SARCOIDOSIS
Introduction
Sarcoidosis is a multisystem inflammatory disease of uncertain etiology associated with the accumulation of noncaseating granulomas in clinically involved tissues and, occasionally, in asymptomatic tissues. This disease has been reported worldwide in all sexes, ages, and ethnic groups, and the disease manifestations have been widely depicted in the literature since it was initially described in 1877.
Epidemiology
The incidence of sarcoidosis varies considerably worldwide, with the highest annual incidence reported in patients of northern European and African-American ancestry. It typically develops before the age of 50 years, and incidence peaks between the ages of 20 to 39. Females are affected more commonly than males worldwide.
Possible Etiologies
The precise etiology and pathogenesis of sarcoidosis is still unknown, although our knowledge of immunopathogenic mechanisms has advanced in the last decade. Current evidence would suggest that there is not a single etiology for this condition and that there are multiple causes of sarcoidosis accounting for the variety of clinical features that characterize the disease. A variety of agents have been implicated as the inciting antigen in sarcoidosis. Environmental and occupational exposures such as inorganic particles, mold, insecticides, pollens, metalworking, and firefighting have been reported in association with sarcoidosis. Both mycobacterial and propionibacterial DNA and RNA have been detected by polymerase chain reaction (PCR) techniques in lymph nodes affected by sarcoidosis, although no causal relationship has been established. The variety in reported environmental triggers suggests that sarcoidosis may be the result of exaggerated immune responses to more than one antigen.
Genetic Features
Genetic contributions to the development of sarcoidosis have been suspected on the basis of several reports of multiple family members being affected with the disease. Both human leukocyte antigen (HLA) class I and II antigens have been associated with risk of developing sarcoidosis in various studies, including HLA-A1, B8, and DR3 in whites. Some haplotypes appear to predispose to a specific clinical presentation, disease chronicity, or disease severity. For example, HLA-DR3 and DQ2 are associated with an acute Lofgren’s presentation and a good prognosis, but HLA-B5 appears to be associated with chronic disease. Other genes have been implicated in sarcoidosis susceptibility via genome wide linkage and association studies, such as butyrophilin-like 2 gene and annexin A11. Based on the available genetic data and the variability in clinical manifestations, it is doubtful that a single gene defect alone is the cause of sarcoidosis.
Pathogenesis
Sarcoidosis is characterized histologically by the formation of noncaseating epithelioid granulomas. Sarcoid granulomas are dense collections of macrophages and epithelioid cells encircled by lymphocytes, and later by fibroblasts and collagen. Granulomas generally serve to protect the surrounding tissue by confining the inciting pathogen or trigger, thereby containing the inflammatory response. Granuloma formation involves a series of steps, of which the hallmark is the activation of antigen-specific T helper 1 (Th1) lymphocytes via interaction of naïve CD4+ T cells with antigen-presenting cells bearing HLA class II molecules. These Th1 cells secrete the cytokines interleukin-2 (IL-2) and interferon-γ (IFN-γ). Further proliferation and differentiation of T lymphocytes is stimulated by IL-2, in addition to IL-15 and tumor necrosis factor-α (TNF-α) released from macrophages. IFN-γ amplifies the local cellular immune response and is essential to granuloma formation. TNF-α appears to play an important role in perpetuation of the inflammatory response and maintenance of granulomas. Most sarcoidal granulomas resolve spontaneously, but some persist or lead to fibrosis. It is still unclear what determines the eventual outcome of the granulomas in sarcoidosis, but a shift to cytokines produced by Th2 lymphocytes (IL-4, IL-10, and IL-13) may be key to the development of fibrosis in some patients.
Clinical Manifestations and Diagnosis
Sarcoidosis involves the lung most frequently, but up to 30% of patients develop extrapulmonary manifestations. Constitutional symptoms such as fatigue, malaise, fever, and anorexia may also be present, particularly in the elderly. Abnormalities due to sarcoidosis can be seen in any organ, but most clinical disease involves hilar lymphadenopathy, pulmonary disease, skin or eye manifestations, or a combination of these findings.
Pulmonary
Respiratory involvement occurs in 95% of patients, and ranges in presentation from asymptomatic hilar lymphadenopathy to interstitial lung disease with alveolitis. Endobronchial involvement exists in 40% to 70% of patients and is more common in the later stages. These lesions can progress to cause clinically significant airway stenosis infrequently. The sinuses, pharynx, and larynx can also be affected by sarcoidal granulomas. Dry cough, dyspnea, and chest pain are common presenting symptoms, and hemoptysis is generally rare, but when present may indicate aspergillus infection of a cavitary lesion. The stage of pulmonary involvement is based on the chest radiograph, which provides an anatomic guide to lung involvement, but does not indicate disease chronicity. Stage 0 is normal, and stage 1 consists only of bilateral hilar adenopathy. Stage 2 is defined by adenopathy with concurrent pulmonary infiltrates, stage 3 by pulmonary infiltrates only, and stage 4 by reticular opacities or fibrosis with volume loss. Pulmonary function tests can indicate restriction or diffusion capacity abnormalities, but do not correlate with change radiographic staging. High-resolution computed tomography (HRCT) of the lungs can be helpful, particularly in the setting of respiratory symptoms and a normal chest radiograph. Bronchoalveolar lavage (BAL) characteristically shows an elevated CD4/CD8 T cell ratio, but chronic and extrapulmonary disease are associated with increased levels of CD8+ T cells and neutrophils. However, BAL alone cannot establish the diagnosis of sarcoidosis, and transbronchial biopsies of both the upper and lower lobes increase the diagnostic yield.
Dermatologic
Cutaneous manifestations of sarcoid are seen in up to 20% to 30% of patients, and are often present at the time of diagnosis. A wide range of skin lesions have been reported with sarcoidosis, and the most common of these is a maculopapular skin eruption involving the face, neck, and back. Sarcoid nodules tend to occur over the extensor surfaces of the extremities and on the torso. Some subcutaneous nodules remit spontaneously. Plaque-like sarcoidal skin lesions tend to be associated with chronic disease. Lupus pernio refers to an indurated, violaceous, plaque-like eruption that most frequently occurs on the nose, cheeks, chin, and forehead. This manifestation tends to affect black women more commonly and is associated with upper respiratory disease, pulmonary fibrosis, and bony involvement. Erythema nodosum is a panniculitis that most frequently affects women, commonly appearing in the lower extremities below the knees, and tends to be the only sarcoidal lesion associated with pain. It is a component of Lofgren’s syndrome (erythema nodosum, hilar adenopathy, and migratory polyarthritis), and is associated with an acute presentation that generally resolves spontaneously. Biopsies of sarcoidal skin lesions are helpful in establishing the diagnosis, except in the case of erythema nodosum, which is nonspecific and associated with other inflammatory conditions.
Ophthalmologic
Eye involvement occurs in 25% to 80% of patients, and most commonly presents as an acute anterior uveitis with blurred vision and photophobia. Other eye manifestations include posterior uveitis, retinal vasculitis, optic neuritis, keratoconjunctivitis, lacrimal gland enlargement, and conjunctival nodules. Posterior uveitis is frequently accompanied by central nervous system involvement. Because ocular involvement in sarcoidosis can be asymptomatic and lead to visual loss if untreated, a baseline slit-lamp and fundoscopic examination should be performed as a part of the initial evaluation.
Cardiac
The granulomatous inflammation of sarcoidosis can infiltrate multiple areas of the heart including the ventricular septum and conduction system, leading to cardiomyopathy, arrhythmias, complete heart block, and sudden death. Papillary muscle involvement and pericardial effusions have also been documented. It does not generally cause valvular disease. Symptomatic involvement occurs in 5% of patients with sarcoidosis, but some studies have demonstrated that it may be more prevalent at autopsy (20% to 67%). Cardiac magnetic resonance imaging (MRI) with gadolinium and positron emission tomography (PET) scanning can be useful in the diagnosis of cardiac sarcoidosis. However, the diagnostic yield of the endomyocardial biopsy in sarcoidosis is characteristically low, owing to the irregular distribution of granulomas in cardiac tissue.
Neurologic
Only 5% to 10% of all patients with sarcoidosis present with neurologic symptoms, but up to 25% have central nervous system (CNS) involvement at autopsy. It can occur alone or in combination with pulmonary and/or other extrapulmonary manifestations. Most CNS manifestations are due to granulomatous infiltration of the basal meningeal tissues or nearby structures, and include mass lesions, lymphocytic meningitis, hypothalamic hypopituitarism, central diabetes insipidus, hydrocephalus, seizures, psychosis, cognitive dysfunction and cranial nerve palsies. The most common neurologic presentation is a unilateral facial nerve palsy. MRI with gadolinium is the best imaging modality in the evaluation of sarcoidosis involving the brain, spinal cord, or meninges. Cerebral spinal fluid (CSF) may demonstrate multiple abnormalities, including elevated protein, low glucose, lymphocytic pleocytosis, oligoclonal bands, elevated opening pressure, and elevated angiotensin-converting enzyme (ACE) level. Brain biopsies are invasive and generally of low diagnostic yield, so other more accessible biopsy sites are preferred whenever possible.
Musculoskeletal
Involvement of the musculoskeletal system can occur in up to 10% of patients with sarcoidosis including the joints, muscle, and bone. Arthralgias are the most common musculoskeletal symptom (70%). Acute arthritis can present alone or as a part of Lofgren’s syndrome, which is characterized by hilar adenopathy, acute polyarthritis, and erythema nodosum. This type of arthritis usually involves the ankles or knees, is self-limiting, and tends to resolve within 2 years. Close to a third of these patients may progress to a more chronic type of arthritis. Several types of chronic joint involvement have been reported including dactylitis, non-deforming arthritis, Jaccoud-type arthropathy, joint swelling due to a sarcoidal bone lesion, and chronic joint effusions. Myositis due to sarcoid has been reported both as an acute presentation, and also as a more insidious disease. Electromyography (EMG) can reveal a myopathic pattern, and open surgical biopsies may reveal granulomatous inflammation. Plain radiographs of joints are frequently normal except for soft tissue swelling. Cystic phalangeal lesions can occur but do not seem to correlate with the arthritis or symptoms. Sclerotic bone lesions of the axial skeleton have also been reported, but are of unclear clinical consequence. Arthrocentesis of an affected joint typically yields minimal, mildly inflammatory synovial fluid with a predominance of lymphocytes. Arthroscopic synovial biopsies can reveal typical noncaseating granulomas, but closed needle biopsies are of little diagnostic value. Overall, the diagnosis of musculoskeletal involvement in sarcoidosis can be challenging, unless more commonly involved organ systems are concurrently affected. Therefore, it is important to fully evaluate the chest, skin, and eyes of a patient in whom musculoskeletal sarcoidosis is suspected.
Other
Painless peripheral lymphadenopathy is not uncommon in acute and chronic sarcoidosis. Parotid glands, thyroid, liver, and spleen can be infiltrated in patients with known sarcoidosis. Gastrointestinal granulomatous ulcerations and pancreatic involvement have been reported, but are rare manifestations. Increased intestinal absorption of calcium can occur due to overproduction of 1, 25-hydroxyvitamin D as it is converted by sarcoidal macrophages from the less active metabolite 25-hydroxyvitamin D. This can lead to hypercalciuria, hypercalcemia, nephrocalcinosis, and nephrolithiasis. Fortunately, renal failure due to granulomatous infiltration is rare.
A 44-year-old woman presents to the rheumatology clinic with a 2-week history of large, painful red “lumps” that developed over her legs below the knees. She also notes progressive pain, redness, and swelling involving her left ankle over the last week, which has caused her to walk with a limp. She denies any high fever, dyspnea, cough, or chest pain, but reports malaise, muscle aches, and generalized fatigue. Her examination is notable for normal vital signs, lung, and cardiac exam. There are four large erythematous subcutaneous nodules over the lower extremities below the knees that are tender to palpation. The left ankle examination reveals a moderate effusion associated with mild erythema and warmth. There is mild discomfort with range of motion. Laboratory studies include a normal complete blood count (CBC) with differential. A comprehensive metabolic panel demonstrated a normal rheumatoid factor, anti-CCP antibody serum uric acid and a slightly elevated calcium of 10.5 mg/dL. Erythrocyte sedimentation rate (ESR) of 38 mm/h, and a C-reactive protein (CRP) of 2.0 mg/dL were noted. An attempted arthrocentesis of the left ankle did not yield any synovial fluid. Radiograph of the left ankle was normal except for diffuse soft tissue swelling, and chest radiograph revealed bilateral hilar lymphadenopathy but was otherwise normal. The patient was diagnosed with acute sarcoidosis presenting as Lofgren’s syndrome based on her clinical presentation, and no further diagnostic work-up was pursued. Naproxen 500 mg twice daily was started due to the painful arthritis involving her left ankle, and her symptoms were significantly improved 1 week later. She reported resolution of her skin lesions and joint swelling after 4 weeks, and remained asymptomatic at her 1-year follow-up visit.
Discussion of Case Study 1
Patients who present with a classic Lofgren’s triad of erythema nodosum, arthritis, and bilateral hilar lymphadenopathy may not need a biopsy, so long as there is no alternative explanation for the symptoms and they resolve promptly without complication. Fever is a common occurrence in Lofgren’s syndrome but is not always present. Tissue biopsy should be pursued whenever possible if a reasonably accessible lesion is present, such as lymph nodes, dermatologic lesions, cutaneous nodules, and enlarged parotid or lacrimal glands. Biopsy of erythema nodosum in sarcoidosis is not recommended because it will show a nonspecific panniculitis rather than granulomas. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first line of treatment for arthralgias and mild arthritis, and glucocorticoids are generally reserved for organ dysfunction or progressive disease that does not respond to NSAIDs. It is important to recognize that this presentation of sarcoidosis is typically self-limiting and associated with a benign prognosis.
A 50-year-old man is referred to rheumatology clinic 10 months after being diagnosed with stage III pulmonary sarcoidosis and bilateral anterior uveitis. His primary complaints have been dyspnea and fatigue, and uveitis was found incidentally on his baseline ophthalmologic exam. He was initially started on prednisone 60 mg daily, but has been unable to wean below 20 mg without experiencing recurrent dyspnea. Transbronchial biopsies at the time of diagnosis were consistent with granulomatous inflammation, and bacterial and fungal cultures were negative. Pulmonary function tests showed mild restricton with a reduced diffusion capacity, and his oxygen saturations decreased to 86% with ambulation. He is currently on 30 mg of prednisone daily and his oxygen saturations are maintaining at 89% to 91% with ambulation. He has only mild dyspnea on exertion. His exam is notable for moon facies and central obesity, and his blood pressure is 146/88. His lung examination reveals few basilar rales, but is otherwise unremarkable. Methotrexate is initiated at 7.5 mg once weekly, and up titrated over 6 weeks to 15 mg weekly. He tolerates the methotrexate well and is able to wean down to 10 mg of prednisone daily over the following 6 months and repeat pulmonary studies are stable. His follow-up eye examinations are without evidence of recurrent uveitis.
Discussion of Case Study 2
This case illustrates the need for additional immunosuppressive therapy, particularly in the setting of a high corticosteroid requirement and evidence of medication toxicity. Although many patients with sarcoidosis undergo spontaneous remission, less than 30% of patients with stage III pulmonary disease undergo remission. Oral corticosteroids are the first-line treatment for symptomatic or progressive stage II and III lung disease. Randomized, controlled data assessing the use of additional immunosuppressive therapy in sarcoidosis is limited, and primarily based on small studies and case reports. In a patient who experiences significant glucocorticoid side effects, develops progressive disease despite adequate dosing glucocorticoids, or is unable to taper to less than 15 mg daily, alternative or additional immunosuppressive therapy should be considered. One randomized, controlled trial compared methotrexate to placebo in patients being treated with corticosteroids, and found that it was effective as a steroid-sparing agent. However, there were no differences between the groups in terms of pulmonary measures. Other alternative cytotoxic agents that can be considered in this setting include azathioprine and cyclophosphamide.
CASES
Treatment
The goal of therapy in sarcoidosis is to suppress the inflammatory response, reduce granuloma burden, and prevent irreversible damage from disease progression. Corticosteroids are the most commonly used agents for control of symptoms and disabling systemic involvement, due to their potent effects on the inflammatory response. However, it is important to note that there have been no well-controlled trials documenting improvement in long-term outcomes with this therapy. Because the majority of patients with sarcoidosis are not disabled by the disease, the decision to start corticosteroid therapy should involve careful consideration of prognostic signs, risks, and benefits. The optimal dose of corticosteroid is the lowest dose necessary to adequately control symptoms and disease progression in patients in whom this therapy is indicated.
Therapy with corticosteroids is indicated in pulmonary sarcoidosis when there are progressive symptoms, worsening radiographic changes, or deterioration in lung function. In extrapulmonary sarcoidosis, the threshold for treatment of neurologic, cardiac, ocular, and renal involvement is lower because the complications are more serious in nature. Other indications for corticosteroids include severe constitutional symptoms, hepatic insufficiency, neuropathy, upper airway involvement, and disfiguring skin disease. Use of additional immunosuppressive therapy in the treatment of sarcoidosis is generally reserved for those who do not respond adequately to corticosteroids, develop intolerable side effects, or are unable to wean to lower doses of corticosteroids without disease recurrence.
Pulmonary
The following symptoms are indications for treatment of pulmonary sarcoidosis:
- 1.
Progressive dyspnea, cough, chest pain, or hemoptysis
- 2.
A fall in total lung capacity of at least 10 percent, forced vital capacity of 15%, or in diffusing capacity of 20%
- 3.
Worsening interstitial opacities, cavities, fibrosis, honeycombing, or signs of new pulmonary hypertension on imaging
Corticosteroids are generally started at 0.5 to 1 mg/kg ideal body weight, and the patient is reevaluated at 4 to 6 weeks. The dose is then tapered by 5 to 10 mg every 4 to 8 weeks down to a goal of half of the starting dose. The dose should be tapered until achieving an acceptable maintenance dose, preferably to doses no greater than 10 to 15 mg daily. A total course of treatment of 1 year is recommended, but a slightly longer course may be required if exacerbations of disease are frequent and require periods of higher corticosteroid dosing.
Adverse glucocorticoid effects, progression of disease despite adequate dosing, and inability to wean to lower doses of medication, are among the primary reasons for considering additional immunosuppressive therapy. As noted in the discussion of Case 2, methotrexate is most commonly used as a steroid-sparing agent in this setting based on a randomized, controlled trial demonstrating efficacy when used for this purpose. However, successful use of other therapies such as azathioprine, leflunomide, cyclophosphamide, cyclosporine, and infliximab has been reported in small trials and case reports.
Ophthalmologic
Anterior uveitis can generally be treated with topical cycloplegics (e.g., scopolamine or atropine), and topical steroids (e.g., prednisolone acetate). Oral steroids may be used in severe or recalcitrant cases. Granulomatous infiltration of the lacrimal glands and surrounding structures or panuveitis require oral corticosteroids or periocular subtenon steroid injections every 3 to 4 weeks. Optic neuritis is always treated with systemic corticosteroid therapy. Successful treatment of chronic uveitis has been reported with other immunosuppressive therapies such as methotrexate, azathioprine, and infliximab.
Dermatologic
Limited, nondisfiguring skin lesions of sarcoidosis, such as small plaques and papules, may be treated with topical or intralesional corticosteroids. Erythema nodosum is usually self-limited, and, therefore, requires no specific treatment. Lupus pernio and larger plaques can lead to permanent scarring and therefore need more aggressive therapies such as systemic corticosteroids, methotrexate, and antimalarials. There are anecdotal reports of successful treatment with cyclosporine, chlorambucil, retinoids, photochemotherapy (PUVA), minocycline, and thalidomide.
Cardiac
Because cardiac sarcoidosis can be associated with high morbidity and mortality rates, treatment is usually aggressive. Ventricular arrhythmias and cardiomyopathy should be treated early and with high doses of prednisone of 60 mg per day or greater. Tapering of prednisone to lower doses of 10 to 15 mg over 6 months is recommended. Other immunosuppressive agents such as cyclophosphamide, methotrexate, azathioprine, and chlorambucil have been used with limited success in refractory cases. In patients with recurrent ventricular arrhythmias, implantable defibrillators have been used.
Neurologic
Randomized, controlled data addressing the treatment of neurosarcoidosis are lacking, but recommendations are made on consensus that these patients should be treated with corticosteroids. Severity of disease coupled with initial response to therapy dictate dose and duration of treatment. Prednisone is typically started at doses of 60 to 80 mg per day and then tapered according to the severity of the underlying neurologic disease. As in cardiac sarcoidosis, other immunosuppressive agents such as methotrexate, antimalarials, azathioprine, cyclophosphamide, cyclosporine, and infliximab have been used with some success in treatment of refractory cases of neurosarcoidosis. Cranial or spinal irradiation has also been used in refractory cases, usually in addition to immunosuppressive therapy.
Musculoskeletal
Lofgren’s arthritis or periarthritis does not usually require treatment beyond NSAIDs, because it tends to be self-limiting. If NSAIDs at maximum doses do not provide adequate relief, colchicine, hydroxychloroquine, or moderate doses of glucocorticoids can be used. In refractory cases or in chronic arthritis requiring higher doses of steroids, weekly low-dose methotrexate can be effective. Sarcoidosis involving the bone generally responds inadequately to treatment with corticosteroids. Acute sarcoidal myositis responds much better to corticosteroid therapy than chronic muscle disease overall.
Renal and Hypercalcemia
Treatment of hypercalcemia and hypercalciuria is indicated if there is significant concern for nephrolithiasis, nephrocalcinosis, or worsening renal insufficiency. These conditions respond very well to moderate doses of oral prednisone, but there is evidence suggesting that agents such as chloroquine and ketoconazole can achieve a more prolonged response on calcium levels.
Refractory Disease and Future Therapy
Because TNF-α appears to play a key role in the formation of granulomas, this cytokine would appear to be a reasonable target for inhibition in the treatment of sarcoidosis and other granulomatous diseases. Use of thalidomide and pentoxifylline in the treatment of sarcoidosis has been proposed on this basis, but further studies are necessary. Infliximab, a chimeric anti-TNF-α monoclonal antibody, has demonstrated some benefit in the treatment of refractory pulmonary and extrapulmonary sarcoidosis. However, TNF-α blockade using the dimeric fusion protein etanercept has not yielded the same results, although efficacy is similar between the two drugs in the treatment of rheumatoid arthritis. This suggests that simple neutralization of TNF-α, despite its role in granuloma formation and maintenance, is not sufficient in producing a sustained remission. A better understanding of the immunopathogenesis of sarcoidosis is necessary in the development of targeted treatments addressing this complicated disease.
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