Given that the ultimate treatment goal with rheumatoid arthritis (RA) is to inhibit progressive joint damage, imaging is very important. We herein introduce the current situation of standardized ultrasonography of joints in Japan, usefulness of musculoskeletal ultrasonography in the diagnosis and treatment of RA and differential diagnosis of RA using imaging modalities.
    RA is diagnosed based on the Classification Criteria for Rheumatoid Arthritis advocated by the ACR/EULAR in 2010. If it is possible to evaluate joint swelling and pain and demonstrate the presence of synovitis visually, the diagnostic accuracy can be further improved. Also, it will become able to assess RA comprehensively by considering joint changes over time by musculoskeletal ultrasonography in addition to clinical assessment including DAS.
    In January 2010, the Japan College of Rheumatology Committee for the Standardization of Musculoskeletal Ultrasonography was established; “Guidelines for Imaging Technique of Musculoskeletal Ultrasonography” and “Guidelines for Evaluation of Musculoskeletal Ultrasonography” were published in February 2011 and in May 2014, respectively. This standardization has enabled anybody to obtain images on joints, tendons and abnormal blood flow using the same imaging technique. The Guidelines also provide classification of severity of joint synovitis and vaginal synovitis, pitfalls for capturing images and correction in difference between device models.
    Conventionally, radiography, MRI and CT scans have been used as imaging modalities for diagnosis of RA. These Guidelines for Musculoskeletal Ultrasonography have positioned these imaging techniques as more advanced imaging tools, which has enabled these techniques to be more frequently and actively applied in clinical practice. It may also be significant in differentiating RA from the other diseases more readily.

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    Lupus nephritis (LN) is one of the serious complications to be forced to dialysis due to end stage renal disease in systemic lupus erythematosus. LN is classified in class I-VI and recommended the individual treatment in each class by 2003 International Society of Nephrology/Renal Pathology Society classifications because renal prognosis is different. It is desirable to be diagnosed of the assessment in histological findings by the kidney biopsy, but the procedure is invasive. Therefore we examined the usefulness of the LN disease activity assessment as noninvasive inspection about Kim-1 (Kidney injury molecule-1) reported as urinary biomarker in acute kidney injury. Urinary Kim-1 level in active LN is increased compared with that in inactive LN and tubular Kim-1 expression is correlated with the glomerular crescent formation and sclerosis, and interstitial inflammation in the kidney. In addition, we treated with anti-Tim-1 (T cell immunoglobulin mucin domains-1) antibody in MRL-Faslpr mouse as LN model mouse. Anti-Tim-1 antibody improved the survival rate, reduced proteinuria, and improved of the renal tissue injury. Anti-Tim-1 also suppressed the inflammatory cytokines and increased the population of regulatory T and B cells.
    These results indicated that Kim-1 is not only the useful tool of urinary biomarker in LN, but also the target in the treatment in the future.

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Objective: Long term use of biologic agent (BIO) in patients with rheumatoid arthritis (RA) sometimes results in secondary failure or causes adverse events. Abatacept (ABT) is known to inhibit the CD28:CD80/86 pathway resulting in downregulation of T cell activation. We hypothesize that the biological effects are regained by administration of ABT in the case of secondary failure.
Method: Twenty-one RA (15 female, mean age =of 61 years) were enrolled in this trial.
The mean duration of illness was 13 years. The biologic effects of first BIO continued at least 6 months in these cases whose mean dosing period was 37 months. After discontinuation of first BIO, ABT was dosed twice at two-week intervals (500mg or 750mg depending on the body weight). The DAS28CRP index was evaluated at the time of first BIO discontinuation, and 3 months and 6 months after ABT administration.
Results: The DAS28CRP index was significantly (p<0.01) improved after 3 months (3.17±1.44) and 6 months (2.62±0.98) after ABT administration compared with that at the time of the first BIO discontinuation (4.84±0.73).
Conclusion: In the 21 RA patients that had experienced secondary failure of the first BIO, the disease activity declined after administration of ABT. These results suggest the utility of ABT administration to overcome secondary failure in patients with RA.

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Objectives: Iguratimod (IGU) is the newest disease-modifying anti-rheumatic drug (cs-DMARDs) received regulatory approval in 2012. The efficacy of IGU was investigated with 133 RA patients at the authors' hospital.
Methods: Of the 133 RA patients who had been administered IGU at the authors' hospital since September 2012, the survey covered the 65 patients with whom analysis was possible. These consisted of 61 females and 4 males. The mean age was 57±13 years, and the mean disease duration was 1.0±3.7 years. Of the 65 patients, 51 (78.4%) were concomitantly administered methotrexate, and the mean methotrexate dose was 10.4 mg/week. Using DAS28CRP, the efficacy was evaluated, and the maintenance rate, safety, etc., were investigated.
Results: Alleviation according to the DAS28CRP was shown from week 4 of IGU administration. At week 12, 55% of patients showed remission or low disease activity; and at week 24, 37% showed remission, and 18% showed low or no disease activity. The maintenance rate for these effects was 77%.
Conclusions: The development of effects with IGU was at least as favorable as with other cs-DMARDs, and it is an excellent drug with respect to efficacy and maintenance rate. It is expected that it will constitute an effective therapeutic agent for RA in future.

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Objectives: To evaluate the efficacy and safety of denosumab treatment for 1 year to osteoporosis in patients with rheumatoid arthritis (RA).
Methods: Patients with RA received subcutaneous injection of denosumab 60mg at baseline, 6 months and 12 months. Assessments included bone mineral density (BMD) of the lumbar spine and femoral neck (0 and 12 months), levels of serum tartrate-resistant acid phosphatase 5b (TRACP-5b) and urinary pentosidine (0, 6 and 12 months), and levels of serum intact type I procollagen N-terminal propeptide (P1NP) (0 and 6 months).
Results: There were 32 consecutive patients and we excluded 3 patients with loss of follow-up. Mean changes in lumbar and femoral neck BMD at 12 months were +3.4% (p<0.0001) and +1.1% (NS), respectively. Mean changes in levels of serum TRACP-5b, P1NP (at 6 months) and urinary pentosidine at 12 months were -36.4% (p=0.0061), -30.1% (p=0.0088) and -10.3% (NS), respectively. Three (11.1%) new vertebral fractures and two (6.9%) hip fractures occurred. One case of osteonecrosis of the jaw was reported.
Conclusions: In patients with RA, denosumab treatment for 1 year provided favorable benefits.

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    A post-marketing all-patient surveillance of canakinumab (Ilaris® s.c. 150 mg) is under way to assess its safety and efficacy in Japanese patients with cryopyrin-associated periodic syndrome. We report an interim analysis 3 years post-launch of all patients who received canakinumab in daily medical practice. A total of 55 patients were registered at 36 clinics or hospitals, with 48 included in a data lock as of 31 December 2014. 47/48 were included in the safety population, with one was excluded for off-label use. The mean age of the patients at treatment initiation was 20.8 years. Majority of patients has MWS (n=22), followed by NOMID (n=18) and FCAS (n=7). Adverse drug reactions (ADRs) were reported in 34.0% of the patients. Nasopharyngitis (8.5%) and upper respiratory tract infection (6.4%) were most frequent. Five patients experienced nine serious ADRs (two events of gastrointestinal haemorrhage and one event each of bronchitis, bronchopneumonia, subcutaneous abscess, streptococcal infection, neutropenia, dizziness postural, and deafness transitory), all of which resolved. Forty-six patients were included in the efficacy population, with 28 started receiving canakinumab after launch. At each time-point (24 to 104 weeks), 80-90% of the patients remained flare free after the most recent remission. The remaining 18 patients started canakinumab in the clinical trial; at all time-points after switch to the marketed product, a similar percentage of patients had no flare after the most recent remission. The interim analysis showed no additional risks of canakinumab and relapse suppression was maintained in many of the patients. We will continue to assess the safety and efficacy of canakinumab through this surveillance.

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    Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA) and has various pharmacological modes of action. Among nodular manifestations in RA, studies have suggested roles for causative contributors to the underlying pathogenesis in MTX-related nodular diseases, however, the actual mechanisms are still unclear. Histopathological diversity exists in nodules in patients with RA because of rheumatoid disease activity, MTX-induced adverse effects, and in situ reactivated Epstein-Barr virus (EBV) which often occurs in MTX-associated lymphoproliferative disorders (LPDs).
    We described 3 patients with RA, whose nodules were quite different among histopathological characteristics. Although susceptibility to MTX-related nodular lesions may be related to genetic factors, one possible mechanism for the disease pertains to an MTX-induced increase in adenosine release from infiltrating monocytes, and this secreted adenosine may enhance nodule formation via ligation of adenosine A1 receptors on macrophages in susceptible patients, suggesting the presence of different pathological mechanisms and MTX susceptibilities. Thus, patients with RA may have various types of nodules, including those of rheumatoid neutrophilic dermatitis, and other types containing rheumatoid nodules, which are the most common extra-articular rheumatoid manifestation, MTX-induced accelerated rheumatoid nodulosis, and also cases of EVB-associated lymphomatoid granulomatosis and MTX-LPD.
    A variety of histopathological findings in nodules in patients with RA taking MTX correlate closely with rheumatoid activity, host immune function, and modes of MTX action. Therefore, rheumatologists should carefully review histological diversity of nodular lesions. Clinical awareness of the importance in morphological diversity of nodules and prudent decisions are critical to reach accurate diagnosis and achieve timely management of cases with nodular lesions that develop after the administration of MTX.

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    We report two autopsy cases of Sjögren syndrome (SjS) with rare malignant lymphoma lesions. The first patient was an 83-year-old woman with rheumatoid arthritis and SjS. She had the chief complaint of edema in both lower limbs. Computed tomography (CT) and magnetic resonance imaging revealed a mass lesion in her uterus. The other SjS patient was an 83-year-old man with the chief complaint of fever. His CT showed masses in both adrenal glands. Owing to their poor general condition, we could not perform biopsy for diagnosis of these tumors while they lived. Autopsies revealed the presence of diffuse large B-cell lymphoma in both patients. To our knowledge, this is the first report of rare lymphoma lesions in the uterus and in both adrenal glands in patients with SjS. Malignant lymphoma occurring in unusual organs should be considered in differential diagnosis of tumors in patients with SjS.

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    A 68-year-old male was diagnosed as having localized nodular pulmonary amyloidosis by open lung biopsy in 1994. Depositions of non-amyloid A type amyloid protein were detected in histochemical and immunohistochemical specimens. We have observed this patient by intermittent chest radiographs or CTs for 21 years. He has remained relatively asymptomatic except that the size and number of lung nodules have grown slowly during the period of observation. Because there are few reports of long-term observation of localized nodular pulmonary amyloidosis, this case is suggested to be worthy of report.

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