Subcutaneous sarcoidosis of the extremities]

A 65-year-old man was referred to our hospital due to abnormal chest roentgenograms showing bilateral hilar enlargement with diffuse micronodular opacities. He presented with uveitis and elevated serum ACE and tested negative for tuberculin response. Transbronchial lung biopsies as well as bronchoalveolar lavage were performed and yielded a diagnosis of sarcoidosis. Several months later, the patient showed multiple subcutaneous nodules around the knee joints and elbow joints with exacerbation of intrapulmonary lesions. A skin biopsy revealed multiple foci of typical non-caseating epithelioid cell granulomata. These pulmonary and subcutaneous lesions rapidly resolved in response to the systemic administration of corticosteroids. Subcutaneous sarcoidosis may be a subacute variant of sarcoidosis associated with systemic involvement.     

Sarcoidosis induced by interferon therapy for chronic myelogenous leukaemia

A 31-year-old male was diagnosed as having chronic myelogenous leukaemia and has been treated with hydroxyurea and interferon-α since February 1995. After 16 months, he complained of low-grade fever and a cough. Bilateral hilar lymph node enlargement was detected on the chest X-ray film and multiple subcutaneous erythematous nodules appeared. A skin biopsy revealed subcutaneous sarcoid granuloma. Two months after the cessation of interferon therapy, the subcutaneous nodules and the hilar lymph node enlargement resolved. It is possible that continuous interferon administration can promote granuloma formation in sarcoidosis by activating T cells and macrophages.     

Systemic sarcoidosis during interferon-alpha therapy for chronic hepatitis C virus infection

A 62-year-old white woman with chronic hepatitis C virus infection was diagnosed with systemic sarcoidosis during treatment with interferon-alpha. Seventeen cases of sarcoidosis associated with interferon treatment have been reported, with only 8 inpatients with chronic hepatitis C virus infection. Our patient, with no past history of sarcoidosis, developed subcutaneous sarcoid nodules, arthritis, uveitis, pneumonitis and heart involvement two months after she was started on treatment with interferon-alpha. Her symptoms resolved when she began corticosteroid therapy and interferon-alpha was stopped. This case report suggests that exogenous interferon-alpha may trigger or contribute to the development of this multisystem granulomatous disorder in which interferon-gamma and CD4 + T-lymphocyte are mainly involved. Patients should be monitored during and following interferon-alpha therapy, since the autoimmune diseases induced by interferon therapy do not always improve after cessation of treatment.     

Sarcoidosis caused by interferon therapy

Interferon alpha (IFN-alpha) is an immunomodulator that is used as an antiviral agent in active chronic viral hepatitis C. IFN therapy can cause an induction or exacerbation of sarcoidosis. Although several reports in the gastroenterology literature have suggested an association between IFN therapy and sarcoidosis, this association has rarely been described elsewhere. A 47-year-old woman developed sarcoidosis after cessation of treatment with IFN and ribavirin for chronic hepatitis C. Her sarcoidosis showed liver, pulmonary and skin involvement. She continues to be monitored regularly in the Department of Pulmonary Diseases without steroid therapy. Her sarcoidosis improved spontaneously. We conclude that patients should be monitored for sarcoidosis during and after IFN therapy.     

Development of interferon induced sarcoidosis in a patient with familial mediterranean fever

A 42-year-old male patient, who had been on colchicine therapy for familial mediterranean fever admitted with dyspnea on exertion. He had a history of interferon-alpha (IFN-alpha) administration. The chest X-ray showed diffuse distribution of reticulonodular opacities in both lungs. A computerized tomography scan of the lungs revealed mediastinal and bilateral hilar lymphadenopathies, translucent densities, consolidations, reticular opacities and subpleural milimetric cystic spaces. Pulmonary-function studies demonstrated defects in diffusing and vital capacity. Histopathological evaluation was compatible with granulomatous lymphadenitis. The patient was diagnosed as having pulmonary sarcoidosis. He reflects the characteristics of IFN-induced sarcoidosis, but the duration between the cessation of IFN therapy and the development of symptoms is 42 months, which is longer than usually expected. In this case, history of IFN-alpha administration led us to suspect sarcoidosis because of a possible association between IFN therapy and the development of sarcoidosis.     

Pulmonary sarcoidosis during interferon therapy: a rare or underestimated event?

Interferon (IFN)-alpha with or without ribavirin is the treatment of choice for patients with chronic HCV-related hepatitis. Cough and dyspnea during IFN therapy are often regarded as a side effect and not as a possible sign of the onset of a pulmonary interstitial disease. It may therefore be claimed that the likelihood that patients treated with IFN develop sarcoidosis is being underestimated. Although they are not conventionally classified as etiopathologic agents of sarcoidosis, the IFNs have been proven to be capable of triggering macrophages and of promoting the expression of class II HLA antigens. It is therefore possible that IFN-alpha treatment could trigger macrophages and promote the polarization of the immune response towards Th1 in the presence of particular susceptibility conditions, thus starting the series of events that lead to the onset of sarcoidosis. We describe a case of pulmonary sarcoidosis in a 33-year-old patient treated with IFN-alpha2b and ribavirin for chronic HCV-related hepatitis after 6 months of therapy. The case we report here brings forth the issue of a possible underestimation of the real incidence of sarcoidosis during IFN therapy and highlights the need for more attention to and a more careful evaluation of respiratory symptoms manifesting in treated patients.     

Evolution of previous sarcoidosis under type 1 interferons given for severe associated disease.

Sarcoidosis is a granulomatous disorder with a well-known T helper (Th) type 1 cell commitment and a key pathogenic role of interferon (IFN)-gamma. However, little is known about the influence of type 1 IFNs, such as IFN-alpha and IFN-beta, on the course of previous sarcoidosis. The aim of this study was to determine whether type 1 IFNs can safely be used in patients with sarcoidosis for severe associated disease. The present study examined a series of four patients with sarcoidosis, treated by IFN-alpha or IFN-beta for viral hepatitis (three cases) or multiple sclerosis (one case). IFN was initiated soon after apparent recovery (three cases) or during a worsening phase of sarcoidosis (one case). Hydroxychloroquine was added in the case with active disease. Patients received interferon for 6-24 months and had close monitoring during and after IFN therapy. Interestingly, no recurrence or exacerbation of sarcoidosis had occurred at 4 yrs of follow up. Two patients were cured from viral hepatitis, whilst treatment for another failed. No neurological progression was observed in the remaining patient. This series suggests that, despite the T helper type 1 phenotype of sarcoid granulomatous reaction, type 1 interferons do not exacerbate sarcoidosis in remission and this makes their use possible if indicated. However, their effect in persistent forms of the disease needs further evaluation.     

Systemic sarcoidosis presenting as a granulomatous tattoo reaction secondary to interferon-alpha treatment for chronic hepatitis C and review of the literature

Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Immune alterations involving heightened T-helper-1 responses have been proposed to play a major role in the pathogenesis of sarcoidosis. Interferon-alpha therapy and hepatitis C infection have been implicated in the development of a variety of autoimmune diseases. However, despite the wide use of IFN-alpha therapy for hepatitis C, only a few cases of sarcoidosis have been reported in this context. We report the case of a 42-year-old white female with hepatitis C, who developed systemic sarcoidosis shortly after therapy with IFN-alpha2b. The disease was heralded by the appearance of a cutaneous sarcoid/ foreign body granulomatous reaction at the site of an old tattoo. The sarcoidosis responded to a short course of oral prednisone therapy. We also reviewed the other reported cases and discussed the possible immunological mechanisms involved.     

Development of sarcoidosis during etanercept therapy

This report describes a 65-year-old woman who developed granulomatous lesions consistent with sarcoidosis during etanercept therapy for rheumatoid arthritis. Hilar and mediastinal lymphadenopathy and multiple nodules in both lung fields developed 21 months after administration of etanercept. Noncaseating epithelioid cell granulomas consistent with sarcoidosis were detected in a lung biopsy specimen and in the parietal pleura obtained via thoracotomy. Diseases showing similar histologic changes were excluded, and a diagnosis of sarcoidosis was made. Etanercept was discontinued, which resulted in symptomatic relief, improvement of oxygenation and radiologic findings. There is substantial evidence of tumor necrosis factor-alpha involvement in the induction and maintenance of granuloma formation; however, we should keep in mind that granulomatous disease, such as sarcoidosis, can develop during treatment with a tumor necrosis factor-alpha blocking agent, such as etanercept.     

Fulminant hepatic failure in a case of autoimmune hepatitis in hepatitis C during peg-interferon-alpha 2b plus ribavirin treatment

A 27-year-old Caucasian female with hepatitis C virus (HCV) infection treated with interferon (IFN) who developed severe autoimmune hepatitis (AIH) is described. The infecting viral strain was of genotype Ib and the pre-treatment HCV viral load was at a high level. The patient was treated with pegylated IFN-alpha 2b and ribavirin,and her HCV-RNA became negative at wk 12,but after that she developed fulminant hepatic failure. The patient recovered after steroid pulse therapy consisting of methylprednisolone 1000 mg/d for three days which was administered twice. A needle liver biopsy revealed the typical pathological findings of AIH.     

Sarcoidosis presenting as antinuclear antibody positive glomerulonephritis.

A 43 year old woman who initially presented with the nephrotic syndrome, glomerulonephritis, and antinuclear antibodies (ANAs) was given the diagnosis of systemic lupus erythematosus (SLE). One year later the patient developed progressive subcutaneous nodules on her forearms, with histopathology of non-caseating granulomas. Further evaluation of the patient showed mediastinal lymphadenopathy and interstitial lung disease with numerous granulomas, establishing the diagnosis of sarcoidosis. The presence of autoimmune antibodies and glomerulonephritis has been reported in sarcoidosis, but this case is believed to be the first in which both glomerulonephritis and ANAs are present in a sarcoid patient.     

Loss of interferon antibodies during prolonged continuous interferon-alpha 2a therapy in hairy cell leukemia.

Although highly active in hairy cell leukemia (HCL), interferons (IFN) are not curative in this disease; current data indicate that prolonged IFN therapy will be necessary to control disease in the majority of patients. We previously observed acquired IFN resistance in association with neutralizing IFN-alpha 2a antibodies in small numbers of patients with HCL. This finding suggests that the requisite long-term therapy may be compromised if there is an increasing incidence over time of neutralizing antibodies. We performed a follow-up study of IFN antibodies in our patients receiving continuous IFN therapy. All 16 patients who were previously antibody negative remained so. Surprisingly, all nine patients who previously had non-neutralizing IFN antibodies became antibody negative after a median of 14.5 months. Moreover, 3 of 10 patients who had neutralizing antibodies became antibody negative and five had only non-neutralizing antibodies a median of 10 months from the time neutralizing antibody had first been detected. Only two patients had persisting neutralizing antibodies. Inhibition of neopterin synthesis, inhibition of generation of 2', 5' oligoadenylate synthetase activity, and inability to detect IFN in serum after subcutaneous injection of IFN-alpha 2a was observed only in the one patient tested with neutralizing IFN antibodies confirming that these antibodies have functional significance in vivo. We conclude that, although neutralizing IFN antibodies inhibit the effectiveness of IFN in vivo, these antibodies are produced only transiently during long-term therapy. The long-term effectiveness of this drug will not likely be affected in most patients by neutralizing antibody.     

Interferon-alpha-associated sarcoidosis responsive to infliximab therapy

Sarcoidosis, a multisystem disease characterized by noncaseating granulomas, has been reported to be associated with interferon alpha (IFN-alpha) therapy for hepatitis C infection. INF-alpha is known to stimulate T helper cells with a Th1 profile immune response, which is the key immunologic event of a sarcoid granuloma formation. We report a patient treated with IFN-alpha who developed hypercalcemia and renal insufficiency as presenting clinical manifestation of sarcoidosis. Prednisone therapy was effective in controlling hypercalcemia but had to be discontinued due to an increase in hepatitis C viral RNA count. Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor alpha was used as therapy in our patient for its known potent anti-inflammatory effects. The patient received three doses of infliximab (5 mg/kg) and achieved a rapid decline in serum calcium to normal levels in 7 days; the serum calcium level has remained normal 3 months after the last infusion.     

A patient with pleural thickening of sarcoidosis]

We report a 51-year-old woman with characteristic pleural involvement of sarcoidosis. Video-assisted thoracoscopic examination identified diffuse pleural thickening in the right lung, which coincided in distribution with parenchymal reticular shadows demonstrated with high-resolution thoracic CT scan. Biopsied specimens revealed epithelioid cell granuloma with noncaseating necrosis and multi-nucleated giant cells in the parenchymal lung tissue. Infiltration of inflammatory cells was demonstrated in the thickened pleural tissue, but no typical sarcoid lesion. This pleural lesion was considered as pleural involvement of sarcoidosis, since deterioration of the pleural thickening was accompanied with progression of a parenchymal sarcoid lesion during the period of two months after biopsy. Video-assisted thoracoscopy and high-resolution CT scan both supported the diagnosis of sarcoidosis with pleural involvement.     

Sarcoidosis and interferon therapy: report of five cases and review of the literature

BACKGROUND: Sarcoidosis is a multi-system disease of unknown etiology. Interferons (IFN) have been implicated in its pathogenesis. The objective of this study was to examine the causal relationship between sarcoidosis and IFN therapy. METHODS: Patients admitted for sarcoidosis (n=60) were reviewed for a history of IFN therapy. In addition, all cases of sarcoidosis in a cohort of hepatitis C-infected patients treated with IFN-alpha (n=1159) were analyzed. RESULTS: Five patients with prior IFN-alpha therapy and sarcoidosis were identified; an additional 23 have been reported in the literature. The median age of the 28 reported patients was 50 years, 16 (57%) were female, and 16 (57%) had isolated cutaneous disease. The median time to diagnosis was 4 months (range 1-16 months) following the introduction of IFN. A remission was observed in all patients with adequate follow-up (n=27): 15 (53%) upon dosage reduction or IFN discontinuation, seven (25%) with systemic corticosteroids, three (11%) with topical treatment, and three (11%) despite ongoing IFN therapy. Relapse was observed in both of the patients rechallenged with IFN. CONCLUSIONS: There is a potential causal relationship between IFN therapy and sarcoidosis. In patients with sarcoidosis in the setting of IFN therapy, the majority respond to IFN withdrawal or dosage reduction; however, some require corticosteroid therapy.     

Chronic sarcoid synovitis in the Caucasian: an arthroscopic and histological study.

Chronic synovitis is a rare complication of sarcoidosis, virtually confined to the black population. Synovial histology may be nonspecific or show typical sarcoid granulomata. We report 2 cases of chronic sarcoid synovitis in Caucasians. Histology showed typical granulomata in one patient, whose distinctive arthroscopic appearance is discussed.     

Manifestation of sarcoidosis during interferon and ribavirin therapy for chronic hepatitis C: a report of two cases

Two patients with chronic hepatitis C were treated with alpha 2 beta (alpha2beta) interferon and ribavirin for 6 months. Neither patient responded to therapy. Both patients developed painless skin nodules, the histology of which was compatible with sarcoidosis. During therapy, both patients also had an elevation of angiotensin converting enzyme (ACE) levels. ACE levels reverted to normal and the skin lesions resolved a few months after cessation of interferon/ribavirin therapy. A repeat liver biopsy in one patient at the end of therapy revealed multiple hepatic granulomas (which were not evident on biopsy before therapy). In conclusion, interferon/ribavirin therapy can evoke a sarcoid-like response, with skin lesions, hepatic granuloma, and elevation of ACE levels. These appear to have been reversible in the above cases.     

Pericardial tamponade in sarcoidosis

A woman with a three month history of progressive right heart failure was found to have sarcoid pericarditis complicated by pericardial tamponade. The pericardial fluid was serosanguineous, and numerous nodules were noted on the parietal and visceral pericardium. Non-caseating granulomas were found in biopsy specimens of the pericardium, lung and skin. Right-sided heart failure in sarcoidosis is usually attributed to cor pulmonale or primary myocardial sarcoid. Pericardial tamponade should be considered in patients who present with sarcoidosis complicated by right heart failure.     

A case of systemic sarcoidosis diagnosed initially by tonsillar biopsy, with discontinuous nodules in a straight line in the subcutaneous tissue of the upper arm]

A 31-year-old woman was admitted due to swollen cervical lymph nodes and swollen tonsils. These did not respond to treatment by antibiotics, and histological findings of epithelioid cell granulomas were obtained by tonsillar biopsy. After corticosteroid therapy in the subcutaneous tissue of the upper arm 5 nodules were found discontinuously in a straight line. A biopsy of one of these nodules revealed non-caseous epithelioid cell granuloma with Langhans giant cells in the superficial lymph nodes. Her older brother was strongly suspected to have neurogenic sarcoidosis. Familial sarcoidosis was considered related to this case.