Efficacy and Safety of Intravenous Golimumab in Ankylosing Spondylitis Patients With Early and Late Disease Through One Year of the GO-ALIVE Study.

BACKGROUND/OBJECTIVE: This post hoc analysis assessed efficacy and safety of intravenous (IV) golimumab in ankylosing spondylitis (AS) patients with early disease (ED) versus late disease (LD). METHODS: The phase 3, double-blind, GO-ALIVE study randomized patients to IV golimumab 2 mg/kg at weeks 0 and 4 and then every 8 weeks through week 52, or placebo at weeks 0, 4, and 12 with crossover to IV golimumab at week 16. Clinical efficacy was assessed by ≥20% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS20), ≥50% improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI 50), and Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3 (inactive disease). Using self-reported duration of inflammatory back pain (IBP), patients were grouped into quartiles: first = ED and fourth = LD. Descriptive statistics summarized efficacy and safety findings through 1 year. RESULTS: Early disease patients (n = 60) were ~10 years younger and had shorter median AS (IBP) symptom duration (2-3 years) versus LD patients (n = 52; 21-24 years). At week 16, numerically higher proportions of golimumab- than placebo-treated patients achieved ASAS20 (ED: 71% vs. 32%; LD: 67% vs. 21%), BASDAI 50 (ED: 40% vs. 12%; LD: 33% vs. 7%), and ASDAS <1.3 (ED: 17% vs. 4%; LD 8% vs. 0%) regardless of IBP duration. Efficacy was durable through 1 year of treatment; however, response rates were numerically higher in patients with ED versus LD. Through week 60, adverse events and serious adverse events, respectively, were reported by 46% and 3% of ED patients and 61% and 2% of LD patients. CONCLUSION: Prompt diagnosis of AS and early treatment with IV golimumab may yield more robust improvements in disease activity.

Guselkumab in biologic-naive patients with active psoriatic arthritis (DISCOVER-2): a double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: The interleukin-23 (IL-23)/T-helper 17 cell pathway is implicated in psoriatic arthritis pathogenesis. Guselkumab, an IL-23 inhibitor that specifically binds the IL-23 p19 subunit, significantly and safely improved psoriatic arthritis in a phase 2 study. DISCOVER-2 was a phase 3 trial to assess guselkumab in biologic-naive patients with psoriatic arthritis. METHODS: This phase 3, double-blind, placebo-controlled study was done at 118 sites in 13 countries across Asia, Europe, and North America. We enrolled biologic-naive patients with active psoriatic arthritis (at least five swollen joints, at least five tender joints, and C-reactive protein ≥0·6 mg/dL) despite standard therapies. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline disease-modifying antirheumatic drug use and C-reactive protein concentration) to subcutaneous injections of guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) response at week 24 in all patients per assigned treatment group. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03158285 (active, not recruiting). FINDINGS: From July 13, 2017, to Aug 3, 2018, 1153 patients were screened, of whom 741 were randomly assigned to receive guselkumab every 4 weeks (n=246), every 8 weeks (n=248), or placebo (n=247). One patient in the every 4 weeks group and one in the placebo group did not start treatment, and the remaining 739 patients started treatment; 716 patients continued treatment up to week 24. Significantly greater proportions of patients in the guselkumab every 4 weeks group (156 [64%] of 245 [95% CI 57-70]) and every 8 weeks group (159 [64%] of 248 [58-70]) than in the placebo group (81 [33%] of 246 [27-39]) achieved an ACR20 response at week 24 (percentage differences vs placebo 31% [95% CI 22-39] for the every 4 weeks group and 31% [23-40] for the every 8 weeks group; both p<0·0001). Up to week 24, serious adverse events occurred in eight (3%) of 245 patients receiving guselkumab every 4 weeks (three serious infections), three (1%) of 248 receiving guselkumab every 8 weeks (one serious infection), and seven (3%) of 246 receiving placebo (one serious infection). No deaths occurred. INTERPRETATION: Guselkumab, a human monoclonal antibody that specifically inhibits IL-23 by binding the cytokine's p19 subunit, was efficacious and demonstrated an acceptable benefit-risk profile in patients with active psoriatic arthritis who were naive to treatment with biologics. These data support the use of selective inhibition of IL-23 to treat psoriatic arthritis. FUNDING: Janssen Research and Development.

Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Many patients with psoriatic arthritis have an inadequate response to tumor necrosis factor (TNF) inhibitors. Guselkumab, a specific inhibitor of interleukin-23 (IL-23) via IL-23 p19 subunit binding, significantly improved psoriatic arthritis signs and symptoms with an acceptable safety profile in a phase 2 trial. METHODS: This multicentre, double-blind, randomised, placebo-controlled, phase 3 trial was done at 86 sites in 13 countries across Asia, Australasia, Europe, and North America and enrolled adults with active psoriatic arthritis (at least three swollen and three tender joints; and C-reactive protein ≥0·3 mg/dL) despite standard therapies. Eligibility criteria included inadequate response to or intolerance of standard treatment, including at least 4 months of apremilast, at least 3 months of non-biologic disease-modifying antirheumatic drugs (DMARDs), or at least 4 weeks of non-steroidal anti-inflammatory drugs for psoriatic arthritis. About 30% of study participants could have previously received one or two TNF inhibitors. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline DMARD and previous TNF inhibitor use) to subcutaneous guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or matching placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 24 in all patients per assigned treatment group using non-responder imputation. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03162796 (active, not recruiting). FINDINGS: From Aug 28, 2017, to Aug 17, 2018, we screened 624 patients, of whom 381 were randomly assigned and treated with guselkumab every 4 weeks (n=128), guselkumab every 8 weeks (n=127), or placebo (n=126). 362 patients continued study treatment up to week 24. The primary endpoint was met: ACR20 at week 24 was achieved by significantly greater proportions of patients in the guselkumab every 4 weeks group (76 [59%] of 128 [95% CI 50-68]) and every 8 weeks group (66 [52%] of 127 [43-61]) than in the placebo group (28 [22%] of 126 [15-30]), with percentage differences versus placebo of 37% (95% CI 26-48) for the every 4 weeks group and 30% (19-41) for the every 8 weeks group (both p<0·0001). Serious adverse events up to week 24 occurred in no patients receiving guselkumab every 4 weeks, four (3%) patients receiving guselkumab every 8 weeks, and five (4%) patients receiving placebo. Up to week 24, one patient in the placebo group died from cardiac failure and two had serious infections; no guselkumab-treated patient died or had serious infections. INTERPRETATION: Guselkumab demonstrated a favourable benefit-risk profile and might be an effective treatment option for patients with active psoriatic arthritis. FUNDING: Janssen Research and Development.

Resolution of enthesitis by guselkumab and relationships to disease burden: 1-year results of two phase 3 psoriatic arthritis studies.

OBJECTIVE: To further characterize the effect of guselkumab, a selective IL-23p19-subunit inhibitor approved for PsA, on enthesitis and assess relationships between enthesitis resolution and patient status/outcomes. METHODS: Adults with active PsA despite standard therapies in the phase 3 DISCOVER-1 and DISCOVER-2 studies were randomized 1:1:1 to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, week 4, Q8W; or placebo through week 20 followed by guselkumab 100 mg Q4W. Independent assessors evaluated enthesitis using the Leeds Enthesitis Index (LEI; total score 0-6). Enthesitis findings through week 24 were pre-specified to be pooled across studies; post hoc and week 52 analyses also employed pooled data. RESULTS: Among 1118 randomized, treated patients in DISCOVER-1 and 2 who had ≥1 LEI site evaluated, 65% had enthesitis at baseline. These patients exhibited numerically more swollen and tender joints, systemic inflammation and impaired physical function than patients without enthesitis. Guselkumab Q4W and Q8W were superior to placebo in resolving pre-existing enthesitis at week 24 (45 and 50% vs 29%; both adjusted P = 0.0301). Enthesitis resolution rates continued to rise; 58% of guselkumab-randomized patients achieved resolution at week 52, including patients with mild (LEI = 1; 70-75%), moderate (LEI = 2; 69-73%) or severe (LEI = 3-6; 42-44%) enthesitis at baseline. Among guselkumab-randomized patients with resolved enthesitis at week 24, 42% achieved minimal disease activity at week 52, vs 17% of patients with unresolved enthesitis. CONCLUSION: Guselkumab resulted in higher proportions of PsA patients with resolved enthesitis by week 24, with maintenance of resolution rates through 1 year. As enthesitis confers greater disease burden, sustained resolution could portend better patient outcomes. CLINICAL TRIAL REGISTRATION: DISCOVER 1 (NCT03162796) and DISCOVER 2 (NCT03158285).

Open-label phase 3 study of intravenous golimumab in patients with polyarticular juvenile idiopathic arthritis.

OBJECTIVES: To assess efficacy, pharmacokinetics (PK) and safety of intravenous (i.v.) golimumab in patients with polyarticular-course JIA (pc-JIA). METHODS: Children aged 2 to <18 years with active pc-JIA despite MTX therapy for ≥2 months received 80 mg/m2 golimumab at weeks 0, 4, then every 8 weeks through week 52 plus MTX weekly through week 28. The primary and major secondary endpoints were PK exposure and model-predicted steady-state area under the curve (AUCss) over an 8-week dosing interval at weeks 28 and 52, respectively. JIA ACR response and safety were also assessed. RESULTS: In total, 127 children were treated with i.v. golimumab. JIA ACR 30, 50, 70, and 90 response rates were 84%, 80%, 70% and 47%, respectively, at week 28 and were maintained through week 52. Golimumab serum concentrations and AUCss were 0.40 µg/ml and 399 µg ⋅ day/ml at week 28. PK exposure was maintained at week 52. Steady-state trough golimumab concentrations and AUCss were consistent across age categories and comparable to i.v. golimumab dosed 2 mg/kg in adults with rheumatoid arthritis. Golimumab antibodies and neutralizing antibodies were detected via a highly sensitive drug-tolerant assay in 31% (39/125) and 19% (24/125) of patients, respectively. Median trough golimumab concentration was lower in antibody-positive vs antibody-negative patients. Serious infections were reported in 6% of patients, including one death due to septic shock. CONCLUSION: Body surface area-based dosing of i.v. golimumab was well tolerated and provided adequate PK exposure for clinical efficacy in paediatric patients with active pc-JIA.ClinicalTrials.gov number NCT02277444.

Effects of Intravenous Golimumab on Health-Related Quality of Life in Patients with Ankylosing Spondylitis: 28-Week Results of the GO-ALIVE Trial.

OBJECTIVE: Evaluate the effect of intravenous golimumab on health-related quality of life (HRQoL) in patients with ankylosing spondylitis (AS) through week 28 of the phase III, multicenter, randomized, double-blind, placebo-controlled GO-ALIVE study. METHODS: Adult patients (n = 208) were randomized to IV golimumab 2 mg/kg (n = 105) at weeks 0, 4, and 12 and every 8 weeks or placebo (n = 103) at weeks 0, 4, and 12, with crossover to golimumab 2mg/kg at weeks 16, 20, and every 8 weeks. General HRQoL was evaluated using the Short Form Health Survey (SF-36) Physical Component Summary/Mental Component Summary (PCS/MCS), and the EQ VAS, and AS disease-specific HRQoL was assessed using the Ankylosing Spondylitis Quality of Life (ASQoL) instrument. RESULTS: Mean improvements from baseline in SF-36 PCS were greater in the golimumab group versus the placebo group at weeks 8 and 16 (6.8 vs 2.1 and 8.5 vs 2.9, respectively; P < .001); similar results were observed for SF-36 MCS (5.6 vs 1.7 and 6.5 vs 0.8, respectively; P < .001). Mean improvement in each of 8 subscale scores of the SF-36 were also greater for golimumab-treated patients versus placebo at weeks 8 and 16. Mean improvements in EQ VAS and ASQoL were greater in the golimumab group versus placebo at week 8 and week 16. Greater proportions of golimumab-treated patients had clinically meaningful improvement in SF-36 PCS, SF-36 MCS, EQ VAS, and ASQoL at weeks 8 and 16; improvements in SF-36 PCS/MCS, EQ VAS, and ASQoL were maintained through week 28. CONCLUSIONS: Golimumab-treated patients had greater mean improvements in HRQoL measures compared with placebo through week 16. Clinically meaningful improvements were observed as early as week 8 and continued through week 28.

Effects of Intravenous Golimumab on Health-Related Quality of Life in Patients With Psoriatic Arthritis: 24-Week Results of the GO-VIBRANT Trial.

OBJECTIVES: Evaluate the effects of intravenous golimumab 2 mg/kg on multiple domains of health-related quality of life (HRQoL) in adult patients with active psoriatic arthritis (PsA). METHODS: In this phase III, randomized, double-blinded, placebo-controlled study, adults with active PsA were randomized in a 1:1 ratio to receive intravenous (IV) infusions of placebo (n = 239) or golimumab 2 mg/kg (n = 241) at weeks 0, 4, 12, and 20. Physical function was assessed using the Health Assessment Questionnaire-Disability Index (HAQ-DI). HRQoL was assessed using the 36-item Short-Form Health Survey Physical and Mental Component Summary (SF-36 PCS/MCS) scores, the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, EQ VAS, and the Dermatology Life Quality Index (DLQI). RESULTS: Patients in the golimumab group had greater mean changes from baseline in HAQ-DI compared with placebo at weeks 8 (-0.52 vs -0.10), 14 (-0.60 vs -0.12), and 24 (-0.63 vs -0.14). Mean improvements from baseline in SF-36 PCS (8.0 vs 1.7), SF-36 MCS (5.0 vs 1.2), EQ VAS (17.2 vs 3.7), FACIT-Fatigue (7.9 vs 2.0), and DLQI (-7.2 vs -1.7) were also greater in the golimumab group versus placebo at week 8 and were maintained or increased through week 24. Greater proportions of golimumab-treated patients had improvements greater than or equal to the minimal clinically important difference (MCID) for HAQ-DI, SF-36 PCS/MCS, EQ VAS, FACIT-Fatigue, and DLQI scores at weeks 14 and 24. CONCLUSION: Improvements in HRQoL were greater in the IV golimumab group compared with placebo and were evident at week 8 and sustained through week 24.

Spinal mobility in the cervical and lumbar spine correlates with magnetic resonance imaging findings for inflammatory and structural changes in patients with active ankylosing spondylitis.

OBJECTIVES: We aimed to assess relationships between single Bath Ankylosing Spondylitis Metrology Index (BASMI) components and corresponding spinal segment magnetic resonance images (MRI) in anti-tumour-necrosis-factor-treated AS patients. METHODS: Using available MRI and BASMI data from the GO-RAISE trial (n=91 patients), MRI scores for active inflammatory (ASspiMRI-a) and chronic structural (ASspiMRI-c) changes in cervical and lumbar spine segments were compared with BASMI cervical (cervical-rotation [CR] angle, tragus-to-wall [TTW] distance) and lumbar (lumbar flexion [LF], lateral-lumbar-flexion [LLF]) spine component scores (linear definition). Generalised linear models were employed to assess relationships between BASMI components and ASspiMRI-a/ASspiMRI-c measurements at baseline and for week-14 (golimumab/placebo groups) and week-104 (all golimumab-treated) change scores. RESULTS: Baseline lumbar ASspiMRI-a scores correlated with LF and LLF (ß=0.231 and 0.238, respectively; both p<0.01), while this was less prominent for ASspiMRI-c scores and LLF (ß=0.142, p=0.04). A significant but weak correlation was found between changes from baseline to week 104 in cervical spine ASspiMRI-c score and TTW distance among all treated patients (ß=0.161, p=0.003). CONCLUSIONS: Detailed assessments indicated baseline spinal mobility impairment in patients with active AS correlated weakly with MRI-detected lumbar spinal inflammation; correlations with chronic, structural damage/changes were very weak. Improved, less variable MRI and spinal metrology assessments are needed for future clinical research.

Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a randomised, double-blind, placebo-controlled, phase 2 study.

BACKGROUND: Guselkumab, a human monoclonal antibody that binds to the p19 subunit of interleukin 23, has been approved for the treatment of moderate-to-severe psoriasis. Psoriatic arthritis is a common comorbidity of psoriasis with an umet need for novel treatments. We assessed the efficacy and safety of guselkumab in patients with active psoriatic arthritis. METHODS: We did a randomised, double-blind, placebo-controlled, phase 2a trial at 34 rheumatology and dermatology practices in Canada, Germany, Poland, Romania, Russia, Spain, and the USA. Eligible participants were aged 18 years or older with active psoriatic arthritis and plaque psoriasis affecting at least 3% of their body surface area, with three or more of 66 tender joints and three or more of 68 swollen joints, who had an inadequate response or intolerance to standard treatments. We randomly assigned patients (2:1) via a central interactive web-response system using computer-generated permuted blocks with a block size of six, stratified by previous anti-tumour necrosis factor-α use, to receive subcutaneous guselkumab 100 mg or placebo at week 0, week 4, and every 8 weeks thereafter for 24 weeks. Patients, investigators, and site staff were masked to treatment assignment until final database lock at week 56. At week 16, patients with less than 5% improvement in swollen and tender joint counts were eligible for early escape to ustekinumab. At week 24, the remaining placebo-treated patients crossed over to receive guselkumab 100 mg at weeks 24, 28, 36, and 44 and guselkumab-treated patients received a placebo injection at week 24, followed by guselkumab injections at weeks 28, 36, and 44. The primary endpoint was the proportion of patients with at least 20% improvement at week 24 in signs and symptoms of psoriatic arthritis according to American College of Rheumatology criteria (ACR20) in the modified intention-to-treat population (ie, all randomly assigned patients who received at least one dose of study treatment). Safety analyses included patients according to the study drug received. This study is registered with ClinicalTrials.gov, number NCT02319759. FINDINGS: Between March 27, 2015, and Jan 17, 2017, we randomly assigned 149 patients to treatment: 100 to guselkumab and 49 to placebo. 17 (35%) of 49 patients in the placebo group and ten (10%) of 100 patients in the guselkumab group were eligible for early escape to ustekinumab at week 16. 29 (59%) of 49 patients in the placebo group crossed over and received guselkumab at week 24. Three (6%) of 49 patients in the placebo group, one (3%) of 29 patients who crossed over from placebo to guselkumab, and six (6%) of 100 patients in the guselkumab group discontinued study treatment before week 44. 58 (58%) of 100 patients in the guselkumab group and nine (18%) of 49 patients in the placebo group achieved an ACR20 response at week 24 (percentage difference 39·7% [95% CI 25·3-54·1]; p<0·0001). Between week 0 and week 24, 36 (36%) of 100 guselkumab-treated patients and 16 (33%) of 49 placebo-treated patients had at least one adverse event. The most frequent adverse event was infection in both groups (16 [16%] of 100 patients in the guselkumab group vs ten [20%] of 49 patients in the placebo group). The prevalence of adverse events between week 0 and week 56 in guselkumab-treated patients (51 [40%] of 129) indicated no disproportional increase with longer guselkumab exposure. No deaths occurred. INTERPRETATION: Guselkumab, a novel anti-interleukin 23p19 antibody, significantly improved signs and symptoms of active psoriatic arthritis and was well tolerated during 44 weeks of treatment. The results of this study support further development of guselkumab as a novel and comprehensive treatment in psoriatic arthritis. FUNDING: Janssen Research & Development.

Immunogenicity of golimumab and its clinical relevance in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

OBJECTIVE: Golimumab immunogenicity was extensively studied during clinical development. As anti-drug antibody (ADA) detection with the standard bridging EIA (original-EIA) can yield false-negative results or underestimate ADA incidence and titres due to drug interference, a more sensitive assay was needed to determine clinical impact. METHODS: A highly sensitive drug-tolerant EIA (DT-EIA) was developed and cross-validated against the original-EIA. Samples from phase-3 subcutaneous golimumab rheumatological trials (GO-FORWARD-rheumatoid arthritis, GO-REVEAL-psoriatic arthritis, GO-RAISE-ankylosing spondylitis) were then retested. Associations between ADAs and golimumab pharmacokinetics, efficacy and safety were assessed. RESULTS: The DT-EIA was more sensitive than the original-EIA and capable of detecting ADAs amid golimumab concentrations far exceeding those in immunogenicity test samples. Consequently, an 8-fold increase in the incidence of ADAs was observed with the DT-EIA (31.7%) vs original-EIA (4.1%) in the studies. Most ADA-positive patients identified by the DT-EIA had lower antibody titres, while most with higher titres were previously identified as ADA-positive by the original-EIA. With the DT-EIA, ADA-positive patients generally had lower trough serum golimumab concentrations than ADA-negative patients; however, ADA impact on serum golimumab concentrations was more notable at higher ADA titres (⩾100). No impact of ADAs on clinical efficacy or injection-site reactions was evident. CONCLUSION: ADA incidence was expectedly higher using the DT-EIA vs original-EIA; newly detected ADAs were characterized mostly by low titres, with no impact on clinical efficacy or injection-site reactions, consistent with previously observed original-EIA results. Golimumab immunogenicity with the DT-EIA is consistent with existing knowledge regarding the clinical relevance of ADAs detected with the original-EIA in patients with rheumatological disorders. TRIAL REGISTRATION: NCT00264550, NCT00265096, NCT00265083.

Golimumab 3-year safety update: an analysis of pooled data from the long-term extensions of randomised, double-blind, placebo-controlled trials conducted in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis.

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.

Effects of golimumab, an anti-tumour necrosis factor-α human monoclonal antibody, on lipids and markers of inflammation.

OBJECTIVES: To assess the effect of golimumab, with or without methotrexate (MTX), on serum lipids and inflammatory markers of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) in two phase 3, randomised, placebo-controlled trials (GO-BEFORE and GO-FORWARD). METHODS: Patients in GO-BEFORE (n=637, MTX-naïve) and GO-FORWARD (n=444, MTX-inadequate response) were randomised to placebo+MTX, golimumab 100 mg+placebo, golimumab 50 mg+MTX, or golimumab 100 mg+MTX. Subcutaneous injections (placebo and golimumab) were given every 4 weeks. Patients with an insufficient response entered early escape at week 16 (GO-FORWARD) or 28 (GO-BEFORE). All placebo+MTX patients in GO-FORWARD crossed over to golimumab 50 mg+MTX at week 24. Changes from baseline to weeks 14 (GO-FORWARD) or 24 (GO-BEFORE), and 52 in serum lipid levels and inflammatory markers were assessed. RESULTS: At week 14 in the GO-FORWARD trial, total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) increased in golimumab+MTX patients versus MTX-only patients (16.00 vs 2.00 (p<0.001); 3.00 vs 0.00 (p<0.05); 8.00 vs 4.00 (p<0.001); respectively); favourable changes in LDL subfractions were only observed in golimumab-treated patients. At week 24 in GO-BEFORE, TC and LDL increased, and LDL subfractions improved in the MTX-only and golimumab+MTX groups. Inflammatory markers of CVD risk improved significantly with golimumab+MTX versus placebo+MTX in both studies and were generally maintained through week 52. Atherogenic indices were generally stable. CONCLUSIONS: While TC and LDL levels increased mildly in RA patients receiving golimumab+MTX, atherogenic indices generally remained stable, favourable changes in LDL subfractions were observed, and inflammatory markers improved.

Insights into the efficacy of golimumab plus methotrexate in patients with active rheumatoid arthritis who discontinued prior anti-tumour necrosis factor therapy: post-hoc analyses from the GO-AFTER study.

OBJECTIVE: Evaluate golimumab in patients with active rheumatoid arthritis (RA) and previous tumour necrosis factor-α (TNF) inhibitor use. METHODS: Patients (n=461) previously receiving ≥1 TNF inhibitor were randomised to subcutaneous injections of placebo, golimumab 50 mg or golimumab 100 mg q4 weeks. Primary endpoint (≥20% improvement in American College of Rheumatology (ACR20) criteria at week 14) findings have been reported for all patients in the trial. Reported herein are further assessments of efficacy/safety among patients receiving golimumab+methotrexate (MTX). RESULTS: Among efficacy-evaluable patients who received MTX at baseline, more receiving golimumab+MTX (n=201) than placebo+MTX (n=103) achieved ACR20 (40.8% vs 14.6%), ACR50 (20.9% vs 3.9%), and ACR70 (11.4% vs 2.9%) responses at week 24. Among the 137 patients who had received only one prior TNF inhibitor (adalimumab, n=33; etanercept, n=47; and infliximab, n=57), week 24 ACR20 rates were 30.3%, 46.8% and 50.9%, respectively, and thus lowest among those who previously used adalimumab. ACR20 response rates were 44.5% (61/137), 36.2% (17/47) and 23.5% (4/17) among patients who had received one, two or three TNF inhibitors, respectively. Adverse event (AE) rates were comparable across type/number of prior anti-TNF agents, but appeared somewhat higher among patients who discontinued previous TNF inhibitor(s) due to intolerance (37/49, 75.5%) versus lack of efficacy (LOE, 113/191, 59.2%). CONCLUSIONS: Patients with active RA previously treated with ≥1 TNF inhibitor had clinically relevant improvement with golimumab+MTX, which appeared somewhat enhanced among those who received only etanercept or infliximab as their prior TNF inhibitor. Golimumab+MTX safety appeared similar across patients, regardless of TNF inhibitor(s) previously used, with fewer AEs occurring among patients who discontinued prior therapy for LOE.

Early MRI measures independently predict 1-year and 2-year radiographic progression in rheumatoid arthritis: secondary analysis from a large clinical trial.

OBJECTIVE: To determine if early MRI measures predict X-ray progression at 1 and 2 years in a large RA trial cohort. DESIGN: This study included 256 methotrexate (MTX)-naïve RA patients from a randomised placebo-controlled trial of golimumab (GO-BEFORE). MRIs of wrist and 2nd-5th metacarpophalangeal joints at 0, 12, 24, 52 and 104 weeks were obtained and scored using the RAMRIS system. Multivariable logistic regression examined if baseline and early change (weeks 12/24) in RAMRIS scores independently predicted progression of the van der Heijde-Sharp (vdHS) score and MRI erosion score at 1 and 2 years of follow-up. RESULTS: High baseline score and poor improvement over the first 24 weeks in synovitis (p=0.003 and p=0.003, respectively) and in bone oedema (p=0.02 and p=0.001, respectively) were independent predictors of X-ray progression at 1 year. Associations were significant or tended towards an association at 2 years. An increase in RAMRIS bone erosion >0.5 at weeks 12 and 24 also predicted X-ray progression (p<0.003). Poor 12-week improvement in bone oedema was associated with X-ray and MRI progression at 1 year (p<0.05). Regression models that incorporated baseline and 12-week and 24-week changes in MRI measures of synovitis (AUC=0.71) and bone oedema (AUC=0.70) improved the prediction of X-ray progression at 1 year above clinical disease activity alone (AUC=0.66, p<0.04). CONCLUSIONS: Baseline and early changes in MRI measures independently predicted X-ray and MRI progression at later time-points. The predictive validity established here supports potential use in shorter-duration studies to determine efficacy of RA therapies in preventing structural damage.

Safety and efficacy of golimumab in Chinese patients with active ankylosing spondylitis: 1-year results of a multicentre, randomized, double-blind, placebo-controlled phase III trial.

OBJECTIVE: The aim of this study was to assess the efficacy and safety of golimumab in Chinese patients with active AS. METHODS: Two hundred and thirteen patients were randomized in a 1:1 ratio to receive either s.c. injections of placebo from weeks 0 to 20 followed by golimumab 50 mg from weeks 24 to 48 (group 1, n = 105) or golimumab 50 mg from weeks 0 to 48 (group 2, n = 108), both every 4 weeks. Placebo crossover occurred at week 24, while early escape was at week 16. The primary endpoint was an improvement of at least 20% in the Assessment of SpondyloArthritis international Society (ASAS20) criteria at week 14. Major secondary endpoints included week 24 ASAS20 response and week 14 change scores for BASFI and BASMI. RESULTS: Golimumab treatment elicited significantly better responses than placebo in week 14 ASAS20 response [49.1% (53/108) vs 24.8% (26/105), respectively, P < 0.001], week 24 ASAS20 response (50.0% vs 22.9%, P < 0.001) and mean improvements in BASFI (-1.26 vs 0.11, P < 0.001) and BASMI (-0.42 vs -0.19, P = 0.021) scores at week 14. Additionally, golimumab treatment led to significant improvements in the mental and physical components of health-related quality of life (HRQoL) and sleep problems at week 24, all of which were further improved through week 52. During the 16-week placebo-controlled study period, 31.4% and 30.6% of patients had adverse events (AEs) in groups 1 and 2, respectively; similar AE reporting rates were observed through week 24 (34.3% and 32.0%) and among the golimumab-treated patients through week 56 (41.2%). CONCLUSION: Golimumab significantly reduced clinical symptoms/signs and improved physical function, range of motion and HRQoL in Chinese patients with active AS without unexpected safety concerns. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01248793.

Effect of golimumab on carotid atherosclerotic disease measures and cardiovascular events in inflammatory arthritides.

OBJECTIVE: The objective of this study was to assess the effect of golimumab on carotid ultrasound measures and cardiovascular serious adverse events (SAEs) in patients with inflammatory arthritides. METHODS: An exploratory carotid artery ultrasound substudy was performed in the GO-BEFORE study of methotrexate (MTX)-naive rheumatoid arthritis patients, with ultrasounds performed at weeks 0, 24, and 52 to measure common carotid artery intima-media thickness, distensibility coefficient, interadventitial diameter, and plaque count. Cardiovascular SAEs reported over 2 years of follow-up were assessed in 5 golimumab phase 3 clinical trials of patients with rheumatoid arthritis (GO-BEFORE, GO-FORWARD, and GO-AFTER), psoriatic arthritis (GO-REVEAL), and ankylosing spondylitis (GO-RAISE). In GO-BEFORE and GO-FORWARD, patients received placebo + MTX, golimumab 50 mg + MTX, or golimumab 100 mg +/- MTX at baseline and every 4 weeks; in the other 3 trials, patients received placebo or golimumab 50 or 100 mg. RESULTS: The carotid ultrasound substudy showed inconsistent changes in common carotid artery intima-media thickness in the golimumab + MTX groups over time, and there was large variability in the measurements. Increases in interadventitial diameter were observed in the golimumab 100 mg + placebo group, but not in the golimumab + MTX groups. There were no significant differences in the distensibility coefficient and plaque count between the golimumab and placebo groups. Very few patients overall experienced a cardiovascular SAE, and the incidence of cardiovascular SAEs was not statistically different between the golimumab and placebo groups. CONCLUSIONS: The results of the carotid ultrasound substudy were inconclusive, and no increase or decrease in cardiovascular SAEs was observed following 2 years of treatment with golimumab with or without MTX.

The effect of golimumab on haemoglobin levels in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis.

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 (≥ 15 and <60 ng/ml) and anaemia of inflammation (≥ 60 ng/ml). Changes from baseline to weeks 14 and 24 in haemoglobin level were compared between treatment groups using an analysis of variance on the van der Waerden normal scores. RESULTS: At baseline, 21% of RA patients, 9% of PsA patients and 15% of AS patients had anaemia. Of these, 24%, 57% and 25%, respectively, had anaemia of inflammation. The median increase from baseline to week 14 in the haemoglobin level of anaemic patients was 0.3 g/dl in the control group and 0.9 g/dl in the golimumab group (P < 0.001). Haemoglobin levels improved within the subgroups of patients with anaemia of mixed aetiology (control, 0.4 g/dl vs golimumab, 0.7 g/dl) (P = 0.305) and with anaemia of inflammation (0.2 vs 1.4 g/dl, respectively) (P < 0.001). CONCLUSION: Compared with the control group, patients receiving golimumab treatment had significantly improved haemoglobin levels, particularly among patients with anaemia of inflammation.

Interferon-γ release assay versus tuberculin skin test prior to treatment with golimumab, a human anti-tumor necrosis factor antibody, in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.

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-Guérin (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.

Guselkumab Modulates Differentially Expressed Genes in Blood of Patients With Psoriatic Arthritis: Results from Two Phase 3, Randomized, Placebo-Controlled Trials.

OBJECTIVE: To evaluate gene expression in blood of patients with psoriatic arthritis (PsA) versus healthy controls and identify changes associated with guselkumab treatment. METHODS: Whole blood transcriptome profiling via paired-end RNA sequencing was conducted using samples from DISCOVER-1 and DISCOVER-2 at baseline (n = 673) and at weeks 4 and 24 from a representative subgroup that received placebo or guselkumab (n = 227 [longitudinal PsA cohort]). Baseline samples were compared with demographically matched healthy controls (n = 21). Guselkumab-mediated changes in gene expression were assessed in participants from the longitudinal PsA cohort who did versus did not achieve at least 20% improvement in American College of Rheumatology response criteria (ACR20) or at least 75% improvement in Psoriasis Area and Severity Index (PASI75). Differential gene expression was analyzed using edgeR. RESULTS: At baseline, 355 upregulated and 314 downregulated genes (PsA-associated genes) were identified in patients with PsA versus healthy controls. Upregulated genes were related to neutrophil, mononuclear cell, and CD11b+ gene sets. No cell type-specific gene sets were identified among downregulated genes. Most PsA-associated genes were modulated by guselkumab treatment. At week 24, genes downregulated by guselkumab were enriched with neutrophil, monocyte, eosinophil, and macrophage gene sets; genes upregulated by guselkumab were enriched with B cell, T cell, and natural killer cell gene sets. Reductions in expression of upregulated PsA-associated gene sets were more pronounced in ACR20 and PASI75 responders than in nonresponders. CONCLUSION: These findings suggest a dysregulation of immune cell profiles in blood from patients in the baseline PsA cohort that approached levels in healthy controls after guselkumab treatment.