Methotrexate treatment in juvenile localized scleroderma: A randomized,double‐blind,placebo‐controlled trial

Objective

Juvenile localized scleroderma is a chronic progressive fibrotic disorder of the skin that causes permanent disability and aesthetic damage. This study was undertaken to assess the safety and efficacy of methotrexate (MTX) in the treatment of juvenile localized scleroderma.

Methods

In this double‐blind study, patients with active juvenile localized scleroderma were randomized (2:1) to receive oral MTX (15 mg/m², maximum 20 mg) or placebo once weekly, for 12 months or until treatment failure. Both groups received oral prednisone (1 mg/kg/day, maximum 50 mg) for the first 3 months. A target lesion was evaluated clinically, with infrared thermography and using a computerized scoring system with skin score rate (SSR) evaluation. Response to treatment was defined as the absence of new lesions, SSR ≤1, and a decrease in lesion temperature of at least 10% compared to baseline. Treatment failure was defined as the occurrence of new lesions, SSR >1, or increased lesion temperature. All analyses were done on the intent‐to‐treat population.

Results

Of the 85 patients screened, 70 (ages 6–17 years) were randomized (46 to the MTX group, 24 to the placebo group). The mean disease duration was 2.3 years. After an initial response in all patients, disease relapsed in 15 MTX‐treated patients (32.6%) and 17 placebo‐treated patients (70.8%) (P < 0.005). New lesions appeared in 3 MTX‐treated patients (6.5%) versus 4 placebo‐treated patients (16.7%). The mean SSR decreased from 1 to 0.79 in the MTX group and increased from 1 to 1.1 in the placebo group, and the mean target lesion temperature decreased by 44.4% in the MTX group versus 12.1% in the placebo group. Twenty‐six patients in the MTX group (56.5%) and 11 patients in the placebo group (45.8%) developed mild side effects related to treatment. None of the side effects were severe enough to necessitate treatment discontinuation.

Conclusion

Our findings indicate that MTX is efficacious in the treatment of juvenile localized scleroderma and is well tolerated.

     

Febuxostat,a novel nonpurine selective inhibitor of xanthine oxidase: A twenty‐eight–day,multicenter, phase II,randomized, double‐blind,placebo‐controlled,dose‐response clinical trial examining safety and efficacy in patients with gout

Objective

Gout affects ∼1–2% of the American population. Current options for treating hyperuricemia in chronic gout are limited. The purpose of this study was to assess the safety and efficacy of febuxostat, a nonpurine selective inhibitor of xanthine oxidase, in establishing normal serum urate (sUA) concentrations in gout patients with hyperuricemia (≥8.0 mg/dl).

Methods

We conducted a phase II, randomized, double‐blind, placebo‐controlled trial in 153 patients (ages 23–80 years). Subjects received febuxostat (40 mg, 80 mg, 120 mg) or placebo once daily for 28 days and colchicine prophylaxis for 14 days prior to and 14 days after randomization. The primary end point was the proportion of subjects with sUA levels <6.0 mg/dl on day 28.

Results

Greater proportions of febuxostat‐treated patients than placebo‐treated patients achieved an sUA level <6.0 mg/dl at each visit (P < 0.001 for each comparison). The targeted sUA level was attained on day 28 in 0% of those taking placebo and in 56% of those taking 40 mg, 76% taking 80 mg, and 94% taking 120 mg of febuxostat. The mean sUA reduction from baseline to day 28 was 2% in the placebo group and 37% in the 40‐mg, 44% in the 80‐mg, and 59% in the 120‐mg febuxostat groups. Gout flares occurred with similar frequency in the placebo (37%) and 40‐mg febuxostat (35%) groups and with increased frequency in the higher dosage febuxostat groups (43% taking 80 mg; 55% taking 120 mg). During colchicine prophylaxis, gout flares occurred less frequently (8–13%). Incidences of treatment‐related adverse events were similar in the febuxostat and placebo groups.

Conclusion

Treatment with febuxostat resulted in a significant reduction of sUA levels at all dosages. Febuxostat therapy was safe and well tolerated.

     

Tofacitinib (CP‐690,550) in patients with rheumatoid arthritis receiving methotrexate: Twelve‐month data from a twenty‐four–month phase III randomized radiographic study

Objective

The purpose of this 24‐month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Data from a planned 12‐month interim analysis are reported.

Methods

In this double‐blind, parallel‐group, placebo‐controlled study, patients receiving background MTX were randomized 4:4:1:1 to tofacitinib at 5 mg twice daily, tofacitinib at 10 mg twice daily, placebo to tofacitinib at 5 mg twice daily, and placebo to tofacitinib at 10 mg twice daily. At month 3, nonresponder placebo‐treated patients were advanced in a blinded manner to receive tofacitinib as indicated above; remaining placebo‐treated patients were advanced at 6 months. Four primary efficacy end points were all analyzed in a step‐down procedure.

Results

At month 6, response rates according to the American College of Rheumatology 20% improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo (51.5% and 61.8%, respectively, versus 25.3%; both P < 0.0001). At month 6, least squares mean (LSM) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06, respectively, versus 0.47 for placebo (P = 0.0792 and P ≤ 0.05, respectively). At month 3, LSM changes in the Health Assessment Questionnaire disability index score for tofacitinib at 5 mg and 10 mg twice daily were –0.40 (significance not declared due to step‐down procedure) and –0.54 (P < 0.0001), respectively, versus –0.15 for placebo. At month 6, rates of remission (defined as a value <2.6 for the 4‐variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate) for tofacitinib at 5 mg and 10 mg twice daily were 7.2% (significance not declared due to step‐down procedure) and 16.0% (P < 0.0001), respectively, versus 1.6% for placebo. The safety profile was consistent with findings in previous studies.

Conclusion

Data from this 12‐month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX.

     

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.

     

A randomized controlled trial to evaluate the slow‐acting symptom‐modifying effects of colchicine in osteoarthritis of the knee: A preliminary report

Objective

To determine if colchicine added to nimesulide may have a beneficial effect on osteoarthritis (OA) of the knee.

Methods

Colchicine 0.5 mg twice daily or placebo was added to nimesulide (a nonsteroidal antiinflammatory drug) in 36 patients with OA of the knee in a randomized, double‐blind, placebo‐controlled trial over a 5‐month period.

Results

The 30% improvement rate at 20 weeks was higher in the colchicine group than in the control group receiving placebo, as measured by total Western Ontario and McMaster University Osteoarthritis scores (57.9% versus 23.5%) and visual analog scale for index knee pain (52.6% versus 17.6%) (primary measures of response). The significance persisted on combined analysis by Mantel‐Haenszel test (P = 0.062). Comparison of means also showed significant improvement in the colchicine group versus the control group in a multivariate analysis performed using T² test (P = 0.0115).

Conclusion

Among patients with OA of the knee, the group receiving colchicine plus nimesulide exhibited significantly greater symptomatic benefit at 20 weeks than did the control group receiving nimesulide plus placebo.

     

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.

     

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.

     

Pregabalin for the treatment of fibromyalgia syndrome: Results of a randomized,double‐blind,placebo‐controlled trial

Objective

Fibromyalgia syndrome (FMS) is characterized by widespread musculoskeletal pain and lowered pain threshold. Other prominent symptoms include disordered sleep and fatigue. FMS affects an estimated 2% of the population, predominantly women. This trial was designed to evaluate the efficacy and safety of pregabalin, a novel α₂‐δ ligand, for treatment of symptoms associated with FMS.

Methods

This multicenter, double‐blind, 8‐week, randomized clinical trial compared the effects of placebo with those of 150, 300, and 450 mg/day pregabalin on pain, sleep, fatigue, and health‐related quality of life in 529 patients with FMS. The primary outcome variable was the comparison of end point mean pain scores, derived from daily diary ratings of pain intensity, between each of the pregabalin treatment groups and the placebo group.

Results

Pregabalin at 450 mg/day significantly reduced the average severity of pain in the primary analysis compared with placebo (−0.93 on a 0–10 scale) (P ≤ 0.001), and significantly more patients in this group had ≥50% improvement in pain at the end point (29%, versus 13% in the placebo group; P = 0.003). Pregabalin at 300 and 450 mg/day was associated with significant improvements in sleep quality, fatigue, and global measures of change. Pregabalin at 450 mg/day improved several domains of health‐related quality of life. Dizziness and somnolence were the most frequent adverse events. Rates of discontinuation due to adverse events were similar across all 4 treatment groups.

Conclusion

Pregabalin at 450 mg/day was efficacious for the treatment of FMS, reducing symptoms of pain, disturbed sleep, and fatigue compared with placebo. Pregabalin was well tolerated and improved global measures and health‐related quality of life.

     

Long‐term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: The study on osteoarthritis progression prevention,a two‐year,randomized, double‐blind,placebo‐controlled trial

Objective

To assess the long‐term effects of chondroitins 4 and 6 sulfate (CS) on the radiographic progression of, and symptom changes associated with, knee osteoarthritis (OA).

Methods

We performed an international, randomized, double‐blind, placebo‐controlled trial in which 622 patients with knee OA were randomly assigned to receive either 800 mg CS (n = 309 patients) or placebo (n = 313 patients) once daily for 2 years. Radiographs of the target knee, using the Lyon schuss view, were obtained at the time of enrollment and at 12, 18, and 24 months. The minimum joint space width (JSW) of the medial compartment of the tibiofemoral joint was assessed by digital image analysis. The primary outcome was the loss in minimum JSW over 2 years.

Results

The intent‐to‐treat analysis demonstrated a significant reduction (P < 0.0001) in minimum JSW loss in the CS group (mean ± SEM −0.07 ± 0.03 mm) as compared with the placebo group (−0.31 ± 0.04 mm). The percentage of patients with radiographic progression ≥0.25 mm was significantly reduced in the CS group compared with the placebo group (28% versus 41% [P < 0.0005]; relative risk reduction 33% [95% confidence interval 16–46%]). The number of patients needed to treat was 8 (95% confidence interval 5–17). Pain improved significantly faster in the CS group than in the placebo group (P < 0.01). There were no differences in safety between groups.

Conclusion

The long‐term combined structure‐modifying and symptom‐modifying effects of CS suggest that it could be a disease‐modifying agent in patients with knee OA.

     

Evaluation of the structure‐modifying effects of diacerein in hip osteoarthritis: ECHODIAH,a three‐year,placebo‐controlled trial

Objective

To evaluate the ability of diacerein, an interleukin‐1β inhibitor, to slow the progressive decrease in joint space width observed in patients with hip osteoarthritis (OA).

Methods

In this randomized, double‐blind, placebo‐controlled 3‐year study, 507 patients with primary OA of the hip (by the American College of Rheumatology criteria) received diacerein (50 mg twice a day) or placebo. The minimal hip joint space width was measured by a central reader on yearly pelvic radiographs, using a 0.1‐mm–graduated magnifying glass.

Results

Baseline characteristics were comparable in the 2 treatment groups (255 patients receiving diacerein, 252 receiving placebo); 238 patients (47%) discontinued the study, mainly because of adverse events in the diacerein group (25% versus 12% with placebo) and because of inefficacy in the placebo group (14% versus 7% with diacerein). The percentage of patients with radiographic progression, defined by a joint space loss of at least 0.5 mm, was significantly lower in patients receiving diacerein than in patients receiving placebo, both in the intent‐to‐treat analysis and in the completer analysis (50.7% versus 60.4% [P = 0.036] and 47.3% versus 62.3% [P = 0.007], respectively). In those patients who completed 3 years of treatment, the rate of joint space narrowing was significantly lower with diacerein (mean ± SD 0.18 ± 0.25 mm/year versus 0.23 ± 0.23 mm/year with placebo; P = 0.042). Diacerein had no evident effect on the symptoms of OA in this study. However, a post hoc covariate analysis that took into account the use of analgesics and antiinflammatory drugs showed an effect of diacerein on the Lequesne functional index. Diacerein was well tolerated during the 3‐year study. The most frequent adverse events were transient changes in bowel habits.

Conclusion

This study confirms previous clinical findings indicating that the demonstration of a structure‐modifying effect in hip OA is feasible, and shows, for the first time, that treatment with diacerein for 3 years has a significant structure‐modifying effect as compared with placebo, coupled with a good safety profile. The clinical relevance of these findings requires further investigation.

     

Golimumab in psoriatic arthritis: One‐year clinical efficacy,radiographic, and safety results from a phase III,randomized, placebo‐controlled trial

Objective

Golimumab, administered subcutaneously every 4 weeks, has been shown to be effective in reducing the signs and symptoms of active psoriatic arthritis (PsA) through week 24 of the GO‐REVEAL study. Herein we report 1‐year clinical, radiographic, and safety findings.

Methods

Adult patients with active PsA (≥3 swollen and ≥3 tender joints) were randomly assigned to receive subcutaneous placebo, golimumab 50 mg, or golimumab 100 mg every 4 weeks through week 20. At week 16, patients with <10% improvement from baseline in swollen and tender joint counts entered a blinded early escape phase, with placebo crossover to golimumab 50 mg, golimumab 50 mg increased to 100 mg, and golimumab 100 mg continued at 100 mg. Patients receiving placebo who did not enter the early escape phase crossed over to golimumab 50 mg at week 24. Findings through 1 year are reported, including the second of 2 coprimary end points (i.e., change from baseline to week 24 in PsA‐modified Sharp/van der Heijde score [SHS]).

Results

A total of 405 patients were randomized: 113 to placebo and 146 each to the golimumab 50 mg and 100 mg groups. Mean changes in PsA‐modified SHS from baseline to week 24 for the combined golimumab 50 mg and 100 mg group (−0.09) and the golimumab 50 mg group (−0.16) were significantly different versus placebo (0.27) (P = 0.015 and P = 0.011, respectively). Radiographic benefit was maintained through week 52 with golimumab. Clinical efficacy, including improvement in joint and skin responses and physical function, was maintained through 1 year. The frequency/types of adverse events were similar to those reported through week 24.

Conclusion

Treatment of PsA with golimumab inhibited structural damage progression and demonstrated continued clinical efficacy and safety through 1 year.

     

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.

     

Efficacy and safety of adalimumab in patients with ankylosing spondylitis: Results of a multicenter,randomized, double‐blind,placebo‐controlled trial

Objective

To evaluate the safety and efficacy of adalimumab, a fully human recombinant IgG1 monoclonal antibody that specifically targets human tumor necrosis factor, in patients with active ankylosing spondylitis (AS).

Methods

This was a multicenter, randomized (2:1 ratio), double‐blind, placebo‐controlled study to evaluate a subcutaneous injection of adalimumab, 40 mg every other week, compared with placebo for 24 weeks. The primary efficacy end point was the percentage of patients with a 20% response according to the ASsessment in Ankylosing Spondylitis International Working Group criteria for improvement (ASAS20) at week 12. Secondary outcome measures included the ASAS20 at week 24 and multiple measures of disease activity, spinal mobility, and function, as well as ASAS partial remission.

Results

At week 12, 58.2% of adalimumab‐treated patients (121 of 208) achieved an ASAS20 response, compared with 20.6% of placebo‐treated patients (22 of 107) (P < 0.001). More patients in the adalimumab group (45.2% [94 of 208]) than in the placebo group (15.9% [17 of 107]) had at least a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index at week 12 (P < 0.001). Significant improvements in the ASAS40 response and the response according to the ASAS5/6 criteria at weeks 12 and 24 were also demonstrated (P < 0.001). Partial remission was achieved by more adalimumab‐treated patients than placebo‐treated patients (22.1% versus 5.6%; P < 0.001). Adalimumab‐treated patients reported more adverse events (75.0% versus 59.8% of placebo‐treated patients; P < 0.05), but there was no statistically significant difference in the incidence of infections. Most adverse events were mild or moderate in severity.

Conclusion

Adalimumab was well‐tolerated during the 24‐week study period and was associated with a significant and sustained reduction in the signs and symptoms of active AS.

     

Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: A double‐blind,randomized, placebo‐controlled trial

Objective

To evaluate whether treatment with prasterone (dehydroepiandrosterone [DHEA]) would allow the dosage of prednisone (or an equivalent corticosteroid) to be reduced to ≤7.5 mg/day for 2 months or longer while maintaining stable or reduced disease activity in steroid‐dependent women with systemic lupus erythematosus (SLE).

Methods

In a double‐blind, randomized trial, 191 female SLE patients receiving prednisone (10–30 mg/day) were treated daily with either placebo, 100 mg of oral prasterone (an adrenal androgen), or 200 mg of oral prasterone for 7–9‐months. At monthly intervals, corticosteroid dosages were reduced by algorithm in patients whose SLE Disease Activity Index (SLEDAI) score was stable or improved. Patients for whom a sustained reduction in the dosage of prednisone (≤7.5 mg/day) was achieved for at least the last 2 months of the 7–9‐month treatment period were classified as responders.

Results

Response rates were 41% in the placebo group, 44% in the 100‐mg prasterone group, and 55% in the 200‐mg group (P = 0.110, 200 mg versus placebo). Among the 137 subjects (45 in the placebo group, 47 in the 100‐mg group, and 45 in the 200‐mg group) who had active disease at baseline (defined as SLEDAI score >2), 29%, 38%, and 51%, respectively, were responders (P = 0.031 for 200 mg prasterone versus placebo). Acne was the most common adverse event but was generally mild. Clinical and laboratory changes primarily reflected androgenic effects of prasterone.

Conclusion

Among women with lupus disease activity, reducing the dosage of prednisone to ≤7.5 mg/day for a sustained period of time while maintaining stabilization or a reduction of disease activity was possible in a significantly greater proportion of patients treated with oral prasterone, 200 mg once daily, compared with patients treated with placebo.

     

Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: A double‐blind trial

Objective

To evaluate the efficacy and safety of tacrolimus as monotherapy in controlling the signs and symptoms of patients with rheumatoid arthritis (RA).

Methods

This was a 6‐month, phase III, double‐blind, multicenter study. Patients with active RA who had discontinued all disease‐modifying antirheumatic drugs (DMARDs) for an appropriate washout period (at least 1 month) and who, after the washout period, had a stable joint count (at least 10 tender/painful joints and 7 swollen joints) were stratified according to DMARD intolerance or DMARD resistance, and randomized to receive a single daily oral dose of placebo, tacrolimus 2 mg, or tacrolimus 3 mg.

Results

A total of 464 patients received at least 1 dose of study drug. Baseline characteristics were similar among the 3 treatment groups. American College of Rheumatology 20% improvement (ACR20) success (defined as completion of 6 months of treatment and an ACR20 response at the month 6 visit) for the placebo, tacrolimus 2 mg, and tacrolimus 3 mg groups was 10.2%, 18.8% (P < 0.05 versus placebo), and 26.8% (P < 0.0005 versus placebo), respectively. At the end of treatment, the ACR20 and ACR50 response rates in the 3‐mg group were 32.0% (P < 0.005 versus placebo) and 11.8% (P < 0.05 versus placebo), respectively. DMARD‐intolerant patients had better ACR response rates than did DMARD‐resistant patients. Although serum creatinine levels increased by ≥40% from baseline at some time during the trial in 20% and 29% of patients receiving tacrolimus 2 mg/day and 3 mg/day, respectively, the serum creatinine level remained within the normal range throughout the trial in ∼90% of patients.

Conclusion

Tacrolimus, at dosages of both 2 mg/day and 3 mg/day, is efficacious and safe as monotherapy for patients with active RA, but treatment with the 3‐mg dose of tacrolimus resulted in generally better ACR response rates.

     

Dehydroepiandrosterone treatment of women with mild‐to‐moderate systemic lupus erythematosus: A multicenter randomized,double‐blind,placebo‐controlled trial

Objective

To evaluate the efficacy and tolerability of dehydroepiandrosterone (DHEA) at a dosage of 200 mg/day in adult women with active systemic lupus erythematosus (SLE).

Methods

In a multicenter randomized, double‐blind, placebo‐controlled trial, 120 adult women with active SLE received oral DHEA (200 mg/day; n = 61) or placebo (n = 59) for 24 weeks. The primary end point was the mean change from baseline in the Systemic Lupus Activity Measure (SLAM) score at 24 weeks of therapy. Secondary end points included time to first flare, change in SLE Disease Activity Index (SLEDAI) score, and physician's and patient's global assessment scores at week 24.

Results

The two groups were well balanced for baseline characteristics. Mean reductions in SLAM scores from baseline were similar and were not statistically significantly different between treatment groups (DHEA −2.6 ± 3.4 versus placebo −2.0 ± 3.8, mean ± SD). The number of patients with flares was decreased by 16% in the DHEA group (18.3% of DHEA‐treated patients versus 33.9% of placebo‐treated patients; P = 0.044, based on time to first flare). The mean change in the patient's global assessment was statistically significant between the two groups (DHEA −5.5 versus placebo 5.4; P = 0.005). The number of patients with serious adverse events, most of which were related to SLE flare, was significantly lower in DHEA‐treated patients compared with placebo‐treated patients (P = 0.010). Expected hormonal effects, including increased testosterone levels and increased incidence of acne, were observed. No life‐threatening reactions or serious safety issues were identified during this study.

Conclusion

The overall results confirm that DHEA treatment was well‐tolerated, significantly reduced the number of SLE flares, and improved patient's global assessment of disease activity.

     

Oral apremilast in the treatment of active psoriatic arthritis: Results of a multicenter,randomized, double‐blind,placebo‐controlled study

Objective

To evaluate the efficacy and safety of apremilast, a novel, orally available small molecule that specifically targets phosphodiesterase 4, in the treatment of active psoriatic arthritis (PsA).

Methods

This phase II, multicenter, randomized, double‐blind, placebo‐controlled study included the following: a 12‐week treatment phase, with patients receiving placebo, apremilast 20 mg twice per day, or apremilast 40 mg once per day; a 12‐week treatment‐extension phase, with patients in the placebo group re‐randomized to receive apremilast; and a 4‐week observational phase after treatment cessation. The primary end point was the proportion of patients achieving the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. Safety assessments included adverse events (AEs), physical examinations, vital signs, laboratory parameters, and electrocardiograms.

Results

Of the 204 patients with PsA who were randomized to a treatment group, 165 completed the treatment phase. At the end of the treatment phase (week 12), 43.5% of patients receiving apremilast 20 mg twice per day (P < 0.001) and 35.8% of those receiving 40 mg once per day (P = 0.002) achieved an ACR20 response, compared with 11.8% of those receiving placebo. At the end of the treatment‐extension phase (week 24), >40% of patients in each group (patients receiving apremilast 20 mg twice per day, patients receiving apremilast 40 mg once per day, and patients in the placebo group re‐randomized to receive apremilast) achieved the ACR20 level of improvement. Most patients in the treatment phase (84.3%) and treatment‐extension phase (68.3%) reported ≥1 AE. Diarrhea, headache, nausea, fatigue, and nasopharyngitis were reported most frequently; most events were mild or moderate. No clinically relevant laboratory or electrocardiographic abnormalities were reported.

Conclusion

Treatment with apremilast at a dosage of 20 mg twice per day or 40 mg once per day demonstrated efficacy in comparison with placebo and was generally well tolerated in patients with active PsA. The balance of efficacy, tolerability, and safety supports further study of apremilast in PsA.

     

Long‐term high‐physiological‐dose growth hormone reduces intra‐abdominal fat in HIV‐infected patients with a neutral effect on glucose metabolism

Objectives

The aim of the study was to investigate the effect of long‐term high‐physiological‐dose recombinant human growth hormone (rhGH) therapy on fat distribution and glucose metabolism in HIV‐infected patients.

Methods

Forty‐six HIV‐infected Caucasian men on highly active antiretroviral therapy (HAART), with an age range of 21–60 years and no significant comorbidity, were included in this randomized, placebo‐controlled, double‐blind, single‐centre trial. Twenty‐eight subjects were randomized to 0.7 mg/day rhGH, and 18 subjects to placebo, administered as daily subcutaneous injections between 1 and 3 pm for 40 weeks. Endpoints included changes in visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), limb fat mass, percentage of limb fat, plasma lipids, insulin resistance and glucose tolerance.

Results

VAT and trunk fat mass decreased significantly in the GH group compared with the placebo group [−19 cm² (−11%) vs. 12 cm² (6%), P=0.03, and −548 g (−9%) vs. 353 g (6%), P<0.01, respectively]. The beneficial fat redistribution in the GH group occurred without concomitant changes in subcutaneous fat at the abdomen or extremities. rhGH therapy was well tolerated. Insulin resistance, glucose tolerance, and total plasma cholesterol and triglycerides did not significantly change during intervention.

Conclusions

Daily 0.7 mg rhGH treatment for 40 weeks reduced abdominal visceral fat and trunk fat mass in HIV‐infected patients. This treatment appeared to be safe with respect to glucose tolerance and insulin sensitivity.

     

A phase II,randomized, double‐blind,placebo‐controlled,dose‐ranging study of belimumab in patients with active systemic lupus erythematosus

Objective

To assess the safety, tolerability, biologic activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE).

Methods

Patients with a Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score ≥4 (n = 449) were randomly assigned to belimumab (1, 4, or 10 mg/kg) or placebo in a 52‐week study. Coprimary end points were the percent change in the SELENA–SLEDAI score at week 24 and the time to first SLE flare.

Results

Significant differences between the treatment and placebo groups were not attained for either primary end point, and no dose response was observed. Reductions in SELENA–SLEDAI scores from baseline were 19.5% in the combined belimumab group versus 17.2% in the placebo group. The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group. However, the median time to first SLE flare during weeks 24–52 was significantly longer with belimumab treatment (154 versus 108 days; P = 0.0361). In the subgroup (71.5%) of serologically active patients (antinuclear antibody titer ≥1:80 and/or anti–double‐stranded DNA [anti‐dsDNA] ≥30 IU/ml), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA–SLEDAI score (?28.8% versus ?14.2%; P = 0.0435), physician's global assessment (?32.7% versus ?10.7%; P = 0.0011), and Short Form 36 physical component score (+3.0 versus +1.2 points; P = 0.0410). Treatment with belimumab resulted in a 63–71% reduction of naive, activated, and plasmacytoid CD20+ B cells, and a 29.4% reduction in anti‐dsDNA titers (P = 0.0017) by week 52. The rates of adverse events and serious adverse events were similar in the belimumab and placebo groups.

Conclusion

Belimumab was biologically active and well tolerated. The effect of belimumab on the reduction of SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than to SOC alone.