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| Joan Bathon, M.D. and Alan Matsumoto, M.D. | |||||||||||||||||||||||||||
Infliximab (Remicade)
Infliximab (Remicade) Infliximab is labeled Pregnancy Category B. In animal studies with an analogous TNF antibody, no evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed. This study evaluated the outcome of 59 pregnancies identified in the infliximab postmarketing safety. Treating physicians were contacted to document pregnancy outcome and collect additional information. Results: 102 pregnancies were identified in women with Crohns disease or RA treated with infliximab; outcome information was available for patients. The majority of these had Crohns disease, and the average age was 28. 36 of the pregnancies resulted in live births, 10 in miscarriage, 8 in therapeutic termination; 27 pregnancies were ongoing, and 27 were lost to followup. Of the 36 live births, 2 had complications. One infant died 3 weeks following birth and one was born with tetralogy of Fallot. The incidences of live births, miscarriages and therapeutic terminations were reported to be consistent with those observed in a national cohort of healthy women. Conclusion: Based on the data available in the postmarketing safety database, pregnant women exposed to infliximab have observed outcomes consistent with those expected in healthy women. Editorial Comments: These data are encouraging though inconclusive. Postmarketing data are complicated by reporting bias and insufficient information in many cases. Furthermore, most of the cases of pregnancy were in women with Crohns disease, a disease in which infliximab is generally used in single dose for acute flares or for fistulas. The effects of continuous dosing, such as in RA, are less clear. Also, the incidence of concomitant use of methotrexate was not discussed. Nonetheless, these findings are encouraging. (top of section) (top of page)
Etanercept (Enbrel) Abstracts 150 Global safety and efficacy of up to five years of etanercept (Enbrel) Therapy. Abstracts 151 Etanercept (Enbrel) in Early Erosive Rheumatoid Arthritis (ERA trial): Observations at 3 years. Abstracts 152 Etanercept (Enbrel) in addition to methotrexate (MTX) in rheumatoid arthritis: Long-term observations. In the first, data from 1960 patients in Europe and North America were combined and evaluated; some of these patients have received 5 years of etanercept therapy. In the second, patients from the early RA trial (Bathon et al; NEJM 2000) in which MTX was compared to etanercept, were allowed during the third year to switch from MTX to etanercept, or to add etanercept to MTX, or to increase their dose of etanercept from 10 mg to 25 mg. In the third study, patients who participated in the study by Weinblatt et al (NEJM 1999) comparing etanercept + MTX to MTX alone were also followed into their third year. In all three studies, the safety profiles in etanercept and etanercept + MTX treated patients were fairly benign. The incidence of serious infection requiring IV antibiotics and/or hospitalization (0.04 per patient year) did not increase during long-term follow-up and was not different from that of the control groups during the double-blind portions of the studies. Likewise, the incidence of malignancies was not different from that of the SEER database in non-RA populations. Efficacy with long-term etanercept treatment was sustained and a significant percentage of patients in each open-label study achieved zero joint counts (approximately 25%) and zero HAQ scores (21%). In the open label extension of the ERA trial (Abstract 151), patients previously on MTX experienced significant additional improvement when Enbrel was added or substituted. In patients in the long-term etanercept + MTX trial (Abstract 152), 68% of patients were able to reduce their MTX, and 29% completely discontinued their MTX. Conclusions: Etanercept continues to have an excellent safety profile for the treatment of RA for up to 5 years. Clinical efficacy is sustained for the duration of the treatment. Editorial Comment: We have to keep in mind that long-term open label trials are complicated by selection bias. Patients who did not respond well to etanercept and/or who had significant adverse reactions are likely to have dropped out of the studies by now. Thus, the long-term efficacy and safety profiles could be less favorable than they appear in these data.
(top of section) (top of page) D2E7 (Adalimumab) | |||||||||||||||||||||||||||
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Tumor necrosis factor (TNF) plays an important role in preventing and/or limiting infections by intracellular organisms such as Mycobacteria tuberculosis and Listeria monocytogenes. At last years ACR meeting, we heard from the FDA of unexpectedly frequent reports of tuberculosis extracted from post-marketing data in patients receiving TNF inhibitors, especially infliximab. The following set of abstracts present updates on infections in RA patients treated with etanercept and infliximab. Abstract 725 Infections Associated with Etanercept Treatment of Rheumatoid Arthritis: 2 years of Experience in the "real world". Abstract 153 Tuberculosis Reports with Etanercept (Enbrel) Therapy. Abstract 318 Tuberculosis Rates are Not Increased in Rheumatoid Arthritis. Abstract 319 Acute Life-Threatening Histoplasmosis Complicating the Use of Infliximab and Etanercept. In the first abstract, Belostocki et al reviewed the incidence of any infection in a cohort of patients who were followed for one year prior to treatment with etanercept, and for two years after etanercept therapy was begun. These patients are followed in a community practice setting. The incidence of infections, in general, increased in the cohort of 90 patients from 32 per year in the year prior to etanercept, to 46 and 35 per year in the first and second years after beginning etanercept, respectively. However, the majority of the infections in all three years were respiratory and were non-serious. There was only one serious infection in each of the three years (requiring IV antibiotics and/or hospitalization). There were no incident cases of tuberculosis. In the second abstract, the incidence of reported cases of TB, using the manufacturers world-wide safety database, and post-marketing safe reports, was evaluated. Through April 2001, over 103,000 patients world-wide have received etanercept, and only 9 cases of TB have been reported. Unlike experience with infliximab, there was no consistent temporal association between introduction of etanercept therapy and the onset of clinical TB. 19 patients with a history of TB and 7 with a history of a positive PPD were enrolled in etanercept clinical trials, and reactivation of TB was not observed in any of these individuals. It is important to compare the incidence of TB in etanercept treated patients with the appropriate control - that is, RA patients who have not received anti-TNF therapy. In the third abstract, Wolfe et al attempted to elucidate this number. They surveyed 10,782 RA patients during 3 consecutive 6-month periods between July 1998 and June 2000 for lifetime and previous 6 month TB related events and hospitalizations. The cumulative use of corticosteroids, etanercept and infliximab in the group during this time period was 54.6%, 11.5% and 0.7%, respectively. During the study period, only 1 of 10, 782 RA patients developed active TB, for an annual incidence of 6.2 per 100,000 patients. For comparison, the annual incidence of TB in the US in 1998 was 6.8 per 100,000. Thus, RA patients (in whom use of anti-TNF therapy is low) do not exhibit increased rates of active TB compared to the overall US population. Finally, in the last abstract, the database for the Adverse Event Reporting System was evaluated for reports of histoplasmosis in patients treated with etanercept and infliximab. 9 cases of life-threatening histoplasmosis were reported in infliximab treated patients (denominator = 121,000 patients world-wide) and 1 case in etanercept treated patients (denominator = 95,000 patients world-wide). Editorial Comment: In post-marketing surveillance of reports of adverse events, etanercept appears to be associated with a lower frequency of opportunistic infections (TB, histoplasmosis and others) than infliximab. Although these agents have similar, high affinity for the TNF molecule, the dissociation of infliximab ("off rate") from TNF is much slower than that of etanercept. This may result in much more profound and prolonged reductions in TNF levels with infliximab, and may explain the apparent higher rate of opportunistic infections. RA and Crohns patients in whom TB, histoplasmosis and other opportunistic infections have been reported are usually on other immunosuppressive agents as well, including prednisone, methotrexate and other drugs. Thus, caution and close monitoring for infection are indicated in any immune suppressed patient receiving a TNF inhibitor. | |||||||||||||||||||||||||||
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Anakinra (Kineret) Anakinra is a receptor antagonist of IL-1. The purpose of this study was to evaluate the safety of anakinra in patients with RA already taking etanercept. Methods: 58 patients receiving the usual dose of etanercept (25 mg SQ twice weekly) were treated with anakinra 1 mg/kgday SQ in a multicenter, single arm, open-label study for 24 weeks. Subjects were required to have 6 swollen and 6 tender joints, no other DMARDs within 4 weeks. Results: Baseline characteristics of the study population were 86% white, 85% female, mean weight 81.1 kg, mean age 48.9, mean duration on etanercept 14.4 months, and mean duration of RA 11.9 years. 21 patients (36%) subjects discontinued early of whom 11 had adverse events and 7 reported lack of efficacy. The most common adverse events were injection site reactions (83%), repiratory complaints (53%), systemic symptoms (31%), gastrointestinal complaints (26%), nervous system symptoms (19%), and others (19%). 28 (48%) experienced 48 infectious episodes. Four (7%) required hospitalization (2 cellulitis and 2 community acquired pneumonias). All other infectious episodes were considered mild to moderate. No TB or other opportunistic infections were reported. Conclusions: The investigators concluded that the safety profile with combination therapy was not markedly different when compared with either drug alone. Editorial Comment: 7% hospitalization rate for serious infections is disturbing. FDA guidelines for anakinra currently warn against concomitant use with anti-TNF agents until the incidence of infection is better elucidated. A study is currently underway to examine the efficacy and safety profiles of concomitant anti-IL1 and anti-TNF strategy. | |||||||||||||||||||||||||||
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Late Breaking Abstract LB-7 Etoricoxib in the Treatment of Rheumatoid Arthritis: A 12-week Placebo Controlled and Active-comparator; Double Blind U.S. Study. Celecoxib (Celebrex) and rofecoxib (Vioxx) are selective COX-2 agents commonly used for the treatment of rheumatoid arthritis. They have both been studied in long term trials showing efficacy similar to non-selective NSAIDs and less gastrointestinal toxicity. BY comparison with these agents, etoricoxib demonstrates greater in vitro selectivity for COX-2. The current study examines the efficacy and safety of etoricoxib in rheumatoid arthritis. Methods: 816 patients with RA who had flared after stopping NSAIDs were randomized to etoricoxib 90 mg qd, naproxen 500 mg bid and placebo (2:2:1). Primary outcome measures at 12 weeks were tender and swollen joint count, and investigator global assessment. Secondary outcomes were ACR 2O response and the rest of the components of the ACR response criteria. Results: In all of the primary and secondary endpoints, etoricoxib showed significant improvements over both the placebo and naproxen groups. Percentage of patients achieving an ACR 20 response over 12 weeks was 21%, 53% and 39% for the placebo, etoricoxib and naproxen groups respectively. Active drugs and placebo were well tolerated with similar rates of adverse events. Editorial Comment: While it is not surprising that etoricoxib was effective in RA, it is surprising that it was shown to be significantly superior to naproxen. This differs from all of the prior studies in RA and OA that show the selective COX-2 inhibitors to be equal in efficacy to the older non-selective NSAIDs. Certainly this result will need to be repeated and I suspect that in future studies, etoricoxib will also be shown to be similar in efficacy to other selective COX-2 inhibitors. However, it is intriguing to ponder whether the greater COX-2 selectivity of etoricoxib confers an advantage. The study is not powered to assess GI or cardiovascular toxicity issues. Abstract 1896 Valdecoxib, A New Cox-2 Specific Inhibitor is Effective in Treating the Signs and Symptoms of Rheumatoid Arthritis. Valdecoxib is a new selective COX-2 inhibitor greater Cox-2 selectivity than either celecoxib or rofecoxib. Similar to abstract LB-7, this study examines the efficacy and safety of valdecoxib in rheumatoid arthritis. Methods: 1089 patients were randomized to receive placebo, naproxen 500 mg bid or valdecoxib 10 mg qd, 20 mg qd, 40 mg q. Results:
Editorial comment: Not surprisingly, valdecoxib was shown to be efficacious in the treatment of RA and similar to naproxen. The three doses of valdecoxib showed similar efficacy as well. | |||||||||||||||||||||||||||
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CTLA4g and LEA29Y CTLA4g and LEA29Y CTLA4g and LEA29Y bind to B7 receptors on antigen presenting cells, thereby preventing T-cell proliferation and cytokine proeduction. This study assessed the safety and preliminary efficacy of these medications in subjects with rheumatoid arthritis. Editorial Comment: These data were presented at the 2001 Conference on Innovative Therapies in Autoimmune Diseases meeting in San Francisco and at the 2001 EULAR meetings. Please access these links for a summary of the data and editorial comments. (top of section) (top of page) Anti-Interleukin-6 (IL-6) IL-6 is a proinflammatory cytokine and elevated IL-6 levels are observed in the sera and synovial fluid of RA patients. MRA is a recombinant humanized anti-human IL-6 receptor monoclonal antibody that inhibits the binding of IL-6 to its receptor. Methods: 45 patients with active RA were allocated to four treatment groups to receive a single IV dose of either 0.1, 1.0, 5.0 or 10.0 mg/kg of MRA or placebo. The primary endpoint was the percentage of patients who achieved an ACR20 response at week 2. Results: Baseline demographic data were similar among treatment groups. A significant difference was observed between the 5.0 mg/kg and placebo groups at week 2 (p=0.011). Five (55.6%) of the 5.0 mg/kg group and no plaebo patients demonstrated ACR20 responses. There was no statistical difference in ACR20 response rates between placebo and the other MRA dosage groups, although there was a trend favoring the 10 mg/kg group. Baseline disease activity scores (DAS) ranged from 6.5 to 6.9. At week 2, the DAS for the 5.0 and 10.0 mg/kg groups were 4.8 and 4.7, respectively. ESR and CRP in the 5 and 10 mg/kg groups normalized 1 week after treatment and remained normal for 3 weeks. The most common adverse event reported was diarrhea, occurring in 17.8% of patients. One patient died due to myocardial infarction but this was not felt to related to study medication. Conclusion: This study suggests that anti-IL-6 therapy may improve signs and symptoms of RA. The apparent therapeutic dose of MRA in this single dose study was at least 5 mg/kg. Editorial Comment: IL-6 is more distal on the inflammatory pathway than TNF and IL-1, and TNF and IL-1 have broader proinflammatory actions than IL-6 (in fact, they induce IL-6). Insofar as anti-TNF and anti-IL1 therapies have been shown to be very effective at lowering IL-6 levels, as well as a myriad of other proinflammatory cytokines, prostanoids and metalloproteases, the rationale for directed anti-IL-6 therapy remains elusive. Anti-IL6 therapy may be useful, however, in elucidating which manifestations of disease are related to IL-6 alone. (top of section) (top of page) Anti-C5 Antibody (h5G1.1) Complement activation may play a role in the evolution and propagation of inflammation in rheumatoid arthritis. h5G1.1 is a humanized monoclonal antibody that binds omplement component C5 preventing its cleavage to C5a and C5b. Mechanistically, h5G1.1 may have beneficial effects for the treatment of rheumatoid arthritis by the preventing the formation of the membrane attack complex and the decreasing the levels of C5a, a potent neutrophil chemotactic agent. Previously, a single dose (8 mg/kg) of an anti-C5 antibody was shown to suppress serum complement activity for 10 days, and to improve clinical parameters and CRP for 7 days. Methods: 209 patients with RA on methotrexate were randomized to the following h5G1.1 treatment arms: (1) placebo, (2) 8 mg/kg Q2 weeks, (3) 8 mg/kg weekly for 5 weeks then Q 4 weeks, (4) 8 mg/kg weekly for 5 weeks then Q 2 weeks. Results: ACR 20 response was 18%, 19%, 44%, 25%. Only treatment group 3 reached statistical significance. The drug was well tolerated. Editorial Comment: This is a novel agent for RA with a reasonable theorectical mechanism of action. It is disappointing that there was no dose response seen between groups 3 and 4, although the 44% response seen in group 3 is encouraging. These results do appear to warrant support for further trials, perhaps with a randomization of patients into treatment groups based upon the degree of complement activation at baseline. Data with h5G1.1 in systemic lupus were presented at the 2001 Conference on Innovative Therapies in Autoimmune Diseases meeting in San Francisco.
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