Obesity, Adipokines, and Chronic and Persistent Pain in Rheumatoid Arthritis.

We aimed to determine whether adipokines are associated with pain and polysymptomatic distress in patients with rheumatoid arthritis (RA) over time in a large patient registry. The cohort study was conducted in a subset of Forward; a patient-based multi-disease, multipurpose rheumatic disease registry with patients enrolled from community-based rheumatology practices across the U.S. Adipokines (adiponectin, leptin, and fibroblast growth factor[FGF]-21) were measured on stored serum as part of a multi-analyte panel. Body mass index (BMI), pain, polysymptomatic distress, and other patient-reported outcomes (PROs) were reported on biannual questionnaires. Linear regression was used to evaluate independent associations between BMI, adipokines, and PROs. Cox proportional hazards models evaluated independent associations between adipokines and clinically meaningful changes in pain over time (change in numerical rating>1.1 [range 0-10], sustained over 1 year). Among 645 patients included in these analyses, there were significant differences in RA characteristics, comorbidity, PROs, and adipokines across obesity categories. Of note, severely obese patients were more likely to experience greater pain, polysymptomatic distress, and fatigue. Patients with higher FGF-21 levels had higher pain and polysymptomatic stress at baseline, were more likely to use opioids, and were more likely to have sustained worsening pain over time [HR (per 1 SD) (95% CI): 1.22 (1.02,1.46) P = .03] independent of BMI. Obesity and elevated levels of FGF-21 are associated with pain and polysymptomatic distress in RA. Elevated FGF-21 levels may help identify those at risk of worsening pain trajectories over time, independent of BMI. PERSPECTIVE: This study characterizes the relationship between severe obesity and pain and polysymptomatic distress in patients with rheumatoid arthritis and demonstrates that the adipocytokine fibroblast growth factor-21 is independently associated with pain and predicts a worsening trajectory over time. Further mechanistic studies are needed.

Clinical Features Associated With Rate of Fractures in Patients With Systemic Sclerosis: A US Cohort Study.

OBJECTIVE: Systemic sclerosis (SSc) is associated with several specific risk factors for fracture due to the complications of the disease and related medications. The present study was undertaken to examine the relationship between SSc-associated clinical features and fracture rate in a large US cohort. METHODS: Participants with SSc in FORWARD, The National Databank for Rheumatic Diseases, were included (1998-2019). Age- and sex-matched individuals with osteoarthritis (OA) from the same database were included as comparators. The primary end point was self-reported major osteoporotic fracture. Cox proportional hazards models were used to study the associations between risk factors and fractures. RESULTS: The study included 922 individuals (SSc patients, n = 154; OA patients, n = 768). Eighty-seven percent were female, with a mean age of 57.8 years. Fifty-one patients developed at least 1 fracture during a median of 4.2 years (0.5-22.0 years) of follow-up. Patients with SSc had more frequent fractures compared to OA comparators (hazard ratio [HR] 2.38 [95% confidence interval (95% CI) 1.47-3.83]). Among patients with SSc, a higher Rheumatic Disease Comorbidity Index score (HR 1.45 [95% CI 1.20-1.75]) and a higher Health Assessment Questionnaire disability index score (HR 3.83 [95% CI 2.12-6.93]) were associated with more fractures. Diabetes mellitus (HR 5.89 [95% CI 2.51-13.82]) and renal disease (HR 2.43 [95% CI 1.10-5.37]) were independently associated with fracture among SSc patients relative to SSc patients without these comorbidities. CONCLUSION: Our findings highlight factors associated with fracture among patients with SSc. Disability as measured by the HAQ DI is a particularly strong indicator of fracture rate in SSc. Improving SSc patients' functional status, where possible, may lead to better long-term outcomes.

Examining Rehabilitation Dose in Adults With Rheumatoid Arthritis: Association With Baseline Factors and Change in Clinical Outcomes.

OBJECTIVE: To evaluate the association of baseline factors with rehabilitation dose and the association of rehabilitation dose with meaningful change in physical function, pain, and fatigue over 6 months among adults with rheumatoid arthritis (RA). METHODS: Using data from the National Databank for Rheumatic Diseases registry, we extracted baseline characteristics and self-reported physical function (Health Assessment Questionnaire), pain (visual analog scale [VAS]), fatigue (VAS), rehabilitation dose (low: 1-2 visits, medium: 3-8 visits, high: >8 visits), and follow-up outcomes 6 months later. Changes in clinical outcomes were categorized as improved, no change, or worsened. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) using proportional odds logistic regression models to examine the association of the baseline factors with rehabilitation dose and the association of rehabilitation dose with changes in clinical outcomes, adjusting for potential confounders. RESULTS: The sample included 1,381 adults with a new episode of rehabilitation (dose: low 27%, medium 42%, high 31%). Worse baseline physical function (adjusted OR 1.29 [95% CI 1.04-1.60]), but not pain (adjusted OR 1.04 [95% CI 0.99-1.10]) or fatigue (adjusted OR 0.98 [95% CI 0.93-1.03]), were associated with a higher rehabilitation dose. A high rehabilitation dose was associated with a favorable change in physical function (OR 1.51 [95% CI 1.14-1.98]), pain (OR 1.44 [95% CI 1.06-1.96]), and fatigue (OR 1.45 [95% CI 1.06-1.99]) compared to a low dose; only the association with physical function change persisted in adjusted models (adjusted OR 1.41 [95% CI 1.03-1.92]). CONCLUSION: Using real-world data, this study supports a higher rehabilitation dose to improve physical function in adults with RA.

Rheumatic disease patient decision-making about COVID-19 vaccination: a qualitative analysis.

BACKGROUND: Although patients with rheumatic and musculoskeletal diseases (RMDs) are at increased risk for adverse outcomes of COVID-19 illness compared to healthy controls, they also have lower rates of willingness to be vaccinated. Previous research has identified reasons for vaccine hesitancy among patients with RMDs (such as concerns about side effects and flares), but little is known about what these reasons mean in the context of patients' lives, or how vaccine decision making is experienced from a patient perspective. Our objective was to describe decision-making about COVID-19 vaccination among RMD patients. METHODS: Participants in a RMD registry were invited to complete monthly online surveys regarding COVID-19 vaccination from March-June 2021. We qualitatively analyzed comments from two open-ended survey questions reporting general experiences with vaccination and side effects. Comments were coded for attitudes towards COVID-19 vaccination, vaccine access, rheumatologic medication management around vaccination, and vaccine side effects. Themes were identified for the process and context of COVID-19 vaccine decisions, patient motivations for receiving or avoiding vaccination, and consistency of peri-vaccine medication management with current ACR guidelines. RESULTS: We analyzed 710 comments from 537 respondents. Commenting respondents had a mean age of 64 years, were 87% female, 94% white, and 93% received/intended to receive ≥ 1 dose of a COVID-19 vaccine. Desire for protection and a return to normal routines motivated some commenters to get vaccinated, while concerns about vaccine side effects motivated others to delay or avoid vaccination. Several commenters reported disease flares following vaccination. Some commenters did not consult their providers about vaccination and failed to withhold immunomodulatory medications during vaccination, while others withheld medications more conservatively than recommended by current ACR guidelines, either on their own or directed by their provider. CONCLUSIONS: While most commenters were vaccine-accepting, challenges to COVID-19 vaccine uptake in the RMD population may include fears of side effects, including worsened RMD symptoms, and perceptions that vaccination is unnecessary. Addressing these concerns and beliefs may be critical for promoting vaccination in this population.

Increase in Cannabis Use Among Adults With Rheumatic Diseases: Results From a 2014-2019 United States Observational Study.

OBJECTIVE: Despite advances in treatments and outcomes among patients with rheumatic diseases, there is an unmet need in pain management. Cannabis has emerged as a potential opioid-sparing alternative, with arthritic pain as a commonly cited reason for medicinal cannabis use. However, little is known, and we set out to understand patterns of cannabis use in a US-wide rheumatic disease population. METHODS: The study included participants in FORWARD, The National Databank for Rheumatic Diseases. Participants were asked in 2014 and 2019 about their past and current cannabis use. Demographic characteristics, patient-reported outcomes, medications, comorbidities, and diagnoses were compared between cannabis users and non-users with t-tests, chi-square tests, logistic regression, and geographic assessment. RESULTS: Among 11,006 respondents, cannabis use increased from 6.3% in 2014 to 18.4% in 2019, with the greatest prevalence of use in states where cannabis use was legalized. Most users (74% and 62% in 2014 and 2019, respectively) reported that cannabis was effective in the relief of arthritis symptoms. Cannabis users were more likely to be taking weak opioids (odds ratio 1.2 [95% confidence interval 1.0, 1.5], P = 0.03), to have a history of smoking tobacco (odds ratio 1.7 [95% confidence interval 1.5, 2.1], P < 0.001), and had worse measures on all assessed patient-reported outcomes. CONCLUSION: Reported cannabis use in this cohort increased significantly between 2014 and 2019. Characteristics of users suggest that those who try cannabis are feeling worse symptomatically, and their pain management needs may not be adequately addressed by other therapies. The association between cannabis, opioids, and patient-reported outcomes highlight areas for future work.

Changes in Disease-Modifying Antirheumatic Drug Treatment for Patients With Rheumatoid Arthritis in the US During the COVID-19 Pandemic: A Three-Month Observational Study.

OBJECTIVE: To understand medication, lifestyle, and clinical care changes of persons with rheumatoid arthritis (RA) during the first months (March 2020 through May 2020) of the COVID-19 pandemic in the US. METHODS: Data were collected from adults with RA participating in FORWARD, The National Databank for Rheumatic Diseases observational registry, who answered COVID-19 web-based surveys in May 2020 and previously provided baseline characteristics and medication use prior to the US COVID-19 pandemic. We compared medication changes by disease-modifying antirheumatic drug (DMARD) exposure in logistic models that were adjusted for age, sex, comorbidities including pulmonary and cardiovascular diseases, education level, health insurance status, RA disease activity, fatigue, and polysymptomatic distress. RESULTS: Of 734 respondents, 221 (30%) reported medication changes. Among respondents who experienced a medication change, i.e., "medication changers/changers," glucocorticoids (GCs) were more commonly used compared to respondents who did not experience a medication change ("non-changers") (33% versus 18%). Non-hydroxychloroquine conventional DMARDs were less commonly used in changers compared to non-changers pre-COVID-19 (49% versus 62%), and changers reported more economic hardship during the COVID-19 pandemic compared to non-changers (23% versus 15%). While JAK inhibitor use was associated with the likelihood of a medication change, with an odds ratio (OR) of 1.9 (95% confidence interval [95% CI] 1.0, 3.4), only pre-COVID GC use remained a strong predictor for medication change in multivariable models (OR 3.0 [95% CI 1.9, 4.9]). Change in care was observed to have a significant association with pulmonary disease (OR 2.9 [95% CI 1.3, 6.5]), worse RA disease activity (OR 1.1 [95% CI 1.0, 1.1]), and GC use (OR 1.6 [95% CI 1.0, 2.5]). While the incidence of medication changes was the same before and after the American College of Rheumatology (ACR) guidance for the management of rheumatic disease in adult patients during the COVID-19 pandemic were first published in April 2020, self-imposed changes in medication were approximately twice as likely before publication of the guidelines, and physician-guided changes were more likely after publication. CONCLUSION: Persons with RA in the US made substantial medication changes during the first three months of the COVID-19 pandemic, and changes among persons with RA after publication of the ACR guidance in April 2020 were made with increased physician guidance.

Probiotic Use and Psoriatic Arthritis Disease Activity.

OBJECTIVE: Probiotics have been hypothesized to mediate inflammation through gut microbiome modulation. Spondyloarthropathies have subclinical gut inflammation associated with inflammatory disease that may benefit from probiotic use. We aimed to evaluate associations between probiotic use and patient-reported outcomes in patients with psoriatic arthritis (PsA). METHODS: Using FORWARD, The National Databank for Rheumatic Diseases, we examined probiotic use among patients with PsA and rheumatoid arthritis (RA), a comparator in which gut inflammation is less clearly related to pathogenesis. Patient-reported outcome measures such as pain and physical function were compared for probiotic users and nonusers among patients with PsA and RA. Patients were propensity score-matched for taking a probiotic by demographics and nonmedication supplements. RESULTS: More patients have reported probiotic use over the past decade, with less than 1% reporting use in 2008 and approximately 7% in 2018. Probiotic users are more likely to be white women with higher education, income, and supplement use. Following propensity score matching, probiotic users with PsA had significantly lower Short Form 36 Physical Component Summary (SF-36 PCS) scores and higher pain scores than nonusers with PsA (33.11 ± 11.50 vs. 40.82 ± 11.03; P = 0.04 and 4.78 ± 3.09 vs. 3.00 ± 2.58; P = 0.03). There were no significant differences in Patient Activity Scale II, Health Assessment Questionnaire II, SF-36 PCS, and Short Form 36 Mental Component Summary scores or pain among users with PsA before and after probiotic initiation. CONCLUSION: We found increasing probiotic use in patients with PsA and important differences between users and nonusers. After accounting for these differences, we found no statistical difference in health outcomes after probiotic use.

Experiences of Patients With Rheumatic Diseases in the United States During Early Days of the COVID-19 Pandemic.

OBJECTIVE: Patients with rheumatic diseases such as rheumatoid arthritis (RA) and lupus have increased risk of infection and are treated with medications that may increase this risk yet are also hypothesized to help treat COVID-19. We set out to understand how the COVID-19 pandemic has impacted the lives of these patients in the United States. METHODS: Participants in a US-wide longitudinal observational registry responded to a supplemental COVID-19 questionnaire by e-mail on March 25, 2020, about their symptoms, COVID-19 testing, health care changes, and related experiences during the prior 2 weeks. Analysis compared responses by diagnosis, disease activity, and new onset of symptoms. Qualitative analysis was conducted on optional free-text comment fields. RESULTS: Of the 7061 participants invited to participate, 530 responded, with RA as the most frequent diagnosis (61%). Eleven participants met COVID-19 screening criteria, of whom two sought testing unsuccessfully. Six others sought testing, three of whom were successful, and all test results were negative. Not quite half of participants (42%) reported a change to their care in the prior 2 weeks. Qualitative analysis revealed four key themes: emotions in response to the pandemic, perceptions of risks from immunosuppressive medications, protective measures to reduce risk of COVID-19 infection, and disruptions in accessing rheumatic disease medications, including hydroxychloroquine. CONCLUSION: After 2 weeks, many participants with rheumatic diseases already had important changes to their health care, with many altering medications without professional consultation or because of hydroxychloroquine shortage. As evidence accumulates on the effectiveness of potential COVID-19 treatments, effort is needed to safeguard access to established treatments for rheumatic diseases.

Comparative molecular characterization of typical and exceptional responders in glioblastoma.

Glioblastoma (GBM) is the most common and the deadliest type of primary brain tumor, with a median survival time of only 15 months despite aggressive treatment. Although most patients have an extremely poor prognosis, a relatively small number of patients survive far beyond the median survival time. Investigation of these exceptional responders has sparked a great deal of interest and is becoming an important focus in the field of cancer research. To investigate the molecular differences between typical and exceptional responders in GBM, comparative analyses of somatic mutations, copy number, methylation, and gene expression datasets from The Cancer Genome Atlas were performed, and the results of these analyses were integrated via gene ontology and pathway analyses to assess the functional significance of the differential aberrations. Less severe copy number loss of CDKN2A, lower expression of CXCL8, and FLG mutations are all associated with an exceptional response. Typical responders are characterized by upregulation of NF-κB signaling and of pro-inflammatory cytokines, while exceptional responders are characterized by upregulation of Alzheimer's and Parkinson's disease pathways as well as of genes involved in synaptic transmission. The upregulated pathways and processes in typical responders are consistently associated with more aggressive tumor phenotypes, while those in the exceptional responders suggest a retained ability in tumor cells to undergo cell death in response to treatment. With the upcoming launch of the National Cancer Institute's Exceptional Responders Initiative, similar studies with much larger sample sizes will likely become possible, hopefully providing even more insight into the molecular differences between typical and exceptional responders.

A new rhesus macaque assembly and annotation for next-generation sequencing analyses.

BACKGROUND: The rhesus macaque (Macaca mulatta) is a key species for advancing biomedical research. Like all draft mammalian genomes, the draft rhesus assembly (rheMac2) has gaps, sequencing errors and misassemblies that have prevented automated annotation pipelines from functioning correctly. Another rhesus macaque assembly, CR_1.0, is also available but is substantially more fragmented than rheMac2 with smaller contigs and scaffolds. Annotations for these two assemblies are limited in completeness and accuracy. High quality assembly and annotation files are required for a wide range of studies including expression, genetic and evolutionary analyses. RESULTS: We report a new de novo assembly of the rhesus macaque genome (MacaM) that incorporates both the original Sanger sequences used to assemble rheMac2 and new Illumina sequences from the same animal. MacaM has a weighted average (N50) contig size of 64 kilobases, more than twice the size of the rheMac2 assembly and almost five times the size of the CR_1.0 assembly. The MacaM chromosome assembly incorporates information from previously unutilized mapping data and preliminary annotation of scaffolds. Independent assessment of the assemblies using Ion Torrent read alignments indicates that MacaM is more complete and accurate than rheMac2 and CR_1.0. We assembled messenger RNA sequences from several rhesus tissues into transcripts which allowed us to identify a total of 11,712 complete proteins representing 9,524 distinct genes. Using a combination of our assembled rhesus macaque transcripts and human transcripts, we annotated 18,757 transcripts and 16,050 genes with complete coding sequences in the MacaM assembly. Further, we demonstrate that the new annotations provide greatly improved accuracy as compared to the current annotations of rheMac2. Finally, we show that the MacaM genome provides an accurate resource for alignment of reads produced by RNA sequence expression studies. CONCLUSIONS: The MacaM assembly and annotation files provide a substantially more complete and accurate representation of the rhesus macaque genome than rheMac2 or CR_1.0 and will serve as an important resource for investigators conducting next-generation sequencing studies with nonhuman primates. REVIEWERS: This article was reviewed by Dr. Lutz Walter, Dr. Soojin Yi and Dr. Kateryna Makova.