The Janus kinase/signal transduction and activator of transcription (JAK-STAT) signaling pathway is implicated in the pathogenesis of inflammatory and autoimmune diseases including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Many cytokines involved in the pathogenesis of autoimmune and inflammatory diseases use JAKs and STATs to transduce intracellular signals. Mutations in JAK and STAT genes cause a number of immunodeficiency syndromes, and polymorphisms in these genes are associated with autoimmune diseases. The success of small-molecule JAK inhibitors (Jakinibs) in the treatment of rheumatologic disease demonstrates that intracellular signaling pathways can be targeted therapeutically to treat autoimmunity. Tofacitinib, the first rheumatologic Jakinib, is US Food and Drug Administration (FDA) approved for rheumatoid arthritis and is currently under investigation for other autoimmune diseases. Many other Jakinibs are in preclinical development or in various phases of clinical trials. This review describes the JAK-STAT pathway, outlines its role in autoimmunity, and explains the rationale/pre-clinical evidence for targeting JAK-STAT signaling. The safety and clinical efficacy of the Jakinibs are reviewed, starting with the FDA-approved Jakinib tofacitinib, and continuing on to next-generation Jakinibs. Recent and ongoing studies are emphasized, with a focus on emerging indications for JAK inhibition and novel mechanisms of JAK-STAT signaling blockade.
Objective To update evidence‐based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). Methods We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat‐to‐target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel. Results Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co‐administration of low‐dose methotrexate with TNFi is not recommended, nor is a strict treat‐to‐target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended. Conclusion These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.
Objective To update evidence‐based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). Methods We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat‐to‐target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel. Results Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co‐administration of low‐dose methotrexate with TNFi is not recommended, nor is a strict treat‐to‐target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended. Conclusion These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.
Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study’s primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, −26.5), cholesterol efflux capacity (p = 0.08, CI 95%: −0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.
Objective. Autoreactive IgE antibodies have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). We hypothesize that omalizumab, a monoclonal antibody binding IgE, may improve SLE activity by reducing type I interferon (IFN) production by hampering plasmacytoid dendritic cells and basophil activation. This study was undertaken to assess the safety, tolerability, and clinical efficacy of omalizumab in mild to moderate SLE.Methods. Sixteen subjects with SLE and a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≥4 and elevated autoreactive IgE antibody levels were randomized to receive omalizumab or placebo (2:1) for 16 weeks, followed by 16 weeks of open-label treatment and a 4-week washout period. The SLEDAI-2K score, British Isles Lupus Assessment Group index (BILAG 2004) score, and physician's global assessment of disease activity were recorded at each visit. The type I IFN-induced gene signature was determined using quantitative polymerase chain reaction.Results. Omalizumab was well tolerated with no allergic reactions, and mostly mild adverse events comparable to those experienced with placebo treatment. SLEDAI-2K scores improved in the omalizumab group compared to the placebo group at week 16 (P = 0.038), as well as during the open-label phase in subjects initially receiving placebo (P = 0.02). No worsening in BILAG scores or the physician's global assessment was detected. There was a trend toward a reduction in IFN gene signature in subjects treated with omalizumab (P = 0.11), especially in subjects with a high baseline IFN signature (P = 0.052).Conclusion. Our findings indicate that omalizumab is well tolerated in SLE and is associated with improvement in disease activity. Larger randomized clinical trials will be needed to assess the efficacy of omalizumab in patients with SLE.
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