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Activation of the innate immune system is commonly associated with depression. Immunomodulatory drugs may have efficacy for depressive symptoms that are co-morbidly associated with inflammatory disorders. We report a large-scale re-analysis by standardized procedures (mega-analysis) of patient-level data combined from 18 randomized clinical trials conducted by Janssen or GlaxoSmithKline for one of nine disorders (N = 10,743 participants). Core depressive symptoms (low mood, anhedonia) were measured by the Short Form Survey (SF-36) or the Hospital Anxiety and Depression Scale (HADS), and participants were stratified into high (N = 1921) versus low-depressive strata based on baseline ratings. Placebo-controlled change from baseline after 4–16 weeks of treatment was estimated by the standardized mean difference (SMD) over all trials and for each subgroup of trials targeting one of 7 mechanisms (IL-6, TNF-α, IL-12/23, CD20, COX2, BLγS, p38/MAPK14). Patients in the high depressive stratum showed modest but significant effects on core depressive symptoms (SMD = 0.29, 95% CI [0.12–0.45]) and related SF-36 measures of mental health and vitality. Anti-IL-6 antibodies (SMD = 0.8, 95% CI [0.20–1.41]) and an anti-IL-12/23 antibody (SMD = 0.48, 95% CI [0.26–0.70]) had larger effects on depressive symptoms than other drug classes. Adjustments for physical health outcome marginally attenuated the average treatment effect on depressive symptoms (SMD = 0.20, 95% CI: 0.06–0.35), but more strongly attenuated effects on mental health and vitality. Effects of anti-IL-12/23 remained significant and anti-IL-6 antibodies became a trend after controlling for physical response to treatment. Novel immune-therapeutics can produce antidepressant effects in depressed patients with primary inflammatory disorders that are not entirely explained by treatment-related changes in physical health.

Exposure-response modeling is important to optimize dose and dosing regimen in clinical drug development. The joint modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript presents the results of joint modeling of continuous and ordered categorical endpoints in the latent variable IDR modeling framework through the sharing of model parameters, with an application to the exposure-response modeling of sirukumab. Sirukumab is a human anti- interleukin-6 (IL-6) monoclonal antibody that binds soluble human IL-6 thus blocking IL-6 signaling, which plays a major role in the pathophysiology of rheumatoid arthritis (RA). A phase 2 clinical trial was conducted in patients with active RA despite methotrexate therapy, who received subcutaneous (SC) administration of either placebo or sirukumab of 25, 50 or 100 mg every 4 weeks (q4w) or 100 mg every 2 weeks (q2w). Major efficacy endpoints were the 20, 50, and 70% improvement in the American College of Rheumatology (ACR20, ACR50, and ACR70) disease severity criteria, and the 28-joint disease activity score using C-reactive protein (DAS28). The ACR endpoints were treated as ordered categorical and DAS28 as continuous. The results showed that, compared with the common approach of separately modeling the endpoints, the joint model could describe the observed data better with fewer parameters through the sharing of random effects, and thus more precisely characterize the dose-response relationship. The implications on future dose and dosing regimen optimization are discussed in contrast with those from landmark analysis.

The population pharmacokinetics of sirukumab, a human immunoglobulin G1κ monoclonal antibody against interleukin-6, were characterized in patients with moderately to severely active rheumatoid arthritis in 4 phase 3 studies (SIRROUND-D, -T, -H, and -M). A total of 17 034 serum concentrations were analyzed from 1991 rheumatoid arthritis patients who received subcutaneous administration of sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. A stepwise confirmatory population PK analysis was conducted to accommodate the staged data release and the sparse sampling nature of phase 3 studies and to assess the potential covariate influences in an unbiased and timely manner. The base model, that is, a 1-compartment linear model with first-order absorption and first-order elimination, was prespecified based on prior information from a phase 2 study along with information about phase 3 study design. The covariate model was also prespecified based on pharmacological/physiological relevance and sample size. After the primary covariate analysis, a simplified model was produced by removing covariates with effect sizes

Cytokines, including interleukin-6 (IL-6), modulate neuronal plasticity and stress coping. Depressive symptoms and major depressive disorder (MDD) have been associated with changes in cytokines and their signaling. The current study examined the effect of IL-6 monoclonal antibody administration on depressive symptoms in patients with rheumatoid arthritis (RA) or multicentric Castleman's disease (MCD). The data were obtained from two phase 2, double-blind, placebo-controlled trials designed to test the efficacy of sirukumab in RA (N=176) or of siltuximab in MCD (N=65), and were analyzed post hoc to investigate the effects of these IL-6 antibodies on depressive symptoms. The SF-36 questionnaire items on depressed-mood and anhedonia were combined as the measure for depressive symptoms. The study participants were grouped by the presence/absence of prevalent depressed mood and anhedonia (PDMA, meaning either depressed mood or anhedonia was present at least 'most of the time' and the other at least 'some of the time' for four weeks) at baseline; 26.1% of the RA sample and 15.4% of the MCD sample met criteria for PDMA at baseline. Compared with placebo, sirukumab and siltuximab produced significantly greater improvements on depressive symptoms. To account for an effect on mood due to changes in RA or MCD, the analysis was (1) adjusted for symptom severities using DAS28-CRP for RA and MCDOS for MCD alone or together with bodily pain and physical functioning, and (2) performed within RA and MCD non-responders. Improvement in depressive symptoms remained significant in the treated group for both drugs. The significance over placebo was also observed in the siltuximab study. The improvement in depressive symptoms by sirukumab correlated positively with the baseline soluble IL-6 receptor levels. The data together suggest that the IL-6 antibodies improve depressive symptoms in patients with RA and MCD. Further studies are needed to elucidate to what extents the IL-6 antibodies improve depressive symptoms through improving primary disease dependent and independent mechanisms, especially in RA patients, and the brain mechanisms underlying depressive symptom improvements.

ObjectivesInterleukin-6 (IL-6) is implicated in rheumatoid arthritis (RA) pathophysiology. Unlike IL-6 receptor inhibitors, sirukumab is a human monoclonal antibody that selectively binds to the IL-6 cytokine. The phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group SIRROUND-D study (ClinicalTrials.gov identifierNCT01604343) evaluated the efficacy and safety of sirukumab in patients with active RA refractory to disease-modifying antirheumatic drugs.MethodsPatients were randomised 1:1:1 to treatment with sirukumab 100 mg every 2 weeks, 50 mg every 4 weeks or placebo every 2 weeks subcutaneously. Results through week 52 are reported.ResultsOf 1670 randomised patients, significantly more patients achieved American College of Rheumatology 20% (ACR20) response at week 16 (coprimary endpoint) with sirukumab 100 mg every 2 weeks (53.5%) or 50 mg every 4 weeks (54.8%) versus placebo (26.4%; both pConclusionsSirukumab 100 mg every 2 weeks and 50 mg every 4 weeks led to significant reductions in RA symptoms, inhibition of structural damage progression and physical function and quality of life improvements, with an expected safety profile.Trial registration numberNCT01604343; Results.

Objective.Assess 5-year golimumab (GOL) safety in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS).Methods.Subcutaneous (SC) GOL (50 mg or 100 mg every 4 weeks) was evaluated in phase 3 trials of patients with active RA, PsA, and AS. Safety data through Year 5 were pooled across 3 RA trials [1 each evaluating methotrexate (MTX)-naive, MTX-experienced, and antitumor necrosis factor (TNF)-experienced patients], 1 PsA trial, and 1 AS trial. Data summarized was derived from both placebo-controlled (through weeks 24–52) and uncontrolled study periods. For adverse events (AE) of special interest [serious infections (SI), opportunistic infections (OI), deaths, malignancies, demyelination, tuberculosis (TB)], incidence per 100 patient-years (pt-yrs) was determined.Results.Across all trials, 639 patients received placebo and 2228 received SC GOL 50 mg only (n = 671), 50 mg and 100 mg (n = 765), or 100 mg only (n = 792). Safety followup extended for averages of 28.5 and 203.2 weeks for placebo and GOL, respectively. Respective placebo and GOL AE incidence/100 pt-yrs (95% CI) through Year 5 were 4.86 (2.83–7.78) and 3.29 (2.92–3.69) for SI, 0.00 (0.00–0.86) and 0.23 (0.14–0.35) for TB, 0.00 (0.00–0.86) and 0.22 (0.13–0.34) for OI, 0.00 (0.00–0.86) and 0.10 (0.05–0.20) for lymphoma, 0.00 (0.00–0.86) and 0.08 (0.03–0.17) for demyelination, and 0.29 (0.01–1.59) and 0.41 (0.29–0.57) for death. TB, OI, lymphoma, and demyelination incidence appeared to be higher among patients receiving GOL 100 mg only.Conclusion.SC GOL safety through Year 5 remained consistent with previously reported Year 3 findings and with other TNF antagonists. Numerically higher incidences of TB, OI, lymphoma, and demyelination were observed with 100 mg versus 50 mg. Clinicaltrials.gov identifiers: NCT00264537 (GO-BEFORE), NCT00264550 (GO-FORWARD), NCT00299546 (GO-AFTER), NCT00265096 (GO-REVEAL), and NCT00265083 (GO-RAISE).

Objective To assess the efficacy and safety of sirukumab, an anti-interleukin-6 monoclonal antibody, for the treatment of patients with active lupus nephritis (LN). Methods Patients with class III or class IV LN (as determined by renal biopsy within 14 months of randomization) who had persistent proteinuria (>0.5 gm/day) despite receiving immunosuppressive therapy and who were being treated with stable doses of a renin-angiotensin system blocker were randomized (5:1) to receive treatment with sirukumab at a dose of 10 mg/kg intravenously (n = 21) or placebo (n = 4) every 4 weeks through week 24. The primary end point was the percent reduction in proteinuria (measured as the protein-to-creatinine [P:C] ratio in a 12-hour urine collection) from baseline to week 24. Results Twenty-five patients were enrolled, of whom 19 (76.0%) completed treatment through week 24 and 6 (24.0%) discontinued the study agent early, with 5 of the 6 discontinuing due to adverse events. At week 24, the median percent change in proteinuria from baseline to week 24 in sirukumab-treated patients was 0.0% (95% confidence interval -61.8, 39.6). In contrast, the 4 placebo-treated patients showed an increase in proteinuria (median percent reduction -43.3%) at week 24. Of note, a subset of 5 sirukumab-treated patients had ≥50% improvement in their P:C ratio through week 28. In the sirukumab group, 47.6% of patients experienced ≥1 serious adverse event through week 40; most were infection-related. No deaths or malignancies occurred. No serious adverse events were observed in the 4 placebo-treated patients. Conclusion This proof-of-concept study did not demonstrate the anticipated efficacy nor did it demonstrate an acceptable safety profile for sirukumab treatment in this population of patients with active LN receiving concomitant immunosuppressive treatment.

Objective.Serum C-reactive protein (CRP) associates with radiographic progression in patients with ankylosing spondylitis (AS) untreated with tumor necrosis factor (TNF) antagonists. We assessed correlations between serum CRP and radiographic progression/magnetic resonance imaging (MRI)-detected inflammation after 2 years of anti-TNF therapy.Methods.Patients with active AS receiving golimumab (GOL)/placebo through Week 16 (early escape) or Week 24 (crossover by design), followed by GOL through 4 years, had sera/images obtained through Week 208. Lateral spinal radiographs and spinal MRI were scored with the modified Stoke AS Spine Score (mSASSS) and the AS spine MRI activity (ASspiMRI-a) score, respectively. ANOVA assessed differences based on CRP levels and mSASSS progression. The relationships between CRP levels and mSASSS/ASspiMRI-a were assessed by Spearman correlation and logistic regression.Results.Of the randomized GO-RAISE patients, 299 (84.0%) had pre- and posttreatment spinal radiographs. Larger proportions of patients with Week 104 CRP ≥ 0.5 mg/dl (n = 47) versus < 0.5 mg/dl (n = 236, 40.4% vs 22.9%, p = 0.0121) had mSASSS changes ≥ 2 at Week 104. Across several visits, serum CRP demonstrated weak associations with mSASSS change (rs ≤ 0.21, p < 0.05, n = 262–293) and moderate associations with ASspiMRI-a change (rs = −0.33 to 0.54, p < 0.05, n = 65–89). Higher baseline CRP was associated with increased risk for syndesmophytes at Week 104/Week 208, and large, short-term decreases in CRP from baseline to Week 14/Week 24 also yielded increased syndesmophyte formation risk.Conclusion.Elevated CRP after 2 years of anti-TNF treatment correlated with greater radiographic progression risk at 4 years. Elevated CRP at baseline or Week 14/Week 24 of anti-TNF treatment weakly predicted subsequent radiographic progression and modestly predicted residual spinal inflammation in patients with AS treated with anti-TNF. Findings are useful regarding new treatment options in patients treated with anti-TNF. ClinicalTrials.gov: NCT00265083.

ObjectiveInterleukin (IL)-6 is a pleiotropic cytokine involved in the pathophysiology of rheumatoid arthritis (RA). Sirukumab is a human monoclonal antibody that binds to IL-6 with high affinity and specificity.MethodsThis long-term extension (LTE) study of the SIRROUND-D and SIRROUND-T studies assessed long-term safety and efficacy of sirukumab in adults with moderate-to-severe RA refractory to conventional disease-modifying antirheumatic drug therapy or antitumor necrosis factor agents. Patients received sirukumab 100 mg subcutaneously (SC) every 2 weeks (q2w) or sirukumab 50 mg SC every 4 weeks (q4w).Results1820 patients enrolled in the LTE; median exposure was 2.34 and 2.07 years in sirukumab 50 mg q4w and 100 mg q2w groups, respectively. Adverse events (AEs) occurred in similar proportions between groups, with the exception of major adverse cardiovascular events (MACE), which were more common in the 50 mg q4w versus 100 mg q2w group (2.2% vs 1.0%), and injection-site reactions, more common in the 100 mg q2w group versus 50 mg q4w group (7.5% vs 3.7%). The most common serious AEs were infections (10% of the patients); 32 (1.8%) patients died during the study (primarily from serious infection and MACE). Malignancies were reported in 24 (1.3%) patients. Gastrointestinal perforations, hepatobiliary abnormalities and changes in laboratory parameters were rare. Reductions in RA signs and symptoms and improvements in physical function were maintained throughout the LTE.ConclusionsThe safety profile of sirukumab in the LTE remained consistent with that reported in SIRROUND-D and SIRROUND-T and efficacy was maintained.Trial registration numberNCT01856309.

To characterize the dose-exposure-response relationship of sirukumab, an anti-interleukin 6 human monoclonal antibody, in the treatment of moderately to severely active rheumatoid arthritis (RA), we conducted exposure-response (E-R) modeling analyses based on data from two pivotal phase 3 placebo-controlled trials of sirukumab in patients with RA who were inadequate responders to nonbiologic disease-modifying antirheumatic drugs or anti-tumor necrosis factor α agents. A total of 2176 patients were included for the analyses and received subcutaneous administration of either placebo or sirukumab 50 mg every 4 weeks or 100 mg every 2 weeks. The clinical endpoints were 20%, 50%, and 70% improvement in the American College of Rheumatology response criteria (ie, ACR20, ACR50, and ACR70), and 28-joint Disease Activity Index Score (DAS28) using C-reactive protein. To provide a thorough assessment of the sirukumab E-R relationship, 2 pharmacokinetic/pharmacodynamic modeling approaches were implemented, including joint longitudinal modeling (ie, indirect response modeling of the time course of the 2 clinical endpoints) and landmark analyses (ie, direct linking of selected pharmacokinetic parameters to response at week 16 or 24). Results from both modeling analyses were generally consistent, and collectively suggested that the sirukumab subcutaneous dose of 50 mg every 4 weeks would produce near-maximal efficacy. No covariates identified in the E-R modeling analyses would have a significant impact on dose-response. Despite body weight and comorbid diabetes having significant effect on sirukumab exposure, simulations suggested that their effect on efficacy was small. Our work provides a comprehensive evaluation of sirukumab E-R to support dose recommendations in patients with RA.

To evaluate the efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis (RA) uncontrolled by disease-modifying antirheumatic drugs.This subgroup analysis based on a double-blind, placebo-controlled, 52-week phase 3 study (SIRROUND-D) assessed American College of Rheumatology (ACR) 20 response at week 16 and van der Heijde-modified Sharp score (vdH-S) at week 52 (coprimary endpoints).A total of 168 (Japanese)/1670 patients received sirukumab 50 mg/4 weeks (q4w, n = 58), 100 mg/every 2 weeks (q2w, n = 54), or placebo (n = 56) subcutaneously. Significantly more patients achieved ACR20 response at week 16 with sirukumab (50 mg q4w: 69.0%; 100mg q2w: 66.7%) vs. placebo (21.4%; p .001). Median change from baseline in total vdH-S score at week 52 was significantly lower with sirukumab (50 mg q4w: 0.3, p = .024; 100 mg q2w: 0.0, p = .002) vs. placebo (1.3). Sirukumab consistently showed greater improvements in secondary endpoints at weeks 24 and 52. Nasopharyngitis, elevated liver enzymes, injection site erythema and upper respiratory tract infections were the common treatment-emergent adverse events (TEAEs). Incidences of TEAEs and serious AEs were consistent between sirukumab groups through week 52.Sirukumab showed clinically meaningful improvements consistent with significant improvements in the global study. No new safety signals were observed.

Summary Background Ustekinumab is a monoclonal antibody targeting interleukin (IL)-12 and IL-23 and is approved for the treatment of plaque psoriasis, psoriatic arthritis, and Crohn's disease. IL-12 and IL-23 have been implicated in systemic lupus erythematosus. We aimed to assess the efficacy and safety of ustekinumab for the treatment of systemic lupus erythematosus in patients with moderate-to-severe disease activity despite conventional treatment. Methods This was a multicentre, double-blind, phase 2, randomised, controlled trial of adult patients with active, seropositive systemic lupus erythematosus, done at 44 private practices and academic centres in Argentina, Australia, Germany, Hungary, Mexico, Poland, Spain, Taiwan, and the USA. Eligible adults were aged 18–75 years, weighed at least 35 kg, and had a diagnosis of systemic lupus erythematosus at least 3 months before the first administration of study drug. Eligible patients were randomly assigned (3:2) to the ustekinumab or placebo group using an interactive web response system with stratification by skin biopsy, lupus nephritis presence, baseline systemic lupus erythematosus medications and systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) score combined factor, site, region, and race. Patients and investigators were masked to treatment allocation. Patients received an intravenous infusion of ustekinumab (260 mg for patients weighing 35–55 kg, 390 mg for patients weighing >55 kg and ≤85 kg, and 520 mg for patients weighing >85 kg) followed by subcutaneous injections of ustekinumab 90 mg every 8 weeks or intravenous infusion of placebo at week 0 followed by subcutaneous injections of placebo every 8 weeks, both in addition to standard-of-care therapy. The primary endpoint was the proportion of patients achieving a SLEDAI-2K responder index-4 (SRI-4) response at week 24. Efficacy analyses were done in a modified intention-to-treat population of patients who received at least one dose (partial or complete, intravenous or subcutaneous) of their randomly assigned study treatment. Safety analyses were done in all patients who received at least one dose of study treatment, regardless of group assignment. This study is registered at ClinicalTrials.gov, number NCT02349061. Findings Between Oct 6, 2015, and Nov 30, 2016, 166 patients were screened, of whom 102 were randomly assigned to receive ustekinumab (n=60) or placebo (n=42). At week 24, 37 (62%) of 60 patients in the ustekinumab group and 14 (33%) of 42 patients in the placebo group achieved an SRI-4 response (percentage difference 28% [95% CI 10–47], p=0·006). Between week 0 and week 24, 47 (78%) of 60 patients in the ustekinumab group and 28 (67%) of 42 patients in the placebo group had at least one adverse event. Infections were the most common type of adverse event (27 [45%] in the ustekinumab group vs 21 [50%] in the placebo group). No deaths or treatment-emergent opportunistic infections, herpes zoster, tuberculosis, or malignancies occurred between weeks 0–24. Interpretation The addition of ustekinumab to standard-of-care treatment resulted in better efficacy in clinical and laboratory parameters than placebo in the treatment of active systemic lupus erythematosus and had a safety profile consistent with ustekinumab therapy in other diseases. The results of this study support further development of ustekinumab as a novel treatment in systemic lupus erythematosus. Funding Janssen Research & Development, LLC.

ObjectivesThe phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group SIRROUND-D study evaluated long-term efficacy and safety of the interleukin (IL)-6 inhibitor, sirukumab, in patients with active rheumatoid arthritis (RA) refractory to disease-modifying antirheumatic drugs (DMARDs).MethodsPatients were randomised 1:1:1 to sirukumab 100 mg every 2 weeks (q2w), 50 mg every 4 weeks or placebo q2w subcutaneously. Patients initially randomised to placebo were rerandomised at Weeks 18, 40 or 52 to one of the sirukumab groups until Week 104.ResultsOf 1670 randomised patients, 1402 were included in the full analysis set and 1269 in the radiographic analysis set at Week 104. American College of Rheumatology scores, Disease Activity Score based on C-reactive protein, Clinical Disease Activity Index and clinically meaningful improvements in patient-reported outcomes were sustained at Week 104 among patients initially randomised to sirukumab. Placebo patients subsequently rerandomised to sirukumab showed clinical improvements at Week 104 that were comparable to results among patients initially randomised to sirukumab. Radiographic progression from Week 52 to Week 104 was comparable between all groups whether initially randomised to sirukumab or subsequently rerandomised to sirukumab from placebo. No new safety signals were identified in the extended exposure period compared with the initial 52 weeks of treatment.ConclusionsSirukumab treatment resulted in sustained reductions in clinical signs and symptoms and minimal progression in radiographic damage over 2 years among patients with RA refractory to DMARDs. The safety profile of sirukumab was as expected for an anti-IL-6 agent, with no new signals reported.

ObjectiveThis randomised, double-blind, parallel-group, phase 3 study compared monotherapy with sirukumab, an anti–interleukin-6 cytokine monoclonal antibody, with adalimumab monotherapy in patients with rheumatoid arthritis (RA).MethodsBiologic-naïve patients with active RA who were inadequate responders or were intolerant to, or inappropriate for, methotrexate were randomised to subcutaneous sirukumab 100 mg every 2 weeks (n=187), sirukumab 50 mg every 4 weeks (n=186) or adalimumab 40 mg every 2 weeks (n=186). Primary endpoints at week 24 were change from baseline in Disease Activity Score in 28 joints (DAS28) using erythrocyte sedimentation rate (ESR) and proportion of patients achieving an American College of Rheumatology (ACR) 50 response; these endpoints were tested in sequential order. This study is registered at EudraCT (number: 2013-001417-32) and ClinicalTrials.gov (number: NCT02019472).ResultsSignificantly greater improvements from baseline in mean (SD) DAS28 (ESR) were observed at week 24 with sirukumab 100 mg every 2 weeks (−2.96 (1.580)) versus adalimumab 40 mg every 2 weeks (−2.19 (1.437); PConclusionSirukumab monotherapy showed greater improvements in DAS28 (ESR), but similar ACR50 response rates, versus adalimumab monotherapy.

Objective To assess pooled golimumab safety up to year 3 of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) trials. Methods Golimumab 50 and 100 mg, administered subcutaneously (SC) every 4 weeks (q4wk), were assessed in patients with active RA (methotrexate-naïve, methotrexate-experienced and anti-TNF (tumour necrosis factor)-experienced), PsA or AS, despite conventional therapy. Placebo control continued up to week (wk) 24 (wk 52, methotrexate-naïve), with early escape at wk 16 (wk 28, methotrexate-naïve); subsequently, all patients received golimumab 50 or 100 mg q4wk. After the blinded controlled period, golimumab doses could be adjusted per investigator discretion. Pooled safety analyses reported herein include data from placebo-controlled and uncontrolled study periods up to wk 160. Determinations of incidences/100 patient-years (pt-yrs) for rare events also included RA patients from a phase IIb trial. Results Across five phase III trials of SC golimumab, 639 patients received placebo and 2226 received golimumab 50 mg (n=1249) and/or 100 mg (n=1501) up to wk 160 (patients may be included in more than one group because non-responders were allowed early escape); 1179 patients were treated for ≥156 weeks. For placebo, golimumab 50 mg and golimumab 100 mg, respective adverse event incidences/100 pt-yrs (95% CIs) up to wk 160 were: 0.28 (0.01 to 1.56), 0.30 (0.12 to 0.62), 0.41 (0.23 to 0.69) for death; 5.31 (3.20 to 8.30), 3.03 (2.36 to 3.82), 5.09 (4.36 to 5.90) for serious infection; 0.00 (0.00 to 0.84), 0.17 (0.05 to 0.44), 0.35 (0.18 to 0.62) for tuberculosis; 0.00 (0.00 to 0.84), 0.13 (0.03 to 0.38), 0.24 (0.10 to 0.46) for opportunistic infection; 0.00 (0.00 to 0.84), 0.00 (0.00 to 0.13), 0.12 (0.03 to 0.30) for demyelination; and 0.00 (0.00 to 0.84), 0.04 (0.00 to 0.24), 0.18 (0.06 to 0.38) for lymphoma. Conclusions SC golimumab safety up to 3 years remained consistent with that of other TNF antagonists. Golimumab 100 mg showed numerically higher incidences of serious infections, demyelinating events and lymphoma than 50 mg; safety follow-up up to year 5 continues.

In the present study, we evaluated relationships between serum biomarkers and clinical/magnetic resonance imaging (MRI) findings in golimumab-treated patients with ankylosing spondylitis. In the GO-RAISE study, 356 patients with ankylosing spondylitis randomly received either placebo (n = 78) or golimumab 50 mg or 100 mg (n = 278) injections every 4 weeks through week 24 (placebo-controlled); patients continuing GO-RAISE received golimumab through week 252. Up to 139/125 patients had sera collected for biomarkers/serial spine MRI scans (sagittal plane, 1.5-T scanner). Two blinded readers employed modified ankylosing spondylitis spine magnetic resonance imaging score for activity (ASspiMRI-a) and ankylosing spondylitis spine magnetic resonance imaging score for chronicity. Spearman correlations (r s) were assessed between serum biomarkers (n = 73) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), C-reactive-protein (CRP)-based Ankylosing Spondylitis Disease Activity Score (ASDAS), modified Stokes Ankylosing Spondylitis Spine Score (mSASSS), and ASspiMRI scores. Serum biomarkers predicting postbaseline spinal fatty lesion development and inflammation were analyzed by logistic regression. Significant, moderately strong correlations were observed between baseline inflammatory markers interleukin (IL)-6, intracellular adhesion molecule-1, complement component 3 (C3), CRP, haptoglobin, and serum amyloid-P and baseline ASDAS (r s = 0.39–0.66, p ≤ 0.01). Only baseline leptin significantly correlated with ASDAS improvement at week 104 (r s = 0.55, p = 0.040), and only baseline IL-6 significantly predicted mSASSS week 104 change (β = 0.236, SE = 0.073, p = 0.002, model R 2 = 0.093). By logistic regression, baseline leptin, C3, and tissue inhibitor of metalloproteinase (TIMP)-1 correlated with new fatty lesions per spinal MRI at week 14 and week 104 (both p

Objective To evaluate the performance of an interferon-γ release assay (IGRA) versus the standard tuberculin skin test (TST) as a screening tool for latent tuberculosis (TB) infection prior to the initiation of anti–tumor necrosis factor therapy in patients with autoimmune inflammatory diseases. Methods This integrated analysis involved screening of patients with rheumatoid arthritis, those with psoriatic arthritis, and those with ankylosing spondylitis from phase III trials of golimumab. The IGRA used to screen for latent TB was the QuantiFERON-TB Gold In-Tube test. Results In this pooled analysis, 2,282 patients underwent both IGRA and TST screening prior to golimumab treatment. Among these patients, 13.8% had at least one test yielding positive findings for latent TB, including 9.4% with positive results by TST, 7.0% with positive results by IGRA, and 2.6% with positive results on both tests. The rate of indeterminate results for TB on IGRA was 1.8%. Agreement between the TST and IGRA results, measured by the kappa coefficient, was 0.22 (95% confidence interval 0.157–0.279; P = 0.021). Among the patients with positive IGRA findings, 36.9% had positive TST findings. Among the patients with positive TST findings, 27.4% had positive IGRA findings. Overall, 781 (34.2%) of the 2,282 patients had previously received the bacillus Calmette-Guerin (BCG) vaccine; among this vaccinated group, the rate of positivity for latent TB by TST was 15.2% (119 of 781), compared to a rate of positivity of 9.1% (71 of 781) by IGRA (P = 0.0002). Among patients who had not received the BCG vaccine, the rate of positivity by TST was 5.0% (62 of 1,248) and the rate of positivity by IGRA was 5.8% (72 of 1,248) (P = 0.3745). When the IGRA was repeated in patients whose results were initially indeterminate, the rate of indeterminate IGRA findings for latent TB was much lower than has been previously reported. Conclusion In the absence of a true gold standard test for latent TB infection, results of this comparison of IGRA and TST in a large cohort of patients with rheumatic diseases suggest that the IGRA provides greater specificity and possibly greater sensitivity than the TST.

Objectives To investigate the relationship between MRI inflammation and measures of clinical disease activity as well as treatment responses in patients with ankylosing spondylitis (AS) treated with a tumour necrosis factor inhibitor. Methods MRI at baseline (n=221), 24 (n=158) and 102 weeks (n=179) were scored for inflammation/activity (MRIa, Berlin scoring system). Treatment responses according to the AS disease activity score (ASDAS), Bath AS disease activity index (BASDAI) and assessment of spondyloarthritis 20 (ASAS20) criteria were calculated. For each treatment response criterion, subgroups of responders and non-responders changes in MRIa scores were compared. Results Higher baseline ASDAS and C-reactive protein (CRP) values were associated with higher baseline MRIa scores and with greater decreases in MRIa scores at follow-up. ASDAS and CRP improvements correlated with MRIa improvement. Stronger correlations were observed for CRP. Differences in MRIa change scores between responders and non-responders were greater when subgroups were defined according to ASDAS response than according to BASDAI or ASAS20 response. Conclusions MRIa correlates better with CRP than with other measures of disease activity. By including both CRP and patient-reported outcomes in its formula, ASDAS has the advantage of providing combined information on objective and subjective measures. As a status and response measure ASDAS better reflects the spinal inflammatory disease process in AS than other composite measures.

ObjectivesTo create a model that provides a potential basis for candidate selection for anti-tumour necrosis factor (TNF) treatment by predicting future outcomes relative to the current disease profile of individual patients with ankylosing spondylitis (AS).MethodsASSERT and GO–RAISE trial data (n=635) were analysed to identify baseline predictors for various disease-state and disease-activity outcome instruments in AS. Univariate, multivariate, receiver operator characteristic and correlation analyses were performed to select final predictors. Their associations with outcomes were explored. Matrix and algorithm-based prediction models were created using logistic and linear regression, and their accuracies were compared. Numbers needed to treat were calculated to compare the effect size of anti-TNF therapy between the AS matrix subpopulations. Data from registry populations were applied to study how a daily practice AS population is distributed over the prediction model.ResultsAge, Bath ankylosing spondylitis functional index (BASFI) score, enthesitis, therapy, C-reactive protein (CRP) and HLA-B27 genotype were identified as predictors. Their associations with each outcome instrument varied. However, the combination of these factors enabled adequate prediction of each outcome studied. The matrix model predicted outcomes as well as algorithm-based models and enabled direct comparison of the effect size of anti-TNF treatment outcome in various subpopulations. The trial populations reflected the daily practice AS population.ConclusionAge, BASFI, enthesitis, therapy, CRP and HLA-B27 were associated with outcomes in AS. Their combined use enables adequate prediction of outcome resulting from anti-TNF and conventional therapy in various AS subpopulations. This may help guide clinicians in making treatment decisions in daily practice.

To evaluate the efficacy and safety of golimumab in patients with ankylosing spondylitis (AS) in the GO-RAISE study.Patients with active AS, a Bath AS Disease Activity Index (BASDAI) scoreor =4, and a back pain score ofor =4 were randomly assigned in a 1.8:1.8:1 ratio to receive subcutaneous injections of golimumab (50 mg or 100 mg) or placebo every 4 weeks. The primary end point was the proportion of patients with at least 20% improvement in the ASsessment in AS (ASAS20) criteria at week 14.At randomization, 138, 140, and 78 patients were assigned to the 50-mg, 100-mg, and placebo groups, respectively. After 14 weeks, 59.4%, 60.0%, and 21.8% of patients, respectively, were ASAS20 responders (P0.001). A 40% improvement in the ASAS criteria at week 24 occurred in 43.5%, 54.3%, and 15.4% of patients, respectively. Patients receiving golimumab also showed significant improvement in the physical and mental component summary scores of the Short Form 36 Health Survey, the Jenkins Sleep Evaluation Questionnaire score, the BASDAI score, and the Bath AS Functional Index score, but not the Bath AS Metrology Index score. Through week 24, 85.6% of golimumab-treated patients and 76.6% of patients in the placebo group hador =1 adverse event, and 5.4% and 6.5% of patients, respectively, hador =1 serious adverse event. Eight golimumab-treated patients and 1 placebo-treated patient had markedly abnormal liver enzyme values (or =100% increase from baseline and a value150 IU/liter), which were transient.Golimumab was effective and well tolerated in a large cohort of patients with AS during a 24-week study period.

Objective.To assess vascular endothelial growth factor (VEGF) correlations with new bone formation and bone marrow edema in patients with ankylosing spondylitis (AS) treated with golimumab (GOL).Methods.Following placebo control (through weeks 16 and 24), GO-RAISE (A Multicenter Randomized, Double-blind, Placebo-controlled Trial of Golimumab, a Fully Human Anti-TNF-α Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Ankylosing Spondylitis; ClinicalTrials.gov: NCT00265083) all patients received GOL; sera/images were available at weeks 0, 104, and 208. Lateral spinal radiographs and magnetic resonance imaging (MRI) were scored using the modified Stokes Ankylosing Spondylitis Spine Score (mSASSS) and the Ankylosing Spondylitis Spinal MRI activity score, respectively.Results.VEGF levels and the mSASSS did not significantly correlate. Logistic regression analyses showed no association between VEGF levels and an increased risk of syndesmophyte formation at weeks 104 and 208. Pretreatment/Week 14 VEGF did not predict MRI scores/changes at Week 104.Conclusion.Serum VEGF did not predict radiographic progression/spinal inflammation in patients receiving antitumor necrosis factor.

Objective Assess golimumab efficacy/safety through 5 years in patients with active ankylosing spondylitis (AS). Methods 356 patients with AS were randomly assigned to placebo, golimumab 50 mg or 100 mg every 4 weeks. At week 16, patients with inadequate response early escaped with blinded dose adjustments (placebo to 50 mg, 50 mg to 100 mg). At week 24, all patients receiving placebo crossed over to 50 mg. Blinded active therapy continued through week 104; from week 104 to week 252, the golimumab dose could be adjusted. Intent-to-treat and observed efficacy data were assessed by randomised treatment groups. Results At week 256, and with >4.5 years of golimumab, overall intent-to-treat Assessment in SpondyloArthritis international Society criteria for 20% improvement (ASAS20) and ASAS40 response rates were 66.0% (235/356) and 57.0% (203/356), respectively; Bath AS Disease Activity Index 50% improvement response was 55.9% (199/356). Observed response rates among the 255 (72%) patients who continued golimumab through week 252 were consistent, albeit somewhat higher. Among patients who increased golimumab from 50 to 100 mg, 60.6% (20/33) and 44.7% (17/38) achieved ASAS20/ASAS40 responses, respectively, following ≥2 consecutive doses of golimumab 100 mg. Golimumab safety through week 268 was similar to that through week 24 regardless of dose. Conclusions Clinical improvements observed in patients treated with golimumab through week 24 were sustained through week 256 (5 years). Long-term golimumab safety is consistent with that of other established tumour-necrosis-factor-antagonists. Trial registration number ClinicalTrials.gov: NCT00265083.

BLyS (also called BAFF, TALL-1, THANK, and zTNF4), a TNF superfamily member, binds two receptors, TACI and BCMA, and regulates humoral immune responses [1–7]. These two receptors also bind APRIL [7–10], another TNF superfamily member. The results from TACI −/− and BCMA −/− mice suggest the existence of additional receptor(s) for BLyS. The TACI knockout gives the paradoxical result of B cells being hyperresponsive, suggesting an inhibitory role for this receptor [11, 12], while BCMA null mice have no discernable phenotype [13]. Here we report the identification of a third BLyS receptor (BR3; BLyS receptor 3). This receptor is unique in that, in contrast to TACI and BCMA, BR3 only binds BLyS. Treatment of antigen-challenged mice with BR3-Fc inhibited antibody production, indicating an essential role for BLyS, but not APRIL, in this response. A critical role for BR3 in B cell ontogeny is underscored by our data showing that the BR3 gene had been inactivated by a discrete, approximately 4.7 kb gene insertion event that disrupted the 3′ end of the BR3 gene in A/WySnJ mice, which lack peripheral B cells.

Objective. To evaluate the effect of golimumab on haemoglobin levels in patients with RA, PsA or AS. Methods. Secondary analysis was performed on integrated data from five randomized controlled studies: three RA, one PsA and one AS (2303 patients total). Golimumab 50 or 100 mg was injected s.c. every 4 weeks with or without MTX. Control groups received placebo injections plus MTX or background therapy. Patients with haemoglobin levels below the age- and sex-specific normal ranges were considered to have anaemia. Ferritin levels were used to distinguish anaemia of mixed aetiology (515 and

ObjectiveWe undertook a 2-part, phase I, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetics of multiple intravenous infusions of sirukumab, a human anti-interleukin-6 monoclonal antibody, in patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE). MethodsIn part A, patients with histologically confirmed CLE were randomized to 4 infusions of placebo or 1, 4, or 10 mg/kg sirukumab every 2 weeks. In part B, SLE patients diagnosed according to American College of Rheumatology criteria with a score of 5-12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index were randomized to 4 infusions of placebo or 10 mg/kg sirukumab every 2 weeks. ResultsWe treated 31 CLE patients (23 with sirukumab, 8 with placebo) and 15 SLE patients (10 with sirukumab, 5 with placebo). Adverse events (AEs) occurred more often with sirukumab than placebo in CLE patients (91% versus 63%) and in SLE patients (90% versus 80%). Sirukumab led to sustained, dose-independent decreases in white blood cell counts, absolute neutrophil counts (neutropenia), and platelet counts (thrombocytopenia) and to minor elevations in total cholesterol levels. The majority of infections were mild respiratory infections. which were reported similarly across CLE cohorts but more often in sirukumab-treated than in placebo-treated SLE patients. Two serious AEs of infection occurred (pneumonia in the 10 mg/kg-treated group and iatrogenic wound infection in the 4 mg/kg-treated group). Sirukumab showed linear pharmacokinetics in CLE patients. Systemic exposure and half-life were comparable between CLE and SLE patients. No patient developed antibodies to sirukumab through 22 weeks. C-reactive protein and serum amyloid A mean concentrations were suppressed with sirukumab from week 1 to week 14. ConclusionTreatment with intravenous sirukumab infusions was generally well tolerated in both CLE and SLE patients with mild, stable, active disease. Sirukumab demonstrated linear pharmacokinetics over the dose range studied and comparable systemic exposure and half-life in CLE and SLE patients. (Less)

Psoriasis is an important clinical feature in ankylosing spondylitis (AS) and spondyloarthritis (SpA) in general,1 with inflammatory spinal disease developing in 5%–25% of psoriasis cases.2 ,3 However, there have been few studies assessing the differences between AS patients with and without concomitant psoriasis.4–9 Our aim was to compare the demographic, clinical and imaging characteristics between AS patients with and without psoriasis. Baseline data from an 80% random sample of the AS Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT) database were used for this analysis. Details of the ASSERT trial and study population have been previously published.10 Briefly, patients with active AS (fulfilling modified New York criteria) for at least 3 months, a Bath AS disease activity index score of at least 4 (range 0–10) and a spinal pain assessment score of at least 4 (range 0–10) were eligible for the study. AS patients with …

ObjectiveIdentify serum biomarkers modulated by golimumab treatment and associated with clinical response in patients with ankylosing spondylitis (AS).MethodsSera were collected at weeks 0, 4 and 14 from 100 patients with active AS in the GO–RAISE study. Patients were randomly assigned subcutaneous injections of placebo, golimumab 50 mg, or golimumab 100 mg every 4 weeks. Samples were tested for select inflammatory, bone and cartilage markers, and protein profiling was also performed.ResultsGolimumab treatment resulted in significant decreases in several serum proteins at weeks 4 and 14 compared with placebo. Patients who achieved clinical response at week 14, as assessed by a ≥20% improvement in the Assessment in SpondyloArthitis international Society response criteria (ASAS 20), demonstrated a distinct biomarker profile with lower levels of acute phase reactants and inflammatory biomarkers compared with patients who did not. Notably, combinations of two or three biomarkers assessed at baseline were predictive of various clinical outcomes (ASAS 20, Bath ankylosing spondylitis disease activity index 50 or Bath ankylosing spondylitis functional index) using a logistic regression analysis, and the overall predictive values for these combined biomarkers were greater than observed for C-reactive protein (CRP) alone.ConclusionGolimumab modulated acute phase reactants and inflammatory markers in patients with active AS. Specific combinations of biomarkers at baseline demonstrated a stronger prediction for clinical efficacy than CRP alone. These data provide insights into the mechanism of golimumab on inflammatory processes driving AS pathology, and may have utility in managing the treatment of patients with AS.

Objective Reactivation of Mycobacterium tuberculosis infection is a major complication in patients treated with anti–tumor necrosis factor (anti-TNF) agents. We report on the 5 cases of active tuberculosis (TB) that developed in the Golimumab Phase III Program (3 with rheumatoid arthritis, 1 with psoriatic arthritis, and 1 with ankylosing spondylitis) through 1 year among 2,210 patients receiving golimumab. Methods Data from global studies were used for an in-depth evaluation of the 5 cases of TB through week 52. Integrated safety data were evaluated for potential hepatotoxicity in patients treated with anti-TB therapy. Results No active TB developed among 317 patients receiving golimumab and treated for latent TB with isoniazid. Active TB occurred in 5 patients not treated with isoniazid by week 52 (in 2 patients by week 24); all of the patients had negative TB screening tests (per the local guidelines) and resided in countries with high background rates of TB. No deaths were due to TB. Across all of the groups (placebo and golimumab), alanine aminotransferase and aspartate aminotransferase elevations occurred in greater proportions of patients treated for latent TB infection versus not treated; elevations were largely mild (

ObjectiveTo assess the efficacy and safety of golimumab over 104 weeks in patients with active ankylosing spondylitis.MethodsAt baseline, patients with active ankylosing spondylitis (n=356) were randomly assigned (1:1.8:1.8) to subcutaneous injections of placebo (group 1), golimumab 50 mg (group 2) or golimumab 100 mg (group 3) every 4 weeks. At week 16, patients in groups 1 and 2 with ResultsAt week 104, 38.5%, 60.1% and 71.4% of patients in groups 1, 2 and 3, respectively, had at least 20% improvement in the Assessment in SpondyloArthritis international Society response criteria (ASAS20); 38.5%, 55.8% and 54.3% had an ASAS40 response and 21.8%, 31.9% and 30.7% were in ASAS partial remission. Mean Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index scores were ConclusionClinical response that was achieved by patients receiving golimumab through 24 weeks was sustained through 52 and 104 weeks. The golimumab safety profile appeared to be consistent with the known safety profile of tumour necrosis factor inhibitors.

ObjectiveTo investigate the relationship between MRI inflammation at the vertebral unit and the formation and growth of syndesmophytes at the same vertebral unit.MethodsAn 80% random sample of the ASSERT database was analysed. MRI were scored using the ankylosing spondylitis (AS) spinal MRI activity score (at baseline, 24 and 102 weeks) and spinal x-rays were scored using the modified Stoke AS spine score (at baseline and 102 weeks). Data were analysed at the patient level and the vertebral unit level using a multilevel approach to adjust for within-patient correlation.ResultsThere was a slightly increased probability of developing syndesmophytes in vertebral units with MRI activity, which was maintained after adjustment for within-patient correlation (per vertebral unit level) and treatment, and after further adjustment for potential confounders, resulting in significant OR ranging from 1.51 to 2.26. Growth of existing syndesmophytes at the vertebral unit level was not associated with MRI activity. At the patient level only a trend for an association was observed.ConclusionMRI inflammation in a vertebral unit slightly increases the propensity to form a new syndesmophyte in the same vertebral unit, but does not predict the growth of already existing syndesmophytes. Despite this association, the large majority of new syndesmophytes developed in vertebral units without inflammation. The subtle association at the vertebral unit level did not translate into an association at the patient level.

Objective Qualitative research among patients with systemic lupus erythematosus (SLE) can identify aspects of the disease relevant to clinical research and practice. A phenomenological, mixed-method approach was used to investigate these disease-driven health issues. Methods A convenience sample of patients with SLE from Los Angeles County, California was recruited from a private, community-based rheumatology practice for participation in focus groups and interviews. Semistructured discussions explored disease manifestations and impact. A self-administered questionnaire evaluated the occurrence and importance of disease issues previously identified from literature. Patient health issues were identified through convergence using 1) qualitative analysis of focus group transcripts and 2) quantitative analysis of the questionnaire. Patients were also asked about their ability to accurately recall disease experiences. Results Focus group participants (n = 23) had a mean age of 43 years and a mean disease duration of 8 years; 19 (83%) were women and 14 (61%) were white. The most frequent health issues identified by focus group transcript analysis were pain (83%), fatigue (61%), work or school impairment (48%), skin manifestations (43%), and skin sensitivity (43%). Questionnaire findings were similar: the most frequent health issues were inability to do previous activities (87%), fatigue (87%), pain (87%), and work or school impairment (83%). Most interviewed patients (7 of 10) reported an ability to accurately recall disease issues between 24 hours and 7 days. Conclusion SLE patients reported signs and symptoms that could significantly impact their functioning in daily life. Treatments that substantially improve these disease manifestations would offer considerable benefit to patients, treating physicians, and general society.

Excerpt Carbamazepine is a drug increasingly used in a number of conditions including seizure disorders, trigeminal neuralgia, peripheral neuropathy, and occasionally psychiatric illness. We report...