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Rheumatology reviews
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Rheumatology reviews Sukhbir Uppal Department of Medicine, University Hospital Sharjah, United Arab Emirates
1.
Rheumatoid arthritis
1.1. Women with RA have a two-fold increased risk of death compared to women without RA: 34 year follow up of 121,700 women RA has been associated with increased mortality compared to general population estimates. The authors of this paper evaluated mortality among women followed prospectively prior to RA diagnosis, directly comparing to women without RA. They conducted a study of RA and mortality among 121,700 women followed from 1976 to 2010 in the Nurses' Health Study (NHS). Models were adjusted for age, demographics and other mortality factors, including physical activity, smoking, obesity, comorbidities, and family history of cancer, CVD, and diabetes. The authors validated 960 incident RA cases and identified 25,699 deaths in 34 years of NHS follow-up. Of the 261 deaths among women with RA, 75 (29%) were from cancer, 58 (22%) were from CVD, and 43 (16%) were from respiratory causes. Compared to women without RA, women with RA had increased all-cause mortality that remained significant after adjusting for age and other mortality factors (HR 2.07, 95% CI 1.83e2.35). Mortality was significantly increased for seropositive (HR 2.33, 95% CI 2.00e2.71) and seronegative RA (HR 1.60, 95% CI 1.30e1.98) compared to non-RA women. Each five years of RA duration conferred a 32% (95% CI 27e36%) increased mortality compared to non-RA. Women with RA had significantly increased risk for mortality from CVD (HR 1.87, 95% CI 1.44e2.43), cancer (HR 1.35, 95% CI 1.07e1.69) and respiratory (HR 4.50, 95% CI 3.28e6.17) causes compared to women without RA. Respiratory mortality for women with seropositive RA was six-fold higher than non-RA women (HR 6.23, 95% CI 4.38e8.85). Thus, in 34 years of prospective follow-up, women diagnosed with RA have a two-fold increased risk of death from any cause compared to women without RA. Respiratory mortality is six-fold higher in seropositive RA and women with RA are significantly more likely to die from CVD and cancer than women without RA. Respiratory mortality appears to be an important but understudied cause of death in
RA. These findings provide evidence of high RA mortality burden that is unexplained by traditional mortality predictors. (ACR 2014 Abstract 818)
1.2. years
70% RA patients discontinue their first biologic in 3
Adherence and persistence to treatment is a cornerstone of treatment success in chronic diseases such as RA. The purpose of this study was to describe biologic treatment discontinuation and assess the predictors of discontinuation in RA patients followed at a Canadian clinic. In this prospective cohort study, adult patients included in the RHUMADATA computerized database with a diagnosis of RA and treated with at least one biologic agent since 2003 were selected. Patients were followed for three years after therapy initiation or until treatment discontinuation. Biologic therapies considered include abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab, and anakinra. A total of 623 eligible patients were treated with at least one biologic. The average time on treatment for the first biologic agent was 1.7 years. In all, 233 (37%), 326 (52%), 405 (65%), and 438 (70%) patients had stopped their first biologic treatment after 6, 12, 24, and 36 months, respectively. In time-to-event analyses, type of work [part time vs. full time; hazard ratio (HR): 1.57; 95% confidence interval (CI): 1.05e2.34] and income [$20,000 to $40,000 vs. less than $20,000 (HR: 1.35; 1.01e1.80) and $80,000 to $100,000 vs. less than $20,000 (HR: 2.16; 1.23e3.80)] were significantly associated with biologic discontinuation over the complete treatment duration. The number of DMARDs used (HR: 0.89; 0.80e0.99) and the use of methotrexate (yes vs. no; HR: 0.80; 0.64e0.99) were associated with a reduced risk of biologic discontinuation. Thus, in this real-life Canadian study, high biologic discontinuation rates were observed over three years. This study also suggests that many clinical and socioeconomic variables are predictors of biologic therapy discontinuation in RA patients. (ACR 2014 Abstract 499)
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1.3. Abatacept, Adalimumab, Etanercept and Infliximab have similar retention rates as first line agents in patients with rheumatoid arthritis who are methotrexate inadequate responders The order of use of biologic agents is still a question for debate. Phase III trial data in MTX-IR patients show comparable efficacy results across biologic agents. This study aimed to assess if patients with RA treated with abatacept after failure of a first line agent (MTX-IR) have a different drug survival rate than patients similarly treated with adalimumab, etanercept or infliximab. RA patients prescribed a first biologic agent after January 1st 2007 were included in the present analysis. We extracted a cohort formed of all patients prescribed abatacept (ABA), adalimumab (ADA), etanercept (ETA) or infliximab (INF) as their first biologic agent. A total 340 patients were included in the cohort. The 5 year retention rate of ABA, ADA, ETA and INF post MTX failure were 64%, 40%, 49% and 42% without significant statistical differences (Log-Rank p ¼ 0.29). Thus, abatacept, adalimumab, etanercept and infliximab after MTX failure have similar 5-years retention rates. (ACR 2014 Abstract 1536)
1.4. In RA patients having failed their first anti-TNF agent, Tocilizumab, an IL-6 inhibitor, has better retention rates than a second anti-TNF agent: comparison with Adalimumab, Etanercept and Infliximab Tocilizumab, as an intravenous agent, has been approved for RA in 2010. It has been demonstrated effective in the treatment of RA either in monotherapy or combo therapy after non-biologic or biologic DMARDS. This paper describes its effectiveness in patients with RA failing a first anti-TNF DMARD and to compare its retention rate versus adalimumab, etanercept and infliximab in the same clinical situation. All patients with RA having failed a first anti-TNF agent and subsequently exposed to tocilizumab after the 1st of January 2005 were extracted from the Rhumadata® database. 4 cohorts were created: One cohort of patients starting tocilizumab and 3 other cohorts starting either adalimumab, etanercept or infliximab. The data from 259 patients prescribed either tocilizumab (53 ¼ 20%), adalimumab (97 ¼ 37%), etanercept (82 ¼ 33%) or infliximab (27 ¼ 10%) as a second biologic agent were extracted from the Rhumadata® registry and clinical database. The four year retention rates of tocilizumab, adalimumab, etanercept and infliximab as second line biologic agents were 44.3%, 27.2%, 37.1% and 34.0% respectively. KaplaneMeier survival analysis revealed significant differences in the drug retention rates (logrank p ¼ 0.0249). Thus, in RA patient having failed their first anti-TNF agent, tocilizumab, an IL-6 inhibitor, could be a more valuable alternative than cycling to a second anti-TNF agent. (ACR 2014 Abstract 502)
1.5. Etanercept biosimilar (HD203) is as effective as etanercept (Enbrel®), in combination with methotrexate (MTX) in patients with RA Etanercept is a recombinant fusion protein that blocks TNF activity. HD203 is a biosimilar of etanercept. The aim of this
study was to evaluate the equivalence in efficacy and to compare the safety of HD203 (biosimilar etanercept) and a reference etanercept, in combination with MTX in patients with RA. Patients with active RA were randomly assigned (1:1) to 25 mg HD203 or reference etanercept, administered subcutaneously twice weekly with MTX for 48 weeks. In total, 294 patients were randomized: 147 to HD203 and 147 to reference etanercept. The proportion of patients achieving ACR20 at week 24 (primary endpoint) was not significantly different for HD203 and reference etanercept and equivalence in efficacy was demonstrated within predefined margins. In addition, there were no statistically significant differences between proportions achieving ACR20 at weeks 12 and 48. Similar trends were seen for ACR50 and ACR70, however the proportion of patients achieving ACR50 at week 24 and 48 was higher with HD203 than with reference etanercept. There were no statistically significant differences between the groups for ACRn, change in DAS28, and EULAR response at week 24 and 48. Analysis of the safety set (HD203, n ¼ 147; reference etanercept, n ¼ 146) revealed no statistically significant difference in the number of treatment-emergent (all-causality) adverse events (AEs): HD203 76.87% vs. reference etanercept 78.08% (p ¼ 0.8040). Furthermore, no statistically significant differences between HD203 and reference etanercept were observed with regards to adverse drug reactions, serious AEs, or discontinuations due to AEs. No unexpected AEs were observed, and few patients tested positive for anti-drug antibodies. Thus, the study met the primary endpoint of demonstrating equivalence in efficacy of HD203 compared with a reference etanercept. HD203 was well tolerated, with a safety profile comparable to that of the reference etanercept in this population of Korean patients with RA. (ACR 2014 Abstract 2825)
1.6. Reducing therapy in RA patients in remission is feasible in a subset of patients Due to improved therapeutic management a steadily increasing number of RA patients reach stable remission of disease. Data on withdrawal of medication after sustained remission are limited, though it is important for economic and safety reasons. The RETRO study represents a real-life study addressing different strategies of reduction of DMARD therapy in RA patients in disease remission. The aim of the study was to evaluate the possibility of tapering and even discontinuation of DMARD therapy in RA patients in stable long-lasting remission and to determine predictors for recurrence of disease. In this phase 3 trial, patients with RA of 12 months were enrolled into the study if they were in clinical remission (DAS28-ESR < 2.6) at stable dose of DMARDs for more than 6 months. Patients on 1 conventional and/or biological DMARDs were included and randomized into three trial arms: Arm 1 (control group) was continuing full-dose conventional and/or biological DMARD treatment for 12 months; arm 2 was reducing the dose of all conventional and/or biological DMARD treatment by 50% for 12 months and arm 3 was
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reducing the dose of all conventional and/or biological DMARD treatment by 50% for 6 months before entirely stopping DMARD. In case of recurrence of disease (DAS > 2.6) the original therapy was restarted. 101 patients finished the one year endpoint: 38 patients in arm 1, 36 patients in arm 2 and 27 patients in arm 3. Of 101 patients, 66.3% were still in remission at 12 mo. Trial arms 2 (38.9%, c2(1) ¼ 5.0, p ¼ 0.036) and 3 (51.9%, c2(1) ¼ 9.6, p ¼ 0.003) significantly differed from the control group (15.8% flare rate) with more patients flaring in reduction arms. However, there was no significant difference between the two reduction arms (c2(1) ¼ 1.1, p ¼ 0.443). A multivariate logistic regression identified ACPA positivity (Wald c2 ¼ 4.5, p ¼ 0.03) and treatment reduction compared to the control group (arm2: Wald c2 ¼ 6.6, p ¼ 0.01, arm3: Wald c2 ¼ 8.8, p ¼ 0.003) as predictors for subsequent flares. Sex, disease duration, remission duration, age, RF, biologic DMARD and remission depth failed to predict recurrence of disease in this study. Thus, this study is a prospective real life treatment strategy study investigating the effect of reduction and discontinuation of DMARD therapy in RA patients in stable remission. Interestingly neither remission depth, nor disease duration at baseline or biological DMARD therapy predicted the recurrence of disease. Presence of ACPA but not RF was the only predictor for recurrence of disease. The data indicate that treatment reduction and even discontinuation is feasible in a subset of RA patients in stable remission. (ACR 2014 Abstract 940)
1.7. ACPA negative patients respond similarly to treatment to ACPA positive patients and both groups require a similar treatment approach This study was conducted to determine the optimal treatment strategy in patients with ACPA negative () RA, as it has been suggested that these patients require a different treatment approach than ACPA positive (þ) patients. 184 ACPA patients were randomized to 1. sequential monotherapy, 2. step-up therapy, 3. initial combination with prednisone, 4. initial combination with infliximab, as were 300 ACPAþ patients. Treatment adjustments were based on 3monthly disease activity score (DAS) measurements, aiming at DAS 2.4. Functional ability (health assessment questionnaire, HAQ), radiographic progression (Sharp van der Heijde score, SHS) and (drug-free) remission (DAS < 1.6) percentages over 10 years were compared between the 4 arms in ACPA patients and between ACPA and ACPAþ patients per randomisation arm. At 3 months, ACPA patients achieved more often DAS 2.4 (52% versus 18%, p < 0.001), remission (17% vs 5%, p < 0.001) and improvement in functioning (mean HAQ 0.6 vs 1.0, p < 0.001) on initial combination therapy than on initial monotherapy. These differences remained until year 1. After 10 years of targeted therapy, over time no differences were retrieved. Drug survival (achieve and maintain DAS 2.4) on methotrexate monotherapy was similar in ACPA and ACPAþ patients (median survival 10 vs 7 months, p ¼ 0.750), as also drug survival on sulphasalazine (2nd step in arm 1 and 2, median survival 3 vs 3 months, p ¼ 0.659). At year 1, in arm 3 18/55
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ACPA (33%) and 31/68 ACPAþ patients (46%) tapered to monotherapy (p ¼ 0.310). In arm 4, 17/43 ACPA (40%) and 38/ 82 ACPAþ patients (46%) discontinued infliximab (p ¼ 0.466). Drug-free remission (DFR) was more often achieved and longer sustained in ACPA than in ACPAþ patients, in all treatment arms (26% vs 8% in arm 1, p ¼ 0.077; 24% vs 9% in arm 2, p ¼ 0.048; 30% vs 2% in arm 3, p ¼ 0.002; 28% vs 6% in arm 4, p < 0.001, median DFR duration averaged in 4 arms 69 vs 32 months, p ¼ 0.073). Over time, radiographic progression (D 0.5 in SHS) in ACPA patients was not different between the 4 arms (p ¼ 0.082). SHS progression was more often observed in ACPAþ patients than in ACPA patients in arm 1, 2 (both p < 0.001) and arm 3 (p ¼ 0.016), but not in arm 4 (p ¼ 0.849). On the short term, patients with ACPA RA benefit more from initial combination therapy with prednisone or infliximab than from monotherapy, as also ACPAþ patients. During subsequent DAS steered therapy, ACPA patients respond similarly to treatment steps in all 4 treatment arms to ACPAþ patients, suggesting that both groups require a similar treatment approach. After 10 years of targeted therapy, ACPA patients achieve more often sustained drug-free remission than ACPA positive patients and show less radiographic progression, except in arm 4. (ACR 2014 Abstract 2502)
2.
Systemic lupus erythematosus
2.1. Sifalimumab, an anti IFN-Alpha monoclonal antibody, reduces SLE disease activity across multiple clinical measures, and has an acceptable safety profile Efficacy and safety of sifalimumab were assessed in a Phase 2b, randomized, double-blind, placebo (PBO)-controlled study in subjects with SLE. Adults (n ¼ 431) with seropositive moderate to severe SLE, despite standard of care treatment, were randomized (1:1:1:1) to monthly IV sifalimumab 200, 600, 1200 mg, or PBO for 1 year. Minimum disease activity for entry: SLEDAI-2K 6 and 1 BILAG A or 2Bs and MDGA 1. Randomization was stratified by disease activity, IFN 4-gene signature, and geographic region. The primary efficacy endpoint was SLE Responder Index response at Day 365. Baseline characteristics were similar across all groups: (mean age 39.4 years; 92.3% female; 58.7% Caucasian, 15.1% Asian, 7.7% black). Subjects had a mean duration of SLE of 8.2 years; SLICC/ACR damage score 0.7; SLEDAI-2K, 11.3. 81.2% had a positive IFN gene signature. Low C3 was seen in 42.9%, low C4 in 26.7% and elevated dsDNA antibody in 26.5% of subjects at baseline. The percentage achieving SRI response at Day 365 were significantly higher for sifalimumab 200, 600, and 1200 mg (58.3%, 56.5%, 59.8%, respectively) vs PBO (45.4%; effect size 1200 mg vs PBO 14.4% points; p ¼ 0.031). Analyses of more stringent SRI endpoints demonstrated even greater discrimination between the 1200 mg dose and PBO. In subjects with moderate/severe baseline mucocutaneous involvement (CLASI 10), significantly higher percentages had a 4 point decrease in CLASI on sifalimumab 200 mg (72.7%) and 1200 mg (73.1%) vs PBO (48.6%). Significant improvements in the sifalimumab vs PBO arms were seen in joint counts and numerical improvements were seen in FACIT-Fatigue scores.
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Baseline low complement levels and elevated dsDNA levels did not normalize over time. A direct comparison of IFN gene signature positive and negative subjects was not possible due to the low proportion of IFN negative subjects but the trend was in favor of signature status driving response. There were six deaths during the study; four deaths in the total sifalimumab group and two deaths in the PBO group. Most commonly reported adverse events (AEs) were similar across groups including worsening SLE (sifalimumab 30.0% vs PBO 34.3%), urinary tract infection (17.6% vs 13.9%), and headache (13.3% vs 13.9%). Serious AEs were reported in 18.3% (sifalimumab) vs 17.6% (PBO) of subjects. Herpes zoster occurred more frequently in sifalimumab groups (200 mg, 4.6%; 600 mg, 3.7%; 1200 mg, 8.4%) vs PBO (0.9%). Thus, in this study, Sifalimumab reduced SLE disease activity across multiple clinical measures, and had an acceptable safety profile in both IFN signature positive and negative subjects. These data support IFN-alpha as a promising therapeutic target in SLE. (ACR 2014 Abstract L4)
3.
Psoriatic arthritis
3.1. Secukinumab, a human anti-interleukin-17a monoclonal antibody, improves active psoriatic arthritis Secukinumab, a human antieIL-17A monoclonal antibody, has shown efficacy in the treatment of psoriasis in phase 3 studies with subcutaneous (s.c.) dosing as well as in the treatment of psoriatic arthritis (PsA) with an intravenous loading and s.c. maintenance dose regimen. This paper presents data from FUTURE 2, the first double-blind, placebo (PBO)-controlled phase 3 study to evaluate secukinumab s.c. loading and maintenance dosing in subjects with PsA. 397 adults with active PsA classified according to CASPAR criteria were randomized to receive s.c. secukinumab (300, 150 or 75 mg) or PBO at baseline, Week (Wk) 1, 2, 3, 4 and the respective dose every 4 wks thereafter. Subjects were stratified according to prior anti-TNF therapy; 65% of subjects were TNF-naı¨ve and 35% were TNF-IR. The primary endpoint was ACR20 response at Wk 24. Secondary endpoints were PASI 75/ 90, DAS28-CRP, Short Form-36 Physical Component Summary (SF-36 PCS), Health Assessment Questionnaire-Disability Index (HAQ-DI), ACR50, dactylitis and enthesitis. At Wk 24, ACR20 responses were significantly greater with secukinumab than PBO: 54.0%, 51.0% and 29.3% vs. 15.3%, with secukinumab 300, 150 and 75 mg vs. PBO, respectively (P < 0.0001 for secukinumab 300 and 150 mg; P < 0.05 for 75 mg vs. PBO), with improvements observed by Wk 3 for secukinumab 300 and 150 mg. Improvements in ACR50/70 responses were observed with secukinumab 300 and 150 mg. Secukinumab 300 and 150 mg also improved PASI 75/90 scores, DAS28-CRP, SF-36 PCS, HAQ-DI, dactylitis and enthesitis vs. PBO. Efficacy was observed with secukinumab 300 and 150 mg in both TNFnaı¨ve and TNF-IR subgroups. Secukinumab 300 mg was associated with greater improvements than the lower doses in ACR responses, PASI 75/90 scores, SF-36 PCS, HAQ-DI, dactylitis and enthesitis in the TNF-IR group. The overall incidence of adverse events (AEs) up to Wk 16 was similar across secukinumab dose groups and placebo; 53.8% of subjects in the
pooled secukinumab group and 58.2% in the PBO group reported an AE; serious AEs were reported in 3.3% and 2.0% of subjects, respectively. Thus, Secukinumab 300 and 150 mg s.c. demonstrated rapid and clinically significant improvements in the signs and symptoms of active PsA. Improvements were demonstrated in TNF-IR and TNF-naı¨ve subjects, validating the efficacy of IL-17 inhibition in this disease across the range of prior treatment history. The safety profile of secukinumab was consistent with that previously reported in subjects with PsA and psoriasis. (ACR 2014 Abstract L1)
4.
Giant cell arteritis
4.1. High resolution MRI of scalp arteries detects GCA with high sensitivity Temporal artery biopsy (TAB) remains the gold standard for the diagnosis of giant cell arteritis (GCA). It is invasive and its sensitivity is limited by segmental arterial involvement. The authors of this study sought to determine the diagnostic accuracy of high-field MRI compared to TAB in patients with suspected GCA. All patients referred for TAB at their center were approached for this study. A high-resolution 3T MRI of the scalp arteries was obtained before the TAB was performed. Arterial abnormalities on MRI were assessed according to a previously published grading scheme, evaluating mural thickness and enhancement based on multiplanar postcontrast T1-weighted spin-echo images. Diagnostic accuracy of MRI was evaluated by comparison with TAB results as a primary analysis. Secondary analyses included comparison to clinician diagnosis and ACR criteria. 171 patients were included in the study. ACR criteria were met in 137 patients (80.1%). Physician diagnosis was available for 162 subjects, with 78 (48.2%) considered as GCA. The MRI showed abnormal scalp arteries in 60 patients (35.1%) while biopsy was positive in 31 (18.1%). MRI was positive in 29 of those 31 patients with positive TAB (Sensitivity 93.6%). MRI was normal in 109 of those 140 with negative TAB (Specificity 77.9%). Relative to TAB, the negative predictive value of MRI was 98.2%. Thus, high-resolution MRI detects biopsy-positive GCA with high sensitivity. A negative MRI is highly predictive of a negative TAB, such that patients with a negative MRI could safely be spared TAB. The significance of a positive MRI is not as well defined, and this should be the focus of future research. (ACR 2014 Abstract 883)
5.
Systemic sclerosis
5.1. Blockade of lysophosphatidic acid receptor 1 could be beneficial as a potential treatment for patients with systemic sclerosis Preclinical genetic and pharmacological studies suggest a role for Lysophosphatidic acid (LPA) involvement in three key processes of systemic sclerosis: fibrosis, microangiopathy and
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immunoinflammation. The authors of this study have assessed SAR100842, a potent selective orally available antagonist of LPA1 receptor and explored safety, skin biomarkers of disease activity and clinical efficacy in patients with diffuse cutaneous SSc (dcSSc) in a phase 2a clinical trial. This was an 8-week double-blind, randomized, placebocontrolled study followed by a 16 week open label extension study with SAR100842. 32 patients with dcSSc <36 months since the onset of the first non-Raynaud's SSc manifestation and an mRSS 15 were included. Patients with severe organ involvement that was deemed unsafe were excluded. Background stable immunosuppressant therapy was allowed. The primary endpoint was safety. Secondary end-points included effect on potential biomarkers from skin biopsies and blood samples as well as change in mRSS and S-HAQ at week 8 and 24 in the modified intent to treat (ITT) population defined as any patient with a post investigational product evaluation in each part of the study. 17 patients were randomized to the placebo group and 15 to the SAR100842 group. 30 patients participated in the extension study. The most frequent adverse events reported under SAR100842 during the blinded period were headache, diarrhea and nausea. No statistically significant difference between the 2 groups was observed in skin biopsy and blood biomarkers at week 8. However, a greater reduction of some skin LPAinduced marker mRNA levels (e.g. Wnt2, PAI1 and SFRP4) was observed in the SAR100842 group compared to placebo, consistent with successful target engagement. At week 8 an improvement in mRSS (median improvement ¼ 4.0 versus 1.0 units) and in HAQ-DI were observed in the SAR100842 group compared to placebo, respectively. The safety profile was good during the extension part. The most frequent adverse events in this part were headache, arthralgia, fatigue and nausea. After 24 weeks of treatment with SAR100842 key skin fibrotic biomarkers (COMP and TSP1) were reduced from baseline. LPA-induced biomarker mRNA levels were improved after 16 weeks of treatment with SAR100842 in the group of patients who initially received placebo. In parallel and of interest, there was a clinically meaningful improvement of clinical parameters. 78.5% of patients achieved MCID estimate of mRSS. (ACR 2014 Abstract 876)
6.
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Knee Injury and Osteoarthritis Outcome Score (KOOS), and the Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) with a Likert scale calculated from the KOOS. Patients are completing the questionnaires and being measured for BMI and % excess weight loss (%EWL) at intervals through 12 months post-op. In total, 175 patients met criteria and consented (89.7% female, mean BMI 43 kg/m2 ±7, range: 32e60, mean age 42 ±11, range: 18e73). X-rays were completed on 160 patients: KL0 ¼ 38, KL1 ¼ 31, KL2 ¼ 33, KL3 ¼ 33, KL4 ¼ 25. The mean preop KOOS scores were 46 (0 ¼ worst, 100 ¼ best) for both pain and ADLs, the mean WOMAC pain score was 11 (0 ¼ best, 20 ¼ worst), and the mean overall WOMAC index was 52 (0 ¼ best, 96 ¼ worst). Higher KL correlated with symptoms; mean KOOS pain was 54, 49 and 37 for KL0, KL1-2, and KL3-4 (p ¼ 0.0006 for KL 1e2 vs 3e4), with similar trends across other KOOS and WOMAC scores. Higher BMI also correlated with worse pre-op knee symptoms, as the quartiles with the lowest and highest BMIs (32e38 and 49e61) had mean KOOS pain scores of 48 and 43. Thus far, 117 patients have had surgery in this study (31 RYGB, 64 sleeve, 22 LAGB). Improvement in average KOOS and WOMAC scores over baseline has been observed at all intervals (46, 36, 31 and 7 responses at 1, 3, 6, 12 month visits), with more improvement farther after surgery. At 6 months post-op, mean KOOS scores improved 29 points for pain, with mean WOMAC pain and index improving by 6 and 22 points. The %EWL correlated with knee symptoms at each interval and for all follow ups combined, as the smallest and largest %EWL quartiles (4e29%, 54e92%) showed mean improvements of 18 and 31 points (p ¼ 0.03) in KOOS pain e mirrored across KOOS and WOMAC scores. RYGB and sleeve yielded higher %EWL than LAGB (44%, 43% vs. 37%) across all intervals, and greater improvement in mean KOOS and WOMAC scores (e.g. mean KOOS pain increased by 28, 29 and 8). Neither presence nor severity of KOA severity affected knee pain improvement from weight loss. These data suggest that bariatric surgery improves patients' KOA pain proportional to weight loss, with durability over time. RYGB and sleeve gastrectomy have more impact on knee symptoms than LAGB. While patients with worse KL grades report more baseline pain and disability, X-ray severity did not impact the response to weight loss. (ACR 2014 Abstract 2246)
Osteoarthritis 7.
6.1. Reduction of knee osteoarthritis symptoms occurs after bariatric surgery Obesity is a modifiable risk factor of knee osteoarthritis (KOA). This is a prospective study to evaluate painful KOA in the obese population, and track whether weight loss after bariatric surgery affects KOA-related pain and physical function. The authors screened consecutive patients (N ¼ 537) prior to laparoscopic adjustable gastric banding (LAGB), sleeve gastrectomy, or gastric bypass (RYGB). Patients age 21 with knee pain for 1 month and a visual analog scale pain score 30 mm were enrolled, excluding lupus, inflammatory arthritis, or psoriasis. Baseline pre-op assessments included X-rays for OA severity by KellgreneLawrence (KL) grade, the
Spondyloarthritis
7.1. Spondyloarthritis is associated with increased cardiovascular and cerebrovascular mortality OnSpA is a population-based study of spondyloarthritis (SpA) based on a provincial population of over 13 million. Patients with SpA are thought to be at increased risk of cardiovascular disease but it is unknown if they have excess vascular mortality. The authors of this work explored risk of vascular mortality and the contributing factors in AS. They performed a population-based, retrospective cohort study on incident SpA patients, age 15 or above, living in Ontario, Canada between April 1995 and March 2011. There were 21,878 SpA cases and 87,504 controls (matched for age,
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gender and socioeconomic status). The primary outcome was a composite event of cardiovascular or cerebrovascular deaths coded as the primary cause on death certificates. Crude and adjusted hazard ratios (HR) were calculated and adjustments were made for coronary and cerebrovascular disease (CAD, CVD), cancer, diabetes, dementia, inflammatory bowel disease, hypertension, chronic kidney disease (CKD) and peripheral vascular disease (PVD). In the SpA cohort 53% were male, with a mean age of 46 ± 16 years, and a follow-up of 169,307 patient-years. Followup for controls was 692,499 patient-years. Crude and adjusted HR (95% CI) for vascular deaths were 1.49 (1.26e1.77) and 1.36 (1.14e1.63) respectively, indicating a 36e49% higher risk of vascular mortality in AS. Crude HR (95%CI) in males and females were 1.63 (1.31e2.03) and 1.31 (1.00e1.71) respectively. Cases and controls had similar prevalence of CAD, CVD, PVD, dementia and diabetes, but IBD (6% vs 4%), hypertension (24% vs 18%) and CKD (2% vs 0.8%) were more common in SpA. The predictors of vascular death were age, male sex, low income, CKD and PVD apart from CAD and CVD. The KM curve showing an increase in vascular mortality in AS patients. This is the first population-based study to demonstrate SpA is associated with significant risk of vascular mortality. These new findings should prompt a comprehensive strategy to screen and treat modifiable vascular risk factors in SpA patients. (ACR 2014 Abstract 2829)
7.2. Increased mortality in ankylosing spondylitis e results from a national population based study Ankylosing spondylitis (AS) is characterized both by inflammation of the axial skeleton and systemic inflammation, and may also involve joints, entheses and other organs. For other rheumatic chronic inflammatory diseases, such as rheumatoid arthritis, an increase in mortality compared to the background population has consistently been shown, whereas for AS, information on survival is scarce. The aims of the present study were to: 1) determine mortality in AS vs the general population, overall and by gender, and 2) to investigate factors associated with death in the AS cohort. From the National Patient Register (NPR) the authors identified a nationwide cohort of patients who were diagnosed with AS at a rheumatology or internal medicine department at least once between Jan 2001 and Dec 2009. A general population comparator, matched on year of birth, gender at the first registered diagnosis year of the AS patient, was identified from the census register, with 5 matched controls per index-patient. Among the 8600 AS patients and the 40,460 controls, there were 496 and 1533 deaths, respectively (34% vs 31% due to cardiovascular disease e CVD). Mortality was increased in AS with an overall IRR of 1.71 (95% CI: 1.55e1.90), as well as for men (IRR ¼ 1.65, 95% CI: 1.47e1.86) and women (IRR ¼ 1.89, 95% CI: 1.55e2.29) in separate analyses. Male gender and higher age predicted death in the AS cohort. In addition, lower level of education and several comorbidities, both general (CVD, diabetes, pulmonary and malignant diseases) and ASrelated (previous small or large joint surgery) were associated with increased risk of death in age/-sex adjusted analyses.
Thus, mortality in this national, population-based AS cohort was increased both in men and women compared to matched controls from the general population. Both general and AS-related comorbidities predicted death suggesting that both traditional and AS-specific risk factors may affect survival. (ACR 2014 Abstract 1804)
7.3. Secukinumab provides rapid and significant improvement of signs and symptoms in patients with active AS, regardless of prior anti-TNF exposure A phase 2, proof-of-concept study indicated that secukinumab, an antieIL-17A monoclonal antibody, suppressed signs and symptoms of active ankylosing spondylitis (AS) by Week (Wk) 6. This paper presents Wk 16 and Wk 52 efficacy and safety data from MEASURE 1, a phase 3 study assessing secukinumab vs. placebo (PBO) in patients (pts) with AS. Pts with active AS fulfilling modified New York Criteria and BASDAI 4, despite current or previous therapy with NSAIDs, DMARDs and/or anti-TNF agents, were randomized to receive: i.v. secukinumab 10 mg/kg (Wk 0, 2, 4) followed by s.c. secukinumab 75 mg every 4 wks (10 IV / 75 SC), s.c. secukinumab 150 mg every 4 wks (10 IV / 150 SC), or PBO on same i.v. and s.c. schedules. PBO pts were re-randomized to secukinumab 75 mg or 150 mg s.c. based on ASAS20 response at Wk 16, with non-responders switched at Wk 16 and responders at Wk 24. The study met its primary efficacy endpoint with a significantly higher ASAS20 response at Wk 16 in the 10 IV / 75 SC (59.7%) and 10 IV / 150 SC (60.8%) groups vs. PBO (28.7%; P < 0.01 for each dose); ASAS20 response rates in TNF-naı¨ve pts were 60.0%, 66.3% and 32.6%, and in the TNF-IR pts were 58.8%, 45.5% and 18.2%, in the 10 IV / 75 SC, 10 IV / 150 SC and PBO groups, respectively (P < 0.01 vs. PBO). Significant improvements with both doses of secukinumab vs. PBO were observed for all pre-specified secondary endpoints at Wk 16, with responses sustained through Wk 52. Onset of action of secukinumab was rapid, with significant improvements in ASAS20, ASAS40, hsCRP, ASAS5/6 and BASDAI seen at Wk 1. Thus, the selective IL-17A inhibitor secukinumab provided rapid and significant improvement of signs and symptoms in pts with active AS, regardless of prior anti-TNF exposure. Improvements were observed from Wk 1 and sustained through 52 wks. Secukinumab was well tolerated through 52 wks with no unexpected safety findings. (ACR 2014 Abstract 819)
8.
Juvenile arthritis
8.1. Therapy with methotrexate and etanercept is better than methotrexate or sulphasalazine monotherapy in recent onset DMARD naı¨ve JIA The BeSt for Kids study compares 3 DMARD strategies in JIA patients, for time to inactive disease, time to flare after DMARD discontinuation, ACRpedi scores, functional ability, safety, and radiological damage. This study follow up will be 2 years. The authors have presented the 3 months clinical outcome of the initial treatments.
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Recent onset, DMARD naı¨ve JIA patients (RF-negative polyarticular, oligoarticular or with psoriasis (ILAR-criteria), <18 months symptom duration) were randomized to 3 treatment strategies: 1. sequential DMARD-monotherapy (starting with sulfasalazine (SSZ) 50 mg/kg/day or methotrexate (MTX) 10 mg/m2/week, based on physician's preference), 2. combination therapy: MTX 10 mg/m2/week and 4 weeks prednisolone-bridging 0.5 mg/kg/day, in 2 weeks tapered to nil, and 3. combination therapy with MTX 10 mg/ m2/week and etanercept 0.8 mg/kg/wk. MTX was combined with folic acid 5 mg/week. NSAIDs and intra-articular steroids were permitted in all patients. Treatment adjustments were made every 3 months after assessment by a trained examiner who remained unaware of allocated treatment group. Target was ACRpedi50 after 3 months and from 6 months of follow-up and onwards the treatment target was inactive disease. From October 2009 to April 2014, 95 children, of which 33% were boys, were enrolled: 32 in arm 1, 32 in arm 2 and 31 in arm 3. Baseline median (IQR) age was 9.1 (4.7e12.9) years. 38% were ANA positive, 12 patients had oligoarticular disease, 68 patients oligoextended/polyarticular JIA and 15 patients had JIA with psoriasis. Baseline median (IQR) ACRpedi scores: VAS physician 49 (40e58) mm, VAS patient 54 (37e70) mm, ESR 6.5 (2e14.8) mm/hr, number of active joints 8 (5e12), number of joints with limited range of motion 3 (1e5), CHAQ score 0.88 (0.63e1.5). In arm 1, 18/32 had started with MTX, the others with SSZ. One patient in arm 1 (lost to FU) and 1 in arm 3
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(uveitis) dropped out before 3 months. Complete visits were included for analysis. By 3 months ACRpedi30 was reached by 14/31 (45%), 15/31 (48%), 20/29 (69%) of patients in arms 1e3, respectively (p ¼ 0.14). ACRpedi50 was reached by 7/31 (23%), 12/31 (39%) and 15/29 (52%) (p ¼ 0.065, arm 1 vs 2 p ¼ 0.17, 2 vs 3 p ¼ 0.31, 1 vs 3 p ¼ 0.019) and ACRpedi70 was reached by 3/31 (10%), 5/31 (16%) and 10/29 (34%) in arms 1e3, respectively (p ¼ 0.045, arm 1 vs 2 p ¼ 0.45, 2 vs 3 p ¼ 0.10, 1 vs 3 p ¼ 0.020). Toxicity (mainly gastrointestinal complaints) was similar in the treatment arms. No serious adverse events were reported. In 2/32, 1/32 and 2/31 patients MTX dose was reduced or switched to subcutaneous and 3/18 patients stopped SSZ after 6 weeks because of nausea, malaise and headache. After 3 months of initial treatment in a three-armed strategy trial, patients with recent onset JIA achieve more clinical improvement (significantly more ACRpedi50 and 70) on initial combination therapy with MTX and etanercept than on initial MTX or SSZ monotherapy. Numerically, response to initial treatment with MTX and prednisolone bridging seems more effective than monotherapy and less effective than combination with etanercept, but these differences were not statistically significant. (ACR 2014 Abstract L2)
Conflicts of interest The author has none to declare.
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Rheumatology reviews Sukhbir Uppal Department of Medicine, University Hospital Sharjah, United Arab Emirates
1.
Rheumatoid arthritis
1.1. Women with RA have a two-fold increased risk of death compared to women without RA: 34 year follow up of 121,700 women RA has been associated with increased mortality compared to general population estimates. The authors of this paper evaluated mortality among women followed prospectively prior to RA diagnosis, directly comparing to women without RA. They conducted a study of RA and mortality among 121,700 women followed from 1976 to 2010 in the Nurses' Health Study (NHS). Models were adjusted for age, demographics and other mortality factors, including physical activity, smoking, obesity, comorbidities, and family history of cancer, CVD, and diabetes. The authors validated 960 incident RA cases and identified 25,699 deaths in 34 years of NHS follow-up. Of the 261 deaths among women with RA, 75 (29%) were from cancer, 58 (22%) were from CVD, and 43 (16%) were from respiratory causes. Compared to women without RA, women with RA had increased all-cause mortality that remained significant after adjusting for age and other mortality factors (HR 2.07, 95% CI 1.83e2.35). Mortality was significantly increased for seropositive (HR 2.33, 95% CI 2.00e2.71) and seronegative RA (HR 1.60, 95% CI 1.30e1.98) compared to non-RA women. Each five years of RA duration conferred a 32% (95% CI 27e36%) increased mortality compared to non-RA. Women with RA had significantly increased risk for mortality from CVD (HR 1.87, 95% CI 1.44e2.43), cancer (HR 1.35, 95% CI 1.07e1.69) and respiratory (HR 4.50, 95% CI 3.28e6.17) causes compared to women without RA. Respiratory mortality for women with seropositive RA was six-fold higher than non-RA women (HR 6.23, 95% CI 4.38e8.85). Thus, in 34 years of prospective follow-up, women diagnosed with RA have a two-fold increased risk of death from any cause compared to women without RA. Respiratory mortality is six-fold higher in seropositive RA and women with RA are significantly more likely to die from CVD and cancer than women without RA. Respiratory mortality appears to be an important but understudied cause of death in
RA. These findings provide evidence of high RA mortality burden that is unexplained by traditional mortality predictors. (ACR 2014 Abstract 818)
1.2. years
70% RA patients discontinue their first biologic in 3
Adherence and persistence to treatment is a cornerstone of treatment success in chronic diseases such as RA. The purpose of this study was to describe biologic treatment discontinuation and assess the predictors of discontinuation in RA patients followed at a Canadian clinic. In this prospective cohort study, adult patients included in the RHUMADATA computerized database with a diagnosis of RA and treated with at least one biologic agent since 2003 were selected. Patients were followed for three years after therapy initiation or until treatment discontinuation. Biologic therapies considered include abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab, and anakinra. A total of 623 eligible patients were treated with at least one biologic. The average time on treatment for the first biologic agent was 1.7 years. In all, 233 (37%), 326 (52%), 405 (65%), and 438 (70%) patients had stopped their first biologic treatment after 6, 12, 24, and 36 months, respectively. In time-to-event analyses, type of work [part time vs. full time; hazard ratio (HR): 1.57; 95% confidence interval (CI): 1.05e2.34] and income [$20,000 to $40,000 vs. less than $20,000 (HR: 1.35; 1.01e1.80) and $80,000 to $100,000 vs. less than $20,000 (HR: 2.16; 1.23e3.80)] were significantly associated with biologic discontinuation over the complete treatment duration. The number of DMARDs used (HR: 0.89; 0.80e0.99) and the use of methotrexate (yes vs. no; HR: 0.80; 0.64e0.99) were associated with a reduced risk of biologic discontinuation. Thus, in this real-life Canadian study, high biologic discontinuation rates were observed over three years. This study also suggests that many clinical and socioeconomic variables are predictors of biologic therapy discontinuation in RA patients. (ACR 2014 Abstract 499)
E-mail address: [email protected]. http://dx.doi.org/10.1016/j.injr.2015.01.005 0973-3698/Copyright © 2015, Indian Rheumatology Association. All rights reserved.
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1.3. Abatacept, Adalimumab, Etanercept and Infliximab have similar retention rates as first line agents in patients with rheumatoid arthritis who are methotrexate inadequate responders The order of use of biologic agents is still a question for debate. Phase III trial data in MTX-IR patients show comparable efficacy results across biologic agents. This study aimed to assess if patients with RA treated with abatacept after failure of a first line agent (MTX-IR) have a different drug survival rate than patients similarly treated with adalimumab, etanercept or infliximab. RA patients prescribed a first biologic agent after January 1st 2007 were included in the present analysis. We extracted a cohort formed of all patients prescribed abatacept (ABA), adalimumab (ADA), etanercept (ETA) or infliximab (INF) as their first biologic agent. A total 340 patients were included in the cohort. The 5 year retention rate of ABA, ADA, ETA and INF post MTX failure were 64%, 40%, 49% and 42% without significant statistical differences (Log-Rank p ¼ 0.29). Thus, abatacept, adalimumab, etanercept and infliximab after MTX failure have similar 5-years retention rates. (ACR 2014 Abstract 1536)
1.4. In RA patients having failed their first anti-TNF agent, Tocilizumab, an IL-6 inhibitor, has better retention rates than a second anti-TNF agent: comparison with Adalimumab, Etanercept and Infliximab Tocilizumab, as an intravenous agent, has been approved for RA in 2010. It has been demonstrated effective in the treatment of RA either in monotherapy or combo therapy after non-biologic or biologic DMARDS. This paper describes its effectiveness in patients with RA failing a first anti-TNF DMARD and to compare its retention rate versus adalimumab, etanercept and infliximab in the same clinical situation. All patients with RA having failed a first anti-TNF agent and subsequently exposed to tocilizumab after the 1st of January 2005 were extracted from the Rhumadata® database. 4 cohorts were created: One cohort of patients starting tocilizumab and 3 other cohorts starting either adalimumab, etanercept or infliximab. The data from 259 patients prescribed either tocilizumab (53 ¼ 20%), adalimumab (97 ¼ 37%), etanercept (82 ¼ 33%) or infliximab (27 ¼ 10%) as a second biologic agent were extracted from the Rhumadata® registry and clinical database. The four year retention rates of tocilizumab, adalimumab, etanercept and infliximab as second line biologic agents were 44.3%, 27.2%, 37.1% and 34.0% respectively. KaplaneMeier survival analysis revealed significant differences in the drug retention rates (logrank p ¼ 0.0249). Thus, in RA patient having failed their first anti-TNF agent, tocilizumab, an IL-6 inhibitor, could be a more valuable alternative than cycling to a second anti-TNF agent. (ACR 2014 Abstract 502)
1.5. Etanercept biosimilar (HD203) is as effective as etanercept (Enbrel®), in combination with methotrexate (MTX) in patients with RA Etanercept is a recombinant fusion protein that blocks TNF activity. HD203 is a biosimilar of etanercept. The aim of this
study was to evaluate the equivalence in efficacy and to compare the safety of HD203 (biosimilar etanercept) and a reference etanercept, in combination with MTX in patients with RA. Patients with active RA were randomly assigned (1:1) to 25 mg HD203 or reference etanercept, administered subcutaneously twice weekly with MTX for 48 weeks. In total, 294 patients were randomized: 147 to HD203 and 147 to reference etanercept. The proportion of patients achieving ACR20 at week 24 (primary endpoint) was not significantly different for HD203 and reference etanercept and equivalence in efficacy was demonstrated within predefined margins. In addition, there were no statistically significant differences between proportions achieving ACR20 at weeks 12 and 48. Similar trends were seen for ACR50 and ACR70, however the proportion of patients achieving ACR50 at week 24 and 48 was higher with HD203 than with reference etanercept. There were no statistically significant differences between the groups for ACRn, change in DAS28, and EULAR response at week 24 and 48. Analysis of the safety set (HD203, n ¼ 147; reference etanercept, n ¼ 146) revealed no statistically significant difference in the number of treatment-emergent (all-causality) adverse events (AEs): HD203 76.87% vs. reference etanercept 78.08% (p ¼ 0.8040). Furthermore, no statistically significant differences between HD203 and reference etanercept were observed with regards to adverse drug reactions, serious AEs, or discontinuations due to AEs. No unexpected AEs were observed, and few patients tested positive for anti-drug antibodies. Thus, the study met the primary endpoint of demonstrating equivalence in efficacy of HD203 compared with a reference etanercept. HD203 was well tolerated, with a safety profile comparable to that of the reference etanercept in this population of Korean patients with RA. (ACR 2014 Abstract 2825)
1.6. Reducing therapy in RA patients in remission is feasible in a subset of patients Due to improved therapeutic management a steadily increasing number of RA patients reach stable remission of disease. Data on withdrawal of medication after sustained remission are limited, though it is important for economic and safety reasons. The RETRO study represents a real-life study addressing different strategies of reduction of DMARD therapy in RA patients in disease remission. The aim of the study was to evaluate the possibility of tapering and even discontinuation of DMARD therapy in RA patients in stable long-lasting remission and to determine predictors for recurrence of disease. In this phase 3 trial, patients with RA of 12 months were enrolled into the study if they were in clinical remission (DAS28-ESR < 2.6) at stable dose of DMARDs for more than 6 months. Patients on 1 conventional and/or biological DMARDs were included and randomized into three trial arms: Arm 1 (control group) was continuing full-dose conventional and/or biological DMARD treatment for 12 months; arm 2 was reducing the dose of all conventional and/or biological DMARD treatment by 50% for 12 months and arm 3 was
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reducing the dose of all conventional and/or biological DMARD treatment by 50% for 6 months before entirely stopping DMARD. In case of recurrence of disease (DAS > 2.6) the original therapy was restarted. 101 patients finished the one year endpoint: 38 patients in arm 1, 36 patients in arm 2 and 27 patients in arm 3. Of 101 patients, 66.3% were still in remission at 12 mo. Trial arms 2 (38.9%, c2(1) ¼ 5.0, p ¼ 0.036) and 3 (51.9%, c2(1) ¼ 9.6, p ¼ 0.003) significantly differed from the control group (15.8% flare rate) with more patients flaring in reduction arms. However, there was no significant difference between the two reduction arms (c2(1) ¼ 1.1, p ¼ 0.443). A multivariate logistic regression identified ACPA positivity (Wald c2 ¼ 4.5, p ¼ 0.03) and treatment reduction compared to the control group (arm2: Wald c2 ¼ 6.6, p ¼ 0.01, arm3: Wald c2 ¼ 8.8, p ¼ 0.003) as predictors for subsequent flares. Sex, disease duration, remission duration, age, RF, biologic DMARD and remission depth failed to predict recurrence of disease in this study. Thus, this study is a prospective real life treatment strategy study investigating the effect of reduction and discontinuation of DMARD therapy in RA patients in stable remission. Interestingly neither remission depth, nor disease duration at baseline or biological DMARD therapy predicted the recurrence of disease. Presence of ACPA but not RF was the only predictor for recurrence of disease. The data indicate that treatment reduction and even discontinuation is feasible in a subset of RA patients in stable remission. (ACR 2014 Abstract 940)
1.7. ACPA negative patients respond similarly to treatment to ACPA positive patients and both groups require a similar treatment approach This study was conducted to determine the optimal treatment strategy in patients with ACPA negative () RA, as it has been suggested that these patients require a different treatment approach than ACPA positive (þ) patients. 184 ACPA patients were randomized to 1. sequential monotherapy, 2. step-up therapy, 3. initial combination with prednisone, 4. initial combination with infliximab, as were 300 ACPAþ patients. Treatment adjustments were based on 3monthly disease activity score (DAS) measurements, aiming at DAS 2.4. Functional ability (health assessment questionnaire, HAQ), radiographic progression (Sharp van der Heijde score, SHS) and (drug-free) remission (DAS < 1.6) percentages over 10 years were compared between the 4 arms in ACPA patients and between ACPA and ACPAþ patients per randomisation arm. At 3 months, ACPA patients achieved more often DAS 2.4 (52% versus 18%, p < 0.001), remission (17% vs 5%, p < 0.001) and improvement in functioning (mean HAQ 0.6 vs 1.0, p < 0.001) on initial combination therapy than on initial monotherapy. These differences remained until year 1. After 10 years of targeted therapy, over time no differences were retrieved. Drug survival (achieve and maintain DAS 2.4) on methotrexate monotherapy was similar in ACPA and ACPAþ patients (median survival 10 vs 7 months, p ¼ 0.750), as also drug survival on sulphasalazine (2nd step in arm 1 and 2, median survival 3 vs 3 months, p ¼ 0.659). At year 1, in arm 3 18/55
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ACPA (33%) and 31/68 ACPAþ patients (46%) tapered to monotherapy (p ¼ 0.310). In arm 4, 17/43 ACPA (40%) and 38/ 82 ACPAþ patients (46%) discontinued infliximab (p ¼ 0.466). Drug-free remission (DFR) was more often achieved and longer sustained in ACPA than in ACPAþ patients, in all treatment arms (26% vs 8% in arm 1, p ¼ 0.077; 24% vs 9% in arm 2, p ¼ 0.048; 30% vs 2% in arm 3, p ¼ 0.002; 28% vs 6% in arm 4, p < 0.001, median DFR duration averaged in 4 arms 69 vs 32 months, p ¼ 0.073). Over time, radiographic progression (D 0.5 in SHS) in ACPA patients was not different between the 4 arms (p ¼ 0.082). SHS progression was more often observed in ACPAþ patients than in ACPA patients in arm 1, 2 (both p < 0.001) and arm 3 (p ¼ 0.016), but not in arm 4 (p ¼ 0.849). On the short term, patients with ACPA RA benefit more from initial combination therapy with prednisone or infliximab than from monotherapy, as also ACPAþ patients. During subsequent DAS steered therapy, ACPA patients respond similarly to treatment steps in all 4 treatment arms to ACPAþ patients, suggesting that both groups require a similar treatment approach. After 10 years of targeted therapy, ACPA patients achieve more often sustained drug-free remission than ACPA positive patients and show less radiographic progression, except in arm 4. (ACR 2014 Abstract 2502)
2.
Systemic lupus erythematosus
2.1. Sifalimumab, an anti IFN-Alpha monoclonal antibody, reduces SLE disease activity across multiple clinical measures, and has an acceptable safety profile Efficacy and safety of sifalimumab were assessed in a Phase 2b, randomized, double-blind, placebo (PBO)-controlled study in subjects with SLE. Adults (n ¼ 431) with seropositive moderate to severe SLE, despite standard of care treatment, were randomized (1:1:1:1) to monthly IV sifalimumab 200, 600, 1200 mg, or PBO for 1 year. Minimum disease activity for entry: SLEDAI-2K 6 and 1 BILAG A or 2Bs and MDGA 1. Randomization was stratified by disease activity, IFN 4-gene signature, and geographic region. The primary efficacy endpoint was SLE Responder Index response at Day 365. Baseline characteristics were similar across all groups: (mean age 39.4 years; 92.3% female; 58.7% Caucasian, 15.1% Asian, 7.7% black). Subjects had a mean duration of SLE of 8.2 years; SLICC/ACR damage score 0.7; SLEDAI-2K, 11.3. 81.2% had a positive IFN gene signature. Low C3 was seen in 42.9%, low C4 in 26.7% and elevated dsDNA antibody in 26.5% of subjects at baseline. The percentage achieving SRI response at Day 365 were significantly higher for sifalimumab 200, 600, and 1200 mg (58.3%, 56.5%, 59.8%, respectively) vs PBO (45.4%; effect size 1200 mg vs PBO 14.4% points; p ¼ 0.031). Analyses of more stringent SRI endpoints demonstrated even greater discrimination between the 1200 mg dose and PBO. In subjects with moderate/severe baseline mucocutaneous involvement (CLASI 10), significantly higher percentages had a 4 point decrease in CLASI on sifalimumab 200 mg (72.7%) and 1200 mg (73.1%) vs PBO (48.6%). Significant improvements in the sifalimumab vs PBO arms were seen in joint counts and numerical improvements were seen in FACIT-Fatigue scores.
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Baseline low complement levels and elevated dsDNA levels did not normalize over time. A direct comparison of IFN gene signature positive and negative subjects was not possible due to the low proportion of IFN negative subjects but the trend was in favor of signature status driving response. There were six deaths during the study; four deaths in the total sifalimumab group and two deaths in the PBO group. Most commonly reported adverse events (AEs) were similar across groups including worsening SLE (sifalimumab 30.0% vs PBO 34.3%), urinary tract infection (17.6% vs 13.9%), and headache (13.3% vs 13.9%). Serious AEs were reported in 18.3% (sifalimumab) vs 17.6% (PBO) of subjects. Herpes zoster occurred more frequently in sifalimumab groups (200 mg, 4.6%; 600 mg, 3.7%; 1200 mg, 8.4%) vs PBO (0.9%). Thus, in this study, Sifalimumab reduced SLE disease activity across multiple clinical measures, and had an acceptable safety profile in both IFN signature positive and negative subjects. These data support IFN-alpha as a promising therapeutic target in SLE. (ACR 2014 Abstract L4)
3.
Psoriatic arthritis
3.1. Secukinumab, a human anti-interleukin-17a monoclonal antibody, improves active psoriatic arthritis Secukinumab, a human antieIL-17A monoclonal antibody, has shown efficacy in the treatment of psoriasis in phase 3 studies with subcutaneous (s.c.) dosing as well as in the treatment of psoriatic arthritis (PsA) with an intravenous loading and s.c. maintenance dose regimen. This paper presents data from FUTURE 2, the first double-blind, placebo (PBO)-controlled phase 3 study to evaluate secukinumab s.c. loading and maintenance dosing in subjects with PsA. 397 adults with active PsA classified according to CASPAR criteria were randomized to receive s.c. secukinumab (300, 150 or 75 mg) or PBO at baseline, Week (Wk) 1, 2, 3, 4 and the respective dose every 4 wks thereafter. Subjects were stratified according to prior anti-TNF therapy; 65% of subjects were TNF-naı¨ve and 35% were TNF-IR. The primary endpoint was ACR20 response at Wk 24. Secondary endpoints were PASI 75/ 90, DAS28-CRP, Short Form-36 Physical Component Summary (SF-36 PCS), Health Assessment Questionnaire-Disability Index (HAQ-DI), ACR50, dactylitis and enthesitis. At Wk 24, ACR20 responses were significantly greater with secukinumab than PBO: 54.0%, 51.0% and 29.3% vs. 15.3%, with secukinumab 300, 150 and 75 mg vs. PBO, respectively (P < 0.0001 for secukinumab 300 and 150 mg; P < 0.05 for 75 mg vs. PBO), with improvements observed by Wk 3 for secukinumab 300 and 150 mg. Improvements in ACR50/70 responses were observed with secukinumab 300 and 150 mg. Secukinumab 300 and 150 mg also improved PASI 75/90 scores, DAS28-CRP, SF-36 PCS, HAQ-DI, dactylitis and enthesitis vs. PBO. Efficacy was observed with secukinumab 300 and 150 mg in both TNFnaı¨ve and TNF-IR subgroups. Secukinumab 300 mg was associated with greater improvements than the lower doses in ACR responses, PASI 75/90 scores, SF-36 PCS, HAQ-DI, dactylitis and enthesitis in the TNF-IR group. The overall incidence of adverse events (AEs) up to Wk 16 was similar across secukinumab dose groups and placebo; 53.8% of subjects in the
pooled secukinumab group and 58.2% in the PBO group reported an AE; serious AEs were reported in 3.3% and 2.0% of subjects, respectively. Thus, Secukinumab 300 and 150 mg s.c. demonstrated rapid and clinically significant improvements in the signs and symptoms of active PsA. Improvements were demonstrated in TNF-IR and TNF-naı¨ve subjects, validating the efficacy of IL-17 inhibition in this disease across the range of prior treatment history. The safety profile of secukinumab was consistent with that previously reported in subjects with PsA and psoriasis. (ACR 2014 Abstract L1)
4.
Giant cell arteritis
4.1. High resolution MRI of scalp arteries detects GCA with high sensitivity Temporal artery biopsy (TAB) remains the gold standard for the diagnosis of giant cell arteritis (GCA). It is invasive and its sensitivity is limited by segmental arterial involvement. The authors of this study sought to determine the diagnostic accuracy of high-field MRI compared to TAB in patients with suspected GCA. All patients referred for TAB at their center were approached for this study. A high-resolution 3T MRI of the scalp arteries was obtained before the TAB was performed. Arterial abnormalities on MRI were assessed according to a previously published grading scheme, evaluating mural thickness and enhancement based on multiplanar postcontrast T1-weighted spin-echo images. Diagnostic accuracy of MRI was evaluated by comparison with TAB results as a primary analysis. Secondary analyses included comparison to clinician diagnosis and ACR criteria. 171 patients were included in the study. ACR criteria were met in 137 patients (80.1%). Physician diagnosis was available for 162 subjects, with 78 (48.2%) considered as GCA. The MRI showed abnormal scalp arteries in 60 patients (35.1%) while biopsy was positive in 31 (18.1%). MRI was positive in 29 of those 31 patients with positive TAB (Sensitivity 93.6%). MRI was normal in 109 of those 140 with negative TAB (Specificity 77.9%). Relative to TAB, the negative predictive value of MRI was 98.2%. Thus, high-resolution MRI detects biopsy-positive GCA with high sensitivity. A negative MRI is highly predictive of a negative TAB, such that patients with a negative MRI could safely be spared TAB. The significance of a positive MRI is not as well defined, and this should be the focus of future research. (ACR 2014 Abstract 883)
5.
Systemic sclerosis
5.1. Blockade of lysophosphatidic acid receptor 1 could be beneficial as a potential treatment for patients with systemic sclerosis Preclinical genetic and pharmacological studies suggest a role for Lysophosphatidic acid (LPA) involvement in three key processes of systemic sclerosis: fibrosis, microangiopathy and
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immunoinflammation. The authors of this study have assessed SAR100842, a potent selective orally available antagonist of LPA1 receptor and explored safety, skin biomarkers of disease activity and clinical efficacy in patients with diffuse cutaneous SSc (dcSSc) in a phase 2a clinical trial. This was an 8-week double-blind, randomized, placebocontrolled study followed by a 16 week open label extension study with SAR100842. 32 patients with dcSSc <36 months since the onset of the first non-Raynaud's SSc manifestation and an mRSS 15 were included. Patients with severe organ involvement that was deemed unsafe were excluded. Background stable immunosuppressant therapy was allowed. The primary endpoint was safety. Secondary end-points included effect on potential biomarkers from skin biopsies and blood samples as well as change in mRSS and S-HAQ at week 8 and 24 in the modified intent to treat (ITT) population defined as any patient with a post investigational product evaluation in each part of the study. 17 patients were randomized to the placebo group and 15 to the SAR100842 group. 30 patients participated in the extension study. The most frequent adverse events reported under SAR100842 during the blinded period were headache, diarrhea and nausea. No statistically significant difference between the 2 groups was observed in skin biopsy and blood biomarkers at week 8. However, a greater reduction of some skin LPAinduced marker mRNA levels (e.g. Wnt2, PAI1 and SFRP4) was observed in the SAR100842 group compared to placebo, consistent with successful target engagement. At week 8 an improvement in mRSS (median improvement ¼ 4.0 versus 1.0 units) and in HAQ-DI were observed in the SAR100842 group compared to placebo, respectively. The safety profile was good during the extension part. The most frequent adverse events in this part were headache, arthralgia, fatigue and nausea. After 24 weeks of treatment with SAR100842 key skin fibrotic biomarkers (COMP and TSP1) were reduced from baseline. LPA-induced biomarker mRNA levels were improved after 16 weeks of treatment with SAR100842 in the group of patients who initially received placebo. In parallel and of interest, there was a clinically meaningful improvement of clinical parameters. 78.5% of patients achieved MCID estimate of mRSS. (ACR 2014 Abstract 876)
6.
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Knee Injury and Osteoarthritis Outcome Score (KOOS), and the Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) with a Likert scale calculated from the KOOS. Patients are completing the questionnaires and being measured for BMI and % excess weight loss (%EWL) at intervals through 12 months post-op. In total, 175 patients met criteria and consented (89.7% female, mean BMI 43 kg/m2 ±7, range: 32e60, mean age 42 ±11, range: 18e73). X-rays were completed on 160 patients: KL0 ¼ 38, KL1 ¼ 31, KL2 ¼ 33, KL3 ¼ 33, KL4 ¼ 25. The mean preop KOOS scores were 46 (0 ¼ worst, 100 ¼ best) for both pain and ADLs, the mean WOMAC pain score was 11 (0 ¼ best, 20 ¼ worst), and the mean overall WOMAC index was 52 (0 ¼ best, 96 ¼ worst). Higher KL correlated with symptoms; mean KOOS pain was 54, 49 and 37 for KL0, KL1-2, and KL3-4 (p ¼ 0.0006 for KL 1e2 vs 3e4), with similar trends across other KOOS and WOMAC scores. Higher BMI also correlated with worse pre-op knee symptoms, as the quartiles with the lowest and highest BMIs (32e38 and 49e61) had mean KOOS pain scores of 48 and 43. Thus far, 117 patients have had surgery in this study (31 RYGB, 64 sleeve, 22 LAGB). Improvement in average KOOS and WOMAC scores over baseline has been observed at all intervals (46, 36, 31 and 7 responses at 1, 3, 6, 12 month visits), with more improvement farther after surgery. At 6 months post-op, mean KOOS scores improved 29 points for pain, with mean WOMAC pain and index improving by 6 and 22 points. The %EWL correlated with knee symptoms at each interval and for all follow ups combined, as the smallest and largest %EWL quartiles (4e29%, 54e92%) showed mean improvements of 18 and 31 points (p ¼ 0.03) in KOOS pain e mirrored across KOOS and WOMAC scores. RYGB and sleeve yielded higher %EWL than LAGB (44%, 43% vs. 37%) across all intervals, and greater improvement in mean KOOS and WOMAC scores (e.g. mean KOOS pain increased by 28, 29 and 8). Neither presence nor severity of KOA severity affected knee pain improvement from weight loss. These data suggest that bariatric surgery improves patients' KOA pain proportional to weight loss, with durability over time. RYGB and sleeve gastrectomy have more impact on knee symptoms than LAGB. While patients with worse KL grades report more baseline pain and disability, X-ray severity did not impact the response to weight loss. (ACR 2014 Abstract 2246)
Osteoarthritis 7.
6.1. Reduction of knee osteoarthritis symptoms occurs after bariatric surgery Obesity is a modifiable risk factor of knee osteoarthritis (KOA). This is a prospective study to evaluate painful KOA in the obese population, and track whether weight loss after bariatric surgery affects KOA-related pain and physical function. The authors screened consecutive patients (N ¼ 537) prior to laparoscopic adjustable gastric banding (LAGB), sleeve gastrectomy, or gastric bypass (RYGB). Patients age 21 with knee pain for 1 month and a visual analog scale pain score 30 mm were enrolled, excluding lupus, inflammatory arthritis, or psoriasis. Baseline pre-op assessments included X-rays for OA severity by KellgreneLawrence (KL) grade, the
Spondyloarthritis
7.1. Spondyloarthritis is associated with increased cardiovascular and cerebrovascular mortality OnSpA is a population-based study of spondyloarthritis (SpA) based on a provincial population of over 13 million. Patients with SpA are thought to be at increased risk of cardiovascular disease but it is unknown if they have excess vascular mortality. The authors of this work explored risk of vascular mortality and the contributing factors in AS. They performed a population-based, retrospective cohort study on incident SpA patients, age 15 or above, living in Ontario, Canada between April 1995 and March 2011. There were 21,878 SpA cases and 87,504 controls (matched for age,
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gender and socioeconomic status). The primary outcome was a composite event of cardiovascular or cerebrovascular deaths coded as the primary cause on death certificates. Crude and adjusted hazard ratios (HR) were calculated and adjustments were made for coronary and cerebrovascular disease (CAD, CVD), cancer, diabetes, dementia, inflammatory bowel disease, hypertension, chronic kidney disease (CKD) and peripheral vascular disease (PVD). In the SpA cohort 53% were male, with a mean age of 46 ± 16 years, and a follow-up of 169,307 patient-years. Followup for controls was 692,499 patient-years. Crude and adjusted HR (95% CI) for vascular deaths were 1.49 (1.26e1.77) and 1.36 (1.14e1.63) respectively, indicating a 36e49% higher risk of vascular mortality in AS. Crude HR (95%CI) in males and females were 1.63 (1.31e2.03) and 1.31 (1.00e1.71) respectively. Cases and controls had similar prevalence of CAD, CVD, PVD, dementia and diabetes, but IBD (6% vs 4%), hypertension (24% vs 18%) and CKD (2% vs 0.8%) were more common in SpA. The predictors of vascular death were age, male sex, low income, CKD and PVD apart from CAD and CVD. The KM curve showing an increase in vascular mortality in AS patients. This is the first population-based study to demonstrate SpA is associated with significant risk of vascular mortality. These new findings should prompt a comprehensive strategy to screen and treat modifiable vascular risk factors in SpA patients. (ACR 2014 Abstract 2829)
7.2. Increased mortality in ankylosing spondylitis e results from a national population based study Ankylosing spondylitis (AS) is characterized both by inflammation of the axial skeleton and systemic inflammation, and may also involve joints, entheses and other organs. For other rheumatic chronic inflammatory diseases, such as rheumatoid arthritis, an increase in mortality compared to the background population has consistently been shown, whereas for AS, information on survival is scarce. The aims of the present study were to: 1) determine mortality in AS vs the general population, overall and by gender, and 2) to investigate factors associated with death in the AS cohort. From the National Patient Register (NPR) the authors identified a nationwide cohort of patients who were diagnosed with AS at a rheumatology or internal medicine department at least once between Jan 2001 and Dec 2009. A general population comparator, matched on year of birth, gender at the first registered diagnosis year of the AS patient, was identified from the census register, with 5 matched controls per index-patient. Among the 8600 AS patients and the 40,460 controls, there were 496 and 1533 deaths, respectively (34% vs 31% due to cardiovascular disease e CVD). Mortality was increased in AS with an overall IRR of 1.71 (95% CI: 1.55e1.90), as well as for men (IRR ¼ 1.65, 95% CI: 1.47e1.86) and women (IRR ¼ 1.89, 95% CI: 1.55e2.29) in separate analyses. Male gender and higher age predicted death in the AS cohort. In addition, lower level of education and several comorbidities, both general (CVD, diabetes, pulmonary and malignant diseases) and ASrelated (previous small or large joint surgery) were associated with increased risk of death in age/-sex adjusted analyses.
Thus, mortality in this national, population-based AS cohort was increased both in men and women compared to matched controls from the general population. Both general and AS-related comorbidities predicted death suggesting that both traditional and AS-specific risk factors may affect survival. (ACR 2014 Abstract 1804)
7.3. Secukinumab provides rapid and significant improvement of signs and symptoms in patients with active AS, regardless of prior anti-TNF exposure A phase 2, proof-of-concept study indicated that secukinumab, an antieIL-17A monoclonal antibody, suppressed signs and symptoms of active ankylosing spondylitis (AS) by Week (Wk) 6. This paper presents Wk 16 and Wk 52 efficacy and safety data from MEASURE 1, a phase 3 study assessing secukinumab vs. placebo (PBO) in patients (pts) with AS. Pts with active AS fulfilling modified New York Criteria and BASDAI 4, despite current or previous therapy with NSAIDs, DMARDs and/or anti-TNF agents, were randomized to receive: i.v. secukinumab 10 mg/kg (Wk 0, 2, 4) followed by s.c. secukinumab 75 mg every 4 wks (10 IV / 75 SC), s.c. secukinumab 150 mg every 4 wks (10 IV / 150 SC), or PBO on same i.v. and s.c. schedules. PBO pts were re-randomized to secukinumab 75 mg or 150 mg s.c. based on ASAS20 response at Wk 16, with non-responders switched at Wk 16 and responders at Wk 24. The study met its primary efficacy endpoint with a significantly higher ASAS20 response at Wk 16 in the 10 IV / 75 SC (59.7%) and 10 IV / 150 SC (60.8%) groups vs. PBO (28.7%; P < 0.01 for each dose); ASAS20 response rates in TNF-naı¨ve pts were 60.0%, 66.3% and 32.6%, and in the TNF-IR pts were 58.8%, 45.5% and 18.2%, in the 10 IV / 75 SC, 10 IV / 150 SC and PBO groups, respectively (P < 0.01 vs. PBO). Significant improvements with both doses of secukinumab vs. PBO were observed for all pre-specified secondary endpoints at Wk 16, with responses sustained through Wk 52. Onset of action of secukinumab was rapid, with significant improvements in ASAS20, ASAS40, hsCRP, ASAS5/6 and BASDAI seen at Wk 1. Thus, the selective IL-17A inhibitor secukinumab provided rapid and significant improvement of signs and symptoms in pts with active AS, regardless of prior anti-TNF exposure. Improvements were observed from Wk 1 and sustained through 52 wks. Secukinumab was well tolerated through 52 wks with no unexpected safety findings. (ACR 2014 Abstract 819)
8.
Juvenile arthritis
8.1. Therapy with methotrexate and etanercept is better than methotrexate or sulphasalazine monotherapy in recent onset DMARD naı¨ve JIA The BeSt for Kids study compares 3 DMARD strategies in JIA patients, for time to inactive disease, time to flare after DMARD discontinuation, ACRpedi scores, functional ability, safety, and radiological damage. This study follow up will be 2 years. The authors have presented the 3 months clinical outcome of the initial treatments.
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Recent onset, DMARD naı¨ve JIA patients (RF-negative polyarticular, oligoarticular or with psoriasis (ILAR-criteria), <18 months symptom duration) were randomized to 3 treatment strategies: 1. sequential DMARD-monotherapy (starting with sulfasalazine (SSZ) 50 mg/kg/day or methotrexate (MTX) 10 mg/m2/week, based on physician's preference), 2. combination therapy: MTX 10 mg/m2/week and 4 weeks prednisolone-bridging 0.5 mg/kg/day, in 2 weeks tapered to nil, and 3. combination therapy with MTX 10 mg/ m2/week and etanercept 0.8 mg/kg/wk. MTX was combined with folic acid 5 mg/week. NSAIDs and intra-articular steroids were permitted in all patients. Treatment adjustments were made every 3 months after assessment by a trained examiner who remained unaware of allocated treatment group. Target was ACRpedi50 after 3 months and from 6 months of follow-up and onwards the treatment target was inactive disease. From October 2009 to April 2014, 95 children, of which 33% were boys, were enrolled: 32 in arm 1, 32 in arm 2 and 31 in arm 3. Baseline median (IQR) age was 9.1 (4.7e12.9) years. 38% were ANA positive, 12 patients had oligoarticular disease, 68 patients oligoextended/polyarticular JIA and 15 patients had JIA with psoriasis. Baseline median (IQR) ACRpedi scores: VAS physician 49 (40e58) mm, VAS patient 54 (37e70) mm, ESR 6.5 (2e14.8) mm/hr, number of active joints 8 (5e12), number of joints with limited range of motion 3 (1e5), CHAQ score 0.88 (0.63e1.5). In arm 1, 18/32 had started with MTX, the others with SSZ. One patient in arm 1 (lost to FU) and 1 in arm 3
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(uveitis) dropped out before 3 months. Complete visits were included for analysis. By 3 months ACRpedi30 was reached by 14/31 (45%), 15/31 (48%), 20/29 (69%) of patients in arms 1e3, respectively (p ¼ 0.14). ACRpedi50 was reached by 7/31 (23%), 12/31 (39%) and 15/29 (52%) (p ¼ 0.065, arm 1 vs 2 p ¼ 0.17, 2 vs 3 p ¼ 0.31, 1 vs 3 p ¼ 0.019) and ACRpedi70 was reached by 3/31 (10%), 5/31 (16%) and 10/29 (34%) in arms 1e3, respectively (p ¼ 0.045, arm 1 vs 2 p ¼ 0.45, 2 vs 3 p ¼ 0.10, 1 vs 3 p ¼ 0.020). Toxicity (mainly gastrointestinal complaints) was similar in the treatment arms. No serious adverse events were reported. In 2/32, 1/32 and 2/31 patients MTX dose was reduced or switched to subcutaneous and 3/18 patients stopped SSZ after 6 weeks because of nausea, malaise and headache. After 3 months of initial treatment in a three-armed strategy trial, patients with recent onset JIA achieve more clinical improvement (significantly more ACRpedi50 and 70) on initial combination therapy with MTX and etanercept than on initial MTX or SSZ monotherapy. Numerically, response to initial treatment with MTX and prednisolone bridging seems more effective than monotherapy and less effective than combination with etanercept, but these differences were not statistically significant. (ACR 2014 Abstract L2)
Conflicts of interest The author has none to declare.
Please cite this article in press as: Uppal S, Rheumatology reviews, Indian Journal of Rheumatology (2015), http://dx.doi.org/ 10.1016/j.injr.2015.01.005