Two cases of skin sarcoidosis were reported by M. Takeya for the first time in Japan in 1921, over 50 years after the first observation of the disease by J. Hutchinson in 1869. The first nationwide survey on sarcoidosis in Japan was conducted by the Provisional Committee for Epidemiological Survey in 1960, resulting in a report of 94 confirmed cases which was presented by K. Nobechi at the 2nd International Conference on Sarcoidosis in June 1960 in Washington DC. The Committee evolved in 1964 into the Japan Sarcoidosis Research Committee which was renamed in 1981 the Japan Sarcoidosis Research Society and in 1987 the Japan Society of Sarcoidosis (later, the Japan Society of Sarcoidosis and Other Granulomatous Disorders), playing the role of a registration center for sarcoidosis cases found by periodically conducted nationwide surveys since 1960. Meanwhile, the former Health and Welfare Ministry's “Intractable Diseases” research project marked its 30th anniversary in 2002. Under the project, starting in 1972, a large-scale research team on sarcoidosis was organized and joint sarcoidosis studies which have produced a mass of research results are ongoing yet today. International conferences and a symposium have already been held 4 times in Japan.

View full abstract

Sarcoidosis, of unknown etiology, may result from exposure of a genetically susceptible subject to a specific environmental agent (s), possibly an infectious one, although none has been identified. Propionibacterium acnes is so far the only bacterium to be isolated from sarcoid lesions. Many genomes of P. acnes have been detected in sarcoid lymph nodes by the quantitative polymerase chain reaction. By in situ hybridization, P. acnes genomes were found in sarcoid lymph nodes in and around sarcoid granulomas. These results point to an etiological link between P. acnes and some cases of sarcoidosis. A recombinant trigger-factor protein (RP35) from P. acnes causes a cellular immune response in some patients with sarcoidosis, but not in subjects without sarcoidosis. RP35 causes pulmonary granulomas in some of the mice sensitized with the protein and adjuvant. P. acnes is the most common bacterium indigenous to the peripheral lung tissues and mediastinal lymph nodes, which may be the reason why these organs are so frequently involved in sarcoidosis. Sarcoid granulomas may be formed by a Thl immune response to one or more antigens of P. acnes indigenous to or proliferating in the affected organs in an individual with a hereditary or acquired abnormality of the immune system.

View full abstract

Despite the extensive investigations into the pathogenesis of sarcoidosis, its etiology is still unknown. Recently, Propionibacterial DNA was isolated by PCR from human sarcoidosis tissues and BAL cells. In this study, we investigated the response of bronchoalveolar lavage (BAL) cells to Propionibacterium acnes (P. acnes). The mean stimulation index of alveolar lymphocytes induced by P. acnes was significantly higher in patients with sarcoidosis compared both to non-sarcoid lung disease and normal subjects. The stimulation indices of sarcoidosis patients closely correlated with the number of lymphocytes and the number of CD4-positive lymphocytes in BAL fluid.
IL-2 production from alveolar lymphocytes induced by P. acnes was significantly increased in patients with sarcoidosis compared to normal subjects or patients with other lung diseases. The responsiveness of alveolar lymphocytes to rIL-2 was elevated in sarcoidosis patients compared to normal subjects. Moreover the expression of IL-2R mRNA both in non-stimulated and P. acnes-stimulated alveolar lymphocytes was increased in sarcoidosis patients. The production of IL-1, TNF-alpha, IL-6 by alveolar macrophages stimulated by P. acnes was higher in patients with sarcoidosis than in normal subjects when those were stimulated both by P. acnes and by LPS.
We demonstrated that P. acnes caused a cellular immune response of BAL cells in patients with sarcoidosis. These data suggest that alveolar lymphocytes from patients with sarcoidosis are sensitized by P. acnes, which might initiate the formation of alveolitis and granulomas at the site of disease.

View full abstract

Sarcoidosis is a systemic granulomaus disorder of unknown etiology. It takes a wide variety of clinical courses depending on the affected organs in each case. We investigated the frequency of an organ being affected in 589 patients with sarcoidosis at the time of diagnosis and for a follow up period of 10 years. The frequency of involvement for the heart, bones, nervous system, skin, and eyes, respectively increased from 0.2% to 4.6%, from 0.2% to 1.2%, from 0.8% to 3.2%, from 3.4% to 5.8% and from 40.3% to 45.8%. We also investigated the usefulness of using ECG, RI images, and UCG, for detection of cardiac involvement of sarcoidosis. UCG detected abnormal findings in some sarcoidosis patients without abnormal ECG. It may detect earlier cardiac involvement of sarcoidosis. In the analysis of postpartum recurrences in sarcoidosis women, recurrences were found in 47 of 53 sarcoidosis patients who had active disease at the time of pregnancy, whereas there were none in the 43 sarcoidosis patients who had inactive disease. Recurrences were observed in 91.5% within 6 months after delivery. When we analyzed the genetic influence of Clara cell 10-kDa protein (CC10) polymorphism (G38A) on the development of sarcoidosis and risk of its progression, the A allele frequency in sarcoidosis was significantly higher than in control subjects. The frequencies of the A/A and G/A genotypes in the progression group were significantly higher than in the regression group of sarcoidosis, suggesting that CC10 G38A polymorphism is closely associated with outcome of sarcoidosis.

View full abstract

In order to elucidate the development of fibrosis and remodeling in the lung with sarcoidosis, we examined sixty-six autopsy lungs. The autopsy cases consisted of 20 pulmonary sarcoidosis, 31 cardiac sarcoidosis, 3 neurosarcoidosis and 12 sarcoidosis without predominant specified organ involvement. Fibrosis derived from granulomas, which was especially localized at the bronchiole and interlobular septae, developed stellate in 77% and band-like fibrosis in 42% of the 66 cases of sarcoidosis. Bronchovascular bundle fibrosis was frequently observed (58%) with accompanying peribronchial atelectasis and may play an important role in the mechanism of the upper lobe contraction. Destruction of lamina elastica of blood vessels involved by granulomata was seen in these fibrous lesions. Upper lobe contraction was seen in 65% of pulmonary sarcoidosis and 32% of cardiac sarcoidosis. Cavitation was seen in the upper lobe in 9 cases of pulmonary sarcoidosis, and aspergillosis was complicated in 8 cases among them. The main cause of cavitation and cystic lesions is considered to be stenosis of the segmental and subsegmental bronchi with granulomatous involvement and peribronchial fibrosis, and further check-valve mechanism of bronchiolar involvement of granulomata and fibrosis. Honeycomb lesion was observed in 50% of pulmonary sarcoidosis. The pathogenesis of honeycomb lesion in pulmonary sarcoidosis is considered to be developed from granuloma to fibrosis in the respiratory bronchiole and alveolar duct wall and periphery of the lobule adjacent to the interlobular spaces and fibrosing alveolitis. In conclusion, the confluence and extent of granulomata in the pulmonary parenchyma, vascular and lymphatic involvement and atelectasis may play important roles in the remodeling of pulmonary sarcoidosis.

View full abstract

We studied the effects of bronchoalveolar lavage (BAL) data on the clinical diagnosis of ocular sarcoidosis. Diagnostic criteria for systemic sarcoidosis in Japan includes histological and clinical data, and the previous criteria for clinical diagnosis was based on 5 systemic data: PPD skin test, serum γ-globulin, angiotensin converting enzyme (ACE), lysozyme, and 67Ga scintigram. BAL was newly added to the 5 systemic data for the basis of clinical diagnosis in 1997, and 3 of the 6 data being positive, including either negative PPD or increased ACE, allow the clinical diagnosis of the disease. In 67 patients with suspected ocular sarcoidosis who remained undiagnosed by the previous criteria, 44 patients were selected for this study. Only 4 patients (9%), having positive BAL data, could be clinically diagnosed by the new criteria. BAL data did not contribute significantly to the diagnostic rate for ocular sarcoidosis suspects. The systemic data may reveal little for ocular sarcoidosis suspects. BAL may be difficult to do in ocular sarcoidosis suspects with slight or moderate ocular lesions.

View full abstract

A 27-year old male had blurred vision caused by bilateral urevitis 1 month before admission. He had left supraclavicular and bilateral hillar lymphadenopathy 10 days before. Biopsy of suparaclavicular lymph node was performed five days before, which revealed sarcoid nodules. From the night before his admission he had productive cough and progressive dyspnea and was admitted urgently due to acute respiratory failure with PaO₂ 54.5mmHg. His chest x-ray showed diffuse consolidations with bilateral hillar lymphadenopathy. His chest HRCT showed diffuse ground glass opacities and bilateral pleural effusions. He underwent BAL and TBLB on the first day of admission. Lymphocytes increased and CD4/CD8 ratio was elevated in BALF. TBLB revealed non-caseous epitheloid cell granulomas in the alveolar septa. He immediately received corticosteroid pulse therapy with mPSL of one gram for three days immediately under the diagnosis of acute respiratory failure caused by pulmonary sarcoidosis. He recovered dramatically and pulmonary infiltrates disappeared immediately after the treatment. He had no organ involvement of sarcoidosis except the eyes, lymph nodes and lungs. With no medication for maintenance after mPSL pulse he has had no relapse so far. We reported a rare case of pulmonary sarcoidosis with acute respiratory failure.

View full abstract

A 40 year old woman with uveitis was diagnosed as having sarcoidosis by the Daniels' lymphnode biopsy. Fibrotic change of the lung had gradually progressed and corticosteroid therapy was considered. But no corticosteroids were prescribed through long term observation over 20 years as a result of the patient's strong objection. Cystic change, thickness around the bronchovascular bundle and volume loss of the lung progressed little by little, and the patient finally developed chronic respiratory failure requiring home oxygen therapy. She died of complication of pulmonary aspergillosis at the age of 62. Pulmonary aspergillosis is well known as a complication of advanced pulmonary sarcoidosis for patients who have undergone corticosteroid therapy. But this case indicates to us that pulmonary aspergillosis is an important complication even for patients who have not undergone corticosteroid therapy.

View full abstract

We report a case of a 53-year-old man who was found to have chest abnormal shadow in a general examination and diagnosed as having Sarcoidosis by TBLB. He was treated with prednisolone for 6 months, but the chest abnormal shadow did not improve. Because he had no respiratory symptom, he did not go to the hospital. In 1992, he suffered from dyspnea when exerting himself and he has been treated with prednisolone (5-20mg/day) from that time on. In March 1994, he became ill of pneumothorax and the dyspnea got worse. In May 2000, home oxygen therapy (HOT) was begun and non-invasive positive pressure ventilation (NIPPV) was started in August 2001. In January 2002, he wanted to receive a lung transplant and came to the department of cancer and thoracic surgery in our hospital. Chest x-ray and CT showed severe constriction, linear shadow, bullous change in bilateral lung and pleural thickening. With regard to pulmonary functions, he demonstrated a restrictive pattern (VC0.831, %VC22.6%, FEV1.0% 79.5%). Arterial gas finding was PaO₂ 57.5torr, PaCO₂ 67.8torr (O₂ 1.251/min). Six minute walk test was 150m (O₂ 1.251/mm). Suffering from progressive lung sarcoidosis unresponsive to medical treatment, he had been receiving HOT and NIPPV. Because it is thought that his prognosis is poor and he has no other organ failure except the lungs, his advanced disease was considered to be appropriate for lung transplantation, and we registered him on the list for lung transplantation.

View full abstract

The prognosis of patients with cardiac sarcoidosis has been improved by the progress of antiarrhythmic drugs, but heart failure death has been reported a lot recently as an important factor affecting prognosis. Case 1 is a 76 year old man. We noted BHL in 1993, and it was diagnosed as sarcoidosis by lung biopsy. He experienced worsening of dry cough and thoracic shadow in 1997 and was readmitted. We recognized diffuse left-ventricular wall hypokinesis by UCG and negative T wave and frequent extrasystoles in ECG, which we had not found in 1993. In this case, it was possible to evaluate cardiac activity by comparing data from the early period of the illness. Case 2 is a 74 year old woman. In 1992, in a general examination, she was first found to have a dry cough and chest abnormal shadow. It was diagnosed as sarcoidosis by skin biopsy. She experienced occasional heart palpitation from about 1996, and in 1998 was admitted as an emergency admission suffering from ventricular tachycardia and having a disturbed mind. Improvement was provided with antiarrhythmic agent, but abnormal ECG such as ST-T changes continued. We report about successive changes in ECG and Holter ECG monitoring.

View full abstract

Because of the marked side effects associated with conticosteroid use, a switch was made to methotrexate therapy in 4 patients with cardiac sarcoidosis and the utility of this agent was investigated. As side effects induced by methotrexate, anaplastic anemia developed in one case and liver dysfunction in two. In the former case, when this agent was discontinued and G-CSF (granulocyte-colony stimulating factor) filgrastim was administered, swift improvement was attained. In the two cases with liver dysfunction, dosage reduction was required. In the remaining case, despite the absence of obvious side effects, the switch to this agent was associated with a resurgence of sarcoidosis activity, necessitating a switch back to cordicosteroid administration. Accumulation of further experience with methotrexate therapy for cardiac sarcoidosis is awaited. Our present experience was not promising in that methotrexate therapy could not be considered effective in 3 of the 4 cases.

View full abstract

A 74-year-old female with evidence of multi-organ involvement of sarcoidosis experienced acute renal failure. Surgical renal biopsy revealed massive sarcoid granulomatous infiltration in the interstitium of unilateral kidney. Corticosteroid therapy promptly improved renal function. This case showed the effectiveness of corticosteroid therapy in granulomatous interstitial nephritis, and suggests the need for early initiation of the therapy to prevent permanent renal dysfunction.

View full abstract

We experienced three cases of subcutaneous sarcoidosis with teleangiectasia. Case 1 was a 23 year old man who experienced generalized superficial lymph node swelling, multiple subcutaneous nodules on extremities, bilateral hilar lymphadenopathy, and a high serum level of angiotensin-converting enzyme. Case 2 was a 36 year old man with subcutaneous nodules on upper extremity, mediastinal lymphadenopathy, and splenomegaly. Case 3 was a 27 year old woman with multiple subcutaneous nodules on extremities and bilateral hilar lymphadenopathy. All cases had asymptomatic subcutaneous nodules, 5-20mm in diameter, with teleangiectasia on the surface of the skin. Subcutaneous lesions of sarcoidosis usually cause no significant changes in the surface of the skin and accompanying teleangiectasia is a rare event. In our case, the extended granulomatous lesions affecting the cutis may continually stimulate the vessels, resulting in the teleangiectasia.

View full abstract

A 61 year old woman complained of slowly progressing flexion contracture of her fingers. She was diagnosed as having muscle sarcoidosis in both limbs and secondary glaucoma due to sarcoid uveitis. Her right fourth, fifth and left fifth fingers were kept flexed on the palm, and could not be extended. An orthopediatric operation was done to remove the white tight tissues which restricted the movement of the fingers, and her contracted fingers could be extended freely. The resected tissues contained nonnecrotizing epithelioid cell granulomas. We reported this case as a rare case with flexor contracture of bilateral fingers due to muscle sarcoidosis.

View full abstract

The patient was a 57 year old male whose initial symptom was general fatigue, followed by lower extremity edema and body weight loss. His laboratory data revealed anemia, kidney and liver dysfunction and his abdominal CT scan showed perirenal hematoma. Angiography findings pointed out multiple micro-artery aneurysm of bilateral renal and liver arteries. Since polyarteritis nodosa was suspected, cyclophosphamide pulse therapy with prednisolone was started. A left abdominal massive bulge turned up next morning. As it gradually enlarged, and severe anemia was found, he was carried to our emergency center in shock status. Emergency angiography disclosed an overflow of posterior branch of left renal artery. His vital sign was stabilized by coiling emboli. After that, he was intubated due to hypoxia, and a respirator was connected to him. Continuous hemodiafiltration was started due to acute renal failure and cordico steroid pulse therapy was started. The laboratory data of inflammation improved remarkably and the titer of myeloperoxidase-anti neutrophil cytoplasmic antibody (MPO-ANCA) decreased. No biopsy was done in this case, but we suggest the diagnosis is polyarteritis nodosa showing positive serum myeloperoxidase-anti neutrophil cytoplasmic antibody (MPO-ANCA) by the clinical and typical angiographic findings. This is an important case with rupture of renal artery aneurysm immediately after cyclophosphamide pulse therapy. We must consider ANCA associated vascuritis in the diagnosis of acute abdomen in aged patients.

View full abstract