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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 determine the responsiveness to therapy and minimum clinically important improvement (MCII) for patient‐reported outcome measures in psoriatic arthritis (PsA) and to examine the impact of baseline disease activity on the ability to demonstrate change. Methods: A longitudinal cohort study was performed within the PsA Research Consortium. Patients completed several patient‐reported outcomes, including the Routine Assessment of Patient Index Data, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Psoriatic Arthritis Impact of Disease 12‐item (PsAID12) questionnaire, and others. The mean change in the scores between visits and standardized response means (SRMs) were calculated. The MCII was calculated as the mean change in score among patients who reported minimal improvement. SRMs and MCIIs were compared among subgroups with moderate to highly active PsA and those with lower disease activity. Results: Among 171 patients, 266 therapy courses were included. The mean ± SD age was 51 ± 13.8 years, 53% were female, and the mean swollen and tender joint counts were 3 and 6, respectively, at baseline. SRMs and MCII for all measures were small to moderate, although greater among those with higher baseline disease activity. BASDAI had the best SRM overall and for less active PsA, and the clinical Disease Activity of PsA (cDAPSA) and PsAID12 were best for those with higher disease activity. Conclusion: SRMs and MCII were relatively small in this real‐world population, particularly among those with lower disease activity at baseline. BASDAI, cDAPSA, and PsAID12 had good sensitivity to change, but selection for use in trials should consider the baseline disease activity of patients to be enrolled. [ABSTRACT FROM AUTHOR]

Objective: To evaluate seroreactivity and disease flares after COVID‐19 vaccination in a multiethnic/multiracial cohort of patients with systemic lupus erythematosus (SLE). Methods: Ninety SLE patients and 20 healthy controls receiving a complete COVID‐19 vaccine regimen were included. IgG seroreactivity to the SARS–CoV‐2 spike receptor‐binding domain (RBD) and SARS–CoV‐2 microneutralization were used to evaluate B cell responses; interferon‐γ (IFNγ) production was measured by enzyme‐linked immunospot (ELISpot) assay in order to assess T cell responses. Disease activity was measured by the hybrid SLE Disease Activity Index (SLEDAI), and flares were identified according to the Safety of Estrogens in Lupus Erythematosus National Assessment–SLEDAI flare index. Results: Overall, fully vaccinated SLE patients produced significantly lower IgG antibodies against SARS–CoV‐2 spike RBD compared to fully vaccinated controls. Twenty‐six SLE patients (28.8%) generated an IgG response below that of the lowest control (<100 units/ml). In logistic regression analyses, the use of any immunosuppressant or prednisone and a normal anti–double‐stranded DNA antibody level prior to vaccination were associated with decreased vaccine responses. IgG seroreactivity to the SARS–CoV‐2 spike RBD strongly correlated with the SARS–CoV‐2 microneutralization titers and correlated with antigen‐specific IFNγ production determined by ELISpot. In a subset of patients with poor antibody responses, IFNγ production was similarly diminished. Pre‐ and postvaccination SLEDAI scores were similar in both groups. Postvaccination flares occurred in 11.4% of patients; 1.3% of these were severe. Conclusion: In a multiethnic/multiracial study of SLE patients, 29% had a low response to the COVID‐19 vaccine which was associated with receiving immunosuppressive therapy. Reassuringly, severe disease flares were rare. While minimal protective levels remain unknown, these data suggest that protocol development is needed to assess the efficacy of booster vaccination. [ABSTRACT FROM AUTHOR]

The article discusses developments in the treatment of psoriatic arthritis (PsA), particularly the adoption of combination immunomodulatory therapies. Also cited are the use of tumor necrosis factor inhibitors (TNFi) to identify the signs and symptoms of PsA, rheumatoid arthritis (RA), and psoriasis, and some TNFis like etanercept, adalimumab, and infliximab.

Objective: Although oral methotrexate (MTX) remains the anchor drug for rheumatoid arthritis (RA), up to 50% of patients do not achieve a clinically adequate outcome. In addition, there is a lack of prognostic tools for treatment response prior to drug initiation. This study was undertaken to investigate whether interindividual differences in the human gut microbiome can aid in the prediction of MTX efficacy in new‐onset RA. Methods: We performed 16S ribosomal RNA gene and shotgun metagenomic sequencing on the baseline gut microbiomes of drug‐naive patients with new‐onset RA (n = 26). Results were validated in an additional independent cohort (n = 21). To gain insight into potential microbial mechanisms, we conducted ex vivo experiments coupled with metabolomics analysis to evaluate the association between microbiome‐driven MTX depletion and clinical response. Results: Our analysis revealed significant associations of the abundance of gut bacterial taxa and their genes with future clinical response (q < 0.05), including orthologs related to purine and MTX metabolism. Machine learning techniques were applied to the metagenomic data, resulting in a microbiome‐based model that predicted lack of response to MTX in an independent group of patients. Finally, MTX levels remaining after ex vivo incubation with distal gut samples from pretreatment RA patients significantly correlated with the magnitude of future clinical response, suggesting a possible direct effect of the gut microbiome on MTX metabolism and treatment outcomes. Conclusion: Taken together, these findings are the first step toward predicting lack of response to oral MTX in patients with new‐onset RA and support the value of the gut microbiome as a possible prognostic tool and as a potential target in RA therapeutics. [ABSTRACT FROM AUTHOR]

Objective: To characterize the hospitalization and death rates among patients with inflammatory arthritis (IA) affected by coronavirus disease 2019 (COVID‐19) and to analyze the associations of comorbidities and immunomodulatory medications with infection outcomes. Methods: Data on clinical and demographic features, maintenance treatment, disease course, and outcomes in individuals with IA (rheumatoid arthritis and spondyloarthritis) with symptomatic COVID‐19 infection were prospectively assessed via web‐based questionnaire followed by individual phone calls and electronic medical record review. Baseline characteristics and medication use were summarized for hospitalized and ambulatory patients, and outcomes with the different medication classes were compared using multivariable logistic regression. Results: A total of 103 patients with IA were included in the study (80 with confirmed COVID‐19 and 23 with high suspicion of COVID‐19). Hospitalization was required in 26% of the participants, and 4% died. Patients who were hospitalized were significantly more likely to be older (P < 0.001) and have comorbid hypertension (P = 0.001) and chronic obstructive pulmonary disease (P = 0.02). IA patients taking oral glucocorticoids had an increased likelihood of being admitted for COVID‐19 (P < 0.001), while those receiving maintenance anticytokine biologic therapies did not. Conclusion: Among patients with underlying IA, COVID‐19 outcomes were worse in those receiving glucocorticoids but not in patients receiving maintenance anticytokine therapy. Further work is needed to understand whether immunomodulatory therapies affect COVID‐19 incidence. [ABSTRACT FROM AUTHOR]

Objective: To characterize patients with systemic lupus erythematosus (SLE) affected by coronavirus disease 2019 (COVID‐19) and to analyze associations of comorbidities and medications on infection outcomes. Methods: Patients with SLE and reverse transcriptase–polymerase chain reaction–confirmed COVID‐19 were identified through an established New York University lupus cohort, query of 2 hospital systems, and referrals from rheumatologists. Data were prospectively collected via a web‐based questionnaire and review of medical records. Data on baseline characteristics were obtained for all patients with COVID‐19 to analyze risk factors for hospitalization. Data were also collected on asymptomatic patients and those with COVID‐19–like symptoms who tested negative or were not tested. Statistical analyses were limited to confirmed COVID‐19–positive patients. Results: A total of 226 SLE patients were included: 41 with confirmed COVID‐19, 19 who tested negative for COVID‐19, 42 with COVID‐19–like symptoms who did not get tested, and 124 who remained asymptomatic without testing. Of the SLE patients with confirmed COVID‐19, hospitalization was required in 24 (59%) and intensive care unit–level of care in 4, and 4 died. Hospitalized patients tended to be older, nonwhite, Hispanic, have higher body mas index (BMI), history of nephritis, and at least 1 comorbidity. An exploratory (due to limited sample size) logistic regression analysis identified race, presence of at least 1 comorbidity, and BMI as independent predictors of hospitalization. Conclusion: In general, the variables predictive of hospitalization in our SLE patients were similar to those identified in the general population. Further studies are needed to understand additional risk factors for poor COVID‐19 outcomes in patients with SLE. [ABSTRACT FROM AUTHOR]

Objective: Intestinal microbiota are associated with the development of inflammatory arthritis. The aim of this study was to dissect intestinal mucosal immune responses in the preclinical phase of arthritis and determine whether the presence of Th17 cells, beyond involvement of the cytokine interleukin‐17 (IL‐17), is required for arthritis development, and whether the involvement of Th17 cells in arthritis depends on the composition of the host microbiota. Methods: Mucosal T cell production of IL‐17, interferon‐γ, tumor necrosis factor α (TNFα), IL‐22, and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) was analyzed by flow cytometry and Luminex assay before arthritis onset in mice immunized to develop collagen‐induced arthritis (CIA). Pathogenic features of arthritis in mice with CIA and mice with antigen‐induced arthritis were compared between Th17 cell–deficient (CD4‐Cre+Rorcflox/flox) and Th17 cell–sufficient (CD4‐Cre−Rorcflox/flox) mice. In addition, the impact of intestinal microbiota on the Th17 cell dependence of CIA was assessed. Results: Lamina propria CD4 T cells were activated before the onset of arthritis in mice with CIA, with marked up‐regulation of several cytokines, including IL‐17A, TNFα, and GM‐CSF. CD4‐Cre+Rorcflox/flox mice showed a specific reduction in intestinal mucosal levels of Th17 cells and partially reduced levels of IL‐17–producing CD8 T cells. However, total levels of IL‐17A, mostly produced by γδ T cells and neutrophils, were unaffected. The severity of arthritis was significantly reduced in Th17 cell–deficient mice, suggesting that Th17 cells have additional, IL‐17A–independent roles in inflammatory arthritis. Accordingly, antigen‐stimulated T cells from Th17 cell–deficient mice produced less IL‐17A, IL‐17F, and GM‐CSF. Importantly, the dependence of CIA on the involvement of Th17 cells was mitigated in the presence of an alternative microbiome. Conclusion: These data from murine models suggest that activation of mucosal immunity precedes the development of arthritis, and also that Th17 cells have a microbiota‐dependent role in arthritis. Therefore, a microbiome‐guided stratification of patients might improve the efficacy of Th17‐targeted therapies. [ABSTRACT FROM AUTHOR]

Objective: To introduce a novel preclinical animal model of psoriatic arthritis (PsA) in R26Stat3Cstopfl/fl CD4Cre mice, and to investigate the role of Th17 cytokines in the disease pathogenesis. Methods: We characterized a novel murine model of Th17‐driven cutaneous and synovio‐entheseal disease directed by T cell–specific expression of a hyperactive Stat3 allele. By crossing R26Stat3Cstopfl/fl CD4Cre mice onto an interleukin‐22 (IL‐22)–knockout background or treating the mice with a neutralizing antibody against IL‐17, we interrogated how these Th17 cytokines could contribute to the pathogenesis of PsA. Results: R26Stat3Cstopfl/fl CD4Cre mice developed acanthosis, hyperkeratosis, and parakeratosis of the skin, as well as enthesitis/tendinitis and periarticular bone erosion in different joints, accompanied by osteopenia. T cell–specific expression of a hyperactive Stat3C allele was found to drive the augmented Th17 response in these animals. Careful characterization of the mouse bone marrow revealed an increase in osteoclast progenitor (OCP) and RANKL‐producing cells, which contributed to the osteopenia phenotype observed in the mutant animals. Abrogation of the Th17 cytokines IL‐17 or IL‐22 improved both the skin and bone phenotype in R26Stat3Cstopfl/fl CD4Cre mice, revealing a central role of Th17 cells in the regulation of OCP and RANKL expression on stromal cells. Conclusion: Perturbation of the IL‐23/Th17 axis instigates Th17‐mediated inflammation in R26Stat3Cstopfl/fl CD4Cre mice, leading to cutaneous and synovio‐entheseal inflammation and bone pathologic features highly reminiscent of human PsA. Both IL‐17A and IL‐22 produced by Th17 cells appear to play critical roles in promoting the cutaneous and musculoskeletal inflammation that characterizes PsA. [ABSTRACT FROM AUTHOR]

Objective: Reactive arthritis (ReA) is an inflammatory disorder occurring several weeks after gastrointestinal or genitourinary tract infections. HLA–B27 positivity is considered a risk factor, although it is not necessarily predictive of disease incidence. Among nongenetic factors, the intestinal microbiome may play a role in disease susceptibility. The objective of this study was to characterize the gut microbiota and host gene interactions in ReA and postinfectious spondyloarthritis. Methods: Adult subjects with peripheral spondyloarthritis and control subjects with preceding infections who did not develop arthritis were prospectively recruited from a geographic region with a high prevalence of ReA. Clinical variables, HLA status, and 16S ribosomal RNA gene sequencing of intestinal microbiota were analyzed. Results: Subjects with ReA showed no significant differences from controls in gut bacterial richness or diversity. However, there was a significantly higher abundance of Erwinia and Pseudomonas and an increased prevalence of typical enteropathogens associated with ReA. Subjects with ultrasound evidence of enthesitis were enriched in Campylobacter, while subjects with uveitis and radiographic sacroiliitis were enriched in Erwinia and unclassified Ruminococcaceae, respectively; both were enriched in Dialister. Host genetics, particularly HLA–A24, were associated with differences in gut microbiota diversity irrespective of disease status. We identified several co‐occurring taxa that were also predictive of HLA–A24 status. Conclusion: This is the first culture‐independent study characterizing the gut microbial community in postinfectious arthritis. Although bacterial factors correlated with disease presence and clinical features of ReA, host genetics also appeared to be a major independent driver of intestinal community composition. Understanding of these gut microbiota–host genetic relationships may further clarify the pathogenesis of postinfectious spondyloarthritides. [ABSTRACT FROM AUTHOR]

The article reviews various studies regarding intestinal microbiome and its role in prosiatic arthritis (PsA), rheumatoid arthritis (RA) and spondyloarthritides (SpA). Topics covered include the composition and function of microbiome, its prokaryotic nature, the hypothesis on toxemic factor and jejunoileal bypass surgery triggering arthritis syndrome. Conclusions indicated the need to explore microbiome aspects as to the dysbiotic process, microbial perturbation and immunosuppressive drugs.

A response from the authors of the article "Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease," published in the 2015 issue is presented.

Objective To characterize the diversity and taxonomic relative abundance of the gut microbiota in patients with never-treated, recent-onset psoriatic arthritis (PsA). Methods High-throughput 16S ribosomal RNA pyrosequencing was utilized to compare the community composition of gut microbiota in patients with PsA (n = 16), patients with psoriasis of the skin (n = 15), and healthy, matched control subjects (n = 17). Samples were further assessed for the presence and levels of fecal and serum secretory IgA (sIgA), proinflammatory proteins, and fatty acids. Results The gut microbiota observed in patients with PsA and patients with skin psoriasis was less diverse when compared to that in healthy controls. This could be attributed to the reduced presence of several taxa. Samples from both patient groups showed a relative decrease in abundance of Coprococcus species, while samples from PsA patients were also characterized by a significant reduction in Akkermansia, Ruminococcus, and Pseudobutyrivibrio. Supernatants of fecal samples from PsA patients revealed an increase in sIgA levels and decrease in RANKL levels. Analysis of fatty acids revealed low fecal quantities of hexanoate and heptanoate in both patients with PsA and patients with psoriasis. Conclusion Patients with PsA and patients with skin psoriasis had a lower relative abundance of multiple intestinal bacteria. Although some genera were concomitantly decreased in both conditions, PsA samples had a lower abundance of reportedly beneficial taxa. This gut microbiota profile in PsA was similar to that previously described in patients with inflammatory bowel disease and was associated with changes in specific inflammatory proteins unique to this group, and distinct from that in patients with skin psoriasis and healthy controls. Thus, the role of the gut microbiome in the continuum of psoriasis-PsA pathogenesis and the associated immune response merits further study. [ABSTRACT FROM AUTHOR]

Objective To profile the abundance and diversity of subgingival oral microbiota in patients with never-treated, new-onset rheumatoid arthritis (RA). Methods Periodontal disease (PD) status, clinical activity, and sociodemographic factors were determined in patients with new-onset RA, patients with chronic RA, and healthy subjects. Multiplexed-454 pyrosequencing was used to compare the composition of subgingival microbiota and establish correlations between the presence/abundance of bacteria and disease phenotypes. Anti- Porphyromonas gingivalis antibody testing was performed to assess prior exposure to the bacterial pathogen P gingivalis. Results The more advanced forms of periodontitis were already present at disease onset in patients with new-onset RA. The subgingival microbiota observed in patients with new-onset RA was distinct from that found in healthy controls. In most cases, however, these microbial differences could be attributed to the severity of PD and were not inherent to RA. The presence and abundance of P gingivalis were also directly associated with the severity of PD and were not unique to RA. The presence of P gingivalis was not correlated with anti-citrullinated protein antibody (ACPA) titers. Overall exposure to P gingivalis was similar between patients with new-onset RA and controls, observed in 78% of patients and 83% of controls. The presence and abundance of Anaeroglobus geminatus correlated with the presence of ACPAs/rheumatoid factor. Prevotella and Leptotrichia species were the only characteristic taxa observed in patients with new-onset RA irrespective of PD status. Conclusion Patients with new-onset RA exhibited a high prevalence of PD at disease onset, despite their young age and paucity of smoking history. The subgingival microbiota profile in patients with new-onset RA was similar to that in patients with chronic RA and healthy subjects whose PD was of comparable severity. Although colonization with P gingivalis correlated with the severity of PD, overall exposure to P gingivalis was similar among the groups. The role of A geminatus and Prevotella/Leptotrichia species in this process merits further study. [ABSTRACT FROM AUTHOR]

Two letters to the editors are presented in response to the articles "Association Between Periodontitis and Hemorrhagic Stroke Among Koreans: A Case-Control Study" by H. D. Kim and colleagues and "Clinical Periodontal and Microbiologic Parameters in Patients With Rheumatoid Arthritis" by D. Ziebolz and colleagues.

A response by J. U. Scher and colleagues to a letter to the editor about their article "Microbiome in inflammatory arthritis and human rheumatic diseases" in the 2016 issue is presented.