Background Two-year results from the 3-part, 5-year, phase 3 TENDER study demonstrated that tocilizumab (TCZ), an anti–interleukin-6 receptor antibody, was effective in the treatment of patients with severe, persistent systemic juvenile idiopathic arthritis (sJIA).1 Objectives To report the long-term safety and efficacy of TCZ in patients with sJIA treated for up to 5 years in the TENDER trial. Methods In part 1, patients (2-17 years) with active sJIA for ≥6 months were randomly assigned 2:1 to receive TCZ (body weight [BW] ≥30 kg, TCZ 8 mg/kg; BW <30 kg, TCZ 12 mg/kg) or placebo every 2 weeks (q2w) for 12 weeks. Patients received open-label TCZ q2w based on BW in part 2 (weeks 12-104) and part 3 (weeks 104-260). In part 3, an alternative dosing regimen in which TCZ and concomitant medications were tapered and discontinued in patients with clinically inactive disease (CID) was optional. Efficacy was assessed in those who entered part 3 (ITT3 population) and up to the point of entry into the alternative dosing schedule; safety was assessed in all patients who entered part 1 (safety population). The primary end point in part 3 was long-term safety. Results Of the 112 patients enrolled in part 1, 89 entered part 3 and were included in the ITT3 population; 66 patients (59%) completed the full 260-week study. Patients in the ITT3 population had a mean (SD) age of 9.5 (4.4) years, and 53% were male. The high proportion of patients achieving JIA ACR 30/50/70/90 responses on entry into part 3 was maintained through week 260 (Table 1). Among the 30 patients who did not enter the alternative dosing regimen and completed the study, 8 (26.7%) met the criteria for CID at week 260. During the study, an additional 39 patients reached and maintained CID for at least 3 months and entered the alternative dosing regimen. Of patients remaining in the study at week 260, 31 received oral glucocorticoids (GCs) and 34 received methotrexate (MTX) at baseline. By the end of the study, 17/31 and 6/34 patients stopped oral GCs and MTX, respectively. The 5-year safety profile for patients on q2w dosing was similar to the 2-year safety profile, with no new safety findings observed (Table 2). Rates/100 patient-years (PY) of adverse events (AEs) and of serious AEs (SAEs) did not increase between year 2 and year 5 (Table 2). Most SAEs were unrelated to study treatment, and infections accounted for nearly half of all SAEs. Four deaths occurred over the 5 years at a rate of 1.1/100 PY; 1 death (sepsis) was possibly related to study treatment. Conclusions These results demonstrate the continued maintenance of efficacy and no change in the safety profile over 5 years of TCZ treatment in patients with sJIA. References De Benedetti F et al. Ann Rheum Dis. 2012;71(suppl 3):425. Disclosure of Interest F. De Benedetti Grant/research support from: Roche, Novartis, Pfizer, Novimmune, Sobi, Consultant for: Roche, Novartis, N. Ruperto Grant/research support from: Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Novartis, Pfizer Inc, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Consultant for: Roche, Speakers bureau: Abbott, AbbVie, Amgen, Astellas, Bristol Myers-Squibb, Boehringer, Celgene, CrescendoBio, EMDSerono, Italfarmaco, Janssen, Medimmune, Novartis, Novonordisk, Pfizer, Sanofi, Reumatic.com, Servier, Sinergie, Takeda, H. Brunner: None declared, C. Keane Employee of: Roche, C. Wells Employee of: Roche, J. Wang Employee of: Roche, I. Calvo: None declared, R. Cuttica: None declared, A. Ravelli Grant/research support from: Pfizer, Consultant for: Novartis, Roche, AbbVie, Bristol-Myers Squibb, Johnson & Johnson, Pfizer, R. Schneider Consultant for: Roche, Novartis, D. Eleftheriou: None declared, C. Wouters: None declared, R. Xavier Consultant for: Roche, Janssen, Pfizer, AstraZeneca, AbbVie, L. Zemel: None declared, E. Baildam Grant/research support from: Roche, Chugai, Speakers bureau: Roche, R. Burgos-Vargas: None declared, P. Dolezalova Grant/research support from: Novartis, Consultant for: Roche, Novartis, Pfizer, S. Garay: None declared, R. Joos: None declared, A. Grom Consultant for: Novartis, Genentech, N. Wulffraat Grant/research support from: European Union (EAHC), Z. Zuber: None declared, F. Zulian: None declared, A. Martini Grant/research support from: Roche, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences GmbH, Consultant for: Roche, Speakers bureau: Roche, Abbott, AbbVie, Amgen, Astellas, Bristol-Myers Squibb, Boehringer, Celgene, CrescendoBio, EMDSerono, Italfarmaco, Janssen, Medimmune, Novartis, Novo Nordisk, Pfizer, Sanofi, Servier, Takeda, D. Lovell Grant/research support from: NIH, Consultant for: AstraZeneca, Bristol-Myers Squibb, AbbVie, Pfizer, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson & Johnson, Biogen, Takeda, Genentech, GlaxoSmithKline, Boehringer Ingelheim, Celgene, Janssen, Speakers bureau: Genentech, Roche, Novartis

JIA ACR30 (62%), JIA ACR50 (59%), JIA ACR70 (54%) and JIA ACR90 (35%) response than ADA monotherapy (53%, 49%, 44% and 26%, respectively). On MTX background therapy and a JIA ACR30 placebo response of 53%, ADA had a higher expected probability of response at JIA ACR30 (76%), JIA ACR50 (75%), JIA ACR70 (66%) and JIA ACR90 (49%) than TCZ (72%, 70%, 61% and 44%, respectively). In neither monotherapy nor combination therapy did differences between TCZ and ADA reach statistical significance. Differences in the study populations, including previous use of biologics, were explored with sensitivity analysis. Conclusion Based on JIA ACR response rates from this analysis, the expected efficacy of ADA vs TCZ appears comparable in pcJIA. These data should be interpreted in the context of differences in the duration of the withdrawal phase, which was shorter in the TCZ study (CHERISH) than in the ADA trial and might have resulted in a smaller difference in the number of flares observed between placebo and TCZ. Differences in previous exposure to biologics might also have affected the results.

Background To date there are no head-to-head trials comparing the efficacy of biologic treatments for polyarticular-course JIA (pcJIA). Objectives To use statistical methods to estimate the relative efficacy of biologic treatments, alone and in combination with methotrexate (MTX), in the management of pcJIA by means of indirect comparison of randomised controlled trials (RCTs). Methods Based on a literature review, we identified RCTs of abatacept,1adalimumab2(ADA), etanercept,3infliximab4and tocilizumab5 (TCZ; CHERISH) in pcJIA. Comparative effectiveness was estimated on the reported American College of Rheumatology response rates (JIA ACR30/50/70/90) measured at the end of the randomised, double-blind phase by means of a Bayesian indirect comparison using a fixed-effects ordered probit model. Probabilities of achieving different levels of JIA ACR response were calculated for biologic treatments and placebo using all observed comparisons. Results The 5 RCTs identified showed differences in reporting JIA ACR responses with regard to methods of non-responder imputation during the blinded, controlled phase, allowing only for the comparison of ADA and TCZ. In the base-case analysis (Figure), for a JIA ACR30 placebo response of 31%, TCZ monotherapy had a higher predicted probability of achieving JIA ACR30 (62%), JIA ACR50 (59%), JIA ACR70 (54%) and JIA ACR90 (35%) vs ADA monotherapy, with 53%, 49%, 44% and 26%, respectively. On MTX background therapy and a JIA ACR30 placebo response of 53%, ADA had a higher expected probability of response at JIA ACR30 (76%), JIA ACR50 (75%), JIA ACR70 (66%) and JIA ACR90 (49%) vs TCZ, with 72%, 70%, 61% and 44%, respectively. In neither monotherapy nor combination therapy did differences between TCZ and ADA reach statistical significance. Differences in the study populations, including previous use of biologics, were explored with sensitivity analysis. Image/graph Conclusions Based on JIA ACR response rates from this analysis, the expected efficacy of ADA vs TCZ appears comparable in pcJIA. These data should be interpreted in the context of differences in the duration of the withdrawal phase, which was shorter in the TCZ study (CHERISH) than in the ADA trial and might have resulted in a smaller difference in the number of flares observed between placebo and TCZ. Differences in previous exposure to biologics might also have affected the results. References Lancet2008;372:383; N Engl J Med 2008;359:810; N Engl J Med 2000;342:763; Arthritis Rheum 2007;56:3096; Unpublished data from CHERISH Disclosure of Interest L. Sawyer Consultant for: F. Hoffmann-La Roche, A. Diamantopoulos Consultant for: F. Hoffmann-La Roche, H. Brunner Shareholder of: PRCSG, Grant/research support from: National Institutes of Health, Lupus Foundation, Cincinnati Center for Clinical and Transplantation Research, Consultant for: Roche, Novartis, GSK, MedImmune, Pfizer, BMS, F. De Benedetti Grant/research support from: Abbott, Pfizer, BMS, Roche, Novimmune, Novartis, SOBI, N. Ruperto Grant/research support from: Abbott, AstraZeneca, BMS Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Consultant for: (to institution) Abbott, AstraZeneca, BMS Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Speakers bureau: Abbott, Boehringer, BMS, Novartis, Astellas, Italfarmaco, MedImmune, Pfizer, Roche, F. Dejonckheere Employee of: Roche, C. Keane Employee of: Roche

Background: Cases series suggest joint hypermobility (JH) is a risk factor for musculoskeletal pain in childhood, but this has not been supported by epidemiological studies. However, the latter have largely comprised small samples, and prospective data based on large cohorts are lacking. We aimed to exploit the Avon Longitudinal Study of Parents and Children (ALSPAC), a unique birth cohort, to determine whether joint hypermobility (JH) in childhood is a risk factor for the subsequent development of musculoskeletal pain. Methods: JH was determined by Beighton score at age 13.8 years in ALSPAC, using a cut-off of >6. Musculoskeletal pain was evaluated by questionnaire at age 17.8 years. Logistic regression analysis was performed in 2901 participants (1267 boys and 1634 girls) with complete data. Results: 4.6% of participants were hypermobile at age 13.8 years. Moderately troublesome musculoskeletal pain at age 17.8 was reported most commonly at the lower back (16.1%), upper back (8.9%), neck (8.6%), shoulder (9.5%), knee (8.8%) and ankle/foot (6.8%). JH was associated with an increased risk of at least moderately troublesome musculoskeletal pain at the shoulder (1.68; 1.04, 2.72), knee (1.83; 1.10, 3.02) and ankle/foot (1.82; 1.05, 3.16) (OR with 95% CI, adjusted for gender, maternal education and BMI). An equivalent relationship was not observed at other sites including the spine, elbows, hands and hips. In analyses examining interactions with obesity, associations between JH and knee pain showed higher ORs in obese participants (1.6 and 11.0 in non-obese and obese participants, respectively, P = 0.04 for obesity interaction). Conclusions: JH represents a risk factor for musculoskeletal pain in adolescence, comprising a specific distribution namely the shoulder, knee and ankle/foot. These relationships were strongest in the presence of obesity, consistent with a causal pathway whereby JH leads to pain at sites exposed to the greatest mechanical forces. Disclosures: The authors have declared no conflicts of interest.

Efficacy and safety of TCZ, an IL-6 receptor inhibitor, were previously demonstrated at wk 40 of CHERISH, a phase 3 trial in patients (pts) with pcJIA [1].

TCZ, an IL-6R inhibitor, is effective in systemic and polyarticular juvenile idiopathic arthritis (sjia, pjia). BW-adjusted, intravenous dosing regimens (TCZ8 mg/kg Q2W for sjia and Q4W for pjia) were assessed in Japanese phase 3 trials. As shown in Results, BW adjustment led to lower TCZ exposure with lower BW; thus, higher doses were proposed for patients (pts) with BW<30 kg in the global TENDER (sjia) and CHERISH (pjia) trials.