Originally described by Boeck in the 1870s, sarcoidosis, or "new flesh formation," refers to the histological hallmark of the disease, noncaseating epithelioid granuloma. The noncaseating granuloma of sarcoidosis is a lesion composed of epithelioid cells that surround a central granular zone in a circular or arc pattern without necrosis.1
The respiratory system is thought to be involved at some point in the lifetime of all patients with sarcoidosis (Figure 1).2 However, the protean clinical manifestations (Table) can masquerade as a number of other disorders, because multiple organs—including the muscles, bones,and joints—can be affected.
Although musculoskeletal manifestations of sarcoidosis usually are not the presenting clinical feature, they are not rare. When looked for, they may provide clues to sarcoidosis when it presents in other tissues. Corticosteroids remain the most effective therapeutic intervention, but given the toxicity associated with their long-term use, management of sarcoid arthropathy, myopathy, and osseous lesions is best guided by the extent to which these manifestations are symptomatic. In this article, we describe our approach to recognizing and managing the musculoskeletal manifestations of sarcoidosis.
CAUSES AND EPIDEMIOLOGY
The etiology of sarcoidosis remains unknown. Men and women of all ages may be affected, but primarily young adults between the second and fifth decades are affected; there is a slight predominance in women. A second peak has been described in women older than 50 years.3,4
Epidemiological data have demonstrated ethnic and regional variations in the clinical presentations, disease course, and genetic susceptibilities of sarcoidosis; the incidence is higher in African Americans and Northern Europeans.5 Familial aggregation and genome-wide association studies have confirmed the genetic susceptibility. The disease therefore is thought to be induced by environmental factors in genetically susceptible persons.
Airborne particulate, viral, or mycobacterial pathogens and occupational exposures have been postulated as potential triggers in the pathogenesis of the disease. The inflammatory response is a cell-mediated aggregation of CD4+ TH1 phenotype lymphocytes with enhanced production of interleukin-12 and interferon-γ within the granulomatous lesions. The otherwise suppressed immunity reflected in the fascinating anergy phenomenon to tuberculin testing is speculated to occur as a consequence of enhanced activity of circulating CD8+ suppressor T lymphocytes and enhanced TH2 responses. However, the exact immunopathogenetic process that culminates in the clinical presentation of sarcoidosis remains elusive.6
Sarcoidosis may involve any organ system, manifesting a wide spectrum of disease severity. Extrapulmonary manifestations are common; they occur in the context of pulmonary features, except in a small minority of patients. Most notably, among patients with neurological involvement, it is important to recognize that the neurological lesions may be the presenting manifestation.
Extrapulmonary features, including musculoskeletal involvement, vary by gender and ethnic origin; the prevalence is higher among women and African Americans. Although reports of the rate of musculoskeletal involvement vary, up to 40% of patients with sarcoidosis have documented musculoskeletal findings.1-9 Musculoskeletal system involvement may be asymptomatic. This is important for clinicians looking for signs of sarcoidosis when considering it in the differential diagnosis of disease involving the eyes, CNS, or visceral organs.5
Arthralgia is reported in up to 70% of patients, often predating other manifestations of the disease.2,6 Lfgren syndrome (LS), originally described in 1952, is classically defined as the triad of acute arthritis, erythema nodosum, and bilateral hilar lymphadenopathy (BHL) of the lungs; it may be associated with fever and anterior uveitis. Reported predominantly in 10% to 39% of patients with early-onset sarcoidosis, LS may be the initial manifestation. 6,8,9 BHL and ankle arthritis or periarthritis are the main features of LS, but the necessity of the presence of erythema nodosum for making this diagnosis has been debated.10,11
The most common presentation of acute arthritis in sarcoidosis is an additive symmetrical oligoarthritis that predominantly involves peripheral large joints; symmetrical polyarthritis and asymmetrical transient polyarthralgia have been described less frequently. Although any joint may be involved, the ankles are the most frequently involved, followed by—in descending order—the knees, wrists, elbows, interphalangeal joints, metacarpophalangeal joints, and shoulders.2,8,12 Synovial fluid is inflammatory with lymphocytic predominance and protein elevation. The spontaneous resolution of arthritis within a few weeks up to 6 months indicates a benign course, but relapses have been reported.9,12
Chronic sarcoid arthritis occurs less frequently than the acute syndromes. It may follow a progressive course, resulting in erosive joint changes and deformity in a limited number of joints8,13 or a course characterized by episodic exacerbations and remissions of symmetrical polyarthritis marked by subsequent joint deformities (eg, Jaccoud deformity).12
Elevation of the rheumatoid factor (RF) level is reported in 10% to 47% of patients and may correlate with elevated levels of circulating IgG.7 As such, the combination of symmetrical polyarthropathy and elevated RF can clinically mimic rheumatoid arthritis. Relative sparing of the small joints of the hands and feet and the absence of radiological changes in sarcoidosis have been offered to aid in differentiation of the diseases,2,6 but these may not always be helpful.
- 1. Wilcox A, Bharadwaj P, Sharma OP. Bone sarcoidosis. Curr Opin Rheumatol. 2000;12:321-330.
- 2. Erb N, Cushley MJ, Kassimos DJ, et al. An assessment of back pain and the prevalence of sacroiliitis in sarcoidosis. Chest. 2005;127:192-196.
- 3. Costabel U, Hunninghake GW. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders. Eur Respir J. 1999;14:735-737.
- 4. Hosoda Y, Sasagawa S, Yasuda N. Epidemiology of sarcoidosis: new frontiers to explore. Curr Opin Pulm Med. 2002;8:424-428.
- 5. ACCESS Research Group. Design of a case control etiologic study of sarcoidosis (ACCESS). J Clin Epidemiol. 1999;52:1173-1186.
- 6. Barnard J, Newman LS. Sarcoidosis: immunology, rheumatic involvement, and therapeutics. Curr Opin Rheumatol. 2001;13:84-91.
- 7. Oreskes I, Siltzbach LE. Changes in rheumatoid factor activity during the course of sarcoidosis. Am J Med. 1968;44:60-67.
- 8. Thelier N, Assous N, Job-Deslandre C, et al. Osteoarticular involvement in a series of 100 patients with sarcoidosis referred to rheumatology departments. J Rheumatol. 2008;35:1622-1628.
- 9. Zisman DA, Shorr AF, Lynch JP 3rd. Sarcoidosis involving the musculoskeletal system. Semin Respir Crit Care Med. 2002;23:555-570.
- 10. Grunewald J, Eklund A. Sex-specific manifestations of Lofgren’s syndrome. Am J Respir Crit Care Med. 2007; 175:40-44.
- 11. Perruquet JL et al. Sarcoid arthritis in a North American Caucasian population. J Rheumatol. 1984;11:521-525.
- 12. Awada H, Abi-Karam G, Fayad F. Musculoskeletal and other extrapulmonary disorders in sarcoidosis. Best Pract Res Clin Rheumatol. 2003;17:971-987.
- 13. Torralba KD, Quismorio FP Jr. Sarcoid arthritis: a review of clinical features, pathology and therapy. Sarcoidosis Vasc Diffuse Lung Dis. 2003;20:95-103.
- 14. Le Roux K, Streichenberger N, Vial C, et al. Granulomatous myositis: a clinical study of thirteen cases. Muscle Nerve. 2007;35:171-177.
- 15. Wirnsberger RM, Drent M, Hekelaar N, et al. Relationship between respiratory muscle function and quality of life in sarcoidosis. Eur Respir J. 1997;10:1450-1455.
- 16. Moore SL, Teirstein AE. Musculoskeletal sarcoidosis: spectrum of appearances at MR imaging. Radiographics. 2003;23:1389-1399.
- 17. Otake S. Sarcoidosis involving skeletal muscle: imaging findings and relative value of imaging procedures. AJR. 1994;162:369-375.
- 18. Otake S, Ishigaki T. Muscular sarcoidosis. Semin Musculoskelet Radiol. 2001;5:167-170.
- 19. Moore SL, Teirstein A, Golimbu C. MRI of sarcoidosis patients with musculoskeletal symptoms. AJR. 2005;185:154-159.
- 20. Judson MA. The diagnosis of sarcoidosis. Clin Chest Med. 2008;29:415-427, viii.
- 21. Yanardag H, Pamuk ON, Kiziltan M, et al. An increased frequency of carpal tunnel syndrome in sarcoidosis. Results of a study based on nerve conduction study. Acta Medica (Hradec Kralove). 2003;46:201-204.
- 22. Shorr AF, Murphy FT, Gilliland WR, Hnatiuk W. Osseous disease in patients with pulmonary sarcoidosis and musculoskeletal symptoms. Respir Med. 2000;94:228-232.
- 23. Mana J. Magnetic resonance imaging and nuclear imaging in sarcoidosis. Curr Opin Pulm Med. 2002;8:457-463.
- 24. Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis. 2000;17:60-66.
- 25. Judson MA, Baughman RP, Costabel U, et al; Centocor T48 Sarcoidosis Investigators. Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial. Eur Respir J. 2008;31:1189-1196.
- 26. Walter MC, Lochmüller H, Schlotter-Weigel B, et al. Successful treatment of muscle sarcoidosis with thalidomide. Acta Myol. 2003;22:22-25.
- 27. Sharma OP. Hypercalcemia in granulomatous disorders: a clinical review. Curr Opin Pulm Med. 2000;6:442-447.