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

Etiology

Despite significant advances in characterizing features of sarcoidosis, the underlying etiology remains to be elucidated. Genetic, environmental, and infectious links have all been suggested with varying levels of supportive evidence. Strong evidence suggests that a genetic component confers increased susceptibility to the disease. Previous genetic studies in sarcoidosis have established a role for variants in the class I and II human leukocyte antigen (HLA) locus, similar to many other autoimmune diseases. Recently, genomewide association studies (GWASs) have been performed in sarcoidosis to more comprehensively detect genes associated with sarcoidosis susceptibility. A recent report from these ongoing studies identified annexin A11 (ANXA11) as a novel non-HLA susceptibility locus for sarcoidosis in 2008.[1] Associations have been found between risk of sarcoidosis and as well as genetic polymorphisms involving the loci coding for tumor necrosis factor-alpha (TNF-α), co-stimulatory molecules on antigen-presenting cells such as CD80 and CD86, chemokine receptors CCR2 and CCR5, and many others.[2,3] These studies have yet to explain much of the heritability of sarcoidosis, and increasing insights into the genetics of sarcoidosis susceptibility and severity are anticipated.

It is unclear whether the Th1 immune response seen in sarcoidosis is directed at one or more specific antigens or is a function of a generalized immune dysfunction, because studies have provided evidence for both propositions. Environmental exposure seems to play a role as well. Modest positive associations have been demonstrated in patients exposed to agricultural settings, mold, mildew, musty odors, and pesticides.[2] Patients isolated from such exposures (e.g., office workers) have a reduced risk of developing sarcoidosis.[2]

Seasonal and geographic clustering of new cases of sarcoidosis,[4] in addition to the apparent transmissibility between organ donors and recipients,[4] support the long-standing notion that an infectious agent may be involved. Numerous studies have demonstrated the presence of mycobacterial antigens within biopsies of sarcoid granulomas, though the association is not consistent because only 26% of samples bear the remnants of the organism.[2,4] DNA and protein fragments from Propionibacterium acnes have been found in sarcoidosis tissues as well, with some evidence suggesting a maladaptive response to the bacterial antigens in affected individuals.[5] The ubiquitous presence of Propionibacteria in even healthy individuals necessitates an understanding of how pathological conversion occurs in sarcoidosis, a topic that warrants further study.[2,4,5] A number of other infectious agents such as Borrelia burgdorferi have also shown positive associations, though the studies have been limited in size and the evidence is not as strong at this time.[5]

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