Severe RA Research Articles

Predictive value of anti-CarP and anti-PAD3 antibodies alone or in combination with RF and ACPA for the severity of rheumatoid arthritis.

The objective of this study was to analyse the predictive value of anti-carbamylated protein (anti-CarP) and anti-peptidyl-arginine deiminase type-3 (anti-PAD3) antibodies, alone or in combination with RF and ACPA, to identify patients at high risk of developing severe RA outcomes. Patients within the Swiss Clinical Quality Management registry with a biobank sample were tested for RF, ACPA, anti-CarP, and anti-PAD3 antibodies. We examined the association of each autoantibody with DAS28, HAQ and radiographic damage (Ratingen) at baseline and longitudinally. Analyses included 851 established RA patients and 516 disease controls [axial spondyloarthritis (axSpA = 320) and PsA (196)]. Anti-CarP and anti-PAD3 antibodies were, respectively, present in 22.4% and 10.7% of the whole RA population, and in 13.2% and 3.8% of the RF and ACPA double seronegative patients. At baseline, RA patients with anti-PAD3 had higher DAS28 (4.2 vs 3.7; P= 0.005) and significantly more radiographic damage (14.9 vs 8.8; P= 0.02) than anti-PAD3-negative patients. In the ACPA-negative subgroup, baseline Ratingen scores were significantly higher in anti-PAD3-positive patients (P= 0.01). The combination of anti-PAD3, RF IgM, and ACPA was associated with significantly higher baseline radiographic scores than the double seropositive group (P= 0.04). The presence of any two of the previous autoantibodies was associated with significantly greater radiographic progression over 10 years than if all were absent (P= 0.02). There were no differences in RA outcome measures with regards to anti-CarP. Anti-PAD3 antibodies are associated with higher disease activity and joint damage scores in RA patients.

Effectiveness of initial methotrexate-based treatment approaches in early rheumatoid arthritis: an elicitation of rheumatologists’ beliefs

Abstract Objectives To quantify rheumatologists’ beliefs about the effectiveness of triple therapy (MTX + HCQ + SSZ) and other commonly used initial treatments for RA. Methods In a Bayesian belief elicitation exercise, 40 rheumatologists distributed 20 chips, each representing 5% of their total weight of belief on the probability that a typical patient with moderate–severe early RA would have an ACR50 response within 6 months with MTX (oral and s.c.), MTX + HCQ (dual therapy) and triple therapy. Parametric distributions were fit, and used to calculate pairwise median relative risks (RR), with 95% credible intervals, and estimate sample sizes for new trials to shift these beliefs. Results In the pooled analysis, triple therapy was perceived to be superior to MTX (RR 1.97; 1.35, 2.89) and dual therapy (RR 1.32; 1.03, 1.73). A pessimistic subgroup (n = 10) perceived all treatments to be similar, whereas an optimistic subgroup (n = 10) believed triple therapy to be most effective of all (RR 4.03; 2.22, 10.12). Similar variability was seen for the comparison between oral and s.c. MTX. Assuming triple therapy is truly more effective than MTX, a trial of 100 patients would be required to convince the pessimists; if triple therapy truly has no–modest effect (RR <1.5), a non-inferiority trial of 475 patients would be required to convince the optimists. Conclusion Rheumatologists’ beliefs regarding the effectiveness of triple therapy vary, which may partially explain the variability in its use. Owing to the strength of beliefs, some may be reluctant to shift, even with new evidence.

ASP5094, a humanized monoclonal antibody against integrin alpha-9, did not show efficacy in patients with rheumatoid arthritis refractory to methotrexate: results from a phase 2a, randomized, double-blind, placebo-controlled trial

BackgroundRheumatoid arthritis (RA) is a chronic, debilitating autoimmune condition characterized by joint synovial inflammation. Current treatments include methotrexate (MTX), biologic agents, and Janus kinase (JAK) inhibitors. However, these agents are not efficacious in all patients and there are concerns regarding side effects and risk of infection as these treatments target immune-related pathways. Overexpression and activation of integrin alpha-9 (α9) on fibroblast-like synoviocytes are associated with RA disease onset and exacerbation. The humanized immunoglobulin G1 monoclonal antibody ASP5094 was designed to inhibit human α9 and is currently under investigation for the treatment of RA.MethodsThis phase 2a, multicenter, randomized, placebo-controlled, double-blind, parallel-group study (NCT03257852) evaluated the efficacy, safety, and biological activity of intravenous ASP5094 10 mg/kg in patients with moderate to severe RA that was refractory to MTX. Patients received ASP5094 or placebo every 4 weeks for a total of three administrations. Both treatment groups used concomitant MTX. The primary efficacy endpoint was the proportion of patients who responded per American College of Rheumatology 50% improvement using C-reactive protein (ACR50-CRP) after 12 weeks of treatment. Biological activity of ASP5094 was assessed via pharmacokinetics and pharmacodynamics of known downstream effectors of α9. Safety was also assessed.ResultsSixty-six patients were enrolled and randomized to placebo (n = 33) or ASP5094 (n = 33). In the primary efficacy analysis, ACR50-CRP response rates were 6.3% and 18.2% at week 12 in the ASP5094 and placebo groups, respectively; a difference of − 11.9, which was not significant (2-sided P value = 0.258). No trends in ACR50 response rates were observed in subgroups based on demographics or baseline disease characteristics, and no significant differences between placebo and ASP5094 were identified in secondary efficacy or pharmacodynamic endpoints, despite achievement of target serum concentrations of ASP5094. Most treatment-emergent adverse events were mild to moderate in severity, and ASP5094 was considered safe and well tolerated overall.ConclusionAlthough no notable safety signals were observed in this study, ASP5094 was not efficacious in patients with moderate to severe RA with an inadequate response to MTX.Trial registrationClinicalTrials.gov, NCT03257852. Registered on 22 Aug. 2017

The impact of disease severity and duration on cost, early retirement and ability to work in rheumatoid arthritis in Europe: an economic modelling study.

ObjectiveRA is a progressive, chronic autoimmune disease. We summarize the impact of disease activity as measured by the DAS in 28 joints (DAS28-CRP scores) and pain on productivity and ability to work using the Work Productivity and Activity Impairment questionnaire (WPAI) scores, in addition to the impact of disease duration on the ability to work.MethodsData were drawn from the Burden of RA across Europe: a Socioeconomic Survey (BRASS), a European cross-sectional study in RA. Analyses explored associations between DAS28-CRP score and disease duration with stopping work because of RA, and regression analyses assessed impacts of pain and DAS28-CRP on early retirement and WPAI.ResultsFour hundred and seventy-six RA specialist clinicians provided information on 4079 adults with RA, of whom 2087 completed the patient survey. Severe disease activity was associated with higher rates of stopping work or early retirement attributable to RA (21%) vs moderate/mild disease (7%) or remission (8%). Work impairment was higher in severe (67%) or moderate RA (45%) compared with low disease activity [LDA (37%)] or remission (28%). Moreover, patients with severe (60%) or moderate pain (48%) experienced increased work impairment [mild (34%) or no pain (19%)]. Moderate to severe pain is significant in patients with LDA (35%) or remission (22%). A statistically significant association was found between severity, duration and pain vs work impairment, and between disease duration vs early retirement.ConclusionResults demonstrate the high burden of RA. Furthermore, subjective domains, such as pain, could be as important as objective measures of RA activity in affecting the ability to work.

P224 A matching-adjusted indirect comparison (MAIC) of upadacitinib versus tofacitinib in csDMARD-IR patients with moderate to severe RA

Abstract Background Upadacitinib (UPA), a JAK1 selective inhibitor, is being investigated as monotherapy and combination therapy with DMARDs for the treatment of moderate-to-severe RA. To date, no head-to-head trials have compared the effectiveness of UPA with tofacitinib (TOFA). Objectives: To compare the efficacy of UPA 15 mg monotherapy and combination therapy with TOFA 5 mg combination therapy using MAICs. Methods Two MAICs were conducted. MAIC is an indirect comparison technique that utilises individual patient data (IPD) for one treatment and aggregate data for the other treatment to provide comparative evidence after balancing differences in patient characteristics. The first MAIC used IPD from the SELECT-MONOTHERAPY trial of UPA monotherapy vs. methotrexate (MTX) and published data from the Oral Standard trial of TOFA+MTX vs. MTX. The second used IPD from the SELECT-COMPARE trial of UPA+MTX vs. adalimumab (ADA)+MTX and published data from the ORAL Strategy trial of TOFA+MTX vs. ADA+MTX. UPA monotherapy was not compared to TOFA monotherapy based on feasibility analysis and trial selection criteria. Patients in the UPA trials were re-weighted based on age, gender, race, swollen joint count 66/28, tender joint count 68/28, C-reactive protein (CRP), and patient’s global assessment, to match the baseline characteristics in each comparator trial. After matching, ACR20/50/70 and clinical remission (SDAI(CRP)≤3.3, CDAI≤2.8, DAS28-ESR/CRP<2.6) were compared for UPA monotherapy vs. TOFA +MTX relative to MTX at month 3 and UPA+MTX vs. TOFA+MTX relative to ADA+MTX at month 3 and 6 using a Wald test. Results After matching, baseline characteristics were balanced across the trial populations. At month 3, UPA monotherapy patients experienced significantly greater improvement in ACR70 compared to TOFA+MTX with a mean difference in difference (DD) of 9.9% (p < 0.05) while UPA+MTX was associated with a higher ACR50 compared to TOFA+MTX with a DD of 12.9% (p < 0.05). At month 6, UPA+MTX patients experienced significantly larger improvement in SDAI/CDAI/DAS28-ESR clinical remission compared to TOFA+MTX with DDs of 9.1% (p < 0.05), 7.5% (p < 0.05), and 11.3% (p < 0.01), respectively. Conclusion The results from MAICs indicate that treatment with UPA 15 mg when used as monotherapy or in combination with MTX appears to produce improved outcomes at 3/6 months as compared to TOFA 5 mg +MTX (mono: ACR70 and combination: ACR50, SDAI, CDAI and DAS28-ESR remission). Disclosures C. Edwards: Consultancies; Honoraria and research support from Abbvie, BMS, Biogen, Celgene, Fresenius, Janssen, Lilly, Mundipharma, Pfizer, MSD, Novartis, Roche, Samsung, Sanofi, UCB. R. Sawant: Corporate appointments; Employee and Stockholder of Abbvie. E.X. Du: Consultancies; Employee of Analysis Group, Inc., which has received consultancy fees from AbbVie to conduct this study. J. Cammarota: Consultancies; Employee of Analysis Group, Inc., which has received consultancy fees from AbbVie to conduct this study. P. Tang: Consultancies; Employee of Analysis Group, Inc., which has received consultancy fees from AbbVie to conduct this study. V. Garg: Corporate appointments; Employee and Stockholder of Abbvie. A. Friedman: Corporate appointments; Employee and Stockholder of Abbvie. K. Betts: Corporate appointments; Employee of Analysis Group, Inc., which has received consultancy fees from AbbVie to conduct this study.

P204 Effect of baricitinib on functional impairment in RA patients with moderate disease activity and an inadequate response to conventional DMARDs

Abstract Background In RA, disease activity correlates with physical function and there is a link between joint damage and functional disability. In many countries, RA patients with inadequate response (IR) to MTX or other conventional DMARDs (cDMARDs) are not eligible for potentially more effective treatments, such as biologic or targeted synthetic DMARDs (tsDMARDs), unless they have high disease activity (HDA). Thus, managing RA patients with persistent moderate disease activity (MDA) despite cDMARD treatment poses a problem. Baricitinib (BARI) is a tsDMARD approved for the treatment of moderate to severe RA in adults. This post-hoc analysis assessed if RA patients with MDA benefit from improved physical function with BARI treatment to the same extent as patients with HDA. Methods Patients analysed were from the modified intention-to-treat populations in the BARI phase 3 studies RA-BEAM (MTX-IR) and RA-BUILD (cDMARD-IR) with moderate to severe disability (HAQ-Disability Index [HAQ-DI] score ≥1), MDA (Simplified Disease Activity Index [SDAI] score 11.1-26.0) or HDA (SDAI score>26.0) and non-missing SDAI data at baseline. All patients fulfilled ACR criteria for RA. Patients from RA-BEAM received BARI 4 mg + MTX once daily (n = 396), adalimumab 40 mg every 2 weeks + MTX (n = 270) or placebo (PBO) + MTX (n = 390); patients from RA-BUILD received BARI 4 mg (n = 189) or 2 mg (n = 186) or PBO (n = 185). Multivariable linear regression (MLR) models were used to estimate mean HAQ-DI scores at baseline and week 24 (W24) for the treatment arms stratified by baseline disease activity (MDA or HDA SDAI). Age, RA duration, BMI, high-sensitivity CRP, baseline SDAI disease activity (MDA/HDA), treatment and treatment-by-baseline SDAI interaction were included as covariates. The MLR model for HAQ-DI at (W24) was further adjusted by baseline HAQ-DI. Results In patients from RA-BEAM with MDA at baseline, the mean adjusted HAQ-DI score at W24 was greater in PBO (1.314) than in BARI 4 mg (0.843) patients (Δ = 0.472; p = 0.001). A similar pattern of improved physical function with BARI was seen in RA-BUILD, but the adjusted mean difference in HAQ-DI score between PBO (1.376) and BARI 4 mg (1.113) was not statistically significant (Δ = 0.263; p = 0.109). In patients with HDA at baseline, the W24 mean adjusted HAQ-DI score was 0.443 points greater (p < 0.001) with PBO (1.387) than with BARI 4 mg (0.944) in RA-BEAM, and 0.257 points greater (p < 0.001) in RA-BUILD. Conclusion MTX-IR and/or cDMARD-IR RA patients with MDA and moderate to severe disability at baseline treated with BARI showed a similar pattern of improvement in physical function vs. PBO-treated patients to that seen in patients with HDA, supporting early use of BARI in MDA patients. As for those with HDA, patients with persistent MDA despite MTX and/or other cDMARD treatment could benefit from access to biologic and tsDMARDs to prevent disability progression. Disclosures B. Kirkham: Consultancies; AbbVie, Eli Lilly, Gilead, Janssen, Novartis, Pfizer. Grants/research support; Eli Lilly, Novartis. E. Nikiphorou: Honoraria; Pfizer, Sanofi, Gilead, Celltrion, Eli Lilly. P. López-Romero: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. I. Kouris: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. T. Holzkaemper: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. L. Zaremba-Pechmann: Other; contractor for Eli Lilly and Company. I. de la Torre: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. P.C. Taylor: Consultancies; AbbVie, Biogen, Galapagos, Gilead, GlaxoSmithKline, Janssen, Eli Lilly, Pfizer, Roche, Sanofi, Nordic Pharma, Fresenius, UCB. Grants/research support; Celgene, Galapagos, Janssen, Eli Lilly.

Study of ATI-450 Plus Methotrexate (MTX) vs MTX Alone in Patients With Moderate to Severe RA

Study of ATI-450 Plus Methotrexate (MTX) vs MTX Alone in Patients With Moderate to Severe RA

P3448Influence of severity of pectus excavatum as indicated by the Haller Index on actual heart compression and ECG findings

Abstract Background Pectus excavatum (PEX) is a depression of the sternum relative to the costal cartilages. The Haller index (HI) is an anatomical indicator of the severity of PEX that is calculated from CT. Purpose We evaluated the influence of anatomical severity of PEX as indicated by HI on the severity of actual heart compression and ECG findings Methods A total of 28 patients (23 males; 20±19 years) with PEX underwent unenhanced CT and ECG. On CT, HI and degree of compression of right (RA) and left atria (LA) were evaluated simultaneously. Results As indicated by CT, the mean HI was 5.80±2.34. We observed 7, 15, 5, and 1 patient with none, mild, moderate, or severe RA compression, respectively. In addition, we observed 8, 13, 4, and 3 patients with none, mild, moderate, or severe LA compressions, respectively. The mean HI was calculated as 4.28±0.92, 5.40±2.01, 6.85±1.81, and 9.61±0.00 in patients with none, mild, moderate, or severe RA, respectively, and the findings were significant (P=0.021). The mean HI was calculated as 4.17±0.91, 5.97±2.23, 5.95±1.51, and 6.69±2.93 in patients with none, mild, moderate, or severe LA compression, respectively, although the findings were not significant (P=0.145). On ECG, a P wave with a negative portion >1 mm in depth and >40 ms in duration in the V1 lead, complete or incomplete right bundle branch block (RBBB), sinus arrhythmia, or right-axis deviation of a QRS wave were diagnosed in 23, 10, 8, and 6 patients, respectively. The HI between patients with (n=23) and without (n=5) a negative portion of the P wave in the V1 lead showed a significant difference (6.45±2.43 vs. 4.62±1.68; P<0.05). The correlation coefficient between absolute values of the maximum negative portion of the P wave in the V1 lead and HI was 0.36 (n=28). The HI between patients with and without a complete or incomplete RBBB showed a significant difference (6.98±2.43 vs. 5.14±2.07; P<0.05). The HI between patients with and without a sinus arrhythmia did not show a significant difference (5.45±2.66 vs. 5.94±2.25). The HI between patients with and without a right axis deviation on a QRS wave also did not show a significant difference (4.76±1.53 vs. 6.08±2.64). The inter-observer agreement of HI between the two observers was 0.978. Haller index and heart compression on CT Conclusion In patients with PEX, compression of RA on CT, a negative portion of the P wave in V1, complete or incomplete RBBB, sinus arrhythmia, and a right axis deviation on a QRS wave are common. The degree of compression of RA on CT, negative portion of the P wave in the V1 lead and complete or incomplete RBBB on ECG are associated with anatomical severity as indicated by the HI. However, our results showed that HI severity was unrelated to either the degree of compression of LA on CT, or sinus arrhythmia and right-axis deviation of the QRS wave on ECG. These observations may be due to variation of location of maximum sternum depression, such as high- or low-positioned dominant-type compressions.

Prevalence and associated factors of subclinical atherosclerosis in rheumatoid arthritis at the university hospital of Kinshasa

BackgroundRheumatoid arthritis (RA) is associated with a 5 to 10 years reduction in life expectancy due to premature atherosclerosis. This reduction is the consequence of traditional cardiovascular risk factors (TCRF) as well as systemic inflammation. The aim of the present study was to describe the prevalence and factors associated with subclinical atherosclerosis in RA at the University Hospital of Kinshasa (UHK).MethodsPatients with a diagnosis of RA based on the 2010 ACR/EULAR criteria were included in this cross-sectional study from 1 June 2014 to 31 May 2015 at the UHK. RA disease activity was measured using the DAS28-ESR. Active RA was defined by a DAS 28 > 2.6. Severe RA was defined by the presence of extra-articular manifestation, joint erosions on X-rays or HAQ ≥0.5. An assessment of subclinical atherosclerosis was performed by the measurement of the carotid intima-media thickness (cIMT) using two-dimensional ultrasonography. Subclinical atherosclerosis was defined by a cIMT ≥0.9 mm. A diagnosis of atheroma plaque was retained when the cIMT was ≥1.5 mm. The association between subclinical atherosclerosis and potential risk factors was modeled using logistic regression analysis.ResultsWe recruited 75 patients. The average age was 51.8 ± 14.6 years, with a sex ratio F/M of 4. The prevalence of subclinical atherosclerosis was 32%. In logistic regression being a woman of ≥55 years old (aOR 10.6, 95% CI [2.087–53.82], p = 0.028), DAS28-ESR > 2.6 (aOR 3.5,95% CI [1.55–10.38], p = 0.044), severe RA (aOR 32.6,95% CI [1.761–60.37],p = 0.035), high blood pressure (aOR 22.4,95% CI [5.04–99.41], p = 0.005) and obesity (aOR 32.3, 95% CI [2.606–40.73], p = 0.026) emerged as factors associated with subclinical atherosclerosis.ConclusionSubclinical atherosclerosis is common in RA patients attending the UHK. It appears to be associated with RA disease activity and severity apart from traditional cardiovascular risk factors. These results suggest that early management of subclinical atherosclerosis targeting remaining RA disease activity and cardiovascular risk factors could slow down progression to clinical cardiovascular disease.

Disease progression in relation to pre-onset parity among women with rheumatoid arthritis

ObjectiveRheumatoid arthritis (RA) often ameliorates during pregnancy and flares postpartum, but the relationship of pregnancy and childbirth to RA prognosis is unclear. We examined RA severity for association with parity prior to RA onset and asked whether time from birth (latency) and/or the mother's HLA genotype influenced results. MethodsA cohort study was conducted of 222 women previously identified in a prospective study of newly diagnosed RA, who returned for follow-up evaluation a median of 8 years later. Stratified analyses using Mantel-Haenszel methods were conducted to evaluate 5 RA severity measures based on hand and wrist radiographs, physical exams, and Health Assessment Questionnaires for association with parity. ResultsOverall, we observed little evidence of altered risk of progression to severe RA in relation to pre-onset parity, adjusting for RA onset age and time to follow-up. Stratifying parous women who had only live births by latency (<15 years/15+ years) showed no difference in risk of severe RA compared to nulligravid women. Live birth deliveries were significantly protective for women with 0 but not for those with 1 or 2 copies of the RA risk-associated HLA-DRB1 shared epitope sequence for erosion score (RR 0.26 95% CI 0.09–0.89) and joint count (RR 0.28 95% CI 0.09–0.87). ConclusionWe observed little evidence of difference in severe RA by pre-onset parity overall. However, among women not predisposed to RA by possessing the risk-associated HLA genotype, parous women who had only live births had lower risk of progression to severe RA as measured by erosion score and joint count.

MIF and MIF2 have distinct but synergistic roles in CIA pathogenesis

Abstract Rheumatoid arthritis (RA) is a relapsing autoimmune disease with progressive joint destruction. High expression alleles of the cytokine macrophage migration inhibitory factor (MIF) are associated with severe erosive RA. MIF and MIF family member D-dopachrome tautomerase (MIF2) signal through the receptor CD74. Previously we reported on the presence of CD74 expressing effector memory T cells in the collagen-induced arthritis (CIA) mouse model and identified CD74+ T cells in human RA synovium fluid. We studied MIF and MIF2 signaling on CD74+ T cells and inflammatory CD74high MΦ in the CIA model. We observed infiltration of CD74+ T cells (1.7 fold increase, p&amp;lt;0.001) and inflammatory CD74high MΦ (2 fold increase, p&amp;lt;0.001) in the joints of WT mice on day 28 post CIA induction. CD74+ T cell infiltration into paws positively correlated with CIA disease score (r=0.731, p=0.003). CD74+ T cells and CD74high MΦ failed to expand or infiltrate in the paws of Mif−/− mice in CIA. Interestingly, CIA induction in Mif2−/− mice expand CD74+ T cells in lymph nodes (0.5 fold increase, p=0.024), but fail to expand in other secondary lymphoid organs or infiltrate joints. Macrophage precursor Gr1high CD74+ monocytes expand in the spleen (3 fold, p&amp;lt;0.001) and blood (1 fold, p&amp;lt;0.001) of Mif2−/− mice, no change in CD74high MΦ levels is observed. The MIF inhibitor MIF098 ameliorates joint inflammation but did not inhibit the expansion or joint infiltration of CD74+ T cells (2 fold, p&amp;lt;0.001), Gr1high CD74+ monocytes, and CD74high MΦ (0.7 fold, p&amp;lt;0.01). Our findings provide evidence for a pathogenic role of novel MIF responsive CD74+ T cell in RA and suggest separate but crucial roles for both MIF and MIF2 in the development and localization for CD74+ T cells and CD74high MΦ in CIA.

Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis.

Tofacitinib and baricitinib are the first orally available, small-molecule inhibitors of Janus kinase (JAK) enzymes to be approved for the treatment of RA. Tofacitinib is a selective JAK1, 3 inhibitor with less activity against JAK2 and TYK2 and baricitinib is a selective, oral JAK1, 2 inhibitor with moderate activity against TYK2 and significantly less activity against JAK3. Both drugs have undergone extensive phase III clinical trials in RA and demonstrated rapid improvements in disease activity, function and patient-reported outcomes as well as disease modification. Tofacitinib 5 mg bd, was approved by the Federal Drug Administration in 2012 for the treatment of RA in patients who are intolerant or unresponsive to MTX. An extended release formulation for the treatment of RA was approved by Federal Drug Administration in 2016. In 2017 the European Medicines Agency approved tofacitinib 5 mg bd in combination with MTX and baricitinib 4 mg and 2 mg once daily for the treatment of moderate to severe active RA in adult patients who are intolerant or unresponsive to one or more conventional synthetic DMARDs.

Effects of concomitant glucocorticoids in TOZURA, a common-framework study programme of subcutaneous tocilizumab in rheumatoid arthritis.

ObjectivesThis post hoc analysis of the TOZURA study programme evaluated the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) as monotherapy or with concomitant conventional synthetic DMARDs (csDMARDs) in patients with RA categorized by baseline glucocorticoid (GC) use.MethodsTOZURA was a multinational, open-label, single-arm, common-framework study programme (11 protocols, 22 countries) in patients with moderate to severe RA in whom csDMARDs or biologic therapies had failed or who were MTX naïve. Patients received once-weekly TCZ-SC 162 mg for ⩾24 weeks as monotherapy or in combination with csDMARDs and/or oral GC use (⩽10 mg/day prednisone or equivalent), which was to be continued unchanged for 24 weeks. Treatment subgroups were defined by baseline GC use and analysed for efficacy and safety.ResultsOf 1804 patients who received TCZ-SC, 145 received monotherapy + GC, 208 received monotherapy without GC, 730 received combination therapy + GC and 721 received combination therapy without GC. The median GC dose in both GC subgroups was 5 mg/day. The proportion of patients who achieved clinical remission, defined as DAS in 28 joints using ESR <2.6, increased similarly from baseline to week 24 in all subgroups. Improvements in patient-reported outcomes were similar in all subgroups. Overall adverse event profiles were generally similar between subgroups, with some slight numerical differences between GC and non-GC subgroups.ConclusionThe incremental efficacy benefits of TCZ-SC as monotherapy and in combination with csDMARDs were similar between patients with and without previous and continued oral GC treatment, with generally similar safety profiles.Trial RegistrationClinicalTrials.gov, http://www.clinicaltrials.gov, NCT01941940, NCT01941095, NCT01951170, NCT01987479, NCT01988012, NCT01995201, NCT02001987, NCT02011334, NCT02031471, NCT02046603, NCT02046616.

Rheumatoid arthritis treated with 6-months of first-line biologic or biosimilar therapy: an updated systematic review and network meta-analysis.

The aim of this study was to estimate the effectiveness of first-line biologic disease modifying drugs(boDMARDs), and their approved biosimilars (bsDMARDs), compared with conventional (csDMARD) treatment, in terms of ACR (American College of Rheumatology) and EULAR (European League against Rheumatism) responses. Systematic literature search, on eight databases to January 2017, sought ACR and EULAR data from randomized controlled trials (RCTs) of boDMARDs / bsDMARDs (in combination with csDMARDs, or monotherapy). Two adult populations: methotrexate (MTX)-naïve patients with severe active RA; and csDMARD-experienced patients with moderate-to-severe active RA. Network meta-analyses (NMA) were conducted using a Bayesian Markov chain Monte Carlo simulation using a random effects model with a probit link function for ordered categorical. Forty-six RCTs met the eligibility criteria. In the MTX-naïve severe active RA population, no biosimilar trials meeting the inclusion criteria were identified. MTX plus methylprednisolone (MP) was most likely to achieve the best ACR response. There was insufficient evidence that combination boDMARDs was superior to intensive (two or more) csDMARDs. In the csDMARD-experienced, moderate-to-severe RA population, the greatest effects for ACR responses were associated with tocilizumab (TCZ) monotherapy, and combination therapy (plus MTX) with bsDMARD etanercept (ETN) SB4, boDMARD ETN and TCZ. These treatments also had the greatest effects on EULAR responses. No clear differences were found between the boDMARDs and their bsDMARDs. In MTX-naïve patients, there was insufficient evidence that combination boDMARDs was superior to two or more csDMARDs. In csDMARD-experienced patients, boDMARDs and bsDMARDs were comparable and all combination boDMARDs / bsDMARDs were superior to single csDMARD.

Tofacitinib in the treatment of patients with rheumatoid arthritis: position statement of experts of the Polish Society for Rheumatology.

Tofacitinib is a newly approved small-molecule targeted synthetic disease-modifying antirheumatic drug. The drug was designed as a selective and specific inhibitor of pro-inflammatory receptor signalling. Tofacitinib inhibits the process of intracellular signalling from the receptor to the cellular nucleus and inhibits the inflammation process via a new pathway (inhibition of the Janus kinases), which is unavailable to biological medicines.Tofacitinib has been approved for use in the treatment of patients with moderate to severe active RA. The drug may be used in combination with methotrexate or another conventional synthetic disease-modifying antirheumatic drug or in monotherapy. The efficacy of tofacitinib has been confirmed in several clinical trials. The drug inhibits radiographic progression of the disease. The innovative mechanism of action of tofacitinib is a noteworthy feature because it offers hope of effective treatment for patients who fail to respond to other drugs. The presented article discusses the mechanism of action and the clinical application of tofacitinib. Tofacitinib represents a new group of disease-modifying antirheumatic drugs that can be placed on an equal footing with biological drugs already available.

Long-term persistence with rituximab in patients with rheumatoid arthritis.

ObjectivesTo investigate the long term persistence of rituximab (RTX) in a large observational RA cohort, investigate persistence of RTX when used as a first or second line biologic DMARD (bDMARD), to characterize subsequent bDMARD treatment following RTX. MethodsPatients with RA starting treatment with RTX (MabThera) between 2008 and 2011 were recruited into the British Society for Rheumatology Biologics Register for RA. Duration of RTX treatment over the first 4 years after initiation was estimated via Kaplan-Meier estimates and the reason for discontinuation was ascertained. Subsequent bDMARD use following RTX discontinuation was characterised. Treatment survival in bDMARD-naïve (first line RTX use) and experienced (second line RTX use) cohorts was described.ResultsOne thousand six hundred and twenty-nine patients were recruited (1371 bDMARD-experienced and 258 bDMARD-naïve). Sixty percent of the whole cohort remained on RTX after 4 years. Ineffectiveness (46%) and death (24%) were the most common reason for RTX discontinuation. RTX discontinuation was associated with RF negativity for the bDMARD-experienced cohort. Of those that discontinued RTX, 46% initiated treatment with another bDMARD, with tocilizumab being the most common.ConclusionThis large study of patients initiating RTX treatment for severe RA found that 60% persisted with treatment after 4 years. This study also identified that RTX is tolerated well when used as a first or second line bDMARD.

Response to baricitinib based on prior biologic use in patients with refractory rheumatoid arthritis.

ObjectiveRA patients who have failed biologic DMARDs (bDMARDs) represent an unmet medical need. We evaluated the effects of baseline characteristics, including prior bDMARD exposure, on baricitinib efficacy and safety. MethodsRA-BEACON patients (previously reported) had moderate to severe RA with insufficient response to one or more TNF inhibitor and were randomized 1:1:1 to once-daily placebo or 2 or 4 mg baricitinib. Prior bDMARD use was allowed. The primary endpoint was a 20% improvement in ACR criteria (ACR20) at week 12 for 4 mg vs placebo. An exploratory, primarily post hoc, subgroup analysis evaluated efficacy at weeks 12 and 24 by ACR20 and Clinical Disease Activity Index (CDAI) ⩽10. An interaction P-value ⩽0.10 was considered significant, with significance at both weeks 12 and 24 given more weight.ResultsThe odds ratios predominantly favored baricitinib over placebo and were generally similar to those in the overall study (3.4, 2.4 for ACR20 weeks 12 and 24, respectively). Significant quantitative interactions were observed for baricitinib 4 mg vs placebo at weeks 12 and 24: ACR20 by region (larger effect Europe) and CDAI ⩽10 by disease duration (larger effect ⩾10 years). No significant interactions were consistently observed for ACR20 by age; weight; disease duration; seropositivity; corticosteroid use; number of prior bDMARDs, TNF inhibitors or non-TNF inhibitors; or a specific prior TNF inhibitor. Treatment-emergent adverse event rates, including infections, appeared somewhat higher across groups with greater prior bDMARD use.ConclusionBaricitinib demonstrated a consistent, beneficial treatment effect in bDMARD-refractory patients across subgroups based on baseline characteristics and prior bDMARD use.Trial registrationClinicalTrials.gov (https://clinicaltrials.gov/), NCT01721044

52-week results of the phase 3 randomized study comparing SB4 with reference etanercept in patients with active rheumatoid arthritis

ObjectiveTo compare the 52-week efficacy and safety of SB4 [an etanercept biosimilar] with reference etanercept (ETN) in patients with active RA.MethodsIn a phase 3, randomized, double-blind, multicentre study, patients with moderate to severe RA despite MTX treatment were randomized to receive 50 mg/week of s.c. SB4 or ETN up to week 52. Efficacy assessments included ACR response rates, 28-joint DAS, Simplified and Clinical Disease Activity Indices and changes in the modified total Sharp score (mTSS). Safety and immunogenicity were also evaluated.ResultsA total of 596 patients were randomized to receive either SB4 (n = 299) or ETN (n = 297) and 505 (84.7%) patients completed 52 weeks of the study. At week 52, the ACR20 response rates in the per-protocol set were comparable between SB4 (80.8%) and ETN (81.5%). All efficacy results were comparable between the two groups and they were maintained up to week 52. Radiographic progression was also comparable and the change from baseline in the mTSS was 0.45 for SB4 and 0.74 for ETN. The safety profile of SB4 was similar to that of ETN and the incidence of anti-drug antibody development up to week 52 was 1.0 and 13.2% in the SB4 and ETN groups, respectively.ConclusionEfficacy including radiographic progression was comparable between SB4 and ETN up to week 52. SB4 was well tolerated and had a similar safety profile to that of ETN.Trial registration numberClinicalTrials.gov NCT01895309, EudraCT 2012-005026-30

Adoptive transfer of a novel MIF receptor (CD74+) expressing memory T cell subpopulation is sufficient to transfer inflammatory arthritis

Abstract Rheumatoid arthritis (RA) is characterized by relapsing disease and progressive autoimmune joint destruction. The mechanism(s) for disease recurrence in previously affected joints is unknown. High expression alleles of the cytokine macrophage migration inhibitory factor (MIF) are associated with severe erosive RA. We report a novel subpopulation of T cells expressing the MIF receptor CD74, which previously has not been considered to be present in T lineage cells. CD74+ T cells comprise 1% of lymph node T cell and exhibit an effector memory phenotype (CD3+ CD74+ CD44+, CD62Llow). Notably, whole genome expression profiling (RNAseq) of CD74+ T cells revealed reduced expression of the immune checkpoint Ctla4 (3.5-fold, p=0.009), and increased expression of Stat4 and Ptpn22 (1.4-fold, p=0.001 and 0.86-fold, p=0.045), three genes that regulate T cell activation and also are linked genetically to RA pathogenesis. In the collagen-induced arthritis (CIA) mouse model of RA, we observed a 2-fold (p=0.023) expansion of CD74+ T cells after disease induction when compared to Mif−/− mice, which show no expansion of CD74+ T cells and reduced disease severity (disease score: WT: 7.8; Mif −/−: 1.4, p&amp;gt;0.001). Notably, adoptive transfer of CD74+ T cells from mice with established CIA into naive mice recapitulated joint inflammation (disease score: 4.3, p=0.001). Disease was not detectable in naïve mice that received CD74-T cells from CIA hosts. This study identifies a novel population of effector memory T cells that are capable of transferring autoimmune joint inflammation. We hypothesize that MIF responsive CD74+ effector memory T cells mediate recurrent joint inflammation and may be amenable to specific targeting by emerging MIF-directed therapies.

Baseline CXCL10 and CXCL13 levels are predictive biomarkers for tumor necrosis factor inhibitor therapy in patients with moderate to severe rheumatoid arthritis: a pilot, prospective study.

BackgroundTNF inhibitors have been used as a treatment for moderate to severe RA patients. However, reliable biomarkers that predict therapeutic response to TNF inhibitors are lacking. In this study, we investigated whether chemokines may represent useful biomarkers to predict the response to TNF inhibitor therapy in RA.MethodsRA patients (n = 29) who were initiating adalimumab or etanercept were recruited from the rheumatology clinics at Cooper University Hospital. RA patients were evaluated at baseline and 14 weeks after TNF inhibitor therapy, and serum levels of CXCL10, CXCL13, and CCL20 were measured by ELISA. Responders (n = 16) were defined as patients who had good or moderate response at week 14 by EULAR response criteria, and nonresponders (n = 13) were defined as having no response.ResultsResponders had higher levels of baseline CXCL10 and CXCL13 compared to nonresponders (p = 0.03 and 0.002 respectively). There was no difference in CCL20 levels. CXCL10 and CXCL13 were highly correlated with each other, and were higher in seropositive RA patients. CXCL10 and CXCL13 levels were decreased after TNF inhibitor therapy in responders. Baseline additive levels of CXCL10 + 13 were correlated with changes in DAS score at 14 weeks after TNF inhibitor therapy (r = 0.42, p = 0.03), and ROC curve analyses for predictive ability of CXCL10 + 13 showed an AUC of 0.83.ConclusionsElevated baseline levels of CXCL10 and CXCL13 were associated with favorable response to TNF inhibitor therapy in RA. Subjects with high CXCL10 and high CXCL13 may represent a subset of RA patients whose inflammatory reactions are primarily driven by TNF.