Kerry Wright

An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis.

BackgroundThe adaptive immune response in rheumatoid arthritis (RA) is influenced by an interaction between host genetics and environment, particularly the host microbiome. Association of the gut microbiota with various diseases has been reported, though the specific components of the microbiota that affect the host response leading to disease remain unknown. However, there is limited information on the role of gut microbiota in RA. In this study we aimed to define a microbial and metabolite profile that could predict disease status. In addition, we aimed to generate a humanized model of arthritis to confirm the RA-associated microbe.MethodsTo identify an RA biomarker profile, the 16S ribosomal DNA of fecal samples from RA patients, first-degree relatives (to rule out environment/background as confounding factors), and random healthy non-RA controls were sequenced. Analysis of metabolites and their association with specific taxa was performed to investigate a potential mechanistic link. The role of an RA-associated microbe was confirmed using a human epithelial cell line and a humanized mouse model of arthritis.ResultsPatients with RA exhibited decreased gut microbial diversity compared with controls, which correlated with disease duration and autoantibody levels. A taxon-level analysis suggested an expansion of rare taxa, Actinobacteria, with a decrease in abundant taxa in patients with RA compared with controls. Prediction models based on the random forests algorithm suggested that three genera, Collinsella, Eggerthella, and Faecalibacterium, segregated with RA. The abundance of Collinsella correlated strongly with high levels of alpha-aminoadipic acid and asparagine as well as production of the proinflammatory cytokine IL-17A. A role for Collinsella in altering gut permeability and disease severity was confirmed in experimental arthritis.ConclusionsThese observations suggest dysbiosis in RA patients resulting from the abundance of certain rare bacterial lineages. A correlation between the intestinal microbiota and metabolic signatures could determine a predictive profile for disease causation and progression.

Rheumatoid arthritis and pregnancy: safety considerations in pharmacological management.

Pregnancy can pose a challenge to the physician caring for women with rheumatoid arthritis (RA). While many women with RA experience a spontaneous improvement in joint pain and inflammation during pregnancy, in others it remains active and they continue to need ongoing therapy. It is important to tailor the treatment regimen so that the disease is stabilized prior to conception and to use medications that are safe throughout pregnancy and lactation. The use of immunomodulating medications considered low risk during pregnancy allows for optimal outcomes. NSAIDs should be avoided in the third trimester. Corticosteroids may be used throughout pregnancy in the lowest effective dose. Antimalarial agents, sulfasalazine and azathioprine are safe options, but methotrexate and leflunomide are contraindicated as they are teratogenic and must, therefore, be withdrawn before a planned pregnancy. The risk for some of the newer biological therapies for RA is not necessarily their proven teratogenicity, but the absence of proven safety for the fetus. As such, it is recommended that abatacept, rituximab and tocilizumab be withheld prior to pregnancy; however, tumour necrosis factor inhibitors and anakinra may be continued until conception. In this review, we provide an overview of the RA treatment issues pre-conception, during pregnancy and in the post-partum period with respect to breastfeeding, and we provide guidelines for drugs that may be used relatively safely for RA management in pregnant women. Where available, pre-conception guidelines for men using these medications for RA are also discussed.

Cardiovascular Comorbidity in Rheumatic Diseases A Focus on Heart Failure

Rheumatic diseases are associated with an increased risk of cardiovascular (CV) mortality attributed to a higher incidence of heart failure (HF) and ischemic heart disease. Although traditional CV risk factors contribute to the increased incidence seen in this population, by themselves they do not account for the increased risk; in fact, obesity and hyperlipidemia may play a paradoxic role. Immune-mediated mechanisms and chronic inflammation likely play a role in the pathogenesis of CV disease in patients with rheumatic diseases. The usual clinical features of ischemic heart disease and HF are less likely to be seen in this patient population.

Time Trends in Incidence, Clinical Features, and Cardiovascular Disease in Ankylosing Spondylitis Over Three Decades: A Population-Based Study

To determine trends in the incidence and clinical presentation of ankylosing spondylitis (AS), the incidence of cardiovascular disease (CVD), and cardiovascular (CV) risk factors among patients with AS and compare the observed incidence of CVD with that predicted by the Framingham Risk Score (FRS).

Safe Use of Antirheumatic Agents in Patients with Comorbidities

The burden of comorbid diseases is high among patients with rheumatoid arthritis (RA). These are often systemic manifestations of RA but may be chronic conditions that predate or develop post-RA diagnosis. Increased mortality in RA is predominantly from nonarticular causes. The expanded armamentarium of disease-modifying drugs and biologics available has revolutionized management of articular disease but has made safe treatment of RA more complex. Drug-induced organ injury and side effects need to be kept in mind when initiating or modifying therapy.

Patient-provider discordance between global assessments of disease activity in rheumatoid arthritis: a comprehensive clinical evaluation

BackgroundDiscordance between patients with rheumatoid arthritis (RA) and their rheumatology health care providers is a common and important problem. The objective of this study was to perform a comprehensive clinical evaluation of patient-provider discordance in RA.MethodsA cross-sectional observational study was conducted of consecutive RA patients in a regional practice with an absolute difference of ≥ 25 points between patient and provider global assessments (possible points, 0–100). Data were collected for disease activity measures, clinical characteristics, comorbidities, and medications. In a prospective substudy, participants completed patient-reported outcome measures and underwent ultrasonographic assessment of synovial inflammation. Differences between the discordant and concordant groups were tested using χ2 and rank sum tests. Multivariable logistic regression was used to develop a clinical model of discordance.ResultsPatient-provider discordance affected 114 (32.5%) of 350 consecutive patients. Of the total population, 103 patients (29.5%) rated disease activity higher than their providers (i.e., ‘positive’ discordance); only 11 (3.1%) rated disease activity lower than their providers and were excluded from further analysis. Positive discordance correlated with negative rheumatoid factor and anticyclic citrullinated peptide antibodies, lack of joint erosions, presence of comorbid fibromyalgia or depression, and use of opioids, antidepressants, or anxiolytics, or fibromyalgia medications. In the prospective study, the group with positive discordance was distinguished by higher pain intensity, neuropathic type pain, chronic widespread pain and associated polysymptomatic distress, and limited functional health status. Depression was found to be an important mediator of positive discordance in low disease activity whereas the widespread pain index was an important mediator of positive discordance in moderate-to-high disease activity states. Ultrasonography scores did not reveal significant differences in synovial inflammation between discordant and concordant groups.ConclusionsThe findings provide a deeper understanding of patient-provider discordance than previously known. New insights from this study include the evidence that positive discordance is not associated with unrecognized joint inflammation by ultrasonography and that depression and fibromyalgia appear to play distinct roles in determining positive discordance. Further work is necessary to develop a comprehensive framework for patient-centered evaluation and management of RA and associated comorbidities in patients in the scenario of patient-provider discordance.

Risk of Malignant Neoplasm in Patients with Incident Rheumatoid Arthritis 1980–2007 in relation to a Comparator Cohort: A Population-Based Study

Objective. To determine whether the incidence of malignancy is increased in patients with rheumatoid arthritis (RA) compared to a matched comparison cohort and to identify risk for any individual malignancy in RA. Methods. A cohort of 813 Olmsted County, Minnesota, residents who first fulfilled 1987 ACR criteria for RA in 1980–2007 was previously identified by medical record review. Medical records of 813 RA cases and a comparison cohort of age and sex matched Olmsted County residents without RA were evaluated retrospectively for cancer occurrence. Patients in both cohorts were followed until death, migration from Olmsted County, or 12/31/2014. Results. The RA and non-RA cohorts (mean age at incidence/index date: 55.9 [SD: 15.7] years; 68.4% females in both cohorts) were followed on average of 14.1 (SD: 7.7) and 14.9 (SD: 8.1) years, respectively. Prior to RA incidence/index date, 52 RA patients and 66 non-RA subjects had malignancies excluding NMSC (p = 0.21). During follow-up, significantly more malignancies occurred in patients with RA (n = 143) than in comparator subjects (n = 118; hazard ratio: 1.32; p = 0.027). Inclusion of NMSC obviated this difference. Conclusion. After excluding NMSC, there was a small to moderately increased risk of malignancies in patients with RA. Cancer surveillance is imperative in all patients with RA.

Clinical Evolution in Patients With New-Onset Inflammatory Back Pain: A Population-Based Cohort Study

Inflammatory back pain (IBP) is often an early manifestation of spondyloarthritis (SpA), but the prognosis of patients with incident IBP is unknown. This study was undertaken to investigate long‐term outcomes in patients with IBP, and predictors of progression to SpA, in a population‐based cohort.

Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound-Guided Synovial Biopsies in Rheumatoid Arthritis

Currently, there are no reliable biomarkers for predicting therapeutic response in patients with rheumatoid arthritis (RA). The synovium may unlock critical information for determining efficacy, since a reduction in the numbers of sublining synovial macrophages remains the most reproducible biomarker. Thus, a clinically actionable method for the collection of synovial tissue, which can be analyzed using high‐throughput strategies, must become a reality. This study was undertaken to assess the feasibility of utilizing synovial biopsies as a precision medicine‐based approach for patients with RA.

ID: 133: SINGLE CELL GENE EXPRESSION IN CLASSICAL MONOCYTES CORRELATES WITH TREATMENT RESPONSE TO TNF-ALPHA INHIBITION IN RHEUMATOID ARTHRITIS

Background In management of rheumatoid arthritis (RA), initiating effective treatment as soon as possible within the so-called therapeutic “window of opportunity” is the strategy, and disease remission is a primary goal. Recent work from our group demonstrated that pre-treatment serum type I IFN-β/α activity ratio>1.3 can predict non-response to anti-TNF-alpha therapy in RA patients. The cellular mechanisms that underlie the IFN-β/α activity ratio that predicts response are not known. Effects of IFN on single immune cells and uncommon cell populations may be masked in whole blood or mixed cell populations. Methods To better understand the underpinnings of the pre-treatment IFN-β/α activity ratio, we used single cell expression analysis to investigate whether monocyte gene expression differs significantly between RA patients according to their pre-TNF-α inhibitor serum IFN-β/α activity ratio. Single classical (CL) and single non-classical (NCL) blood-derived monocytes were isolated from 15 seropositive RA subjects prior to biologic therapy. Total serum type I IFN, IFN-α, and IFN-β activity were measured using a functional reporter cell assay. Subjects were grouped by pre-TNF-α inhibitor serum IFN-β/α activity ratio into two groups, IFN-β/α>1.3 (n=6) and IFN-β/α<1.3 (n=9). Comparisons between groups were by Mann-Whitney. Hierarchical clustering of 87 target genes was done to determine if there were functional gene expression differences between groups. Results Hierarchical clustering revealed striking differences of expression of gene sets in CL monocytes between patients with IFN-β/α<1.3 and IFN-β/α>1.3, the groups which correspond to response/non-response to anti-TNF-α agents. This same clustering was not observed in NCL monocytes, and the differentiation between anti-TNF-α response patient groups was lost when hierarchical clustering was done on total monocytes (CL and NCL). Two major gene sets which differentiated subjects with IFN-β/α>1.3 (non-response to anti-TNF-α group) in CL monocytes included TLR and IFN pathway genes, cell surface markers and cytokines as follows: cluster 1 (TLR2, CD16, JAK1, IFI27, IL1A, and MAVS) and cluster 2 (GMCSF, TLR7, STAT2, ILT7, MYD88). Conclusion These within-cell expression patterns demonstrate biological differences in CL monocytes of RA patients with an IFN-β/α>1.3, the ratio of type I IFNs previously found to be predictive of non-response to anti-TNF-α therapy. Differentiation by gene expression among the response/non-response patient groups is lost when comparing gene expression in single NCL monocytes and single mixed population monocytes (CL and NCL), suggesting that further study of CL monocytes will likely illuminate molecular differences that determine treatment response to TNF-α inhibition in RA. This work will help to develop a more individualized approach to therapy in RA based upon the underlying biology of disease in a given patient.