Pulsed electrical stimulation in patients with osteoarthritis of the knee: follow up in 288 patients who had failed non-operative therapy.

BACKGROUND: Optimized pulsed electrical stimulation (PES) regulates chondrocyte genes, enhances production of cartilage matrix materials, and inhibits production of matrix catabolic factors. METHODS: This prospective, cohort study examined the use of a PES device in treatment of knee osteoarthritis (OA) in patients who had failed non-operative therapy. Primary outcome measures were patient and physician global evaluation, and patient assessment of knee pain. RESULTS: This study included 288 (95 men, 193 women) patients who used the device from 16 to more than 600 days (mean: 889 hours). Improvement in all efficacy variables (p < 0.001) occurred. A dose-response relationship between effect size and hours of usage was observed as cumulative time increased to more than 750 hours. Improvement in patient or physician global occurred in 59.0% of patients who used it less than 750 hours, and for 73.0% of those who used it more than 750 hours. An economic analysis of a sub-group of patients showed that 45.3% reduced nonsteroidal anti-inflammatory drug (NSAID) use by 50.0% or more. CONCLUSIONS: A highly optimized PES device successfully attenuated knee OA symptoms in patients who had failed non-surgical therapy. Less than 250 hours of therapy provided relief, but improvement increased in a dose-response manner after 750 hours of cumulative use.

Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis.

OBJECTIVE: Methotrexate (MTX) is an antifolate agent that is often associated with toxicity. This study investigated whether risk genotypes for folate-dependent enzymes are associated with the toxicity of MTX in patients with rheumatoid arthritis (RA). METHODS: Blood was collected for analysis in a muticenter, cross-sectional study of RA patients who had been receiving MTX for at least 1 month prior to enrollment, and side effects occurring at the time of a single study visit were recorded. Low-penetrance risk genotypes in methylenetetrahydrofolate reductase (MTHFR) 677TT, thymidylate synthase (TSER) *2/*2 (variable number of tandem repeats), amino imidazole ribonucleotide transformylase (ATIC) 347GG, and serine hydroxymethyltransferase (SHMT1) 1420CC were measured and summed to constitute the toxicogenetic index specific to each patient. Statistical analyses consisted of logistic regression models with clustered-center effects, and associations with risk genotypes were expressed as adjusted odds ratios (ORs). RESULTS: Among 214 patients enrolled at 4 study sites, a total of 67 patients (31%) presented with a side effect (gastrointestinal event, headache, lethargy, alopecia, cough, or dyspnea). Risk genotypes associated with side effects in the central nervous system were MTHFR 677TT (OR 3.3, P < 0.01) and SHMT1 1420CC (OR 2.4, P < 0.05). ATIC 347GG was associated with gastrointestinal side effects (OR 3.0, P < 0.01), while TSER*2/*2 (OR 5.4, P < 0.01) and SHMT1 1420CC (OR 3.2, P < 0.01) were associated with alopecia. The toxicogenetic index ranged from 0 to 3 (median 1). An index of 3 was associated with an approximately 7-fold higher likelihood of having a side effect compared with an index of 0 (P < 0.01). CONCLUSION: These data suggest that a composite index of the cumulative risk genotypes in folate-dependent enzymes may be an effective means of profiling RA patients who develop side effects to MTX.

Clinical effects of intraarticular injection of high molecular weight hyaluronan (Orthovisc) in osteoarthritis of the knee: a randomized, controlled, multicenter trial.

OBJECTIVE: To evaluate the efficacy and safety of injection of high molecular weight (HMW) hyaluronan (Orthovisc) in patients with mild, moderate, and severe knee osteoarthritis (OA). METHODS: A randomized, arthrocentesis-controlled, multicenter trial. Patients (n = 372) were randomized to 4 weekly HMW hyaluronan injections (O4, n = 128), 3 weekly HMW hyaluronan injections followed by one arthrocentesis (O3A1, n = 120), or 4 arthrocenteses without injection (control group, A4, n = 124). All patients had knee OA, as determined by Kellgren-Lawrence (K-L) grade, and Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain score > or = 200 mm and < 400 mm in index knee and < 150 mm in contralateral knee. The primary outcome measure was the proportion of patients achieving a 20% relative and 50 mm absolute improvement from baseline in WOMAC pain score at Weeks 8, 12, 16, and 22 post-baseline in the index knee. Secondary outcomes were Patient Global score, Investigator Global score, and Pain on Standing score. RESULTS: The evaluable subgroup consisted of patients with K-L grade 2 or 3 at baseline. The comparison of O4 versus A4 for the primary outcome approached, but did not reach, significance in the evaluable subgroup: 76% of O4 patients had > or = 20% improvement in WOMAC pain score at Week 8 compared to 62% of A4 patients. More O4 patients had > or = 40% improvement in WOMAC pain score compared to A4. The effectiveness of the 3-injection regimen (O3A1) was masked by a possible placebo effect from the needle injection procedure in the A4 (control) group. No differences between groups were observed with respect to incidence of adverse events. CONCLUSION: Our findings indicate that HMW hyaluronan is safe and seems to be effective in the treatment of mild to severe OA of the knee.

Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis.

We investigated whether polymorphisms in reduced folate carrier (SLC19A1 G80A) and gamma-glutamyl-hydrolase (GGH-401C/T) are predictive of methotrexate polyglutamate (MTXPG) levels in patients with rheumatoid arthritis treated with weekly low-dose methotrexate (MTX). Adult patients treated with MTX were enrolled in a multicentred study. Blood was drawn at the time of the visit, DNA was extracted and red blood cell (RBC) MTXPG levels (up to the penta-order of glutamation) were measured by high-performance liquid chromatography-fluorometry. A G80A polymorphism in SLC19A1 and a -401C/T promoter polymorphism in GGH were measured by polymerase chain reaction-restriction fragment length polymorphism. Multivariate linear and logistic regressions were used to predict long-chain RBC MTXPG3-5. In 226 adult patients receiving MTX (median 15 mg range: 5-25 mg) median RBC long-chain MTXPG3-5 was 56 nmol/l (range < 5-224 nmol/l). A total of 35 patients carried the SLC19A1 80AA genotype whereas 36 patients carried the GGH-401TT genotype. Weekly MTX dose, age, presence of the SLC19A1 80AA and GGH-401TT genotypes predicted independently and significantly MTXPG3-5 levels (global r = 0.38; P < 0.0001). Patients with the GGH-401TT genotype were 4.8-fold [odds ratio (OR) 95% confidence interval (CI) 1.8-13.0; P = 0.002] more likely to have MTXPG3-5 below the group median compared to patient carriers of the GGH-401CC or CT genotype. Conversely, those with the SLC19A1 80AA genotype were 3.4-fold more likely to have MTXPG3-5 levels above the group median compared to those with the SLC19A1 80GG or 80GA genotype (OR CI 95% 1.4-8.4; P = 0.007). These data demonstrate that polymorphisms in SLC19A1 and GGH affect polyglutamation of MTX.

Effects of prasterone on disease activity and symptoms in women with active systemic lupus erythematosus.

OBJECTIVE: To determine whether prasterone administration results in improvement or stabilization of systemic lupus erythematosus (SLE) disease activity and its symptoms. METHODS: Women with active SLE were treated with prasterone 200 mg/day plus standard SLE treatments or with placebo plus standard SLE treatments for up to 12 months in this randomized, double-blind investigation conducted at 27 centers. Standard SLE treatments included prednisone (/=6 weeks prior to enrollment and remain unchanged during protocol treatment. Responders were patients who experienced no clinical deterioration and had improvement or stabilization over the duration of the study in 2 disease activity measures (the SLE Disease Activity Index [SLEDAI] and the Systemic Lupus Activity Measure) and 2 quality of life measures (patient's global assessment and the Krupp Fatigue Severity Scale). RESULTS: A total of 381 women with SLE were enrolled. Among patients with clinically active disease at baseline (SLEDAI score >2), 86 of 147 in the prasterone group (58.5%) demonstrated improvement or stabilization without clinical deterioration, as compared with 65 of 146 in the placebo group (44.5%) (P = 0.017). Acne and hirsutism were reported in 33% and 16%, respectively, of the prasterone group and in 14% and 2%, respectively, of the placebo group (P < 0.05 for both comparisons). However, most cases of acne and hirsutism were mild and did not require withdrawal from therapy. Myalgias and oral stomatitis were reported less frequently in the prasterone group (22% and 15%, respectively) than in the placebo group (36% and 23%, respectively) (P < 0.05 for both comparisons). Serum levels of high-density lipoprotein cholesterol, triglycerides, and C3 complement significantly decreased, while levels of testosterone and, to a lesser extent, estradiol increased in the prasterone group. CONCLUSION: In adult women with active SLE, administration of prasterone at a dosage of 200 mg/day improved or stabilized signs and symptoms of disease and was generally well tolerated.

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

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

Avinza - 24-h sustained-release oral morphine therapy.

Avinza is a once-daily, extended-release oral morphine preparation. It has a pharmacokinetic profile that exhibits less peak-to-trough fluctuations in plasma concentration whilst providing analgesia statistically identical to that produced by MS Contin (controlled-release morphine sulfate), Oxycontin (oxycodone HCl controlled-release) and six doses of oral morphine sulfate administered every 4 h. Avinza improves quality of sleep by several measures but interestingly gives the best sleep improvement when given in the morning rather than at night. It causes the same side effects of other opioids: constipation, nausea, vomiting, somnolence and mood swings. Doses of 30 - 60 mg/day have been shown to be well tolerated by patients with osteoarthritis (even in the elderly), who have failed other medications.

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

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

Efficacy of tacrolimus in rheumatoid arthritis patients who have been treated unsuccessfully with methotrexate: a six-month, double-blind, randomized, dose-ranging study.

OBJECTIVE: To assess the efficacy, safety, and optimal dose of tacrolimus monotherapy in patients with rheumatoid arthritis (RA). METHODS: This phase II, randomized, double-blind, placebo-controlled monotherapy study was set in 12 community sites and 9 university-based sites. Two hundred sixty-eight patients with RA who were resistant to or intolerant of methotrexate (mean dose 15.2 mg/week) and had active disease for at least 6 months (mean tender joint count 28.2, mean erythrocyte sedimentation rate 46.5 mm/hour) were randomized to receive treatment after discontinuation of methotrexate. Those who received at least 1 dose of tacrolimus were analyzed; 141 completed the study. Stable dosages of nonsteroidal antiinflammatory drugs and low-dose prednisone were allowed during treatment. All patients were given 1, 3, or 5 mg of tacrolimus or placebo once daily for 24 weeks. The American College of Rheumatology definition of 20% improvement (ACR20) and the tender and swollen joint counts at the end of treatment were the primary outcomes. RESULTS: ACR20 response rates demonstrated a clear dose response. The ACR20 response was observed in 15.5% of patients receiving placebo (95% confidence interval [95% CI] 7.1-23.9%), 29% of the 1 mg tacrolimus group (95% CI 18.3-39.7%) (P < 0.058); 34.4% of the 3 mg group (95% CI 22.7-46.0%) (P < 0.013), and 50% of the 5 mg group (95% CI 37.8-62.3%) (P < or = 0.001). The tender joint count improved statistically significantly in all tacrolimus groups. The swollen joint count, physical function, and patient-assessed pain improved statistically significantly in the 3 mg and 5 mg groups. The incidence of creatinine elevation > or =40% above baseline levels increased in a dose-dependent manner. Dropout rates were high (41-59%) and were more common for inefficacy in the placebo patients (71.4%), whereas they were more common for toxicity in the high-dose tacrolimus groups (31-33%). Discontinuation for creatinine elevation occurred in the 3 mg (3.1%) and 5 mg (10.9%) tacrolimus groups. CONCLUSION: Tacrolimus improved disease activity in methotrexate-resistant or -intolerant patients with RA. A dose response was observed when efficacy and toxicity were assessed at different doses. The optimal dose of tacrolimus appears to be >1 mg but < or=3 mg daily.

Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis.

OBJECTIVE: A dose-response relationship for hydroxychloroquine (HCQ), in terms of the proportion of patients achieving the Paulus 20% criteria for improvement, had previously been observed in patients with rheumatoid arthritis (RA) receiving a 6-week loading regimen of 400, 800, or 1,200 mg HCQ daily. This present retrospective analysis was performed to investigate possible relationships between the blood HCQ and HCQ-metabolite concentrations and measures of efficacy and toxicity. In addition, we sought to ascertain whether further investigation of HCQ/HCQ-metabolite levels might lead to testing of one of these substances as a new antirheumatic drug. METHODS: Patients with active RA (n = 212) began a 6-week, double-blind trial comparing 3 different doses of HCQ at 400, 800, or 1,200 mg/day, followed by 18 weeks of open-label HCQ treatment at 400 mg/day. Patients were repeatedly evaluated for treatment efficacy and toxicity. Blood samples were available from 123 patients for analysis of HCQ, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ) levels using high-performance liquid chromatography. Achievement of the modified Paulus 20% improvement criteria for response in RA was used as the primary efficacy parameter. Spontaneously reported adverse events were categorized and analyzed as toxicity outcome variables. The relationship between response (efficacy and toxicity) and drug levels was evaluated using logistic regression analysis. RESULTS: The subset of patients with blood concentration data was equivalent to the larger study population in all demographic and outcome characteristics. The mean HCQ, DHCQ, and DCQ elimination half-lives were 123, 161, and 180 hours, respectively. There was a positive correlation between the Paulus 20% improvement criteria response and blood DHCQ concentrations during weeks 1-6 (P < 0.001). A potential relationship between ocular adverse events and BDCQ levels was found (P = 0.036). Logistic regression analysis of adverse events data showed that adverse gastrointestinal events were associated with higher HCQ levels (P = 0.001-0.021) during weeks 1, 2, and 3. CONCLUSION: There is a weak, but predictable, relationship between blood DHCQ concentrations and efficacy of treatment with HCQ. In addition, there is an association between gastrointestinal adverse events and elevated blood HCQ concentrations. Further investigation of these relationships is warranted to see if DHCQ may be introduced as a new antirheumatic drug.

Efficacy and safety of a once-daily morphine formulation in chronic, moderate-to-severe osteoarthritis pain: results from a randomized, placebo-controlled, double-blind trial and an open-label extension trial.

A randomized, 4-week, double-blind trial followed by an open-label extension trial assessed the efficacy and safety of a once-daily, extended-release morphine formulation (Avinza (previously referred to as Morphelan)) in 295 patients with chronic, moderate-to-severe osteoarthritis pain who had failed to obtain adequate pain relief with NSAIDs and acetaminophen. Participants received one of four treatments: Avinza 30 mg once daily (QAM or QPM), MS Contin(R) 15 mg twice daily, or placebo twice daily. Patients (n =181) received Avinza QAM or QPM during the 26-week open-label extension trial and could increase their dose to optimize pain control. Avinza and MS Contin reduced pain and improved several sleep measures versus placebo. Analgesic efficacy was comparable between Avinza and MS Contin; however, Avinza QAM demonstrated greater improvements in overall quality of sleep. The most common adverse events were constipation and nausea. The majority of AEs occurred at a similar incidence among the active treatment groups.