A paradigm of difficult-to-treat rheumatoid arthritis: subtypes and early identification.

OBJECTIVES: Multiple failures to biologic or targeted specific disease-modifying anti-rheumatic drugs (b/tsDMARDs) that lead to difficult-to-treat rheumatoid arthritis (D2TRA) may be the result of multi-drug inefficacy or reflect treatment problems related to adverse events, comorbidities, and/or poor adherence. We aimed to characterise a cohort of D2TRA patients in clinical practice, to analyse the differences between D2TRA due to inefficacy versus D2TRA from other causes, and to compare them with non-D2TRA. METHODS: The D2TRA group included patients who were receiving ≥2b/tsDMARDs due to inefficacy (D2TRA-inef cacy) or because of adverse events, poor adherence, contraindications, comorbidities, drug-intolerance, etc. (D2TRA-other). Patients who achieved low disease activity or remission with the rst bDMARD were classified as non-D2TRA patients. For all patients, demographic, clinical characteristics and laboratory parameters were assessed prior to starting the rst b/tsDMARD. Descriptive analysis was performed and bivariate logistic regression models were assembled. RESULTS: In total, 253 patients were included: 131 non-D2TRA and 122 D2TRA [86 (70.5%) D2TRA-inefficacy and 36 (29.5%) D2TRA-other]. Comparison of the two groups of D2TRA patients: no differences in gender, age at start of b/tsDMARD or age at RA diagnosis were found; this was also true of socioeconomic status, frequency of anxiety-depression and other comorbidities. Patients categorised as D2TRA-other had less extra-articular manifestations than D2TRA-inef cacy, as well as lower values of DAS28 at the start of the rst b/tsDMARD. Comparisons of Non-D2TRA patients versus D2TRA-other resulted in the following observations: no differences in sociodemographic characteristics were evident nor were there any differences in terms of disease activity. CONCLUSIONS: Patients with D2TRA-other are indistinguishable from non-D2TRA patients at baseline, indicating the former cohort does not appear to have any predictive value during the early stages of b/tsDMARD treatment, unlike what occurs in patients with D2TRA-inefficacy.

Complete disappearance of pulmonary rheumatoid nodules after long term rituximab treatment: case report.

The natural history of pulmonary rheumatoid nodules in rheumatoid arthritis remains uncertain. We present a case of a patient with rheumatoid arthritis with pulmonary rheumatoid nodules diagnosed while receiving etanercept in whom pulmonary nodules resolved completely after 5 years of rituximab treatment. Rituximab has been evaluated in case series of patients with pulmonary rheumatoid nodules, resulting in most cases in no progression or a reduction in the size of the nodules, although the complete resolution is uncommon probably due to the short follow-up period. Complete disappearance of pulmonary rheumatoid nodules may be expected after long-term treatment with rituximab.

Proliferative synovitis, an ultrasound pattern associated with ACPA-positive patients and erosive disease in rheumatoid arthritis.

OBJECTIVES: To analyse ultrasound (US) differences between rheumatoid arthritis (RA) patients according to autoantibody status and characterise the clinical and radiological features associated with the US pattern of seropositive patients. METHODS: We collected demographic and clinical data and bilateral hand US images of RA patients. We defined an extreme proliferative US pattern, encompassing synovial hypertrophy grade II-III with Power Doppler signal, which we called US proliferative synovitis (US PS). To better characterise US PS, MRI of the dominant hand and immunostaining of synovial biopsies were made in subgroups of 42 and 23 patients, respectively. RESULTS: We included 205 RA patients (84.8% seropositive). No significant differences in disease activity were found according to autoantibody status. US PS was found in 55.5% of seropositive and 16.1% of seronegative patients (p=0.0001). In the multivariate analysis, erosions [OR 4.90 95% CI (2.17-11.07), p=0.0001] and ACPA [OR 3.5 95% CI (1.39-10.7), p=0.009] but not RF status [OR 0.74 95% CI (0.31-1.71), p=0.483] were independently associated with US PS. After a mean follow-up of 46 months, US PS was independently associated with changes in therapy (OR 2.63, 95% CI 1.20-5.77, p=0.016). Ninety-four per cent of joints with US PS had RAMRIS synovitis sub-index grade 2-3. US PS was significantly associated with higher synovial vessel density (p=0.042). CONCLUSIONS: In RA patients, US PS was associated with ACPA status, erosive disease and an enhanced need to change disease-modifying anti-rheumatic drug therapy in the long-term. At synovial level, this US pattern was characterised by higher vessel density.

Biomarkers for treatment change and radiographic progression in patients with rheumatoid arthritis in remission: a 5 year follow-up study.

OBJECTIVE: To identify biomarkers of treatment change and radiographic progression in patients with RA under remission. PATIENTS AND METHODS: RA patients in remission (DAS28-ESR <2.6) were selected and followed up for 5 years. An MRI of the dominant hand and an US assessment of knees/hands and serum levels of inflammation/angiogenesis biomarkers were performed at baseline and at 12th month. Synovial biopsies were obtained in patients with Power Doppler signal. Conventional radiographies of hands/feet were taken at baseline and after 5 years. Radiographic progression was defined as the change in the modified Sharp van der Heijde Score at 5 years >10.47 (small detectable change). RESULTS: Sixty patients were included, 81.6% were ACPA+ and 45% were taking biological DMARDs. At baseline, 66.6% had Power Doppler signal. After 5 years, 73.3% of patients remained in remission. Change of therapy was performed in 20 patients (33.3%) and was associated with BMI [odds ratio (OR) 1.3, 95% CI: 1, 1.7], lack of biological DMARD therapy (OR 24.7, 95% CI: 2.3, 257.2), first-year progression of MRI erosions (OR 1.2, 95% CI: 1, 1.3) and calprotectin serum levels (OR 2.8, 95% CI: 1, 8.2). Radiographic progression occurred in six (10%) patients. These patients had higher first-year progression of MRI erosions (P = 0.03) and bone oedema (P = 0.04). Among 23 patients undergoing synovial biopsy, mast cell density was independently associated with clinical flares. CONCLUSIONS: One-third of RA patients lost clinical remission and changed therapy throughout the 5 years of follow-up, which was independently associated with BMI, lack of biological DMARDs therapy and first-year progression of MRI erosion score and calprotectin serum levels. Significant radiographic progression was uncommon.

Anti-carbamylated proteins antibody repertoire in rheumatoid arthritis: evidence of a new autoantibody linked to interstitial lung disease.

OBJECTIVE: To analyse the association between anti-carbamylated protein antibodies (Anti-CarP) and interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients. METHODS: Cross-sectional study including RA patients fulfilling the 2010 ACR/EULAR criteria. The main population comprised two groups: (1) RA patients diagnosed with RA-ILD (RA-ILD group); (2) RA patients without ILD (non-ILD RA group). Non-ILD RA patients in whom ILD was suspected underwent a diagnostic work-up and, if ILD was diagnosed, were switched to the RA-ILD group. ILD was diagnosed by high-resolution computed tomography and confirmed by a multidisciplinary committee. An independent replication sample was also obtained. Three Anti-CarP IgG autoantibodies against fetal calf serum (Anti-FCS), fibrinogen (Anti-Fib) and chimeric fibrine/filagrine homocitrullinated peptide (Anti-CFFHP) and one Anti-CarP IgA against FCS (Anti-FCS-IgA) were determined by home-made ELISA. Associations between Anti-CarP and ILD were analysed using multivariable logistic regression adjusted by smoking, sex, age, RA disease duration, rheumatoid factor and anticitrullinated protein antibodies. RESULTS: We enrolled 179 patients: 37 (21%) were finally diagnosed with RA-ILD. Anti-CarP specificities were more frequent in RA-ILD patients (Anti-FCS 70% vs 43%; Anti-Fib 73% vs 51%; Anti-CFFHP 38% vs 19%; Anti-CarP-IgA 51% vs 20%, p<0.05 for all comparisons). Serum titers of Anti-CarP were significantly higher in RA-ILD patients. Anti-CarP specificities showed a robust effect towards increasing the odds of ILD in the multivariate analysis (Anti-FCS (OR: 3.42; 95% CI: 1.13 to 10.40), Anti-Fib (OR: 2.85; 95% CI: 0.83 to 9.70), Anti-CFFHP (OR: 3.11; 95% CI: 1.06 to 9.14) and Anti-FCS-IgA (OR: 4.30; 95% CI: 1.41 to 13.04)). Similar findings were observed in the replication sample. CONCLUSIONS: Anti-CarP were strongly associated with ILD. The role of homocitrullination in RA-ILD merits further investigation.

Evaluation of dose-tapering strategies for intravenous tocilizumab in rheumatoid arthritis patients using model-based pharmacokinetic/pharmacodynamic simulations.

PURPOSE: Tocilizumab is a humanized monoclonal antibody approved for rheumatoid arthritis treatment. In clinical practice, empirical dose-tapering strategies are implemented in patients showing sustained remission or low disease activity (LDA) to avoid overtreatment and reduce costs. Since rational adaptive-dosing algorithms taking the full pharmacokinetic (PK)/pharmacodynamic (PD) characteristics into account are currently lacking, we aimed to develop novel tapering strategies and compare them with currently used empirical ones. METHODS: Four strategies were simulated on a virtual population. In all of them, the same initial dose was administered every 28 days for six consecutive months. Then, different strategies were considered: (1) label-dosing; (2) mild empirical dose-tapering; (3) intense empirical dose-tapering; (4) therapeutic drug monitoring (TDM)-guided dose-tapering. The different strategies were evaluated on the proportion of patients who maintain remission/LDA 1 year after the intervention. Cost-savings of direct drug costs were also estimated as relative dose intensity. RESULTS: The overall proportion of simulated patients in remission/LDA after 1 year of the intervention was comparable between the mild empirical and the TDM-guided dose-tapering strategies, and much lower for the intense empirical dose-tapering strategy (80.3%, 78.2%, and 69.0%, respectively). Likewise, 1-year flare rates were lower for the mild empirical and TDM-guided tapering strategies. The relative dose intensity was lowest for the intense empirical dose-tapering, followed by the TDM-guided and the mild empirical dose-tapering approaches (61.2%, 71.0%, and 80.4%, respectively). CONCLUSION: We demonstrated that the TDM-guided strategy using model-based algorithms performed similarly to mild empirical dose-tapering strategies in overall remission/LDA rates but is superior in cost-savings.

Exposure-response modeling of tocilizumab in rheumatoid arthritis using continuous composite measures and their individual components.

AIMS: Tocilizumab has a direct effect on inflammatory markers. Therefore, composite measures for disease activity assessment in rheumatoid arthritis (RA) using these inflammatory markers may not be suitable for tocilizumab treatment. We used a modelling approach to describe the tocilizumab exposure-response relationship and to investigate the different dynamics of the individual components of the routinely used continuous composite measures. METHODS: Pharmacokinetic (PK), clinical and laboratory data were obtained from a prospective, observational, single-centre study involving 35 subjects with RA treated with intravenous tocilizumab. A population PK/pharmacodynamic analysis was performed using nonlinear mixed effects models. RESULTS: The population for model development comprised 1086, 1083 and 1082 observations calculated with the disease activity score based on 28 joint (DAS28) and the simplified and clinical disease activity scores (SDAI, CDAI). The tocilizumab exposure-response relationship was described with an indirect-response model. Two main groups of individual components were identified based on their different dynamics under tocilizumab treatment: (i) tender and swollen joint counts and patient and evaluator global assessment showed a slower decrease of their baseline value (half-life: 4.6 weeks, RSE: 24%) and the need for higher serum drug concentration (EC50 : 4.60 µg/mL, RSE: 103%, IIV: 359%) than (ii) C-reactive protein and erythrocyte sedimentation rate (half-life: 2.3 weeks, RSE 19%; EC50 : 0.878 µg/mL, RSE: 41%, IIV: 238%). CONCLUSION: Our study confirms a different dynamics of the individual components of the most frequently used continuous composite measures under tocilizumab treatment which should be taken into account to avoid misassessment of disease activity.

Fixed dosing of intravenous tocilizumab in rheumatoid arthritis. Results from a population pharmacokinetic analysis.

AIMS: Intravenous tocilizumab is currently dosed on body weight, although a weak correlation between body weight and clearance has been described. The aim of the study was to assess the current dosing strategy and provide a scientific rational for dosing using a modelling and simulation approach. METHODS: Serum concentrations and covariates were obtained from intravenous tocilizumab treated subjects at a dose of 4, 6 or 8 mg every 28 days. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling. The final model was used to simulate tocilizumab exposure to assess a dosing strategy based on body weight or fixed dosing, using as target a cumulative area under the curve at 24 weeks of treatment above 100 × 103  µg h ml-1 . RESULTS: A one-compartment disposition model with parallel linear and nonlinear elimination best described the concentration-time data. The typical population mean values for clearance, apparent volume of distribution, maximum elimination rate and Michaelis-Menten constant were 0.0104 l h-1 , 4.83 l, 0.239 mg h-1 and 4.22 µg ml-1 , respectively. Interindividual variability was included for clearance (17.0%) and volume of distribution (30.8%). Significant covariates for clearance were patient body weight and C-reactive protein serum levels. An estimated exponent for body weight of 0.360 confirms the weak relationship with tocilizumab clearance. Simulations demonstrate that patients with lower weights are at risk of underdosing if the weight-based dosing approach is used. However, fixed-dosing provides a more consistent drug exposure regardless of weight category. CONCLUSIONS: Our study provides evidence to support fixed dosing of intravenous tocilizumab in rheumatoid arthritis patients since it reduces variability in tocilizumab exposure among weight categories compared to the current weight-based dosing approach.

Differing local and systemic inflammatory burden in polyarticular psoriatic arthritis and rheumatoid arthritis patients on anti-TNF treatment in clinical remission.

OBJECTIVES: To analyse clinical, serological and sonographic differences between rheumatoid arthritis (RA) and polyarticular psoriatic arthritis (PsA) patients on anti-TNF therapy in clinical remission. METHODS: Angiogenic and proinflammatory cytokine serum levels were determined by multiplex ELISA in patients with RA and PsA in clinical remission (DAS28-ESR<2.6), clinically-active RA patients (DAS28>3.2) and healthy controls. Ultrasound (US) scans were made of both wrists and hands. RESULTS: 30 RA and 47 PsA patients in remission, 22 active RA patients and 20 healthy controls were included. PsA patients had significantly lower disease activity according to DAS28-ESR (p=0.006) but not according to DAS28-CRP (p=0.319), and lower serum levels of proinflammatory and angiogenic cytokines than RA patients in remission. PsA patients had cytokine levels similar to healthy controls, while RA patients in remission had similar levels to those of active RA patients. Globally, 31 (40.25%) patients in remission had a PD signal and 12 had SH>2 plus PD [1 PsA vs. 11 RA (p=0.0001)], meeting the criteria for ultrasound-defined active synovitis (UdAS). Patients with UdAS had significantly higher levels of IL-6, IL-20, PIGF and SDF1. More PsA patients were on tapered doses of anti-TNF (63.8%), and more frequently as monotherapy (72.3%), compared with RA patients (26.6% and 20%, respectively). CONCLUSIONS: Polyarticular PsA patients in remission had lower levels of local (US synovitis) and systemic inflammation than RA patients in remission, even though a significantly higher percentage of PsA patients were on tapered doses of anti-TNF, mainly in monotherapy.

Calprotectin more accurately discriminates the disease status of rheumatoid arthritis patients receiving tocilizumab than acute phase reactants.

OBJECTIVE: To compare the accuracy of serum calprotectin levels, CRP and ESR in stratifying disease activity in RA patients receiving tocilizumab (TCZ). METHODS: Cross-sectional study of 33 RA patients receiving TCZ. DAS28, Simplified Disease Activity Index, Clinical Disease Activity Index, joint counts and serum levels of CRP, ESR, calprotectin and TCZ were measured. Associations between calprotectin, ESR and CRP and articular indices were analysed by correlation and linear regression. The accuracy and discriminatory capacity of calprotectin was assessed by receiver operating characteristic curves (area under the curve). RESULTS: Calprotectin levels, but not CRP or ESR, were strongly correlated with all composite indices (all r coefficients over 0.50). Calprotectin, but not CRP or ESR, was significantly lower in patients in remission compared with those with low disease activity [1.57 µg/ml (s.d. 1) vs 3.35 µg/ml (s.d. 1), P = 0.001]. In a fully adjusted model (R(2) = 0.82), DAS28-ESR increased 0.48 units per µg/ml calprotectin increase (P < 0.001). Using a DAS28 >3.2 as the reference variable, calprotectin showed an area under the curve of 0.922, and the best cut-off was 5.19 µg/ml (odds ratio 11.5). CRP levels, but not calprotectin, were dependent on detectable TCZ trough serum levels. CONCLUSION: Calprotectin serum levels seem to be an accurate biomarker for assessing disease activity in RA patients receiving TCZ.

Synovial tissue features associated with poor prognosis in inflammatory arthritis.

BACKGROUND: Inflammatory arthritis encompasses a group of immune-mediated diseases characterized by chronic joint inflammation. Despite having pathogenic mechanisms in common, the prognosis of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and undifferentiated arthritis (UA) could be different regarding progression to chronic, to erosive, or to self-limited disease. Our aim was to evaluate the potential association of synovial tissue (ST) inflammatory cell infiltrate, the presence of ectopic lymphoid neogenesis (LN +) structures, and poor prognosis factors (PPF) in patients with RA, PsA, and UA. METHODS: We conducted a retrospective study including patients with active arthritis (RA, PsA, UA) who had ST obtained by rheumatological arthroscopy or ultrasound-guided biopsy. Clinical, demographic, and immunohistochemical data of the synovium was evaluated. Patients with biological therapy at the time of synovial biopsy were excluded. PPF in patients with RA and UA were defined by the presence of anti-cyclic citrullinated peptide antibodies and/or rheumatoid factor, development of bone erosions, or requirement of biological therapy during the follow-up. PPF in patients with PsA were defined as the presence of high levels of acute-phase reactants (ESR/CRP), dactylitis or nail involvement at the time of biopsy, development of bone erosion, or requirement of biological therapy during the follow-up. RESULTS: A total of 88 patients were included: 26 RA, 33 PsA, and 29 UA. All patients were followed up for 5 years after the biopsy. Fourteen (53.84%) RA patients had PPF, and 17 (65.38%) had LN + . LN + was associated with PPF (p 0.038) and biologic therapy initiation (p 0.018). A total of 14 (43.75%) PsA patients had PPF. CD15 infiltrate (410.68 [SD 477.63] cells/mm2) was associated with PPF (p 0.008) in PsA patients. Sixteen (55.17%) patients with UA had PPF, and 13 (44.82%) had LN + . In this group, synovial CD68 + macrophages cells density was negatively correlated with DAS28-CRP (r = - 0.346, p 0.042). CONCLUSIONS: The presence of LN + and higher CD15 + polymorphonuclear cells infiltrate was associated with PPF in RA and PsA, respectively. No associations were found for UA. These findings suggest a great heterogeneity of the ST features and its pathogenic implications in the subtypes of inflammatory arthritis.

Exploring the influence of baseline rheumatoid factor levels on TNF inhibitor retention rate in patients with rheumatoid arthritis: a multicentre and retrospective study.

OBJECTIVE: To assess whether the retention rate of certolizumab pegol (CZP) was longer than that of other tumour necrosis factor inhibitors (TNFi) based on baseline rheumatoid factor (RF) levels. METHODS: Longitudinal, retrospective and multicentre study including patients with RA who were treated with any TNFi (monoclonal antibodies (mAB), etanercept (ETA) or CZP). Log-rank test and Cox regressions were conducted to evaluate the retention rate in the three groups according to the level of RF, with the third quartile of the baseline levels used as cut-off: <200 (

Neutrophilic Activity Biomarkers (Plasma Neutrophil Extracellular Traps and Calprotectin) in Established Patients with Rheumatoid Arthritis Receiving Biological or JAK Inhibitors: A Clinical and Ultrasonographic Study.

INTRODUCTION: This study assesses the accuracy of neutrophil activation markers, including neutrophil extracellular traps (NETs) and calprotectin, as biomarkers of disease activity in patients with established rheumatoid arthritis (RA). We also analyse the relationship between NETs and various types of therapies as well as their association with autoimmunity. METHODS: Observational cross-sectional study of patients with RA receiving treatment with biological disease-modifying antirheumatic drugs or Janus kinase inhibitors (JAK-inhibitors) for at least 3 months. Plasma calprotectin levels were measured using an enzyme-linked immunosorbent assay test kit and NETs by measuring their remnants in plasma (neutrophil elastase-DNA and histone-DNA complexes). We also assessed clinical disease activity, joint ultrasound findings and autoantibody status [reumatoid factor (RF), anti-citrullinated peptide/protein antibodies (ACPAs) and anti-carbamylated protein (anti-CarP)]. Associations between neutrophilic biomarkers and clinical or ultrasound scores were sought using correlation analysis. The discriminatory capacity of both neutrophilic biomarkers to detect ultrasound synovitis was analysed through receiver-operating characteristic (ROC) curves. RESULTS: One hundred fourteen patients were included. Two control groups were included to compare NET levels. The active control group consisted of 15 patients. The second control group consisted of 30 healthy subjects. Plasma NET levels did not correlate with clinical disease status, regardless of the clinic index analysed or the biological therapy administered. No significant correlation was observed between NET remnants and ultrasound synovitis. There was no correlation between plasma NET and autoantibodies. In contrast, plasma calprotectin positively correlated with clinical parameters (swollen joint count [SJC] rho = 0.49; P < 0.001, Clinical Disease Activity Index [CDAI] rho = 0.30; P < 0.001) and ultrasound parameters (rho > 0.50; P < 0.001). Notably, this correlation was stronger than that observed with acute phase reactants. CONCLUSION: While NET formation induced by neutrophils may play a role in RA pathogenesis, our study raises questions about the utility of NET remnants in peripheral circulation as a biomarker for inflammatory activity. In contrast, this study strongly supports the usefulness of calprotectin as a biomarker of inflammatory activity in patients with RA.

Calprotectin in Patients with Rheumatic Immunomediated Adverse Effects Induced by Checkpoints Inhibitors.

BACKGROUND: this is an exploratory study to evaluate calprotectin serum levels in patients with rheumatic immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) treatment. METHODS: this is a retrospective observational study including patients with irAEs rheumatic syndromes. We compared the calprotectin levels to those in a control group of patients with RA and with a control group of healthy individuals. Additionally, we included a control group of patients treated with ICI but without irAEs to check calprotectin levels. We also analysed the performance of calprotectin for the identification of active rheumatic disease using receiver operating characteristic curves (ROC). RESULTS: 18 patients with rheumatic irAEs were compared to a control group of 128 RA patients and another group of 29 healthy donors. The mean calprotectin level in the irAE group was 5.15 µg/mL, which was higher than the levels in both the RA group (3.19 µg/mL) and the healthy group (3.81 µg/mL) (cut-off 2 µg/mL). Additionally, 8 oncology patients without irAEs were included. In this group, calprotectin levels were similar to those of the healthy controls. In patients with active inflammation, the calprotectin levels in the irAE group were significantly higher (8.43 µg/mL) compared to the RA group (3.94 µg/mL). ROC curve analysis showed that calprotectin had a very good discriminatory capacity to identify inflammatory activity in patients with rheumatic irAEs (AUC of 0.864). CONCLUSIONS: the results suggest that calprotectin may serve as a marker of inflammatory activity in patients with rheumatic irAEs induced by treatment with ICIs.

Clinical Patterns and Follow-Up of Inflammatory Arthritis and Other Immune-Related Adverse Events Induced by Checkpoint Inhibitors. A Multicenter Study.

Objectives: To describe different clinical patterns of rheumatic immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICI) and their rheumatic and oncologic outcomes. Methods: We classified clinical syndromes according to five different categories: non-inflammatory arthralgias (NIA), rheumatoid arthritis (RA)-like, psoriatic arthritis (PsA)-like, polymyalgia rheumatica (PMR)-like, and a miscellaneous group of patients with other syndromes. We conducted a baseline visit and then follow-up in order to determine their clinical pattern, treatment response, and outcome. Results: We included 73 patients (64% male) with a mean age of 66.1 ± 11.6 years. Main underlying diagnosis was lung carcinoma in 29 (39%) patients, melanoma in 20 (27%), and renal-urothelial cancer in 11 (15%). Main ICI included Pembrolizumab in 24 (32%), Nivolumab 17 (23%), and Atezolizumab 7 (9 %). Seventeen out of seventy-three patients had an underlying rheumatic disease before ICI treatment. Fourteen patients developed other irAEs before or simultaneously with rheumatic syndromes. Main rheumatic irAEs included: RA-like in 31 (42.4%), NIA in 19 (26.0%), PMR-like in 10 (13.7%), and PsA-like in 5 (6.8%), among others. Median time from ICI to irAEs was 5 months (IQR 3-9). Those patients who received combined therapy, had a trend for an earlier presentation than those who received monotherapy (4.3 months IQR 1.85-17 vs. 6 months IQR 3-9.25, p = NS). Mean follow-up time was 14.0 ± 10.8 (SD, months). At the last visit, 47 % were taking glucocorticoids and 11% DMARD therapy. At the last visit, 13 (17.8%) patients remained with persistent arthritis, 19 (26%) had intermittent flares, and 39 (53.4%) had a self-limited pattern. Only in 15.1% of patients ICI therapy was discontinued. Conclusions: We described different patterns according to treatment and irAEs. Combined ICI therapy had an earlier onset of symptoms. Patients who presented as RA-like, had a higher risk of persistent arthritis. After a mean follow-up of more than 1 year, one-fifth of the patients remained with persistent arthritis and 11% required DMARD therapy.

High Sensitivity C Reactive Protein in Patients with Rheumatoid Arthritis Treated with Antibodies against IL-6 or Jak Inhibitors: A Clinical and Ultrasonographic Study.

BACKGROUND: We examined whether high-sensitivity CRP (hsCRP) reflected the inflammatory disease status evaluated by clinical and ultrasound (US) parameters in RA patients receiving IL-6 receptor antibodies (anti-IL-6R) or JAK inhibitors (JAKi). METHODS: We conducted a cross-sectional study of patients with established RA receiving anti-IL-6R (tocilizumab, sarilumab) or JAKi (tofacitinib, baricitinib). Serum hsCRP and US synovitis in both hands were measured. Associations between hsCRP and clinical inflammatory activity were evaluated using composite activity indices. The association between hsCRP and US synovitis was analyzed. RESULTS: 63 (92% female) patients (42 anti- IL-6R and 21 JAKi) were included, and the median disease duration was 14.4 (0.2-37.5) years. Most patients were in remission or had low levels of disease. Overall hsCRP values were very low, and significantly lower in anti-IL-6R patients (median 0.04 mg/dL vs. 0.16 mg/dL). Anti-IL-6R (82.4%) patients and 48% of JAKi patients had very low hsCRP levels (≤0.1 mg/dL) (p = 0.002). In the anti-IL-6R group, hsCRP did not correlate with the composite activity index or US synovitis. In the JAKi group, hsCRP moderately correlated with US parameters (r = 0.5) but not clinical disease activity, and hsCRP levels were higher in patients with US synovitis (0.02 vs. 0.42 mg/dL) (p = 0.001). CONCLUSION: In anti-IL-6R RA-treated patients, hsCRP does not reflect the inflammatory disease state, but in those treated with JAKi, hsCRP was associated with US synovitis.

Predictive model to identify multiple failure to biological therapy in patients with rheumatoid arthritis.

Background: Despite advances in the treatment of rheumatoid arthritis (RA) and the wide range of therapies available, there is a percentage of patients whose treatment presents a challenge for clinicians due to lack of response to multiple biologic and target-specific disease-modifying antirheumatic drugs (b/tsDMARDs). Objective: To develop and validate an algorithm to predict multiple failure to biological therapy in patients with RA. Design: Observational retrospective study involving subjects from a cohort of patients with RA receiving b/tsDMARDs. Methods: Based on the number of prior failures to b/tsDMARDs, patients were classified as either multi-refractory (MR) or non-refractory (NR). Patient characteristics were considered in the statistical analysis to design the predictive model, selecting those variables with a predictive capability. A decision algorithm known as 'classification and regression tree' (CART) was developed to create a prediction model of multi-drug resistance. Performance of the prediction algorithm was evaluated in an external independent cohort using area under the curve (AUC). Results: A total of 136 patients were included: 51 MR and 85 NR. The CART model was able to predict multiple failures to b/tsDMARDs using disease activity score-28 (DAS-28) values at 6 months after the start time of the initial b/tsDMARD, as well as DAS-28 improvement in the first 6 months and baseline DAS-28. The CART model showed a capability to correctly classify 94.1% NR and 87.5% MR patients with a sensitivity = 0.88, a specificity = 0.94, and an AUC = 0.89 (95% CI: 0.74-1.00). In the external validation cohort, 35 MR and 47 NR patients were included. The AUC value for the CART model in this cohort was 0.82 (95% CI: 0.73-0.9). Conclusion: Our model correctly classified NR and MR patients based on simple measurements available in routine clinical practice, which provides the possibility to characterize and individualize patient treatments during early stages.

Imaging Findings in Patients with Immune Checkpoint Inhibitor-Induced Arthritis.

Immune checkpoint inhibitor (ICI)-induced arthritis is an increasingly recognized adverse event in patients with oncologic disease during immunotherapy. Four patterns are well described, including rheumatoid arthritis (RA)-like, polymyalgia rheumatica (PMR)-like, psoriatic arthritis (PsA)-like, and oligo-monoarthritis, among others. Despite better clinical recognition of these syndromes, information about the main imaging findings is limited. METHODS: We conducted a retrospective observational study including all adult patients referred to the Rheumatology Department of a single-center due to ICI-induced arthritis who underwent imaging studies [ultrasound (US), magnetic resonance imaging (MRI), and 18F-FDG PET/CT)] between January 2017 and January 2022. RESULTS: Nineteen patients with ICI-induced arthritis with at least one diagnostic imaging assessment were identified (15 US, 4 MRI, 2 18F-FDG PET/CT). Most patients were male (84.2%), with a median age at inclusion of 73 years. The main underlying diagnoses for ICI treatment were melanoma in five cases. The distribution of ICI-induced arthritis was as follows: PMR-like (5, 26.2%), RA-like (4, 21.1%), PsA-like (4, 21.1%), and others (6, 31.6%). All RA-like patients had US findings indistinguishable from conventional RA patients. In addition, 3/5 (60%) of PMR-like patients had significant involvement of the hands and wrists. Abnormal findings on MRI or PET-CT were reported by clinical symptoms. No erosions or myofascitis were seen. CONCLUSIONS: ICI-induced arthritis patients present inflammatory patterns on imaging studies similar to conventional inflammatory arthropathies, and therefore these syndromes should be followed carefully and treated according to these findings.