Full-thickness eyelid lesions in sarcoidosis

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Linkage of Type I Interferon Activity and TNF-Alpha Levels in Serum with Sarcoidosis Manifestations and Ancestry

BACKGROUND: Both type I interferon (IFN), also known as IFN-α and tumor necrosis factor alpha (TNF-α) have been implicated in the pathogenesis of sarcoidosis. We investigated serum levels of these cytokines in a large multi-ancestral sarcoidosis population to determine correlations between cytokine levels and disease phenotypes. METHODS: We studied serum samples from 98 patients with sarcoidosis, including 71 patients of African-American ancestry and 27 patients of European-American ancestry. Serum type I IFN was measured using a sensitive reporter cell assay and serum TNF-α was measured using a commercial ELISA kit. Clinical data including presence or absence of neurologic, cardiac, and severe pulmonary manifestations of sarcoidosis were abstracted from medical records. Twenty age-matched non-autoimmune controls were also studied from each ancestral background. Differences in cytokine levels between groups were analyzed with Mann-Whitney U test, and correlations were assessed using Spearman's rho. Multivariate logistic regression models were used to detect associations between cytokines and clinical manifestations. RESULTS: Significant differences in cytokine levels were observed between African- and European-American patients with sarcoidosis. In African-Americans, serum TNF-α levels were significantly higher relative to matched controls (P = 0.039), and patients with neurologic disease had significantly higher TNF-α than patients lacking this manifestation (P = 0.022). In European-Americans, serum type I IFN activity was higher in sarcoidosis cases as compared to matched controls, and patients with extra-pulmonary disease represented a high serum IFN subgroup (P = 0.0032). None of the associations observed were shared between the two ancestral groups. CONCLUSIONS: Our data indicate that significant associations between serum levels of TNF-α and type I IFN and clinical manifestations exist in a sarcoidosis cohort that differ significantly by self-reported ancestry. In each ancestral background, the cytokine elevated in patients with sarcoidosis was also associated with a particular disease phenotype. These findings may relate to ancestral differences in the molecular pathogenesis of this heterogeneous disease

An In Silico Modeling Approach to Understanding the Dynamics of Sarcoidosis

BACKGROUND: Sarcoidosis is a polygenic disease with diverse phenotypic presentations characterized by an abnormal antigen-mediated Th1 type immune response. At present, progress towards understanding sarcoidosis disease mechanisms and the development of novel treatments is limited by constraints attendant to conducting human research in a rare disease in the absence of relevant animal models. We sought to develop a computational model to enhance our understanding of the pathological mechanisms of and predict potential treatments of sarcoidosis. METHODOLOGY/RESULTS: Based upon the literature, we developed a computational model of known interactions between essential immune cells (antigen-presenting macrophages, effector and regulatory T cells) and cytokine mediators (IL-2, TNFα, IFNγ) of granulomatous inflammation during sarcoidosis. The dynamics of these interactions are described by a set of ordinary differential equations. The model predicts bistable switching behavior which is consistent with normal (self-limited) and "sarcoidosis-like" (sustained) activation of the inflammatory components of the system following a single antigen challenge. By perturbing the influence of model components using inhibitors of the cytokine mediators, distinct clinically relevant disease phenotypes were represented. Finally, the model was shown to be useful for pre-clinical testing of therapies based upon molecular targets and dose-effect relationships. CONCLUSIONS/SIGNIFICANCE: Our work illustrates a dynamic computer simulation of granulomatous inflammation scenarios that is useful for the investigation of disease mechanisms and for pre-clinical therapeutic testing. In lieu of relevant in vitro or animal surrogates, our model may provide for the screening of potential therapies for specific sarcoidosis disease phenotypes in advance of expensive clinical trials

Management of extrapulmonary sarcoidosis: challenges and solutions

Khalid Al-Kofahi,1,* Peter Korsten,2,* Christian Ascoli,3 Shanti Virupannavar,4 Mehdi Mirsaeidi,5 Ian Chang,6 Naim Qaqish,7 Lesley A Saketkoo,8 Robert P Baughman,9 Nadera J Sweiss3,4 1Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA; 2Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany; 3Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL, 4Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 5Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Miami Miller School of Medicine, Miami, FL, 6Department of Medicine, Michigan State University College of Osteopathic Medicine, East Lansing, MI, 7Department of Gastroenterology, Hepatology and Nutrition, University of Buffalo, Buffalo, NY, 8New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, 9Department of Medicine, University Medical Center of Cincinnati, Cincinnati, OH, USA *These authors contributed equally to this work Background: Sarcoidosis is a chronic multisystem disease of unknown etiology characterized by noncaseating granulomas that most often involves the lungs, but frequently has extrapulmonary manifestations, which might be difficult to treat in individual patients. Objective: To review different disease manifestations, focusing on extrapulmonary organ systems, and to provide treatment options for refractory cases. Materials and methods: We performed a literature search using Medline and Google Scholar for individual or combined keywords of “sarcoidosis, extrapulmonary, treatment, kidney, neurosarcoidosis, cardiovascular, gastrointestinal, transplantation, musculoskeletal, rheumatology, arthritis, and skin”. Peer-reviewed articles, including review articles, clinical trials, observational trials, and case reports that were published in English were included. References from retrieved articles were also manually searched for relevant articles.Results and conclusion: Isolated involvement of a single organ or organ system is rare in sarcoidosis, and thus all patients must be thoroughly evaluated for additional disease manifestations. Cardiac sarcoidosis and neurosarcoidosis may be life-threatening. Clinicians need to assess patients comprehensively using clinical, laboratory, imaging, and histopathological data to recommend competently the best and least toxic treatment option for the individual patient. Keywords: sarcoidosis, immunosuppressive agents, chronic granulomatous diseases, diagnostic test