ASSOCIATION OF PHYSICIAN OF INDIA

Sarcoidosis remains an enigma for many reasons. The diversity of clinical presentations suggests it may be better considered a syndrome with different etiological agents rather than a single disease. The morphological appearances of non-caseating granuloma are not specific for sarcoidosis. Often the diagnosis is made on clinical grounds without histological or other proof. This review will look at the current epidemiological knowledge, possible etiological agents, the pathogenesis, clinical dilemmas and therapeutic problems. Much of the epidemiological knowledge is based on work performed more than 30 years, although work in the last 5 years has helped clarify some of the issues. However, the major access study:- A case controlled etiologic sarcoidosis study will not report until after the year 2000. A major problem has been the variable presentation and the fact that many patients may be asymptomatic or have minimal symptoms for which they do not seek help. Sartwell (1) in a cohort study of more than one million Navy recruits reviewed their chest X-rays and identified 134 cases of sarcoidosis of whom 65 (48.5%) were asymptomatic. Few studies have looked at the overall population allowing comparison between ethnic groups. Early studies suggest African Americans are 10 to 17 times more likely to be affected than caucasians (2,3). In Caucasians the annual sarcoid incidence has been reported as between 1.2 and 19 cases per 100,000. A recent study reflecting the urban and suburban areas of Detroit found only a 3 or 4 greater times incidence amongst African Americans compared with local Caucasians (4). Females are more frequently affected in both groups. The majority of cases occurred under 50 years of age. The lifetime risk of sarcoidosis in African American men and women was 2.1% and 2.7% and for Caucasian males and females 0.7 and 1% respectively. The disease appeared to be more aggressive in the African Americans. A clustering of cases has led investigators to consider a number of environmental risk factors including pollen from pine trees and wood fuels (5,6) but most intriguing is the inverse relationship with cigarette smoking (7). There is no doubt that exposure to certain metals eg balinium, aluminium, rare earths, copper (8,9) can produce caseating granuloma similar to those found in sarcoidosis. The possible role of mycobacterial infections in the causation of sarcoid has generated enormous interest over many years. Recent studies involving molecular biological techniques, eg polymerase chain reactions (PCR) (10) and some experimental animal studies (11) have suggested that mycobacterial species such as M avium may be responsible for a small number of sarcoid cases (12, 13). However the causal agent in the majority of cases remains unclear. Familial sarcoidosis was first reported in Germany in 1923 by Martenstein. Interest in possible genetic factors has continued since then. In a recent study involving 1,082 consecutive sarcoid patients Harrington (14) identified 14% of cases with first or second-degree relatives:- 17% in African Americans but only 6% in Caucasians. Further studies by Rybicick et al (15) detected hetrogenecity in familial risk suggesting major gene involvement in sarcoidosis but further studies are required. There would appear to be both environmental and genetic factors operative in the development of sarcoidosis. Much work over recent years has established the role of lymphocytes and cytokines in the development and resolution of sarcoid granuloma (16,17). Within the lung activated T cells and alveolar macrophages accumulate at the site of inflammation (18). There is evidence of expansion of oligoclonal populations of CD4 T cells in response to local antigen formation leading to an exaggerated immunological response and that the T cell numbers fall with spontaneous resolution or treatment (19,20). Cytokines produced by T cells and macrophages cause immuno competent cells to congregate, proliferate, differentiate and become active at the centre of inflammation (21). Further liberation of cytokines by activated cells induces granuloma formation and subsequent fibrosis (22,23). TH1 CD4 cells regulate granuloma formation and the TH2 CD4 cells fibrosis. Differences in the balance between the cytokines produced by each of these cells in any area determines the phase of activity. A similar reaction is postulated for other sites of sarcoid development. The production of cytokines from CH1 CD4 cells produces a type I response which is blocked by corticosteroids (24). Recent studies with Pentoxifylline which blocks type I cytokine production has had a favourable effect in sarcoidosis (25). Thalidomide has a similar action (26). This opens up the possibility of new treatments for the disease. The Kveim test is useful in diagnosis being positive in 85-90% of classical cases of acute sarcoid but in only 33% in long standing fibrotic disease (27). Some doubts have been raised about injecting material obtained from another patient with possible transmission of disease leading some authorities to withdraw the material. Hopes that analysis of Kveim material might throw light on the etiology of sarcoidosis have not so far been realised. Raised serum ACE activity is found in active granuloma formation and can be used to follow the activity of the disease (28). However, the test lacks sensitivity and specificity. The lungs are involved in over 90% of cases but practically any organ may be affected (29) either singly or in combination. Pulmonary sarcoidosis may be classified according to the relative hilar gland and parenchymal involvement into: stage 1 with bilateral hilar gland enlargement (BHL) without radiological parenchymal infiltrates, stage 2 – BHL with pulmonary infiltrates, stages 3 pulmonary infiltrates without BHL and stage 4 parenchymal fibrosis and distortion. Fibre-optic bronchoscopy with multiple bronchial and transbronchial biopsies is useful in confirming the diagnosis (30). Mediastinoscopy and open lung biopsy may also be used. Lofgrens syndrome a combination of BHL, erythema nordosa and fever with or without arthritis or uveitis is diagnostic of sarcoid usually being self limiting and rarely requiring treatment unless there is significant systemic upset (31). Parenchymal involvement confirmed by transbronchial lung biopsy is very common even in BHL with normal radiological appearances. Many patients with radiological evidence of pulmonary infiltrates have no or few symptoms. The longer the infiltrate persists and greater the likelihood of developing progressive pulmonary fibrosis often in the mid zones on X-ray (32). Late stage irreversible fibrosis occurs in the upper lobes with elevation of the hilar shadows. In long-standing chronic persistent pulmonary sarcoid hilar and pulmonary calcification may be seen (33). Fatalities from respiratory failure have been reported in between 1 and 4% of advanced cases of pulmonary sarcoidosis. The decision as to which patients to treat requires careful assessment of the activity, severity and rate of progression of the disease. Spontaneous remissions occur in 60-90% of stage 1 disease, 40-70% in stage 2, 10-20% in stage 3 but zero percent in stage 4 (34). The spectrum of clinical manifestations of sarcoidosis are protean. Parotid gland enlargement, fever, uveitis and cranial nerve palsies (Heerfordts syndrome) are invariably the result of sarcoidosis (35). Ocular involvement can involve any part of the eye or orbit (36) with uveitis occurring in up to 50% of cases (37). In a series of 224 patients with ocular sarcoidosis, anterior uveitis occurred in 66%, posterior uveitis in 14%, both anterior and posterior uveitis in 13%, conjunctivitis in 17 and lachrymal gland involvement in 7 (38). Acute anterior uveitis occurs early in the disease and is often self-limiting or responds to corticosteroids with few late sequelae. Chronic anterior uveitis is more indolent being associated with lupus pernia and lung infiltrates and make cause significant late sequelae. The early use of topical steroids is essential to prevent visual loss. Posterior uveitis is potentially more serious and may be associated with CNS involvement. Cutaneous involvement has been reported in up to 35% of cases being more frequent in females and includes erythema nordosum, lupus pernio, plaques, rashes, skin nodules and infiltration of scars (keloids) (39, 40). Lupus pernio, the most characteristic sarcoid skin lesion is a chronic violaceous indurated skin lesion with a predilection for the nose, ears, lips and face (41) and usually associated with progressive sarcoidosis involving other organs. Prognosis in lupus pernio is poor, response to intra lesional or oral steroids occurs in fewer than 30% of cases with relapse on withdrawal of treatment. Anti malarials may be helpful in its treatment (39). Involvement of the liver and spleen is common, often asymptomatic but can cause abdominal pain, malaise, fatigue and hyper-splenism (42, 43, 44). The frequency of liver granuloma varies with the stage of the disease occurring in 90% of acute early cases of sarcoid but only 60% of those with chronic lesions (45). Mild cholestatic abnormalities of liver function are found in about 25% (46). Chronic liver involvement may progress to portal hypertension, oesophageal varices and hepatic failure. The presence of non-caseating sarcoid like granuloma on liver biopsy without evidence of sarcoidosis in other organs may present diagnostic problems. Abdominal CT scanning is useful in defining involvement and following the progress in hepatic and splenic disease. Corticosteroids have been shown to be effective in splenic involvement but less so with hepatic. While involvement of the skeletal muscles is often mild, transient and self-limiting occurring in the early stages in up to 50% (47), cardiac involvement is always potentially serious. While clinical evidence of cardiac involvement has been recognised in only 2-5% (48) autopsy studies report up to 50% cardiac involvement (49). In Japan myocardial involvement accounts for 77% of sarcoid deaths but lower mortality (50%) is reported from the United States (50,51). Cardiac involvement eg arrhythmias, intractable cardiac failure, pericardial effusion, capillary muscle dysfunction, ventricular aneurysms, can occur at any time during the course of the disease and may be the presenting features. High dose corticosteroids are indicated and in recalcitrant cases immunosuppressive, cytotoxic or anti malarial drugs should be added. Anti arrhythmic agents, pace makers and aneursymal resections may be required. Clinically recognisable involvement of the CNS has been reported in up to 7% of cases, although at post mortem granulomas were reported in 14% of cases (52, 53). Seizures occur in up to 15% of patients with CNS sarcoid and may be the presenting features (54). Other manifestations include cranial nerve palsies, meningitis, hypothalamic and pituitary lesions, space occupying lesions, hydrocephalus, peripheral neuropathy, spinal cord involvement and dementia (55). Seventh nerve palsy occurs in up to 67% of patients (56) often in association with parietal gland enlargement and uveitis and often resolving spontaneously. Diabetes insipidus, hypo-pituitarism and hyper-prolactineamia may result from lesions around the hypothalamus (57). Both CT and MRI scans may be helpful in diagnosis and following the course of CNS sarcoidosis (58). Inter cranial lesions may be multiple presenting as well defined, hyper dense, enhancing lesions surrounding by oedema (53). Up to 90% of patients with acute or sub acute CNS sarcoidosis responds favourably to corticosteroids (59). In non-responsive cases the chronic sequelae may be serious with a mortality of 10% (59). Immuno suppressive, anti malarials and radiotherapy may help in some resistant cases (60). Most patients with sarcoidosis never require specific treatment. Indications for therapy depend on the organ involve and the severity and nature of symptoms. Aggressive treatment is warranted for life threatening, respiratory, neurological and myocardial or sight threatening ocular disease, progressive or chronic symptomatic disease or chronic hypercalcaemia (61). Corticosteroids remain the mainstay of treatment reversing or ameliorating the manifestations of the disease. Short-term effects may be dramatic but relapses may occur in up to 50% of cases on stopping treatment (62). The side effects of corticosteroid therapy need to be considered. Most studies have assessed the effects of steroids on the pulmonary complications but due to spontaneous recovery and variations on the duration and doses of treatment results of many studies are difficult to interpret, particularly when looking at the effect of 5 years. However, the recent British Thoracic Study which observed stage 2 and 3 pulmonary disease for 6 months before, randomising into treatment with steroids for 24 months or withholding treatment showed radiological and functional benefits after 5 years (63) in the steroid group. Anti-malarials are helpful in selected patients with cutaneous, osseous or optic sarcoid (64, 65). A variety of other agents eg Methotrexate, Azothiaprine, Cyclophosphamide, Chlorambucal and Cyclosporrins have been used with varying reports or success but good control trials are lacking (66). This review of necessity has to be limited mixing scientific advance with clinical management looking at areas of interest. It highlights the many unanswered questions about this disease which remains fascinating and at times frustrating.