I am honored to report my history of sarcoidosis investigation for which I received the fourth award presented by the Japanese Society of Sarcoidosis and Other Granulomatous Disorders. In this abstract, I would like to mention the following items extracted from the full paper: the relation between eye and lung involvement with sarcoidosis, analysis of sudden cardiac death of sarcoidosis, association of propionibacterium acnes on pathogenesis of sarcoidosis, oxidative stress on host response in pathogenesis of sarcoidosis, epidemiology and historical analysis of Japanese sarcoidosis, and basic analysis toward the development of a diagnostic kit for sarcoidosis. I hope I can continue to further investigate sarcoidosis, and contribute to further advance of sarcoidosis research in Japan.
There are several pathophysiological processes in the cases of pulmonary hypertension in patients with sarcoidosis. Pulmonary fibrosis causes pulmonary hypertension by reducing vascular beds. A few reports identified a possibility of veno-occlusive lesions as the cause of pulmonary hypertension in patients with sarcoidosis. Oppression due to lymphadenopathy may cause pulmonary hypertension which can be treated by corticosteroids. Although its recognition seems to be not yet widespread, the presence of pulmonary hypertension is a factor contributing to the intractability of sarcoidosis. Here, we try to review the backgrounds, frequency, diagnostic approach, and therapeutic topics.
Myocardial involvement of sarcoidosis occurs more frequently in Japan than in the United States and European countries, and is responsible for the major part of deaths from sarcoidosis. But, antemortem diagnosis of cardiac involvement remains difficult due to its subtle and latent characteristic. Cardiac involvement is not often revealed until autopsy or extraction at heart transplant. The reason why the diagnosis of cardiac involvement is difficult is that the clinical manifestations are various and not specific, and the diagnostic rate with endomyocardial biopsy is low. There are few diagnostic tools specific for cardiac sarcoidosis. But, in recent years newer imaging techniques, cardiac MRI and PET, are evolving for determining cardiac involvement. This review describes the current status of the diagnosis and treatment of this condition.
The pathomechanism of muscle fiber destruction in muscular sarcoidosis, especially nodular type, may be caused by direct invasion of inflammatory cells rather than by mechanical compression or ischemia. The invasive cells consist of macrophages, epithelioid cells and lymphocytes, enter into muscle fibers during the process of granuloma formation. Furthermore, protease cathepsin B, m-calpain and ubiquitin-proteasome, which are derived from epithelioid cells and macrophages in granulomas, apparently play an important role in muscle fiber destruction. Muscular sarcoidosis manifesting acute myositis or chronic myopathy is discussed along with a review of the literature. Some patients with nodular muscular sarcoidosis extending to all limb muscles or trunk were reported. These patients, however, did not develop any muscle weakness and wasting for a long time, suggesting that the pathomechanism of muscle fiber destruction may be different in chronic myopathic form from that in nodular muscular sarcoidosis. Some muscular sarcoidosis presenting clinical features, especially progressive muscular weakness and wasting, of acute myositis or chronic myopathy are associated with autoimmune myopathies such as dermatomyositis, myositis-overlap syndrome, or myasthenia gravis.
The aim of this study is to investigate whether airway dimensions and lung densities assessed by computed tomography associate with pulmonary function in patients with sarcoidosis. CT scanning was performed in forty-three sarcoidosis patients, and lung densities were measured using in-house software. Mean and standard deviation of lung density, kurtosis and skewness of lung density histograms were calculated. Tracheal area and airway wall area/total airway area (WA%) of the right apical bronchus was also measured. Pulmonary function tests were performed on the same day. Increased standard deviation of lung density and decreased kurtosis and skewness of lung density histograms were all associated with decreased total lung capacity, vital capacity and diffusion capacity. Increased standard deviation of lung density was also associated with decreased %FEV1 and %PEF. There was a positive correlation between tracheal area corrected by body surface area and %PEF, and negative correlation between WA% and %PEF. Thus, in sarcoidosis, densitometry is a useful novel method for assessing the severity of pulmonary sarcoidosis, by quantifying parameters reflecting functional impairment.
Minocycline or doxycycline of 100mg or more per day were prescribed for 51 sarcoidosis cases (male/female; 15/36) with or without general symptoms. Out of them, 22 cases (43.1%, male/female; 6/16) were intolerable to continue the treatment for a minimum of three months due to adverse effects. The effectiveness of the treatment was evaluated according to the residual 29 cases (male/female; 9/20, Mino/Doxy; 27/2, age ranging 70 to 71). Target lesions or general symptoms were as follows: 16 skins, ten lungs, three muscles, seven others and 11 general symptoms. The number of the patients who responded to TC treatment in one or more lesions or general symptoms was six (20.7%) of the 29 cases. The responses appeared within two months since the beginning of tetracycline treatment. Response rate in each organ or general symptom was 18.8% (3 of 16) in skin lesions, 0% (0 of 10) in pulmonary lesions, 33.3% (1 of 3) in muscle lesions, 0% (0 of 7) in other organs and 18.2% (2 of 11) in general symptoms. We should consider the possibility of these effects coming from not only mere anti-bacterial effect but immunomodulatory effect.
A 22-year-old male was admitted to our hospital with high fever and arthralgia. He had a family history of sarcoidosis of the mother's sister and mother's cousin. He visited his family doctor complaining of continuing fever for one month and multiple arthralgia. His initial chest X-ray and CT showed bilateral hilar and mediastinal lymphadenopathy. Chest CT showed no pulmonary abnormality. Pathology of lung specimen obtained by trans-bronchial lung biopsy showed noncaseating epithelioid cell granuloma, suggesting sarcoidosis. No lymphocyte monoclonality was seen in this specimen. His symptom disappeared only with non-corticosteroid anti-inflammatory agents, and hilar and mediastinal lymphadenopathy on chest X-ray disappeared after one year follow up. Human leukocyte antigen (HLA) typing of this patient and his aunt showed A31 as the same locus.
The case presented was a 55 year old woman, who was noted as having abnormal chest shadows during a routine health check up in 2004. The chest X-ray showed bilateral hilar and mediastinal lymphadenopathy. The histological diagnosis of the lung specimens was sarcoidosis. Since February 2005, she has begun to complain of salivary hyposecretion and a feeling of dry eyes. By further examination it was found that she also suffered from the histological and clinical evidence of Sjögren's syndrome. In May, the left cervical lymph nodes had become palpable. After an administration of prednisolone, the swelling of these lymph nodes was temporarily reduced, but then lymph node swelling appeared again; rapidly becoming larger and accompanied with minor tenderness. The microscopic findings of biopsy specimens showed Hodgkin's lymphoma. Cases of sarcoidosis coexisting with Sjögren's syndrome or Hodgkin's lymphoma have occasionally been reported. To the best our knowledge, a patient with sarcoidosis, complicated with both Sjögren's syndrome and Hodgkin's lymphoma has never been published. The precise mechanism or possible cause and effect relation among these diseases are unknown at present. But as these lesions developed during the same period, a common immunopathogenesis might exist in the background, mainly concerning T lymphocytes. For this reason, we should carefully treat patients with sarcoidosis, being aware of the possible coexistence of autoimmune disorders or other malignant diseases.
A 25-year-old man, tattooed on the whole body before six years, noticed a fever and dry cough from the middle of June 2006. He complained of persisting cough and shortness of breath. As his family doctor mentioned abnormalities on chest X-ray and CT, he was referred to our hospital. On admission, he showed WBC 8, 200/μL, CRP 0.03mg/dL and KL-6 277U/mL. There were no abnormalities in the physical examination except the whole body tattoo. Bronchoalveolar lavage fluid (BALF) showed lymphocyte 42.6% (CD4/CD8 2.49). Biopsy specimen obtained from Video-assisted thoracoscopic surgery (VATS) showed non-caseating epithelioid cell granulomas accompanied with Masson body and black pigmentation. Skin biopsy of a tattoo site showed non-caseating epithelioid cell granulomas with black pigments.
A 30-year-old man was seen in the ophthalmology department due to blurred vision. He was suspected of having either tuberculous uveitis or sarcoidosis. The patient was referred to our department for further testing. On chest CT, mild swelling of the mediastinal and bilateral hilar lymph nodes was noted. However, serum ACE activity and γ-globulin fraction levels were normal. The patient had a weak positive tuberculin skin test, and the QuantiFERON®TB-2G (QFT) results were positive. In the bronchoalveolar lavage fluid (BALF), lymphocyte count was 13.6% and the CD4/CD8 ratio was low (0.72). Real-time endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) showed a granulomatous lesion, but a definite diagnosis could not be made. The patient was diagnosed as having sarcoidosis based on pathological examination of hilar lymph nodes obtained by thoracoscopic biopsy. Since the patient had atypical clinical test findings, it was difficult to differentiate sarcoidosis from tuberculosis. Therefore, we present this sarcoidosis patient and discuss his test findings.
When a 59-year-old woman visited our hospital in June 2003, she complained of having slight exertional dyspnea since December 2002. She had bilateral hilar lymphadenopathy and bilateral reticular shadows at lower lung with high 4/8 ratio in BAL fluid. Serum ACE level and PPD skin test were negative. She was diagnosed as having sarcoidosis. Hepatic dysfunction was also found. During follow-up without treatment in our outpatient department, exertional dyspnea gradually worsened and marked hypoxemia was shown. She was admitted to our hospital in June 2006. Chest CT showed bilateral basilar reticular opacities which were the same as CT at the first visit, but abdominal CT showed gastric varices and liver cirrhosis. Blood examination showed hepatic dysfunction but viral hepatitis was ruled out, and primary sclerosing cholangitis, primary biliary liver cirrhosis, and autoimmune hepatitis were negative serologically. We performed a liver biopsy which showed liver cirrhosis and non-caseating epithelioid cell granulomas. In addition, we found extrapulmonary accumulation in pulmonary blood flow scintigraphy and diagnosed it as hepatopulmonary syndrome with liver cirrhosis and non-caseating epithelioid cell granulomas, because no shunt was found.
A 54 year old woman developed cardiac sarcoidosis ten years after having been diagnosed with sarcoidosis (eye, lung) at the age of 44. Electrocardiogram and ultrasonic cardiogram did not detect any abnormality until 53 years old. Although electrocardiogram was still within normal range, a left ventricular apical aneurysm was first detected by ultrasonic cardiogram at 54 years old. Sarcoidosis granuloma was diagnosed in myocardial biopsy. This case indicates that cardiac sarcoidosis occasionally develops well after the diagnosis of sarcoidosis, and that cardiac sarcoidosis will occasionally develop in the form of a left ventricular apical aneurysm with no steroid treatment. It is necessary to periodically check the heart over the long term for a sarcoidosis patient. Since an electrocardiogram is sometimes normal in cardiac sarcoidosis, additional ultrasonic cardiogram may be useful to detect this disease.
A woman with sarcoidosis showed progressive parenchymal shadows of the lung with worsening cough and sputum. Clarithromycin at a daily dose of 400mg for 3 months was not sufficiently effective for symptom relief. However, the chest shadows and her symptoms promptly disappeared following the addition of minocycline at a daily dose of 200mg. In view of other cases previously reported, the efficacy of minocycline is comparatively clear for sarcoidosis. The elucidation of the mechanism for this difference from the viewpoints of both antibacterial and immunomodulatory effects will create a stir in the controversies as to the etiology of sarcoidosis.
A 74 year old woman visited a hospital complaining of right cervical lymphadenopathy. The cervical lymph node was removed and histology revealed non-caseating epithelioid cell granuloma, suspicious of Sarcoidosis. She was referred to our hospital for further examination. We diagnosed her as having sarcoidosis, based on biopsy of the right knee skin and findings of bronchoalveolar lavage fluid. Later, right cervical lymph node and parotid gland became enlarged. As she did not agree to take corticosteroids because she had diabetes mellitus, we chose Minocycline hydrochloride. Minocycline treatment induced the size reduction of cervical lymph node and parotid gland. A second biopsy of cervical lymph node was carried out with informed consent. Histopathology of lymph node revealed massive hyalinization with remnant of regressive granuloma and giant cells. Immunohistochemical study of monoclonal antibody against P. acnes lipoteichoic acid (PAB) revealed positive granules in the granuloma before Minocycline treatment, whereas PAB positive granules were found in giant cells around hyalinization and PAB had no reaction in the hyalinization after therapy. This case demonstrates that Minocycline induced reduction of granuloma but PAB positive granules remain, suggesting that Minocycline acts as an immunomodulator in addition to suppressing intracellular bacteria.
Sarcoidosis is the leading cause of uveitis in Japan. Sarcoidosis is known to exhibit characteristic ocular manifestations and systemic abnormalities which are helpful for its diagnosis. Recently, the diagnostic criteria for sarcoidosis were revised by the Japan Society of Sarcoidosis and Other Granulomatous Disorders. The new diagnostic criteria for ocular sarcoidosis were evaluated by ophthalmologists and are reported by Mami Ishihara. Although sarcoidosis is a major disease in regard to uveitis worldwide, there is no internationally accepted diagnostic set of criteria available. To establish diagnostic criteria for ocular sarcoidosis acceptable internationally, the 1st International Workshop on Ocular Sarcoidosis was held in Tokyo in 2006. Hiroshi Takase introduced the details of the international diagnostic criteria for ocular sarcoidosis. Kohei Sonoda reported how to treat intraocular inflammation in sarcoidosis and Nobuyuki Ohguro reported the treatment for ocular complications.
This paper listed ocular findings characteristic for sarcoidosis, which are listed in the Guideline for Diagnosis of Ocular Lesions-a part of the new Diagnostic Standard and Guideline for Sarcoidosis-2006, All the items of the new Guideline for Diagnosis of Ocular Lesions have a high specificity of more than 80% and the Guideline as a whole also has high sensitivity and specificity. With the revised diagnostic procedure, an approach will be provided as to how we make the diagnosis when we suspect sarcoidosis from ocular findings. The addition of BHL (bilateral hilar lymphadenopathy) as one of the systemic examination items, that are required for making diagnosis, has facilitated clinical-based diagnosis of sarcoidosis, especially in cases of uveitis patients with BHL. It is expected that an increased rate of diagnosis for sarcoidosis will result.
Sarcoidosis is one of the major uveitis entities in many countries and ethnic groups. Because international diagnostic criteria are still not available at present, an international workshop on ocular sarcoidosis was held in Tokyo Japan, 2006 by members of an international study group consisting of uveitis specialists and pulmonologists from 10 countries. Diagnostic criteria of ocular sarcoidosis were worked out based on 7 suggestive ocular signs, 5 supporting investigational tests, and histopathological examination resulting in 4 levels (I-IV) of certainty. When these criteria were evaluated for 370 patients with uveitis, high values of the diagnostic parameter were obtained for all 7 suggestive ocular signs and for 4 out of 5 of the supporting investigational tests. These international diagnostic criteria for ocular sarcoidosis should be improved by evaluation in other countries.
Due to chronic intraocular inflammation, various irreversible changes in the eye, such as cataract, glaucoma, macular edema, intraocular neovascularization and proliferative intraocular changes are observed in sarcoidosis patients. We need to pay special attention to these ocular complications. The basic therapy for uveitis associated with sarcoidosis is a combination of topical steroid and mydriatics. There are several types of topical steroid therapy, including eye drops, subconjunctival injection, subtenon injection, retrobulbar injection and vitreous cavity injection. Recently, the pars plana steroid implant was invented and a medical trial study using this device for refractory uveitis is ongoing in Japan. Systemic steroid therapy was performed for ocular sarcoidosis patients, but limited to cases resistant to topical steroid therapy. Moreover, surgical management has come to be selected for severe complications.
Sarcoidosis is a multisystem granulomatous disease. Since the clinical course of intraocular inflammation in ocular sarcoidosis usually shows a chronic course, we often experience secondary lesions consequent to primary granulomatous inflammation. Cataract, glaucoma, cystoid macular edema, and epi-retinal membrane are the representative ocular complications associated with ocular sarcoidosis. Although medical treatment is essential for the primary lesions, surgical procedures are sometimes required in the management of these secondary lesions.
Last year, we reported our analysis of the pathologically-confirmed sarcoidosis cases newly diagnosed in 2004. The number of newly registered sarcoidosis patients accepted as having this intractable disease in 2004 were 1, 679, of which 652 had insufficient histopathological findings and excluded from the former analysis. Not Pathologically unconfirmed sarcoidosis cases newly diagnosed in 2004 were eligible for this study. The age-specific incidence rates of both, as seen in a distribution graph, display a similar biphasic pattern, but the second peak was slightly higher in the not pathologically-confirmed group. Abnormalities detected in routine medical examination and subjective symptoms, and the female ratio showed similar frequencies in both groups. In the not pathologically-confirmed group visual disturbance was significantly higher (28.8% vs 46.2%) and skin symptom was significantly lower (9.6% vs 1.4%) than the pathologically-confirmed group. Subjects who had sarcoidosis manifestations only in locations difficult to biopsy (e.g. eye) might have been excluded from the pathologically-confirmed group and those easy to biopsy (e.g. skin) might have been included in the pathologically-confirmed group.