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.

Characterising polymyalgia rheumatica on whole-body 18F-FDG PET/CT: an atlas.

The impact of modern imaging in uncovering the underlying pathology of PMR cannot be understated. Long dismissed as an inflammatory syndrome with links to the large vessel vasculitis giant cell arteritis (GCA), a pathognomonic pattern of musculotendinous inflammation is now attributed to PMR and may be used to confirm its diagnosis. Among the available modalities, 18F-fluorodeoxyglucose (18F-FDG) PET/CT is increasingly recognized for its high sensitivity and specificity, as well as added ability to detect concomitant large vessel GCA and exclude other relevant differentials like infection and malignancy. This atlas provides a contemporary depiction of PMR's pathology and outlines how this knowledge translates into a pattern of findings on whole body 18F-FDG PET/CT that can reliably confirm its diagnosis.

Test-retest reliability of pain VAS/NRS, stiffness VAS/NRS, HAQ-DI and mHAQ in polymyalgia rheumatica: An OMERACT study.

OBJECTIVE: To examine the test-retest reliability of four measurement instruments in polymyalgia rheumatica (PMR): pain severity visual analogue scale (VAS) / numerical rating score (NRS), stiffness severity VAS/NRS, the Health Assessment Questionnaire-Disability Index (HAQ-DI) and the modified Health Assessment Questionnaire (mHAQ). METHOD: Two prospectively collected datasets were used. All participants had a diagnosis of PMR and only those with stable disease were included in analyses. Measurement instruments were administered twice, with a testing interval of two to six weeks. The intra-class correlation coefficient (ICC) was calculated using a two-way mixed effects model looking for absolute agreement. ICC values of 0.8-0.9 were deemed representative of good test-retest reliability, whilst values >0.9 were representative of excellent test-retest reliability. RESULTS: From the first dataset, 38 participants were analysed. The ICC between baseline and 2 weeks for pain VAS, stiffness VAS, HAQ-DI and mHAQ were 0.84, 0.82, 0.92 and 0.92 respectively. From the second dataset, 58 participants were included in the analysis for pain NRS, 59 for stiffness NRS and 78 for mHAQ. The ICC between baseline and follow-up for pain NRS, stiffness NRS and mHAQ were 0.80, 0.83 and 0.87 respectively. CONCLUSION: Pain severity VAS/NRS, stiffness severity VAS/NRS, HAQ-DI and mHAQ all demonstrate good to excellent test-retest reliability in a PMR patient population.

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.

Diagnosis of septic arthritis in the acute care setting: the value of routine intra-operative sample culture.

Objective: Diagnosing septic arthritis can be challenging and frequently involves clinical assessment, laboratory investigations and synovial fluid analysis. We sought to determine the utility of synovial aspiration and intra-operative synovial fluid and tissue culture for the accurate diagnosis of septic arthritis. Methods: We carried out a retrospective review of the records of patients referred to a tertiary orthopaedic unit with possible septic arthritis between 2015 and 2019 inclusive, including clinical and laboratory data for this cohort study. Performance characteristics were determined for synovial aspiration, intra-operative synovial fluid and tissue culture in diagnosing expert review-determined true septic arthritis. Concordance between discharge diagnosis, antibiotic prescribing and true septic arthritis was determined. Results: Of 268 patients identified with suspected septic arthritis, 143 underwent both synovial fluid aspiration and intra-operative synovial fluid and tissue biopsy culture. True septic arthritis was not differentiated significantly by laboratory parameters including serum white cell count (WCC), CRP or synovial WCC. Considering only patients with negative pre-operative synovial aspirate cultures, intra-operative samples led to diagnosis of true septic arthritis in 6 of 63 patients [number needed to treat (NNT) 10.5]. For all patients sampled in theatre, positive synovial tissue biopsy was the only evidence of true septic arthritis in six (NNT 23.9). Despite insufficient microbiological evidence, 27 of the 59 patients who did not have septic arthritis received a discharge diagnosis of septic arthritis, 26 of whom were discharged with antibiotics. Conclusion: Intra-operative sample collection, particularly tissue biopsy, increases the likelihood of a true septic arthritis diagnosis. Such measures might help to reduce diagnostic ambiguity in clinical practice and might therefore reduce overtreatment.

Artificial Intelligence and Deep Learning for Rheumatologists.

Deep learning has emerged as the leading method in machine learning, spawning a rapidly growing field of academic research and commercial applications across medicine. Deep learning could have particular relevance to rheumatology if correctly utilized. The greatest benefits of deep learning methods are seen with unstructured data frequently found in rheumatology, such as images and text, where traditional machine learning methods have struggled to unlock the trove of information held within these data formats. The basis for this success comes from the ability of deep learning to learn the structure of the underlying data. It is no surprise that the first areas of medicine that have started to experience impact from deep learning heavily rely on interpreting visual data, such as triaging radiology workflows and computer-assisted colonoscopy. Applications in rheumatology are beginning to emerge, with recent successes in areas as diverse as detecting joint erosions on plain radiography, predicting future rheumatoid arthritis disease activity, and identifying halo sign on temporal artery ultrasound. Given the important role deep learning methods are likely to play in the future of rheumatology, it is imperative that rheumatologists understand the methods and assumptions that underlie the deep learning algorithms in widespread use today, their limitations and the landscape of deep learning research that will inform algorithm development, and clinical decision support tools of the future. The best applications of deep learning in rheumatology must be informed by the clinical experience of rheumatologists, so that algorithms can be developed to tackle the most relevant clinical problems.

Subclinical giant cell arteritis in new onset polymyalgia rheumatica A systematic review and meta-analysis of individual patient data.

OBJECTIVES: To determine the prevalence and predictors of subclinical giant cell arteritis (GCA) in patients with newly diagnosed polymyalgia rheumatica (PMR). METHODS: PubMed, Embase, and Web of Science Core Collection were systematically searched (date of last search July 14, 2021) for any published information on any consecutively recruited cohort reporting the prevalence of GCA in steroid-naïve patients with PMR without cranial or ischemic symptoms. We combined prevalences across populations in a random-effect meta-analysis. Potential predictors of subclinical GCA were identified by mixed-effect logistic regression using individual patient data (IPD) from cohorts screened with PET/(CT). RESULTS: We included 13 cohorts with 566 patients from studies published between 1965 to 2020. Subclinical GCA was diagnosed by temporal artery biopsy in three studies, ultrasound in three studies, and PET/(CT) in seven studies. The pooled prevalence of subclinical GCA across all studies was 23% (95% CI 14%-36%, I2=84%) for any screening method and 29% in the studies using PET/(CT) (95% CI 13%-53%, I2=85%) (n=266 patients). For seven cohorts we obtained IPD for 243 patients screened with PET/(CT). Inflammatory back pain (OR 2.73, 1.32-5.64), absence of lower limb pain (OR 2.35, 1.05-5.26), female sex (OR 2.31, 1.17-4.58), temperature >37° (OR 1.83, 0.90-3.71), weight loss (OR 1.83, 0.96-3.51), thrombocyte count (OR 1.51, 1.05-2.18), and haemoglobin level (OR 0.80, 0.64-1.00) were most strongly associated with subclinical GCA in the univariable analysis but not C-reactive protein (OR 1.00, 1.00-1.01) or erythrocyte sedimentation rate (OR 1.01, 1.00-1.02). A prediction model calculated from these variables had an area under the curve of 0.66 (95% CI 0.55-0.75). CONCLUSION: More than a quarter of patients with PMR may have subclinical GCA. The prediction model from the most extensive IPD set has only modest diagnostic accuracy. Hence, a paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed.

Neutrophil to lymphocyte ratio predicts glucocorticoid resistance in polymyalgia rheumatica.

AIM: Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) correlate with disease activity in several rheumatic diseases; however, their utility in polymyalgia rheumatica (PMR) remains unclear. This study evaluated their relationship with disease activity and glucocorticoid resistance in PMR. METHOD: Data for disease activity (PMR-AS) and full blood examination was obtained from a prospective observational cohort comprising newly diagnosed, steroid-naïve PMR patients treated with low-dose glucocorticoid therapy. Glucocorticoid resistance was defined as non-response to prednisolone 15 mg/d or initial response followed by flare (PMR-AS ≥ 9.35 or ∆ ≥6.6) upon weaning to 5 mg/d. Univariable Bayesian linear regression analysis of the relationship between PMR-AS (baseline and mean) and NLR and PLR was performed. Predictors of glucocorticoid resistance were identified using a multivariable outcome model, with variables derived from Bayesian model selection. RESULTS: Of the 32 included patients, 16 (50%) fulfilled the primary outcome measure of glucocorticoid resistance. These participants were older, typically female, and had higher baseline C-reactive protein than their glucocorticoid-responsive counterparts. A statistically significant relationship was identified between PMR-AS and both NLR (odds ratio [OR] 28.1; 95% CI 1.6-54.7) and PLR (OR 40.6; 95% CI 10.1-71.4) at baseline, with PLR also found to correlate with disease activity during follow-up (OR 15.6; 95% CI 2.7-28.2). Baseline NLR proved a statistically significant predictor of glucocorticoid-resistant PMR (OR 14.01; 95% CI 1.49-278.06). CONCLUSION: Baseline NLR can predict glucocorticoid resistance in newly diagnosed PMR patients. Both NLR and PLR may be reliable biomarkers of disease activity in PMR.

Abnormalities at three musculoskeletal sites on whole-body positron emission tomography/computed tomography can diagnose polymyalgia rheumatica with high sensitivity and specificity.

PURPOSE: To evaluate the sensitivity and specificity of PET/CT findings in PMR and generate a diagnostic algorithm utilizing a minimum number of musculoskeletal sites. METHODS: Steroid-naïve patients with newly diagnosed PMR (2012 EULAR/ACR classification criteria) were prospectively recruited to undergo whole-body 18F-FDG PET/CT. Each PMR case was age- and sex-matched to four PET/CT controls. Control scan indication, diagnosis and medical history were extracted from the clinical record. Qualitative and semi-quantitative scoring (maximum standardized uptake value [SUVmax]) of abnormal 18F-FDG uptake at 21 musculoskeletal sites was undertaken for cases and controls. Results informed the development of a novel PET/CT diagnostic algorithm using a classification and regression trees (CART) method. RESULTS: Thirty-three cases met the inclusion criteria and were matched to 132 controls. Mean age was 68.6 ± 7.4 years for cases compared with 68.2 ± 7.3 for controls, and 54.5% were male. Median CRP was 49 mg/L (32-65) and ESR 41.5 mm/h (24.6-64.4) in the PMR group. The predominant control indication for PET/CT was malignancy (63.6%). Individual musculoskeletal sites proved insufficient for diagnostic purposes. A novel algorithm comprising 18F-FDG uptake ≥ 2 adjacent to the ischial tuberosities in combination with either abnormalities at the peri-articular shoulder or interspinous bursa achieved a sensitivity of 90.9% and specificity of 92.4% for diagnosing PMR. CONCLUSIONS: The presence of abnormal 18F-FDG uptake adjacent to the ischial tuberosities together with findings at the peri-articular shoulder or interspinous bursa on whole-body PET/CT is highly sensitive and specific for a diagnosis of PMR. TRIAL REGISTRATION: Clinical Trial Registration: Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au , ACTRN1261400696695.

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.

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.