Rheumatoid Arthritis: Weaver AL

Weaver AL. · University of Nebraska Medical Center, Omaha, NE, USA. · Rheumatology (Oxford). · Pubmed #15150428 links to  free full text

Abstract: The past decade has seen a shift in the paradigm for RA management. DMARDs have been introduced at earlier stages of disease in an effort to slow or stop radiographic disease progression before irreversible joint damage, work disability, functional decline and other adverse outcomes are seen. Although often effective, DMARDs have been limited in treatment durability over the long term due to side-effects and declining efficacy. Combination regimens, often involving weekly methotrexate as the anchor drug, have been used increasingly to overcome the limitations of DMARD monotherapy. The advent of biological therapies that specifically target key proinflammatory cytokines, believed to be important in disease pathogenesis, provides several new treatment options. In controlled clinical trials, the IL-1 blocker anakinra (r-metHuIL-1ra) significantly reduced the clinical signs and symptoms of RA when used alone or in combination with weekly methotrexate. The TNF inhibitors etanercept, infliximab and adalimumab have shown similar efficacy; indeed, higher response rates for clinical and radiological parameters have been seen with the TNF blockers. Importantly, each of these biological response modifiers significantly reduced radiographic disease progression in 6- to 12-month studies, and some radiographic data extend to 24 months. Despite these promising findings, it remains to be determined whether slowing radiographic progression will translate into significant improvements in long-term outcomes.

Mikuls TR, Weaver AL. · Section of Rheumatology and Immunology, University of Nebraska Medical Center and the Omaha Veterans' Administration Medical Center, 983025 Nebraska Medical Center, Omaha, NE 68198, USA. · Curr Rheumatol Rep. · Pubmed #14531954 No free full text.

Abstract: Tumor necrosis factor-alpha (TNFa) plays a central role in rheumatoid arthritis (RA) pathogenesis. There are currently three available anti-TNFa agents for the treatment of RA--adalimumab, etanercept, and infliximab. These targeted therapies have select advantages over traditional disease-modifying antirheumatic drugs (DMARDs), agents that have long been the mainstay of RA treatment. Compared with conventional DMARDs, TNFa inhibitors display a rapid onset of action and have shown a significant effect in retarding the radiographic joint destruction that often characterizes RA disease progression. Although anti-TNFa drugs represent an important advance in RA treatment, postmarketing reports of serious infections, as well as other adverse events, highlight the need for continued postmarketing vigilance with the use of these agents. This review evaluates the unique attributes of the available TNFa inhibitors, focusing specifically on recent reports providing important insight into the understanding of drug-related efficacy and toxicity.

Weaver AL. · Arthritis Center of Nebraska, Lincoln 68506, USA. · Clin Ther. · Pubmed #11589252 No free full text.

Abstract: BACKGROUND: Rofecoxib is a member of a subgroup of nonsteroidal anti-inflammatory drugs (NSAIDs) known as cyclooxygenase-2 (COX-2)-selective inhibitors. It has been studied in adult and elderly patients in a number of painful conditions (primary dysmenorrhea, acute pain after dental and orthopedic surgery, osteoarthritis [OA], and rheumatoid arthritis). OBJECTIVE: This review discusses the clinical pharmacology of and clinical experience with rofecoxib, and the role of COX-2-selective inhibitors in clinical practice. METHODS: Pertinent studies were identified through searches of MEDLINE and EMBASE, as well as the Web sites and proceedings of relevant scientific meetings. RESULTS: Although the published literature is limited, the data indicate that rofecoxib is an effective analgesic agent for the painful conditions in which it has been studied. As a COX-2-selective inhibitor, rofecoxib offers safety advantages over traditional NSAIDs. In clinical trials, gastrointestinal (GI) toxicity, including mucosal damage, perforation, ulcers, and bleeding, occurred significantly less often in healthy volunteers and patients treated with rofecoxib than in those who received NSAIDs such as ibuprofen, naproxen, or diclofenac (all comparisons, P < 0.001). In terms of renal toxicity, rofecoxib does not appear to offer a safety advantage over traditional NSAIDs. Rofecoxib has not been shown to affect platelets (bleeding time and platelet aggregation), unlike traditional NSAIDs. CONCLUSIONS: Rofecoxib is an appropriate choice for patients who do not obtain adequate analgesia with acetaminophen and those who have not obtained adequate analgesia from, cannot tolerate, or are at risk for GI toxicity with traditional NSAIDs. Patients who require chronic analgesic medication (ie, those with OA), including those who take other medications daily for comorbid conditions, may also benefit from the once-daily dosing regimen of rofecoxib.

Bradley JD, Dmitrienko AA, Kivitz AJ, Gluck OS, Weaver AL, Wiesenhutter C, Myers SL, Sides GD. · Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. · J Rheumatol. · Pubmed #15742431 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy and safety of a selective inhibitor of secretory phospholipase (sPLA2), LY333013, in the treatment of rheumatoid arthritis (RA). METHODS: Two hundred and fifty-one patients with active RA despite treatment with one or more disease modifying antirheumatic drugs (DMARD) received oral doses of LY333013 (50, 250, and 1000 mg) or placebo once daily for 12 weeks. Concomitant low-dose glucocorticoids (< or = 10 mg/day prednisone equivalent) were allowed. Clinical improvement was assessed using the response criteria of the American College of Rheumatology (ACR20), and safety was evaluated with respect to adverse events and laboratory test abnormalities. RESULTS: The demographic characteristics of the treatment groups were similar. Dose-response relationships were found for ACR20 responses (p = 0.058) and reductions in C-reactive protein (p = 0.058) at week 1. The proportions of patients with an ACR20 response subsequently increased in all study groups including the placebo group at weeks 4 and 8, and the initial treatment benefit was lost. Adverse events were generally mild in severity and not associated with treatment. CONCLUSION: Treatment with LY333013 for 12 weeks was well tolerated but ineffective as an adjunct to DMARD treatment of active RA.

Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, Wasko MC, Moreland LW, Weaver AL, Markenson J, Cannon GW, Spencer-Green G, Finck BK. · Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, 1000 Welch Road #203, Palo Alto, CA 94304, USA. · Arthritis Rheum. · Pubmed #12115173 links to  free full text

Abstract: OBJECTIVE: To compare the clinical and radiographic outcomes in patients with rheumatoid arthritis (RA) who received monotherapy with either etanercept or methotrexate (MTX) for 2 years and to assess the safety of this therapy. METHODS: In the Enbrel ERA (early rheumatoid arthritis) trial, 632 patients with early, active RA were randomized to receive either twice-weekly subcutaneous etanercept (10 mg or 25 mg) or weekly oral MTX (mean dosage 19 mg per week) for at least 1 year in a double-blind manner. Following the blinded phase of the trial, 512 patients continued to receive the therapy to which they had been randomized for up to 1 additional year, in an open-label manner. Radiograph readers remained blinded to treatment group assignment and the chronologic order of images. RESULTS: At 24 months, more 25-mg etanercept patients than MTX patients met American College of Rheumatology 20% improvement criteria (72% and 59%, respectively; P = 0.005), and more had no increase in total score and erosion scores on the Sharp scale (P = 0.017 and P = 0.012, respectively). The mean changes in total Sharp score and erosion score in the 25-mg etanercept group (1.3 and 0.66 units, respectively) were significantly lower than those in the MTX group (3.2 and 1.86 units, respectively; P = 0.001). Significantly more patients in the 25-mg etanercept group (55%) than in the MTX group (37%) had at least 0.5 units of improvement in the Health Assessment Questionnaire disability index (P < 0.001). Fewer patients in the etanercept group than in the MTX group experienced adverse events or discontinued treatment because of adverse events. CONCLUSION: Etanercept as monotherapy was safe and was superior to MTX in reducing disease activity, arresting structural damage, and decreasing disability over 2 years in patients with early, aggressive RA.

Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, Genovese MC, Wasko MC, Moreland LW, Weaver AL, Markenson J, Finck BK. · Johns Hopkins Asthma and Allegy Center, Johns Hopkins University, Baltimore, MD 21224, USA. · N Engl J Med. · Pubmed #11096165 links to  free full text

Abstract: BACKGROUND: Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown. METHODS: We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. RESULTS: As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate. CONCLUSIONS: As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.

Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC, Isakson PC, Verburg KM, Yu SS, Zhao WW, Geis GS. · Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass 02215, USA. · JAMA. · Pubmed #10580457 links to  free full text

Abstract: CONTEXT: In vitro studies have shown that celecoxib inhibits cyclooxygenase 2 (COX-2) but not COX-1, suggesting that this drug may have anti-inflammatory and analgesic activity without adverse upper gastrointestinal (GI) tract effects that result from COX-1 inhibition. OBJECTIVE: To test whether celecoxib has efficacy as an anti-inflammatory and analgesic with reduced GI tract mucosal damage compared with conventional nonsteroidal anti-inflammatory drugs in patients with rheumatoid arthritis. DESIGN: Randomized, multicenter, placebo-controlled, double-blind trial lasting 12 weeks, with follow-up at weeks 2, 6, and 12, from September 1996 thorugh February 1998. SETTING: Seventy-nine clinical sites in the United States and Canada. PATIENTS: A total of 1149 patients aged 18 years or older with symptomatic rheumatoid arthritis who met inclusion criteria were randomized; 688 (60%) of these completed the study. INTERVENTIONS: Patients were randomized to receive celecoxib, 100 mg, 200 mg, or 400 mg twice per day (n = 240, 235, and 218, respectively); naproxen, 500 mg twice per day (n = 225); or placebo (n = 231). MAIN OUTCOME MEASURES: Improvement in signs and symptoms of rheumatoid arthritis as assessed using standard measures of efficacy and GI tract safety as assessed by upper GI tract endoscopy before and after treatment, compared among treatment groups. RESULTS: All dosages of celecoxib and naproxen significantly improved the signs and symptoms of arthritis compared with placebo. Maximal anti-inflammatory and analgesic activity was evident within 2 weeks of initiating treatment and was sustained throughout the 12 weeks. The incidence of endoscopically determined gastroduodenal ulcers in placebo-treated patients was 4 (4%) of 99, and the incidences across all dosages of celecoxib were not significantly different (P>.40): 9 (6%) of 148 with 100 mg twice per day, 6 (4%) of 145 with 200 mg twice per day, and 8 (6%) of 130 with 400 mg twice per day. In contrast, the incidence with naproxen was 36 (26%) of 137, significantly greater than either placebo or celecoxib (P<.001). The overall incidences of GI tract adverse effects were 19% for placebo; 28%, 25%, and 26% for celecoxib 100 mg, 200 mg, and 400 mg twice per day, respectively; and 31 % for naproxen. CONCLUSION: In this study, all dosages of celecoxib were efficacious in the treatment of rheumatoid arthritis and did not affect COX-1 activity in the GI tract mucosa as evidenced by less frequent incidence of endoscopic ulcers compared with naproxen.

Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, Weaver AL, Keystone EC, Furst DE, Mease PJ, Ruderman EM, Horwitz DA, Arkfeld DG, Garrison L, Burge DJ, Blosch CM, Lange ML, McDonnell ND, Weinblatt ME. · Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 35294-7201, USA. · Ann Intern Med. · Pubmed #10075615 links to  free full text

Abstract: BACKGROUND: In a phase II study, etanercept (recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein) safely produced rapid, dose-dependent improvement in rheumatoid arthritis over 3 months. OBJECTIVE: To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis. DESIGN: Randomized, double-blind, placebo-controlled trial with blinded joint assessors. SETTING: 13 North American centers. PATIENTS: 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs. INTERVENTION: Twice-weekly subcutaneous injections of etanercept, 10 or 25 mg, or placebo for 6 months. MEASUREMENTS: The primary end points were 20% and 50% improvement in disease activity according to American College of Rheumatology (ACR) responses at 3 and 6 months. Other end points were 70% ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months. RESULTS: Etanercept significantly reduced disease activity in a dose-related fashion. At 3 months, 62% of the patients receiving 25 mg of etanercept and 23% of the placebo recipients achieved 20% ACR response (P < 0.001). At 6 months, 59% of the 25-mg group and 11% of the placebo group achieved a 20% ACR response (P < 0.001); 40% and 5%, respectively, achieved a 50% ACR response (P < 0.01). The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56% and 47% in the 25-mg group and 6% and -7% in the placebo group (P < 0.05). Significantly more etanercept recipients achieved a 70% ACR response, minimal disease status (0 to 5 affected joints), and improved quality of life. Etanercept was well tolerated, with no dose-limiting toxic effects. CONCLUSIONS: Etanercept can safely provide rapid, significant, and sustained benefit in patients with active rheumatoid arthritis.

Cohen SB, Cohen MD, Cush JJ, Fleischmann RM, Mease PJ, Schiff MH, Simon LS, Weaver AL. · The University of Texas Southwestern Medical Center, Office of Continuing Education, 5323 Harry Hines Blvd., Dallas, TX 75390-9059. · J Rheumatol Suppl. · Pubmed #19193621 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic, multisystem, inflammatory disorder of the joints that affects about 1% of the world population. The ultimate goals of therapy include remission of disease and prevention of joint damage. Reaching these goals has become a realistic outcome for an increasing number of patients as treatment options have expanded over the past 3 decades. In addition to older therapies, such as methotrexate (MTX), other disease modifying drugs (DMARD), and tumor necrosis factor (TNF) inhibitors, newer biologic treatments have become available. For the substantial number of patients who experience an inadequate response to standard medications, biologic response modifiers (BRM) provide an important therapeutic alternative. The availability of multiple treatment options in the absence of clear definitions or criteria for remission and inadequate response, however, makes clinical decisions about measuring outcomes, predicting response to treatment, and prescribing pharmacologic therapies challenging. In this program, distinguished rheumatologists weigh the evolving body of clinical evidence to draw sound conclusions and resolve key issues in managing inadequate response to treatment and in achieving optimal outcomes in RA.

Cannon GW, Pincus SH, Emkey RD, Denes A, Cohen SA, Wolfe F, Saway PA, Jaffer AM, Weaver AL, Cogen L, Schindler JD. · Division of Rheumatology, University of Utah, Salt Lake City, UT 84132, USA. · Arthritis Rheum. · Pubmed #18240222 links to  free full text

Abstract: One hundred five patients were enrolled in a 12-week, randomized, prospective, double-blind, placebo-controlled trial of recombinant human gamma-interferon (rHu gamma-IFN) for the treatment of rheumatoid arthritis. Fifty-four patients received rHu gamma-IFN and 51 received placebo. Forty-two patients in each group completed the 12-week trial. Some clinical improvement occurred in both groups of patients. Although the improvement with rHu gamma-IFN was greater than that with placebo, the differences were generally not statistically significant.

Weaver AL. · Division of Rheumatology, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Mod Rheumatol. · Pubmed #17143658 No free full text.

Abstract: The last decade has seen a marked increase in the elucidation of cellular and molecular factors involved in chronic inflammatory processes that contribute to the pathogenesis of rheumatoid arthritis (RA). Multiple lines of evidence have demonstrated a critical role for the proinflammatory cytokine tumor necrosis factor (TNF) in the perpetuation of inflammatory synovitis and the subsequent destruction of cartilage and bone that leads to the functional disability observed in RA. In the light of these discoveries, new therapeutics have been developed to target TNF. The consistent efficacy demonstrated by these agents for the treatment of RA has validated TNF as an important mediator of the chronic inflammatory events and structural damage that occur with the disease. Three of these agents (etanercept, infliximab, and adalimumab) have been approved by the United States Food and Drug Administration (FDA) over the last 5 years for treatment of moderately to severely active RA. This article will first explain the role of TNF in inflammation and RA, and then compare and contrast the mechanisms of action, efficacy, and safety profiles of the various FDA-approved TNF inhibitors, as well as offer potential explanations for the clinical differences observed between these agents, especially with regard to safety.

Weaver AL. · University of Nebraska Medical School, Omaha, Nebraska, USA. · J Clin Rheumatol. · Pubmed #17041440 No free full text.

Abstract: Current understanding of the mechanisms behind the pathogenesis of rheumatoid arthritis (RA) has led to the development of therapies involving biologic agents that target specific mediators of the disease process. Although the biologic agents used to treat RA share the ability to alter the cytokine cascade, they differ in ways that are clinically important. For example, they vary with regard to how they block cytokine activity (ie, as receptors, as receptor blockers, or as anticytokine antibodies) and the particular cytokine they target (eg, tumor necrosis factor [TNF] versus interleukin-1). Biologic therapies for RA also differ in mode of administration. Several are administered subcutaneously, whereas others are given intravenously. They also have molecular dissimilarities that result in differences in pharmacokinetics (ie, long versus medium half-life) and that may influence their safety profiles.Some biologic agents, such as the TNF inhibitors etanercept and infliximab, have been rigorously examined for long-term safety and efficacy, whereas other agents, like the TNF inhibitor adalimumab, have not. Differences between the various biologic agents may relate to the usefulness of each individual drug as a long-term treatment in RA. For example, the need for physician visits may impact the practicality of drugs that are administered intravenously. Also, physicians should be aware that use of cytokine inhibitors increases the risk of infection. The prevalence of tuberculosis during therapy with infliximab exceeds the background rate in patients with RA. Accordingly, physicians should be familiar with the updated warnings in the package inserts that accompany these drugs.

Weaver AL, Lautzenheiser RL, Schiff MH, Gibofsky A, Perruquet JL, Luetkemeyer J, Paulus HE, Xia HA, Leff JA, Anonymous00550. · University of Nebraska Medical Center, Omaha, NE, USA. · Curr Med Res Opin. · Pubmed #16393444 No free full text.

Abstract: OBJECTIVE: To evaluate the effectiveness of select biologics, methotrexate (MTX), and other disease-modifying anti-rheumatic drugs (DMARDs) in the management of adult rheumatoid arthritis (RA) in routine clinical practice. RESEARCH DESIGN AND METHODS: RADIUS (Rheumatoid Arthritis DMARD Intervention and Utilization Study) comprises two prospective, 5-year, observational registries of over 10 000 patients. Over 4600 patients who initiated MTX or a biologic regimen (etanercept [ETN], infliximab [INF], ETN + MTX, and INF + MTX) and who had at least one on-regimen, follow-up evaluation, were included in this analysis. Adalimumab was not included because it had not yet received FDA approval at RADIUS initiation. Other common DMARD regimens (N = 762) were also compared with MTX. Patients who initiated less commonly used regimens, such as anakinra or cyclosporine, and those who did not have at least one on-regimen, follow-up evaluation, were not eligible for this analysis. Because ESR/CRP measurements were often not available, a modified ACR20 response (mACR20), defined as three out of four response criteria excluding ESR/CRP, was used to assess response at 12 months. Logistic regression analysis was performed to control for baseline covariates that may affect outcomes. MAIN OUTCOME MEASURES: The primary endpoint was the proportion of patients who achieved a mACR20 response at 12 months post-RADIUS entry. RESULTS: After adjusting for baseline covariates, patients receiving either ETN + MTX or ETN monotherapy were more likely to achieve a mACR20 response at 12 months than patients receiving MTX alone (odds ratio [OR] 1.29, 95% confidence interval [CI] 1.09-1.52; p < 0.01 and OR 1.23, 95% CI 1.02-1.47; p < 0.05, respectively). Conversely, patients treated with MTX + leflunomide (LEF) were less likely to achieve a mACR20 response than those receiving MTX alone (OR 0.68, 95% CI 0.48-0.96; p < 0.05). Significant differences were not observed between patients receiving MTX alone and either INF + MTX, MTX + hydroxychloroquine, MTX + hydroxychloroquine + sulfasalazine, INF monotherapy, or LEF monotherapy. CONCLUSION: These data from routine rheumatology clinical practice settings highlight the effectiveness of common biologic and DMARD therapies, and provide additional data beyond those of randomized, controlled trials.

Fleischmann RM, Baumgartner SW, Tindall EA, Weaver AL, Moreland LW, Schiff MH, Martin RW, Spencer-Green GT. · University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA. · J Rheumatol. · Pubmed #12672185 No free full text.

Abstract: OBJECTIVE: Approximately 3% of the US population over the age of 65 years has rheumatoid arthritis (RA). We compared the safety and efficacy of etanercept (Enbrel) in patients with RA who were > or = 65 years to those < 65 years in open-label and double-blind, randomized clinical trials. METHODS: Patients from 4 double-blind, randomized controlled trials and 5 open-label trials were included in this retrospective analysis. Patients were grouped by age (< 65 or > or = 65 yrs) at time of study entry. All patients received etanercept subcutaneously twice weekly. Improvement in signs and symptoms was assessed by the proportion of patients who achieved the American College of Rheumatology definition of improvement (ACR 20). The ACR 50 and ACR 70 responses were calculated in an analogous fashion. Safety was assessed at regularly scheduled visits. RESULTS: Of 1128 patients enrolled in etanercept trials, 197 (17%) were > or = 65 years of age. Clinical response was rapid and sustained and did not differ between age groups. At one year, 69% of patients < 65 years and 66% of patients > or = 65 years met the ACR 20. Forty percent of the patients > or = 65 years met the ACR 50 and 17% met the ACR 70. Etanercept was well tolerated. Although injection site reactions, headache, and rhinitis occurred somewhat more frequently in younger patients, the overall rates and types of other adverse events were comparable in both groups. CONCLUSION: Etanercept is a new treatment option for older patients with RA and has substantial benefit and comparable safety regardless of patient age.