Jacques Caldwell

Low dose long-term corticosteroid therapy in rheumatoid arthritis: An analysis of serious adverse events

PURPOSE The purpose of this study was to better define the toxicity of low dose (less than or equal to 15 mg/d prednisone or equivalent) long-term (greater than 1 year) corticosteroids in the treatment of rheumatoid arthritis (RA). PATIENTS AND METHODS We examined an historical cohort of 112 RA patients on low dose (6.1 +/- 3.1 mg/d, mean +/- SD) long-term (6.2 +/- 4.6 years) prednisone (CS) and compared them to 112 matched RA patients not using prednisone (CO). CS were matched one-to-one with CO for sex (75% women), age (+/- 5 yrs), race (98% white), and duration of disease (+/- 5 yrs). Subjects were determined by review of unselected medical records from three distinct rheumatology practice settings. For CS, charts were abstracted from the date of prednisone start for predefined adverse events (AEs). RESULTS Ninety-two (92) AEs were noted in CS versus 31 in CO and included: fracture (CS:21 versus CO:8), serious infections (CS:14 versus CO:4), gastrointestinal (GI) bleed or ulcer (CS:11 versus CO:4), and cataracts (CS:17 versus CO:5). At time of first AE, CS prednisone average dose was 7.0 +/- 2.6 mg with a duration of 4.9 +/- 3.9 years. Stepwise multiple logistic regression analysis was used to create a model which included all clinically relevant variables and all parameters significantly different at the cohort inception. Prednisone average dose of greater than 10 to less than or equal to 15 mg/d correlated most strongly with the development of an AE (Odds Ratio (OR) = 32.3, 95% Confidence Interval (CI) 4.6, 220). Average prednisone 5 to 10 mg (OR = 4.5, 95% CI 2.1, 9.6), RA nodules (OR = 3.9, 95% CI 1.9, 8.0), and bony erosions (OR = 2.4, 95% CI 1.2, 4.7) also entered the final model. Kaplan Meier survival curves for the development of the first AE showed a dose-response relationship between prednisone and AE occurrence, independent of rheumatoid nodules. Subset analyses utilized a nested case control design for the development of three serious AEs: fractures, serious infections, and GI events. These analyses revealed possible relationships between prednisone use and the development of each specific AE (prednisone use OR: fracture 3.9, 95% CI 0.8, 18.1; infection 8.0, 95% CI 1.0, 64.0; and GI event 3.3, 95% CI 0.9, 12.1). CONCLUSIONS Although disease severity is an important confounding factor, low dose long-term prednisone use equal to or greater than 5 mg/d is correlated with the development of specific adverse events in a dose-dependent fashion.

Concomitant Leflunomide Therapy in Patients with Active Rheumatoid Arthritis despite Stable Doses of Methotrexate: A Randomized, Double-Blind, Placebo-Controlled Trial

Context Several disease-modifying antirheumatic drugs (DMARDs) slow disease progression in patients with rheumatoid arthritis. Many experts prefer methotrexate, although trials do not uniformly show that it is superior to other DMARDs. It is not known whether combining methotrexate with a second DMARD is better than prescribing methotrexate alone. Contribution This 24-week, randomized, double-blind, placebo-controlled trial shows that leflunomide added to ongoing stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis improves clinical outcomes compared with methotrexate alone. Cautions Some adverse effects, such as diarrhea, were more common with combination therapy. All patients receiving DMARD therapy need close monitoring for toxicities. The Editors Rheumatoid arthritis has considerable societal costs (1-5). Many patients with rheumatoid arthritis become disabled within a few years of disease onset (4, 5). Methotrexate is the standard treatment for rheumatoid arthritis. During the past several years, investigators have found that some disease-modifying antirheumatic drugs can increase the efficacy of methotrexate monotherapy (6-9). Methotrexate is an antimetabolite and immunomodulator that affects many intracellular metabolic pathways of purine metabolism (10). The precise intracellular biochemical pathway responsible for the observed clinical benefits of methotrexate in the treatment of rheumatoid arthritis is still the subject of some debate (11), but methotrexate is thought to act primarily on purine pathways of cellular metabolism (10). Leflunomide (Arava, Aventis Pharmaceuticals, Bridgewater, New Jersey) also has antimetabolic effects, inhibiting pyrimidine intracellular pathways (12). Leflunomide has been shown to be effective for rheumatoid arthritis in double-blind, placebo-controlled trials (13, 14). Given the diverse intracellular pathways affected by both drugs, the combination of leflunomide and methotrexate has the potential for biochemical synergy. The possibility of increased benefits should be weighed against the possible toxicities of this combination. Abnormal aminotransferase levels have been seen with both methotrexate (15) and leflunomide (14) monotherapy in patients with rheumatoid arthritis. In a small open study, we previously observed that the combination of methotrexate and leflunomide led to considerable clinical improvements and reversible elevations in aminotransferase levels (16). We therefore sought to determine whether similar results could be achieved in a large, double-blind investigation of the combination of these two antimetabolic agents. Methods Patients The study sample consisted of 263 patients who had rheumatoid arthritis as defined by American College of Rheumatology (ACR) criteria (17). Patients were 18 to 75 years of age and were receiving stable dosages of methotrexate (15 to 20 mg/wk, or 10 to 15 mg/wk if this was the maximum tolerated dose). Patients were recruited from active outpatient practice centers, and study participants were approached without a particular schema. Eligible patients had active rheumatoid arthritis despite at least 6 months of methotrexate therapy, including stable dosage for at least 8 weeks. Patients with active rheumatoid arthritis were defined as meeting three of the following criteria on two different evaluations, 7 to 21 days apart: at least nine tender joints, at least six swollen joints, at least 45 minutes of morning stiffness, and an erythrocyte sedimentation rate of at least 28 mm/h. Previous disease-modifying antirheumatic drugs, not including ongoing methotrexate, had failed in 11 patients. Patients receiving corticosteroids were required to have been taking a stable daily dose of 10 mg or less for at least 30 days before study drug administration, and the corticosteroid dose was required to remain constant throughout the study. Complete exclusion criteria are listed in Appendix Table 1. Study Design The 24-week, randomized, double-blind, placebo-controlled study, with evaluations occurring at 4-week intervals (Figure 1), was conducted in 20 centers in the United States and Canada between September 1998 and June 2000. The primary objective was to evaluate the efficacy and safety of adding leflunomide or placebo to stable methotrexate therapy in patients with active rheumatoid arthritis. All participants provided written consent, and the institutional review board at each center approved the protocol. Figure 1. Patient eligibility, randomization, assignment, and discontinuation. Include no wish to continue in study, poor adherence to treatment, protocol violation, and moving away from the study area. A randomization schedule, generated by and stored with Quintiles, Inc., Kansas City, Missouri, was used to assign sequential numbers to randomly allocated treatment codes. Randomization was done by using the Aventis standard random-code generator. Investigators allocated numbers to patients, beginning with the lowest available number. Quintiles, Inc., packaged and labeled the study medication. The randomization code used was concealed from investigators and patients throughout the study. Randomization was stratified by center. A set of 500 random numbers was generated, with treatment groups randomly assigned in a balanced manner (1:1 ratio) within each block of four consecutive random numbers (block size, 4). A set of these blocks was then sent to each investigative center. This method is identical to stratification by center because centers are balanced with respect to treatment assignment. Patients were randomly assigned to receive leflunomide, 100 mg/d, for 2 days followed by 10 mg/d or matching placebo. If substantial adverse events occurred, this dose could be reduced to 10 mg every other day. If 10 mg/d was tolerated but active disease, as defined earlier, was still present at week 8 or thereafter, an increase to 20 mg of leflunomide or matching placebo per day was required. If substantial adverse events occurred while the patient was taking 20 mg of the study drug per day, a one-time dose reduction to 10 mg/d was allowed at the discretion of the investigator. At least 1 mg of folate supplementation per day was mandated by the protocol. Adherence to study medication, assessed at each visit by tablet counts (actual number of tablets returned compared with number expected to be returned), was similar in the two groups. The mean adherence for all patients in the intention-to-treat sample was 98.0% (98.5% for those receiving placebo and 97.4% for those receiving leflunomide). In the placebo group and leflunomide group, respectively, 90.2% (120 of 133 patients) and 87.7% (114 of 130 patients) had adherence rates of 80% to 120%. Measurement of Efficacy The primary efficacy variable was the rate at which the intention-to-treat sample achieved 20% improvement in ACR criteria (ACR20) at the end of the study. To be classified as having achieved ACR20, patients were required to complete 24 weeks of treatment and meet ACR20 response criteria at end of the study (13). The ACR20 criteria were developed to define improvement in rheumatoid arthritis (18). Clinical improvement is indicated by 20% improvement in tender and swollen joint counts and 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, pain intensity, physical function or disability measure, and level of acute-phase reactant (19). All ACR assessments were performed by the investigators, and the same assessor performed all analyses throughout the study whenever possible to increase the reliability of the assessment. Patients who discontinued therapy before the end of week 24 or for whom data were insufficient to assess ACR20 response at week 24 were classified as nonresponders for the primary analysis. Count of tender joints was based on 68 joint assessments, and count of swollen joints was based on 66 joint assessments. Percentage changes in tender joint and swollen joint counts were based on the number of evaluable joints at a visit. Joints that had been replaced or had been injected with corticosteroids within 4 weeks before the assessment were considered nonevaluable. Secondary outcomes included ACR50 and ACR70 responder rates at week 24 (analyses of responders at study end for the nonprimary efficacy measures). The ACR50 and ACR70 were defined as at least 50% and 70% improvement, respectively, in the same criteria used to calculate ACR20 response. Secondary efficacy variables also included change from baseline to end point in each of the individual components of the ACR response criteria and change from baseline to week 24 in levels of rheumatoid factor. Mean changes from baseline in individual efficacy measures are shown in Appendix Table 2. Measurement of Safety Safety was evaluated by adverse event reports; laboratory assays for changes in hematologic characteristics, blood chemistry, urinalysis, and liver function; and physical examination. Potential adverse events were assessed by using open-ended questions at each study visit. The assessor was blinded to reported toxicities and to any additional information obtained at the visit. The study protocol provided recommendations for dosage change and discontinuation of drug therapy, without unblinding, when patients were found to have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values greater than two times the upper limit of normal. Investigators decreased the dose of the study medication if, on repeated analysis at 72 hours, test values remained greater than two times but less than or equal to five times the upper limit of normal; only one dose adjustment was allowed before discontinuation of therapy with the study drug. Therapy with the study drug was also discontinued in patients with persistent elevations of aminotransferase enzyme levels to more than two times the upper limit of normal on repeated te

Auranofin therapy and quality of life in patients with rheumatoid arthritis. Results of a multicenter trial

In a six-month, randomized, double-blind study at 14 centers, auranofin (3 mg twice daily) was compared with placebo in the treatment of patients with classic or definite rheumatoid arthritis. All patients had unremitting disease for at least the previous six months and at least three months of therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs, oral steroids, and analgesics were allowed throughout the trial. Efficacy was analyzed in 154 patients who received auranofin and 149 who received placebo. To reflect an expanded view of outcome assessment, the measures used included some 20 nontraditional measures of functional performance, pain, global impression, and utility (worth or value) in addition to five standard clinical measures of rheumatoid synovitis (e.g., number of tender joints). The nontraditional measures were mainly in the form of structured questionnaires administered by trained interviewers. To minimize the statistical problem of multiple comparisons, most of the measures were grouped into four composites--clinical (standard measures), functional, global, and pain--and the treatment effect for each composite was tested at the 0.0125 level of significance. Auranofin was superior to placebo in the clinical (p = 0.003), functional (p = 0.001), and global (p = 0.007) composites and trended similarly in the pain composite (p = 0.021). Individual measures within the composites consistently favored auranofin. Other measures, not part of the composites, also favored auranofin, including a patient utility measure designed for this study, the PUMS (p = 0.002). Results confirm the hypothesis that the favorable effect of auranofin on clinical synovitis is accompanied by improvements across a range of outcomes relevant to the patients quality of life.

Two‐year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate

OBJECTIVE Three 6-12-month, double-blind, randomized, controlled trials have shown leflunomide (LEF; 20 mg/day, loading dose 100 mg x 3 days) to be effective and safe for the treatment of rheumatoid arthritis (RA). This analysis of the North American trial assessed whether the clinical benefit evident at month 12 was sustained over 24 months of treatment with LEF as compared with the efficacy and safety of methotrexate (MTX), an equivalent disease-modifying antirheumatic drug, at 24 months. METHODS The year-2 cohort, comprising patients continuing into the second year of treatment with > or = 1 dose of study medication and > or = 1 followup visit after week 52, consisted of 235 patients (LEF n = 98; placebo n = 36; MTX n = 101). The mean (+/- SD) maintenance dose of LEF was 19.6 +/- 1.99 mg/day in year 2 and that of MTX was 12.6 +/- 4.69 mg/week. Statistical analyses used an intent-to-treat (ITT) approach. Statistical comparisons of the active treatments only were prospectively defined in the protocol. RESULTS In total, 85% and 79% of LEF and MTX patients, respectively, who entered year 2 completed 24 months of treatment. From month 12 to month 24, the American College of Rheumatology improvement response rates of > or = 20% (LEF 79% versus MTX 67%; P = 0.049), > or = 50% (LEF 56% versus MTX 43%; P = 0.053), and > or = 70% (LEF 26% versus MTX 20%; P = 0.361) were sustained in both of the active treatment groups. The mean change in total Sharp radiologic damage scores at year 2 compared with year 1 and baseline (LEF 1.6 versus MTX 1.2) showed statistically equivalent sustained retardation of radiographic progression in the active treatment groups. Maximal improvements evident at 6 months in the Health Assessment Questionnaire (HAQ) disability index (HAQ DI) and the physical component score of the Medical Outcomes Survey 36-item short form were sustained over 12 months and 24 months; improvement in the HAQ DI with LEF4(-0.60) was statistically significantly superior to that with MTX (-0.37) at 24 months (P = 0.005). Over 24 months in the ITT cohort, serious treatment-related adverse events were reported in 1.6% of the LEF-treated patients and 3.7% of the MTX-treated patients. Frequently reported adverse events included upper respiratory tract infections, diarrhea, nausea and vomiting, rash, reversible alopecia, and transient liver enzyme elevations. CONCLUSION The safety and efficacy of LEF and MTX were maintained over the second year of this 2-year trial. Both active treatments retarded radiographic progression over 24 months. LEF was statistically significantly superior to MTX in improving physical function as measured by the HAQ DI over 24 months of treatment. Results indicate that LEF is a safe and effective initial treatment for active RA, with clinical benefit sustained over 2 years of treatment without evidence of new or increased toxicity.

Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: Results of a one-year, randomized, clinical trial in patients with osteoarthritis of the knee and hip

OBJECTIVE To compare the clinical efficacy of rofecoxib, a specific inhibitor of cyclooxygenase 2 (COX-2), with that of diclofenac in patients with osteoarthritis (OA) and to evaluate the safety and tolerability of rofecoxib. METHODS We performed a randomized, double-blind, active comparator-controlled trial in 784 adults with OA of the knee or hip. Patients were randomized to 1 of 3 treatment groups: 12.5 mg of rofecoxib once daily, 25 mg of rofecoxib once daily, and 50 mg of diclofenac 3 times daily. Clinical efficacy and safety were evaluated over a 1-year continuous treatment period. RESULTS Rofecoxib at dosages of 12.5 and 25 mg demonstrated efficacy that was clinically comparable to that of diclofenac, as assessed by all 3 primary end points according to predefined comparability criteria. Results from secondary end points were consistent with those of the primary end points. There were small statistical differences favoring diclofenac for 2 of the end points. All treatments were well tolerated. CONCLUSION Rofecoxib was well tolerated and provided efficacy that was clinically comparable, according to predefined statistical criteria, to that of 150 mg of diclofenac per day in this 1-year study. Specific inhibition of COX-2 provided therapeutic efficacy in OA.

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.

Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid arthritis treated with methotrexate: results of a multicentred cross sectional observational study

Objective: To investigate the contribution of red blood cell (RBC) methotrexate polyglutamates (MTX PGs), RBC folate polyglutamates (folate PGs), and a pharmacogenetic index to the clinical status of patients with rheumatoid arthritis treated with MTX. Methods: 226 adult patients treated with weekly MTX for more than 3 months were enrolled at three sites in a multicentred cross sectional observational study. Clinical status was assessed by the number of joint counts, physician’s global assessment of disease activity, and a modified Health Assessment Questionnaire (mHAQ). RBC MTX PG and folate PG metabolite levels were measured by high performance liquid chromatography fluorometry and radioassay, respectively. A composite pharmacogenetic index comprising low penetrance genetic polymorphisms in reduced folate carrier (RFC-1 G80A), AICAR transformylase (ATIC C347G), and thymidylate synthase (TSER*2/*3) was calculated. Statistical analyses were by multivariate linear regression with clinical measures as dependent variables and metabolite levels and the pharmacogenetic index as independent variables after adjustment for other covariates. Results: Multivariate analysis showed that lower RBC MTX PG levels (median 40 nmol/l) and a lower pharmacogenetic index (median 2) were associated with a higher number of joint counts, higher disease activity, and higher mHAQ (p<0.09). Multivariate analysis also established that higher RBC folate PG levels (median 1062 nmol/l) were associated with a higher number of tender and swollen joints after adjustment for RBC MTX PG levels and the pharmacogenetic index (p<0.05). Conclusion: Pharmacogenetic and metabolite measurements may be useful in optimising MTX treatment. Prospective studies are warranted to investigate the predictive value of these markers for MTX efficacy.

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.

Efficacy and safety of intraarticular sodium hyaluronate in knee Osteoarthritis

A prospective, multicenter, randomized, double-blind, controlled trial was conducted in 226 patients with knee osteoarthritis to evaluate the safety and efficacy of intraarticular injections of sodium hyaluronate. Patients were randomized to three weekly injections of 30 mg sodium hyaluronate or physiologic saline (control) and were observed for an additional 25 weeks. In comparison with the control group, among patients who completed at least 15 weeks of the study and whose Western Ontario and McMaster Universities Osteoarthritis Index pain score for the contralateral knee was less than 12 at baseline, sodium hyaluronate injection resulted in improvement in Western Ontario and McMaster Universities Osteoarthritis Index pain score, patient and investigator global assessments, and pain on standing from Weeks 7 to 27. Fifty-eight percent of patients treated with sodium hyaluronate achieved a 5-unit or greater improvement in mean pain score from Weeks 7 through 27, compared with 40% of control patients. In addition, nearly twice as many patients treated with sodium hyaluronate as with saline (30% versus 17%, respectively) achieved a net improvement of at least 7 units. In contrast to treatment with saline, Western Ontario and McMaster Universities Osteoarthritis Index pain score for the contralateral knee was inversely related to the magnitude of improvement after treatment with sodium hyaluronate. Few side effects were attributed to treatment, and no differences between treatment groups were seen in this respect (sodium hyaluronate, nine [8%]; saline, 11 [10%]). The incidence of injection site reactions was low (sodium hyaluronate, 1.2%; saline, 1.5%). The results indicate that sodium hyaluronate treatment is well tolerated and produces statistically and clinically significant improvement of symptoms in patients with mild to moderate knee osteoarthritis in whom pain in the contralateral knee is relatively modest.

The Prosorba column for treatment of refractory rheumatoid arthritis: A randomized, double-blind, sham-controlled trial

OBJECTIVE To evaluate the efficacy and safety of the Prosorba column as a treatment for rheumatoid arthritis (RA) in patients with active and treatment-resistant (refractory) disease. METHODS A sham-controlled, randomized, double-blind, multicenter trial of Prosorba versus sham apheresis was performed in patients with RA who had failed to respond to treatment with methotrexate or at least 2 other second-line drugs. Patients received 12 weekly treatments with Prosorba or sham apheresis, with efficacy evaluated 7-8 weeks after treatment ended. Patients were characterized as responders if they experienced improvement according to the American College of Rheumatology (ACR) response criteria at the efficacy time point. A data safety monitoring board (DSMB) evaluated interim analyses for the possibility of early completion of the trial. RESULTS Patients in the trial had RA for an average of 15.5 years (range 1.7-50.6) and had failed an average of 4.2 second-line drug treatments prior to entry. After the completion of treatment of 91 randomized patients, the DSMB stopped the trial early due to successful outcomes. Of the 47 patients in the Prosorba arm, 31.9% experienced ACR-defined improvement versus 11.4% of the 44 patients in the sham-treated arm (P = 0.019 after adjustment for interim analysis). When results from 8 additional patients, who had completed blinded treatments at the time of DSMB action, were added to the analysis (n = 99), results were unchanged. The most common adverse events were a short-term flare in joint pain and swelling following treatment, a side effect that occurred in most subjects at least once in both treatment arms. Other side effects, although common, occurred equally as frequently in both treatment groups. CONCLUSION Apheresis with the Prosorba column is an efficacious treatment for RA in patients with active disease who have failed other treatments.