Sarcoidosis

Introduction
More than a century after its initial description, sarcoidosis remains a biological and clinical enigma. An etiologic source has yet to be identified, diagnostic tests are largely non-specific and therapy, limited for the most part to severe cases, produces inconsistent results and often fails to halt disease progression. In about 80% of cases, sarcoidosis is self-limiting, resulting in minimal symptomatology, discomfort, or debilitation. The vast majority of patients recover without treatment, and many do not have relapses. Diagnosis may even occur as a result of a chance finding, such as enlarged lymph nodes on routine physical examination or granulomatous pulmonary lesions detected by a screening chest x-ray. Misdiagnosis occurs with regularity. The remaining 20% of sarcoidosis patients face potentially significant debilitation and disfigurement. In severe cases, especially those with multi-organ involvement, sarcoidosis can become life-threatening. In some patients the condition advances in a slow, insidious fashion. Tools are lacking to separate patients who are likely to have progressive disease from those who will have a benign clinical course. More than a century after its initial description, sarcoidosis remains a biological and clinical enigma. Within the past two or three years, several findings have provided insight into the pathogenesis and etiology of sarcoidosis, including a possible association with mycobacteria, parallels with conditions that mimic sarcoidosis, and elucidation of underlying immunologic mechanisms. Some of the findings have emerged as a result of ongoing work at the National Jewish Medical and Research Center, where researchers and clinicians evaluate a substantial population of sarcoidosis patients. The population includes many patients with severe disease, as well as those whose condition has been misdiagnosed or undiagnosed.

Etiology and Pathogenesis
The classic definition of sarcoidosis is a granulomatous disorder of unknown origin, typically characterized by enhanced cellular immune response at involved sites. That vague description reflects the continuing uncertainty that surrounds the origin of sarcoidosis. Nevertheless, recent findings have helped shed light on questions related to what sarcoidosis is and is not. Almost since its initial clinical characterization, sarcoidosis has been viewed widely as a pathologic relative of tuberculosis, a postulate fueled in no small part by sarcoidosis' predilection for pulmonary involvement. The postulate has never been proved. However, within the past two years, published studies have demonstrated that certain DNA fingerprints of mycobacteria are present in some -- certainly not all -- sarcoidosis patients. Further research is needed to clarify this association and its significance in pathogenesis since treatment of sarcoidosis with anti-tuberculosis medication has proved ineffective. A second recent development in sarcoidosis etiology involves the recognition that at least some cases labeled as sarcoidosis are in fact inflammatory reactions to one or more metals. One well-identified mimicker of sarcoidosis is chronic beryllium disease, also known as chronic berylliosis. Beryllium is a metal used in the manufacture of ceramics, nuclear weapons, computers, dental alloys, automobiles, and electronics. As an example of the diagnostic misidentification, investigators at National Jewish recently described a patient whose symptoms and clinical findings had for years been incorrectly labeled as sarcoidosis. In fact, the patient's husband was regularly exposed to beryllium at work. The patient apparently developed beryllium disease after intermittent exposure to metal in her husband's clothing. The case emphasizes the need to rule out all other possible causes of granulomatous lung disease, including occupational and environmental exposures, before arriving at a sarcoidosis diagnosis. As a second example, a group of lifeguards at an indoor swimming pool developed shortness of breath and cough initially diagnosed as "sarcoidosis". Subsequent evaluation determined the lifeguards had hypersensitivity pneumonitis due to exposures in the humid, moldy pool area. Hypersensitivity pneumonitis is a sarcoid-like lung disease caused by inhalation of organic dusts, such as non-infectious parts of mold or bacterial cell walls. The two examples underscore the point that sarcoidosis remains a diagnosis of exclusion and that the exclusion process should include a careful look at the patient's occupational and environmental history. The basic mechanisms of sarcoidosis pathogenesis are under intense investigation. Within the past two years, the most compelling evidence to date has emerged that sarcoidosis arises from a reaction to an antigen. For many years, physicians have speculated that the pathologic lesion in sarcoidosis -- the non-caseating granuloma -- results from a delayed-typed hypersensitivity response to an antigen. Recently, researchers at National Jewish have reported that T-cells of sarcoidosis patients develop in a clonal fashion. T-cell populations with a specific cellular identity have been isolated from the lungs of sarcoidosis patients. The findings demonstrate that these T-cells are reacting to a particular antigen and that the disease process is antigen driven. . . . certain DNA fingerprints of mycobacteria are present in some -- certainly not all -- sarcoidosis patients. Emergence of sarcoidosis appears to depend not only upon the presence of antigen and the clonal expansion of a set of T-lymphocytes but also upon the release of key pro-inflammatory proteins called cytokines. Recent research at National Jewish has shown that these macrophage-derived cytokines, including tumor necrosis factor-alpha and interleukin-6, are found in abundance in the lungs of patients with sarcoidosis. These cytokines directly and indirectly lead to the recruitment and activation of other immunologically active cells, resulting in granuloma formation and perpetuation. The role of autoimmunity in sarcoidosis remains unresolved and controversial. The finding that granulomatous lung disease can evolve from beryllium exposure has bearing on the arguments. At the most basic level, autoimmunity is defined as the failure of the immune system to distinguish between "self" and "non-self". Particles of beryllium, and perhaps other metals, appear to be too small to serve as antigens. However, some evidence suggests the metals may bind to native proteins, and the immune system sees the resulting self-non-self complex as foreign.

Manifestations
Sarcoidosis is most commonly localized to the thorax but can affect any organ system in the body. Between 80% and 90% of patients will have pulmonary involvement. Cutaneous and ocular lesions occur in about 25% of patients. Cardiac lesions are estimated to occur in 5% to 25% of patients. Hepatic involvement is common on autopsy, but the lesions usually do not produce symptoms. Lymphadenopathy occurs in the majority of patients, predominantly in the hilar and mediastinal nodes but also generalized. As previously indicated, many patients are asymptomatic, the diagnosis made during a routine examination or evaluation for an unrelated condition. Some patients, present with constitutional symptoms, including fever, malaise, fatigue, and weight loss. Pulmonary involvement can cause dyspnea, with or without exertion. A persistent, dry cough and atypical chest pain are often reported. Skin lesions may appear as a rash or as nodules, often on the face, arms, or lower leg. The nodules generally are painless but can be disfiguring. In patients with erythema nodosum due to sarcoidosis, skin lesions can be painful. Fortunately, this subset of patients has a high rate of spontaneous remission. Ocular involvement may present as a disturbance in visual acuity. Lesions may arise on the cornea, iris, retina, or conjunctiva. Chronic ocular involvement can lead to glaucoma, cataract formation, and retinal neovascularization. Symptomatic cardiac involvement is fairly uncommon, but presents most often as a bundle block or complete heart block. Asymptomatic cardiac involvement is thought to occur in a significant percentage of patients with associated hypertension, so that distinguishing the role of sarcoidosis in symptomatic disease from other etiologies of rhythm disturbance can be difficult. Cor pulmonale can arise as a complication of pulmonary involvement and lead to secondary cardiac manifestations, as right atrial dilatation and right ventricular hypertrophy develop.

Diagnosis
Given the high incidence of pulmonary involvement, perhaps the most useful diagnostic tool is the chest x-ray. By and large, laboratory tests are non-specific. The key in choosing laboratory tests is to select tests that help to exclude the known causes of granulomatous disease. Hypercalcemia and hypercalciuria are common laboratory findings in sarcoidosis, but either finding can occur with a large number of other conditions. A common question about testing concerns the value of the serum angiotensin converting enzyme (ACE) test. Though elevated in up to 80% of sarcoidosis patients, ACE levels also can be elevated in other pathologic processes. As such, the test is not specific for sarcoidosis. Macrophages inside granulomas are a major source of ACE. Serum ACE activity estimates the total granuloma burden in the body and tends to decrease as the disease remits, so it may be helpful as a marker of disease activity and of therapeutic response but not as a diagnostic test. Some researchers have advocated the use of gallium scans for evidence of a sarcoidal inflammatory response, but enthusiasm for the test has waned significantly in recent years. A gallium scan is costly, non-specific, and an inconvenient way of monitoring disease activity. The test may sometimes be helpful in spotting extrathoracic sites of inflammation, including the parotid gland and ocular involvement. High resolution computed tomography (CT) of the thorax provides superior visualization of the lung parenchyma. The technique can be performed with most CT scanners and is more sensitive than conventional CT or chest x-ray. While highly suggestive of sarcoidosis, CT scan findings are not pathognomonic. CT can be helpful in defining the presence and distribution of lymph nodes, the pattern of parenchymal involvement (e.g., peribronchiolar) and the presence or absence of pleural involvement. ...sarcoidosis remains a diagnosis of exclusion. Sarcoidosis patients typically exhibit cutaneous anergy in response to skin testing. However, other clinical situations also can account for anergy, notably other causes of immunosuppression or the use of immunosuppressive therapies. The Kviem test has received considerable attention in the sarcoidosis literature as a potentially more specific diagnostic tool. The test involves subcutaneous injection of spleen homogenate obtained from a sarcoidosis patient. Following injection, one must biopsy the reaction to verify that a granulomatous skin reaction has occurred. The material is not readily available and not standardized. The mechanism of action for the Kviem reagent is not known. At this point, the test should not be considered a standard clinical tool. The diagnosis of sarcoidosis hinges largely on the demonstration of non-caseating granulomas at one or more sites of involvement. Out-patient fiberoptic bronchoscopy with transbronchial lung biopsies has a yield of greater than 90%, even in patients with predominantly extrathoracic disease. Alternatively, medastinoscopy for lymph node biopsies, skin biopsies, and parotid gland biopsies may be helpful when these organs are involved.

Ultimately, a definitive diagnosis can be reached only by:

(1) demonstration of non-caseating granulomas in an involved organ
(2) identification of the typical clinical picture
(3) exclusion of all other diagnostic possibilities

Classification of Granulomatous Disorders
Infections	Immunologic Abberations
Fungi Histoplasma Coccidioides Blastomyces Sporotbrix Aspergillus Cryptococcus   Protozoa Toxoplasma Leishmania   Metazoa Toxocara Schistosoma Spirochaetes T. pallidum T. pertunue T. carateum Mycobacteria M. tuberculosis M. lepra M. Kanasasii M. marinum M.avian-intrarellulare Bacille Calmette-Guerin (BCG) vaccine Bacteria Brucella Yersinia Other Infections Cat Scratch Lymphogranuloma Neoplasia Carcinoma Sea urchin spine injury Pinealoma Dysgerminoma Other Disorders in Differential Diagnosis Seminoma Reticulum cell sarcoma Malignant nasal granuloma Chemicals Aluminum Beryllium Titanium Zirconium Silica	Sarcoidosis Crohn's disease Primary biliary cirrhosis Wegener's granulomatosis Giant-cell arteritis Peyronie's disease Hypogammaglobulinema Systemic lupus erythematosus Lymphomatoid granulomastosis Histiocytosis X Hepatic granulomatous disease Immune complex disease Rosenthal-Melkersson syndrome Churg-Strauss allergic Granulomatosis Leukocyte Oxidase Defect Chronic granulomatous Disease of childhood Extrinsic Allergic Alveolitis (Hypersensitivity Pneumonitis) Farmer's lung Bird fancier's Mushroom worker's Suberosis (cork dust) Bagassosis Maple bark stripper's Paprika splitter's Coffee bean Spatlese lung Other Disorders Whipple's disease Pyrexia of unknown origin Radiotherapy Cancer chemotherapy Panniculitis Chalazion Sebaceous cyst     Wegener's granulomatosis Lymphomatoid granulomatosis Churg-Strauss Syndrome Bronchocentric granulomatosis (with and without asthma) Multi-center lung cancer Lymphoma Lymphangitii carcinomatosis Local sarcoidal reaction Starch

Treatment
For the 80% of patients who are asymptomatic or who have only mild symptoms, no treatment is often the best treatment. In the majority of cases, the disease will regress spontaneously. No suitable explanation has been found for the regression phenomenon, although removal from the putative antigen exposure might possibly lead to remission. All patients should be followed closely and evaluated carefully for evidence of symptomatic or physiologic worsening, since even some asymptomatic patients may gradually progress. Some patients may require acute treatment until the condition improves or regresses. As an example, a patient who presents with acute dyspnea and low oxygen levels would require oxygen supplementation to relieve the acute symptoms, and most physicians would begin a course of oral corticosteroids to hasten the recovery, rather than waiting to see whether the disease regresses spontaneously. Moreover, treatment of ocular lesions is indicated in virtually all cases. In general, palliative therapy probably does not affect the course of the disease. Physicians should consider treatment only to address symptoms that affect patients' activities of daily living. For the remaining 20% of patients who have disabling disease, the major question is when to begin therapy, and only secondarily, which agent to use. Despite the absence of controlled clinical trials, oral corticosteroids represent the mainstay of sarcoidosis therapy. No consensus exists about when to initiate steroid therapy, an uncertainty that owes largely to a lack of understanding and agreement about what constitutes active and progressive disease states. Patients with multi-organ involvement tend to be at higher risk for progression and complications, but that does not always occur. Young African-American men have the highest sarcoidosis incidence and mortality; yet, not all of them require steroid therapy. Chronicity, extent of granuloma burden and specific organ involvement (especially the combination of lungs and heart) have all been offered as a potential indicators of the need to initiate steroid therapy. The decision to initiate steroid therapy is further complicated by the knowledge that the treatment does not guarantee protection from pulmonary fibrosis and permanent functional impairment. Nonetheless, most physicians consider a trial of steroid therapy warranted because at least temporary disease regression can be achieved in the majority of patients. If steroids are not initiated, patients should have careful follow-up. Evaluations should include a thorough review of symptoms and signs, as well as pulmonary function tests, radiography to monitor for progression, and perhaps tests to monitor for progression, and perhaps tests to monitor the status of other involved organs (e.g., slit-lamp exams). Measurement of gas exchange with exercise is probably the most sensitive way to monitor subtle changes in the extent of interstitial lung disease. If the disease demonstrates progression, a trial of steroids should be initiated. The dose usually is tapered slowly over about a year to help ensure that a dose-related disease flare will be recognized before proceeding to a lower dose. Some patients require low-dose steroids indefinitely if the disease flares repeatedly below a critical dosage. After corticosteroids, perhaps the next best known sarcoidosis therapies are other immunosuppressive agents, such as cyclosporine and methotrexate. Mounting clinical evidence shows that immunosuppressives offer a highly variable therapeutic benefit. At this point, the immunosuppressives should be viewed as second-line therapy after steroid failure or intolerance has been documented. A variety of other agents have been tried (and are still used by some physicians) when steroid therapy fails to control sarcoidosis. The list includes azathioprine, cyclophosphamide, colchicine, chlorambucil, and chloroquine. However, none has produced consistent results. About 10% of patients with pulmonary lesions will have endobronchial sarcoidosis. Recent evidence has suggested that patients with endobronchial involvement may respond with high-dose inhaled corticosteroids, while avoiding the increased absorption that occurs with systemic dosing. Clinical studies at National Jewish also have suggested a role for balloon bronchoplasty in patients with endobronchial involvement and bronchial stenosis. Such patients tend to have air flow obstruction on lung function tests, as opposed to the more typical sarcoidosis presentation of restrictive physiology. Critical stenoses identified by fiberoptic bronchoscopy are dilated mechanically to widen the more proximal bronchial passages. The procedure is performed on an out-patient basis and has been associated with few complications. Lung transplantation can be considered as the treatment of last resort for intractable sarcoidosis unresponsive to immunotherapy. A note of caution: several researchers have demonstrated development of granulomas in transplanted donor lungs in some cases. Clearly, more effective therapies are needed and may be found through the improved understanding of how cytokines regulate the granulomatous reaction.

Follow-up
A certain subset of patients will have a very gradual, insidious disease progression, resulting in irreversible fibrosis. Such patients can not be identified prospectively with currently available diagnostic means, but dismissing the condition as a benign process is a disservice to patients. For the 80% of patients ... no treatment is often the best treatment. As a result, even patients with apparently "mild" cases of sarcoidosis should be evaluated at regular intervals, such as an annual examination. At the minimum, a prudent approach would incorporate chest x-rays and assessment of lung function with such examinations. With respect to monitoring therapy, numerous tests have been evaluated as potential indicators of disease activity. To date, none has proven more reliable than the combination of symptom reporting, serial clinical examinations and changes in chest x-rays, pulmonary function, and gas exchange. Patients should have regular slit-lamp examinations for eye disease, and 24-hour urine tests for hypercalciuria. Any time a patient is placed on corticosteroids for prolonged periods, the physician should monitor for side effects, such as arterial hypertension, hyperglycemia, cataract formation, hypercalciuria, and bone demineralization.

Conclusion
Sarcoidosis remains a poorly understood granulomatous disease of uncertain origin. Recent clinical and laboratory investigations have provided some insights about the disease process, namely that sarcoidosis:

(1) probably is a cluster of diseases or have multiple causes
(2) may have an infectious origin in some instances
(3) can be mimicked in some cases by reactions to non-infectious antigens, such as metals and organic dusts
(4) is an over-exuberant reaction by the cellular immune system to an antigen. A diagnosis of sarcoidosis can be unsatisfying to the physician and potentially alarming to the patient.

Every effort should be made to exclude other diagnostic possibilities, even in apparently mild forms of sarcoidosis. Chest x-ray and pulmonary function tests are the most useful initial diagnostic tools; other laboratory evaluations are non-specific. Treatment remains problematic because of the condition's uncertain origin and the unreliable response to steroids. The majority of patients with sarcoidosis have a benign clinical course and require no treatment. Still, all patients should be followed at regular intervals and have periodic chest x-rays and pulmonary function tests to evaluate for evidence of progressive disease and for the need to initiate therapy.