Rheumatologic Manifestations of Sarcoidosis

Nadera J. Sweiss, M.D.; Karen Patterson, M.D.; Ray Sawaqed, M.D.; Umair Jabbar; Peter Korsten, M.D.; Kyle Hogarth, M.D.; Robert Wollman, M.D.; Joe G.N. Garcia, M.D.; Timothy B. Niewold, M.D.; Robert P. Baughman, M.D.

Disclosures

Semin Respir Crit Care Med. 2010;31(4):463-473. 

In This Article

Rheumatologic Manifestations of Sarcoidosis

Sarcoidosis and Lupus Erythematosis

Systemic lupus erythematosis (SLE) may develop in the context of sarcoidosis. SLE is usually suspected when patients with sarcoidosis develop a butterfly rash or discoid lesions. The characteristic appearance of a butterfly rash is a large, erythematous patch usually confined to the nose and cheeks.[6] SLE discoid lesions are scaly, circular lesions with depigmented centers surrounded by an erythematous perimeter. Sarcoid and discoid lupus skin changes may coexist in the same lesion (Fig. 1). The treatment options for sarcoidosis and SLE are challenging and should be individualized. The use of anti-TNF-α agents may be associated with drug-induced lupus and should be avoided in patients who have active systemic lupus.

Figure 1.

A photograph of the frontal area showing erythematous rash. Biopsy confirmed features of discoid lupus and noncaseating granulomas in the same lesion.

Osseous Sarcoidosis

Osseous lesions are found in up to 13% of patients with sarcoidosis.[7] Because osseous sarcoidosis is often asymptomatic, this estimation may not reflect the true prevalence.[8] The presence of sarcoidosis in the bones typically correlates with cutaneous lesions and progressive disease.[9,10] In osseous sarcoidosis, bilateral involvement of the phalanges of the hand and feet is most common,[11] but any bone may be affected. Reports of leg (e.g., tibial), skull, rib, sternal, and vertebral involvement are rare but do exist.[7,8,11,12] When present, symptoms include focal pain, swelling and erythema in the subcutaneous tissue around the involved bone site.[10] Osseous sarcoidosis is detected by magnetic resonance imaging (MRI), bone scans, or plain film imaging. A specific diagnostic algorithm has yet to be defined.[12]

Axial Sarcoidosis Involvement of the axial skeleton as a specific form of osseous sarcoid is rare and can be misdiagnosed as sacroiliitis by plain radiograph. Sometimes, vertebral lesions are asymptomatic and never require treatment. In other cases, vertebral sarcoidosis may be the presenting symptom; when it is symptomatic, it is often quite painful.[13] Lesions may be predominantly lytic, sclerotic, or a mixture of the two, as determined by radiographic images of the lower dorsal, upper lumbar, and cervical vertebrae.[14] MRI has been suggested as the preferred imaging modality because it can differentiate sacroiliitis from osseous lesions of sarcoidosis, and it can guide selection of biopsy sites to confirm the diagnosis histopathologically if that is indicated.[14] MRI findings include multifocal lesions that are hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging.[13,15] MRI findings in osseous sarcoid are not specific, and metastatic cancer, myeloma, lymphoma, and tuberculosis must be considered,[16] making biopsy an important diagnostic step. Optimal treatment of axial sarcoidosis remains controversial. There are no controlled clinical trials, but corticosteroid-based regimens are the standard of care. Other treatment options, including TNF-α inhibitors (infliximab and adalimumab), have been described in cases of refractory to standard treatment.[17]

Sacroiliac Joint Involvement Sacroiliitis, arthritis of the sacroiliac joints, may cause lower back pain and stiffness, with pain extending from the lower back to the buttocks. Although it is rare, sacroiliitis may occur in patients with sarcoidosis. Evidence for sacroiliitis as a manifestation of sarcoidosis comes mostly from isolated cases.[18] The frequency of sacroiliitis in sarcoidosis was 6.6% in one study.[19] Noncaseating granulomas have been seen on biopsy of the sacroiliac joint, which supports an etiologic role of sarcoidosis in sacroiliitis in patients with both conditions.[20] However, sacroiliitis may present in the context of other rheumatologic conditions, such as reactive arthritis, ankylosing spondylitis, and psoriatic spondyloarthropathy, which may coexist with sarcoidosis, and these conditions should therefore be ruled out patients with sarcoid and sacroiliitis findings.[19] Typically, the back pain of sacroiliitis can be managed with physiotherapy and analgesia. However, in the context of sarcoidosis, inflammatory back disease may be more effectively treated with targeted therapies, including antiinflammatory medication and local steroid injections.[19]

Sarcoid Myopathy

Sarcoid myopathy occurs more frequently than osseous sarcoid, affecting up to 75% of all individuals with sarcoidosis. Similar to bone involvement, myopathy is associated with chronic disease. Muscle involvement is often asymptomatic. In suspected cases, muscle biopsy reveals noncaseating granulomas (Fig. 2). Helpful imaging techniques include MRI, computed tomographic (CT) scan, or positron emission tomography (PET) where myopathy appears as star-shaped lesions within the muscle.[9,21,22] Sarcoid myopathy may manifest as nodular myopathy, chronic myopathy, or acute myositis.[23] Nodular myopathy is rare[24] and manifests as multiple, tumorlike, palpable nodules in the muscles.[25] Chronic myopathy occurs when myopathy is present in multiple muscle groups. Corticosteroids have been used to treat chronic myopathy, but patients—who tend to be severely disabled—rarely improve.[25] Corticosteroids, azathioprine, and methotrexate are used for severe, symptomatic nodular and chronic sarcoid myopathy, but optimal treatment strategies have not been fully established,[24] and patients who are already significantly disabled rarely improve.

Figure 2.

Presence of noncaseating granulomas in muscle in sarcoid myopathy.

The least common type of sarcoid myopathy is acute myositis. It usually occurs in the setting of acute arthritis but due to a low prevalence its normal characteristics, prognosis, and preferred treatment approaches are not well defined.[22,25,26] It tends to occur early in the course of sarcoidosis and in patients younger than 40 years old.[25,27] Patients with acute myositis typically have muscle swelling and experience diffuse pain emanating from the calf or thigh. Sometimes, sarcoid myositis may lead to contracture of the muscle and hypertrophy.[28] Nonspecific associated symptoms include fatigue and fever.[27] Generalized muscle weakness occurs infrequently.[27] Because the clinical presentation of patients with acute myopathy can mimic polymyositis (i.e., elevated muscle enzymes and abnormal findings on electromyogram), muscle biopsy may be needed to distinguish between the two conditions. Methotrexate has shown efficacy in the treatment of acute sarcoid myositis.[23] The role of intravenous immunoglobulins, mycophenolate, and anti-TNF-α therapy in muscle sarcoidosis is not well defined.

Although there is no apparent pathophysiological link, an association between sarcoid and inclusion body myositis was reported in 1986.[29] However, very few cases—eight as of 2008—have been reported.[30,30a] Of note, the immunopathology of both diseases involves Th1-mediated immunity, and some evidence suggests that muscle involvement in sarcoid may lead to the development of inclusion body myositis,[30] although a detailed understanding of the relationship between these two diseases is not yet fully known.

Sarcoidosis and Vasculitis

Systemic vasculitis associated with sarcoidosis is uncommon but can cause significant morbidity when it occurs. Vasculitis in patients with sarcoidosis can affect vessels that range in size from small to large and may manifest as cutaneous lesions, neuropathy, pulmonary hypertension, or systemic vasculitis.[23] Other symptoms that have been reported in a few cases of sarcoid vasculitis include Takayasu-like aortitis, vasculitis of the aortic branches, glomerulonephritis, and transient cerebral ischemia.[31] In our experience a subset of patients with sarcoidosis may have positive antineutrophilic cytoplasmic antibodies (ANCAs) in the absence of systemic vasculitis (unpublished data). However, the role of these antibodies in the pathogenesis of sarcoid vasculitis remains unknown.

Treatment of sarcoid vasculitis with corticosteroids may be successful initially, but relapse is common. Anecdotal reports suggest that corticosteroids may be helpful but the length of therapy is unknown. Similarly, the role of steroid-sparking agents remains undefined. According to new data from the Rituximab for ANCA-Associated Vasculitis (RAVE) trial, rituximab is noninferior to cyclophosphamide in treating vasculitis.[32] The role of rituximab in sarcoidosis is not yet defined but we are currently conducting a pilot study of rituximab in pulmonary sarcoidosis.

Sjögren Syndrome and Sarcoidosis

  • Occasionally sarcoidosis and Sjögren syndrome, both chronic inflammatory conditions that can affect the salivary glands, occur simultaneously, although the incidence of coexistence is unknown.[33] Dryness and diffuse swelling of oral mucosal tissues can be the first symptom of sarcoidosis.[34] Both sarcoidosis and Sjögren syndrome have an insidious onset, and patients who do not present with other manifestations of sarcoidosis may appear to have isolated Sjögren syndrome.[35] However, a detailed medical history, salivary gland biopsy, and serologies can help distinguish between the two conditions. Certain systemic complications such as uveitis, when present, can be more supportive of a diagnosis of sarcoid. Also, while patients with either sarcoidosis or Sjögren syndrome may demonstrate reduced stimulated secretory function of the parotid glands, sarcoid patients will not have elevated salivary sodium concentrations and globular sialectasia, which are features unique to Sjögren syndrome.[36] Finally, elevated levels of SSA and SSB antibodies are usually positive in Sjögren syndrome and are not seen in sarcoidosis. Making a diagnosis of Sjögren syndrome currently requires sarcoidosis to be ruled out first. However, with accumulating evidence that Sjögren syndrome and sarcoidosis can coexist these criteria may change, and clinicians may need to evaluate for both conditions to determine whether a patient suffers from a single or a combined disorder.[23,35] Objective evaluation of keratoconjunctivitis sicca by ophthalmologic exam is helpful as a baseline measurement. Lip biopsy may also be useful in making a Sjögren syndrome diagnosis. However, not all patients who have clear criteria for Sjögren syndrome require a lip biopsy, particularly individuals taking immunosuppressives in whom a lip biopsy might appear normal. A retrospective study found that the presence of sicca symptoms and positive serology accurately predict the outcomes of lip biopsies, suggesting that there is not a large role for lip biopsy in making an accurate diagnosis.[37]

  • Studies show that a cyclosporine ophthalmic emulsion (Restasis, Allergan, Inc., Irvine, CA) may be helpful to control sicca.[38] However, the exact role of cyclosporine ophthalmic emulsion, and other agents, including pilocarpine hydrochloride (Salagen, Eisai, Inc., Woodcliff Lake, NJ) and cevimeline hydrochloride (Evoxac, Daiichi Sankyo, Inc., Parsippany, NJ), in the treatment of sicca associated with sarcoidosis is not well defined.

Articular Involvement

Up to 25% of patients with sarcoidosis have joint involvement.[39–42] Japanese people with sarcoidosis are a notable exception, with very few cases of sarcoid arthritis reported and only 1.6% of patients with arthralgia.[43,44] Traditionally, sarcoidosis arthritis is classified into two types: an acute, transient type, or a persistent, chronic type. The latter type is rare, occurring in only 1 to 4% of patients.[45]

Acute Sarcoid Arthritis Acute sarcoid arthritis often occurs in the context of Löfgren syndrome, which is defined as the triad of erythema nodosum, bilateral hilar lymphadenopathy, and the presence of arthritis or arthralgias. A seasonal association between the initial presentation of acute sarcoid arthritis has been reported in some studies. Evidence suggests that initial presentations are clustered in the springtime, a notable difference from other arthritides, which tend to occur equally throughout the year.[42,46,47]

Visser and colleagues proposed a set of criteria for clinicians to use as a guide to help diagnose sarcoid arthritis. According to these criteria, making a diagnosis of articular sarcoidosis in patients who have three of the following four characteristics is 99% sensitive and 93% specific: (1) erythema nodosum, (2) symptom duration less than 2 months, (3) age less than 40, and (4) symmetrical ankle arthritis.[42] Involvement of the ankle in acute sarcoid arthritis has been reported in 77 to 100% of patients, and symmetrical involvement occurs in most of those cases.[41,42,46,47,49] Following the ankle, the next most common sites of pain and inflammation are the knee, wrist, and metacarpophalangeal joints. Patients frequently have an increased erythrocyte sedimentation rate,[42,47] but other associated findings in acute sarcoid arthritis may vary among patients. For example, erythema nodosum may or may not be present. In the literature, the incidence is wide ranging (25 to 87.8%).[42,44,46–49] Similarly, fever is noted in only one third of patients in some reports but in up to two thirds of patients in other case series.[41,42,46,47]

In the vast majority of cases, acute sarcoid arthritis has a benign, self-limited course, with minimal to no joint destruction. The average duration of symptoms is approximately 2 to 3 months, and most patients go into remission by 6 months after receiving nonsteroidal antiinflammatory drugs or steroids.[39,41,46–51]

Chronic Sarcoid Arthritis Chronic sarcoid arthritis typically occurs in the setting of systemic sarcoidosis. Chronic sarcoid arthritis typically involves the knees, ankles, wrists, hands, and/or feet. Joint destruction or Jaccoud deformity, when it occurs, is due to persistent inflammation.[40,41] Joint effusions, synovitis, or even nodular proliferation of the synovium presenting as an intraarticular knee mass may also be present.[45] The differential diagnosis of chronic sarcoid arthritis includes reactive arthritis and rheumatoid arthritis, which should be considered, particularly if there is symmetric disease and an elevated rheumatoid factor. Synovial fluid analysis typically reveals a milder inflammatory infiltrate in sarcoid arthritis than rheumatoid arthritis or infectious arthritis, although sometimes a synovial biopsy may be needed to definitely distinguish rheumatoid arthritis from sarcoid arthritis.[40]

Monoarthritis, Oligoarthritis, Polyarthritis The majority of cases of sarcoid arthritis, whether acute or chronic, are oligoarthritic or polyarthritic (i.e., involving three or more joints). When patients with sarcoidosis present with symmetric polyarthritis, especially of the small joints of the hands, clinicians should evaluate patients for concomitant rheumatoid arthritis. Differentiating between the various types of arthritis should be based on clinical laboratory evaluations and radiographic imaging. Psoriatic arthritis, reactive arthritis, and gouty arthritis should also be considered in patients with sarcoidosis who present with oligoarthritis or monoarthritis. In immunocompromised patients, infectious arthritis needs to be excluded.

Monoarthritis is rare, although the incidence is variable in literature reports, with one prospective study citing only one of 28 patients having single joint involvement and another study reporting 21% of patients with Löfgren syndrome with single joint involvement.[41,49] Similar to a polyarthritis presentation, when patients present with monoarthritis they should be evaluated for gouty arthritis and septic arthritis as well as CPP (calcium pyrophosphate)-positive arthritis.

Periarthritis Patients with sarcoid arthritis often have periarticular inflammation.[52,9] Despite swelling around the joints, individuals with periarthritis generally maintain normal range of motion.[52]

At times it may be difficult to distinguish between arthritis or periarthritis. Kellner and colleagues performed ultrasonography on 24 patients who presented with sarcoidosis involving the joints. Twenty of the 24 patients had subcutaneous or periarticular inflammation. Although eight patients had tenosynovitis, only six had discernible joint effusions.[53] When diagnosing periarthritis, it is important to exclude lymphangitis, gonococcal infection, and human immunodeficiency virus (HIV) infection, especially in those who may be at risk for developing these infections.

Costochondral Involvement Costochondral rib junctions and chondrosternal joints of the chest wall occasionally become inflamed in patients with sarcoidosis. This complication, sometimes referred to as Tietze syndrome, creates intense pain that can radiate throughout the chest cavity. Usually, only the second or third rib and associated cartilage is affected. Analgesics are commonly used for pain control, although corticosteroids may be helpful in severe cases. Other than sarcoidosis, rheumatologic diseases, and infectious and neoplastic disorders should be considered in the differential diagnosis for costochondral symptoms.[54] In our own clinical experience, we have injected corticosteroids directly into the costochondral joint in some patients in order to avoid systemic effects of oral corticosteroids.

Gout in Sarcoidosis A relationship between gout and sarcoidosis has been appreciated for decades, although these observations were initially controversial. The first reported case of sarcoidosis, by Jonathan Hutchinson more than 120 years ago, was found to have coexistent sarcoidosis and gout.[55] Interestingly, renal failure from gout was said to be the cause of eventual death of this patient. However, it has been suggested that sarcoidosis-associated hypercalcemia, hypercalciuria, or kidney stones may have been the true culprit.[55] Later, Löfgren noted the association between sarcoidosis and altered urate metabolism, specifically leading to hyperuricemia. Kaplan and Klatskin then reported three cases of presumed simultaneous sarcoidosis, psoriasis, and gout. Despite the fact that the authors later concluded that these patients actually suffered from sarcoid arthritis that mimicked gout, they established a relationship between gout and sarcoidosis, of which clinicians are now aware.[56,57] Differentiating between gout and sarcoid arthritis remains difficult since hyperuricemia can be present in both.[58] Because both conditions are associated with increased morbidity, and because treatments differ considerably, correctly distinguishing between gout and sarcoid arthritis is important. The diagnosis of gouty arthritis should be confirmed by joint aspiration and documentation of the presence of sodium monourate crystals because the presence of hyperuricemia alone is not sufficient for a diagnosis of gouty arthritis.

Sarcoidosis and Psoriatic Arthritis Approximately 6% of all patients with sarcoidosis develop a psoriatic arthritis form of arthritis.[42] The hallmark feature of psoriatic arthritis is dactylitis, characterized by sausage-shaped digits.[59,60] The pathophysiology in psoriatic arthritis in sarcoid may be different from that of nonsarcoid dactylitis. The management of psoriatic arthritis in sarcoidosis includes use of immunosuppressive, antiinflammatory, and biologic therapies.[59,60] Of these agents, accumulating evidence supports that patients with psoriatic arthritis in the context of sarcoidosis may benefit from treatment with infliximab in particular.[59] Although anti-TNF-α therapy is helpful in psoriasis,[61] it may also paradoxically induce progressive psoriasis, and patients on these medications should be followed carefully.[62]

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