Atacicept in patients with rheumatoid arthritis: Results of a multicenter,phase ib,double‐blind,placebo‐controlled,dose‐escalating,single‐ and repeated‐dose study

Objective

Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation‐inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes.

Methods

In this multicenter, phase Ib, randomized, placebo‐controlled, dose‐escalating trial, 73 patients were enrolled into 6 escalating‐dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2‐week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose.

Results

Atacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment‐related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti–citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a dose‐related decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3‐month treatment. Little effect on the erythrocyte sedimentation rate or C‐reactive protein levels was seen.

Conclusion

Atacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.

     

Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: Results of a phase II,randomized, placebo‐controlled,dose‐finding trial

Objective

To assess the efficacy, safety, and biologic activity of atacicept in patients with rheumatoid arthritis (RA) in whom the response to treatment with tumor necrosis factor antagonists was inadequate.

Methods

The Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial (AUGUST I) was a multicenter, phase II, double‐blind, placebo‐controlled dose‐finding study involving 256 patients randomized 1:1:1:1 to receive atacicept (25 mg, 75 mg, or 150 mg) or placebo twice weekly for 4 weeks, then weekly for 21 weeks, with a 13‐week treatment‐free followup period (week 38). The primary end point was a response at week 26 according to the American College of Rheumatology criteria for 20% improvement in disease severity, using the C‐reactive protein level.

Results

No statistically significant differences were observed in the efficacy end points at week 26 (P = 0.410 for overall treatment effect). However, atacicept significantly reduced immunoglobulin and rheumatoid factor (RF) levels, but not anti–citrullinated protein antibody levels, in a dose‐dependent manner, with levels returning toward baseline values during followup. The effects of treatment on IgG‐RF and IgA‐RF were more pronounced than the effects on total IgG and IgA. Adverse events (AEs), including serious AEs, leading to withdrawal were more common among patients treated with atacicept compared with placebo. AEs were variable in nature, and no dose‐dependent trends were observed. The frequency of infection‐related AEs was similar across treatments. No notable effect of treatment on immunization status (protective versus nonprotective titer) was observed after initiation of treatment.

Conclusion

This study did not meet the primary efficacy end point. However, clear biologic activity consistent with the proposed mechanism of action was observed. The results suggest that decreasing the expression of RF may not be sufficient to induce clinical improvement in RA. The safety of atacicept was considered acceptable in this patient population.

     

Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a phase II,randomized, placebo‐controlled trial

Objective

To assess the efficacy, safety, and biologic activity of atacicept in tumor necrosis factor antagonist–naive patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate.

Methods

In this phase II study, patients with active RA (n = 311) were randomized 1:1:1:1 to receive placebo, atacicept 150 mg weekly with or without a 4‐week loading period (twice‐weekly dosing), or open‐label adalimumab 40 mg every other week, for 25 weeks. The primary end point was 20% improvement in disease severity according to the American College of Rheumatology criteria, assessed using the C‐reactive protein level (ACR20‐CRP), at week 26. Secondary end points included additional assessments of efficacy, biologic activity, and safety.

Results

The proportion of patients meeting the primary end point (ACR20‐CRP response) did not differ significantly in the atacicept groups and the placebo group (46% in the placebo group, 45% in the atacicept loading group, and 58% in the atacicept nonloading group). In contrast, an ACR20‐CRP response was observed in 71% of patients in the adalimumab group (P < 0.001 versus placebo). ACR50‐CRP response rates were significantly higher in all active‐treatment groups compared with placebo, but ACR70‐CRP response rates were superior only in the adalimumab group. Atacicept treatment reduced the levels of serum IgG, IgA, and IgM rheumatoid factor and the levels of circulating mature B cells and plasma cells. The effects of treatment were similar with and without loading. Immunoglobulin levels returned toward baseline values during the treatment‐free followup period (week 38). The most frequent adverse events associated with atacicept represented common illnesses. No serious infections occurred among patients treated with atacicept.

Conclusion

The primary end point (ACR20‐CRP response) was not met despite significant biologic effects of atacicept that were consistent with its proposed mechanism of action. Modest effects of atacicept were seen for some secondary efficacy end points. Treatment with atacicept raised no new safety concerns.

     

Therapeutic benefit of blocking interleukin‐6 activity with an anti–interleukin‐6 receptor monoclonal antibody in rheumatoid arthritis: A randomized,double‐blind,placebo‐controlled,dose‐escalation trial

Objective

To investigate the safety and efficacy of MRA, a recombinant human anti–interleukin‐6 (anti–IL‐6) receptor monoclonal antibody of the IgG1 subclass that inhibits the function of IL‐6, in patients with established rheumatoid arthritis (RA).

Methods

A randomized, double‐blind, placebo‐controlled, dose‐escalation trial was conducted in 45 patients with active RA, as defined by the American College of Rheumatology (ACR) revised criteria. Patients were sequentially allocated to receive a single intravenous dose of either 0.1, 1, 5, or 10 mg/kg of MRA or placebo. The primary efficacy end point was meeting the ACR 20% response criteria at week 2 after treatment.

Results

Demographic features were similar between treatment groups. At week 2, a significant treatment difference was observed between the 5 mg/kg of MRA and placebo, with 5 patients (55.6%) in the MRA cohort and none in the placebo cohort achieving ACR 20% improvement. There was no statistically significant difference in the ACR 20% response between the other 3 MRA cohorts and placebo at week 2. The mean disease activity score at week 2 in those who received 5 mg/kg and 10 mg/kg of MRA was 4.8 and 4.7 (P < 0.001 and P < 0.001 by analysis of variance), respectively. These mean scores were statistically significantly lower than those in the 0.1‐ and 1‐mg/kg MRA and the placebo cohorts (6.4, 6.2, and 7.0, respectively). The erythrocyte sedimentation rate and C‐reactive protein values fell significantly in the 5‐ and 10‐mg/kg MRA cohorts and normalized 2 weeks after treatment. Seventeen patients (5, 4, 6, 2, and 0 patients in the placebo, 0.1‐, 1‐, 5‐, and 10‐mg/kg MRA cohorts, respectively) required corticosteroid or disease‐modifying antirheumatic drug treatment because of active disease before study end. They were regarded as nonresponders from the time they received these treatments. Diarrhea was the most common adverse event, occurring in 8% of patients. Seven patients (15.6%) reported a severe adverse event (3, 1, 2, and 2 patients in the placebo, 0.1‐, 1‐, and 10‐mg/kg MRA cohorts). There were no serious adverse events that were thought to be related to the study drug.

Conclusion

This is the first randomized controlled trial showing that inhibition of IL‐6 significantly improved the signs and symptoms of RA and normalized the acute‐phase reactants. Further research with multiple dosing is necessary to define the most appropriate therapeutic regimen of MRA in RA.

     

Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: Results of a phase I,placebo‐controlled,double‐blind,dose‐escalation study

Objective

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies and inflammation in multiple organ systems. Elevation of messenger RNA levels of interferon (IFN)–regulated genes (IRGs) has been described in the peripheral blood of SLE patients and has been associated with disease activity. The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of rontalizumab, a humanized IgG1 monoclonal antibody that neutralizes IFNα, were assessed in a phase I dose‐escalation study of single and repeat doses of rontalizumab in adults with mildly active SLE. The present report describes the safety results and the impact of rontalizumab on expression of IRGs, IFN‐inducible proteins, and autoantibodies.

Methods

Patients were enrolled into dose groups ranging from 0.3 to 10 mg/kg, administered via intravenous (IV) or subcutaneous routes. Expression levels of 7 IRGs and IFN‐inducible serum proteins were monitored as potential biomarkers for the PD activity of rontalizumab.

Results

An acceptable safety profile was demonstrated for rontalizumab in patients with SLE. Prespecified criteria for dose‐limiting toxicity were not met. The incidence of serious adverse events was comparable across cohorts. The PK properties were as expected for an IgG1 monoclonal antibody and were proportional to dose. Following administration of rontalizumab, a rapid decline in the expression of IRGs was observed in the 3 mg/kg and 10 mg/kg IV cohorts, and this effect could be sustained with repeat dosing. There was no apparent decline in the levels of IFN‐inducible proteins or levels of anti–double‐stranded DNA and anti–extractable nuclear antigen autoantibodies following treatment with rontalizumab.

Conclusion

The preliminary safety, PK profile, and observed PD effects of rontalizumab support further evaluation of its safety and efficacy in SLE.

     

LY2439821, a humanized anti–interleukin‐17 monoclonal antibody,in the treatment of patients with rheumatoid arthritis: A phase I randomized,double‐blind,placebo‐controlled,proof‐of‐concept study

Objective

We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti–interleukin‐17 (anti–IL‐17) monoclonal antibody, in a first in‐human trial in rheumatoid arthritis (RA) patients taking oral disease‐modifying antirheumatic drugs (DMARDs).

Methods

This randomized, double‐blind, placebo‐controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10.

Results

Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all‐LY2439821–combined groups (−2.3, −2.4, and −2.3, respectively) than in the placebo group (−1.7) at week 10 (P ≤ 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821‐treated patients than in placebo‐treated patients at multiple time points. There was no apparent dose‐response relationship in treatment‐emergent adverse events.

Conclusion

LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL‐17 as a potential novel goal for the treatment of RA.

     

Treatment of rheumatoid arthritis with humanized anti–interleukin‐6 receptor antibody: A multicenter,double‐blind,placebo‐controlled trial

Objective

Interleukin‐6 (IL‐6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL‐6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL‐6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti–IL‐6 receptor antibody, MRA, in patients with RA.

Methods

In a multicenter, double‐blind, placebo‐controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria.

Results

Treatment with MRA reduced disease activity in a dose‐dependent manner. At 3 months, 78% of patients in the 8‐mg group, 57% in the 4‐mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8‐mg group versus placebo). Forty percent of patients in the 8‐mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4‐mg, and 8‐mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti‐DNA antibodies. Anti‐MRA antibodies were detected in 2 patients.

Conclusion

Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.

     

Sifalimumab,a Human Anti–Interferon‐α Monoclonal Antibody,in Systemic Lupus Erythematosus: A Phase I Randomized,Controlled, Dose‐Escalation Study

Objective

To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate‐to‐severe systemic lupus erythematosus (SLE).

Methods

In this multicenter, double‐blind, placebo‐controlled, sequential dose‐escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment‐emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed.

Results

Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate‐to‐severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment‐emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n = 4) versus 2.5% (n = 1). Serum sifalimumab concentrations increased in a linear and dose‐proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline.

Conclusion

The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.

     

Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: A phase II,four‐week,multicenter, randomized,double‐blind,placebo‐controlled trial

Objective

To compare the efficacy and tolerability of the novel cyclooxygenase 2‐selective inhibitor lumiracoxib with placebo and diclofenac in osteoarthritis (OA).

Methods

Adults (n = 583) with knee or hip OA were randomized to receive for 4 weeks lumiracoxib 50, 100, or 200 mg twice daily or 400 mg once daily; placebo; or diclofenac 75 mg twice daily. Efficacy assessments included overall joint pain intensity and Western Ontario and McMaster Universities Osteoarthritis Index subscales; tolerability was evaluated by adverse event and physician reporting.

Results

All lumiracoxib doses were superior to placebo in relieving pain, improving stiffness, and improving physical function after 4 weeks. At study endpoint, pain relief was comparable among all lumiracoxib dosages and similar to diclofenac. Lumiracoxib tolerability was superior to diclofenac and comparable to placebo.

Conclusion

Lumiracoxib provides predictable and sustained relief from pain, stiffness, and impaired physical function in OA. Lumiracoxib shows clinically comparable efficacy and superior tolerability to diclofenac.

     

Treatment of rheumatoid arthritis with anakinra,a recombinant human interleukin‐1 receptor antagonist,in combination with methotrexate: Results of a twenty‐four–week,multicenter, randomized,double‐blind,placebo‐controlled trial

Objective

To evaluate the efficacy and safety of anakinra in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA).

Methods

Patients with moderate‐to‐severe active RA who were receiving MTX for 6 consecutive months, with stable doses for ≥3 months (those with disease duration of >6 months but <12 years) were randomized into 6 groups: placebo or 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg of anakinra administered in a single, daily, subcutaneous injection. The primary efficacy end point was the proportion of subjects who met the American College of Rheumatology 20% improvement criteria (attained an ACR20 response) at week 12.

Results

A total of 419 patients were randomized in the study. Patient demographics and disease status were similar in the 6 treatment groups. The ACR20 responses at week 12 in the 5 active treatment plus MTX groups demonstrated a statistically significant (P = 0.001) dose‐response relationship compared with the ACR20 response in the placebo plus MTX group. The ACR20 response rate in the anakinra 1.0‐mg/kg (46%; P = 0.001) and 2.0‐mg/kg (38%; P = 0.007) dose groups was significantly greater than that in the placebo group (19%). The ACR20 responses at 24 weeks were consistent with those at 12 weeks. Similar improvements in anakinra‐treated subjects were noted in individual ACR components, erythrocyte sedimentation rate, onset of ACR20 response, sustainability of ACR20 response, and magnitude of ACR response. Anakinra was safe and well tolerated. Injection site reaction was the most frequently noted adverse event, and this led to premature study withdrawal in 7% (1.0‐mg/kg group) to 10% (2.0‐mg/kg group) of patients receiving higher doses.

Conclusion

In patients with persistently active RA, the combination of anakinra and MTX was safe and well tolerated and provided significantly greater clinical benefit than MTX alone.

     

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.

     

Low‐dose naltrexone for the treatment of fibromyalgia: Findings of a small,randomized, double‐blind,placebo‐controlled,counterbalanced, crossover trial assessing daily pain levels

Objective

To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low‐dose naltrexone on daily self‐reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue.

Methods

Thirty‐one women with fibromyalgia participated in the randomized, double‐blind, placebo‐controlled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain.

Results

When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low‐dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low‐dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty‐two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low‐dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low‐dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported.

Conclusion

The preliminary evidence continues to show that low‐dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well‐tolerated. Parallel‐group randomized controlled trials are needed to fully determine the efficacy of the medication.

     

Double‐blind randomized controlled clinical trial of the interleukin‐6 receptor antagonist,tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate

Objective

To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti–interleukin‐6 (IL‐6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA).

Methods

The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo.

Results

A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose‐related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C‐reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high‐density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX.

Conclusion

These results indicate that targeted blockade of IL‐6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.

     

A randomized,placebo‐controlled,double‐masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis

Objective

To investigate the safety and efficacy of etanercept in the treatment of uveitis associated with juvenile idiopathic arthritis (JIA).

Methods

Children who met the American College of Rheumatology diagnostic criteria for JIA with active uveitis, who had anterior chamber cells of ≥1+ or requiring topical corticosteroid ≥3 times daily, and who were on a stable regimen for arthritis treatment were eligible. Study participants received etanercept (0.4 mg/kg) or placebo administered subcutaneously twice weekly for 6 months. All participants received open‐label etanercept for an additional 6 months.

Results

Five patients received placebo and 7 received etanercept. Three of the 7 patients treated with etanercept and 2 of the 5 placebo‐treated patients were considered ophthalmic successes (P = 1.0). One patient in each treatment group was considered a treatment failure. Three of the 7 etanercept‐treated and 2 of the 5 placebo‐treated patients were neither successes nor failures by our definition. There were no serious adverse events for any patient during the entire study period. Reports of minor infections were comparable in each treatment group, 71% for etanercept and 60% for placebo (P = 0.58).

Conclusion

In this small pilot study there was no apparent difference in the anterior segment inflammation between patients treated with etanercept and placebo. The stringent criteria used to measure ophthalmic success of treatment and the small patient population limit the implications of our findings.

     

Benefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthritis: A double‐blind,placebo‐controlled study

Objective

To examine the safety and efficacy of an extract of Tripterygium wilfordii Hook F (TWHF) in the treatment of patients with rheumatoid arthritis (RA).

Methods

An ethanol/ethyl acetate extract from the roots of TWHF was prepared and used in a prospective, double‐blind, placebo‐controlled study in patients with longstanding RA in whom conventional therapy had failed. Patients were randomly assigned to receive either placebo or low‐dose (180 mg/day) or high‐dose (360 mg/day) extract for 20 weeks, followed by an open‐label extension period. Clinical responses were defined as 20% improvement in disease activity according to the American College of Rheumatology criteria. Side effects were actively queried and recorded at each visit.

Results

A total of 35 patients were enrolled in the trial; 21 patients completed the 20‐week study. One patient from each group withdrew because of side effects. Twelve, 10, and 10 patients in the placebo, low‐dose, and high‐dose groups, respectively, completed at least 4 weeks of treatment. Of these patients, 8 and 4 in the high‐dose and low‐dose groups, but none in the placebo group, met criteria for clinical response. Four, 4, and 7 patients in the placebo, low‐dose, and high‐dose groups, respectively, were enrolled in the open‐label extension; of these, 2, 4, and 5 patients, respectively, met criteria for clinical response. The most common side effect was diarrhea, which caused 1 patient in the high‐dose group to withdraw from the trial. No patients withdrew because of adverse events during the open‐label extension.

Conclusion

The ethanol/ethyl acetate extract of TWHF shows therapeutic benefit in patients with treatment‐refractory RA. At therapeutic dosages, the TWHF extract was well tolerated by most patients in this study.

     

Intraarticular injection of anakinra in osteoarthritis of the knee: A multicenter,randomized, double‐blind,placebo‐controlled study

Objective

To evaluate the clinical response, safety, and tolerability of a single intraarticular injection of anakinra in patients with symptomatic osteoarthritis (OA) of the knee.

Methods

Patients with OA of the knee were enrolled in a multicenter, double‐blind, placebo‐controlled study and randomized 2:1:2 to receive a single intraarticular injection of placebo, anakinra 50 mg, or anakinra 150 mg in their symptomatic knee. Patients were evaluated for 12 weeks postinjection. The primary end point was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score from baseline to week 4. Safety assessments included the evaluation of adverse events (AEs), laboratory tests, and vital signs. Pharmacokinetic parameters were assessed in a subset of patients.

Results

Of 170 patients who enrolled, 160 (94%) completed the study. The mean improvements from baseline to week 4 in the WOMAC score were not statistically different between the placebo group and the patients who received 50 mg of anakinra (P = 0.67) or 150 mg of anakinra (P = 0.77). Anakinra was well tolerated. No withdrawals due to AEs or serious AEs, and no serious infections or deaths were reported. No clinically significant trends were noted in laboratory values or vital signs. Pharmacokinetic parameters demonstrated that the mean terminal half‐life of anakinra in serum after intraarticular injection was ∼4 hours.

Conclusion

Anakinra was well tolerated as a single 50‐mg or 150‐mg intraarticular injection in patients with OA of the knee. However, anakinra was not associated with improvements in OA symptoms compared with placebo.

     

High versus low dosing of oral colchicine for early acute gout flare: Twenty‐four–hour outcome of the first multicenter,randomized, double‐blind,placebo‐controlled,parallel‐group,dose‐comparison colchicine study

Objective

Despite widespread use of colchicine, the evidence basis for oral colchicine therapy and dosing in acute gout remains limited. The aim of this trial was to compare low‐dose colchicine (abbreviated at 1 hour) and high‐dose colchicine (prolonged over 6 hours) with placebo in gout flare, using regimens producing comparable maximum plasma concentrations in healthy volunteers.

Methods

This multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study compared self‐administered low‐dose colchicine (1.8 mg total over 1 hour) and high‐dose colchicine (4.8 mg total over 6 hours) with placebo. The primary end point was ≥50% pain reduction at 24 hours without rescue medication.

Results

There were 184 patients in the intent‐to‐treat analysis. Responders included 28 of 74 patients (37.8%) in the low‐dose group, 17 of 52 patients (32.7%) in the high‐dose group, and 9 of 58 patients (15.5%) in the placebo group (P = 0.005 and P = 0.034, respectively, versus placebo). Rescue medication was taken within the first 24 hours by 23 patients (31.1%) in the low‐dose group (P = 0.027 versus placebo), 18 patients (34.6%) in the high‐dose group (P = 0.103 versus placebo), and 29 patients (50.0%) in the placebo group. The low‐dose group had an adverse event (AE) profile similar to that of the placebo group, with an odds ratio (OR) of 1.5 (95% confidence interval [95% CI] 0.7–3.2). High‐dose colchicine was associated with significantly more diarrhea, vomiting, and other AEs compared with low‐dose colchicine or placebo. With high‐dose colchicine, 40 patients (76.9%) had diarrhea (OR 21.3 [95% CI 7.9–56.9]), 10 (19.2%) had severe diarrhea, and 9 (17.3%) had vomiting. With low‐dose colchicine, 23.0% of the patients had diarrhea (OR 1.9 [95% CI 0.8–4.8]), none had severe diarrhea, and none had vomiting.

Conclusion

Low‐dose colchicine yielded both maximum plasma concentration and early gout flare efficacy comparable with that of high‐dose colchicine, with a safety profile indistinguishable from that of placebo.

     

Treatment of giant cell arteritis using induction therapy with high‐dose glucocorticoids: A double‐blind,placebo‐controlled,randomized prospective clinical trial

Objective

Glucocorticoid (GC) therapy for giant cell arteritis (GCA) is effective but requires prolonged administration, resulting in adverse side effects. The goal of the current study was to test the hypothesis that induction treatment with high‐dose pulse intravenous (IV) methylprednisolone permits a shorter course of therapy.

Methods

Twenty‐seven patients with biopsy‐proven GCA were enrolled in a randomized, double‐blind, placebo‐controlled study to receive IV methylprednisolone (15 mg/kg of ideal body weight/day) or IV saline for 3 consecutive days. All patients were started on 40 mg/day prednisone and followed the same tapering schedule as long as disease activity was controlled. The numbers of patients with disease in remission after 36, 52, and 78 weeks of treatment and taking ≤5 mg/day prednisone were compared. Cumulative prednisone dose, number of relapses, and development of adverse GC effects were assessed.

Results

Ten of the 14 IV GC–treated patients, but only 2 of 13 control patients, were taking ≤5 mg/day prednisone at 36 weeks (P = 0.003). This difference was maintained; there was a higher number of sustained remissions after discontinuation of treatment in the IV GC–treated group and a lower median daily dose of prednisone at 78 weeks (P = 0.0004). The median cumulative dose of oral prednisone, excluding the IV GC dose, was 5,636 mg in the IV GC–treated group compared with 7,860 mg in the IV saline–treated group (P = 0.001).

Conclusion

Initial treatment of GCA with IV GC pulses allowed for more rapid tapering of oral GCs and had long‐term benefits, with a higher frequency of patients experiencing sustained remission of their disease after discontinuation of treatment.

     

Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: A randomized,double‐blind,placebo‐controlled trial in asymptomatic antiphospholipid antibody–positive individuals

Objective

To determine the efficacy of a daily dose of 81 mg aspirin in primary thrombosis prevention in asymptomatic, persistently antiphospholipid antibody (aPL)–positive individuals (those with positive aPL but no vascular and/or pregnancy events).

Methods

The Antiphospholipid Antibody Acetylsalicylic Acid (APLASA) study was a multicenter, randomized, double‐blind, placebo‐controlled clinical trial in which asymptomatic, persistently aPL‐positive individuals were randomized to receive a daily dose of 81 mg of aspirin or placebo. In a separate observational and parallel study, asymptomatic, persistently aPL‐positive individuals who were taking aspirin or declined randomization were followed up prospectively.

Results

In the APLASA study, 98 individuals were randomized to receive aspirin or placebo (mean ± SD followup period 2.30 ± 0.95 years), of whom 48 received aspirin and 50 received placebo. In the observational study, 74 nonrandomized individuals were followed up prospectively (mean ± SD followup period 2.46 ± 0.76 years); 61 received aspirin and 13 did not. In the APLASA study, the acute thrombosis incidence rates were 2.75 per 100 patient‐years for aspirin‐treated subjects and 0 per 100 patient‐years for the placebo‐treated subjects (hazard ratio 1.04, 95% confidence interval 0.69–1.56) (P = 0.83). Similarly, in the observational study, the acute thrombosis incidence rates were 2.70 per 100 patient‐years for aspirin‐treated subjects and 0 per 100 patient‐years for those not treated with aspirin. All but 1 patient with thrombosis in either study had concomitant thrombosis risk factors and/or systemic autoimmune disease at the time of thrombosis.

Conclusion

Our results suggest that asymptomatic, persistently aPL‐positive individuals do not benefit from low‐dose aspirin for primary thrombosis prophylaxis, have a low overall annual incidence rate of acute thrombosis, and develop vascular events when additional thrombosis risk factors are present.

     

Efficacy and tolerability of a selective α2C‐adrenergic receptor blocker in recovery from cold‐induced vasospasm in scleroderma patients: A single‐center,double‐blind,placebo‐controlled,randomized crossover study

Objective

OPC‐28326 is a selective α‐adrenergic antagonist with preferential binding to the α_2C‐adrenergic receptor (α_2C‐AR) subtype. This study observed the effect of OPC‐28326 on skin temperature and digital blood flow following an acute cold challenge in patients with Raynaud's phenomenon secondary to scleroderma.

Methods

The study was designed as a single‐center, double‐blind, placebo‐controlled, randomized, 3‐period crossover study of OPC‐28326 (oral doses of 10 mg or 40 mg) or placebo. The primary outcome measures were the time to recover 50% and 70% of the fall (induced by cold challenge) in baseline digital skin temperature.

Results

Twelve of 13 enrolled patients completed the study. The mean time to achieve 50% and 70% recovery of the change in prechallenge digital skin temperature was shorter after the OPC‐28326 40‐mg dose than after placebo (50% recovery at 5.8 minutes versus 10.0 minutes [P = 0.02]; 70% recovery at 13.8 minutes versus 19.5 minutes [P = 0.01]). These recovery times tended to be shorter in the 10 mg OPC‐28326 group as well, but the difference versus placebo was not significant (50% recovery at 9.0 minutes versus 10.0 minutes [P = 0.65]; 70% recovery at 15.3 minutes versus 19.5 minutes [P = 0.07]). Total digital blood flow tended to be lower prior to the cold challenge and after administration of 40 mg OPC‐28326, as compared with that after placebo, but the difference was not significant. Symptoms that were potentially drug‐related were reported more frequently with 40 mg OPC‐28326 than with 10 mg OPC‐28326 or with placebo, but none were serious or sustained.

Conclusion

OPC‐28326 at doses of 10 mg and 40 mg was well tolerated during this study. The shorter time to skin temperature recovery after 40 mg OPC‐28326 suggests that selective α_2C‐AR blockade improves digital skin perfusion during recovery from cooling in patients with Raynaud's phenomenon secondary to scleroderma.