Background/Purpose: Psoriatic arthritis (PsA) is a heterogeneous inflammatory arthritis affecting multiple clinical domains. If left untreated, it has the potential for significant morbidity and disability. Prior to the introduction of TNF-alpha inhibitors (TNFi), therapeutic options were limited. Agents that block the IL-17 pathway (IL-17i) were recently FDA-approved, showing remarkable improvement in psoriasis, as well as similar efficacy to TNFi in PsA. Surprisingly, IL-17i are not effective for all autoimmune conditions, and appear to exacerbate Crohn’s disease, even leading to de novo intestinal inflammation. Because IL-17 plays a physiologic role in maintaining gut epithelial health and fighting extracellular bacteria and fungi, we propose that intestinal inflammation occurs as a result of microbial dysbiosis. The goal of this study was to better understand the interaction between IL-17i and the microbiome in humans and mice.

Methods: Fecal samples were collected from subjects with PsA pre- and post-treatment with secukinumab (n=9), an anti-IL-17A monoclonal antibody, and adalimumab (n=10), a TNFi, which served as the control. In parallel, fecal pellets were collected from wild type mice pre- and post-exposure to anti-IL-17 or MOPC isotype control antibodies. Samples underwent DNA extraction, amplification, and 16S rRNA gene sequencing with Illumina MiSeq. Analysis was performed with Quantitative Insights into Microbial Ecology (QIIME) and R. Additionally, short and medium chain fatty acids (SCFA/MCFA) were measured utilizing liquid chromatography coupled with mass spectrometry (LC-MS/MS).

Results: PsA subjects treated with IL-17i did not show differences in overall microbial alpha or beta diversity pre- and post-treatment. However, there was a significant shift in the Firmicutes to Bacteroidetes ratio after just five weeks of therapy. Subjects clustered into two well-defined groups based on expansion or contraction of the Clostridiales taxa. Relative abundance of Clostridiales correlated with levels of the SCFA acetate (r=0.4, p=0.09) and the MCFA hexanoate (r=0.4, p=0.09). These differences were absent in TNFi-treated controls. Similarly, mice exposed to anti-IL-17 antibody showed parallel perturbations in microbiota composition as demonstrated by alpha (p<0.05) and beta diversity (p<0.05), with expansion of Clostridia and related taxa (p<0.05).

Conclusion: We characterized the effects of biologic therapies on gut microbiota composition and metabolites in human PsA and in mice. Treatment with IL-17i leads to a gut microbial dysbiosis not seen with TNFi. Further studies to understand the downstream effects of these perturbations may allow for the development of precision medicine approaches to PsA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-effect-of-biologic-therapies-on-the-gut-microbial-composition-in-psoriatic-arthritis/