Sarcoidosis

Sarcoidosis

Sarcoidosis is a multisystemic disorder of unknown cause that is characterized by the formation of immune granulomas in involved organs [1–4].

Sarcoidosis affects primarily young and middle-aged adults. A prevailing hypothesis is that various unidentified antigens, either infectious or environnemental, could trigger an exaggerated immune reaction in genetically susceptible hosts [2]. The clinical expression of sarcoidosis is protean, in particular as regards the number and sites of involved organs. The lung and the lymphatic system are predominantly affected but virtually virtually every organ may be affected. Skin, eyes, peripheral lymph nodes and liver are each involved in 10–25% of cases. The evolution and severity of the disease are highly variable. Whilst spontaneous resolution occurs in the majority of cases within 12–36 months, some patients experience a prolonged and serious course [3]. Pulmonary fibrosis is the most frequent severe manifestation, accounting for the major cause of morbidity and mortality in western countries [3]. Other severe manifestations of the disease consist of cardiac, neurological, ocular, kidney or laryngeal localizations. Sarcoidosis can also induce abnormal metabolism of vitamin D3 within granulomatous lesions and hypercalcemia [5]. Mortality attributable to sarcoidosis is estimated at between 0.5 and 5% [6] and results from lung, heart and central nervous system localizations [3].

Although not always required, the mainstay of sarcoidosis treatment is systemic corticosteroids [7, 8]. Corticosteroids impeed the formation of granulomas and, as a result, are largely efficient against most active clinical manifestations. However, treatment is merely suspensive with frequent relapses when withdrawal is too rapid. Furthermore, the adverse side effects of corticosteroids are substantial. Other immunosuppressive agents and aminoquinolins can be employed as sparing drugs or as alternative options to corticosteroid therapy in patients with unsatisfactory response or poor tolerance with corticosteroids, or when high doses of corticosteroids are needed for a long time [8]. Recent advances on the knowledge of sarcoidosis pathogeny suggest that the overproduction of tumor necrosis factor α (TNF-α) at the sites of disease plays a pivotal role [2]. Interstingly, most agents that are effective in sarcoidosis also appear to have antiTNF-α properties, either specifically or as part of broad effects [4].

Sarcoidosis is an ubiquitary disease with an incidence varying according to age, sex, race and geographic origin [1, 3, 4, 9]. Sarcoidosis incidence is globally estimated at around 16.5/100,000 in men and 19/100,000 in women [10]. The lifetime incidence is higher in women (1.3%) than in men (1%), and in Blacks (2.4%) than in Caucasians (0.8%) [10, 11]. Although possible at all ages, a predilection is observed between 25 and 40 years in both genders at least in Scandinavian countries and Japan [3, 10], and a second peak of incidence has been reported in women over 50 years of age in some but not all published series [10]. The incidence of sarcoidosis is remarkably low before 15 years (1/100,000) and exceptional before 4 years (0.06/100,000) [12]. The clinical expression and severity of sarcoidosis depend upon epidemiological factors. Erythema nodosum is seen in 3–44% of cases but it is far more frequent in women than in men, in Caucasians than in Blacks or in Japanese and in northern than in southern european countries [1, 3, 12]. In Blacks, the disease is more likely to be disseminated, showing a higher frequency of ophtalmological, cutaneous, hepatic and lymphatic localizations [9] and it is undeniably more severe [3]. In Japanese patients, cardiac and ophthalmological involvement is common [3]. Sarcoidosis is generally sporadic but a familial aggregation is found in 1.7–17% of cases [12, 13]. The risk of sarcoidosis is increased in the family of an index case with siblings having the highest relative risk (odd ratio = 5.8) [13]. Interestingly, there are strands of evidence provided by familial sarcoidosis supporting the role of genetic factors: the similarity of phenotypical presentation among families, the similarity of the mother/children and father/children ratios, and the higher incidence and phenotypical resemblance between homozygotic twins than between heterozygotic twins.

Time and space-related clusters, tracing case contacts and cases of possible transmission of sarcoidosis via transplantation all suggest the role of transmissible agents either of infectious or of environnemental origin, although not identified yet [14].

Sarcoidosis is considered as the consequence of a chronic immunological response associating a genetic susceptibility and specific infectious or environmental factors [15–17]. Sarcoid granuloma, the typical elementary microscopical lesion, is an immune granuloma resulting from a specific cell-mediated immune response to a likely poorly degradable antigenic agent. Numerous cytokines and other mediators are produced by both activated macrophages and T lymphocytes during granulomatous responses. A number of data suggest that interferon gamma (IFN-γ) and cytokines such as TNF-α, IL-12 and IL-18 play a critical role in the formation of granulomatous lesions [15]. Pathological similarities between sarcoidosis and tuberculosis have led for a long time to the suggestion that mycobacteria are the cause of sarcoidosis [16]. However, the studies attempting to isolate mycobacteria in sarcoid tissues, even those using the most sensitive polymerase chain reaction (PCR) techniques, failed to detect mycobacterial DNA. Propiniobacterium acnes has also been incriminated as a causative agent but its role has not yet been ascertained. Finally, it has been shown that the incidence of sarcoidosis is influenced by genetic susceptibilities and particularly by polymorphisms involving immunity [17]. It seems very probable that genetic factors have also an important effect on disease presentation, progression and overall prognosis [3, 17].

No cause of sarcoidosis has yet been comfirmed, despite numerous searches using most emerging diagnostic tools. Several reasons could explain the difficulty to determine an etiology in such a context [16]. First, sarcoidosis may well not be a unique disease with a unique cause. Second, the causal agent may be a yet unidentified microorganism. Last, the mechanism underlying sarcoidosis may result not only from a single organism or antigen but also be related to the presence of adjuvant factors.

The presentation of sarcoidosis depends on epidemiological factors such as age, sex and race, the duration of the disease and the sites of involvement. Asymptomatic presentations, erythema nodosum and hypercalcemia are more frequent in Europeans, while symptomatic and multivisceral presentations are more frequent in Afro-Americans [1–4, 9]. Overall, sarcoidosis is mostly revealed in the following circumstances: (i) respiratory symptoms, firstly persistant dry cough in around 30% cases, (ii) extrathoracic localizations, mainly peripheral lymph nodes, eyes or skin, (iii) constitutional symptoms such as fatigue (27%), weight loss (28%), fever (10–17%) or night sweats and (iv) erythema nodosum (3–44%) [1, 3, 4, 18]. Erythema nodosum is usually associated with bilateral intrathoracic lymphadenopathies defining "Löfgren's syndrome" which is a benign form of the disease. Constitutional symptoms, particularly asthenia, are often present and can be a disabling problem [18]. Finally, an incidental discovery of sarcoidosis in asymptomatic patients with chest X-ray aberrations is not uncommon (8–60%) [19].

The diagnosis of sarcoidosis relies on clinico-radiographical presentation and evidence of non caseating granulomas on biopsy specimens after appropriate exclusion of other granulomatous disorders [3, 24]. Diagnosis may benefit from the amalgamation of other supporting arguments such as typical findings on HRCT, CD4/CD8 T lymphocyte ratio higher than 3.5 in BAL, SACE level twice higher than the upper normal limit or typical abnormal calcium metabolism.

Most recommended sites to obtain a histological confirmation are mucosal or transbronchial biopsy through fiberoptic bronchoscopy [3, 24], skin lesions, peripheral lymphadenopathy, conjonctival nodules or lip biopsy of accessory salivary glands. Sampling hilar or mediastinal lymph nodes through transbronchial needle aspiration or mediastinoscopy may be required [3, 24, 25]. Videothoracoscopic lung biopsy may rarely be necessary, while other sites can be guided by clinical findings. The diagnostic yield of all these procedures is more than 90% [3]. Some very typical cases like Löfgren's syndrome may obviate an immediate invasive biopsy procedure but histologic confirmation is mandatory in difficult cases or before treatment initiation.

Gallium-67-citrate (⁶⁷Ga) scintigraphy has long been used as a diagnostic tool in sarcoidosis [38] but is only rarely done now. Uptakes of ⁶⁷Ga is seen in intrathoracic and various extrathoracic localizations of the disease. The current indications of ⁶⁷Ga scintigraphy are as follows: (i) to substantiate the diagnosis in difficult cases, particularly in those with normal chest-X ray and a suspicion of sarcoidosis, when the "lambda plus panda" patterns is found, which is almost pathognomonic of the disease, (ii) to identify other clinically silent extra-pulmonary uptakes and provide potential sites for biopsies, (iii) and to assess activity in difficult cases such as stage IV disease in which whether or not to initiate potentially toxic therapy is a dilemma. Recently, an increasing literature on 18F-fluoro-2-deoxyglucose positron emission tomography (¹⁸FDG PET) in sarcoidosis has been published, but its role remains to be delineated [38]. Moreover, one should bear in mind the high level of radiation dose delivered by these isotopic investigations.

Other granulomatous diseases need to be ruled out before the diagnosis of sarcoidosis is ascertained [3, 24]. In almost all cases, clinical history, epidemiology with an appropriate investigation of exposure to infections such as tuberculosis or to beryllium inhalation, together with a proper evaluation of all tests are sufficient to discriminate between sarcoidosis and other granulomatous disorders. Tuberculosis, some fungal infections, chronic beryllium disease, granulomatous disorder induced by interferon α and β or intravesical BCG therapy or associated with common variable immunodeficiency are those conditions which can best mimic sarcoidosis. In infants under four years old, the Blau syndrome has to be considered before sarcoidosis, specially in the absence of thoracic involvement. Loco-regional granulomatous reactions satellite of breast or lung carcinoma and of lymphomas are rarely difficult to differenciate from sarcoidosis as well as other granulomatous disorders of unknown cause like Crohn's disease or Wegener granulomatosis.

Sarcoidosis is generally a time-limited disease that lasts for 12–36 months in half cases, for less than 5 years in most remaining cases and occasionnally for multiple decades [3]. Serial assessments are warranted until disease recovery in order to appreciate individual evolution. A minimum delay of three years is necessary after discontinuation of therapy before healing can be established [3].

The most valid prognostic factors remain the mode of onset, the disease extent and chest-X ray staging. An acute onset with Löfgren's syndrome or asymptomatic bilateral hilar lymphadenopathy usually confers a self-limiting course [1–4]. On the other hand, Black race, age of onset > 40 years, lupus pernio, chronic uveitis, sinonasal or osseous localizations, central nervous system or cardiac involvement, chronic hypercalcemia, nephrocalcinosis and stage III and IV are linked to more severe long-standing evolution [3, 20, 34, 35]. Procedures aimed to stage disease activity, particularly gallium scanning and BAL, have been proved to be disappointing in prognosis assessment.

The most severe and frequent complication of sarcoidosis is the occurrence of pulmonary fibrosis. This is usually associated with chronic dyspnea and frank impairment of pulmonary function. Pulmonary fibrosis is the most frequent cause of respiratory failure and results in the majority of deaths related to sarcoidosis in western countries. Pulmonary fibrosis is the consequence of chronic unremitting granulomatous process in the lung. The concern about the development of pulmonary fibrosis is the reason for treating cases of sarcoidosis with persistant pulmonary infiltration.

Airway obstruction can be due to several mechanisms in sarcoidosis: bronchial distortion secondary to pulmonary fibrosis, direct localization of granulomas in the airways, or more seldom extrinsic bronchial compression by hilar or mediastinal lymphadenopathy.

Pulmonary hypertension, i.e. increased pulmonary arterial pressure usually occurs in end-stage fibrotic cases. The severity of pulmonary hypertension is often out of proportion to pulmonary function impairement, which implies the role of alternative mechanisms including specific involvement of small lung vessels by sarcoidosis [39]. Pulmonary hypertension is a strong predictive indicator of mortality.

Mycetoma formation is a recognized complication of advanced pulmonary fibrosis and it is believed to be associated with an increased risk of death because of severe bleeding or underlying respiratory insufficiency.

Some other severe localizations may also punctuate the evolution of sarcoidosis. In cardiac sarcoidosis, episodes of sustained ventricular tachycardia coupled with left ventricular dilatation are associated with an increased risk of death [40]. Central nervous system sarcoidosis may represent the third cause of death after lung and cardiac localizions. Various other conditions, even though non lethal, can be associated with important discomfort and disability: disgracious skin manifestations, particularly lupus pernio, sinonasal and laryngeal localizations, renal manifestations and severe ocular localizations. Overall, 10–20% of sarcoidosis patients suffer from permanent sequelae [3]. Treatments which are often given for long periods of time are frequently the source of various troublesome adverse effects. This is particularly the case with corticosteroids that may be responsible for overweight, systemic arterial hypertension, diabetes mellitus, myopathy, buffalo neck etc.

The appropriate therapy for sarcoidosis has not yet been well defined for all patients [3, 7, 9]. Between 30 and 70% of patients never require therapy. In the other cases, a treatment, often corticosteroids, is necessary, either at the onset of the disease or during follow-up because of various consequences.

Cardiac, neurological, renal, ocular sarcoidosis not responding to topical therapy and malignant hypercalcemia always necessitate systemic therapy. Incapacitating general symptoms may lead to short-course corticosteroid therapy [1–4, 7, 8]. For pulmonary disease, systemic therapy is recommended in patients with stage II or III who are symptomatic or who disclose significant deterioration in serial pulmonary function tests and/or chest X-ray. Treatment is clearly not indicated in asymptomatic stage I. In Löfgren syndrome, erythema nodosum justifies non-steroidal anti-inflammatory drugs or colchicine for some weeks (but rarely corticosteroids) taking into account the usually good prognosis in this setting. Stage IV with advanced pulmonary fibrosis is usually poorly or not at all affected by systemic therapy. However, a trial of therapy to identify residual inflammation is warranted particularly in patients with persistent signs of activity. For pulmonary sarcoidosis, protocols suggest the initial dose of 20 to 40 mg daily of prednisone or its equivalent on alternate days. Higher dosage may be necessary to control cardiac, neurologic, renal, ophtalmologic and laryngeal involvement. After 4 weeks to 3 months therapy, posology is tapered. Therapy must be maintained for at least 12 months [3]. Some patients experience repeated relapses and may require long-term low-dose therapy during years.

Antimalarial drugs are a treatment of choice for mild isolated cutaneous lesions [3, 8]. Aminoquinolins are also helpful for hypercalcemia. Methotrexate has been the most extensively used among cytotoxics. Methotrexate is effective in pulmonary and most extra-pulmonary manisfestations, particularly skin, ophthalmic, nervous system and musculoskeletal localizations [8]. Methotrexate-induced hepatotoxicity occurs in about 10% of patients with sarcoidosis treated for more than two years. Azathioprine has clearly proved benefit as a corticosteroid sparing agent. Cyclophosphamide has been occasionally offered in refractory disease with interesting results in cortico-resistant cardiac and neurologic sarcoidosis. Thalidomide has demonstrated efficacy for lupus pernio unresponsive to prior therapy. However, its effect on pulmonary disease is unclear. Moreover, the side-effects of thalidomide can be extremely serious. TNF-α inhibitors have led to a dramatic improvement in small series or several case reports with refractory lupus pernio, uveitis or central nervous system localization. Recently, a double-blind study demonstrated a short-timed efficiency of infliximab in severe pulmonary localizations [41]. Yet, etanercept seems less promising as shown in a prospective open-label phase-2 trial. Controlled studies are needed to clearly identify the patients who may profit from these novel therapies.

Currently available agents for the prevention of glucocorticoid-induced osteoporosis may not be safe in sarcoidosis. Vitamin D should be avoided. Calcium supplementation may be given to patients without hypercalciuria under periodic survey of calcium metabolism. Bisphosphonates are also efficient in this setting.

Symptomatic treatments and recommendations may be given in sarcoidosis: low calcium diet and avoidance of sunlight exposure, supplemental oxygen, cardiac drugs, implantable pacemakers or cardiovertible-defibrillator, hormonal substitution, anti-epileptic agents.

Lung, liver and heart transplantation have been successfully performed in patients with end-stage refractory sarcoidosis [42]. Medical therapy must have been exhausted before candidates are selected for transplantation.