ObjectivesTo detail the greatest areas of unmet scientific and clinical needs in rheumatology.MethodsThe 21st annual international Advances in Targeted Therapies meeting brought together more than ...100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. During the meeting, breakout sessions were convened, consisting of 5 disease-specific groups with 20–30 experts assigned to each group based on expertise. Specific groups included: rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus and other systemic autoimmune rheumatic diseases. In each group, experts were asked to identify unmet clinical and translational research needs in general and then to prioritise and detail the most important specific needs within each disease area.ResultsOverarching themes across all disease states included the need to innovate clinical trial design with emphasis on studying patients with refractory disease, the development of trials that take into account disease endotypes and patients with overlapping inflammatory diseases, the need to better understand the prevalence and incidence of inflammatory diseases in developing regions of the world and ultimately to develop therapies that can cure inflammatory autoimmune diseases.ConclusionsUnmet needs for new therapies and trial designs, particularly for those with treatment refractory disease, remain a top priority in rheumatology.
Objective
To evaluate the efficacy and safety of ABT‐494, a selective JAK‐1 inhibitor, in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX).
...Methods
Three hundred RA patients receiving stable doses of MTX were randomly assigned equally to receive immediate‐release ABT‐494 at 3, 6, 12, or 18 mg twice daily, 24 mg once daily, or placebo for 12 weeks. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12, as determined using the last observation carried forward method.
Results
At week 12, the proportion of ACR20 responses was higher with ABT‐494 (62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively) than with placebo (46%) (using nonresponder imputation) (P < 0.05 for the 6, 12, and 24 mg doses). There was a significant dose‐response relationship among all ABT‐494 doses (P < 0.001). The proportions of patients achieving ACR50 and ACR70 responses were significantly higher for all ABT‐494 doses (except the 12 mg dose for the ACR70 response) than for placebo, as were changes in the Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP). Rapid improvement was demonstrated by significant differences in ACR20 response rates and changes in the DAS28‐CRP for all doses compared with placebo at week 2 (the first postbaseline visit). The incidence of adverse events was similar across groups; most were mild, and infections were the most frequent. One serious infection (community‐acquired pneumonia) occurred with ABT‐494 at 12 mg. There were dose‐dependent increases in high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) cholesterol, but the LDL cholesterol:HDL cholesterol ratios were unchanged through week 12. Mean hemoglobin levels remained stable at lower doses, but decreases were observed at higher doses.
Conclusion
This study evaluated a broad range of doses of ABT‐494 in RA patients with an inadequate response to MTX. ABT‐494 demonstrated efficacy, with a safety and tolerability profile similar to that of other JAK inhibitors.
Objective
To assess the frequency of cardiovascular and venous thromboembolic events in clinical studies of baricitinib, an oral, selective JAK1 and JAK2 inhibitor approved in more than 50 countries ...for the treatment of moderately‐to‐severely active rheumatoid arthritis (RA).
Methods
Data were pooled from 9 RA studies. Placebo comparison up to 24 weeks included data from 6 studies. Randomized dose comparison between baricitinib doses of 2 mg and 4 mg used data from 4 studies and from the associated long‐term extension study. The data analysis set designated “All‐bari‐RA” included all baricitinib exposures at any dose.
Results
Overall, 3,492 RA patients received baricitinib (7,860 patient‐years of exposure). No imbalance compared to the placebo group was seen in the incidence of major adverse cardiovascular events (MACE) (incidence rates IRs of 0.5 per 100 patient‐years for placebo and 0.8 per 100 patient‐years for 4 mg baricitinib), arterial thrombotic events (ATE) (IRs of 0.5 per 100 patient‐years for placebo and 0.5 per 100 patient‐years for 4 mg baricitinib), or congestive heart failure (CHF) broad term (IRs of 4.3 per 100 patient‐years for placebo and 2.4 per 100 patient‐years for 4 mg baricitinib). Deep vein thrombosis (DVT)/pulmonary embolism (PE) were reported in 0 of 1,070 patients treated with placebo and 6 of 997 patients treated with 4 mg baricitinib during the placebo‐controlled period; these events were serious in 2 of 6 patients, while all 6 had risk factors and 1 patient developed DVT/PE after discontinuation of the study drug. In the 2 mg–4 mg‐extended data analysis set, IRs of DVT/PE were comparable between the doses across event types (IRs of 0.5 per 100 patient‐years in those receiving 2 mg baricitinib and 0.6 per 100 patient‐years in those receiving 4 mg baricitinib). In the All‐bari‐RA data analysis set, the rates were stable over time, with an IR of DVT/PE of 0.5 per 100 patient‐years.
Conclusion
In RA clinical trials, no association was found between baricitinib treatment and the incidence of MACE, ATE, or CHF. With regard to incidence of DVT/PE, 6 events occurred in patients treated with 4 mg baricitinib, but no cases of DVT/PE were reported in the placebo group. During longer‐term evaluation, the incidence of DVT/PE was similar between the baricitinib dose groups, with consistent IR values over time, and this was similar to the rates previously reported in patients with RA.
Objective
Clazakizumab is a humanized monoclonal antibody that binds to the interleukin‐6 (IL‐6) cytokine. This study was undertaken to evaluate the efficacy and safety of clazakizumab in combination ...with methotrexate (MTX) or clazakizumab monotherapy versus MTX alone in patients with rheumatoid arthritis (RA) and an inadequate response to MTX.
Methods
In this multinational, phase IIb, randomized, double‐blind, placebo‐controlled, dose‐ranging study, patients were randomized to receive 1) once‐monthly subcutaneous (SC) clazakizumab at 25, 100, or 200 mg plus MTX, 2) once‐monthly SC clazakizumab at 100 mg or 200 mg as monotherapy, or 3) MTX plus placebo (i.e., MTX alone). Adalimumab (40 mg) plus MTX was included as an active reference. The primary end point was the American College of Rheumatology 20% (ACR20) improvement response rate at week 12. Secondary end points included ACR20, ACR50, and ACR70 response rates as well as protocol‐defined remission rates and Health Assessment Questionnaire disability index scores at weeks 12 and 24.
Results
In total, 418 patients were randomized, and baseline characteristics were balanced across the treatment groups. Patients receving clazakizumab had significantly greater ACR20 response rates at week 12 compared with patients receiving MTX alone (76.3%, 73.3%, and 60.0% of patients in the clazakizumab 25, 100, and 200 mg plus MTX groups, respectively, and 55.0% and 61.0% of patients in the clazakizumab 100 and 200 mg monotherapy groups, respectively, versus 39.3% of patients receiving MTX alone; P < 0.05 for all comparisons). At week 24, all clazakizumab groups had higher ACR20, ACR50, and ACR70 response rates and higher remission rates compared with MTX alone. Rates of serious adverse events ranged from 8.3% to 13.6% in the clazakizumab treatment groups, compared with 3.3% in the MTX alone group. Changes in laboratory data were consistent with the pharmacologic effects of IL‐6 blockade.
Conclusion
In patients with RA and an inadequate response to MTX, treatment with clazakizumab in combination with MTX or clazakizumab monotherapy was well tolerated, and patients achieved significant improvements in disease activity, including higher rates of remission, as compared with patients receiving MTX alone.
Spleen tyrosine kinase (Syk) is an important modulator of immune signaling. In this randomized trial involving patients with active rheumatoid arthritis, there was a higher ACR 20 response rate with ...R788, an oral inhibitor of Syk, than with placebo at 6 months.
Spleen tyrosine kinase (Syk) is an intracellular cytoplasmic tyrosine kinase that is an important mediator of immunoreceptor signaling in macrophages, neutrophils, mast cells, and B cells. Syk is present in the synovium of patients with rheumatoid arthritis, and activation of Syk is important for cytokine and metalloproteinase production induced by tumor necrosis factor α in fibroblast-like synoviocytes from patients with rheumatoid arthritis.
1
In rodent models of collagen-induced arthritis,
2
R788 (fostamatinib disodium), an oral prodrug that is rapidly converted to a potent and relatively selective inhibitor of Syk (R406),
3
had potent antiinflammatory activity, suggesting a role for Syk inhibition in the . . .
Objective
Seropositivity for anti–citrullinated protein antibody (ACPA)/rheumatoid factor (RF) in rheumatoid arthritis (RA) is associated with increased overall mortality; however, the association ...between antibody titers and mortality is not well established. Investigating relationships between antibody titers and mortality may clarify their role in RA pathogenesis. This study was undertaken to evaluate the association of antibody titers with mortality and its modification by disease‐modifying antirheumatic drugs (DMARDs).
Methods
Eligible patients with established RA were identified through administrative claims data linked to laboratory results (2005–2016). Patients were categorized by positivity status for ACPA, RF, or both. Patients were further divided into groups by autoantibody titers. DMARD‐exposed patients were categorized into biologic DMARD (bDMARD) and conventional DMARD (cDMARD) subcohorts. Crude mortality rates/1,000 patient‐years and Kaplan‐Meier curves were compared between antibody categories. Adjusted Cox proportional hazards regression and sensitivity (propensity‐matched patients) analyses were conducted.
Results
Overall, 53,849 and 79,926 patients had evaluable ACPA and RF status, respectively. For both autoantibodies, mortality rates were significantly higher in seropositive versus seronegative patients (risk increase of 48.0% and 44.0% in ACPA‐ and RF‐positive patients, respectively; P < 0.001 each). Mortality rates were greatest in patients with higher versus lower autoantibody titers (ACPA hazard ratio HR 1.60 95% confidence interval (95% CI) 1.45–1.76; RF HR 1.78 95% CI 1.66–1.91). In cDMARD‐exposed patients, HRs were higher in seropositive versus seronegative cohorts; in bDMARD‐exposed patients, there was no difference in mortality by serostatus.
Conclusion
Elevated ACPA/RF titers were independently associated with increased mortality among patients with RA and persisted in patients treated with cDMARDs but not with bDMARDs.
We aimed to mine the data in the Electronic Medical Record to automatically discover patients' Rheumatoid Arthritis disease activity at discrete rheumatology clinic visits. We cast the problem as a ...document classification task where the feature space includes concepts from the clinical narrative and lab values as stored in the Electronic Medical Record.
The Training Set consisted of 2792 clinical notes and associated lab values. Test Set 1 included 1749 clinical notes and associated lab values. Test Set 2 included 344 clinical notes for which there were no associated lab values. The Apache clinical Text Analysis and Knowledge Extraction System was used to analyze the text and transform it into informative features to be combined with relevant lab values.
Experiments over a range of machine learning algorithms and features were conducted. The best performing combination was linear kernel Support Vector Machines with Unified Medical Language System Concept Unique Identifier features with feature selection and lab values. The Area Under the Receiver Operating Characteristic Curve (AUC) is 0.831 (σ = 0.0317), statistically significant as compared to two baselines (AUC = 0.758, σ = 0.0291). Algorithms demonstrated superior performance on cases clinically defined as extreme categories of disease activity (Remission and High) compared to those defined as intermediate categories (Moderate and Low) and included laboratory data on inflammatory markers.
Automatic Rheumatoid Arthritis disease activity discovery from Electronic Medical Record data is a learnable task approximating human performance. As a result, this approach might have several research applications, such as the identification of patients for genome-wide pharmacogenetic studies that require large sample sizes with precise definitions of disease activity and response to therapies.
Abstract Objectives An estimated 5–20% of patients with rheumatoid arthritis (RA) fail multiple treatments and are considered ‘difficult-to-treat’ (D2T), posing a substantial clinical challenge for ...rheumatologists. A European League Against Rheumatism (EULAR) task force proposed a definition of D2T-RA in 2021. We applied EULAR’s D2T definition in a cohort of patients with established RA to assess prevalence, and we compared clinical characteristics of participants with D2T-RA with matched comparisons. Methods Data from the longitudinal Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) registry were used. Participants were classified as D2T if they met EULAR’s definition. A comparison group of non-D2T-RA patients were matched 2:1 to every D2T patient, and differences in characteristics were evaluated in descriptive analyses. Prevalence rates of D2T were estimated using Poisson regression. Results We estimated the prevalence of D2T-RA to be 14.4 (95% CI: 12.8, 16.3) per 100 persons among 1581 participants with RA, and 22.3 (95% CI: 19.9, 25.0) per 100 persons among 1021 who were biologic/targeted synthetic DMARD experienced. We observed several differences in demographics, comorbidities and RA disease activity between D2T-RA and non-D2T-RA comparisons. Varying EULAR sub-criteria among all participants in BRASS resulted in a range of D2T-RA prevalence rates, from 0.6 to 17.5 per 100 persons. Conclusion EULAR’s proposed definition of D2T-RA identifies patients with RA who have not achieved treatment targets. Future research should explore heterogeneity in these patients and evaluate outcomes to inform the design of future studies aimed at developing more effective RA management protocols.
ObjectivesDespite the therapeutic value of current rheumatoid arthritis (RA) treatments, agents with alternative modes of action are required. Mavrilimumab, a fully human monoclonal antibody ...targeting the granulocyte–macrophage colony-stimulating factor receptor-α, was evaluated in patients with moderate-to-severe RA.MethodsIn a phase IIb study (NCT01706926), patients with inadequate response to ≥1 synthetic disease-modifying antirheumatic drug(s), Disease Activity Score 28 (DAS28)−C reactive protein (CRP)/erythrocyte sedimentation rate ≥3.2, ≥4 swollen joints despite methotrexate (MTX) were randomised 1:1:1:1 to subcutaneous mavrilimumab (150, 100, 30 mg), or placebo every other week (eow), plus MTX for 24 weeks. Coprimary outcomes were DAS28−CRP change from baseline to week 12 and American College of Rheumatology (ACR) 20 response rate (week 24).Results326 patients were randomised (150 mg, n=79; 100 mg, n=85; 30 mg, n=81; placebo, n=81); 305 completed the study (September 2012–June 2013). Mavrilimumab treatment significantly reduced DAS28−CRP scores from baseline compared with placebo (change from baseline (SE); 150 mg: −1.90 (0.14), 100 mg: −1.64 (0.13), 30 mg: −1.37 (0.14), placebo: −0.68 (0.14); p<0.001; all dosages compared with placebo).Significantly more mavrilimumab-treated patients achieved ACR20 compared with placebo (week 24: 73.4%, 61.2%, 50.6% vs 24.7%, respectively (p<0.001)). Adverse events were reported in 43 (54.4%), 36 (42.4%), 41 (50.6%) and 38 (46.9%) patients in the mavrilimumab 150, 100, 30 mg eow and placebo groups, respectively. No treatment-related safety signals were identified.ConclusionsMavrilimumab significantly decreased RA disease activity, with clinically meaningful responses observed 1 week after treatment initiation, representing a novel mechanism of action with persuasive therapeutic potential.Trial registration numberNCT01706926; results.
Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized.
To identify clinical risk factors, ...autoantibodies, and biomarkers associated with the presence of RA-ILD.
Subjects enrolled in Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR.
A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD.
Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA-ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.
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