Which advanced treatment should be used following the failure of a first-line anti-TNF in patients with rheumatoid arthritis? 15 years of evidence from the Quebec registry RHUMADATA.

BACKGROUND: Since 2000, advanced therapies (AT) have revolutionized the treatment of moderate to severe rheumatoid arthritis (RA). Randomized control trials as well as observational studies together with medication availability often determine second-line choices after the failure of first Tumor Necrosis Factor inhibitors (TNFi). This led to the observation that specific sequences provide better long-term effectiveness. We investigated which alternative medication offers the best long-term sustainability following the first TNFi failure in RA. METHODS: Data were extracted from RHUMADATA from January2007. Patients were followed until treatment discontinuation, loss to follow-up, or November 25, 2022. Kaplan-Meier and Cox regression models were used to compare discontinuation between groups. Missing data were imputed, and propensity scores were computed to reduce potential attribution bias. Complete, unadjusted, and propensity score-adjusted imputed data analyses were produced. RESULTS: 611 patients (320 treated with a TNFi and 291 treated with molecules having another mechanism of action (OMA)) were included. The mean age at diagnosis was 44.5 and 43.9 years, respectively. The median retention was 2.84 and 4.48 years for TNFi and OMAs groups. Using multivariable analysis, the discontinuation rate of the OMA group was significantly lower than TNFi (adjHR: 0.65; 95% CI: 0.44-0.94). This remained true for the PS-adjusted MI Cox models. In a stratified analysis, rituximab (adjHR: 0.39; 95% CI: 0.18-0.84) had better retention than TNFi after adjusting for patient characteristics. CONCLUSION: Switching to an OMA, especially rituximab, in patients with failure to a first TNFi appears to be the best strategy as a second line of therapy.

Canadian Rheumatology Association/Spondyloarthritis Research Consortium of Canada Living Treatment Recommendations for the Management of Axial Spondyloarthritis.

OBJECTIVE: To provide a set of living treatment recommendations that will provide contemporary guidance on the management of patients with axial spondyloarthritis (axSpA) in Canada. METHODS: The Spondyloarthritis Research Consortium of Canada (SPARCC), in conjunction with the Canadian Rheumatology Association, organized a treatment recommendations panel composed of rheumatologists, researchers, allied health professionals, and a patient advocate. A Grading of Recommendations Assessment, Development, and Evaluation (GRADE)-ADOLOPMENT approach was used in which existing guidelines were adopted or adapted to a Canadian context. Recommendations were also placed in a health equity framework. RESULTS: 56 recommendations were made for patients with active axSpA, stable axSpA, active or stable axSpA, comorbidities, and for assessment, screening, and imaging. Recommendations were also made for principles of management, disease monitoring, and ethical considerations. CONCLUSION: These living treatment recommendations will provide up to date guidance for the management of axSpA for Canadian practice. As part of the living model, they will be updated regularly as changes occur in the treatment landscape.

Impact of anti-rheumatic treatment on the individual components of the ACR composite score in patients with rheumatoid arthritis: real-world data.

OBJECTIVES: Standard criteria for measuring treatment efficacy in patients with rheumatoid arthritis (RA) include American College of Rheumatology (ACR) response rates, which require meeting a threshold of ≥20/50/70% improvement in several physician- and patient-reported measures. We aimed to evaluate the impact of csDMARDs, TNF inhibitors (TNFi), and tofacitinib (TOFA) on ACR components in real-life practice. METHODS: Clinical data of RA patients with a CDAI >10 at the time they started a treatment were pooled from two registries: Ontario Best Practices Research Initiative (OBRI) and RHUMADATA. Endpoints included proportions of patients achieving: ACR20/50/70 responses, ≥20/50/70% improvements and mean percentage improvement in individual ACR components at Month 6. We also adjusted for potential confounders to compare impact of these medications on outcomes of interest. RESULTS: A total of 669 patients were included (csDMARD, n=157, TNFi, n=252; TOFA, n=260). An overall higher proportion in all three-medication groups achieved ≥20/50/70% improvement in primary ACR components vs. secondary components. Among secondary components, ≥20/50/70% improvement rates were numerically highest for PhGA and lowest for HAQ-DI and pain. Among ACR20/50/70 responders for all medications, the mean percentage improvement was more than 80% for primary components, and ranged from 30% to 80% for secondary components. A significantly lower proportion of patients in TNFi group achieved to at least 50% improvement in pain compared to TOFA after adjusting. CONCLUSIONS: In this real-world practice, physician-reported measures contribute slightly more to overall ACR20/50/70 responses. Pain was the most important factor in achieving an ACR50 TOFA users, possibly reflecting the different effects of JAKi on pain.

Having More Tender Than Swollen Joints Is Associated With Worse Patient-Reported Outcomes in Patients With Early RA.

BACKGROUND/OBJECTIVE: In patients with rheumatoid arthritis (RA), high tender-swollen joint differences (TSJDs) have been associated with worse outcomes. A better understanding of the phenotype and impact of high TSJD on patient-reported outcomes (PROs) in early RA may lead to earlier personalized treatment targeting domains that are important to patients today. Our objectives were to evaluate the impact of TSJD on updated PROs in patients with early RA over 1 year and to determine differences in associations by joint size. METHODS: This longitudinal cohort study followed patients with active, early RA enrolled in the Canadian Early Arthritis Cohort between 2016 and 2022, who completed clinical assessments and PROMIS-29 measures over 1 year. Twenty-eight joint counts were performed and TSJDs calculated. Adjusted associations between TSJD and PROMIS-29 scores were estimated using separate linear-mixed models. Separate analyses of large versus small-joint TJSDs were performed. RESULTS: Patients with early RA (n = 547; 70% female; mean [SD] age, 56 [15] years; mean [SD] symptom duration, 5.3 [2.9] months) were evaluated. A 1-point increase in TSJD was significantly associated with worse PROMIS T-scores in all domains: physical function (adjusted regression coefficient, -0.27; 95% confidence interval [CI], -0.39, -0.15), social participation (adjusted regression coefficient, -0.34; 95% CI, -0.50, -0.19), pain interference (adjusted regression coefficient, 0.49; 95% CI, 0.35, 0.64), sleep problems (adjusted regression coefficient, 0.29; 95% CI, 0.16, 0.43), fatigue (adjusted regression coefficient, 0.34; 95% CI, 0.18, 0.50), anxiety (adjusted regression coefficient, 0.23; 95% CI, 0.08, 0.38), and depression (adjusted regression coefficient, 0.20; 95% CI, 0.06, 0.35). Large-joint TSJD was associated with markedly worse PROs compared with small-joint TSJD. CONCLUSIONS: Elevated TSJD is associated with worse PROs particularly pain interference, social participation, and fatigue. Patients with more tender than swollen joints, especially large joints, may benefit from earlier, targeted therapeutic interventions.

"From Where I Stand": using multiple anchors yields different benchmarks for meaningful improvement and worsening in the rheumatoid arthritis flare questionnaire (RA-FQ).

PURPOSE: The Rheumatoid Arthritis Flare Questionnaire (RA-FQ) is a patient-reported measure of disease activity in RA. We estimated minimal and meaningful change from the perspective of RA patients, physicians, and using a disease activity index. METHODS: Data were from 3- to 6-month visits of adults with early RA enrolled in the Canadian Early Arthritis Cohort. Participants completed the RA-FQ, the Patient Global Assessment of RA, and the Patient Global Change Impression at consecutive visits. Rheumatologists recorded joint counts and MD Global. Clinical Disease Activity Index (CDAI) scores were computed. We compared mean RA-FQ change across categories using patients, physicians, and CDAI anchors. RESULTS: The 808 adults were mostly white (84%) women (71%) with a mean age of 55 and moderate-high disease activity (85%) at enrollment. At V2, 79% of patients classified their RA as changed; 59% were better and 20% were worse. Patients reporting they were a lot worse had a mean RA-FQ increase of 8.9 points, whereas those who were a lot better had a -6.0 decrease. Minimal worsening and improvement were associated with a mean 4.7 and - 1.8 change in RA-FQ, respectively, while patients rating their RA unchanged had stable scores. Physician and CDAI classified more patients as worse than patients, and minimal and meaningful RA-FQ thresholds differed by group. CONCLUSION: Thresholds to identify meaningful change vary by anchor used. These data offer new evidence demonstrating robust psychometric properties of the RA-FQ and offer guidance about improvement or worsening, supporting its use in RA care, research, and decision-making.

Does the Type of Failure and the Choice of the Second Biologic Influence Response and Persistence on Medication in Rheumatoid Arthritis?

BACKGROUND: The type of failure may predict response to a second biologic. We evaluated the response to a second tumor necrosis factor inhibitor (TNFi) or non-TNFi in patients failing their initial TNFi, either primarily or secondarily. METHODS: Patients with rheumatoid arthritis who were biologic-naive and had a Clinical Disease Activity Index (CDAI) >10, who started their first TNFi for ≥3 months and then switched to a second biologic, were included in the study. Secondary failure was defined as 2 consecutive low-CDAI visits and then switching to a second biologic while they had moderate/severe CDAI. Primary failure was defined if it did not meet the definition of secondary failure, or if they had at least 1 moderate/severe CDAI after 3 months on treatment. We used multivariable logistic regression comparing primary versus secondary failure for achievement of CDAI ≤10 (primary outcome) and minimal clinically important differences (secondary outcome) at 6 months after switch. RESULTS: Of the 462 patients included, 64.3% and 35.7% stopped the first TNFi because of a primary and secondary failure, respectively. Patients with primary failure had a more severe disease (CDAI mean, 26.39 vs. 21.61; p < 0.001). The likelihood of achieving CDAI ≤10 (odds ratio, 4.367; 95% confidence interval, 2.428-7.856) and minimal clinically important difference (odds ratio, 2.851; 95% confidence interval, 1.619-5.020) was significantly higher for secondary than primary failure regardless of choice of a second agent. CONCLUSION: Patients with rheumatoid arthritis with secondary failure to a first TNFi responded better to a second biologic agent, regardless of the choice of biologic.

Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial.

BACKGROUND: Ixekizumab, a high-affinity interleukin-17A (IL-17A) monoclonal antibody, has previously shown efficacy in radiographic axial spondyloarthritis (also known as ankylosing spondylitis). We aimed to evaluate the efficacy and safety of ixekizumab, an IL-17 inhibitor, in non-radiographic axial spondyloarthritis. Here, we report the primary results of COAST-X. METHODS: COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged ≥18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Patients were randomly assigned (1:1:1) to receive subcutaneous 80 mg ixekizumab every 4 weeks (Q4W) or every 2 weeks (Q2W), or placebo. Changing background medications or switching to open-label ixekizumab Q2W, or both, was allowed after week 16 at investigator discretion. Primary endpoints were Assessment of SpondyloArthritis international Society-40 (ASAS40) response (defined as an improvement of 40% or more and an absolute improvement from baseline of 2 units or more [range 0-10] in at least three of the four domains [patient global, spinal pain, function, and inflammation] without any worsening in the remaining one domain) at weeks 16 and 52. Patients who switched to open-label ixekizumab were imputed as non-responders in logistic regression analysis. This trial is registered with ClinicalTrials.gov, number NCT02757352. FINDINGS: Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled (105 to placebo, 96 to ixekizumab Q4W, and 102 to ixekizumab Q2W). Both primary endpoints were met: ASAS40 at week 16 (ixekizumab Q4W: 34 [35%] of 96, p=0·0094 vs placebo; ixekizumab Q2W: 41 [40%] of 102, p=0·0016; placebo: 20 [19%] of 105) and ASAS40 at week 52 (ixekizumab Q4W: 29 [30%] of 96, p=0·0045; ixekizumab Q2W: 32 [31%] of 102, p=0·0037; placebo: 14 [13%] of 105). 60 (57%) of 104 patients in the placebo group, 63 (66%) of 96 in the ixekizumab Q4W group, and 79 (77%) of 102 in the ixekizumab Q2W group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events in the ixekizumab groups were nasopharyngitis and injection site reaction. Of the treatment-emergent adverse events of special interest, there was one case of serious infection in the ixekizumab Q4W group. The frequency of serious adverse events was low (four [1%] of 302) and similar across the three groups. There were no malignancies or deaths. No new safety signals were identified. INTERPRETATION: Ixekizumab was superior to placebo for improving signs and symptoms in patients with non-radiographic axial spondyloarthritis at weeks 16 and 52. Reports of adverse events were similar to those of previous ixekizumab studies. Ixekizumab offers a potential therapeutic option for patients with non-radiographic axial spondyloarthritis who had an inadequate response or were intolerant to NSAID therapy. FUNDING: Eli Lilly and Company.

Switching between Janus kinase inhibitor upadacitinib and adalimumab following insufficient response: efficacy and safety in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate efficacy and safety of immediate switch from upadacitinib to adalimumab, or vice versa, in patients with rheumatoid arthritis with non-response or incomplete-response to the initial therapy. METHODS: SELECT-COMPARE randomised patients to upadacitinib 15 mg once daily (n=651), placebo (n=651) or adalimumab 40 mg every other week (n=327). A treat-to-target study design was implemented, with blinded rescue occurring prior to week 26 for patients who did not achieve at least 20% improvement in both tender and swollen joint counts ('non-responders') and at week 26 based on Clinical Disease Activity Index (CDAI) >10 ('incomplete-responders') without washout. RESULTS: A total of 39% (252/651) and 49% (159/327) of patients originally randomised to upadacitinib and adalimumab were rescued to the alternate therapy. In both switch groups (adalimumab to upadacitinib and vice versa) and in non-responders and incomplete-responders, improvements in disease activity were observed at 3 and 6 months following rescue. CDAI low disease activity was achieved by 36% and 47% of non-responders and 45% and 58% of incomplete-responders switched to adalimumab and upadacitinib, respectively, 6 months following switch. Overall, approximately 5% of rescued patients experienced worsening in disease activity at 6 months postswitch. The frequency of adverse events was similar between switch groups. CONCLUSIONS: These observations support a treat-to-target strategy, in which patients who fail to respond initially (or do not achieve sufficient response) are switched to a therapy with an alternate mechanism of action and experience improved outcomes. No new safety findings were observed despite immediate switch without washout.

Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme.

OBJECTIVES: This integrated analysis presents the safety profile of upadacitinib, a Janus kinase inhibitor, at 15 mg and 30 mg once daily in patients with moderately to severely active rheumatoid arthritis (RA). METHODS: Treatment-emergent adverse events (TEAEs) and laboratory data from five randomised, placebo- or active-controlled phase III trials of upadacitinib for patients with RA were analysed and summarised. Exposure-adjusted event rates are shown for placebo (three trials; 12/14 weeks), methotrexate (two trials; mean exposure: 36 weeks), adalimumab (one trial; mean exposure: 42 weeks), upadacitinib 15 mg (five trials; mean exposure: 53 weeks) and upadacitinib 30 mg (four trials; mean exposure: 59 weeks). RESULTS: 3834 patients received one or more doses of upadacitinib 15 mg (n=2630) or 30 mg (n=1204), for a total of 4020.1 patient-years of exposure. Upper respiratory tract infection, nasopharyngitis and urinary tract infection were the most commonly reported TEAEs with upadacitinib. Rates of serious infection were similar between upadacitinib 15 mg and adalimumab but higher compared with methotrexate. Rates of herpes zoster and creatine phosphokinase (CPK) elevations were higher in both upadacitinib groups versus methotrexate and adalimumab, and rates of gastrointestinal perforations were higher with upadacitinib 30 mg. Rates of deaths, malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs) were similar across treatment groups. CONCLUSION: In the phase III clinical programme for RA, patients receiving upadacitinib had an increased risk of herpes zoster and CPK elevation versus adalimumab. Rates of malignancies, MACEs and VTEs were similar among patients receiving upadacitinib, methotrexate or adalimumab. TRIAL REGISTRATION NUMBERS: SELECT-EARLY: NCT02706873; SELECT-NEXT: NCT02675426; SELECT-COMPARE: NCT02629159; SELECT-MONOTHERAPY: NCT02706951; SELECT-BEYOND: NCT02706847.

An open-label randomized controlled trial of DMARD withdrawal in RA patients achieving therapeutic response with certolizumab pegol combined with DMARDs.

OBJECTIVES: The objective of this trial was to compare effectiveness of certolizumab pegol added to conventional synthetic DMARDs (csDMARDs) in RA patients, followed by continuing vs discontinuing background csDMARDs after treatment response. METHODS: Patients with active RA who had certolizumab pegol added to their existing csDMARD regimen due to inadequate response were eligible. At 3 or 6 months, patients who achieved a change (Δ) in DAS28 of ⩾1.2 were randomized to continue combination therapy (COMBO) or withdraw csDMARD therapy (MONO) (unblinded). The primary outcome was non-inferiority of stopping vs continuing csDMARD(s) in terms of maintaining ΔDAS28 ⩾ 1.2 or achieving DAS28 low disease activity at 18 months (non-inferiority margin: 15 percentile units). RESULTS: A total of 125 patients were enrolled, 88 randomized to COMBO (n = 43) or MONO (n = 45). No significant differences were observed between groups in baseline age, gender, race, RF status or prior biologics (16% vs 11%). Although the rate of ΔDAS28 ⩾ 1.2 and/or DAS28 low disease activity achievement at 18 months was clinically comparable between the two groups (72% vs 69%), non-inferiority assumptions were not met [absolute risk difference (upper limit of 90% CI): 2.6% (19.1%)]. Similar baseline-adjusted improvements were seen in DAS28 (COMBO vs MONO: -2.3 vs -2.1; P = 0.49) and all endpoints were not statistically different including 59% vs 56% achieved DAS28 low disease activity, 69% vs 59% ΔDAS28 ⩾ 1.2, and 41% each remission. CONCLUSION: Among RA patients achieving a therapeutic response on combination therapy with certolizumab pegol and csDMARDs, withdrawing csDMARDs was not non-inferior to maintaining csDMARDs but improvements were sustained in both groups at 18 months.

An international, multicentre, double-blind, randomized study (DISSCO): effect of diacerein vs celecoxib on symptoms in knee osteoarthritis.

OBJECTIVE: The objective of this study was to investigate whether diacerein has comparable efficacy with celecoxib in pain reduction for treatment in symptomatic knee OA patients. METHODS: This randomized double-blind multicentre non-inferiority trial evaluated diacerein vs celecoxib treatment in patients with Kellgren-Lawrence grade 2-3 and pain scoring ≥4 (10-cm VAS). Patients were randomized to 6 months of treatment with diacerein 50 mg (n = 187) once daily for 1 month and twice daily thereafter, or celecoxib 200 mg (n = 193) once daily. The primary outcome was the change in WOMAC pain score (0-50 cm) at 6 months, and the secondary outcomes were WOMAC sub-scores, VAS pain score, and the OMERACT-OARSI responder rate. RESULTS: In the per protocol population, the adjusted mean change from baseline in the WOMAC pain score was -11.1 ( 0.9) with diacerein (n = 140) and -11.8 (0.9) with celecoxib (n = 148). The intergroup difference was 0.7 (95% CI: -1.8, 3.2; P = 0.597), meeting the non-inferiority margin. Supportive analysis of the intention-to-treat population gave similar results. Other outcomes showed no significant difference between treatment groups. The incidence of treatment-related adverse events was low and balanced between groups, but a greater incidence of diarrhoea occurred with diacerein (10.2% vs 3.7%). Diarrhoea was considered mild-to-moderate in all but one case with complete resolution. CONCLUSIONS: Diacerein was non-inferior to celecoxib in reducing knee OA pain and improving physical function. Diacerein also demonstrated a good safety profile. TRIAL REGISTRATION: A multicentre study on the effect of DIacerein on Structure and Symptoms vs Celecoxib in Osteoarthritis is a National Institutes of Health (NCT02688400) and European Clinical Trial Database (2015-002933-23) registered phase III (Canada) or IV (Europe) study.

Experience with tofacitinib in Canada: patient characteristics and treatment patterns in rheumatoid arthritis over 3 years.

OBJECTIVES: To describe characteristics, treatment patterns and persistence in patients with RA treated with tofacitinib, an oral Janus kinase inhibitor, in Canadian clinical practice between 1 June 2014 and 31 May 2017. METHODS: Data were obtained from the tofacitinib eXel support programme. Baseline demographics and medication history were collected via patient report/special authorization forms; reasons for discontinuation were captured by patient report. Treatment persistence was estimated using Kaplan-Meier methods, with data censored at last follow-up. Cox regression was applied to analyse baseline characteristics associated with treatment discontinuation. RESULTS: The number of patients with RA enrolled from 2014 to 2017 was 4276; tofacitinib utilization increased during that period, as did the proportion of biologic (b) DMARD-naïve patients prescribed tofacitinib. Of patients who initiated tofacitinib, 1226/3678 (33.3%) discontinued, mostly from lack of efficacy (35.7%) and adverse events (26.9%). Persistence was 62.7% and 49.6% after 1 and 2 years of treatment, respectively. Prior bDMARD experience predicted increased tofacitinib discontinuation (vs bDMARD-naïve, P < 0.001). Increased retention was associated with older age (56-65 years and >65 years vs ⩽45 years; P < 0.05), and time since diagnosis of 15 to <20 years (vs <5 years; P < 0.01). In bDMARD-naïve, post-1 bDMARD, post-2 bDMARD and post-⩾3 bDMARD patients, median survival was >730, 613, 667 and 592 days, respectively. CONCLUSION: Since 2014, tofacitinib use in Canadian patients with RA increased, especially among bDMARD-naïve/post-1 bDMARD patients. Median drug survival was ∼2 years. Likelihood of persistence increased for bDMARD-naïve (vs bDMARD-experienced) patients and those aged ⩾56 (vs ⩽45) years.

Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Upadacitinib is a selective inhibitor of Janus kinase 1 and was efficacious in phase 2 studies in patients with moderate-to-severe rheumatoid arthritis. We aimed to assess the efficacy of upadacitinib in patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). METHODS: This study is a double-blind, placebo-controlled trial at 150 sites in 35 countries. We enrolled patients aged 18 years or older with active rheumatoid arthritis for 3 months or longer, who had received csDMARDs for at least 3 months with a stable dose for at least 4 weeks before study entry, and had an inadequate response to at least one of the following csDMARDs: methotrexate, sulfasalazine, or leflunomide. Using interactive response technology, we randomly assigned patients receiving stable background csDMARDs (2:2:1:1) to receive a once-daily extended-release formulation of upadacitinib 15 mg or 30 mg, or placebo, for 12 weeks. Patients, investigators, and the funder were masked to allocation. After 12 weeks, patients taking placebo received 15 mg or 30 mg of upadacitinib once daily, according to the prespecified randomisation assignment. The primary endpoints were the proportion of patients at week 12 who achieved 20% improvement in American College of Rheumatology criteria (ACR20), and a 28-joint disease activity score using C-reactive protein (DAS28[CRP]) of 3·2 or less. We did efficacy analyses in the full analysis set of all randomly assigned patients who received at least one dose of study drug, and used non-responder imputation for assessment of the primary outcomes. This study is registered with ClinicalTrials.gov, number NCT02675426. FINDINGS: Between Dec 17, 2015, and Dec 22, 2016, 1083 patients were assessed for eligibility, of whom 661 were recruited and randomly assigned to receive upadacitinib 15 mg (n=221), upadacitinib 30 mg (n=219), or placebo (n=221). All patients received at least one dose of study drug, and 618 (93%) completed 12 weeks of treatment. At week 12, ACR20 was achieved by 141 (64%; 95% CI 58-70) of 221 patients receiving upadacitinib 15 mg and 145 (66%; 60-73) of 219 patients receiving upadacitinib 30 mg, compared with 79 (36%; 29-42) of 221 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of 3·2 or less was met by 107 (48%; 95% CI 42-55) patients receiving upadacitinib 15 mg and 105 (48%; 41-55) patients receiving upadacitinib 30 mg, compared with 38 (17%; 12-22) patients receiving placebo (p<0·0001 for each dose vs placebo). Adverse events were reported in 125 (57%) of 221 patients receiving upadacitinib 15 mg, 118 (54%) of 219 patients receiving upadacitinib 30 mg, and 108 (49%) of 221 patients receiving placebo. The most frequently reported adverse events (≥5% of patients in any group) were nausea (16 [7%] of 221 in the upadacitinib 15 mg group; three [1%] of 219 in the upadacitinib 30 mg group; and seven [3%] of 221 in the placebo group), nasopharyngitis (12 [5%]; 13 [6%]; and nine [4%]), upper respiratory tract infection (12 [5%]; 12 [5%]; and nine [4%]), and headache (nine [4%]; seven [3%]; and 12 [5%]). More infections were reported for upadacitinib (64 [29%] of 221 patients receiving 15 mg and 69 [32%] of 219 patients receiving 30 mg) versus placebo (47 [21%] of 221 patients). There were three herpes zoster infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, and one [<1%] in the upadacitinib 30 mg group) and one primary varicella zoster virus infection (one [<1%] in the upadacitinib 30 mg group), two malignancies (both in the upadacitinib 30 mg group), one adjudicated major adverse cardiovascular event (in the upadacitinib 30 mg group), and five serious infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, three [1%] in the upadacitinib 30 mg group). No deaths were reported during the trial. INTERPRETATION: Patients with moderately to severely active rheumatoid arthritis who received upadacitinib (15 mg or 30 mg) in combination with csDMARDs showed significant improvements in clinical signs and symptoms. FUNDING: AbbVie Inc.

Safety and effectiveness of upadacitinib or adalimumab plus methotrexate in patients with rheumatoid arthritis over 48 weeks with switch to alternate therapy in patients with insufficient response.

BACKGROUND: In SELECT-COMPARE, a randomised double-blind study, upadacitinib 15 mg once daily was superior to placebo or adalimumab on background methotrexate (MTX) for treating rheumatoid arthritis signs and symptoms and inhibited radiographical progression versus placebo at 26 weeks. Here we report 48-week safety and efficacy in patients who continued their original medication or were rescued to the alternative medication for insufficient response. METHODS: Patients on MTX received upadacitinib 15 mg, placebo or adalimumab for 48 weeks. Rescue without washout, from placebo or adalimumab to upadacitinib or upadacitinib to adalimumab occurred if patients had <20% improvement in tender joint count (TJC) or swollen joint count (SJC) (weeks 14/18/22) or Clinical Disease Activity Index (CDAI) >10 (week 26); remaining placebo patients were switched to upadacitinib at week 26. Efficacy was analysed by randomised group (non-responder imputation), as well as separately for rescued patients (as observed). Treatment-emergent adverse events per 100 patient-years were summarised. RESULTS: Consistent with responses through week 26, from weeks 26 to 48, responses by randomised group including low disease activity, clinical remission and improvements in pain and function remained superior for upadacitinib versus adalimumab; radiographical progression remained lower for upadacitinib versus placebo (linear extrapolation). Although both switch groups responded, a higher proportion of patients rescued to upadacitinib from adalimumab achieved CDAI ≤10 at 6 months postswitch versus patients rescued from upadacitinib to adalimumab. Safety at week 48 was comparable to week 26. CONCLUSION: Upadacitinib+MTX demonstrated superior clinical and functional responses versus adalimumab+MTX and maintained inhibition of structural damage versus placebo+MTX through week 48. Patients with an insufficient response to adalimumab or upadacitinib safely achieved clinically meaningful responses after switching to the alternative medication without washout.

Clinical peripheral enthesitis in the DESIR prospective longitudinal axial spondyloarthritis cohort.

OBJECTIVES: We aimed to describe the prevalence and characteristics of peripheral enthesitis in recent onset axial spondyloarthritis, estimate the incidence of peripheral enthesitis over time, and determine the factors associated with the presence of peripheral enthesitis. METHODS: 708 patients with recent onset axial spondyloarthritis were enrolled in the DESIR cohort ( prospective multi-centre, longitudinal). Data regarding the patients and spondyloarthritis characteristics at baseline with a specific focus on enthesitis and occurrence of peripheral enthesitis were collected during the five years of follow-up. RESULTS: At inclusion, 395 patients (55.8%) reported peripheral enthesitis. The locations were mainly the plantar fascia (53.7%) and the Achilles tendon (38.5%). During the 5-year follow-up period, 109 additional patients developed peripheral enthesitis resulting in an estimated (Kaplan-Meier method) percentage of 71% (95% CI: 68-75). Variables associated with peripheral enthesitis in the univariate analysis were: older age, male gender, absence of HLA B27, MRI sacroiliitis and fulfilled Modified NY criteria, presence of anterior chest wall pain, peripheral arthritis, dactylitis, psoriasis, high BASDAI, BASFI, mean score ASAS-and the use of NSAIDs. Only the history of anterior chest wall pain and of peripheral arthritis were retained in the multivariate analysis (odds ratio (OR)=1.6 [95% confidence interval [1.1-2.3], and OR=2.1 [1.4-3.0], respectively). CONCLUSIONS: This study highlights the high prevalence of peripheral enthesitis in recent onset axial spondyloarthritis, and suggests that in combination with peripheral arthritis, enthesitis might have an impact on the burden of the disease.

Loss of health related quality of life following low-trauma fractures in the elderly.

BACKGROUND: To estimate the long-term change in health related quality of life (HRQoL) following low-trauma fractures among individuals receiving home care (HC) services or living in long-term care (LTC) facilities using linked healthcare administrative data from Ontario, Canada. METHODS: HRQoL was estimated using the Health Utility Index (HUI-2) with the InterRai Minimum Data Set (MDS), a mandatory questionnaire for LTC and HC in the province of Ontario (population 14 million). The HUI-2, a validated HRQoL instrument, allows the calculation of health utility where 0 represents death and 1 the best imaginable health state. For reference, the HUI-2 utility value for Canadians aged 80-84 years is 0.61 and the minimal clinically important difference is 0.03. The MDS was linked to Ontario acute care databases for fiscal years 2007-2011 to identify low-trauma fractures using ICD-10-CA codes. Regression models were used to identify predictors of change in HRQoL from pre-fracture levels to 3 years post fracture for several populations. Low-trauma fractures included hip, humerus, vertebral, wrist, multiple and other. RESULTS: Twenty-three thousand six-hundred fifty-five unique patients with low-trauma fractures were identified with pre- and post-fracture HRQoL assessments, of which 5057 individuals had at least 3 years of follow-up. Compared to patients receiving HC services (N = 3303), individuals residing in LTC (N = 1754) were older, taking more medications, and had more comorbidities. LTC patients had more hip fractures (49 % of total versus 29 %). For all fracture types, HRQoL decreased immediately following fracture. Although levels rebounded after the first month, HRQoL up to 36 months never returned to pre-fracture levels even for non-hip fracture. For both HC and LTC cohorts, clinically important and statistically significant decreases in HUI-2 utility scores were observed 36 months post fracture. Of the 6 HUI-2 domains, mobility had the largest impact on change in HRQoL. Regression analysis indicated that living with a musculoskeletal disorder or a neurological condition and living in LTC were associated with greater decrements in utility following a fracture. CONCLUSIONS: Based on the analysis of one of the largest studies on HRQoL to date, among individuals living in LTC facilities or receiving HC services, fractures have a significant permanent impact on HRQoL up to 3 years following fracture.

Hospitalization for musculoskeletal disorders in rheumatoid arthritis patients: a population-based study.

BACKGROUND: Rheumatoid arthritis (RA) patients failing disease modifying antirheumatic drugs (DMARDs) may undergo anti-Tumor Necrosis Factor (anti-TNF) therapy. Using the Quebec health services administrative databases, we examined the rates of musculoskeletal (MSD)-related hospitalizations among RA patients receiving anti-TNF, DMARDs, and neither of those therapies (non-users). METHODS: Matched cohort analyses were performed separately in 2002-2006 and 2007-2011. In each cohort, DMARD and non-user groups were formed to 3-1 match the anti-TNF users on age, sex, date of RA diagnosis, high-dimensional propensity score and date of the first anti-TNF dispensation (index-date). Non-users did not use DMARDs or anti-TNF drugs during the year before the index-date and in the 90 days post, but used at least one of these medications in the study period. RESULTS: During 2002-2006, 557 anti-TNF users were matched to 1144 DMARD users and to 656 non-users, compared to 690, 1651, and 532 patients, respectively during 2007-2011. The crude rates of MSD-related hospitalizations in the anti-TNF, DMARD and non-users groups were respectively: 8.2/100, 6.4/100 and 10.5/100 patient-years in 2002-2006, and 6.9/100, 4.8/100, and 8.6/100 patient-years in 2007-2011. In multivariable Cox regression models, the hazard ratios of MSD-related hospitalizations (95 % confidence interval) were: 0.95 (0.60; 1.50) for anti-TNF and 0.69 (0.46; 1.02) for DMARD users, versus non-users in 2002-06, and 0.65 (0.37; 1.14) and 0.40 (0.24; 0.66), respectively in 2007-2011. CONCLUSION: The MSD-related hospitalization risk was lower in RA patients using DMARD therapy and similar in those using anti-TNF therapy with or without DMARDs as compared to those not using either of these therapies during the study period.

Psoriasis and Smoking: A Systematic Literature Review and Meta-Analysis With Qualitative Analysis of Effect of Smoking on Psoriasis Severity.

BACKGROUND: Smoking has been associated with psoriasis prevalence and severity. OBJECTIVE: To evaluate prevalence of smoking in patients with psoriasis and to examine the relationship between smoking and psoriasis severity. METHODS: MEDLINE, EMBASE, and Cochrane databases (1960-2012) and conference proceedings (2010-2012) were systematically searched using keywords relevant to psoriasis and smoking. Controlled studies addressing psoriasis and smoking status were included. A meta-analysis for the relative risk of smoking in psoriasis patients was performed. RESULTS: Meta-analysis identified a significant association between smoking and psoriasis with a relative risk of 1.88 (95% CI, 1.66-2.13) for smoking in patients with psoriasis versus patients without psoriasis. Eight articles of 11 with data on smoking and psoriasis severity suggested that severity increases with smoking status. CONCLUSIONS: This literature review is in favor of a positive association between the prevalence of smoking and psoriasis as well as an association between smoking and severity of psoriasis.

The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis.

The objective of this systematic literature review was to determine the association between cardiovascular events (CVEs) and antirheumatic drugs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA)/psoriasis (Pso). Systematic searches were performed of MEDLINE, EMBASE and Cochrane databases (1960 to December 2012) and proceedings from major relevant congresses (2010-2012) for controlled studies and randomised trials reporting confirmed CVEs in patients with RA or PsA/Pso treated with antirheumatic drugs. Random-effects meta-analyses were performed on extracted data. Out of 2630 references screened, 34 studies were included: 28 in RA and 6 in PsA/Pso. In RA, a reduced risk of all CVEs was reported with tumour necrosis factor inhibitors (relative risk (RR), 0.70; 95% CI 0.54 to 0.90; p=0.005) and methotrexate (RR, 0.72; 95% CI 0.57 to 0.91; p=0.007). Non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of all CVEs (RR, 1.18; 95% CI 1.01 to 1.38; p=0.04), which may have been specifically related to the effects of rofecoxib. Corticosteroids increased the risk of all CVEs (RR, 1.47; 95% CI 1.34 to 1.60; p<0.001). In PsA/Pso, systemic therapy decreased the risk of all CVEs (RR, 0.75; 95% CI 0.63 to 0.91; p=0.003). In RA, tumour necrosis factor inhibitors and methotrexate are associated with a decreased risk of all CVEs while corticosteroids and NSAIDs are associated with an increased risk. Targeting inflammation with tumour necrosis factor inhibitors or methotrexate may have positive cardiovascular effects in RA. In PsA/Pso, limited evidence suggests that systemic therapies are associated with a decrease in all CVE risk.