonary capillary basement membrane, and the amino acid residues at positions 17–31 on the N-terminal side (epitope A; EA) and those at positions 127–141 on the C-terminal side (epitope B; EB) have been identified.^263,264 Usually, these epitopes are buried in the basement membrane, but, if the basement membrane of the lung or kidney is damaged due to infection such as influenza, smoking, or inhaled toxic substances, the α-chain hexamer is disassociated to expose the epitopes in the α3 and 5 chains, and anti-GBM antibody is produced.²⁶⁴ When it binds with the basement membrane antigen of the renal glomeruli or pulmonary capillaries, T-lymphocyte-mediated immune responses are induced, and disruption of the basement membrane and vasculitis occur due to local infiltration of inflammatory cells and subsequent inflammatory reactions.

3. Pathological Findings

By light microscopy, pathological features of severe crescentic necrotizing glomerulonephritis are observed. Immunofluorescence shows linear GBM staining for IgG is observed along the capillary walls.

4. Signs and Symptoms

In addition to symptoms due to nephritis and lung hemorrhage, systemic symptoms such as malaise, fever, body weight loss, and arthralgia are observed frequently.²⁶² The symptoms observed at the onset are most frequently non-specific ones such as malaise and fever. Macroscopic hematuria is also a relatively frequent finding. It is also important to check a history of smoking and recent infection.

5. Laboratory Findings

In nearly all patients, hematuria, nephritic urinalysis findings, an elevated serum Cr level, and signs of marked inflammation are observed. Proteinuria of varying degrees is also observed, and it occasionally reaches nephrotic ranges. Anemia is also severe in many patients. Checking of anti-GBM antibody, which becomes positive, is essential for the definitive diagnosis. The anti-GBM antibody level is parallel to the disease activity and often becomes negative as the disease is treated.

Patients in whom both anti-GBM antibody and ANCA are positive (double positive) have been known, and ANCA (typically MPO-ANCA) is positive in about 20–30% of the patients with anti-GBM-antibody glomerulonephritis.²⁶⁵ Conversely, anti-GBM antibody is positive in about 5–10% of the patients with ANCA-associated vasculitis.^266,267

6. Diagnosis and Diagnostic Criteria

Table 25 shows the diagnostic criteria for anti-GBM antibody glomerulonephritis as a designated intractable disease in Japan.

Table 25. Diagnostic Criteria for Anti-GBM Antibody Glomerulonephritis

1. Nephritic urinalysis findings such as hematuria (often microscopic, rarely macroscopic), proteinuria, and urinary cast are observed.

2. Serum anti-GBM antibody is positive.

3. Linear deposits of immunoglobulin along the glomerular loop wall and necrotizing crescentic glomerulonephritis are demonstrated by renal biopsy.

“Anti-GBM nephritis” is definitively diagnosed when 1 and 2 or 1 and 3 of the above findings are positive.

7. Policies and Guidelines of Treatment

Table 26 shows recommendations about treatments for anti-GBM disease.

Table 26. Recommendations and Evidence Levels Concerning Treatments for Anti-GBM Antibody Disease

	Recommendations	Levels of evidence
Glucocorticoid (GC)	I	B
Steroid pulse therapy	IIa	B
Cyclophosphamide (CY)	I	B
Plasma exchange	I	B
Rituximab (RTX)*	III	C

*Uncovered by health insurance in Japan.

7.1 Initial Treatment

The treatment for anti-GBM disease is determined in consideration of the presence or absence of organ lesions (kidney, lung lesions) and the disease severities.

7.1.1 When Non-Dialysis-Dependent RPGN or Lung Hemorrhage Is Noted

Usually, PSL is administered at 1 mg/kg/day (started by steroid pulse therapy using mPSL), and triplet combination therapy consisting of PSL, IVCY (500–750 mg/m²/month) or oral CY (1–2 mg/kg/day), and plasma exchange is carried out (recommendation class: I, evidence level: B). The dose of IVCY is adjusted according to the age and serum Cr level.

7.1.2 When Severe Renal Impairment Requiring Dialysis Is Present, and Recovery From Renal Failure Cannot Be Expected

The treatments are decided in consideration of the general conditions including the presence or absence of lung lesions.

7.2 Maintenance Therapy

After the initial treatment, PSL and CY are gradually reduced, and immunosuppressive therapy is usually continued for 6–12 months. Long-term maintenance therapy is usually unnecessary without relapse of the disease.

7.3 Comments About Treatments

The objective of treatment is to control the progression of nephritis and lung hemorrhage as soon as possible and to remove anti-GBM antibody that causes the disease immediately. Intensive anti-inflammatory therapy (GC including steroid pulse therapy), elimination of anti-GBM antibody (plasma exchange), and suppression of anti-GBM antibody production (GC and immunosuppressive therapy) are carried out simultaneously as soon as possible.²⁶⁸ Plasma exchange has recently been covered by health insurance in Japan, up to 2 courses of 7 sessions within two weeks each.

8. Prognosis

Once anti-GBM antibody becomes negative, and clinical remission is obtained, relapse of the disease is rare thereafter. Therefore, maintenance therapy is usually unnecessary. However, as cases of relapse after a long interval from the onset have also been reported, follow-up is essential.²⁶⁹ In patients who are also positive for ANCA, relapse tends to be observed more frequently than in those positive for anti-GBM antibody alone.

X. Urticarial Vasculitis

1. Definition and Epidemiology

Long-persisting urticarial and cutaneous leukocytoclastic angiitis are observed. There is a report that about 20% of patients diagnosed with urticarial had urticarial vasculitis.²⁷⁰

The disease is classified into primary and secondary as well as hypocomplementemic and normocomplementemic types. Hypocomplementemic urticarial vasculitis was newly adopted by CHCC 2012 along with anti-C1q vasculitis as its another name.¹

2. Pathogenesis

The disease, in which immunoglobulin and complement are deposited in the wall of the affected vessels, belongs to immune complex vasculitides. Viral infections (hepatitis B, hepatitis C) and collagen are known to be included as causative disorders of secondary urticarial vasculitis. The collagen-like region of C1q, which is the antigen for anti-C1q antibody, hepatitis virus, and drugs have been suggested as causes of the disease.²⁷¹

3. Pathological Findings

Neutrophil-dominant perivascular infiltration, red blood cell extravasation, and fibrinoid deposits are observed in small arteries and veins in the upper and middle layers of the dermis. Deposits of immunoglobulin and complement are also observed. Mehregan et al. reported that immunoglobulin and complement deposits are observed in the cutaneous basement membrane in 69.6% and in the dermal capillary wall in 86.9% of the patients in hypocomplementemic cases but in 17.8% and 28.9%, respectively in those with normocomplementemic cases.²⁷² Sanchez et al. showed that the positive rate increases even in the normocomplementemic type if systemic symptoms are present.²⁷³

4. Signs and Symptoms

Persisting (often for 24 hours or longer) urticarial is accompanied by signs and symptoms such as purpura, livedo reticularis, erythema, bullae, mixed presence of bloody bullae, burning sensation, and pain. Some patients exhibit ring-shaped or wood grain-like urticarial (Figure 38).

Figure 38.

Wheals and purpura with ring-shaped or wood grain-like distribution observed in a patient with urticarial vasculitis.

While 54% of the hypocomplementemic patients were diagnosed with SLE during the course of the disease,²⁷⁴ only 3% of the normocomplementemic patients were reported to have developed SLE.²⁷¹ Hypocomplementemic urticarial vasculitis with characteristic systemic symptoms such as arthritis, renal symptoms, gastrointestinal symptoms, and ophthalmic symptoms is called hypotemplementemic urticarial vasculitis syndrome (HUVS). Kidney impairment is more likely to follow a serious course in children.²⁷⁵ Ophthalmic symptoms are observed in 15% of patients with SLE, but symptoms including episcleritis and uveitis are noted in 61% of patients with HUVS.²⁷⁴

5. Laboratory and Imaging Findings

5.1 Histopathological Examinations

Necrotizing vasculitis is detected, but fibrinoid degeneration is unlikely to occur, because the capillary wall is primarily affected (called leukocytoclastic vasculitis). Neutrophil infiltration is unclear because of edema due to urticarial. Deposits of immunoglobulin and complement are noted in the vascular wall.

5.2 Seroimmunological Examinations

Measurement of complements. Since there is the possibility of systemic vasculitis, ANCA and cryoglobulin are measured. With secondary pathogenesis in mind, anti-nuclear antibody (ANA), and-dsDNA antibody, anti-SSA antibody, and anti-SSB antibody are examined.

ANA is positive in 95% of SLE patients and 61–71% of HUVS patients²⁷⁴ and negative in 5% and 66%, respectively.²⁷⁶ There are reports that anti-dsDNA antibody is positive in ≥70% of the SLE patients and 17% of HUVS patients²⁷⁴ but negative in 5–30% and 83%, respectively,²⁷⁶ and that anti-C1q antibody is observed in 38–61% of SLE patients^277,278 and 100% of HUVS patients.²⁷⁹

6. Diagnosis and Diagnostic Criteria

Urticarial vasculitis is definitively diagnosed based on persisting urticarial and necrotizing vasculitis demonstrated by skin biopsy (Evidence level: C). Schwartz et al. required fulfillment of the presence of urticarial and hypocomplementemia and at least 2 of cutaneous vasculitis, arthritis, glomerulonephritis, episcleritis or uveitis, recurrent abdominal pain, and anti-C1q antibody in blood for the diagnosis of HUVS.

7. Policies and Guidelines of Treatment

Table 27 shows recommendations concerning treatments for urticarial vasculitis. Treatment is initiated with anti-histamine and anti-allergic agents (recommendation class: IIb, evidence level: C). However, anti-histamine/anti-allergic drugs are reported to be ineffective.^280,281 For patients with severe skin symptoms or organ disorders, GC is selected (recommendation class: IIa, evidence level: C). A dose of 20–30 mg/day is necessary,^273,282 and steroid pulse therapy was reportedly necessary for conditions complicated by SLE.^283,284 For patients who show serious systemic symptoms or GC resistance, the concomitant use of CyA, AZA or CY can be an option^285–287 (recommendation class: IIb, evidence level: C). In addition, plasma exchange,²⁸⁸ IVIG,²⁸⁹ and RTX, an anti-CD20 antibody preparation,²⁸⁷ have also been reported (recommendation class: IIb, evidence level: C).

Table 27. Recommendations and Evidence Levels Concerning Treatments for Urticarial Vasculitis

	Recommendations	Levels of evidence
Anti-histamine/anti-allergic drugs	IIb	C
Glucocorticoid (GC)	IIa	C
Cyclosporine (CyA)*	IIb	C
Azathioprine (AZA)*	IIb	C
Cyclophosphamide (CY)*	IIb	C
Plasma exchange*	IIb	C
High-dose i.v. immunoglobulin therapy*	IIb	C
Rituximab (RTX)*	IIb	C
NSAIDs*	IIb	C
Colchicine*	IIb	C
Hydroxychloroquine*	IIb	C
Rectisol*	IIb	C

*Uncovered by health insurance in Japan.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been reported by Millns et al.²⁹⁰ and Mehregan²⁷² to be effective (recommendation class: IIb, evidence level: C). Colchicine²⁹¹ and hydroxychloroquine²⁹² have been selected as first-line treatments based on the results of retrospective studies (recommendation level: IIb, evidence level: C). Rectisol is considered effective in patients who secondarily develop SLE^293,294 (recommendation class: IIb, evidence level: C).

8. Prognosis

Systemic symptoms are absent or mild in normocomplementemic urticarial vasculitis but severer in the hypocomplementemic type.

XI. IgA Vasculitis (Henoch-Schönlein Purpura)

1. Definition and Epidemiology

Henoch- Schönlein purpura (HSP) was renamed as IgA vasculitis.^1,295 The disease is classified as a small vessel vasculitis based on the size of the affected vessels. It may occur in people of all ages but most frequently affects those aged 3–10 years and appears to have a slight predilection for boys. It is a common vasculitis in children.²⁹⁶ It is reportedly complicated by glomerulonephritis in about 50–80% of adults and 20–50% of children.²⁹⁷

2. Pathogenesis

The pathogenesis remains unclear.

3. Pathological Findings

Histologically, the disease is characterized by infiltration of inflammatory cells, which are primarily multinuclear leukocytes, around small vessels and IgA deposits in vessel walls. In the skin, histological features of leukocytoclastic necrotizing small-vessel vasculitis accompanied by dermal hemorrhage are observed. In the renal glomeruli, deposits of IgA and C3 are observed primarily in the mesangial region by immunofluorescent staining similarly to IgA nephropathy.

4. Signs and Symptoms

In children, 50% of the patients have a history of upper respiratory infection as an antecedent infection. The symptoms are purpura (100%), arthritis (80%), abdominal pain (60%), and nephritis (50%).²⁹⁷

4.1 Skin Signs and Symptoms

Symmetric palpable purpura with punctate distribution are observed in the lower limbs and back in nearly all patients (Figure 39).

Figure 39.

Skin findings in a patient with IgA vasculitis. Punctate, dark red, palpable purpura is observed in the bilateral lower legs. (Provided by Prof. Tamihiro Kawakami, Tohoku Medical and Pharmaceutical University)

4.2 Joint Symptoms

Pain and swelling of joints are observed in 70–80% of the patients.

4.3 Gastrointestinal Symptoms

Symptoms including abdominal pain, vomiting, bloody stools, and melena are observed in 50–70% of the patients.

4.4 Renal Symptoms

Abnormal urinalysis findings often appear within a few days to 1 month after the onset of vasculitis. The onset is with hematuria alone in 15%, hematuria+proteinuria in 38%, acute nephritic syndrome in 15%, nephritis+nephrotic syndrome in 23%, and nephrotic syndrome in 8%.

5. Laboratory and Imaging Findings

The platelet count is normal, and indices of the clotting system such as the prothrombin time and partial thromboplastin time are also normal. The plasma factor XIII activity is reduced in about 3/4 of the patients and decreases with exacerbation of the clinical condition. The serum IgA level increases in about 40–60% of the patients in an early stage of the disease. Rumpel-Leede test is positive, which indicates weakening of the capillary resistance, in about 30% of the patients.

Patients with IgA vasculitis complicated by glomerulonephritis show hematuria (microscopic, macroscopic), erythrocyte deformation in urine sediment, granular cast and red blood cell cast, and proteinuria of varying degrees depending on the severity of nephritis.

6. Diagnosis and Diagnostic Criteria

In children, IgA vasculitis can be diagnosed if 2 or more of the 4 classification criteria of the American College of Rheumatology²⁹⁸ are met: [(1) palpable purpura, (2) acute abdominal colic, (3) presence of granulocytes in the walls of small arteries and veins on biopsy, and (4) age of ≤20 years]. Histopathological examinations by biopsy show features of leukocytoclastic vasculitis with infiltration of multinuclear leukocytes and monocytes around small vessels and deposits of IgA, C3, and IgG in vascular walls. Adult purpura nephritis was designated as an intractable disease in July 2015 and is classified according to the criteria by the American College of Rheumatism.^298,299

The renal tissue classification of purpura nephritis by the International Study of Kidney Disease in Children (ISKDC)³⁰⁰ is shown below.

Grade I  Minimal changes

Grade II   Mesangial proliferation alone

Grade III a) focal, b) diffuse mesangial proliferation; crescents<50% of glomeruli

Grade IV a) focal, b) diffuse mesangial proliferation; crescents 50–75% of glomeruli

Grade V a) focal, b) diffuse mesangial proliferation; crescents >75% of glomeruli

Grade VI Membranoproliferative glomerulonephritis

7. Policies and Guidelines of Treatment

Table 28 shows recommendations about treatment for IgA vasculitis.

Table 28. IgA Recommendations and Evidence Levels About Treatments for IgA Vasculitis

	Recommendations	Levels of evidence
Extrarenal manifestations (skin symptoms, arthralgia, abdominal pain)
Anti-histamine drugs	IIb	C
Non-steroidal anti-inflammatory drugs (NSAIDs)	IIa	C
Glucocorticoid (GC)	IIa	C
Dried human factor XIII concentrate	IIa	B
Renal symptoms
Antiplatelet drugs	IIb	C
Glucocorticoid (GC)	IIa	C
Steroid pulse therapy+Urokinase*+cyclophosphamide (CY)	IIa	C
GC+azathioprine (AZA)	IIa	C
GC+mycophenolate mofetil (MMF)*	IIb	C
GC+cyclosporine (CyA)*	IIb	C
Plasma exchange therapy*	IIb	C
Cyclophosphamide (CY)	III	B
Tonsillectomy*+steroid pulse therapy	IIa	C

*Uncovered by health insurance in Japan.

7.1 Treatment for Extrarenal Manifestations

Rest is maintained, and symptomatic treatments are performed depending on the symptoms.

1) Anti-histamine drugs are administered for painful edema and itching of the skin (recommendation class: IIb, evidence level: C)

2) Non-steroidal anti-inflammatory drugs (NSAIDs) are administered for joint symptoms (recommendation class: IIa, evidence level: C)

3) If severe abdominal symptoms cannot be controlled even by the administration of analgesics, glucocorticoid (GC) is administered, tapered, and discontinued after 1–2 weeks.^301,302 (recommendation class: IIa, evidence level: C)

4) If a decrease in the plasma factor XIII level to 90% or less is accompanied by abdominal symptoms and joint symptoms, the administration of dried human clotting factor XIII concentrate should be considered (recommendation class: IIa, evidence level: B)

5) In children, the administration of GC at the onset does not contribute to a decrease in the rate of subsequent occurrence of nephritis or abdominal symptoms.^303–305 The KDIGO guidelines recommend no use of GC to prevent the occurrence of nephritis³⁰⁶ (recommendation class: III, evidence level: B)

7.2 When Complicated by Nephritis

ISKDC class I–II: Antiplatelets are often administered (recommendation class: IIb, evidence level: C).

ISKDC class III–VI: The following treatments are considered.

1) GC (PSL 1 mg/kg/day)³⁰¹ (recommendation class: IIa, evidence level: C)

2) Steroid pulse therapy+iv urokinase*+oral CY³⁰⁷ (recommendation class: IIa, evidence level: C)

3) AZA+GC combination therapy^308,309 (recommendation class: IIa, evidence level: C)

4) MMF alone*³¹⁰ or MMF*+GC combination therapy³¹¹ adults) (recommendation class: IIb, evidence level: C)

5) CyA* alone³¹² or CyA*+GC combination therapy³¹³ (recommendation class: IIb, evidence level: C)

6) Plasma exchange therapy* (recommendation class: IIb, evidence level: C): There are reports that plasma exchange was effective in children.^314,315

7) CY alone³¹⁶ or IVCY+GC combination therapy³¹⁷ is not effective (recommendation class: III, evidence level: B)

8) There is a report suggesting the effectiveness of tonsillectomy*+steroid pulse therapy also for purpura nephritis³¹⁸ (recommendation class: IIa, evidence level: C)

*Not covered by health insurance in Japan

The above recommendations are based primarily on reports concerning children, but the KDIGO guidelines suggest treating adults with nephritis complicating adult IgA vasculitis similarly to children.³⁰⁶

8. Prognosis

The prognosis of IgA vasculitis is basically favorable, and the disease often follows a monophasic course and is remitted spontaneously in several weeks. Relapse is observed in 10–20% of the patients and the episode occasionally persists for more than a year.

In children, nephritis is observed in about half the patients, but exacerbation to end-stage renal disease is rare. In adults, 85% of the patients suffer nephritis, which often develops into end-stage renal disease, and the prognosis is poorer than in children.

XII. Cryoglobulinemic Vasculitis

1. Definition and Epidemiology

Cryoglobulin (CG) is protein that precipitates in serum or plasma at a low temperature and dissolves when heated to 37℃. Since cryoglobulinemia is asymptomatic in some patients, a condition that exhibits clinical features of immune complex-mediated vasculitis is called cryoglobulinemic vasculitis (CV).^245,319

CV may be a primary disorder without an underlying disorder, or a secondary disorder. Cryoglobulinemia occurs secondarily to HCV infection in 40–65% and collagen disease in 15–25% of the patients.^320–323

2. Pathogenesis

Cryoglobulinemia is classified into 3 types (Table 29).^324,325 Recently, essential CV has decreased to about 10% or less with accumulation of anti-HCV antibody-positive cases.^326,327

Table 29. Cryoglobulin Classification

	Type I	Type II	Type III
Components	Simple	Mixed	Mixed
	Monoclonal immunoglobulins (IgG, IgM, or IgA) or Bence Jones protein/ monoclonal free light chains	Monoclonal immunoglobulins (IgM, IgG, or IgA) and polyclonal immunoglobulin (mostly IgG)	Polyclonal immunoglobulins of all isotypes
Pathological features	Microthrombosis	Immune complex-mediated vasculitis	Immune complex-mediated vasculitis
Disease association	• Waldenstrom’s macroglobulinemia • Multiple myeloma • Monoclonal gammopathy associated with lymphoproliferative disorder • Light chain disease	• Hepatitis C • Essential cryoglobulinemia • Sjogren’s syndrome • Rheumatoid arthritis • Chronic lymphocytic leukemia	• Essential cryoglobulinemia • Sjogren’s syndrome • Systemic lupus erythematosus • Viral infections (Hepatitis B and C, CMV, EBV, HIV) • Endocarditis, other bacterial infections • Biliary cirrhosis

(Reproduced from Brouet JC, et al. 1974³²⁴ and Motyckova G, et al. 2011.³²⁵ Motyckova G, Murali M., Am J Hematol 2011³²⁵ with modification, John Wiley and Sons. (c) 2011, Wiley-Liss, Inc.)

3. Pathological Findings

Type I shows microthrombi due to non-inflammatory eosinophilic amorphous substances can be detected in the kidney and skin-biopsy specimens. In Types II and III, necrotizing vasculitis in small vessels of the upper and middle layers of the dermis is observed. Histological findings of membranoproliferative glomerulonephritis are characteristic in the kidney.

4. Clinical Features

See Table 30.³²⁵

Table 30. Clinical and Laboratory Features of Cryoglobulinemia

Clinical manifestations	Type I	Type II	Type III
Arthralgia > arthritis	+	++	+++
Purpura	+	+++	+++
Gangrene/acrocyanosis	+++	+	±
Hyperviscosity	+++	±	−
Hematologic	++	±	±
Renal	+	++	+
Neurologic	+	++	++
Liver	±	++	+++
Lung	−	+	+
C3	Normal	Decreased	Decreased
C4	Normal	Decreased	Decreased
CH50	Normal	Decreased	Decreased
RF	+	++	++
Autoantibodies (ANA, etc.)	−	++	++
Hepatitis B	−	+	+
Hepatitis C	−	+++	+++

ANA, antinuclear antibodies, RF, rheumatoid factor; Hematologic features include thrombosis and bleeding and spurious/artifact thrombocytosis. (Reproduced from Motyckova G, Murali M., Am J Hematol 2011³²⁵ with modification, John Wiley and Sons. (c) 2011, Wiley-Liss, Inc.)

5. Laboratory and Imaging Findings

If vasculitic lesions associated with cold exposure are noted, examinations for serum CG and causative disorders (lymphoproliferative disease, hepatitis virus infection, collagen disease, etc.) should be performed.

6. Diagnosis and Diagnostic Criteria

As a result of a multicenter collaborative study in Europe, preliminary classification criteria for CV have been proposed (Table 31).³²⁸

Table 31. Preliminary Criteria for Classification of Cryoglobulinemic Vasculitis

Satisfied if at least two of the three items (questionnaire, clinical, laboratory) are positive the patient must be positive for serum cryos in at least 2 determinations at ≥12 week interval
(i) Questionnaire item: at least two out of the following
• Do you remember one or more episodes of small red spots on your skin particularly involving the lower limbs?
• Have you ever had red spots on your lower extremities which leave a brownish color after their disappearance?
• Has a doctor ever told you that you have viral hepatitis?
(ii) Clinical item: at least three out of the following four (present or past)
• Constitutional symptoms	Fatigue Low grade fever (37–37.9℃, >10 days, no cause) Fever (>38℃, no cause) Fibromyalgia
• Articular involvement	Arthralgias Arthritis
• Vascular involvement	Purpura Skin ulcers Necrotizing vasculitis Hyperviscosity syndrome Raynaud’s phenomenon
• Neurological involvement	Peripheral neuropathy Cranial nerve involvement Vasculitic CNS involvement
(iii) Laboratory item: At least 2 out of the 3 questions. (present)
• Reduced serum C4
• Positive serum rheumatoid factor
• Positive serum M component

CG, cryoglobulin; CV, cryoglobulinemic vasculitis. (Cited from Ann Rheum Dis De Vita S, Soldano F, Isola M, et al. 2011,³²⁸ with permission from BMJ Publishing Group Ltd.)

7. Policies and Guidelines for Treatment

Table 32 shows recommendations about treatments for CV.

Table 32. Recommendations and Evidence Levels About Treatments for CV

	Recommendations	Levels of evidence
Glucocorticoid (GC)	IIa	B
Cyclophosphamide (CY)	IIa	B
Rituximab (RTX)*	IIa	B
Plasma exchange therapy*	IIb	C

*Uncovered by health insurance in Japan.

In addition to avoiding cold exposure and keeping warm, analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) are used. If there are rapidly progressive organ disorders, the use of glucocorticoid (GC) (including pulse therapy)+RTX (often 375 mg/m²/week×4 times) or CY (2 mg/kg/day) (recommendation class: IIa, evidence level: B) is recommended. If RTX cannot be used, treatment using CY is recommended.^329–331

In secondary cryoglobulinemia, treatments for the primary disorder are performed in addition to immunosuppressants (recommendation class: IIa, evidence level: B).^331–333 For essential cryoglobulinemia, combination therapy of GC and RTX is recommended (recommendation class: IIa, evidence level: B).

Plasma exchange therapy should be considered in cases with (1) hyperviscosity syndrome, (2) acute respiratory insufficiency, alveolar hemorrhage, and acute mesenteric vasculitis,³³⁴ and (3) RPGN requiring dialysis³³⁰ (recommendation class: IIb, evidence level: C). RTX and plasma exchange therapy are not covered by health insurance in Japan.

8. Prognosis

Regarding the prognosis of mixed cryoglobulinemia without the involvement of HCV infection, the 5-year survival rate is 79%. Age (≥65 years or older), sex (male), complication by respiratory and gastrointestinal lesions, and renal failure are important prognostic factors.³²⁷

XIII. Behçet’s Disease

1. Definition and Epidemiology

1.1 Definition

Behçet’s disease is an inflammatory disorder characterized by oral aphtha, skin symptoms, ophthalmic lesions, and genital ulcers.³³⁵ Vascular involvement is one of serious manifestations which appear in some patients.^336,337

1.2 Epidemiology

There are about 20,000 patients with Behçet’s disease in Japan. The frequency of vascular involvement has been reported 6.3–15.3%.³³⁶

2. Signs and Symptoms

2.1 Deep-Vein Thrombosis

Deep-vein thrombosis is the most common vascular lesion and prevalent in the lower extremities.^336,337 More serious venous lesions such as superior vena cava syndrome, Budd-Chiari syndrome, and cerebral venous sinus thrombosis can occur.^336,338

2.2 Aneurysms and Arterial Occlusion

Aneurysms and arterial occlusions develop in the large and medium-sized arteries. Aortic insufficiency cause by aneurysm is associated with poor prognosis.^336,337,339 Peripheral aneurysms, which are often at risk of rupture and bleeding, are multiple in the one-third of the patients.^336,340 An arterial occlusion causes the local ischemic symptoms.

2.3 Pulmonary Artery Involvement

Rupture of pulmonary artery aneurysm causes fatal hemoptysis.^336,341 The pulmonary lesions are commonly complicated with pre-existing deep-vein thrombosis. Frequency of the lesions is low in Japanese patients compared with the other regions.

3. Laboratory and Imaging Findings

3.1 Laboratory Findings

There is no specific data for Behçet’s disease. A pathergy test, HLA-B*51, A*26, and inflammatory responses on blood tests are listed as suggestive findings in the diagnostic criteria of the MHLW of Japan.

3.2 Imaging Findings

3.2.1 Venous Lesions

Venous thrombotic lesions are illustrated by ultrasonography and contrast-enhanced CT.^336,337

3.2.2 Arterial Lesions

Contrast-enhanced CT is a standard modality to detect arterial lesions.^336,337 PET-CT (not approved),³³⁶ which simultaneously assesses the morphological changes and localization of inflammation, is considered promising.

3.2.3 Pulmonary Lesions

Pulmonary artery aneurysms are examined by chest CT scan after screening of chest radiography. Lung perfusion scintigraphy is helpful to detect occlusive lesions in the pulmonary vessels.^336,341

4. Diagnosis and Diagnostic Criteria

4.1 Diagnosis

The diagnosis of Behçet’s disease is made based on combinations of symptoms, according to the diagnostic criteria of the MHLW, Japan. Table 33 compares the MHLW criteria with other sets of representative international criteria.^342,343 In addition, local assessment of the vascular lesions is essential.³³⁷

Table 33. Comparison of Diagnostic Criteria for Behçet’s Disease

	MHLW337	ISG342	ITR-ICBD343
Oral aphtha	Major symptom	Essential	2
Skin symptoms	Major symptom	✓	1
Ophthalmic lesions	Major symptom	✓	2
Ulcer of the vulva	Major symptom	✓	2
Arthritis	Minor symptom
Epididymitis	Minor symptom
Intestinal lesions	Minor symptom
Vascular lesions	Minor symptom		1
Nerve lesions	Minor symptom		1
Pathergy test	Suggestive finding	✓	(1)
HLA-B51 A26	Suggestive finding

Diagnoses according to the MHLW criteria.

(1) Complete form: Appearance of the 4 Major symptoms during the course.

(2) Incomplete type: 3 Major symptoms, 2 Major symptoms+2 Minor symptoms, typical ophthalmic symptoms+1 other Major symptom or 2 Minor symptoms.

(3) Suspected: Appearance of some Major symptoms, typical Minor symptoms recurring or exacerbated.

(4) Variant types: (a) Intestinal type, (b) Vascular type, (c) Neurological type.

Behçet’s disease can be diagnosed or classified by the ISG criteria, which require oral aphtha plus 2 or more symptoms out of four symptoms indicated by (✓), or by the ITR-ICBD criteria in which the total score is more than 4.

ISG: International Study Group for Behçet’s Disease; ITR-ICBD: International Team for the Revision of the International Criteria for Behçet’s Disease (from Japan Intractable Diseases Information Center, Behçet’s disease,³³⁷ International Study Group for Behçet’s Disease. 1990,³⁴² International Team for the Revision of the International Criteria for Behçet’s Disease (ITR-ICBD). 2014³⁴³)

4.2 Differential Diagnosis

4.2.1 Venous Lesions

Major differential diagnoses include idiopathic venous thrombosis, congenital thrombotic tendency (protein C deficiency, protein S deficiency, antithrombin III deficiency, etc.), antiphospholipid antibody syndrome, surgical invasion, malignant neoplasm, and local compression.

4.2.2 Arterial Lesions

Arterial lesions that should be differentiated from Behçet’s disease include Takayasu arteritis, GCA, PAN, infectious aneurysm, and Buerger disease and arteriosclerosis obliterans.

4.2.3 Pulmonary Lesions

Hughes-Stovin syndrome is characterized by pulmonary artery aneurysms and venous thrombosis without the mucocutaneous and ocular symptoms.

5. Policies and Guidelines of Treatment

Table 34 summarizes recommendations for treatments of Behçet’s disease, according to the guidelines from Behçet’s Disease Research Committee (BDRC), MHLW, Japan.

Table 34. Recommendations and Evidence Levels About Treatments for Behçet’s Disease

	Recommendations	Levels of evidence
Glucocorticoid (GC)	IIa	B
Azathioprine (AZA)	IIa	B
Cyclophosphamide (CY)	IIa	B
Cyclosporine (CyA)	IIb	C
Methotrexate (MTX)*	IIb	C
TNF inhibitors	IIb	B
Anticoagulants	IIa	C
Vascular reconstruction	IIb	B
Endovascular treatment	IIb	B
Perioperative immunosuppressive therapy	IIa	B

*Uncovered by health insurance in Japan.

5.1 Pharmacological Therapy

5.1.1 Glucocorticoid/Immunosuppressants/Biologics

a. Combination of GC and AZA (recommendation class: IIa, evidence level: B)

For acute deep venous thrombosis, 0.5–1 mg/kg of PSL is given as the initial therapy followed by gradually tapering while concomitantly using AZA.^344–346

b. Combination of GC and CY (recommendation class: IIa, evidence level: B)

For severe venous lesions and aneurysms, high-dose GC including steroid pulse therapy and IVCY (1,000 mg/month) are conducted as the remission induction therapy followed by maintenance therapy using oral PSL and AZA.

c. TNF Inhibitors (recommendation class: IIb, evidence level: B)

Sporadic case reports have shown efficacy of anti-TNF monoclonal antibody for serious forms of vascular involvement in Behçet’s disease. IFX has been approved since 2015 in Japan.

5.1.2 Anticoagulant Therapy (recommendation class: IIa, evidence level: C)

Anticoagulant therapy is not recommended by EULAR, though retrospective studies have shown warfarin is used frequently in Japan and other countries.^{337,345–347} The guidelines by BDRC, MHLW, Japan recommends the use of anticoagulants or antiplatelet drugs in patients having risk of bleeding.³³⁷

5.2 Surgery and Endovascular Treatment

5.2.1 Operative Indication (recommendation class: IIb, evidence level: B)

Rupture or impending rupture of aneurysm and arterial occlusion are indications for surgery. Postoperative complications such as suture failure, occlusion, and anastomotic aneurysm are frequent.^336,348

5.2.2 Perioperative Immunosuppressive Therapy (recommendation class: IIa, evidence level: B)

The perioperative concomitant use of immunosuppressive therapy has been shown to prevent post-operative complications and relapses.^336,349

5.2.3 Catheterization and Endovascular Treatment (recommendation class: IIb, evidence level: B)

Endovascular treatment is optional for some patients.^350–352

6. Prognosis

Several studies have shown that vascular lesions, particularly arterial lesions, are critical prognostic factors of Behçet’s disease.³⁵³ The vascular involvement such as pulmonary artery aneurysm, aortic aneurysm, and Budd-Chiari syndrome can be fatal.

XIV. Malignant Rheumatoid Arthritis

1. Definition and Epidemiology

Vasculitis of small and medium-sized vessels associated with rheumatoid arthritis (RA) is called rheumatoid vasculitis (RV). Malignant RA (MRA) is Japan’s original concept defined as “RA that has a severe clinical condition due to extra-articular symptoms including vasculitis”,³⁵⁴ and is not synonymous with RV. A clinical profile of MRA is shown in Figure 40.

Figure 40.

Clinical features of malignant rheumatoid arthritis. RA (Progressive and destructive synovitis/RF positive/ACPA positive)

MRA is observed in 0.6–1.0% of the patients with RA, the peak age at the diagnosis is 60–69 years, and the male/female ratio is 1:2 (Figure 25).¹¹ The incidence of RV has been decreasing recently.³⁵⁵ Risk factors for RV include HLA-C*03,³⁵⁶ male sex, a long duration of illness, severe RA, and the presence of peripheral/cerebral vascular lesions.

2. Pathogenesis

The pathogenesis of MRA is unclear, but mechanisms including an involvement of auto-antibody targeted to blood vessels, induction of inflammation due to deposition of immune complexes, and local activation of cellular immunity have been suggested.

3. Pathological Findings

Infiltration of mononuclear cells and neutrophils into the vascular wall are observed, and it is accompanied by necrosis, leukocytoclast, and features of destruction of the vascular wall including rupture of the elastic lamina. MRA is classified into the systemic vasculitis type characterized by necrotizing vasculitis of muscular arteries and peripheral arteritis type characterized by fibrous proliferation of the intima and endarteritis obliterans. Generally, the pathological findings are primarily those of leukocytoclastic vasculitis accompanied by deposits of immune complex in lesions of small arteries, capillaries, and small vessels, and pauci-immune type in lesions of medium-sized arteries and glomeruli.

4. Signs and Symptoms

MRA is more frequent in long-standing RA with advanced joint destruction,³⁵⁷ and rheumatoid nodules are often observed. Systemic type of MRA follows an acute course and causes symptoms such as a fever of ≥38℃, body weight loss, purpura, episcleritis, myalgia, interstitial pneumonia, pleurisy, mononeuritis multiplex, and gastrointestinal bleeding. Interstitial lesions of the lung often progress chronically but occasionally show an acute or subacute course.

5. Laboratory and Imaging Findings

Findings including inflammatory reaction, hypergammaglobulinemia, anti-citrullinated peptide antibody (ACPA), immune complexes, and a decrease in complement are observed. The rheumatoid factor (RF) level is high.

6. Diagnosis and Diagnostic Criteria

The diagnostic criteria shown in Table 35³⁵⁸ are used.

Table 35. Diagnostic Criteria for Malignant Rheumatoid Arthritis (Rheumatoid Vasculitis)

1. Clinical features

(1) Mononeuritis multiplex: Sensory and/or motor disturbance may present.

(2) Skin ulcer or infarction or finger gangrene: Not including lesions due to infection or injury.

(3) Subcutaneous nodules: Subcutaneous nodules may be present in the apophyseal area, extensor surfaces, and tissues surrounding joints.

(4) Episcleritis or iritis: Conditions confirmed by ophthalmologists, not including those due to other causes.

(5) Exudative pleuritis or pericarditis: Not including those due to other causes such as infection. The presence of pleurodesis alone should not be considered a positive finding.

(6) Myocarditis: Diagnosis should be made on the basis of clinical findings, inflammatory reactions, muscle enzyme levels, ECG, and echocardiography, among other parameters.

(7) Interstitial pneumonia or pulmonary fibrosis: Diagnosis should be made on the basis of physical findings, chest X-ray, and pulmonary function testing, regardless of the extent of lesions.

(8) Organ infarction: Infarction of intestine, myocardium, lungs, and other organs caused by ischemia or necrosis due to vasculitis.

(9) Elevated RF: RF should be positive at a titer of 1:2,560 or higher in ≥2 sessions of the RAHA or RAPA test (or ≥960 IU/mL on quantification of RF).

(10) Decreased serum complement level or the presence of immune complexes in blood: A decrease in serum complement level should be demonstrated by a decrease in serum concentration of a complement component such as C3 and C4 or a decrease of CH50-induced complement activation in ≥2 sessions. The presence of immune complexes in blood should be demonstrated on the basis of C1q binding activity in >2 sessions.

2. Histological findings

Biopsy of skin, muscle, nerve, or other affected organs should reveal the presence of necrotic vasculitis, granulomatous vasculitis, or occlusive endoangiitis in small- or medium-sized vessels.

3. Diagnosis

Diagnosed as malignant rheumatoid arthritis (MRA) when the 2010 ACR/EULAR criteria for classification of rheumatoid arthritis are fulfilled, and when

(1) 3 or more of the clinical signs and symptoms (1)∼(10) are observed, or

(2) at least 1 of the clinical signs and symptoms (1)∼(10) and histological findings in 2. are present.

4. Differential diagnosis

MRA should be differentiated from infection, secondary amyloidosis, and adverse reactions to drugs (drug-induced interstitial pneumonia, drug-induced vasculitis, etc.). In amyloidosis, amyloid deposits are demonstrated in the stomach, rectum, skin, kidney, or liver by biopsy. Attention to overlap syndrome with connective tissue diseases other than RA (e.g., SLE, scleroderma, and polymyositis) is also necessary. Sjögren’s syndrome most frequently complicates RA and is also observed in about 10% of the patients with MRA. Felty’s syndrome should also be differentiated from MRA, but it shows leukocytopenia, splenomegaly, and increased susceptibility to infection.

RAHA, rheumatoid arthritis hemagglutination; RAPA, rheumatoid arthritis particle agglutination; RF, rheumatoid factor; ACR, American College of Rheumatology; EULAR, European League Against Rheumatism (from Malignant Rheumatoid Arthritis, MHLW of Japan³⁵⁸).

7. Policies and Guidelines of Treatment

Table 36 shows recommendations about treatments for MRA. The dosage/regimen of MTX and bDMARDs are the same as those for the treatment of usual RA.

Table 36. Recommendations and Evidence Levels About Treatments for Malignant Rheumatoid Arthritis

	Recommendations	Levels of evidence
Glucocorticoid (GC)	IIa	C
Steroid pulse therapy	IIb	C
Methotrexate (MTX)	IIa	C
Azathioprine (AZA)	IIa	C
Cyclophosphamide (CY)	IIa	B
TNF inhibitors	IIa	B
Tocilizumab (TCZ)	IIa	C
Rituximab (RTX)*	IIb	B
Abatacept	IIb	C

*Uncovered by health insurance in Japan. Note: MTX and biological drugs are covered by health insurance for rheumatoid arthritis.

MTX is administered for active RA without contraindications (recommendation class: IIa, evidence level: C) in patients with MRA. Glucocorticoid (GC) is administered at a medium dose (0.5 mg/kg/day as PSL) or less if there are only skin lesions and serositis but at a high dose (1 mg/kg/day as PSL) including steroid pulse therapy for acute/subacute interstitial pneumonia, mononeuritis multiplex, and multiple organ involvement.

For severe systemic vasculitis, IVCY (500–700 mg/m²/month) or oral CY (1–2 mg/kg/day) may be used (recommendation class: IIa, evidence level: B). AZA (1–2 mg/kg/day) is used for mild cases and as maintenance therapy³⁵⁹ (recommendation class: IIa, evidence level: C). bDMARDs such as TNF inhibitors and IL-6 inhibitors are used for RV that occurs during the administration of MTX,³⁶⁰ but the occurrence of vasculitis associated with the administration of these drugs has also been reported.^361–365 There is also a report that plasma exchange therapy, leukocytapheresis, and IVIG³⁶⁶ (not covered by health insurance in Japan) were effective in treatment-resistant and severe cases.

8. Prognosis

The 1-, 5-, and 10-year survival rates of patients with systemic RV are 89.6, 47.7, and 26%, respectively,³⁵⁵ and no improvement is observed compared with the past. According to a domestic epidemiological survey, the outcome was alleviation in 21%, no change in 26%, exacerbation in 31%, death in 14%, and unknown/others in 8%, and the most frequent cause of death was respiratory failure.³⁶⁷

Acknowledgments

The drafting of the present guideline in Japanese was started in December 2015. The manuscript was evaluated by the Independent Assessment Committee in September 2017. The completed Japanese version was published online in March 2018. The English translation of the digest version was started by Medical English Service, Ltd. in July 2018. Collection, revision, and management were conducted by H. Yoshifuji and supervised by M. Isobe. The COI of group members are shown in Appendix 2.

Appendix 1. JCS Joint Working Group

Chair:

• Mitsuaki Isobe, Sakakibara Heart Institute

Members:

• Koichi Amano, Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University

• Yoshihiro Arimura, Department of Rheumatology and Nephrology, Kyorin University School of Medicine / Internal Medicine, Kichijoji Asahi Hospital

• Shouichi Fujimoto, Department of Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of Miyazaki

• Masayoshi Harigai, Department of Rheumatology, School of Medicine, Tokyo Women’s Medical University

• Hitoshi Hasegawa, Department of Hematology, Clinical Immunology, and Infectious Diseases, Ehime University Graduate School of Medicine

• Akihiro Ishizu, Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University

• Shuichi Ito, Department of Pediatrics, Graduate School of Medicine, Yokohama City University

• Shinya Kaname, Department of Nephrology and Rheumatology, Kyorin University School of Medicine

• Shigeto Kobayashi, Department of Internal Medicine, Juntendo Koshigaya Hospital

• Yoshinori Komagata, Department of Nephrology and Rheumatology, Kyorin University School of Medicine

• Kimihiro Komori, Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine

• Issei Komuro, Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine

• Tetsuro Miyata, Vascular Center, Sanno Hospital and Sanno Medical Center

• Tatsuhiko Miyazaki, Department of Pathology, Gifu University Hospital

• Kei Takahashi, Department of Pathology, Toho University Ohashi Medical Center

• Kazuo Tanemoto, Department of Cardiovascular Surgery, Kawasaki Medical School

• Hidehiro Yamada, Medical Center for Rheumatic Diseases, Seirei Yokohama Hospital

• Akitoshi Yoshida, Asahikawa Medical University

• Takashi Wada, Department of Nephrology and Laboratory Medicine, Graduate School of Medical Sciences, Kanazawa University

Collaborators:

• Hiroaki Dobashi, Division of Hematology, Rheumatology and Respiratory Medicine Department of Internal Medicine, Faculty of Medicine, Kagawa University

• Yoshinori Inoue, Ambulatory Vascular Surgical Clinic Tokyo

• Tamihiro Kawakami, Division of Dermatology, Tohoku Medical and Pharmaceutical University

• Reiko Kinouchi, (1) Medicine and Engineering Combined Research Institute, Asahikawa Medical University, (2) Department of Ophthalmology, Asahikawa Medical University

• Hisanori Kosuge, Department of Cardiology, Tokyo Medical University

• Atsushi Kurata, Department of Molecular Pathology, Tokyo Medical University

• Yasuhiro Maejima, Department of Cardiovascular Medicine, Tokyo Medical and Dental University

• Kenji Nagasaka, Department of Rheumatology, Ome Municipal General Hospital

• Yoshikazu Nakaoka, Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute

• Takahiro Okazaki, Vice-Director, Shizuoka Medical Center, National Hospital Organization

• Mitsuho Onimaru, Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University

• Hideki Ota, Department of Advanced MRI Collaboration Research, Tohoku University Graduate School of Medicine

• Ken-ei Sada, Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

• Kunihiro Shigematsu, Department of Vascular Surgery, International University of Health and Welfare Mita Hospital

• Eiichi Suematsu, Division of Internal Medicine and Rheumatology, National Hospital Organization, Kyushu Medical Center

• Eijun Sueyoshi, Department of Radiological Science, Nagasaki University Graduate School of Biomedical Sciences

• Takahiko Sugihara, Department of Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University

• Hitoshi Sugiyama, Department of Human Resource Development of Dialysis Therapy for Kidney Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

• Mitsuhiro Takeno, Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine

• Naoto Tamura, Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine

• Michi Tsutsumino, Institute of Rheumatology, Tokyo Women’s Medical University

• Haruhito A. Uchida, Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

• Hajime Yoshifuji, Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University

• Yoshiko Watanabe, Frist Department of Physiology, Kawasaki Medical School

Independent Assessment Committee:

• Takeshi Kimura, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine

• Shin-ichi Momomura, Saitama Medical Center Jichi Medical University

• Toyoaki Murohara, Department of Cardiology, Nagoya University Graduate School of Medicine

• Shoichi Ozaki, Division of Rheumatology and Allergology, Department of Internal Medicine, St. Marianna University School of Medicine

• Hiroshi Shigematsu, Clinical Research Center for Medicine, International University of Health and Welfare

• Keiko Yamauchi-Takihara, Health and Counseling Center, Osaka University

(*The affiliations of the authors and independent assessment committee members are as of April 2019)

Appendix 2. Disclosure of Potential Conflicts of Interest (COI): JCS 2017 Guideline on Management of Vasculitis Syndrome

Author	Employment or supervisory position (private firm)	Shareholder	Patent royalty	Reward	Manuscript fee	Research fund offered	Scholarship donation/endowed chair	Other rewards	Declaration concerning spouse/relatives within the first degree or those who share the income/property
Chair: Mitsuaki Isobe				Daiichi Sankyo Co., Ltd.		Chugai Pharmaceutical Co., Ltd. Ono Pharmaceutical Co., Ltd.	Teijin Pharma Ltd. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Co., Ltd. Ono Pharmaceutical Co., Ltd. Mitsubishi Tanabe Pharma Corporation.
Member: Koichi Amano				Pfizer Japan Inc. Chugai Pharmaceutical Co., Ltd. Mitsubishi Tanabe Pharma Corporation. AbbVie Eli Lilly Japan K.K.			Chugai Pharmaceutical Co., Ltd. Asahi Kasei Pharma
Member: Shuichi Ito				Sanofi K.K.			Astellas Pharma Inc. Pfizer Japan Inc.
Member: Shinya Kaname							Chugai Pharmaceutical Co., Ltd. Astellas Pharma Inc.
Member: Issei Komuro				Actelion Pharmaceuticals Japan Ltd. MSD Daiichi Sankyo Co., Ltd. Takeda Pharmaceutical Co., Ltd. Mitsubishi Tanabe Pharma Corporation. Boehringer Ingelheim Ono Pharmaceutical Co., Ltd. Toa Eiyo Ltd. Amgen Astellas BioPharma K.K.		Ono Pharmaceutical Co., Ltd.	Astellas Pharma Inc. Edwards Lifesciences Corporation. Otsuka Pharmaceutical Co., Ltd. Kowa Pharmaceutical Co., Ltd. Daiichi Sankyo Co., Ltd. Sumitomo Dainippon Pharma Co., Ltd. Takeda Pharmaceutical Co., Ltd. Mitsubishi Tanabe Pharma Corporation. Teijin Pharma Ltd. Nipro Terumo Corporation.
Member: Kimihiro Komori				Daiichi Sankyo Co., Ltd.			Otsuka Pharmaceutical Co., Ltd. Sanofi-aventis K.K. Daiichi Sankyo Co., Ltd.
Member: Masayoshi Harigai				Chugai Pharmaceutical Co., Ltd. Teijin Pharma Ltd.		Eisai Co., Ltd. Teijin Pharma Ltd.	Mitsubishi Tanabe Pharma Corporation. Ayumi Pharmaceutical Corporation. Nippon Kayaku Co., Ltd. Takeda Pharmaceutical Co., Ltd. Chugai Pharmaceutical Co., Ltd. Taisho Toyama Pharmaceutical Co., Ltd. Abbvie
Member: Tetsuro Miyata				Daiichi Sankyo Co., Ltd. Bayer Yakuhin, Ltd			Daiichi Sankyo Co., Ltd.
Member: Hidehiro Yamada				Chugai Pharmaceutical Co., Ltd.
Member: Akitoshi Yoshida						Topcon Corporation Bayer Yakuhin, Ltd	Abbott Medical Optics Inc. Otsuka Pharmaceutical Co., Ltd. HOYA Alcon Japan Ltd. Santen Pharmaceutical Co., Ltd. Senju Pharmaceutical Co., Ltd. Hokkaido Welfare Federation of Agricultural Cooperatives · HOYA Corporation.
Member: Takashi Wada				Kyowa Hakko Kirin Co., Ltd.		Shiseido Japan Co., Ltd.	Kyowa Hakko Kirin Co., Ltd. Chugai Pharmaceutical Co., Ltd.
Collaborator: Haruhito A. Uchida							Kawanishi Holdings, Inc. MSD Chugai Pharmaceutical Co., Ltd. Boehringer Ingelheim
Collaborator: Hideki Ota							Canon Medical Systems Corporation
Collaborator: Takahiro Okazaki							Actelion Pharmaceuticals Japan Ltd.
Collaborator: Reiko Kinouchi							Ain Pharmaciez Inc.
Collaborator: Ken-ei Sada				Chugai Pharmaceutical Co., Ltd.
Collaborator: Eiichi Suematsu							AstraZeneca
Collaborator: Takahiko Sugihara				Mitsubishi Tanabe Pharma Corporation. Chugai Pharmaceutical Co., Ltd.
Collaborator: Mitsuhiro Takeno				Celgene			Novartis Eisai Co., Ltd.
Collaborator: Naoto Tamura				AbbVie Mitsubishi Tanabe Pharma Corporation. Janssen Pharmaceutical K.K. Bristol-Myers Squibb Co.			Chugai Pharmaceutical Co., Ltd. Asahi Kasei Pharma Corporation. Bayer Yakuhin, Ltd MSD Astellas Pharma Inc. Mitsubishi Tanabe Pharma Corporation. Takeda Pharmaceutical Co., Ltd. Actelion Pharmaceuticals Japan Ltd. Eisai Co., Ltd.
Collaborator: Yoshikazu Nakaoka				Chugai Pharmaceutical Co., Ltd.			Chugai Pharmaceutical Co., Ltd. Bayer Yakuhin, Ltd
Collaborator: Hajime Yoshifuji				Chugai Pharmaceutical Co., Ltd.			Astellas Pharma Inc.

Member: Yoshihiro Arimura: None.

Member: Akihiro Ishizu: None.

Member: Shigeto Kobayashi: None.

Member: Yoshinori Komagata: None.

Member: Kei Takahashi: None.

Member: Kazuo Tanemoto: None.

Member: Hitoshi Hasegawa: None.

Member: Shouichi Fujimoto: None.

Member: Tatsuhiko Miyazaki: None.

Collaborator: Yoshinori Inoue: None.

Collaborator: Mitsuho Onimaru: None.

Collaborator: Tamihiro Kawakami: None.

Collaborator: Atsushi Kurata: None.

Collaborator: Hisanori Kosuge: None.

Collaborator: Kunihiro Shigematsu: None.

Collaborator: Eijun Sueyoshi: None.

Collaborator: Hitoshi Sugiyama: None.

Collaborator: Michi Tsutsumino: None.

Collaborator: Hiroaki Dobashi: None.

Collaborator: Kenji Nagasaka: None.

Collaborator: Yasuhiro Maejima: None.

Collaborator: Yoshiko Watanabe: None.

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