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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.
Tracking Results
Patients in the IL-17 inhibitor cohort were older and more predominantly women than in the TNF inhibitor group. However, neither parameter reached statistical significance. The majority of patients had PsA. Nine subjects had psoriasis (64.3%) and were diagnosed with peripheral PsA (35.7%), axial PsA (7.1%), peripheral/axial PsA (28.6%) and axial SpA (21.4%).
In the TNF inhibitor cohort, all patients had psoriasis and either peripheral PsA (53.3%) or a combination of peripheral/axial PsA (46.7%).
About one-third of patients in each cohort had elevated C-reactive protein levels (28.6% in the IL-17 group, compared with 33.3% in the TNF inhibitor group).
The authors found an average expansion of Clostridiales and Erysipelotrichales and reduction of Bacteroidales in those with PsA and SpA compared with healthy subjects. They also found an average expansion of Clostridiales and reduction of Bacteroidales after TNF inhibitor therapy compared with baseline, and an average reduction of Clostridiales with concomitant expansion of Bacteroidales after IL-17 inhibitor therapy, compared with baseline. Prominent shifts in Clostridiales relative abundance were seen with IL-17 inhibitor therapy, which were less pronounced with TNF inhibitor therapy.
Treatment with an IL-17 inhibitor also was associated with a “robust expansion” of Candida (29% of cohort) and C. albicans (21% of cohort) in a subset of patients, although a smaller subject group had a similar reduction in Candida.
Although the authors found various correlations with intestinal inflammatory mediators, none of the participants had clinically evident gut inflammation.
Ileal biopsies performed in a separate cohort of five patients showed clinically overt Crohn’s disease was associated with an expansion of IL-25/IL-17E-producing tuft cells and group 2 innate lymphoid cells, compared with levels before treatment with IL-17 inhibitors. Other research groups have shown microbial changes after biologic therapies, including a significant reduction in Escherichia coli after adalimumab, that appeared to make the microbiome more similar to the composition of healthy individuals.2
In the current study, limitations stated by the authors include small cohort sizes, subject recruitment from different geographical areas, a phenotypically heterogenous population and different drugs used in the TNF inhibitor cohort. This type of study will need validation in larger prospective cohorts, the authors write. “Extending our results would also help us understand whether baseline gut microbiota can be used as predictors of biologic therapy response, as in the case of cancer immunotherapies.”
“Although our study was correlative in nature, requiring validation and expansion, a better understanding of the biologic-associated gut microbial perturbations could potentially lead to precision medicine approaches in spondyloarthritis and psoriatic arthritis, as well as the ability to predict individuals who are at risk for adverse events,” says study author Julia Manasson, MD, Division of Rheumatology, Department of Medicine, New York University Grossman School of Medicine.
The study authors are working on further research to characterize gut microbial signatures of PsA in populations of genetically similar and identical individuals to control for confounding HLA. They are also exploring how microbial signatures in PsA can be altered with medium-chain fatty acid supplementation.
Additional Perspective
Joerg Ermann, MD, a rheumatologist with Brigham and Women’s Hospital, Boston, found the research important because it emphasizes the bi-directional relationship between intestinal microbiota and the human immune system. The study would have been stronger with a larger sample size and better matched experimental groups, he says.
“I think this is an interesting research direction, but results need to be confirmed with a bigger study and subjects randomized to the different treatments. Ideally, one would tag on fecal sample collection to clinical trials,” Dr. Ermann says. He does not think the research into gut microbiota findings is currently of major interest to pharmaceutical companies developing drugs for spondyloarthritis. However, this might change under the influence of studies like the one by Manasson et al.
The field needs a better understanding of who will respond to a specific therapy and who might develop inflammatory bowel disease or other side effects. The analysis of fecal microbiota is a promising approach to the development of much needed biomarkers.
Vanessa Caceres is a medical writer in Bradenton, Fla.
References
- Manasson J, Coras R, Guma M. Interleukin-17 inhibition in spondyloarthritis is associated with subclinical gut microbiome perturbations and a distinctive interleukin-25-driven intestinal inflammation. Arthritis Rheumatol. 2020 Apr;72(4):645–657.
- Busquets D, Mas-de-Xaxars T, Lopez-Siles M, et al. Anti-tumour necrosis factor treatment with adalimumab induces changes in the microbiota of Crohn’s disease. J Crohns Colitis. 2015 Oct;9(10):899–906.
