Safety and efficacy of long‐term intraarticular steroid injections in osteoarthritis of the knee: A randomized,double‐blind,placebo‐controlled trial

Objective

To evaluate the safety and efficacy of long‐term intraarticular (IA) steroid injections for knee pain related to osteoarthritis (OA).

Methods

In a randomized, double‐blind trial, 68 patients with OA of the knee received IA injections of triamcinolone acetonide 40 mg (34 patients) or saline (34 patients) into the study knee every 3 months for up to 2 years. The primary outcome variable was radiologic progression of joint space narrowing of the injected knee after 2 years. Measurements of minimum joint space width were performed by an automated computerized method on standardized fluoroscopically guided radiographs taken with the patient standing and with the knee in a semiflexed position. The clinical efficacy measure of primary interest was the pain subscale from the Western Ontario and McMaster Universities OA Index (WOMAC). Efficacy measures of secondary interest were the total score on the WOMAC, physician's global assessment, patient's global assessment, patient's assessment of pain, range of motion (ROM) of the affected knee, and 50‐foot walking time. Clinical symptoms were assessed just before each injection.

Results

At the 1‐year and 2‐year followup evaluations, no difference was noted between the two treatment groups with respect to loss of joint space over time. The steroid‐injected knees showed a trend toward greater symptom improvement, especially at 1 year, for the WOMAC pain subscale, night pain, and ROM values (P = 0.05) compared with the saline‐injected knees. Using area under the curve analyses, knee pain and stiffness were significantly improved throughout the 2‐year study by repeated injections of triamcinolone acetonide, but not saline (P < 0.05).

Conclusion

Our findings support the long‐term safety of IA steroid injections for patients with symptomatic knee OA. No deleterious effects of the long‐term administration of IA steroids on the anatomical structure of the knee were noted. Moreover, long‐term treatment of knee OA with repeated steroid injections appears to be clinically effective for the relief of symptoms of the disease.

     

Gabapentin in the treatment of fibromyalgia: A randomized,double‐blind,placebo‐controlled,multicenter trial

Objective

To assess the efficacy and safety of gabapentin in patients with fibromyalgia.

Methods

A 12‐week, randomized, double‐blind study was designed to compare gabapentin (1,200–2,400 mg/day) (n = 75 patients) with placebo (n = 75 patients) for efficacy and safety in treating pain associated with fibromyalgia. The primary outcome measure was the Brief Pain Inventory (BPI) average pain severity score (range 0–10, where 0 = no pain and 10 = pain as bad as you can imagine). Response to treatment was defined as a reduction of ≥30% in this score. The primary analysis of efficacy for continuous variables was a longitudinal analysis of the intent‐to‐treat sample, with treatment‐by‐time interaction as the measure of effect.

Results

Gabapentin‐treated patients displayed a significantly greater improvement in the BPI average pain severity score (P = 0.015; estimated difference between groups at week 12 = −0.92 [95% confidence interval −1.75, −0.71]). A significantly greater proportion of gabapentin‐treated patients compared with placebo‐treated patients achieved response at end point (51% versus 31%; P = 0.014). Gabapentin compared with placebo also significantly improved the BPI average pain interference score, the Fibromyalgia Impact Questionnaire total score, the Clinical Global Impression of Severity, the Patient Global Impression of Improvement, the Medical Outcomes Study (MOS) Sleep Problems Index, and the MOS Short Form 36 vitality score, but not the mean tender point pain threshold or the Montgomery Asberg Depression Rating Scale. Gabapentin was generally well tolerated.

Conclusion

Gabapentin (1,200–2,400 mg/day) is safe and efficacious for the treatment of pain and other symptoms associated with fibromyalgia.

     

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.

     

Efficacy of celecoxib,a cyclooxygenase 2–specific inhibitor,in the treatment of ankylosing spondylitis: A six‐week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug

Objective

To evaluate the short‐term efficacy of celecoxib, a cyclooxygenase 2–specific inhibitor, in the treatment of ankylosing spondylitis (AS).

Methods

The study was a 6‐week randomized, double‐blind, placebo‐controlled trial with 3 treatment arms: placebo, ketoprofen 100 mg twice daily, and celecoxib 100 mg twice daily. Patients who had AS according to the modified New York criteria, without peripheral synovitis and with active disease (pain ≥40 mm on a 100‐mm visual analog scale [VAS] and an increase in pain of at least 30% after nonsteroidal antiinflammatory drug withdrawal) were eligible for study. Primary outcome measures were change in pain intensity (VAS) and change in functional impairment (Bath Ankylosing Spondylitis Functional Index [BASFI]).

Results

Of the 246 randomized patients, 76 were allocated to receive placebo, 90 ketoprofen, and 80 celecoxib. There were no statistically significant differences between treatment groups at study entry. During the 6 weeks of the study, the decrease in pain and functional impairment was greater in the active treatment groups than in the placebo group, with a trend in favor of celecoxib when the 2 active treatments were compared. The mean changes were −13 mm, −21 mm, and −27 mm (P = 0.006) for pain and 1, −6, and −12 (P = 0.0008) for BASFI score in the placebo, ketoprofen, and celecoxib groups, respectively. During treatment, the number of patients reporting epigastric pain was 6 (8%), 13 (14%), and 10 (13%) in the placebo, ketoprofen, and celecoxib groups, respectively.

Conclusion

The results of this study confirm the clinically relevant antiinflammatory effect of celecoxib at a 200‐mg daily dosage, with significant improvement of both pain and function in patients with AS.

     

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.

     

Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: Results of a randomized,double‐blind,placebo‐controlled trial

Objective

To assess the efficacy and safety of milnacipran at a dosage of 100 mg/day (50 mg twice daily) for monotherapy treatment of fibromyalgia.

Methods

A double‐blind, placebo‐controlled trial was performed to assess 1,025 patients with fibromyalgia who were randomized to receive milnacipran 100 mg/day (n = 516) or placebo (n = 509). Patients underwent 4–6 weeks of flexible dose escalation followed by 12 weeks of stable‐dose treatment. Two composite responder definitions were used as primary end points to classify the response to treatment. The 2‐measure composite response required achievement of ≥30% improvement from baseline in the pain score and a rating of “very much improved” or “much improved” on the Patient's Global Impression of Change (PGIC) scale. The 3‐measure composite response required satisfaction of these same 2 improvement criteria for pain and global status as well as improvement in physical function on the Short Form 36 (SF‐36) physical component summary (PCS) score.

Results

After 12 weeks of stable‐dose treatment, a significantly greater proportion of milnacipran‐treated patients compared with placebo‐treated patients showed clinically meaningful improvements, as evidenced by the proportion of patients meeting the 2‐measure composite responder criteria (P < 0.001 in the baseline observation carried forward [BOCF] analysis) and 3‐measure composite responder criteria (P < 0.001 in the BOCF). Milnacipran‐treated patients also demonstrated significantly greater improvements from baseline on multiple secondary outcomes, including 24‐hour and weekly recall pain score, PGIC score, SF‐36 PCS and mental component summary scores, average pain severity score on the Brief Pain Inventory, Fibromyalgia Impact Questionnaire total score (all P < 0.001 versus placebo), and Multidimensional Fatigue Inventory total score (P = 0.036 versus placebo). Milnacipran was well tolerated by most patients, with nausea being the most commonly reported adverse event (placebo‐adjusted rate of 15.8%).

Conclusion

Milnacipran administered at a dosage of 100 mg/day improved pain, global status, fatigue, and physical and mental function in patients with fibromyalgia.

     

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.

     

Steroid injection for osteoarthritis of the hip: A randomized,double‐blind,placebo‐controlled trial

Objective

To determine the efficacy of fluoroscopically guided corticosteroid injection for hip osteoarthritis (OA) in a randomized, double‐blind, placebo‐controlled trial.

Methods

Fifty‐two patients with symptomatic hip OA were randomly allocated to receive placebo (10 mg bipuvicaine, 2 ml saline) (n = 21) or corticosteroid treatment (10 mg bipuvicaine, 40 mg triamcinolone hexacetonide) (n = 31). Patients were followed up for 1, 2, 3, and 6 months. The primary outcome measure was the pain improvement response, defined as a 20% decrease in the Western Ontario and McMaster Universities OA Index (WOMAC) pain score (on 5 100‐mm visual analog scales [VAS]) (WOMAC20) from baseline to 2 months postinjection. Secondary outcomes were a 50% decrease in the WOMAC pain score (WOMAC50), changes in other WOMAC subscale scores, patient's global assessment of health (on a 100‐mm VAS), and Short Form 36 (SF‐36) quality of life indices. Analyses were based on the intent‐to‐treat principle.

Results

The mean WOMAC pain score fell 49.2% (decreasing from 310.1 mm to 157.4 mm) at 2 months postinjection in patients receiving corticosteroid, compared with a decrease of 2.5% (from 314.3 mm to 306.5 mm) in the placebo group (P < 0.0001). The proportion of WOMAC20 responders at 2 months' followup was significantly higher in the corticosteroid group (67.7%) compared with the placebo group (23.8%) (P = 0.004); similar proportions of WOMAC50 responders were observed between groups (61.3% in the corticosteroid group versus 14.3% in the placebo group; P = 0.001). Response differences were maintained at 3 months' followup (58.1% responders in the corticosteroid group versus 9.5% responders in the placebo group; P = 0.004). Significant differences in the WOMAC stiffness and physical function scores (P < 0.0001), patient's global health scores (P = 0.005), and SF‐36 physical component scores (P = 0.04) were observed, with patients in the corticosteroid group showing greater improvements. There were no differences in the frequency of adverse events between groups.

Conclusion

This placebo‐controlled trial confirms that corticosteroid injection can be an effective treatment of pain in hip OA, with benefits lasting up to 3 months in many cases. Future studies should address questions related to the benefits of repeated steroid injection and the effects of this treatment on disease modification.

     

Adalimumab in severe and acute sciatica: A multicenter,randomized, double‐blind,placebo‐controlled trial

Objective

Based on several experimental results and on a preliminary study, a trial was undertaken to assess the efficacy of adalimumab, a tumor necrosis factor α inhibitor, in patients with radicular pain due to lumbar disc herniation.

Methods

A multicenter, double‐blind, randomized controlled trial was conducted between May 2005 and December 2007 in Switzerland. Patients with acute (duration of <12 weeks) and severe (Oswestry Disability Index score of >50) radicular leg pain and imaging‐confirmed lumbar disc herniation were randomized to receive as adjuvant therapy either 2 subcutaneous injections of adalimumab (40 mg) at 7‐day intervals or matching placebo. The primary outcome was the score for leg pain, based on a visual analog scale (0–100 mm), which was recorded every day for 10 days and at 6 weeks and 6 months.

Results

Of the 265 patients screened, 61 were enrolled; 31 patients were assigned to receive adalimumab, and 4 patients in the placebo group were lost to followup. Over time, the course of leg pain was more favorable in the adalimumab group than in the placebo group (P = 0.002). However, the effect size was relatively small, and at the last followup visit the difference was 13.8 (95% confidence interval −11.5, 39.0). Compared with patients in the placebo group, approximately twice as many patients in the adalimumab group fulfilled the criteria for “responders” and for “low residual disease impact” (P < 0.05), and fewer surgical discectomies were performed (6 versus 13 in the placebo group; P = 0.04).

Conclusion

The addition of a short course of adalimumab to the treatment regimen of patients experiencing acute and severe sciatica resulted in a small decrease in leg pain and in significantly fewer surgical procedures.

     

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.

     

Effects of tumor necrosis factor blockade on cardiovascular risk factors in psoriatic arthritis: A double‐blind,placebo‐controlled study

Objective

To conduct a robust, double‐blind, placebo‐controlled study examining the effects of tumor necrosis factor (TNF) modulation on concentrations of traditional and novel cardiovascular disease risk factors in patients with an inflammatory condition.

Methods

In this double‐blind study, 127 patients with psoriatic arthritis (PsA) and active psoriasis were randomized to 1 of 3 treatment arms (placebo, onercept 50 mg, or onercept 100 mg for 12 weeks). Traditional and novel biochemical risk factors were evaluated at baseline and at the end of the treatment period.

Results

At baseline, an elevated C‐reactive protein (CRP) level correlated positively with lipoprotein(a) (Lp[a]), intercellular adhesion molecule 1, interleukin‐6, and homocysteine levels but was inversely correlated with concentrations of all other lipid moieties and sex hormone binding globulin (SHBG). Onercept at a dose of 100 mg induced significant (P ≤ 0.002) reductions in the levels of CRP (−14.0 versus 6.5 mg/liter with placebo), Lp(a) (−3.11 versus 1.52 mg/dl with placebo), and homocysteine (−1.72 versus 0.34 μmoles/liter with placebo) and an increase in the SHBG concentration (4.3 versus −1.3 mmoles/liter with placebo). The 100‐mg dose of onercept was also associated with significant (P < 0.05) increases in the level of circulating apolipoprotein AI (Apo A‐I) (4.0 versus −5.6 mg/dl with placebo); however, levels of Apo B (6.3 versus −0.4 mg/dl with placebo) and triglycerides (0.09 versus 0.04 mmoles/liter) were also increased.

Conclusion

This study is the first to demonstrate that targeting the TNF pathway can significantly decrease Lp(a) and homocysteine levels and elevate Apo A‐I and SHBG concentrations. These data support an important precursor role for high‐grade inflammation in modulating these putative risk parameters. However, TNF blockade–induced increases in triglyceride and Apo B levels were unexpected and suggest that it is not possible, on the basis of biochemical changes in isolation, to suggest that cardioprotection would necessarily follow; rather, direct measures of atherosclerotic progression with TNF blockade (e.g., using carotid ultrasound) would be better.

     

Two‐year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: A randomized,double‐blind,placebo‐controlled extension trial

Objective

To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids.

Methods

This is a 12‐month extension of a previously completed 1‐year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence.

Results

The mean (±SEM) lumbar spine BMD increased by 2.8 ± 0.6%, 3.9 ± 0.7%, and 3.7 ± 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P ≤ 0.001) and decreased by −0.8 ± 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P ≤ 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P ≤ 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P ≤ 0.05). Bone turnover markers (N‐telopeptides of type I collagen and bone‐specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P ≤ 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups.

Conclusion

Alendronate is an effective, well‐tolerated therapy for the prevention and treatment of glucocorticoid‐induced osteoporosis, with sustained treatment advantages for up to 2 years.

     

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.

     

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.

     

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.

     

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.

     

Effects of a stress‐reduction program on psychological function,pain, and physical function of systemic lupus erythematosus patients: A randomized controlled trial

Objective

To assess the effects of a stress‐reduction program on pain, psychological function, and physical function in persons with systemic lupus erythematosus (SLE) who experience pain.

Methods

Ninety‐two SLE patients were assigned randomly to receive either biofeedback‐assisted cognitive‐behavioral treatment (BF/CBT), a symptom‐monitoring support (SMS) intervention, or usual medical care (UC) alone.

Results

BF/CBT participants had significantly greater reductions in pain and psychological dysfunction compared with the SMS group (pain, P = 0.044; psychological functioning, P < 0.001) and the UC group (pain, P = 0.028; psychological functioning, P < 0.001). BF/CBT had significantly greater improvement in perceived physical function compared with UC (P = 0.035), and improvement relative to SMS was marginally significant (P = 0.097). At a 9‐month followup evaluation, BF/CBT continued to exhibit relative benefit compared with UC in psychological functioning (P = 0.023).

Conclusion

This study supports the utility of a brief stress management program for short‐term improvement in pain, psychological function, and perceived physical function among persons with SLE who experience pain.

     

Correlation of polymorphic variation in the promoter region of the interleukin‐1β gene with secretion of interleukin‐1β protein

Objective

Significant variation in interleukin‐1β (IL‐1β) protein secretion between subjects has been observed when using a lipopolysaccharide (LPS)/ATP–mediated ex vivo blood stimulation assay. To explore the potential relationships between genetic polymorphisms in the IL1B cytokine gene and cellular responses to inflammatory stimuli such as LPS, we investigated the hypothesis that polymorphisms within the promoter and exon 5 of the IL1B gene contribute to the observed differences in IL‐1β protein secretion.

Methods

The IL1B gene polymorphisms C−511T, T−31C, and C3954T were tested for association with LPS‐induced secretion of IL‐1β protein as measured by an ex vivo blood stimulation assay. Samples from 2 independent study populations (n = 31 and n = 25) were available for use in the ex vivo assay after consent was obtained to analyze the DNA.

Results

A specific haplotype, composed of the T allele at −511 and the C allele at −31, was significantly associated with a 2–3‐fold increase in LPS‐induced IL‐1β protein secretion. This association was observed in both of the independent study populations (P = 0.0084 and P = 0.0017).

Conclusion

These data suggest that polymorphisms within the promoter region of the IL1B gene contribute to observed differences in LPS‐induced IL‐1β protein secretion.

     

Symptomatic effects of chondroitin 4 and chondroitin 6 sulfate on hand osteoarthritis: A randomized,double‐blind,placebo‐controlled clinical trial at a single center

Objective

To evaluate the symptomatic effects of highly purified chondroitin 4 and chondroitin 6 sulfate (CS) therapy in patients with osteoarthritis (OA) of the hand.

Methods

This investigator‐initiated, single‐center, randomized, double‐blind, placebo‐controlled clinical trial included 162 symptomatic patients with radiographic evidence of hand OA (American College of Rheumatology criteria). Inclusion criteria included patient's assessment of global spontaneous hand pain of at least 40 mm on a 0–100‐mm visual analog scale (VAS) and functional impairment of at least 6 (0–30 scale) on the Functional Index for Hand OA (FIHOA) in the most symptomatic hand. Patients received either 800 mg of CS (n = 80 patients) or placebo (n = 82 patients) once daily for 6 months and were analyzed in an intent‐to‐treat approach. The two primary outcomes were the change in the patient's assessment of global spontaneous hand pain and in hand function (by FIHOA score) from baseline to month 6. Secondary outcomes were improvement in grip strength, duration of morning stiffness, acetaminophen consumption, and the investigator's global impression of treatment efficacy.

Results

There was a significantly more pronounced decrease in the patient's global assessment of hand pain in the CS group than in the placebo group (difference VAS scores −8.7 mm; P = 0.016). Hand function improved significantly more in the CS group than in the placebo group (difference in FIHOA scores −2.14; P = 0.008). There was a statistically significant between‐group difference in favor of CS for the duration of morning stiffness and for the investigator's global impression of treatment efficacy. Changes in grip strength, acetaminophen consumption, and safety end points were not significantly different between the two groups.

Conclusion

This study demonstrates that CS improves hand pain and function in patients with symptomatic OA of the hand and shows a good safety profile.