Sarcoidosis

Sarcoidosis: An Enigmatic Disease

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Patient Case

Cindy is a 39-year-old nurse who works in a 200-bed hospital in a medium size city that is a worldwide tourist destination. She presented to her primary care provider with chief complaints of fatigue, cough, and shortness of breath following an upper respiratory infection that has persisted for more than three weeks. The patient did not receive antibiotic therapy at the onset of symptoms, assuming a viral infection. She was absent from work for three days. She denies weight loss or night sweats. The patient’s mother was diagnosed with sarcoidosis six years ago, at age 65. Cindy’s chest x-ray revealed hilar lymphadenopathy and evidence of calcification of nodes. Her laboratory workup revealed a serum calcium level of 11.3 mEq/dL and urinary calcium of 325 mg/24 hr. On pulmonary function testing, she had a forced vital capacity (FVC) of 80% of predicted. Lung biopsy confirmed granulomatous lesions consistent with the diagnosis of sarcoidosis, but testing of the specimen failed to demonstrate a causative agent, such as bacteria. The patient was started on prednisone, 30 mg/d, and was scheduled to be seen in one month. One month later, she reported improvement in her symptoms, but not resolution. The patient remained on the corticosteroid regimen for an additional two months, at which time her disease appeared to be in remission and treatment was stopped. She is seen twice annually by her pulmonologist.

Introduction

When British Prime Minister Winston Churchill described Russia as “a riddle, wrapped in a mystery, inside an enigma,” he could have been describing sarcoidosis. Defined as a multisystem noncaseating granulomatous disease of uncertain etiology, sarcoidosis has challenged patients and their providers since its initial description in the late 1800s. At present, there is no single diagnostic test, nor any definitive laboratory or imaging study specific for sarcoidosis, nor is there an approved specific therapy. A high index of suspicion, based on knowledge of the wide range of potential signs and symptoms, is an essential tool for the clinician in identifying patients with sarcoidosis. Sarcoidosis remains a diagnosis of exclusion.[1]

Epidemiology and Clinical Presentation

Sarcoidosis occurs throughout the world and can occur at any age. However, the peak incidence appears to be between the ages of 20 to 39 years.[1] In Scandinavian countries, the incidence is bimodal—occurring at one peak at ages 25 to 29, and then again at ages 65 to 69.[2] While sarcoidosis afflicts all races and genders, it is more common in women and among blacks. Among black Americans the prevalence rate is approximately three times the rate seen in white Americans.[3,4] While income and socioeconomic status do not affect risk, they are associated with poorer outcomes. Estimates of its prevalence vary widely. In Northern Europe and the United States, it is estimated that sarcoidosis occurs in 5-40/100,000 persons.[1,5] An interesting report from central Ohio found an increase in the incidence of sarcoidosis; better patient ascertainment and improved diagnostic methods are the suggested reason for the increase.[6]

The signs and symptoms in patients with sarcoidosis also vary both in organ system affected and in severity of disease. It is most commonly seen in the lungs, skin, and eyes, but can also affect the central nervous system, lymph nodes, joints, and/or cardiac system; 90% of patients manifest thoracic involvement.[1,3,5,7] In its cutaneous forms, it has been described as “the great imitator” because it can resemble common disorders and it can mimic rare conditions.[8] Among the more common cutaneous manifestations are erythema nodosum that is often accompanied by unilateral or bilateral hilar and/or right paratracheal lymphadenopathy, anterior uveitis, and/or polyarthritis which is referred to as Lofgren’s syndrome. Other skin lesions associated with sarcoidosis include macular or papular lesions, scaly plaque lesions, and annular lesions.[8]

Cardiac involvement occurs in 20% to 30% of patients with the disease, and yet only 5% of patients with sarcoidosis have clinical manifestations of cardiac disease.[5] Some patients may be asymptomatic at the time of diagnosis, while others have an acute onset of symptoms such as fatigue, chest pain, and dyspnea (Table 1). Many patients require no treatment, other patients require aggressive treatment; as many as 30% of patients develop chronic, progressive disease, and a small percentage (5%) of patients succumb to the disease.[1,3,5,9]

Diagnostic Workup

A careful history will not only explore the onset and nature of the patient’s symptoms, but should also delve into the patient’s family history. Studies have shown that this disease tends to be found among relatives. A genetic predisposition has been suggested by a higher incidence among monozygous twins, as well as by the differences in disease severity between racial groups.[5,10] A Case-Control Etiologic Sarcoidosis Study (ACCESS) found that sarcoidosis patients were five times more likely to report a parent or sibling with sarcoidosis than were healthy control patients.[11]

The diagnostic evaluation of patients suspected of having this disorder should include chest x-ray, positron emission, magnetic resonance imaging, or computer tomography.[4] X-rays have been used to assign stages (1-4) of sarcoidosis, and while some assert this radiographic assessment is helpful in predicting outcome, others feel it does not correlate well with outcome[4,7] (Table 2). Even though pulmonary function testing does not always correlate with radiographic findings, pulmonary function studies are also important to identify obstructive or restrictive disease; 65% of patients with sarcoidosis have impaired pulmonary function.[1] It is important to also evaluate serum calcium because patients with sarcoidosis frequently have hypercalcemia and hypercalciuria. If these conditions go untreated, patients can develop nephrocalcinosis and ultimate progress to renal failure.[12]

The laboratory workup should include a complete blood count and/or complete metabolic panel, guided by the patient’s presenting symptoms. For example, patients with sarcoidosis, like the patient described, frequently have hypercalcemia and hypercalciuria. Thus, evaluation of liver function, renal function, and other organ function is indicated. In addition, serum angiotensin converting enzyme is elevated in a significant percentage of patients with sarcoidosis (50%-80%) and may indicate active disease, particularly in patients with chest involvement. However, because angiotensin-converting enzyme (ACE) can also be elevated in a number of other conditions, such as lymphoma, hepatitis, tuberculosis (TB), and hyperthyroidism, it is not a specific indicator of sarcoidosis, and is controversial.[1,4] Similarly, immunoglobulins, particularly IgM, IgG, and IgA, may be elevated in patients with sarcoidosis, and this finding may help differentiate sarcoidosis from common immunodeficiency disorders which are characterized by low levels.[9] More recently, Hattori and colleagues have suggested that IgE levels may be low in patients with sarcoidosis.[13] Where possible, a biopsy specimen from the affected organ such as the skin, peripheral lymph nodes, lacrimal glands, or conjunctiva should be obtained.[1] Because a significant number of patients have pulmonary involvement, fiberoptic transbronchial biopsies are frequently performed.[1,14]

The granuloma of sarcoidosis typically contains a central follicular area with macrophages, epithelioid cells, and multinucleated giant cells, surrounded by lymphocytes, fibroblasts, and monocytes at the periphery. However, to distinguish these granuloma from those caused by other disorders, cultures, and stains for acid-fast bacilli, fungi, and bacteria are very important.

Immunopathogenesis and Environmental Factors

Over the past two decades, researchers have gained a greater understanding of the pathogenesis of sarcoidosis with respect to potential triggering factors. With that understanding, insights into potential treatment options have emerged targeting specific aspects of the immunopathogenesis. While studies have failed to show a causative role, investigators have posited an important triggering role for environmental factors, such as infection, occupational exposure to fine particulates, and chemicals in genetically susceptible individuals.[1,3,15-17]

As noted by Saidha et al, one enduring theory is that an infectious agent plays an important triggering role in the development of sarcoidosis. Recent studies have shown that pathogens such as Mycobacterium spp, particularly Mycobacterium Tuberculosis (Mtb), occur in patients with sarcoidosis more frequently than in healthy individuals. DNA for the protein Mtb catalase-peroxidase (mKatG) has been found in 38% of biopsy specimens of sarcoidosis patients. Propionibacterium acnes, as well as viruses, have also been implicated in sarcoidosis.[14-16]

Interestingly, initial reports from the site of the World Trade Center disaster indicated that within the first year of exposure to building dust, workers had a higher than expected incidence of sarcoidosis than the general public. However, continuing studies have failed to show typical clinical features of sarcoidosis and a phenotypically distinct form of sarcoidosis is suspected.[15-18]

The ACCESS study data indicated that exposure to environmental factors such as bacteria increased the risk of sarcoidosis in genetically susceptible patients.[19,20] When exposed to an antigen in the environment, antigen-presenting cells interact with CD4+ T cells in a way that stimulates fibroblast proliferation and collagen production. This can lead to progressive pulmonary fibrosis which occurs in 20% to 25% of patients.[21]

Treatment Options

Understanding these complex inflammatory pathways has been important in developing treatment approaches for those patients who do not go into remission. The mainstay of therapy for sarcoidosis has been corticosteroids. As was the case with Cindy, prednisone in a dose of 20 to 40 mg/day is generally initiated at the time of diagnosis and is usually prescribed for one to three months. If the patient responds to this regimen, a tapering dosage schedule may be used.[22.23] Thirty percent of sarcoidosis patients have chronic progressive disease.[24] Thus, if the patient fails to respond, the dose may be increased or another approach may be indicated. Inhaled corticosteroids have been used and studied, but they are less effective than oral steroids. They may have a role in patients whose primary symptom is cough or as maintenance therapy.[25] A number of other agents, based on the mechanism of anti-inflammatory properties, have been suggested. These alternatives, often used initially in combination with corticosteroids, include methotrexate, thalidomide, pentoxifylline, hydroxychloroquine, azathioprine, leflunomide, and infliximab.[24-26] All of these corticosteroid-sparing alternative therapies have been shown to have beneficial effects in some patients, particularly those with chronic, recurrent/relapsing sarcoidosis.[23-24] Since most of these agents require up to nine months to achieve peak effects, steroids should be slowly tapered after the alternative drug is added. However, it should be noted that the effects are modest, are not seen in all patients, and all have significant adverse effects, ranging from nausea and diarrhea to bone marrow suppression, hepatitis, TB, and malignancy[23,25-27] (Table 3). Most suppress immunity. Because of the adverse effects, patients who receive these drugs require monitoring.

As research continues to build upon our current understanding of the pathogenesis of sarcoidosis insights into the role of current medications and development of targeted therapies to improve the lives of patients with sarcoidosis will likely be developed.

Sally Farrand
Published May 8, 2012

 

References

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