Anti-IL-17 therapy in treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trials

Abstract

IL-17 has a role in inflammation in RA, and its levels in joints correlate with disease severity. Multiple RCTs have been performed to study effects of anti-IL-17 agents. The objective of this study was to perform a systematic review and meta-analysis to analyze the efficacy and safety of anti-IL-17 agents in the management of RA. This work is based on a systematic review of studies retrieved by a sensitive search strategy in PubMed, EMBASE and Cochrane CENTRAL from inception through 9/7/15. Study selection criteria were the following: adult patients (age ≥ 18 years) with RAs, random selection of patients for anti-IL-17 therapy and treatment response compared to placebo. We performed systematic literature review per PRISMA guideline and two investigators independently selected seven randomized clinical trials (RCTs) for meta-analysis. We used random effect model calculating odds ratio (OR) and 95 % confidence interval (CI) to measure the efficacy with ACR20/50/70 responses and the safety with adverse events. Seven studies with total of 1226 patients including 905 in anti-IL-17 group and 321 in placebo were included in the meta-analysis. Anti-IL-17 was effective in achieving ACR20 and ACR50 compared to placebo (OR 2.47, 95 % CI 1.29-4.72, P = 0.006, I (2) 77 % and OR 2.94, 95 % CI 1.37-6.28, P = 0.005, I (2) 64 %, respectively). Data analysis for ACR70 showed a favorable trend toward anti-IL-17 (OR 2.62, 95 % CI 1-6.89, P = 0.05, I (2) 15 %). Subgroup analysis of ACR20 for individual anti-IL-17 agents showed that ixekizumab was more effective than placebo, while secukinumab showed a trend toward achieving the ACR20 response. However, brodalumab was not effective compared to placebo. Safety analysis did not show increased risk of any or serious adverse effects by anti-IL-17 compared to placebo (OR 1.23, 95 % CI 0.94-1.61, P = 0.13, I (2) = 0 % and OR 1.28, 95 % CI 0.57-2.88, P = 0.55, I (2) = 0 %, respectively). This meta-analysis concludes that anti-IL-17 is effective in the treatment of RA without increased risk of any or serious adverse effects; however, the results are limited by significant heterogeneity and small duration of studies.

The role of neutrophils and NETosis in autoimmune and renal diseases

“…Anti-TNF monoclonal antibodies are now the mainstay of rheumatoid arthritis treatment 160 and anti-IL-17 monoclonal antibodies have also shown some efficacy for the treatment of this disease 161 . Similarly, modulating IL-17 signalling, which is required for the development of lupus glomerulonephritis, with monoclonal antibodies is a potential therapeutic strategy for the treatment of SLE, especially in cases with kidney involvement 131 .…”

Functional and phenotypic heterogeneity of Th17 cells in health and disease

“…In patients with RA, IL‐17 + FoxP3 + T cells can be identified in RA synovia and this provides further evidence of Treg/Th17 transdifferentiation . Although some clinical trials have not shown efficacy when using anti‐IL‐17 therapy for RA, there is evidence for increased Th17 cells following anti‐TNFα therapy . Moreover, evidence from phase two clinical trials with methotrexate, or in anti‐TNFα nonresponsive patients, indicates that disease in some RA patients is driven by Th17 cells and that treatment with anti‐IL‐17 antibody could be therapeutically beneficial (Table ) …”

“…35 Although some clinical trials have not shown efficacy when using anti-IL-17 therapy for RA, there is evidence for increased Th17 cells following anti-TNFα therapy. 4,55,56 Moreover, evidence from phase two clinical trials with methotrexate, or in anti-TNFα nonresponsive patients, indicates that disease in some RA patients is driven by Th17 cells and that treatment with anti-IL-17 antibody could be therapeutically beneficial (Table 2). 57 RA is traditionally associated with the presence of rheumatoid factors and anticyclic citrullinated peptide autoantibodies.…”

Yin and yang of interleukin-17 in host immunity to infection

“…Similarly, excessive IL-17 leads to the upregulation of neutrophil-attracting chemokines and subsequent neutrophil infiltration and inflammation during COPD 166, 167 . A number of biologic drugs targeting IL-17A/F and IL-17RA are being used or evaluated as treatment options against several diseases, such as COPD 168 , psoriasis, and RA, with impressive efficacy 169, 170 . However, IL-17 is strongly associated with the protection against Mtb clinical isolates and fungal infections.…”