Tofacitinib as monotherapy following methotrexate withdrawal in patients with psoriatic arthritis previously treated with open-label tofacitinib plus methotrexate: a randomised, placebo-controlled substudy of OPAL Balance.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. This study evaluated the efficacy and safety of tofacitinib 5 mg twice daily monotherapy after methotrexate withdrawal. METHODS: OPAL Balance was an open-label, long-term extension study of tofacitinib in patients with psoriatic arthritis who participated in the OPAL Broaden and OPAL Beyond phase 3 studies. This 12-month, randomised, double-blind, placebo-controlled, methotrexate withdrawal substudy (50 centres, 14 countries) included patients from OPAL Balance who completed tofacitinib treatment for 24 months or more (≥3 months' stable tofacitinib 5 mg twice daily) and were receiving methotrexate (7·5-20 mg/week). Patients were blindly randomised (1:1) using interactive response technology and received open-label tofacitinib 5 mg twice daily with either placebo (tofacitinib 5 mg twice daily plus placebo group) or continued methotrexate (tofacitinib 5 mg twice daily plus methotrexate group). Patients were masked to placebo or methotrexate, with identical capsules used. Coprimary endpoints were changes from substudy baseline in psoriatic arthritis disease activity score (PASDAS) and health assessment questionnaire-disability index (HAQ-DI) at month 6 in all randomised patients with one or more substudy drug dose. Safety was assessed throughout. No specific statistical hypothesis (either superiority or non-inferiority) was tested. The study (OPAL Balance) is registered with ClinicalTrials.gov (NCT01976364) and is complete. FINDINGS: Between Oct 30, 2017, and May 20, 2019, 180 patients from OPAL Balance who were eligible for the substudy were randomly assigned to treatment (90 patients received tofacitinib 5 mg twice daily plus placebo and 89 patients assigned to tofacitinib plus methotrexate; one patient was not treated because of randomisation error). At month 6, least squares mean (LSM) changes in PASDAS were 0·23 (SE 0·08) for tofacitinib 5 mg twice daily plus placebo and 0·14 (0·08) for tofacitinib 5 mg twice daily plus methotrexate (treatment difference LSM 0·09 [95% CI -0·13 to 0·31]), and changes in HAQ-DI were 0·04 (0·03) and 0·02 (0·03), respectively (treatment difference 0·03 [-0·05 to 0·10]). Rates of adverse events, discontinuations because of adverse events, adverse events of special interest, and laboratory changes were generally similar between treatment groups, although liver enzyme elevations were more common with tofacitinib 5 mg twice daily plus methotrexate than tofacitinib 5 mg twice daily plus placebo. Flares of worsening symptoms was reported in one (1%) of 90 patients in the tofacitinib 5 mg twice daily plus placebo group (recorded as psoriatic arthropathy). INTERPRETATION: Some patients with psoriatic arthritis who are stable on tofacitinib 5 mg twice daily with background methotrexate might be able to discontinue methotrexate without clinically meaningful changes in disease activity and safety. FUNDING: Pfizer Inc.

Neoplasm Risk in Rheumatic Diseases Has No Correlation With Conventional Synthetic Disease-Modifying Anti-rheumatic Drugs Usage-A Population-Based Nested Case-Control Study.

Objectives: To investigate whether there is an elevated neoplasm risk in patients with rheumatic diseases treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Methods: A population-based nested case-control study was performed by retrieving all patients newly diagnosed with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriatic arthritis (PsA) or psoriasis vulgaris (PsO) from the 2000 Longitudinal Health Insurance Database (LHID 2000) in Taiwan. Two hundred and sixty-one patients with neoplasm from 1997 to 2013 were enrolled in this study, and controls were matched in a 1:1 ratio with age, sex, and year of enrollment. Composition of demographic indices, comorbidities, medication usage, and differences in days of prescription of different medications between neoplasm and neoplasm-free (control) groups were compared. Results: Between the control and neoplasm groups, no differences in ratio were observed in the usage of hydroxychloroquine (50.96 vs. 49.04%, p = 0.6616), methotrexate (26.82 vs. 27.59%, p = 0.8441), azathioprine (3.45 vs. 3.07%, p = 0.8052), and cyclophosphamide (1.15 vs. 2.30%, p = 0.3131) from enrollment to index date. Medications within 3 years before the index date in patients that had ≥3 months of comparable duration also showed no difference (hydroxychloroquine: 33.06 vs. 30.25%, p = 0.6404; methotrexate: 20.66 vs. 25.21%, p = 0.4018; azathioprine: 2.48 vs. 2.52%, p = 0.9835; cyclophosphamide: 0.83 vs. 0.84%, p = 0.9906). We also made a subgroup analysis focusing on RA and SLE patients; no difference between control and neoplasm group in both the ratio of usage and days of prescription of hydroxychloroquine, methotrexate, azathioprine, and cyclophosphamide was observed. Conclusion: Neoplasm risk in patients with rheumatic diseases has no correlation with csDMARD usage.

Liver-related long-term outcomes of thiazolidinedione use in persons with type 2 diabetes.

BACKGROUND & AIMS: Studies have described prominent histologic improvement in patients with nonalcoholic steatohepatitis (NASH) using thiazolidinedione (TZD); however, these were all short term with moderate sample size, no liver-related long-term outcomes could be noted. METHODS: This retrospective cohort study enrolled patients with newly diagnosed type 2 diabetes mellitus (T2DM) from Taiwan's National Health Insurance Research Database between 1 January 2000 and 31 December 2013. We matched TZD users and nonusers at a 1:1 ratio through propensity score matching. This study included 5095 paired TZD users and nonusers. Cox proportional hazard models were used to compare the risks of cirrhosis, hepatic decompensation, hepatic failure and all-cause mortality between TZD users and nonusers. The Kaplan-Meier method was used to compare the cumulative incidence of these main outcomes. RESULTS: The incidence rates of cirrhosis, hepatic decompensation, hepatic failure and all-cause mortality during follow-up were 0.77 vs 1.95, 1.43 vs 1.75, 0.36 vs 0.70, and 4.89 vs 3.78 per 1000 person-years between TZD users and nonusers. The adjusted hazard ratios of cirrhosis, hepatic decompensation, hepatic failure and all-cause mortality were 0.39 (95% confidence interval [CI]: 0.21-0.72), 0.86 (95% CI: 0.52-1.44), 0.46 (95% CI: 0.18-1.17) and 1.18 (95% CI: 0.87-1.61) respectively. CONCLUSIONS: Our study demonstrated that TZD use could significantly lower the risk of cirrhosis. In clinical settings, TZD use might be able to improve liver-related long-term outcomes.

Long-term effects of interleukin-17A inhibition with secukinumab in active ankylosing spondylitis: 3-year efficacy and safety results from an extension of the Phase 3 MEASURE 1 trial.

OBJECTIVES: Secukinumab, a fully human anti-IL-17A monoclonal antibody, provided rapid and sustained improvements in signs and symptoms of ankylosing spondylitis (AS) over 2 years in the Phase 3 MEASURE 1 trial. Here, we report efficacy and safety after 3 years of treatment. METHODS: AS subjects completing 2 years of treatment every 4 weeks with subcutaneous secukinumab 150 or 75 mg (following intravenous loading or initial placebo treatment to 16/24 weeks) entered a separate 3-year extension study (NCT01863732). Assessments included ASAS20/40, ASAS5/6, BASDAI, BASDAI 50, BASFI, BASMI, SF-36 physical component summary, ASAS partial remission and ASDAS-CRP. Results were also analysed by prior anti-TNF treatment status. RESULTS: Among 290 subjects completing the core trial, 274 entered the extension study, with 260 subjects (94.9%) completing 156 weeks of treatment. ASAS20/40 response (observed) was 80.2%/61.6% in the IV→150 mg group and 75.5%/50.0% in the IV→75 mg group after 156 weeks. Sustained improvements were also seen in BASDAI, BASFI, BASMI and across all other endpoints regardless of previous exposure to anti-TNF agents. Mean secukinumab exposure was 964.3 days (137.8 weeks). Discontinuation rates were low, and secukinumab had a favourable safety profile, consistent with previous reports. Exposure-adjusted incidence rates for serious infections, Candida infections, Crohn's disease, ulcerative colitis, malignant/unspecified tumours, and adjudicated major adverse cardiac events were 1.1, 0.4, 0.5, 0.1, 0.5 and 0.7 per 100 subject-years, respectively. CONCLUSIONS: Secukinumab provided sustained efficacy in signs, symptoms and physical function in subjects with AS over 3 years. No new safety signals were observed.

Rheumatic diseases are associated with a higher risk of dementia: A nation-wide, population-based, case-control study.

AIM: Previous research demonstrated the possible relevance of dementia and rheumatic diseases. This population-based study aims to investigate the association of rheumatic diseases and dementia. METHODS: The data of this case-control study was extracted from the Taiwan National Health Insurance Research Database. Diagnosis of dementia and rheumatic diseases mentioned in this study were retrieved by the International Classification of Diseases-9 code. We recruited cases (n = 10 180) with dementia and controls (n = 61 080) during 2000-2010, by matching on age, gender and index date with a match ratio 1 : 6. The Chi-square test was used to calculate the baseline characteristics of the cases and controls for categorical variables such as age and gender. Simple conditional and multivariable conditional logistic regression models were used to estimate crude and adjusted odds ratios. RESULTS: Statistical significance was observed in Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), and osteoarthritis (OA) among females (P < 0.05 for SS and SLE; P < 0.01 for OA), and in SS, psoriatic arthritis (PsA) and OA among males (P < 0.01 for SS; P < 0.05 for PsA and OA). Further, we also demonstrated a significant difference in SLE and OA among the younger group (age = 40-64) (P < 0.01 for SLE and OA), and in SS and OA among the older group (age â‰§ 65) (P < 0.01 for SS and OA). CONCLUSION: In this population-based case-control study, we found that patients with rheumatoid arthritis, SS, SLE, PsA and OA are significantly associated with a higher risk of dementia than those without rheumatic diseases. We hypothesized that inflammation and medications are two possible mechanisms.

Efficacy and safety of secukinumab in Asian patients with active ankylosing spondylitis: 52-week pooled results from two phase 3 studies.

AIM: To evaluate efficacy and safety of secukinumab in Asian patients with active ankylosing spondylitis (AS) via a pooled subgroup analysis from two phase 3 studies, MEASURE 1 (NCT01358175) and MEASURE 2 (NCT01649375). METHODS: In MEASURE 1, patients were randomized to intravenous secukinumab 10 mg/kg or placebo at baseline, Weeks 2 and 4, followed by subcutaneous (s.c.) secukinumab 150 mg, 75 mg or placebo every 4 weeks (q4w) at Week 8. In MEASURE 2, patients were randomized to s.c. secukinumab 150 mg, 75 mg or placebo at baseline, Weeks 1, 2 and 3, and q4w starting at Week 4. Efficacy outcomes were SpondyloArthritis International Society (ASAS) 20/40, high-sensitivity C-reactive protein (hsCRP), ASAS5/6, Bath Ankylosing Spondylitis Disease Activity Index, Short Form-36 physical component summary, AS quality of life (QoL), ASAS partial remission, and Ankylosing Spondylitis Disease Activity Score - CRP at Weeks 16 and 52. Due to lack of efficacy, the secukinumab 75 mg dose in MEASURE 2 was excluded from this pooled Asian subgroup analysis. Safety analysis included patients who received ≥ 1 dose of study treatment. RESULTS: Of 517 patients enrolled into the MEASURE studies, 69 (13.3%) were Asians: 46 in pooled secukinumab and 23 in placebo. At Week 16, ASAS20/40 responses in Asian patients were 69.6%/43.5% with pooled secukinumab versus 26.1%/17.4% with placebo, which were comparable with rates reported in the overall study population. Secukinumab improved predefined efficacy endpoints at Week 16, with responses sustained through Week 52. Secukinumab was well tolerated in Asian patients, with a safety profile consistent with that reported in the overall study population. CONCLUSION: Secukinumab improved signs and symptoms, physical function, and disease-specific QoL in Asian patients with active AS.

Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study.

OBJECTIVES: To compare efficacy and safety of various doses of tofacitinib, an oral Janus kinase inhibitor, with placebo in patients with active ankylosing spondylitis (AS, radiographic axial spondyloarthritis). METHODS: In this 16-week (12-week treatment, 4-week washout), phase II, multicentre, dose-ranging trial, adult patients with active AS were randomised (N=51, 52, 52, 52, respectively) to placebo or tofacitinib 2, 5 or 10 mg twice daily. The primary efficacy endpoint was Assessment of SpondyloArthritis International Society 20% improvement (ASAS20) response rate at week 12. Secondary endpoints included objective measures of disease activity, patient-reported outcomes and MRI of sacroiliac joints and spine. Safety was monitored. RESULTS: Emax model analysis of the primary endpoint predicted a tofacitinib 10 mg twice daily ASAS20 response rate of 67.4%, 27.3% higher than placebo. Supportive normal approximation analysis demonstrated tofacitinib 5 mg twice daily ASAS20 response rate significantly higher than placebo (80.8% vs 41.2%; p<0.001); tofacitinib 2 and 10 mg twice daily demonstrated greater response rate than placebo (51.9% and 55.8%, respectively; not significant). Secondary endpoints generally demonstrated greater improvements with tofacitinib 5 and 10 mg twice daily than placebo. Objective (including MRI) endpoints demonstrated clear dose response. Adverse events were similar across treatment groups with no unexpected safety findings. Dose-dependent laboratory outcome changes returned close to baseline by week 16. CONCLUSIONS: Tofacitinib 5 and 10 mg twice daily demonstrated greater clinical efficacy versus placebo in reducing signs, symptoms and objective endpoints of active AS in adult patients with a similar 12-week safety profile as reported in other indications. TRIAL REGISTRATION NUMBER: NCT01786668.

Identification of RGS1 as a candidate biomarker for undifferentiated spondylarthritis by genome-wide expression profiling and real-time polymerase chain reaction.

OBJECTIVE: To compare gene expression profiles between ankylosing spondylitis (AS) and undifferentiated spondylarthritis (uSpA) patients with inflammatory low back pain. METHODS: Peripheral blood mononuclear cells (PBMCs) from patients with AS, patients with uSpA, and healthy subjects were screened using genome-wide microarrays, followed by validation by real-time polymerase chain reaction (PCR). RESULTS: Microarray profiling and real-time PCR assays showed only minor differences between AS patients and healthy subjects. In contrast, 20 genes were strikingly more highly expressed in uSpA patients. Regulator of G protein signaling 1 (RGS1) was identified as the most useful biomarker for distinguishing uSpA patients, and to a lesser extent AS patients, from control subjects (P = 2.3 x 10(-7) and 6.7 x 10(-3), respectively). These findings were verified in an independent cohort that also included patients with rheumatoid arthritis and patients with mechanical low back pain. The receiver operating characteristic area under the curve values in the first and second cohorts of uSpA patients were 0.99 and 0.93, respectively (P = 1 x 10(-4)). To evaluate the possible derivation of RGS1, we cultured a monocyte-derived cell line with a panel of cytokines and chemokines. RGS1 was significantly induced either by tumor necrosis factor alpha (TNFalpha) or by interleukin-17 (IL-17). CONCLUSION: Our findings indicate that uSpA PBMCs carry strikingly more highly expressed genes compared with PBMCs from AS patients or healthy subjects, and that TNFalpha- and IL-17-inducible RGS1 is a potential biomarker for uSpA, and to a lesser extent for AS, with inflammatory low back pain.

Serum reactivity against Borrelia burgdorferi OspA in patients with rheumatoid arthritis.

Lyme arthritis and rheumatoid arthritis share common clinical features and synovial histology. It is unclear whether they also share similar pathogenesis. Previous studies have shown that the severity and duration of Lyme arthritis correlate directly with serum concentrations of antibody against outer surface protein A (OspA) of the causative pathogen Borrelia burgdorferi. We tested the sera of 68 subjects with rheumatoid arthritis, 147 subjects with other autoimmune diseases, and 44 healthy subjects who had never had Lyme disease, as well as sera of 16 patients who had Lyme disease, for reactivity against the B. burgdorferi OspA protein. The sera of about a quarter of the rheumatoid arthritis patients and a 10th of the autoimmune disease and Lyme disease patients reacted against OspA antigen. Of 50 rheumatoid arthritis patients who could be evaluated for disease severity, a 28-joint count disease activity score of >2.6 was noted for 11 of 15 (73%) patients whose sera reacted against OspA antigen and 13 of 35 (37%; P < 0.05) whose sera were nonreactive. Serum reactivity against OspA antigen is associated with the pathogenesis of rheumatoid arthritis.