Immune Checkpoint Inhibitor-induced Polymyalgia Rheumatica.

Polymyalgia rheumatica (PMR) immune-related adverse events (ICI-PMRs) represent a novel, distinct entity, despite many clinical, laboratory, and imaging similarities to classical PMR. Important questions remain in differentiating ICI-PMR from classical PMR, as well as other immune-related adverse events and PMR mimics. Despite this, ICI-PMR currently takes treatment cues from classical PMR, albeit with considerations relevant to cancer immunotherapy. Comparisons between ICI-PMR and classical PMR may provide further bidirectional insights, especially given that important questions remain unanswered about both diseases. The cause of classical PMR remains poorly understood, and ICI-PMR may represent a model of induced PMR, with important therapeutic implications.

Treatment of polymyalgia rheumatica: British Society for Rheumatology guideline scope.

The last British Society for Rheumatology (BSR) guideline on PMR was published in 2009. The guideline needs to be updated to provide a summary of the current evidence for pharmacological and non-pharmacological management of adults with PMR. This guideline is aimed at healthcare professionals in the UK who directly care for people with PMR, including general practitioners, rheumatologists, nurses, physiotherapists, occupational therapists, pharmacists, psychologists and other health professionals. It will also be relevant to people living with PMR and organisations that support them in the public and third sector, including charities and informal patient support groups. This guideline will be developed using the methods and processes outlined in the BSR Guidelines Protocol. Here we provide a brief summary of the scope of the guideline update in development.

Using Polygenic Risk Scores to Aid Diagnosis of Patients With Early Inflammatory Arthritis: Results From the Norfolk Arthritis Register.

OBJECTIVE: There is growing evidence that genetic data are of benefit in the rheumatology outpatient setting by aiding early diagnosis. A genetic probability tool (G-PROB) has been developed to aid diagnosis has not yet been tested in a real-world setting. Our aim was to assess whether G-PROB could aid diagnosis in the rheumatology outpatient setting using data from the Norfolk Arthritis Register (NOAR), a prospective observational cohort of patients presenting with early inflammatory arthritis. METHODS: Genotypes and clinician diagnoses were obtained from patients from NOAR. Six G-probabilities (0%-100%) were created for each patient based on known disease-associated odds ratios of published genetic risk variants, each corresponding to one disease of rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, spondyloarthropathy, gout, or "other diseases." Performance of the G-probabilities compared with clinician diagnosis was assessed. RESULTS: We tested G-PROB on 1,047 patients. Calibration of G-probabilities with clinician diagnosis was high, with regression coefficients of 1.047, where 1.00 is ideal. G-probabilities discriminated clinician diagnosis with pooled areas under the curve (95% confidence interval) of 0.85 (0.84-0.86). G-probabilities <5% corresponded to a negative predictive value of 96.0%, for which it was possible to suggest >2 unlikely diseases for 94% of patients and >3 for 53.7% of patients. G-probabilities >50% corresponded to a positive predictive value of 70.4%. In 55.7% of patients, the disease with the highest G-probability corresponded to clinician diagnosis. CONCLUSION: G-PROB converts complex genetic information into meaningful and interpretable conditional probabilities, which may be especially helpful at eliminating unlikely diagnoses in the rheumatology outpatient setting.

Imaging of giant cell arteritis - recent advances.

Imaging is increasingly being used to guide clinical decision-making in patients with giant cell arteritis (GCA). While ultrasound has been rapidly adopted in fast-track clinics worldwide as an alternative to temporal artery biopsy for the diagnosis of cranial disease, whole-body PET/CT is emerging as a potential gold standard test for establishing large vessel involvement. However, many unanswered questions remain about the optimal approach to imaging in GCA. For example, it is uncertain how best to monitor disease activity, given there is frequent discordance between imaging findings and conventional disease activity measures, and imaging changes typically fail to resolve completely with treatment. This chapter addresses the current body of evidence for the use of imaging modalities in GCA across the spectrum of diagnosis, monitoring disease activity, and long-term surveillance for structural changes of aortic dilatation and aneurysm formation and provides suggestions for future research directions.

Treatment of axial spondyloarthritis with biologic and targeted synthetic DMARDs: British Society for Rheumatology guideline scope.

Pharmacological management has advanced considerably since the 2015 British Society for Rheumatology axial spondyloarthritis (axSpA) guideline to incorporate new classes of biologic DMARDs (bDMARDs, including biosimilars), targeted synthetic DMARDs (tsDMARDs) and treatment strategies such as drug tapering. The aim of this guideline is to provide an evidence-based update on pharmacological management of adults with axSpA (including AS and non-radiographic axSpA) using b/tsDMARDs. This guideline is aimed at health-care professionals in the UK who care directly for people with axSpA, including rheumatologists, rheumatology specialist nurses, allied health professionals, rheumatology specialty trainees and pharmacists; people living with axSpA; and other stakeholders, such as patient organizations and charities.

Marriage, Children, and Sex-Based Differences in Physician Hours and Income.

Importance: A better understanding of the association between family structure and sex gaps in physician earnings and hours worked over the life cycle is needed to advance policies addressing persistent sex disparities. Objective: To investigate differences in earnings and hours worked for male and female physicians at various ages and family status. Design, Setting, and Participants: This retrospective, cross-sectional study used data on physicians aged 25 to 64 years responding to the American Community Survey between 2005 and 2019. Exposures: Earned income and work hours. Main Outcomes and Measures: Outcomes included annual earned income, usual hours worked per week, and earnings per hour worked. Gaps in earnings and hours by sex were calculated by family status and physician age and, in some analyses, adjusted for demographic characteristics and year of survey. Data analyses were conducted between 2019 and 2022. Results: The sample included 95 435 physicians (35.8% female, 64.2% male, 19.8% Asian, 4.8% Black, 5.9% Hispanic, 67.3% White, and 2.2% other race or ethnicity) with a mean (SD) age of 44.4 (10.4) years. Relative to male physicians, female physicians were more likely to be single (18.8% vs 11.2%) and less likely to have children (53.3% vs 58.2%). Male-female earnings gaps grew with age and, when accumulated from age 25 to 64 years, were approximately $1.6 million for single physicians, $2.5 million for married physicians without children, and $3.1 million for physicians with children. Gaps in earnings per hour did not vary by family structure, with male physicians earning between 21.4% and 23.9% more per hour than female physicians. The male-female gap in hours worked was 0.6% for single physicians, 7.0% for married physicians without children, and 17.5% for physicians with children. Conclusions and Relevance: In this cross-sectional study of US physicians, marriage and children were associated with a greater earnings penalty for female physicians, primarily due to fewer hours worked relative to men. Addressing the barriers that lead to women working fewer hours could contribute to a reduction in the male-female earnings gap while helping to expand the effective physician workforce.

An international survey of current management practices for polymyalgia rheumatica by general practitioners and rheumatologists.

OBJECTIVES: To explore current management practices for PMR by general practitioners (GPs) and rheumatologists including implications for clinical trial recruitment. METHODS: An English language questionnaire was constructed by a working group of rheumatologists and GPs from six countries. The questionnaire focused on: 1: Respondent characteristics; 2: Referral practices; 3: Treatment with glucocorticoids; 4: Diagnostics; 5: Comorbidities; and 6: Barriers to research. The questionnaire was distributed to rheumatologists and GPs worldwide via members of the International PMR/Giant Cell Arteritis Study Group. RESULTS: In total, 394 GPs and 937 rheumatologists responded to the survey. GPs referred a median of 25% of their suspected PMR patients for diagnosis and 50% of these were returned to their GP for management. In general, 39% of rheumatologists evaluated patients with suspected PMR >2 weeks after referral, and a median of 50% of patients had started prednisolone before rheumatologist evaluation. Direct comparison of initial treatment showed that the percentage prescribing >25 mg prednisolone daily for patients was 30% for GPs and 12% for rheumatologists. Diagnostic imaging was rarely used. More than half (56%) of rheumatologists experienced difficulties recruiting people with PMR to clinical trials. CONCLUSION: This large international survey indicates that a large proportion of people with PMR are not referred for diagnosis, and that the proportion of treatment-naive patients declined with increasing time from referral to assessment. Strategies are needed to change referral and management of people with PMR, to improve clinical practice and facilitate recruitment to clinical trials.

Characteristics of rural registered nurses and the implications for workforce policy.

PURPOSE: Rural registered nurses (RNs) play an integral role in providing care for an underserved population with worse health outcomes than urban counterparts. However, little information is available on the profile of this workforce, which is necessary to understand the capacity of these nurses to provide quality and demanded care presently and in the future. METHODS: We utilize data from the American Community Survey to provide a contemporary analysis on the supply of rural RNs in the United States. FINDINGS: While the number of physicians serving rural populations has decreased in recent years, and rural nurse practitioners (NPs) remain in short supply, rural RNs have steadily grown in numbers at a rate comparable to urban RNs. Rural RNs are markedly less diverse than the populations they serve and only half of rural RNs had a bachelor's degree or higher compared to over 70% for urban RNs. In their supply, young rural nurses appear on pace with urban nurses to adequately replace older nurses and continue to grow the workforce, based on data through 2019. CONCLUSIONS: The rural RN workforce is projected to steadily grow amidst declining rural physicians and limited rural NPs. The burgeoning investments in the rural health workforce present opportunities to help diversify, increase educational access, and further rural readiness for rural RNs moving forward.

Is There Still a Role of Plasma Exchange in the Current Management of ANCA-Associated Vasculitides?

PURPOSE OF REVIEW: Plasma exchange (PLEX) is often recommended as an adjunctive therapy for patients with ANCA-associated vasculitis (AAV) in the setting of rapidly progressive glomerulonephritis or diffuse alveolar haemorrhage. Since ANCAs are pathogenic, it seems a reasonable and justified approach to remove them through therapeutic PLEX, as despite advances in immunosuppressive therapy regimens, AAV is associated with significant morbidity and death. However, the association between ANCA levels and mortality or disease activity is uncertain. In addition, any treatment must be judged on the potential risks and benefits of its use. Here, we summarise the current data on PLEX usage in patients with AAV. RECENT FINDINGS: The largest randomised trial to date the Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS) study failed to show added benefit for PLEX on the prevention of death or end-stage renal failure (ESRF) for the management of patients with severe AAV. However, there is a possibility that PLEX delays dialysis dependence and ESRF in the early stages of the disease. Regardless of whether this is only for 3 to 12 months, this could be of clinical significance and a substantial improvement in patient's quality of life. Cost utility analysis and trials including patient-centred outcomes are required to evaluate the use of PLEX. Furthermore, ascertaining those at high risk of developing ESRF could help identify those who may benefit from PLEX the most, and further insights are required in setting of diffuse alveolar haemorrhage.

Nurse Employment During The First Fifteen Months Of The COVID-19 Pandemic.

Analysis of Current Population Survey data suggests a tightening labor market for registered nurses, licensed practical nurses, and nursing assistants, marked by falling employment and rising wages through June 2021. Unemployment rates remain higher in nonhospital settings and among registered nurses and nursing assistants who are members of racial and ethnic minority groups.

Clinical and biomechanical factors associated with falls and rheumatoid arthritis: baseline cohort with longitudinal nested case-control study.

OBJECTIVE: To identify the clinical and biomechanical characteristics associated with falls in people with RA. METHODS: A total of 436 people ≥60 years of age with RA completed a 1 year prospective survey of falls in the UK. At baseline, questionnaires recorded data including personal and medical history, pain and fatigue scores, health-related quality of life (HRQoL), physical activity and medication history. The occurrence of falls wasmonitored prospectively over 12 months by monthly self-reporting. A nested sample of 30 fallers (defined as the report of one or more falls in 12 months) and 30 non-fallers was evaluated to assess joint range of motion (ROM), muscle strength and gait parameters. Multivariate regression analyses were undertaken to determine variables associated with falling. RESULTS: Compared with non-fallers (n = 236), fallers (n = 200) were older (P = 0.05), less likely to be married (P = 0.03), had higher pain scores (P < 0.01), experienced more frequent dizziness (P < 0.01), were frequently taking psychotropic medications (P = 0.02) and reported lower HRQoL (P = 0.02). Among those who underwent gait laboratory assessments, compared with non-fallers, fallers showed a greater anteroposterior (AP; P = 0.03) and medial-lateral (ML) sway range (P = 0.02) and reduced isokinetic peak torque and isometric strength at 60° knee flexion (P = 0.03). Fallers also showed shorter stride length (P = 0.04), shorter double support time (P = 0.04) and reduced percentage time in swing phase (P = 0.02) and in knee range of motion through the gait cycle (P < 0.01). CONCLUSION: People with RA have distinct clinical and biomechanical characteristics that place them at increased risk of falling. Assessment for these factors may be important to offer more targeted rehabilitation interventions.

Impact of COVID-19 pandemic social restriction measures on people with rheumatic and musculoskeletal diseases in the UK: a mixed-methods study.

OBJECTIVES: To determine the impact of COVID-19 pandemic social restriction measures on people with rheumatic and musculoskeletal diseases (RMDs) and to explore how people adapted to these measures over time. DESIGN: Mixed-methods investigation comprising a national online longitudinal survey and embedded qualitative study. SETTING: UK online survey and interviews with community-dwelling individuals in the East of England. PARTICIPANTS: People in the UK with RMDs were invited to participate in an online survey. A subsection of respondents were invited to participate in the embedded qualitative study. PRIMARY AND SECONDARY OUTCOME MEASURES: The online survey, completed fortnightly over 10 weeks from April 2020 to August 2020, investigated changes in symptoms, social isolation and loneliness, resilience and optimism. Qualitative interviews were undertaken assessing participant's perspectives on changes in symptoms, exercising, managing instrumental tasks such a shopping, medication and treatment regimens and how they experienced changes in their social networks. RESULTS: 703 people with RMDs completed the online survey. These people frequently reported a deterioration in symptoms as a result of COVID-19 pandemic social restrictions (52% reported increase vs 6% reported a decrease). This was significantly worse for those aged 18-60 years compared with older participants (p=0.017). The qualitative findings from 26 individuals with RMDs suggest that the greatest change in daily life was experienced by those in employment. Although some retired people reported reduced opportunity for exercise outside their homes, they did not face the many competing demands experienced by employed people and people with children at home. CONCLUSIONS: People with RMDs reported a deterioration in symptoms when COVID-19 pandemic social restriction measures were enforced. This was worse for working-aged people. Consideration of this at-risk group, specifically for the promotion of physical activity, changing home-working practices and awareness of healthcare provision is important, as social restrictions continue in the UK.

Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta.

Proteolysis-targeting chimaeras (PROTACs) are molecules that combine a target-binding warhead with an E3 ligase-recruiting moiety; by drawing the target protein into a ternary complex with the E3 ligase, PROTACs induce target protein degradation. While PROTACs hold exciting potential as chemical probes and as therapeutic agents, development of a PROTAC typically requires synthesis of numerous analogs to thoroughly explore variations on the chemical linker; without extensive trial and error, it is unclear how to link the two protein-recruiting moieties to promote formation of a productive ternary complex. Here, we describe a structure-based computational method for evaluating the suitability of a given linker for ternary complex formation. Our method uses Rosetta to dock the protein components and then builds the PROTAC from its component fragments into each binding mode; complete models of the ternary complex are then refined. We apply this approach to retrospectively evaluate multiple PROTACs from the literature, spanning diverse target proteins. We find that modeling ternary complex formation is sufficient to explain both activity and selectivity reported for these PROTACs, implying that other cellular factors are not key determinants of activity in these cases. We further find that interpreting PROTAC activity is best approached using an ensemble of structures of the ternary complex rather than a single static conformation and that members of a structurally conserved protein family can be recruited by the same PROTAC through vastly different binding modes. To encourage adoption of these methods and promote further analyses, we disseminate both the computational methods and the models of ternary complexes.

Feasibility and Face Validity of Outcome Measures for Use in Future Studies of Polymyalgia Rheumatica: An OMERACT Study.

OBJECTIVE: To survey participants with polymyalgia rheumatica (PMR) to evaluate the face validity, acceptability, and domain match of proposed candidate outcome measures. METHODS: A structured, online, anonymous survey was disseminated by patient support groups through their networks and online forums. The candidate outcome measures comprised (1) visual analog scale (VAS) and numerical rating score (NRS) to assess pain; (2) VAS, NRS, and duration to assess stiffness; (3) the modified Health Assessment Questionnaire and Health Assessment Questionnaire Disability Index to assess physical function; and (4) C-reactive protein and erythrocyte sedimentation rate to assess inflammation. Free-text answers were analyzed using descriptive thematic analysis to determine respondents' views of the candidate instruments. RESULTS: Seventy-eight people with PMR from 6 countries (UK, France, USA, Canada, Australia, and New Zealand) participated in the survey. Most respondents agreed candidate instruments were acceptable or "good to go." Free-text analysis identified 5 themes that participants considered inadequately covered by the proposed instruments. These related to (1) the variability, context, and location of pain; (2) the variability of stiffness; (3) fatigue; (4) disability; and (5) the correlation of inflammatory marker levels and severity of symptoms, sometimes reflecting disease activity and other times not. CONCLUSION: Participants reported additional aspects of their experience that are not covered by the proposed instruments, particularly for the experience of stiffness and effect of fatigue. New patient-reported outcome measures are required to increase the relevance of results from clinical trials to patients with PMR.

Cardiovascular risk factors associated with polymyalgia rheumatica and giant cell arteritis in a prospective cohort: EPIC-Norfolk Study.

OBJECTIVES: PMR and GCA are associated with increased risk of vascular disease. However, it remains unclear whether this relationship is causal or reflects a common underlying propensity. The aim of this study was to identify whether known cardiovascular risk factors increase the risk of PMR and GCA. METHODS: Clinical records were examined using key word searches to identify cases of PMR and GCA, applying current classification criteria in a population-based cohort. Associations between cardiovascular risk factors and incident PMR and GCA were analysed using Cox proportional hazards. RESULTS: In 315 022 person years of follow-up, there were 395 incident diagnoses of PMR and 118 incident diagnoses of GCA that met the clinical definition. Raised diastolic blood pressure (>90 mmHg) at baseline/recruitment was associated with subsequent incident PMR [hazard ratio=1.35 (95% CI 1.01, 1.80) P=0.045], and ever-smoking was associated with incident GCA [hazard ratio=2.01 (95% CI 1.26, 3.20) P=0.003]. Estimates were similar when the analysis was restricted to individuals whose diagnoses satisfied the current classification criteria sets. CONCLUSION: PMR and GCA shares common risk factors with vascular disease onset, suggesting a common underlying propensity. This may indicate a potential for disease prevention strategies through modifying cardiovascular risk.

Toward a Core Outcome Measurement Set for Polymyalgia Rheumatica: Report from the OMERACT 2018 Special Interest Group.

OBJECTIVE: To report the progress of the Outcome Measures in Rheumatology (OMERACT) Polymyalgia Rheumatica (PMR) Working Group in selecting candidate instruments for a core outcome measurement set. METHODS: A systematic literature review identified outcomes measured and instruments used in PMR studies, and a respondent survey and raw data analysis assessed their domain match and feasibility. RESULTS: Candidate instruments were identified for pain [visual analog scale/numerical rating scale (VAS/NRS)], stiffness (VAS/NRS and duration), and physical function (Health Assessment Questionnaire-Disability Index/modified Health Assessment Questionnaire). Domain match and feasibility assessments were favorable; however, validation in PMR was lacking. CONCLUSION: Further assessment of candidate instruments is required prior to recommending a PMR core outcome measurement set.