Olokizumab plus methotrexate: safety and efficacy over 106 weeks of treatment.

OBJECTIVE: To report long-term safety and tolerability of olokizumab (OKZ) in combination with methotrexate (MTX) in subjects with active rheumatoid arthritis (RA), using pooled data from three randomised clinical trials (RCT) followed by open-label extension (OLE) study. METHODS: Cumulative data from three phase 3 core trials and their OLE were analysed. Safety variables assessed included treatment-emergent adverse events (AEs), serious AEs (SAEs), AEs of special interest and laboratory results. Efficacy assessments included ACR20/50/70 responses, Disease Activity Score 28 (C-reactive protein) <3.2, CDAI remission and low disease activity (LDA), SDAI remission and LDA, HAQ-DI decrease of 0.22 unit and Boolean 2.0 remission. RESULTS: A total of 2304 patients received OKZ in combination with MTX either once every 2 weeks or once every 4 weeks. Event rates per 100 patient-years in OKZ every 2 weeks and OKZ every 4 weeks, respectively, were 9.57 and 9.13 for SAEs; 2.95 and 2.34 for serious infections; 0.09 and 0.05 for gastrointestinal perforations; 0.58 and 0.83 for major adverse cardiovascular events; and 0.45 and 0.50 for malignancies. No increase in the rate of any AE was observed over 106 weeks of treatment. The evaluation of laboratory variables demonstrated the expected changes, like neutropenia, elevation of liver enzymes and blood lipids. Clinical response rates remained stable during the OLE. CONCLUSION: The long-term safety and tolerability of OKZ in combination with MTX remained stable. The efficacy of OKZ was maintained through week 106. These findings support OKZ as a treatment option for patients with active RA.

Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: efficacy and safety results of a randomised controlled phase III study.

OBJECTIVES: To assess the efficacy and safety of olokizumab (OKZ), a monoclonal antibody against the interleukin-6 (IL-6) cytokine, versus placebo (PBO) in patients with prior inadequate response to tumour necrosis factor inhibitors (TNFi-IRs). METHODS: In this 24-week multicentre, placebo-controlled, double-blind study, the patients were randomised in a 2:2:1 ratio to receive subcutaneously administered OKZ 64 mg once every 2 weeks (q2w), OKZ 64 mg once every 4 weeks (q4w) or PBO plus methotrexate. At week 16, the patients on PBO were randomised to receive either OKZ regime. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. Disease Activity Score 28-joint count C-reactive protein (DAS28 (CRP))<3.2 at week 12 was the major secondary efficacy endpoint. Safety and immunogenicity were assessed. RESULTS: In 368 patients randomised, ACR20 response rates were 60.9% in OKZ q2w, 59.6% in OKZ q4w and 40.6% in PBO (p<0.01 for both comparisons). Achievement of DAS28 (CRP) <3.2 was significantly different, favouring the OKZ arms. Improvements in efficacy and patient-reported outcomes were maintained throughout 24 weeks and were noted after week 16 in patients who switched from PBO.Dose-related treatment-emergent serious adverse events were 7% in OKZ q2w, 3.2% in OKZ q4w and none in the PBO group. CONCLUSIONS: Direct inhibition of IL-6 with OKZ resulted in significant improvements in the signs and symptoms of rheumatoid arthritis compared with PBO in TNF-IR patients with a similar safety profile as observed for monoclonal antibodies to the IL-6 receptor. TRIAL REGISTRATION NUMBER: NCT02760433.

Efficacy and safety of tildrakizumab in patients with active psoriatic arthritis: results of a randomised, double-blind, placebo-controlled, multiple-dose, 52-week phase IIb study.

OBJECTIVES: To evaluate efficacy and safety of the anti-interleukin-23p19 monoclonal antibody tildrakizumab in patients with psoriatic arthritis (PsA). METHODS: In this randomised, double-blind, placebo-controlled, phase IIb study, patients with active PsA were randomised 1:1:1:1:1 to tildrakizumab 200 mg every 4 weeks (Q4W); tildrakizumab 200, 100 or 20 mg Q12W; or placebo Q4W. Patients receiving tildrakizumab 20 mg or placebo switched to tildrakizumab 200 mg Q12W at W24; treatment continued to W52. The primary efficacy endpoint was proportion of patients with ACR20 response (≥20% improvement by American College of Rheumatology criteria) at W24. Secondary efficacy endpoints were assessed without adjustment for multiplicity. Safety was evaluated from treatment-emergent adverse events (TEAEs). RESULTS: 391/500 patients screened were randomised and treated. At W24, 71.4%-79.5% of tildrakizumab-treated versus 50.6% of placebo-treated patients achieved ACR20 (all p<0.01). Patients receiving tildrakizumab versus placebo generally achieved higher rates of ACR50, Disease Activity Score in 28 joints with C reactive protein <3.2, minimal disease activity and 75%/90%/100% improvement from baseline Psoriasis Area and Severity Index responses at W24 and through W52. Improvement in dactylitis and enthesitis was not observed; results were mixed for other outcomes. Responses in patients switched to tildrakizumab 200 mg at W24 were consistent with treatment from baseline. TEAEs and serious TEAEs occurred in 64.5% and 3.3%, respectively, of all patients through W52 and were comparable among treatment arms. CONCLUSIONS: Tildrakizumab treatment significantly improved joint and skin manifestations of PsA other than dactylitis and enthesitis. Treatment was generally well tolerated through W52. Clinicaltrials.gov NCT02980692.

Abatacept in subjects who switch from intravenous to subcutaneous therapy: results from the phase IIIb ATTUNE study.

OBJECTIVE: To assess safety, immunogenicity and efficacy in rheumatoid arthritis (RA) patients switched from long-term intravenous to subcutaneous (SC) abatacept. METHODS: In this phase IIIb, open-label, single-arm trial, patients who completed ≥4 years of intravenous abatacept (in long-term extensions of two phase III studies) were enrolled to receive SC abatacept (125 mg/week). The primary objective was safety during the first 3 months after switching from intravenous therapy. RESULTS: 123 patients entered the study (mean Disease Activity Score 28 (based on C reactive protein) and HAQ-DI of 3.4 and 0.94, respectively). At month 3, 120 (97.6%) patients were continuing to receive SC abatacept; no patients discontinued due to lack of efficacy. Adverse events (AEs) were reported in 49 (39.8%) patients through month 3. One patient (0.8%) discontinued due to an AE and one patient (0.8%) experienced a serious AE. Two (1.6%) patients had SC injection site reactions (erythema, pain), both with mild intensity. Clinical efficacy was maintained throughout. Limited impact on immunogenicity was observed when switching routes of administration. CONCLUSION: These data demonstrate that patients can switch from long-term monthly intravenous abatacept to a weekly fixed dose of 125 mg SC abatacept with no increased safety concerns. This study further supports SC abatacept as an alternative treatment option for patients with RA.

Depression-, Pain-, and Health-Related Quality of Life in Patients with Systemic Lupus Erythematosus.

Objectives: A significant number of patients with systemic lupus erythematosus (SLE) have depression, and many are untreated. We aim to assess the frequency of moderate to severe depression (MSD) in a multiethnic group of SLE patients with different sociodemographic backgrounds, identify modifiable factors associated with depression, and determine the impact of depression, disease activity, damage, cognitive function, and pain severity on health-related quality of life (HRQoL). Methods: Ninety-nine patients with SLE were evaluated in a cross-sectional study. Sociodemographic data, Beck Depression Inventory (BDI II), SLE disease activity index (SLEDAI-2K), SLICC Damage Index (SLICC-DI), pain severity (10 cm visual analogue scale), cognitive function (Automated Neuropsychologic Assessment Metrics (ANAM)), and the physical (PCS) and mental (MCS) component scores of the Short Form Health Survey (SF-36) were recorded. Bivariate analysis identified potential associations of relevant variables with BDI II and SF-36. Regression analysis determined independent correlates with MSD, PCS, and MCS. Results: Over 50% of subjects (50.5%) were African-American, 37.1% had a family income of ≤$20,000, and 31.3% had MSD. In the bivariate analysis, family income, SLEDAI-2K, cognitive function, and pain severity were associated with MSD. Using binary logistic regression, SLEDAI-2K and pain severity remained independently correlated with MSD (p = 0.004). In the multiple linear regression analysis, pain severity was the only independent correlate of PCS (p < 0.0001), while cognitive function and BDI II were the main factors associated with MCS (p = 0.020 and p < 0.0001, respectively). Conclusion: Pain severity and disease activity are associated with MSD in our unique population, are potentially modifiable, and deserve further attention in the clinic. Depression and pain significantly affect HRQoL and should be aggressively managed.

Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition.

BACKGROUND: A substantial number of patients with rheumatoid arthritis have an inadequate or unsustained response to tumor necrosis factor alpha (TNF-alpha) inhibitors. We conducted a randomized, double-blind, phase 3 trial to evaluate the efficacy and safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis and an inadequate response to at least three months of anti-TNF-alpha therapy. METHODS: Patients with active rheumatoid arthritis and an inadequate response to anti-TNF-alpha therapy were randomly assigned in a 2:1 ratio to receive abatacept or placebo on days 1, 15, and 29 and every 28 days thereafter for 6 months, in addition to at least one disease-modifying antirheumatic drug. Patients discontinued anti-TNF-alpha therapy before randomization. The rates of American College of Rheumatology (ACR) 20 responses (indicating a clinical improvement of 20 percent or greater) and improvement in functional disability, as reflected by scores for the Health Assessment Questionnaire (HAQ) disability index, were assessed. RESULTS: After six months, the rates of ACR 20 responses were 50.4 percent in the abatacept group and 19.5 percent in the placebo group (P<0.001); the respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group (20.3 percent vs. 3.8 percent, P<0.001; and 10.2 percent vs. 1.5 percent, P=0.003). At six months, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the HAQ disability index (47.3 percent vs. 23.3 percent, P<0.001). The incidence of adverse events and peri-infusional adverse events was 79.5 percent and 5.0 percent, respectively, in the abatacept group and 71.4 percent and 3.0 percent, respectively, in the placebo group. The incidence of serious infections was 2.3 percent in each group. CONCLUSIONS: Abatacept produced significant clinical and functional benefits in patients who had had an inadequate response to anti-TNF-alpha therapy.

Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis.

CONTEXT: Hydroxychloroquine, a commonly used antirheumatic medication, has hypoglycemic effects and may reduce the risk of diabetes mellitus. OBJECTIVE: To determine the association between hydroxychloroquine use and the incidence of self-reported diabetes in a cohort of patients with rheumatoid arthritis. DESIGN, SETTING, AND PATIENTS: A prospective, multicenter observational study of 4905 adults with rheumatoid arthritis (1808 had taken hydroxychloroquine and 3097 had never taken hydroxychloroquine) and no diagnosis or treatment for diabetes in outpatient university-based and community-based rheumatology practices with 21.5 years of follow-up (January 1983 through July 2004). MAIN OUTCOME MEASURES: Diabetes by self-report of diagnosis or hypoglycemic medication use. RESULTS: During the observation period, incident diabetes was reported by 54 patients who had taken hydroxychloroquine and by 171 patients who had never taken hydroxychloroquine, with incidence rates of 5.2 per 1000 patient-years of observation compared with 8.9 per 1000 patient-years of observation, respectively (P < .001). In time-varying multivariable analysis with adjustments for possible confounding factors, the hazard ratio for incident diabetes among patients who had taken hydroxychloroquine was 0.62 (95% confidence interval, 0.42-0.92) compared with those who had not taken hydroxychloroquine. In Poisson regression, the risk of incident diabetes was significantly reduced with increased duration of hydroxychloroquine use (P < .001 for trend); among those taking hydroxychloroquine for more than 4 years (n = 384), the adjusted relative risk of developing diabetes was 0.23 (95% confidence interval, 0.11-0.50; P < .001), compared with those who had not taken hydroxychloroquine. CONCLUSION: Among patients with rheumatoid arthritis, use of hydroxychloroquine is associated with a reduced risk of diabetes.

Anti-NR2 antibodies, blood-brain barrier, and cognitive dysfunction.

Cognitive dysfunction (CD) is one of the most common neuropsychiatric manifestations of systemic lupus erythematosus (SLE). In animal models, antibodies to NR2 subunit of N-methyl D-aspartate receptor (anti-NR2) cause memory impairment, but only with blood-brain barrier (BBB) disruption or intrathecal administration. Several studies have failed to find association of aNR2 with CD, but none have assessed BBB integrity. S100B, an astrocyte-specific protein, has been used as biomarker of BBB disruption in traumatic brain injury and some neurodegenerative disorders. Antibodies to this immunologically privileged protein (anti-S100B) might indicate preceding BBB disruption. We hypothesized that aNR2 antibody is pathogenic in SLE patients only with BBB disruption. Demographic, clinical, and laboratory data was collected from patients with SLE. Total throughput score (TTS) of the Automated Neuropsychological Assessment Metrics (ANAM) was used as primary outcome measure. CD was defined as TTS < 1.5 SD below an age-, sex-, and race-matched RA population mean. Serum was analyzed by established ELISA techniques. Fifty-seven patients were evaluated and 12 had CD. Age, ethnicity, and family income were significantly different between the two groups (p < 0.05). In a multiple regression model adjusting for other variables, no significant effects of anti-NR2, S100B, or anti-S100B on TTS were found. Even at high levels of S100B and anti-S100B, no significant influence of anti-NR2 on TTS was found. The anti-NR2 was not associated with CD in SLE even in context of potential BBB disruption. This suggests that, if pathogenic, these antibodies may be produced intrathecally.

Non-criteria anti-phospholipid antibodies and cognitive impairment in SLE.

The pathogenesis of cognitive impairment (CI) in patients with systemic lupus erythematosus (SLE) is unknown. Anti-phospholipid antibodies (APL) have been implicated. The APL which have been evaluated have variably included anti-cardiolipin (ACL) antibodies, lupus anticoagulant (LAC), and antibodies to beta-2 glycoprotein I (ß2GPI). Few studies have examined other APL (so-called non-criteria APL). We evaluated the association of CI with a broad spectrum of non-criteria APL. Subjects meeting SLE classification criteria were recruited from three different patient populations. Cognitive function was assessed with the Automated Neuropsychologic Assessment Metrics (ANAM), a validated computer-based assessment tool. The total throughput score (TTS = number of correct responses/time) was used as the primary outcome measure. The following APL of all three isotypes were assessed by ELISA using standardized techniques: anti-ß2GPI, anti-phosphatidyl ethanolamine (aPE), anti-phosphatidyl choline (aPC), anti-phosphatidyl inositol (aPI), anti-phosphatidyl serine (aPS), anti-phosphatidyl glycerol (aPG), anti-phosphatidic acid (aPA). Fifty-seven (57) patients were evaluated. Of the 57, 12 had definite CI (>1.5 SD below the mean of an age-, sex-, and race-matched RA population). The two groups were significantly different with regard to age, ethnicity, and family income. There was no significant difference between groups with regard to the presence of any non-criteria APL. When titers of specific non-criteria APL were compared with TTS, no significant correlations were found. Using multiple linear regression and adjusting for relevant covariates including age, ethnicity, and family income, neither the presence nor the titer of any non-criteria APL significantly influenced TTS. In this cross-sectional study, non-criteria APL were not associated with CI.

Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate. OBJECTIVE: To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis. DESIGN: 24-week, multicenter, randomized, double-blind, placebo-controlled trial. SETTING: 20 centers in the United States and Canada. PATIENTS: Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months. INTERVENTION: Leflunomide or matching placebo added to existing methotrexate therapy. MEASUREMENTS: The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis. RESULTS: In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate. CONCLUSIONS: Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.

Longterm safety and efficacy of abatacept through 5 years of treatment in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor inhibitor therapy.

OBJECTIVE: To evaluate abatacept safety and efficacy over 5 years in patients with rheumatoid arthritis (RA) who had inadequate response to anti-tumor necrosis factor (TNF) therapy in the ATTAIN trial. METHODS: Patients completing the 6-month, double-blind (DB) placebo-controlled period were eligible to enter the longterm extension (LTE), where all patients received abatacept every 4 weeks (∼10 mg/kg, according to weight range). Safety, efficacy, physical function, and health-related quality of life were monitored throughout. RESULTS: In total, 317 patients (218 DB abatacept, 99 DB placebo) entered the LTE; 150 (47.3%) completed it. Overall incidences of serious adverse events, infections, serious infections, malignant neoplasms, and autoimmune events did not increase during the LTE versus the DB period. American College of Rheumatology responses with abatacept at Month 6 were maintained over 5 years. At Year 5, among patients who received abatacept for 5 years and had available data, 38/103 (36.9%) achieved low disease activity as defined by the 28-joint Disease Activity Score (DAS28)/C-reactive protein (CRP); 23/103 (22.3%) achieved DAS28/CRP-defined remission. Health Assessment Questionnaire response was achieved by 62.5% of patients remaining on treatment at Year 5; mean improvements from baseline in physical component summary and mental component summary scores were 7.34 and 6.42, respectively. High proportions of patients maintained efficacy and physical function benefits or improved their disease state at each timepoint throughout the LTE, if remaining on abatacept treatment. CONCLUSION: Safety remained consistent, and abatacept efficacy was maintained from 6 months to 5 years, demonstrating the benefits of switching to abatacept in this difficult-to-treat population of patients with RA previously failing anti-TNF therapy.

Cognitive dysfunction in patients with systemic lupus erythematosus: a controlled study.

OBJECTIVE: To determine the extent to which cognitive dysfunction (CD) observed in patients with systemic lupus erythematosus (SLE) exceeds that seen in a matched control group of patients with rheumatoid arthritis (RA), and to estimate the prevalence of CD in SLE in a community-based sample. METHODS: A random subsample of 31 patients with SLE was compared to patients with RA matched by age, sex, and race and derived from the same patient population. Cognitive function was assessed by the Automated Neuropsychological Assessment Metrics (ANAM). The primary outcome was the total throughput score (number of correct responses divided by the time taken for those responses averaged over all subtests), adjusted for premorbid intelligence, neuromuscular efficiency, disease activity, damage, depression, fatigue, and health-related quality of life. RESULTS: There were no statistically significant differences in mean throughput scores between patients in the SLE and RA groups in any subtest of the ANAM or in the total throughput score. The frequency of CD, defined as either total scores > 1.5 SD below the mean of the RA population, or 4 or more ANAM subtests each > 1.5 SD below the RA mean, was similar in patients with SLE and in RA controls. CONCLUSION: We found no differences in cognitive function between patients with SLE and RA, suggesting that the CD found in some patients with SLE may represent the consequences of a chronic and/or inflammatory disease rather than SLE-related central nervous system damage.

Monitoring methotrexate toxicity in juvenile idiopathic arthritis.

OBJECTIVE: To determine the frequency of laboratory abnormalities with methotrexate (MTX) use in patients with juvenile idiopathic arthritis (JIA); to identify potential risk factors for MTX toxicity requiring medical interventions; and to compare the frequency of liver function abnormalities in patients treated with MTX to those not treated with MTX. METHODS: Results of MTX surveillance laboratory testing (SLT) available in clinical databases were reviewed for 588 children with JIA. Information on demographics, JIA features, and factors previously associated with increased frequency of SLT abnormalities was obtained. RESULTS: Results of SLT performed in at least 4-month intervals were available for 138 JIA patients whose JIA was not treated with MTX, and for 198 JIA patients treated with MTX plus folic acid. On SLT of the MTX-treated patients, there were 44 of 2650 (1.7%) AST tests and 90 of 2647 (3.4%) ALT tests that exceeded 2 times the upper limit of normal (> 2 ULN) in 30 children (15%). AST or ALT tests at > 2 ULN occurred more often with systemic JIA (p = 0.04), macrophage activation syndrome, during infections, in systemic antibiotic use, and after intensifying JIA drug regimens. AST or ALT results at > 2 ULN were as frequent among MTX-treated children as those not treated with MTX. Renal and hematological abnormalities with MTX were uncommon. CONCLUSION: Liver enzyme abnormalities > 2 ULN are rare in JIA, irrespective of MTX exposure. These data suggest that the adult standard of SLT every 4-8 weeks may not be necessary in children treated with MTX, especially if certain risk factors are absent.

T cell costimulation: a rational target in the therapeutic armamentarium for autoimmune diseases and transplantation.

T cells are central mediators of adaptive immunity. As such, they are involved in both normal immune responses (e.g., rejection of a transplanted organ) and abnormal ones (e.g., rheumatoid arthritis). T cells require both antigen-specific and costimulatory signals for their full activation. Advances in protein engineering and an increased understanding of the immune response have culminated in the evolution and creation of protein therapeutics that target specific costimulatory molecules. The selective costimulation modulator abatacept (CTLA-4Ig) binds to CD80 and CD86, blocking interaction with CD28, and is approved for the treatment of moderate to severe rheumatoid arthritis. Belatacept, currently enrolling phase III trials in renal transplantation, was rationally designed from abatacept to bind with more avidity to CD86, providing the more potent immunosuppressive properties required for immunosuppression in transplantation. This review describes the relevant immunology and summarizes recent clinical findings on these two molecules. Although both inhibit the CD28 costimulatory pathway, they are tailored for specific disease states--abatacept for autoimmune diseases and belatacept for transplantation.

Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial.

OBJECTIVE: To investigate the efficacy and safety of abatacept in combination with etanercept in patients with active rheumatoid arthritis during a 1-year, randomised, placebo-controlled, double-blind phase, followed by an open-label, long-term extension (LTE). METHODS: Patients continued etanercept (25 mg twice weekly) and were randomised to receive abatacept 2 mg/kg (n = 85) or placebo (n = 36). As the effective dose of abatacept was established as 10 mg/kg in a separate trial, all patients received abatacept 10 mg/kg and etanercept during the LTE. RESULTS: A total of 121 patients were randomised; 80 completed double-blind treatment and entered the LTE. During double-blind treatment, the difference in the percentage of patients achieving the primary end point (modified American College of Rheumatology (ACR) 20 response at 6 months) was not significant between groups (48.2% v 30.6%; p = 0.072). At 1 year, no notable changes in modified ACR responses were observed. Subsequent to the dosing change, similar modified ACR responses were seen during the LTE. Significant improvements in quality of life were observed with abatacept and etanercept versus placebo and etanercept in five of the eight short-form 36 subscales at 1 year. More abatacept and etanercept-treated patients experienced serious adverse events (SAEs) at 1 year than patients receiving placebo and etanercept (16.5% v 2.8%), with 3.5% v 0% experiencing serious infections. CONCLUSION: The combination of abatacept (at a dose of 2 mg/kg during the double-blind phase and 10 mg/kg during the LTE) and etanercept was associated with an increase in SAEs, including serious infections, with limited clinical effect. On the basis of the limited efficacy findings and safety concerns, abatacept in combination with etanercept should not be used for rheumatoid arthritis treatment.

Hypertrophic pachymeningitis in rheumatoid arthritis after adalimumab administration.

Tumor necrosis factor-a (TNF-a) inhibition, used in the treatment of rheumatoid arthritis (RA), is associated with central nervous system (CNS) events including new onset and/or exacerbations of pre-existing demyelinating neurological diseases. We describe a patient with refractory RA where adalimumab, a fully humanized IgG1 monoclonal antibody against TNF-a, may have contributed to the development of meningoencephalitis, with brain biopsy suggestive of hypertrophic pachymeningitis, a rare complication of this disease. The patient had recurrence of neurological symptoms upon repeated administration of adalimumab, and resolution of symptoms after withdrawal.

Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion.

OBJECTIVE: T cells are involved in the pathogenesis of rheumatoid arthritis (RA). In animal models of autoimmune diseases, blockade of costimulatory molecules on antigen-presenting cells has been demonstrated to be effective in preventing or treating this disease by preventing T cell activation. To date, the effect of costimulatory blockade in patients with RA is unknown. The goal of this multicenter, multinational study was to determine the safety and preliminary efficacy of costimulatory blockade using CTLA-4Ig and LEA29Y in RA patients who have been treated unsuccessfully with at least 1 disease-modifying agent. METHODS: CTLA-4Ig, LEA29Y (0.5, 2, or 10 mg/kg), or placebo was administered intravenously to 214 patients with RA. Patients received 4 infusions of study medication, on days 1, 15, 29, and 57, and were evaluated on day 85. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (ACR20). All patients were monitored for treatment safety and tolerability. RESULTS: CTLA-4Ig and LEA29Y infusions were well tolerated at all dose levels. Peri-infusional adverse events were carefully monitored, and showed similar incidence across all dose groups with the exception of headaches, which were slightly more frequent in the 2 treatment groups. The incidence of discontinuations due to worsening of RA was 19%, 12%, and 9% at 0.5, 2, and 10 mg/kg, respectively, in the CTLA-4Ig-treated patients and 3%, 3%, and 6% at 0.5, 2, and 10 mg/kg, respectively, in the LEA29Y-treated patients (versus 31% in the placebo group). ACR20 responses on day 85 had increased in a dose-dependent manner (23%, 44%, and 53% of CTLA-4Ig-treated patients and 34%, 45%, and 61% of LEA29Y-treated patients at 0.5, 2.0, and 10 mg/kg, respectively, versus 31% of placebo-treated patients). CONCLUSION: Both of the costimulatory blocking molecules studied were generally safe and well tolerated. As compared with placebo, both CTLA-4Ig and LEA29Y demonstrated efficacy in the treatment of RA.

Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open-label extension of a randomized, double-blind, placebo controlled trial.

OBJECTIVE: To obtain additional safety and efficacy data on leflunomide (LEF) treatment in combination with methotrexate (MTX) therapy in an open-label extension study in patients with rheumatoid arthritis (RA). METHODS: Following a 24 week, randomized, double-blind trial of adding placebo (PLA) or LEF to stable MTX therapy, patients could enter a 24 week extension. Subjects randomized to LEF and MTX continued treatment [(LEF/LEF) + MTX]. Subjects randomized to PLA and MTX switched to LEF (10 mg/day, no loading dose) and MTX [(PLA/LEF) + MTX]. The double-blind regarding initial randomization was maintained. RESULTS: For subjects in the extension phase, American College of Rheumatology 20% (ACR20) responder rates for the (LEF/LEF) + MTX group were maintained from Week 24 (57/96, 59.4%) to Week 48 (53/96, 55.2%). ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [(PLA/LEF) + MTX] from 25.0% (24/96) at Week 24 to 57.3% (55/96) at Week 48. Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially randomized to LEF. Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose. CONCLUSION: Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension. Importantly, ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose, and those who received a loading does of LEF (100 mg/day x 2 days) at randomization. Fewer adverse events were reported in patients switched to LEF without a loading dose.