The Safety and Immunologic Effectiveness of the Live Varicella-Zoster Vaccine in Patients Receiving Tumor Necrosis Factor Inhibitor Therapy : A Randomized Controlled Trial.

BACKGROUND: The safety and effectiveness of live virus vaccines, such as the varicella-zoster vaccine, are unknown in patients with inflammatory diseases receiving immunomodulatory therapy such as tumor necrosis factor inhibitors (TNFis). OBJECTIVE: To evaluate the safety and immunogenicity of the live attenuated zoster vaccine (ZVL) in patients receiving TNFis. DESIGN: Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02538341). SETTING: Academic and community-based rheumatology, gastroenterology, and dermatology practices. PATIENTS: Adults aged 50 years or older receiving TNFis for any indication. INTERVENTION: Random assignment to ZVL versus placebo. MEASUREMENTS: Glycoprotein enzyme-linked immunosorbent assay (gpELISA) and enzyme-linked immunosorbent spot (ELISpot) from serum and peripheral blood mononuclear cells measured at baseline and 6 weeks after vaccination. Suspected varicella infection or herpes zoster was clinically assessed using digital photographs and polymerase chain reaction on vesicular fluid. RESULTS: Between March 2015 and December 2018, 617 participants were randomly assigned in a 1:1 ratio to receive ZVL (n = 310) or placebo (n = 307) at 33 centers. Mean age was 62.7 years (SD, 7.5); 66.1% of participants were female, 90% were White, 8.2% were Black, and 5.9% were Hispanic. The most common TNFi indications were rheumatoid arthritis (57.6%) and psoriatic arthritis (24.1%); TNFi medications were adalimumab (32.7%), infliximab (31.3%), etanercept (21.2%), golimumab (9.1%), and certolizumab (5.7%). Concomitant therapies included methotrexate (48.0%) and oral glucocorticoids (10.5%). Through week 6, no cases of confirmed varicella infection were found; cumulative incidence of varicella infection or shingles was 0.0% (95% CI, 0.0% to 1.2%). At 6 weeks, compared with baseline, the mean increases in geometric mean fold rise as measured by gpELISA and ELISpot were 1.33 percentage points (CI, 1.17 to 1.51 percentage points) and 1.39 percentage points (CI, 1.07 to 1.82 percentage points), respectively. LIMITATION: Potentially limited generalizability to patients receiving other types of immunomodulators. CONCLUSION: This trial informs safety concerns related to use of live virus vaccines in patients receiving biologics. PRIMARY FUNDING SOURCE: The National Institute of Arthritis and Musculoskeletal and Skin Diseases and the American College of Rheumatology.

Efficacy and safety of the biosimilar ABP 501 compared with adalimumab in patients with moderate to severe rheumatoid arthritis: a randomised, double-blind, phase III equivalence study.

OBJECTIVES: ABP 501 is a Food and Drug Administration-approved biosimilar to adalimumab; structural, functional and pharmacokinetic evaluations have shown that the two are highly similar. We report results from a phase III study comparing efficacy, safety and immunogenicity between ABP 501 and adalimumab. METHODS: In this randomised, double-blind, active comparator-controlled, 26-week equivalence study, patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate were randomised (1:1) to ABP 501 or adalimumab (40 mg) every 2 weeks. Primary endpoint was risk ratio (RR) of ACR20 between groups at week 24. Primary hypothesis that the treatments were equivalent would be confirmed if the 90% CI for RR of ACR20 at week 24 fell between 0.738 and 1.355, demonstrating that ABP 501 is similar to adalimumab. Secondary endpoints included Disease Activity Score 28-joint count-C reactive protein (DAS28-CRP). Safety was assessed via adverse events (AEs) and laboratory evaluations. Antidrug antibodies were assessed to determine immunogenicity. RESULTS: A total of 526 patients were randomised (n=264, ABP 501; n=262 adalimumab) and 494 completed the study. ACR20 response at week 24 was 74.6% (ABP 501) and 72.4% (adalimumab). At week 24, the RR of ACR20 (90% CI) between groups was 1.039 (0.954, 1.133), confirming the primary hypothesis. Changes from baseline in DAS28-CRP, ACR50 and ACR70 were similar. There were no clinically meaningful differences in AEs and laboratory abnormalities. A total of 38.3% (ABP 501) and 38.2% (adalimumab) of patients tested positive for binding antidrug antibodies. CONCLUSIONS: Results from this study demonstrate that ABP 501 is similar to adalimumab in clinical efficacy, safety and immunogenicity in patients with moderate to severe RA. TRIAL REGISTRATION NUMBER: NCT01970475; Results.

Maintenance of remission following 2 years of standard treatment then dose reduction with abatacept in patients with early rheumatoid arthritis and poor prognosis.

OBJECTIVES: To evaluate maintenance of response while reducing intravenous abatacept dose from ~10 mg/kg to ~5 mg/kg in patients with early rheumatoid arthritis (RA) who achieved disease activity score (DAS)28 (erythrocyte sedimentation rate, ESR) <2.6. METHODS: This 1-year, multinational, randomised, double-blind substudy evaluated the efficacy and safety of ~10 mg/kg and ~5 mg/kg abatacept in patients with early RA with poor prognosis who had reached DAS28 (ESR) <2.6 at year 2 of the AGREE study. The primary outcome was time to disease relapse (defined as additional disease-modifying antirheumatic drugs, ≥2 courses high-dose steroids, return to open-label abatacept ~10 mg/kg, or DAS28 (C reactive protein) ≥3.2 at two consecutive visits). RESULTS: 108 patients were randomised (~10 mg/kg, n=58; ~5 mg/kg, n=50). Three and five patients, respectively, discontinued, and four per group returned to open-label abatacept. Relapse over time and the proportion of patients relapsing were similar in both groups (31% (~10 mg/kg) vs 34% (~5 mg/kg); HR: 0.87 (95% CI 0.45 to 1.69)). Mean steady-state trough serum concentration for the ~10 mg/kg group was 20.3-24.1 µg/mL, compared with 8.8-12.0 µg/mL for the ~5 mg/kg group. CONCLUSIONS: This exploratory study suggests that abatacept dose reduction may be an option in patients with poor prognosis early RA who achieve DAS28 (ESR) <2.6 after ≥1 year on abatacept (~10 mg/kg). TRIAL REGISTRATION NUMBER: NCT00989235.

Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial.

OBJECTIVE: To assess the safety of rituximab in combination with a tumor necrosis factor (TNF) inhibitor and methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: Adult patients with active RA (≥ 5 swollen and ≥ 5 tender joints) receiving a stable dose of MTX (10-25 mg/week) and stable dose of TNF inhibitor (etanercept or adalimumab) for ≥ 12 weeks were randomized 2:1 to receive one course of rituximab or placebo, given intravenously at a dose of 2 × 500 mg. The primary end point was the proportion of patients developing ≥ 1 serious infection through week 24. RESULTS: Fifty-one patients were treated with either rituximab or placebo in combination with background MTX and a TNF inhibitor. Baseline characteristics were generally balanced between groups, except for corticosteroid usage (36% in the rituximab arm versus 17% in the placebo arm). A serious infection (pneumonia) was observed in 1 patient (3%) in the rituximab group after 14.4 patient-years of exposure (6.95 events per 100 patient-years, 95% confidence interval 0.98-49.35), compared with none in the placebo group at week 24. Infections were reported in 18 patients (55%) and 11 patients (61%) in the rituximab and placebo groups, respectively. Grade 3 infections were reported in 3 patients (9%) receiving rituximab and in none of the patients receiving placebo. No grade 4 infections were observed, nor were there any opportunistic, fungal, or tuberculosis infections. Serious adverse events (SAEs) were reported in 2 rituximab-treated patients (pneumonia and coronary artery occlusion), whereas there were no SAEs reported in placebo-treated patients. At week 24, the percentage of patients achieving an American College of Rheumatology 20% (ACR20) improvement response was 30% in the rituximab group compared with 17% in the placebo group, and ACR50 responses were achieved by 12% and 6% of patients, respectively. CONCLUSION: The preliminary safety profile of rituximab in combination with a TNF inhibitor and MTX was consistent with the safety profile of rituximab in combination with MTX in other RA trials without a TNF inhibitor, with no new safety signals observed. SAEs were numerically more frequent in the rituximab group, and there was no clear evidence of an efficacy advantage in patients receiving rituximab in combination with a TNF inhibitor and MTX.

Reducing Immunogenicity of Pegloticase With Concomitant Use of Mycophenolate Mofetil in Patients With Refractory Gout: A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: Pegloticase is used for the treatment of severe gout, but its use is limited by immunogenicity. This study was undertaken to evaluate whether mycophenolate mofetil (MMF) prolongs the efficacy of pegloticase. METHODS: Participants were randomized 3:1 to receive 1,000 mg MMF twice daily or placebo for 14 weeks, starting 2 weeks before receiving pegloticase and continuing while receiving intravenous pegloticase 8 mg biweekly for 12 weeks. Participants then received pegloticase alone from week 12 to week 24. The primary end points were the proportion of patients who sustained a serum urate level of ≤6 mg/dl at 12 weeks and the rate of adverse events (AEs). Secondary end points included 24-week durability of serum urate level ≤6 mg/dl. Fisher's exact test and Wilcoxon's 2-sample test were used for analyses, along with Kaplan-Meier estimates and log rank tests. RESULTS: A total of 32 participants received ≥1 dose of pegloticase. Participants were predominantly men (88%), with a mean age of 55.2 years, mean gout duration of 13.4 years, and mean baseline serum urate level of 9.2 mg/dl. At 12 weeks, a serum urate level of ≤6 mg/dl was achieved in 19 (86%) of 22 participants in the MMF arm compared to 4 (40%) of 10 in the placebo arm (P = 0.01). At week 24, the serum urate level was ≤6 mg/dl in 68% of MMF-treated patients versus 30% of placebo-treated patients (P = 0.06), and rates of AEs were similar between groups, with more infusion reactions occurring in the placebo arm (30% versus 0%). CONCLUSION: Our findings indicate that MMF therapy with pegloticase is well tolerated and shows a clinically meaningful improvement in targeted serum urate level of ≤6 mg/dl at 12 and 24 weeks. This study suggests an innovative approach to pegloticase therapy in gout.

Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates.

OBJECTIVES: To report results of subgroup analyses of bone mineral density (BMD) and bone turnover markers from a randomised, double-blind, placebo-controlled, phase II study of denosumab, an investigational RANKL inhibitor, in patients with rheumatoid arthritis (RA) concurrently receiving treatment with bisphosphonates or glucocorticoids. METHODS: Patients received subcutaneous placebo (n=75), denosumab 60 mg (n=71) or denosumab 180 mg (n=72) at baseline and 6 months. Assessments included dual x-ray absorptiometry scans of the lumbar spine and hip, and determination of levels of serum type I C-telopeptide (sCTx-I) and serum procollagen 1N-terminal peptide (P1NP). RESULTS: Denosumab treatment increased mean lumbar spine and hip BMD and reduced sCTx-I and P1NP compared with placebo through 12 months, regardless of baseline BMD or marker levels or concomitant bisphosphonate or glucocorticoid use. CONCLUSIONS: This study extends evidence that denosumab increases BMD and reduces bone turnover in patients with RA and may provide a new therapeutic option for reducing systemic bone loss in patients with RA.

Selective costimulation modulation with abatacept: a look at quality-of-life outcomes in patients with rheumatoid arthritis.

OBJECTIVES: To highlight the importance of improving quality of life (QoL) in patients with rheumatoid arthritis (RA) and to provide a summary of the QoL benefits provided by abatacept in patients who have an inadequate response to disease-modifying antirheumatic drugs (DMARDs) and/or tumor necrosis factor (TNF) antagonists. METHODS: A literature search of the MEDLINE, EMBASE, and BIOSIS databases was performed using the terms "abatacept," "cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)" and "ORENCIA," with the coindexing terms: "abatacept," "CTLA-4," and "ORENCIA." Only articles presenting primary data on QoL outcomes from randomized, placebo-controlled clinical trials of abatacept were included in the review. RESULTS: The literature search initially yielded 220 articles. A total of 8 articles fulfilled the inclusion criteria described above and are reviewed here. In clinical trials to date, abatacept treatment has been shown to improve QoL in patients who have an inadequate response to traditional DMARDs and TNF antagonists. CONCLUSIONS: Improvements in QoL are rated by patients as 1 of the most important benefits of an effective treatment; however, inclusion of QoL measurements in clinical trials as a measure of efficacy is a relatively recent event. Abatacept has been shown to alleviate both the physical and the emotional/social burdens that RA imposes on the patient, including improvements in day-to-day activity and reducing sleep problems and fatigue in patients with RA who have an inadequate response to DMARDs and/or TNF antagonists.

Changes in biomarkers of inflammation and bone turnover and associations with clinical efficacy following infliximab plus methotrexate therapy in patients with early rheumatoid arthritis.

OBJECTIVE: To determine if changes in biomarkers of inflammation and bone turnover in response to treatment with infliximab plus methotrexate (MTX) versus MTX alone are associated with improvement in clinical measures of signs, symptoms, and structural damage in early rheumatoid arthritis. METHODS: Sera were collected from patients in the ASPIRE study who received 3 mg/kg (n = 48) or 6 mg/kg infliximab plus MTX (n = 55), or MTX alone (n = 41). Several baseline biomarker levels correlated with changes in median percentage of American College of Rheumatology improvement (ACR-N), 50% improvement in ACR response (ACR50), and van der Heijde-modified Sharp score (vdHSS) at Week 54. RESULTS: Infliximab plus MTX treatment resulted in more rapid decreases in levels of matrix metalloproteinase-3 (MMP-3), intercellular cell adhesion molecule-1, interleukin 8 (IL-8), and tumor necrosis factor-a than treatment with MTX alone. Baseline levels and decreases from baseline to Weeks 6 and 54 in MMP-3 correlated with improvement in ACR-N response at Week 54. An increase in IL-8 levels from baseline to Week 54 correlated with worsening in vdHSS at Week 54 in the MTX-alone group. Regression analysis of markers at baseline showed that MMP-3 was the only variable associated with ACR50 response and less worsening in vdHSS at Week 54. CONCLUSION: Treatment with infliximab plus MTX resulted in a rapid decrease in inflammation markers. MMP-3 levels at different timepoints were consistently associated with clinical improvements at Week 54 in the infliximab plus MTX group, while increases in IL-8 levels correlated with a worsening in vdHSS at Week 54 in the MTX-alone group.

Longterm reduction of back pain risk in women with osteoporosis treated with teriparatide compared with alendronate.

OBJECTIVE: To compare the effects on back pain of teriparatide versus alendronate, we analyzed the reporting of back pain in a head to head comparator trial and a followup study. METHODS: In the comparator trial, women were randomized to receive either daily self-injected teriparatide 40 microg plus an oral placebo (n = 73), or daily oral alendronate 10 mg plus self-injected placebo (n = 73). Treatment was for a median 14 months. After completion of the comparator trial, 72% of these patients enrolled in a nontreatment followup study. Adverse events were recorded at each comparator trial visit and followup study visit, and the incidence of new or worsening back pain in each group was compared. RESULTS: During the comparator trial, compared with women randomized to alendronate 10 mg, women randomized to teriparatide 40 microg had reduced risk for any back pain (relative risk 0.27, 95% CI 0.09-0.82) and moderate or severe back pain (relative risk 0.19, 95% CI 0.04-0.86). The differences in the reporting of back pain between the teriparatide treated women and the alendronate treated women were sustained during an interval including the comparator trial plus 18 additional months. During an interval including the comparator trial plus 30 additional months, teriparatide treated patients had numerically fewer occurrences of back pain and moderate or severe back pain. CONCLUSION: Compared with women randomized to alendronate 10 mg, women randomized to teriparatide 40 microg had reduced risk of back pain during the trial and 2.5 years of followup.

Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial.

OBJECTIVE: To determine the clinical efficacy, safety, and immunogenicity of abatacept (CTLA-4Ig), a selective costimulation modulator, in patients with rheumatoid arthritis (RA) that has remained active despite methotrexate (MTX) therapy. METHODS: This was a 12-month, multicenter, randomized, double-blind, placebo-controlled study. A total of 339 patients with active RA despite MTX therapy were randomly assigned to receive 10 mg/kg abatacept (n = 115), 2 mg/kg abatacept (n = 105), or placebo (n = 119). This report focuses on the results observed at month 12 of a phase IIb trial. RESULTS: A significantly greater percentage of patients treated with 10 mg/kg abatacept met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at 1 year compared with patients who received placebo (62.6% versus 36.1%; P < 0.001). Greater percentages of patients treated with 10 mg/kg abatacept also achieved ACR50 responses (41.7% versus 20.2%; P < 0.001) and ACR70 responses (20.9% versus 7.6%; P = 0.003) compared with patients who received placebo. For patients treated with 10 mg/kg abatacept, there were also statistically significant and clinically important improvements in modified Health Assessment Questionnaire scores compared with patients who received placebo (49.6% versus 27.7%; P < 0.001). Abatacept at a dosage of 10 mg/kg elicited an increase in rates of remission (Disease Activity Score in 28 joints of <2.6) compared with placebo at 1 year (34.8% versus 10.1%; P < 0.001). The incidence of adverse events was comparable between the groups, and no significant formation of neutralizing antibodies was noted. CONCLUSION: Abatacept was associated with significant reductions in disease activity and improvements in physical function that were maintained over the course of 12 months in patients with RA that had remained active despite MTX treatment. Abatacept was found to be well tolerated and safe over the course of 1 year. Abatacept in combination with MTX has the potential to play an important role in future RA therapy.

Infliximab in the treatment of recalcitrant idiopathic orbital inflammation.

A 15-year-old boy had bilateral idiopathic orbital inflammation refractory to treatment with corticosteroids. He was not only unresponsive to subsequent therapy with methotrexate but also had elevation of serum liver enzymes. In an attempt to minimize further side effects of corticosteroids and to avoid external beam radiation in an adolescent, we began treatment with infliximab, an anti-tumor necrosis-alpha antibody. His symptoms resolved and his disease has not recurred. Use of infliximab may be useful in the treatment of recalcitrant idiopathic orbital pseudotumor.

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.

Open label study to assess infliximab safety and timing of onset of clinical benefit among patients with rheumatoid arthritis.

OBJECTIVE: To assess the timing of onset of clinical benefit following the initial infusion of infliximab and to obtain additional safety experience of infliximab when given in an office setting to patients with rheumatoid arthritis (RA). In addition, the safety of reducing the infusion time from 2 hours to 1 hour was evaluated. METHODS: Patients (n = 553) with active RA despite receiving methotrexate (MTX) were treated with infliximab 3 mg/kg given over 2 h at baseline (Week 0), and Weeks 2, 6, and 14 in this multicenter open-label trial. Patients continued to receive a stable dose of MTX (> or = 7.5 mg/wk). At selected sites, patients tolerating the first 4 infusions were eligible to receive 2 additional infusions at twice the usual infusion rate (given over 1 h). Patients returned for efficacy assessments at 48 h following the initial infusion and several times throughout study participation. RESULTS: By 48 h following the first infusion, significant (p < 0.001) improvements were observed in duration of morning stiffness (34% mean improvement), physician's global disease assessment scores (30%), patient's global disease assessment scores (25%), and patient's pain assessment scores (30%). By Week 16, 52 to 63% mean improvements in these efficacy variables were observed (p < 0.001), the significant improvement was maintained through the end of study participation in the subset of patients who received the additional 1 h infliximab infusions. Through 16 weeks, 10% (54/553) of patients reported an adverse event associated with at least 1 of the 4 infusion procedures; the majority were mild and transient in nature. In the subset of 197 patients who received 2 additional infusions over 1 h, no increase in the frequency or severity of infusion-related adverse events was observed compared to the 2 h infusion. CONCLUSION: Infliximab administered to patients with RA in an outpatient setting resulted in significant clinical improvement within 48 h that was sustained with additional infusions. Approximately 10% of patients experienced an infusion reaction, highlighting the need for direct supervision over patient treatment. Patients who tolerated infliximab infusions given over 2 h also tolerated a 1 h infusion.