Sarcoidosis

Does this patient have sarcoidosis?

Sarcoidosis is a highly variable multisystem inflammatory disorder of unknown etiology, potentially involving any organ system. The clinical course is also quite variable with some patients never needing treatment while others require immediate aggressive therapies. Well-described clinical scenarios of sarcoidosis include incidental bilateral hilar lymphadenopathy seen on plain chest x-ray, Lofgren’s syndrome (the triad of erythema nodosum, periarthritis, and bilateral hilar lymphadenopathy), and Heerfordt’s syndrome (uveitis and parotiditis).

Sarcoidosis can be associated with a variety of characteristic skin rashes such as lupus pernio and is a common cause of uveitis. However, individual cases will reflect specific organ system involvement, in potentially any combination. Accordingly, pulmonary involvement can present as dyspnea or cough, bone or joint involvement as skeletal or articular pain, muscle involvement as weakness, cardiac involvement as an infiltrative cardiomyopathy or arrhythmia, neural involvement as neurologic deficits, and so forth.

The possibility of sarcoidosis should be considered whenever the clinician is faced with evidence of a multisystem inflammatory disease for which other potential diagnoses are not forthcoming. The pathognomonic feature of the disorder is the finding of non-caseating granulomas in affected tissue (Figure 1). Even so, the diagnosis of sarcoidosis remains a clinical one, since granulomatous inflammation may be found in many immunologic, infectious, neoplastic, drug or environmental exposures, or other conditions, all of which need to be adequately excluded.

Figure 1.

What tests to perform?

Laboratory testing

There are no specific laboratory tests that are diagnostic for sarcoidosis. Complete blood count, comprehensive metabolic panel, and urinalysis may help to assess extent of organ involvement, as well as to identify potential for drug toxicities which may help determine the most appropriate pharmacologic intervention. Hypercalcemia, sometimes symptomatic, is seen in as many as one sixth of patients, typically in the setting of normal serum PTH, normal or increased serum 1,25-OH dyhydroxy-vitamin D, and low serum 25-OH vitamin D. The erythrocyte sedimentation rate and C-reactive protein levels may offer objective measures of systemic inflammation, and serum angiotensin converting enzyme (ACE) titers may be elevated in some patients with sarcoidosis, but these tests are neither specific nor sensitive and it is essential that the clinician does not place more weight on them than on good clinical acumen. Other laboratory tests should be monitored according to the specific clinical picture at hand (e.g., serum muscle enzymes in patients with sarcoid myopathy, serum liver panel for hepatic disease, etc.).

Imaging

Conventional chest radiography can offer important prognostic information and should be obtained in all patients with sarcoidosis because pulmonary involvement is present in the majority of patients. Pulmonary disease is graded with increasing severity from Scadding stages 0 through 4 (Figure 2). Additionally, high-resolution chest computed tomography is useful in identifying active inflammatory interstitial lung disease. A baseline electrocardiogram should also be obtained as cardiac disease can be insidious. Other forms of imaging are dictated by specific clinical manifestations (e.g., conventional radiography for bone disease, ultrasonography for joint disease, echocardiography for cardiac disease, magnetic resonance imaging (MRI) for central nervous system disease, etc.). Positron emission tomography (PET) is currently generating a great deal of interest as a sensitive and specific means of identifying and monitoring sites of active inflammation body-wide. Although its overall role remains to be determined. PET scanning may be particularly useful in the assessment of organs such as the heart or central nervous system for which other diagnostic modalities are not readily available.

Figure 2.

Biopsy

The most important diagnostic test for sarcoidosis is the biopsy. Sarcoid granulomas are classically non-caseating and are usually described as “tightly formed”. There must be no evidence of infectious organisms, neoplastic processes, or foreign bodies. Ideally, since sarcoidosis is a multisystem disease, granulomas should be identified in at least two organ systems if possible, in order to best ensure an accurate diagnosis. However, because tissue sampling from multiple sites may not always be possible, the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) recently convened an international panel of experts representing many different subspecialties to identify clinical, laboratory, or radiologic findings which might serve as surrogates for histologic documentation in cases where non-caseating granulomatous inflammation has already been established at a separate site. And so, for example, typical lupus pernio skin lesions, hypercalcemia (with normal serum PTH, normal/increased serum 1,25-OH dyhydroxy-vitamin D, and low serum 25-OH vitamin D), or positive gallium uptake in the salivary glands (i.e., “panda sign”) are all considered to be highly probable to be representative of sarcoidosis involvement of that specific organ system, if a biopsy from a different site (e.g., lymph node) has already demonstrated non-caseating granulomas.

Overall interpretation of test results

As the presentation and course of sarcoidosis are extremely variable, the prognosis of sarcoidosis cannot be generalized. Diagnostic testing can reveal the breadth of organ involvement, but even then, there are no definitive indices as to progression of disease. Although it is fair to say that visceral organ involvement portends increased morbidity and mortality, vigilant monitoring may often be more appropriate than pharmacologic intervention. For example, as many as 90% of patients with stage 1 and 70% of patients with stage 2 pulmonary disease go into clinical remissions without treatment. Pulmonary hypertension, cardiac involvement, cor pulmonale, nephrocalcinosis, lupus pernio, and hepatomegaly are some poor prognostic manifestations.

Controversies in diagnostic testing

The Kveim test is of historical interest but of limited utility. This test involves the intradermal inoculation of an extract of a spleen with known sarcoid involvement. A nodule may form at the site of inoculation after 4 to 6 weeks, which can then be biopsied. The presence of non-caseating granulomas is highly specific for the diagnosis of sarcoidosis. Unfortunately, the test is not particularly sensitive, and there is no standard reagent. The Kveim test is not approved by the Food and Drug Administration. The serum ACE level is another test historically associated with sarcoidosis. Although inadequately sensitive or specific diagnostically, it can sometimes be used to monitor therapeutic response in select patients.

How should patients with sarcoidosis be managed?

Ensuring an accurate diagnosis is the first and most important step in managing sarcoidosis. This involves verifying the pathologic data as well as excluding alternative diagnoses.

The next step is to stage the disease by determining the breadth of systemic involvement, assessing the severity of specific organ dysfunction, and gauging the degree of active inflammation and potential for progression. Staging enables the clinician to tailor therapy to the individual case at hand. Often, vigilant monitoring alone is appropriate. When pharmacologic intervention is required, the use of targeted therapies initially is recommended if possible (e.g., topical or injected ophthalmic corticosteroids for uveitis). However, when systemic therapy is deemed necessary, systemic corticosteroids are usually the mainstay of treatment to effect prompt suppression of inflammation. However, because of heightened appreciation for the toxicities of corticosteroids, immunomodulatory agents are now more widely used to reduce corticosteroid exposure and to maintain chronic control over the disease with fewer adverse drug effects.

Cardiac involvement is particularly challenging because the patient is often asymptomatic, and there is no ideal monitoring modality. Although clinically apparent myocardial involvement occurs in only 5% of patients, it is second only to respiratory failure as the cause of death in sarcoidosis, sometimes presenting as arrhythmia or sudden death. Accordingly, the involvement of a knowledgeable cardiologist is essential, and advanced testing techniques such as cardiac MRI, cardiac PET scanning, and electrophysiologic studies may be necessary. Implantable cardioverter defibrillators are frequently recommended.

What happens to patients with sarcoidosis?

The clinical course of sarcoidosis is exceedingly variable and is dependent on the nature and degree of specific organ system involvement. In epidemiological studies, mortality rates have been difficult to assess because of many factors including projected high numbers of undiagnosed individuals, geographical and ethnic differences, referral biases, and phenotypic variability. Nonetheless, respiratory failure and cardiac causes are the two most common causes of death in patients with sarcoidosis.

Physiologic and/or pathophysiologic implications

Morbidity from sarcoidosis results from unchecked inflammation resulting in irreversible fibrosis and damage in affected organs. Hence, the goal of early intervention is to induce and maintain suppression of the inflammatory process. Once damage has occurred, however, therapy is relegated to supporting the residual function of the injured target organ.

Pharmacological considerations

When possible, pharmacologic therapy should be targeted to affected organs. This would include ophthalmic corticosteroid eye drops or injections for uveitis, intralesional corticosteroid injections for appropriate rashes, or non-steroidal anti-inflammatory agents for inflammatory arthritis.

Systemic therapy is instituted when targeted modalities are not feasible, ineffective, or unavailable. Systemic corticosteroids such as prednisone or methylprednisolone are typical first-line agents when rapid suppression of inflammation is desired. If corticosteroid requirements are excessive, then immunomodulatory agents are used for long-term control of disease. These may include non-immunosuppressive agents such as anti-malarial agents (e.g., hydroxychloroquine or chloroquine) or thalidomide for non-visceral disease, or agents with clearly immunosuppressive effects such as methotrexate, mycophenolate mofetil, azathioprine, leflunomide, and rarely cyclophosphamide for more severe disease. There has been much recent favorable interest in the use of monoclonal antibodies against tumor necrosis factor-alpha (e.g. infliximab and adalimumab) for particularly difficult or complex cases. Several prospective, double-blinded, randomized placebo-controlled trials have demonstrated the effectiveness of infliximab and adalimumab in pulmonary, cutaneous, and multi-organ disease.

What has not been established clearly is the duration of treatment of any medication. In one fairly large retrospective study of patients with stabilized cardiac sarcoidosis, withdrawal of corticosteroid therapy led to an increased risk of cardiac mortality. The effects of discontinuing steroid-sparing agents have not been rigorously studied.

How to utilize team care?

Care should be coordinated by a physician comfortable with multisystem diseases but will frequently involve multiple specialists and subspecialists as appropriate to the case at hand. All patients should have a pulmonologist for ongoing monitoring, since the majority of patients develop some degree of pulmonary disease. Rheumatologists are typically consulted when systemic pharmacologic therapies are required because of their familiarity with corticosteroid and immunomodulatory medications or when there is question whether a musculoskeletal complaint is attributable to sarcoidosis.

Are there clinical practice guidelines to inform decision making?

A joint statement released by the American Thoracic Society, the European Respiratory Society, and WASOG in 1999 continues to serve as an important embarkation point towards the current understanding and clinical management of sarcoidosis.

As noted above, recently updated recommendations from WASOG may further help the clinician to more readily make the diagnosis of sarcoidosis without undue reliance on invasive testing. Also of importance, with the emergence of methotrexate and anti-TNF antibodies in the treatment of sarcoidosis as beneficial steroid-sparing agents, proposed guidelines for the use of these medications have been published.

Limitations

The phenotypic heterogeneity of the disease continues to present challenges in conducting clinical trials. Well-designed studies have been typically limited to narrowly defined patient groups (e.g., pulmonary disease), the results of which are often not generalizable to all sarcoid patients.

Other considerations

One area of active interest is that of vitamin D supplementation in patients with sarcoidosis. Hypercalcemia is a well-documented potential complication of sarcoidosis, caused by the excessive production of 1,25-OH dyhydroxy-vitamin D3 (calcitriol) in granulomas. In addition, there are data which suggest vitamin D may have a positive feedback paracrine effect and promote granulomatous inflammation. Vitamin D supplementation could then, in theory, exacerbate hypercalcemia or potentiate granuloma formation. On the other hand, it is established that patients with sarcoidosis are at increased risk for insufficiency fractures, due to the disease itself as well as due to medications such as corticosteroids, and that the many patients in fact are deficient in serum vitamin D. At present, studies appear to suggest that vitamin D supplementation is generally safe, with a real but very small risk of inciting hypercalcemia, but have not yet shown to provide benefit in protection against bone loss and fractures.

What is the evidence?

Baughman, RP, Drent, M, Kavuru, M, Judson, MA, Costabel, U, du Bois, R. “Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement”. . vol. 174. 2006. pp. 795-8. (Multicenter, randomized, double-blind, placebo-controlled trial demonstrating the benefit of infliximab anti-TNF therapy in patients with chronic pulmonary sarcoidosis.)

Bolland, MJ, Wilsher, ML, Grey, A, Horne, AM, Fenwick, S, Gamble, GD. “Randomised controlled trial of vitamin D supplementation in sarcoidosis”. BMJ Open. vol. 3. 2013. pp. e003562(Small randomized, placebo-controlled trial on the effects of cholecalciferol supplementation in normocalcemic patients with sarcoidosis.)

Cremers, JP, Drent, M, Bast, M, Shigemitsu, H, Baughman, RP, Valeyre, D. “Multinational evidence-based World Association of Sarcoidosis and Other Granulomatous Diseases recommendations for the use of methotrexate in sarcoidosis: integrating systematic literature research and expert opinion of sarcoidologists worldwide”. Curr Opin Pulm Med. vol. 19. 2013. pp. 545-61. (Proposed guidelines for the use of methotrexate in sarcoidosis.)

Drent, M, Cremers, JP, Jansen, TL, Baughman, RP. “Practical eminence and experience-based recommendations for use of TNF-a inhibitors in sarcoidosis”. Sarcoidosis Vasc Diffuse Lung Dis. vol. 31. 2014. pp. 91-107. (Proposed guidelines for the use of TNF-a inhibitors in sarcoidosis.)

Govender, P, Berman, JS. “The diagnosis of sarcoidosis”. Clin Chest Med. vol. 36. 2015. pp. 585-602. (Practical review of diagnostic issues and dilemmas in sarcoidosis with a comprehensive discussion of specific organ systems.)

Hunninghake, GW, Costabel, U, Ando, M, Baughmann, R, Cordier, JF, du Bois, R. “ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders”. . vol. 16. 1999. pp. 149-73. (Foundational reference for contemporary work related to sarcoidosis.)

Judson, MA, Baughman, RP, Costabel, U, Flavin, S, Lo, KH, Kavuru, MS. “Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomized trial”. Eur Respir J. vol. 31. 2008. pp. 1189-96. (Multicenter, randomized, double-blind, placebo-controlled trial demonstrating the benefits of infliximab anti-TNF therapy in extra-pulmonary sarcoidosis.)

Judson, MA, Costabel, U, Drent, M, Wells, A, Maier, Koth, L. “The WASOG sarcoidosis organ assessment instrument: update of a previous clinical tool”. Sarcoidosis Vasc Diffuse Lung Dis. vol. 31. 2014. pp. 19-27. (Update on a diagnostic instrument to aid in assessing organ involvement.)

Mehta, D, Mori, N, Goldbarg, SH, Lubitz, S, Wisnivesky, JP, Teirstein, A. “Primary prevention of sudden death in silent cardiac sarcoidosis: role of programmed ventricular stimulation”. . vol. 4. 2011. pp. 43-8. (Discussion of the particular challenges of cardiac sarcoidosis and a potential strategy for identifying patients at risk for malignant arrhythmias.)

Pariser, RJ, Paul, J, Hirano, S, Torosky, C, Smith, M. “A double-blind, randomized, placebo-controlled trial of adalimumab in the treatment of cutaneous sarcoidosis”. J Am Acad Dermatol. vol. 68. 2013. pp. 765-73. (Randomized, double-blind, placebo-controlled trial demonstrating the benefits of adalimumab anti-TNF therapy in cutaneous sarcoidosis.)

Treglia, G, Taralli, S, Giordano, A. “Emerging role of whole-body 18F-fluorodeoxyglucose positron emission tomography as a marker of disease activity in patients with sarcoidosis: a systematic review”. . vol. 28. 2011. pp. 87-94. (Discussion of the potential role of PET scanning as a powerful diagnostic tool and as a modality for monitoring response to therapy.)

Wijsenbeek, MS, Culver, DA. “Treatment of sarcoidosis”. Clin Chest Med. vol. 36. 2015. pp. 751-67. (Overview of treatment strategies and medical armamentarium for managing sarcoidosis.)

Yee, AMF, Pochapin, MB. “Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy”. . vol. 135. 2001. pp. 27-31. (First report of anti-TNF therapy for sarcoidosis, notably in a patient with refractory, multisystem, extrapulmonary disease)

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