The Effects of IL-17A Inhibitors on the Microbiota

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The use of an interleukin (IL) 17A inhibitor resulted in gut microbial dysbiosis and features of subclinical intestinal inflammation in a subgroup of psoriatic arthritis (PsA) and spondyloarthritis (SpA) patients, according to a multidisciplinary, collaborative study across several institutions published in Arthritis & Rheumatology.¹

Understanding the downstream effects of these perturbations is an important step toward the development of precision medicine approaches to SpA and PsA.

Previous research has shown that intestinal dysbiosis is associated with autoimmune disorders and chronic inflammatory arthritis, including SpA and PsA, the authors write. The microbiome can also affect the metabolism and bioavailability of drugs. Interleukin-17A inhibitors, in particular, have been associated with both intestinal inflammation and candidiasis. 

Manasson et al. hypothesized that biologic therapies, and IL-17A inhibition in particular, would correlate with perturbations of gut bacterial and fungal communities. 

Study Methods

Patients with PsA and SpA were recruited from clinics at the New York University Grossman School of Medicine, New York, before starting biologic therapy. Study authors collected fecal samples from 15 patients before and six months after the patients started treatment with tumor necrosis factor (TNF) inhibitors. All but one patient had no prior exposure to biologic agents. Fifteen age-, sex- and ethnicity-matched healthy controls were also studied. 

Fecal samples were collected from 14 patients before, five weeks after and three months after the patients started treatment with an IL-17A monoclonal antibody inhibitor (secukinumab). In this cohort, 64% previously demonstrated inadequate response to TNF inhibitors and were switched to IL-17 inhibitor therapy. “This allowed us to observe the natural history of microbiome fluctuation in a typical clinical progression of biologic therapy for SpA and psoriatic disease,” the authors write.

Collected samples underwent 16S rRNA (bacterial), ITS (fungal) and shotgun (metagenomics) sequencing and computational microbiome analysis. 

In addition to standard microbiome-related calculations of diversity and the relative abundance of each taxonomic group, the authors generated bacterial co-occurrence networks and correlated fecal levels of fatty acid metabolites and cytokines/proteins implicated in PsA and SpA pathogenesis or intestinal inflammation with the sequence data. 

The authors also analyzed a separate cohort of five HLA-B27+ SpA and ankylosing spondylitis (AS) patients who developed clinically overt Crohn’s disease after IL-17 inhibitor therapy and five patients who did not develop gut inflammation. Ileal biopsies were obtained before and after treatment, and evaluated for the presence of invasive/adherent bacteria, as well as expression of IL-23/Th-17 related cytokines, IL-25/IL-17E producing cells and type 2 innate lymphoid cells.