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Psoriasis is a chronic inflammatory condition characterized by systemic immune dysregulation. Over the past several years, advances in genetics, microbiology, immunology, and mouse models have revealed the complex interplay between the heritable and microenvironmental factors that drive the development of psoriatic inflammation. In the first of this two-part review series, the authors will discuss the newest insights into the pathogenesis of psoriatic disease and highlight how the evolution of these scientific fields has paved the way for a more personalized approach to psoriatic disease treatment.

Immunomodulatory drugs can inhibit bacterial growth, yet their mechanism of action, spectrum, and clinical relevance remain unknown. Methotrexate (MTX), a first-line rheumatoid arthritis (RA) treatment, inhibits mammalian dihydrofolate reductase (DHFR), but whether it directly impacts gut bacteria is unclear. We show that MTX broadly alters the human gut microbiota. Drug sensitivity varied across strains, but the mechanism of action against DHFR appears conserved between mammalian and bacterial cells. RA patient microbiotas were sensitive to MTX, and changes in gut bacterial taxa and gene family abundance were distinct between responders and non-responders. Transplantation of post-treatment samples into germ-free mice given an inflammatory trigger led to reduced immune activation relative to pre-treatment controls, enabling identification of MTX-modulated bacterial taxa associated with intestinal and splenic immune cells. Thus, conservation in cellular pathways across domains of life can result in broad off-target drug effects on the human gut microbiota with consequences for immune function.

We engineered a machine learning approach, MSHub, to enable auto-deconvolution of gas chromatography-mass spectrometry (GC-MS) data. We then designed workflows to enable the community to store, process, share, annotate, compare and perform molecular networking of GC-MS data within the Global Natural Product Social (GNPS) Molecular Networking analysis platform. MSHub/GNPS performs auto-deconvolution of compound fragmentation patterns via unsupervised non-negative matrix factorization and quantifies the reproducibility of fragmentation patterns across samples.

ObjectiveTo characterize the ecological effects of biologic therapies on the gut bacterial and fungal microbiome in psoriatic arthritis (PsA)/spondyloarthritis (SpA) patients.MethodsFecal samples from PsA/SpA patients pre- and posttreatment with tumor necrosis factor inhibitors (TNFi; n = 15) or an anti-interleukin-17A monoclonal antibody inhibitor (IL-17i; n = 14) underwent sequencing (16S ribosomal RNA, internal transcribed spacer and shotgun metagenomics) and computational microbiome analysis. Fecal levels of fatty acid metabolites and cytokines/proteins implicated in PsA/SpA pathogenesis or intestinal inflammation were correlated with sequence data. Additionally, ileal biopsies obtained from SpA patients who developed clinically overt Crohn's disease (CD) after treatment with IL-17i (n = 5) were analyzed for expression of IL-23/Th17-related cytokines, IL-25/IL-17E-producing cells, and type 2 innate lymphoid cells (ILC2s).ResultsThere were significant shifts in abundance of specific taxa after treatment with IL-17i compared to TNFi, particularly Clostridiales (P = 0.016) and Candida albicans (P = 0.041). These subclinical alterations correlated with changes in bacterial community co-occurrence, metabolic pathways, IL-23/Th17-related cytokines, and various fatty acids. Ileal biopsies showed that clinically overt CD was associated with expansion of IL-25/IL-17E-producing tuft cells and ILC2s (P < 0.05), compared to pre-IL-17i treatment levels.ConclusionIn a subgroup of SpA patients, the initiation of IL-17A blockade correlated with features of subclinical gut inflammation and intestinal dysbiosis of certain bacterial and fungal taxa, most notably C albicans. Further, IL-17i-related CD was associated with overexpression of IL-25/IL-17E-producing tuft cells and ILC2s. These results may help to explain the potential link between inhibition of a specific IL-17 pathway and the (sub)clinical gut inflammation observed in SpA.

Objective: The objective for this study was to evaluate the effects of short chain fatty acids (SCFAs) on arthritic bone remodeling. Methods: We treated a recently described preclinical murine model of psoriatic arthritis (PsA), R26STAT3Cstopfl/fl CD4Cre mice, with SCFA‐supplemented water. We also performed in vitro osteoclast differentiation assays in the presence of serum‐level SCFAs to evaluate the direct impact of these microbial metabolites on maturation and function of osteoclasts. We further characterized the molecular mechanism of SCFAs by transcriptional analysis. Results: The osteoporosis condition in R26STAT3Cstopfl/fl CD4Cre animals is attributed primarily to robust osteoclast differentiation driven by an expansion of osteoclast progenitor cells (OCPs), accompanied by impaired osteoblast development. We show that SCFA supplementation can rescue the osteoporosis phenotype in this model of PsA. Our in vitro experiments revealed an inhibitory effect of the SCFAs on osteoclast differentiation, even at very low serum concentrations. This suppression of osteoclast differentiation enabled SCFAs to impede osteoporosis development in R26STAT3Cstopfl/fl CD4Cre mice. Further interrogation revealed that bone marrow–derived OCPs from diseased mice expressed a higher level of SCFA receptors than those of control mice and that the progenitor cells in the bone marrow of SCFA‐treated mice presented a modified transcriptomic landscape, suggesting a direct impact of SCFAs on bone marrow progenitors in the context of osteoporosis. Conclusion: We demonstrated how gut microbiota‐derived SCFAs can regulate distal pathology (ie, osteoporosis) and identified a potential therapeutic option for restoring bone density in rheumatic disease, further highlighting the critical role of the gut–bone axis in these disorders. [ABSTRACT FROM AUTHOR]

Objective. To evaluate whether the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is a responsive instrument in psoriatic arthritis (PsA) and whether it differentiates between axial and peripheral disease activity in PsA. Methods. Individuals with PsA initiating therapy in a longitudinal cohort study based in the United States were included. Axial PsA (axPsA), most often also associated with peripheral disease, was defined as ful- fillment of the Assessment of Spondyloarthritis international Society axial spondyloarthritis classification criteria or presence of axial disease imaging features. Baseline BASDAI, individual BASDAI items, patient global assessment, patient pain, and Routine Assessment of Patient Index Data 3, and score changes following therapy initiation were descriptively reported. Standardized response means (SRMs) were calculated as the mean change divided by the SD of the change. Results. The mean (SD) baseline BASDAI score at the time of therapy initiation was 5.0 (2.2) among those with axPsA (n = 40) and 4.8 (2.0) among those with peripheral-only disease (n = 79). There was no significant difference in patient-reported outcome scores between the groups. The mean change for BASDAI was similar among axial vs peripheral disease (-0.75 vs -0.83). SRMs were similar across axial vs peripheral disease for BASDAI (-0.37 vs -0.44) and the individual BASDAI items. Conclusion. BASDAI has reasonable responsiveness in PsA but does not differentiate between axPsA and peripheral PsA. (ClinicalTrials.gov: NCT03378336) [ABSTRACT FROM AUTHOR]

Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease hypothesized to promote inflammation via cleavage of protease-activated receptor 1 (PAR1) and PAR2. KLK6 levels are elevated in multiple inflammatory and autoimmune conditions, but no definitive role in pathogenesis has been established. Here, we show that skin-targeted overexpression of KLK6 causes generalized, severe psoriasiform dermatitis with spontaneous development of debilitating psoriatic arthritis-like joint disease. The psoriatic skin and joint phenotypes are reversed by normalization of skin KLK6 levels and attenuated following genetic elimination of PAR1 but not PAR2. Conservation of this regulatory pathway was confirmed in human psoriasis using vorapaxar, an FDA-approved PAR1 antagonist, on explanted lesional skin from patients with psoriasis. Beyond defining a critical role for KLK6/PAR1 signaling in promoting psoriasis, our results demonstrate that KLK6/PAR1-mediated inflammation in the skin alone is sufficient to drive inflammatory joint disease. Further, we identify PAR1 as a promising cytokine-independent target in therapy of psoriasis and psoriatic arthritis., Introduction Psoriasis is a chronic, incurable systemic inflammatory disease with complex and incompletely understood pathogenesis. Two percent to 3% of the population worldwide suffers from psoriasis, and affected individuals show [...]