There is ample evidence for the involvement of IFN-γ in the formation of epithelioid cell granulomas, which are characteristic to sarcoid lesions. However, sarcoidosis does not belong to a typical Th1-type immune pathophysiology, in which only IFN-γ is working. It has a complex aspect in that IL-4 and other cytokines are involved depending on the stages and lesions of the disease. Upstream pathways have recently been elucidated which lead to the induction of IFN-γ. IL-12 and IL-18 are, among other things, play principal roles. Roles of IL-12 in sarcoidosis have already been documented, however, those of IL-18 have remained to be elucidated. Gene polymorphisms of IFN-γ, related cytokines, and signal transducing proteins may affect the occurrence and clinical course of sarcoidosis by modulating the production of IFN-γ.

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Abstract. Clinical and histological features of noninfectious cutaneous granulomatous diseases are reviewed, and their relationship with sarcoidosis is discussed. Granuloma annulare, necrobiosis lipoidica and rheumatoid nodules are histologically characterized by palisading granulomas. Granuloma annulare and necrobiosis lipoidica are considered to be associated with diabetes mellitus. There have been reports of cases complicating these two palisading granulomas and sarcoidosis, although the pathological relationship is unknown. Annular elastolytic giant cell granuloma is expressed by annular skin lesions on sunexposed areas and histological phagocytosis of elastic fibers within giant cells in the dermis. It has been reported that the disease is complicated with sarcoidosis or seems to be in a spectrum of epithelioid cell granulomatous diseases including sarcoidosis in some cases. Since epithelioid cell granulomas with caseous necrosis was observed in lupus miliaris disseminatus faciei (LMDF), the disorder was originally described as tuberculide. However, LMDF is now considered to be a variant of rosacea. There are cases of LMDF that are difficult to be clinically and microscopically discriminated from cutaneous sarcoidosis.

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We studied 90 familial occurrences of Sarcoidosis reported in Japan and investigated the hereditary influence of sarcoidosis. There were 97 relationships in 90 families. They were consisted of 60 sibling pairs (22 sister-brother, 24 sister-sister and 14 brother-brother relations, including 3 monozygotic twins), 26 parent-offspring, 5 aunt-niece/nephew, 4 cousin pairs. Only 2 index cases had an affected spouse. The prevalence rate of familial sarcoidosis (90 families) in Japan appears to be significantly greater than the expected value in the general population estimated using binomial distribution. Furthermore we assessed the genetic mode of sarcoidosis in sarcoidosis patients from Okayama University Hospital. Among 133 patients with sarcoidosis for whom pedigrees could be constructed, 7 patients had a pathological or clinical diagnosis of sarcoidosis in related family members. Mendelian autosomal mode of inheritance were reasonably excluded by inspection of pedigree patterns and by poor fit of corrected ratios within sibships to the expected ratio for all sibships. Hereditability estimated by Falconer's method was 68% in all first-relatives and 69% in sibships, respectively. These data suggest that the observed familial distributions conform to multigenic traits.
A larger sample size for epidemiological study and further investigations of genes concerned with sarcoidosis would permit additional multigenic properties.

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We investigated the incidence and characteristics of sarcoidosis patients who were positive to autoantibodies or complicated with autoimmune diseases. The results revealed that antinuclear antibody and rheumatoid factor were highly positive in sarcoidosis patients. In addition, those patients who were positive to autoantibodies or complicated with autoimmune diseases had a tendency to develop multi-organ disease of sarcoidosis and to be complicated frequently with skin lesions, compared with those who were negative to antinuclear antibody. They also included greater number of female patients older than 40 year-old. We have to pay much attention to those sarcoidosis patients positive to autoantibodies or complicated with autoimmune diseases, because they have the risk to develop a refractory disease.

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About 31.9% of patients with ocular sarcoidosis showed normal-tension-glaucoma mimic symptoms, including an increase of cup-to-disk ratio, peripapillary chorioretinal atrophy, nerve fiber layer defect, etc., even if they have no past histories of the intraocular hypertension. The average duration of sarcoidosis in these patients was 9.8±8.6 years. A decrease in the systolic, diastolic and mean blood flow velocities and an increase in peripheral circulatory resistance indices in the orbital central retinal artery were observed in these patients with ocular sarcoidosis. It is suggested that the long duration of the obliterative vasculitis in ocular sarcoidosis, associated with a decrease in ocular blood flow, may lead the impairment of optic nerve fiber layer followed by a normal-tension-glaucoma mimic condition.

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Chronicity of the clinical course in sarcoidosis is seen in about a half cases of total in general, and studies on its causes and its causal treatment are essential. Nine cardiac sarcoid cases were examined on these subjects. Following to our previous report (Chest, 1992), intrinsic cause (HLA) was studied on the combination of HLA-DR types in 8 cardiac sarcoid cases, compared to 60 sarcoid cases. DR types of high response (HR) to SCW were much higher in cardiac sarcoid cases. Furthermore, as the results of DNA typing of the cardiac sarcoid cases, DRB1 alleles of HR to SCW seem to be detected in high-degree heart block groups, but in groups of benign arrhythmias the combination of DRB1 alleles of high and low responsiveness to SCW were seen except one case. Even in high-degree heart block cases, tonsillectomy or long-term oral hygine proved to be efficient.

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A 58-year-old woman, who had been diagnosed as having pulmonary sarcoidosis seven years earlier and had bilateral hilar lymphadenopathy (BHL), admitted to National Saishundo Hospital because of exertional dyspnea. ECG showed complete atrioventricular (AV) block. Cardiomegaly was disclosed on chest X-ray film although BHL had disappeared. Echocardiography showed thinning of wall and abnormal regional wall motion in the basal portion of the ventricular septum. In addition, ²⁰¹T1 myocardial scintigram showed defects of anterior and posterior septum. These findings led to the diagnosis of cardiac sarcoidosis. Signs and symptoms of cardiac failure subsided after placement of an external cardiac pacemaker and conventional treatment for cardiac failure. After the administration of corticosteroid abnormal findings on ²⁰¹T1 myocardial scintigram improved to a certain degree. On the other hand complete AV block was still present which needed a permanent cardiac pacemaker implantation. Abnormal echocardiographic findings of the basal portion of the ventriculer septum remained unchanged. Since the prognosis of sarcoidosis with cardiac involvement is poor, cardiac involvement should be observed carefully in the follow-up of sarcoidosis patients.

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A 54-year-old Japanese woman, who had been diagnosed as sarcoidosis, was referred to our hospital in July 1992. She noticed hoarseness in March 1989. Laryngeal biopsy failed to clarify the cause of hoarseness. Diagnosis of sarcoidosis was made in September by mediastinal lymph node biopsy. She developed chest pain in August 1990 and cardiovascular examinations were performed. However, there were no abnormalities in electrocardiography and echocardiography. In March 1992, corticosteroid therapy was started because of the enlargement of cardiac silhoutte. She developed frequent premature ventricular contractions and chronic heart failure and was hospitalized in July 1992. Severe left ventricular hypokinesia, marked decrease in LVEF and defect in ²⁰¹Thallium myocardial scintigraphy were shown. She was discharged in December after the iniation of digitalis, diuretic drugs, and antiarrhythmic drugs. She was hospitalized in July 1999 for severe heart failure and died in August. The autopsy revealed noncaseating epithelioid cell granulomas in mediastinal lymph nodes. In the heart muscle, fibrosis and granulomatous changes were observed.

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We reported two cases of sarcoidosis patients who showed hypercalcemia with the elevation of serum PTHrP level. Case one was complicated by rheumatoid arthritis and Sjögren's syndrome showed hypercalcemia fourteen years later the onset of sarcoidosis. Case two was complicated by Sjögren's syndrome and had hypercalcemia with sarcoid myopathy. Both cases showed hypercalcemia and hypercalciuria with the elevation of serum PTHrP levels. However, both cases showed normal 1.25(OH)₂D₃ value and low PTH value during the course of the disease. In case one, serum calcium and PTHrP levels were decreased spontaneously. In case two, hypercalcemia and serum PTHrP level improved with corticosteroid therapy. These data suggested that PTHrP may play a role in the development of hypercalcemia in sarcoidosis.

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A case of sarcoidosis with hypercalcemia and rapidly progressive renal dysfunction is reported. A 71 year-old-female, having been treated for sarcoidosis with no symptoms since 1991, was admitted in July, 1997, for anorexia, elevated levels of serum calcium, and creatinine. Urinalysis showed proteinuria and hematuria. Decreased GFR, and disturbances in tubular function were revealed by renal function tests. The serum ACE level was normal, although the serum lysozyme level was elevated. The serum 1 α 25(OH)₂D₃ level was high for her age and osteoporosis. Both serum intact PTH and PTHrP levels were normal. BHL remained on chest X-ray film and slight accumulations of ⁶⁷Ga-citrate were observed in bilateral hilar regions and kidneys by ⁶⁷Ga scintigraphy. Diet therapy, infusion and diureticus gradually normalized her serum calcium, creatinine and 1 α 25(OH)₂D₃ levels. Steroid was not administered considering her age, hyperlipidemia and hypertension, although a renal biopsy revealed interstitial nephritis. In this case, hypercalcemia seems to have caused the progression of renal dysfunction induced by sarcoid nephronathy.

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The frequency of detecting multiple nodular lesions of the spleen is increasing with the availability of diagnostic tools such as echography and CT. However, it is very difficult to make a definite diagnosis without pathological information. We reported a case of 65-year-old male with asymptomatic multiple nodular lesions in the spleen. He underwent a diagnostic percutaneous needle biospsy of the spleen without any complications. Pathological findings suggested sarcoidosis, which was subsequently confirmed by transbronchial lung biopsy. It has been reported that splenic sarcoid lesions could be found in up to 33% of autopsied sarcoidsis cases, although they rarely caused clinical symptoms during lifetime. Therefore, sarcoidosis should be considered as a differential diagnosis of incidental multiple splenic lesions. In such cases, we believe that needle biopsy of the spleen is a simple and safe means of definite diagnosis.

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A 54-year old woman was admitted to a local hospital with severe muscle pain and solid masses of both legs. She was transfered to our hospital for further examination, because sarcoidosis was suspected by the histological examination of muscle biopsy. A chest X-ray film revealed bilateral hilar lymphadenopathy and diffuse reticulonodular opacities in both lungs. Histological examination of transbronchial lung biopsy specimens showed non-caseous epithelioid cell granulomas, and on these bases a diagnosis of sarcoidosis was made. Her clinical conditions improved, and solid masses subsided after the administration of prednisolone. She had the symptoms of eye and mouth dryness for 2 years, and the diagnosis of Sjögren's syndrome was made by laboratory findings and sialography. This was a rare case of sarcoidosis with symptomatic muscle Involvements and Sjögren's syndrome.

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A 72-year-old woman was pointed out to have mediastinal lymphadenopathy in 1997. She was admitted to our hospital on March 1998 for an evaluation of lymphadenopathy. The diagnosis of sarcoidosis was established by the findings of epithelioid cell granulomas in TBLB specimen, increased percentage of lymphocytes (40%, CD4/CD8 5.7) in BALF, negative culture for tubercle bacilli in BALF, high level of serum ACE, and coincidence of uveitis.
One year after the initial diagnosis of sarcoidosis, she began to have a low-grade fever and was admitted to our hospital again on March 1999. Ziehl-Neelsen staining of the induced sputum revealed Mycobacterium tuberculosis and positive result was also obtained in PCR examination of mycobacterium DNA in the gasric fluid and then we started antituberculosis chemotherapy.
In this case we speculate that mycobacterial infection occurred secondary to sarcoidosis. From this case we would like to emphasize that enough attention should be paid to a complication of tuberculosis in sarcoidosis patients.

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