Validation of the Southend giant cell arteritis probability score in a Scottish single-centre fast-track pathway.

OBJECTIVE: The aim was to provide external validation of the Southend GCA probability score (GCAPS) in patients attending a GCA fast-track pathway (GCA FTP) in NHS Lanarkshire. METHODS: Consecutive GCA FTP patients between November 2018 and December 2020 underwent GCAPS assessment as part of routine care. GCA diagnoses were supported by US of the cranial and axillary arteries (USS), with or without temporal artery biopsy (TAB), and confirmed at 6 months. Percentages of patients with GCA according to GCAPS risk group, performance of total GCAPS in distinguishing GCA/non-GCA final diagnoses, and test characteristics using different GCAPS binary cut-offs were assessed. Associations between individual GCAPS components and GCA and the value of USS and TAB in the diagnostic process were also explored. RESULTS: Forty-four of 129 patients were diagnosed with GCA, including 0 of 41 GCAPS low-risk patients (GCAPS <9), 3 of 40 medium-risk patients (GCAPS 9-12) and 41 of 48 high-risk patients (GCAPS >12). Overall performance of GCAPS in distinguishing GCA/non-GCA was excellent [area under the receiver operating characteristic curve, 0.976 (95% CI 0.954, 0.999)]. GCAPS cut-off ≥10 had 100.0% sensitivity and 67.1% specificity for GCA. GCAPS cut-off ≥13 had the highest accuracy (91.5%), with 93.2% sensitivity and 90.6% specificity. Several individual GCAPS components were associated with GCA. Sensitivity of USS increased by ascending GCAPS risk group (nil, 33.3% and 90.2%, respectively). TAB was diagnostically useful in cases where USS was inconclusive. CONCLUSION: This is the first published study to describe application of GCAPS outside the specialist centre where it was developed. Performance of GCAPS as a risk stratification tool was excellent. GCAPS might have additional value for screening GCA FTP referrals and guiding empirical glucocorticoid treatment.

Real-world experience of effectiveness of non-medical switch from originator to biosimilar rituximab in rheumatoid arthritis.

OBJECTIVE: To evaluate the impact of non-medical switch from rituximab originator (RTX-O) to biosimilar (RTX-B) in patients with RA. METHODS: Between October 2017 and October 2019, all patients on RTX-O in our centre requiring re-treatment were switched to RTX-B unless declined by the patient or specified by the treating clinician. Switch strategy effectiveness was assessed retrospectively using DAS28-CRP(3) and RTX retention, with patients remaining on RTX-O as a comparator group. RESULTS: The number of patients switching to RTX-B was 255/337 (75.7%) while 82 (24.3%) remained on RTX-O. There was no difference in DAS28-CRP(3) 4 months post-RTX-B switch vs the same time point post-RTX-O previous cycle (paired data available in 60%). Eighteen-month retention estimates were 75.6% (95% CI: 69.4, 80.7%) for RTX-B group and 82.3% (95% CI: 70.4, 89.8%) for RTX-O [adjusted hazard ratio 1.52 (95% CI: 0.85, 2.73)]. The number of patients who discontinued RTX-B for loss of effectiveness (LOE) was 42/255 (16.5%), five (2.0%) for adverse effects (AEs). Risk of RTX-B discontinuation was associated with comorbidities and ≥2 previous biologic DMARDs. Risk of adverse outcome RTX cessation was associated with comorbidities, and reduced risk with number of previous RTX-O cycles and pre-switch cycle B cell depletion. The number of patients who switched back to RTX-O was 34/255 (13.3%) (LOE: 30, AEs: 4), while 13/255 (5.1%) started other biologic/targeted synthetic DMARDs. Of patients who switched back for LOE, 28/30 remained on RTX-O at a mean 7.7 months follow-up. CONCLUSION: Non-medical switch to RTX-B was largely effective. Factors associated with RTX-B discontinuation, including comorbidities, previous biologic DMARDs, and RTX-O treatment history, may inform switch decisions. Most patients who switched back to RTX-O for LOE remained on treatment at short-term follow-up.

Real-world single centre use of JAK inhibitors across the rheumatoid arthritis pathway.

OBJECTIVES: To evaluate real-world efficacy of approved JAK inhibitors (JAKi) tofacitinib and baricitinib in a large, single-centre cohort of RA patients across the treatment pathway, including those refractory to multiple biologic drugs. METHODS: All RA patients, treated with tofacitinib (from time of compassionate access scheme) or baricitinib since approval in 2017 had DAS28-CRP scores and components recorded at baseline, 3 and 6 months (with retrospective data for compassionate access scheme). Efficacy was evaluated in the total cohort, each treatment group, and subgroups of number of prior biologic classes failed. RESULTS: One hundred and fifteen patients were treated with a JAKi (tofacitinib 54, baricitinib 69, 8 both); 76.4% female; mean (s.d.) age 57.3 (14.3) years. On average patients had received three previous bDMARDs; 11 (9.6%) were bDMARD naïve. Combined group baseline DAS28-CRP (s.d.) 5.62(1.14) improved by 1.49(1.44) and 1.67(1.61) at 3 and 6 months, respectively, comparable in individual JAKi groups; with 24% in at least low disease activity at 3 months. The biggest improvement was observed in the biologic-naïve group (mean DAS28-CRP improved from 5.16-2.14 after 6 months); while those with prior exposure to minimum three bDMARD classes had DAS28-CRP improvement of >1.2. Five out of 8 patients treated with both JAKi sequentially responded. Twelve patients previously unresponsive to IL-6 blockade responded to JAKi. No unexpected safety events were recorded. Two cases of venous thromboembolism were observed. CONCLUSION: JAK inhibition is effective in a real-world population of RA patients, including in a subset of patients refractory to multiple previous bDMARDs.

Understanding Refractory Rheumatoid Arthritis: Implications for a Therapeutic Approach.

Refractory rheumatoid arthritis (RA) has emerged as an area of unmet need in a landscape of generally well-controlled disease. Whilst most patients are adequately treated on methotrexate and other first-line disease-modifying anti-rheumatic drugs (DMARDs), a proportion requires biologic (b) and targeted synthetic (ts) DMARDs, with a further subsection failing multiple agents. Recent observational studies have adopted working definitions of refractory RA based on number of failed DMARDs, with prevalence estimates of 6-21% depending on threshold and study population. Risk factors include treatment delay, baseline disease activity and function, female gender, smoking, obesity and lower socioeconomic status. Practical and conceptual challenges in defining refractory RA arise from limitations of disease activity scores used to assess response, with attendant misclassification risk of co-existent non-inflammatory pathology, and failure to capture additional outcomes, such as fatigue, that have variable treatment response. Time is an important factor in defining refractory disease; registry studies show that growing treatment options have resulted in rapid b/tsDMARD cycling and earlier refractory status, and refractory RA is itself a dynamic concept, evolving with each new therapeutic class. Whilst the biology underpinning refractory RA remains largely unknown, a general overview of biomarker studies and clinical trials old and new offers insights into prediction of response and treatment failure. Whilst the future holds promise, current data are insufficient to personalise or meaningfully sequence b/tsDMARDs. Therefore, avoidance of a refractory course is best achieved by following proven management paradigms (e.g. early diagnosis and treat-to-target), addressing modifiable risk factors, and considering enrolment in novel trials.