Predicting Inflammatory Arthritis in At-Risk Persons: Development of Scores for Risk Stratification.

BACKGROUND: Inflammatory arthritis (IA) is an immune-related condition defined by the presence of clinical synovitis. Its most common form is rheumatoid arthritis. OBJECTIVE: To develop scores for predicting IA in at-risk persons using multidimensional biomarkers. DESIGN: Prospective observational cohort study. SETTING: Single-center, Leeds, United Kingdom. PARTICIPANTS: Persons with new musculoskeletal symptoms, a positive test result for anticitrullinated protein antibodies, and no clinical synovitis and followed for 48 weeks or more or until IA occurred. MEASUREMENTS: A simple score was developed using logistic regression, and a comprehensive score was developed using the least absolute shrinkage and selection operator Cox proportional hazards regression. Internal validation with bootstrapping was estimated, and a decision curve analysis was done. RESULTS: Of 455 participants, 32.5% (148 of 455) developed IA, and 15.4% (70 of 455) developed it within 1 year. The simple score identified 249 low-risk participants with a false negative rate of 5% (and 206 high-risk participants with a false-positive rate of 72%). The comprehensive score identified 119 high-risk participants with a false-positive rate of 29% (and 336 low-risk participants with a false-negative rate of 19%); 40% of high-risk participants developed IA within 1 year and 71% within 5 years. LIMITATIONS: External validation is required. Recruitment occurred over 13 years, with lower rates of IA in later years. There was geographic variation in laboratory testing and recruitment availability. CONCLUSION: The simple score identified persons at low risk for IA who were less likely to need secondary care. The comprehensive score identified high-risk persons who could benefit from risk stratification and preventive measures. Both scores may be useful in clinical care and should also be useful in clinical trials. PRIMARY FUNDING SOURCE: National Institute for Health and Care Research Leeds Biomedical Research Centre.

Ultrasound in anti-CCP+ at-risk individuals without clinical synovitis: development of a novel 6-joint protocol for feasible risk prediction.

OBJECTIVES: To investigate, in anti-cyclic citrullinated peptide antibody positive individuals with musculoskeletal symptoms but no clinical synovitis (CCP+ at-risk), the additional value of ultrasound (US) for the prediction of inflammatory arthritis (IA). Furthermore, to define a concise US protocol for feasible risk prediction. METHODS: Demographic and clinical data were collected in 417 CCP+ at-risk (Leeds CCP cohort) with a baseline US scan assessing synovitis and bone erosions in 36 joints, and a follow-up duration ≥24 months. Multivariable binary regression models for IA development at 24 months evaluated routine clinical variables associated with IA alone ("clinical" model) and combined with a 36-joint US scanning protocol ("clinical-US extended" model). A "clinical-US short" model was developed. RESULTS: At 24 months, 92/417 (22.1%) CCP+ at-risk developed IA (median time: 7 months, IQR : 3-12). The "clinical-US extended" model performed better than the "clinical" model (AUC 0.788 vs AUC 0.731 respectively, p< 0.001) with an odds ratio for IA development of 3.18 (95% IC 1.80-5.63) for US synovitis and 2.54 (95% IC 1.21-5.37) for bone erosions. The "clinical-US short" model, which retained the wrists, knees and MTP5 joints, performed better (AUC 0.782) than the "clinical" model (p< 0.001) and similarly (difference in Akaike information criteria <2) to the "clinical-US extended" model. CONCLUSIONS: US provides valuable information for predicting progression to IA in CCP+ individuals both alone and in addition to clinical variables. US synovitis was associated with a threefold increase risk of IA development. A concise US protocol of 6 joints provides clinically feasible risk prediction in CCP+ at-risk.

Factors associated with resolution of ultrasound subclinical synovitis in anti-CCP-positive individuals with musculoskeletal symptoms: a UK prospective cohort study.

BACKGROUND: Subclinical synovitis occurs in a third of individuals at risk of rheumatoid arthritis. The objective of this study was to assess the reversibility of subclinical synovitis in individuals at risk of rheumatoid arthritis who are positive for anti-cyclic citrullinated peptide (CCP) antibody with musculoskeletal symptoms and investigate factors associated with its resolution within 12 months. METHODS: We conducted a single-centre, prospective, cohort study in the UK, recruiting individuals aged 18 years or older who were anti-CCP-positive with a new non-specific musculoskeletal symptom but no clinical synovitis. Referrals were made through primary or secondary care. Participants attended a baseline visit, which included a clinical assessment, blood tests, patient questionnaires, and a musculoskeletal ultrasound scan (ie, of wrists and metacarpophalangeal, proximal interphalangeal, and metatarsophalangeal joints), and then follow-up visits every 3 months for the first year, with a repeat ultrasound scan every 12 months. Participants with subclinical synovitis (ie, grey scale ≥1 and power Doppler ≥1) in at least one joint at baseline were selected for this analysis. Investigation of good prognostic factors by 12 months was done first using univariable analysis to identify significant factors in participants with no missing data. Then receiver operating characteristic (ROC) curves were used to establish the optimal cutoffs for significant continuous variables. Finally, a modified Poisson regression approach was performed to identify the best prediction model and was adjusted for confounders, using data from all participants, with missing values imputed. This study is registered with ClinicalTrials.gov, NCT02012764. FINDINGS: Between June 30, 2008, and Feb 24, 2020, 451 participants consented to participate in the CCP study and 122 (27%) individuals had subclinical synovitis at baseline, of whom 90 (74%) had data available at 12 months. Mean age was 54·1 years (SD 12·5), and 63 (70%) of 90 participants were women and 27 (30%) were men. Subclinical synovitis resolved in 43 (48%) of 90 participants, whereas subclinical synovitis persisted in 47 (52%) participants, 27 (57%) of whom developed clinical synovitis within 12 months. In the multivariable analysis, low anti-CCP titre (relative risk [RR] 1·52, 95% CI 1·04-2·22), negative rheumatoid factor (1·54, 0·92-2·58), subclinical synovitis in only one joint (1·62, 1·04-2·50), and an erythrocyte sedimentation rate of 15 mm/h or lower (1·82, 1·15-2·87) were predictors of subclinical synovitis resolution within 12 months (ie, good prognostic factors). ROC curve showed an area under the curve of 0·84 (95% CI 0·76-0·92; p<0·0001). Resolution occurred in seven (100%) of seven participants with all four factors present, and in only one (7%) of 14 participants with none of the factors present. INTERPRETATION: In individuals who were anti-CCP-positive, subclinical synovitis disappeared in approximately half of the participants by 12 months and was associated with the presence of good prognostic factors. Subclinical synovitis should be interpreted in the context of these additional factors. FUNDING: National Institute for Health Research Leeds Biomedical Research Centre.

Effectiveness of SARS-CoV-2 vaccination in patients with rheumatoid arthritis (RA) on DMARDs: as determined by antibody and T cell responses.

OBJECTIVES: To assess antibody and T cell responses to SARS-CoV-2 vaccination in patients with rheumatoid arthritis (RA) on disease-modifying antirheumatic drugs (DMARDs). METHODS: This prospective study recruited 100 patients with RA on a variety of DMARDs for antibody and T cell analysis, pre-vaccination and 4 weeks post-vaccination. Positive antibody response was defined as sera IgG binding to ≥1 antigen. Those that remained seronegative after first vaccination were retested 4 weeks after second vaccination; and if still seronegative after vaccination three. A T cell response was defined an ELISpot count of ≥7 interferon (IFN)γ-positive cells when exposed to spike antigens. Type I IFN activity was determined using the luminex multiplex assay IFN score. RESULTS: After vaccine one, in patients without prior SARS-CoV-2 exposure, 37/83 (45%) developed vaccine-specific antibody responses, 44/83 (53%) vaccine-specific T cell responses and 64/83 (77%) developed either antibody or T cell responses. Reduced seroconversion was seen with abatacept, rituximab (RTX) and those on concomitant methotrexate (MTX) compared to 100% for healthy controls (p<0.001). Better seroconversion occurred with anti-tumour necrosis factor (TNF) versus RTX (p=0.012) and with age ≤50 (p=0.012). Pre-vaccine SARS-CoV-2 exposure was associated with higher quantitative seroconversion (≥3 antibodies) (p<0.001). In the subgroup of non-seroconverters, a second vaccination produced seroconversion in 54% (19/35), and after a third in 20% (2/10). IFN score analysis showed no change post-vaccine. CONCLUSION: Patients with RA on DMARDs have reduced vaccine responses, particularly on certain DMARDs, with improvement on subsequent vaccinations but with approximately 10% still seronegative after three doses.

The Role of Ultrasound Across the Inflammatory Arthritis Continuum: Focus on "At-Risk" Individuals.

In individuals at-risk of developing inflammatory arthritis, the value of an ultrasound (US) scan assessment to predict progression has been demonstrated repeatedly. However, depending on recruitment criteria, these individuals may be at different stages in the arthritis development continuum, therefore representing a heterogeneous population. As a consequence, the predictive value of ultrasound results may differ between cohorts. As other reviews have focused on the challenges in population recruitment or have combined biomarkers predicting value according to one recruitment pathway, we wanted to focus on the sole use of ultrasound assessment and its variation according to population recruitment criteria. In this review, we discuss the use of ultrasound in the different at-risk populations across the inflammatory arthritis disease continuum. This review demonstrates that although some sub-population data is scarce, ultrasound is best predictive in three at-risk populations: those with a positive ACPA test in the context of non-specific MSK symptoms, those with clinically suspect arthralgia and those with palindromic rheumatism. We consider that ultrasound assessment will be a cornerstone in prediction risk modeling and prevention studies of the preclinical phases of IA in the future.