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Emerging Molecular Targets for the Treatment of Refractory Sarcoidosis.

ABSTRACT: Sarcoidosis is a multisystem granulomatous disease of unknown origin that has variable clinical course and can affect nearly any organ. It has a chronic course in about 25% of patients. Corticosteroids (CS) are the cornerstone of therapy but their long-term use is associated with cumulative toxicity. Commonly used CS-sparing agents include methotrexate, cyclophosphamide, azathioprine, and mycophenolate mofetil. Twenty to forty percentage of sarcoidosis patients are refractory to these therapies or develop severe adverse events. Therefore, additional and targeted CS-sparing agents are needed for chronic sarcoidosis. Macrophage activation, interferon response, and formation of the granuloma are mainly mediated by T helper-1 responses. Different pro-inflammatory cytokines such as interleukin (IL)-8, IL-12, IL-6, and tumor necrosis factor-alpha (TNF-?) have been shown to be highly expressed in sarcoidosis-affected tissues. As a result of increased production of these cytokines, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is constitutively active in sarcoidosis. Several studies of biological agents that target TNF-? have reported their efficacy and appear today as a second line option in refractory sarcoidosis. Some case series report a positive effect of tocilizumab an anti-IL-6 monoclonal antibody in this setting. More recently, JAK inhibition appears as a new promising strategy. This review highlights key advances on the management of chronic refractory sarcoidosis. Novel therapeutic strategies and treatment agents to manage the disease are described.

SUBMITTER: Boleto G

PROVIDER: S-EPMC7732552 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Emerging Molecular Targets for the Treatment of Refractory Sarcoidosis.

Boleto Gonçalo G Vieira Matheus M Desbois Anne Claire AC Saadoun David D Cacoub Patrice P

Frontiers in medicine 20201124

Sarcoidosis is a multisystem granulomatous disease of unknown origin that has variable clinical course and can affect nearly any organ. It has a chronic course in about 25% of patients. Corticosteroids (CS) are the cornerstone of therapy but their long-term use is associated with cumulative toxicity. Commonly used CS-sparing agents include methotrexate, cyclophosphamide, azathioprine, and mycophenolate mofetil. Twenty to forty percentage of sarcoidosis patients are refractory to these therapies ...[more]

PMID: 33330556

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Project description:Sarcoidosis is a multi-system disease of unknown etiology characterized by granuloma formation in various organs (especially lung and mediastinohilar lymph nodes). In more than half of patients, the disease resolves spontaneously. When indicated, it usually responds to corticosteroids, the first-line treatment, but some patients may not respond or tolerate them. An absence of treatment response is rare and urges for verifying the absence of a diagnosis error, the good adherence of the treatment, the presence of active lesions susceptible to respond since fibrotic lesions are irreversible. That is when second-line treatments, immunosuppressants (methotrexate, leflunomide, azathioprine, mycophenolate mofetil, hydroxychloroquine), should be considered. Methotrexate is the only first-line immunosuppressant validated by a randomized controlled trial. Refractory sarcoidosis is not yet a well-defined condition, but it remains a real challenge for the physicians. Herein, we considered refractory sarcoidosis as a disease in which second-line treatments are not sufficient to achieve satisfying disease control or satisfying corticosteroids tapering. Tumor necrosis alpha inhibitors, third-line treatments, have been validated through randomized controlled trials. There are currently no guidelines or recommendations regarding refractory sarcoidosis. Moreover, criteria defining non-response to treatment need to be clearly specified. The delay to achieve response to organ involvement and drugs also should be defined. In the past ten years, the efficacy of several immunosuppressants beforehand used in other autoimmune or inflammatory diseases was reported in refractory cases series. Among them, anti-CD20 antibodies (rituximab), repository corticotrophin injection, and anti-JAK therapy anti-interleukin-6 receptor monoclonal antibody (tocilizumab) were the main reported. Unfortunately, no clinical trial is available to validate their use in the case of sarcoidosis. Currently, other immunosuppressants such as JAK inhibitors are on trial to assess their efficacy in sarcoidosis. In this review, we propose to summarize the state of the art regarding the use of immunosuppressants and their management in the case of refractory or multidrug-resistant sarcoidosis.

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Emerging Molecular Targets for the Treatment of Refractory Sarcoidosis.

Publications

Emerging Molecular Targets for the Treatment of Refractory Sarcoidosis.

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