Association of circulating lymphocyte subsets with response to IL17i and TNFi in axial spondyloarthritis.

OBJECTIVES: Biologic disease-modifying anti-rheumatic drugs (b-DMARDs) have qualitatively improved the management of axial spondyloarthritis (axSpA), but up to 30-40% of patients do not respond. Although lymphocytes are clearly implicated in the pathology of SpA, circulating lymphocyte subsets (LS) dynamics has been poorly studied. The objective of this pilot study was to comprehensively analyse circulating LS abnormalities in axSpA, and to determine their potential association with response to b-DMARDs. METHODS: Sixty-nine patients with axSpA and 141 control subjects (HC) were included. The clinical features were measured at baseline, and additionally at 6 months in a subgroup of patients who received TNFi (n=36) or IL17i (n=26). Clinical response was defined as a 50% reduction of BASDAI or decrease in ASDAS of 1.1 point. CD4/CD8 T-cells, B-cells and NK-cells and their subsets were analysed by flow cytometry at inclusion. RESULTS: At baseline, alterations in LS were observed in axSpA with reduced/increased frequencies of 10/27 subsets (p<0.003 after correction) and trends for another 5. There was no association of response to bDMARDs with clinical data. Response to IL17i (61% cases) was associated with a higher frequency of NK-cells (p=0.003), trends for change in naïve/memory-CD8+T-cells (p<0.055) and increased expression of KIR3DL2 on Th17-cells (p=0.052). No LS was associated with response to TNFi (69% cases) although trends were observed (CD4+T-cells subsets, higher IL-6R on CD4+/CD8+T-cells). CONCLUSIONS: This pilot work demonstrated a dysregulation of LS in axSpA. The association observed between several LS and clinical response to IL17i (NK/CD8 subsets/Th17-KIR3DL2) was very different to that observed for TNFi (CD4/IL-6R).

Defining remission in rheumatoid arthritis: does it matter to the patient? A comparison of multi-dimensional remission criteria and patient reported outcomes.

OBJECTIVES: In a cross-sectional study, we evaluated the prevalence of 'multi-dimensional remission' (MDR) and its component parameters, assessed using objective measures in a cohort of RA patients in treatment-induced DAS28-remission, and their relationship with patient-reported outcome measures. We sought to confirm the feasibility and face validity of the MDR construct, providing a platform for future longitudinal studies in which its clinical utility might be further established. METHODS: 605 patients were selected from an inflammatory arthritis register using DAS28(CRP)<2.6. Demographic, clinical and patients reported outcomes (PRO) data were collected. Ultrasound power doppler synovitis (n = 364) and T-cell subsets (n = 297) were also measured. Remission using clinical parameters was defined as: tender and swollen joint count (TJC/SJC) and CRP all ⩽1; ultrasound remission: total power doppler = 0 and T cell remission: positive normalized naïve T-cell frequency. MDR was defined as the achievement of all three dimensions. RESULTS: Overall, only 53% (321/605) of the patients achieved clinical parameters, failures being mainly due to raised CRP (52%), TJC (28)>1 (37%) or SJC (28)>1 (16%). 211/364 (58%) of patients achieved ultrasound remission and 193/297 (65%) patients showed T-cell remission. Complete data were available for 231 patients. MDR was observed in only 35% and was associated with the best (lower) PRO scores (all P ⩽ 0.05 vs non-MDR) when compared with the other definitions of remission assessed. The MDR rate was similar in early and established RA patients on b-DMARDs; however, it was lower in established RA patients who received multiple cs-DMARDs (P = 0.011). CONCLUSIONS: In this study, MDR, which may represent a state closer to normality, was found to occur in about a third of DAS28-remission patients and was associated with better patient-reported outcome measures. MDR could be a novel optimal treatment target, notably from a patient's perspective. The relevance of these findings needs further assessment.

Evaluating the safety and short-term equivalence of colchicine versus prednisone in older patients with acute calcium pyrophosphate crystal arthritis (COLCHICORT): an open-label, multicentre, randomised trial.

BACKGROUND: Acute calcium pyrophosphate crystal arthritis causes intense joint pain mainly affecting older people. Because guidance and evidence remain scarce, management of this disease relies on expert opinion. We therefore aimed to compare the safety and short-term equivalence of low-dose colchicine with oral prednisone in older patients with acute calcium pyrophosphate crystal arthritis. METHODS: We did an open-label, multicentre, randomised, trial (COLCHICORT) at six hospitals in Paris and northern France. We enrolled patients who were admitted to hospital who were 65 years or older and who presented with acute calcium pyrophosphate crystal arthritis with a symptom duration of less than 36 h. Diagnosis of calcium pyrophosphate crystal arthritis was made by the identification of calcium pyrophosphate crystals on synovial fluid analysis or typical clinical presentation (onset of joint pain and swelling). Key exclusion criteria included absence of calcium pyrophosphate crystals on synovial fluid analysis or a history of gout. Participants were randomly allocated (1:1), using a centralised electronic treatment group allocation module, to receive either colchicine 1·5 mg on day 1 and 1 mg on day 2 (ie, the colchicine group) or oral prednisone 30 mg on days 1 and 2 (ie, the prednisone group). The primary outcome was change in joint pain (measured by visual analogue scale [VAS] from 0 mm to 100 mm) at 24 h. Equivalence was determined whether the 95% CI of the between-group difference at 24 h was within the -13 mm to +13 mm margin in the per-protocol analysis. Adverse events were recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). This trial is completed and is registered with ClinicalTrials.gov, NCT03128905. FINDINGS: Between Feb 5, 2018, and May 7, 2022, 111 patients who were admitted to hospital were randomly assigned (57 [51%] to the colchicine group and 54 [49%] to the prednisone group). 95 (86%) of 111 patients were included in the per-protocol analysis (49 [52%] in the colchicine group and 46 [48%] in the prednisone group). The median age was 88·0 years (IQR 82·0-91·0) and 69 (73%) of 95 participants were women and 26 (27%) were men. Acute calcium pyrophosphate crystal arthritis affected mainly the knee in 46 (48%) of 95 participants, the wrist in 19 (20%), and the ankle in 12 (13%). Pain VAS at baseline was 68 mm (SD 17). At 24 h, change in pain VAS was -36 mm (SD 32) in the colchicine group and -38 mm (SD 23) in the prednisone group. The between-group difference in change in pain VAS at 24 h was -1 mm (95% CI -12 to 10), showing equivalence between the two drugs. In the colchicine group, 12 (22%) of 55 patients had diarrhoea, one (2%) had hypertension, and none had hyperglycaemia. In the prednisone group, three (6%) of 54 had diarrhoea, six (11%) had hypertension, and three (6%) had hyperglycaemia. No deaths occurred in the colchicine group; two deaths occurred in the prednisone group, which were deemed unrelated to prednisone (one due to infectious valvular endocarditis leading to heart failure, and one due to a stroke). INTERPRETATION: Colchicine and prednisone exhibit equivalent short-term efficacy for the treatment of acute calcium pyrophosphate crystal arthritis, with different safety profiles in the older population. FUNDING: French Inter-regional Hospital Program of Clinical Research.

T-cell subset abnormalities predict progression along the Inflammatory Arthritis disease continuum: implications for management.

The presence of a disease continuum in inflammatory arthritis (IA) is a recognised concept, with distinct stages from at-risk stage (presence of anti citrullinated-peptide autoantibody) to diagnosis of rheumatoid arthritis (RA), including therapy-induced remission. Despite T-cell dysregulation being a key feature of RA, there are few reports of T-cell phenotyping along the IA-continuum. We investigated the disturbances of naïve, regulatory and inflammation related cell (IRC) CD4+ T-cell subsets in 705 individuals across the IA-continuum, developing a simple risk-score (summing presence/absence of a risk-associated with a subset) to predict progression from one stage to the next. In 158 at-risk individuals, the 3 subsets had individual association with progression to IA and the risk-score was highly predictive (p < 0.0001). In evolving IA patients, 219/294 developed RA; the risk-score included naïve and/or Treg and predicted progression (p < 0.0001). In 120 untreated RA patients, the risk-score for predicting treatment-induced remission using naïve T-cells had an odds ratio of 15.4 (p < 0.0001). In RA patients in treatment-induced remission, a score using naïve T-cells predicted disease flare (p < 0.0001). Evaluating the risk of progression using naïve CD4+ T-cells was predictive of progression along the whole IA-continuum. This should allow identification of individuals at high-risk of progression, permitting targeted therapy for improved outcomes.

Therapeutic Maintenance of Baricitinib and Tofacitinib in Real Life.

BACKGROUND: Janus kinase inhibitors (JAKis) represent a new alternative to treat rheumatoid arthritis (RA). The objective of this study was to evaluate the effectiveness, tolerance profile, and maintenance of these treatments (tofacitinib and baricitinib) in real life. METHODS: All patients in the rheumatology department of Amiens University Hospital treated by JAKis for RA were included from 1 October 2017 to 20 May 2020. Clinical and biological data were provided retrospectively in this observational and single-center study. We aimed to study the JAKi maintenance rate at 12 months and their clinical and biological safety profiles. RESULTS: Fifty-five patients were included. Drug maintenance at 12 months was 67.6%. Factors associated with poorer maintenance were a higher Charlson comorbidity index (HR 1.311 (1.089-1.579); p = 0.0042), a higher age (HR 1.055 (1.015-1.096); p = 0.0067), and corticosteroids therapy at initiation (HR 2.722 (1.006-7.365); p = 0.0487). The clinical and biological safety profile was generally good. CONCLUSIONS: Our study found that a higher Charlson index, age, and corticosteroids appeared to be associated with the earlier discontinuation of treatment. JAKis had a response and tolerance profile in real life at least equivalent to that of biological disease-modifying antirheumatic drugs (bDMARDs).