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ACR 2000 Highlights

Vasculitis

John Stone, M.D., M.P.H.

Methotrexate in Giant Cell Arteritis
The purposes of these trials were the same: to determine if methotrexate (MTX) is an effective steroid-sparing agent in giant cell arteritis (GCA). Surprisingly (and disappointingly), the trials reached opposing conclusions.

Abstract #292 A Multi-Center Placebo-Controlled Study of Methotrexate in Giant Cell Arteritis G Hoffman, M Cid, D Hellman, P Merkel, L Guillevin, H Dickler, L Calabrese, G Locker, K Easley, N Bedocs, P Fortin, J Schousboe, Y Sherrer, H Swanson, B Walsh, W Gross, R Luqmani, G Hunder, M Sneller, J Flynn, J Stone, C Ludivico, K Kalunian.

Overview of study: A multi-center, randomized, double-blinded, placebo-controlled trial of 98 patients with giant cell arteritis. Patients were treated initially with prednisone 1 mg/kg/day (up to 60 mg/day) for one month and was tapered according to a protocol beginning at 4 weeks of therapy. Every other day prednisone (60 mg qod) was achieved after 3 months, and prednisone was tapered off after 6 months (in the absence of disease flares). Either methotrexate (0.15 mg/kg/week, increased to a maximum of 15 mg/week) or placebo began simultaneously with the start of prednisone.

Summary of Findings: Visual loss was high among the patients in this trial: 18% at trial entry and 27% at one-year follow-up. Relapses observed in this trial were high: 35% and 24% in the placebo and methotrexate groups, respectively, at 6 months; and 77% and 58% at 12 months. These differences were not statistically significant (P = 0.26 by log-rank test). There were also no significant differences between groups with regard to the cumulative dose of corticosteroids.

Editorial Comment: This trial is the first clinical trial performed by the International Network for the Study of the Systemic Vasculitides (INSSYS), and the first long-term randomized trial to be conducted in giant cell arteritis. The effort may pave the way for future transoceanic clinical trials in the vasculitides.

The finding of no steroid-sparing effect of methotrexate in this trial was disappointing. Possible explanations include: 1) the relatively small number of patients enrolled compared to the number projected at trial start (n = 300), leaving the trial with limited power to observe differences between groups; 2) the relatively low dose of methotrexate used (maximum weekly dose: 15 mg); and 3) the possibility that MTX has little to no significant clinical effect in giant cell arteritis. The frequency of disease flares in this trial call into question the wisdom of using every other day steroid regimens in giant cell arteritis.

Abstract #1794 A Combined Treatment of Giant Cell Arteritis with Methotrexate and Prednisone: A Randomized, Double-Blind, and Placebo-Controlled Study J Jover, C Hernandes-Garcia, I Morado, E Vargas, A Banares, B Fernandes-Guiterrez.

Overview of study: In contrast to the multi-center design of the INSSYS trial (above), this trial was a single-center trial. The trial was randomized, double-blind, and placebo-controlled. The design of the trial was similar to that of the INSSYS trial, with one possibly important exception: no alternate day corticosteroids were used. The maximum dose of methotrexate employed (15 mg/week) was identical.

Summary of findings: In this trial, the combination of prednisone and methotrexate was superior to prednisone alone in several important outcomes: the percentage of patients experiencing disease relapses (45% versus 84%; P = 0.02); the total number of relapses (12 versus 26; P = 0.004); and the mean cumulative dose of prednisone (4,187 mg versus 5,489 mg; P = 0.009). There were no significant differences between groups in the rate or severity of adverse events.

Editorial Comment: The results of this trial strongly suggest that, contrary to the findings of the INSSYS study, methotrexate plays an important role in the treatment of giant cell arteritis. The differences in the results of the two trials are striking, and we await eagerly the publication of full manuscripts from these trials so that possible explanations can be explored in detail. At the present time, the contrasting steroid tapering regimens appear to be the most obvious difference in the two trials, and one must speculate about the possibility of synergy between methotrexate and prednisone above some certain corticosteroid doses.

Deflazacort in Giant Cell Arteritis
Abstract #578 Deflazacort versus prednisone in patients with giant cell arteritis. A Randomized, Double-Blind Comparative Trial Studying the Effects on Bone Mass Loss P Cacoub, K Chemial, P Khalifa, B Wechsler, C DeGennes, B Verdoncq, N Belmatoug, P Cohen, P Godeau, J Piette.

Overview of study: Deflazacort has long been thought to have a possible bone-sparing effect, compared to other forms of corticosteroids. The purpose of this trial was to compare the impact of deflazacort on bone with that of prednisone in a randomized, blinded trial of patients with giant cell arteritis. Patients in the trial (n = 74) were randomized to receive either deflazacort or prednisone for a minimum of 12 months. All patients received both calcium and Vitmin D, as well. The primary outcome measure was the assessment of bone mineral density (BMD) by DEXA scans at several intervals. A secondary outcome measure in the trial was the incidence of vertebral fractures.

Summary of findings: In short, the trial failed to show any bone-sparing effects of deflazacort compared with prednisone. There were no treatment group differences in either the change in BMD between entry and 12 months (both groups lost BMD), or in the numbers of vertebral fractures as measured by the Meunier index.

Editorial Comment: Unfortunately, deflazacort does not appear to be less deleterious to BMD than prednisone. This study strengthens the argument for more aggressive attention to the preservation of BMD (e.g., the early use of bisphosphonates, calcitonin, etc.) in patients likely to remain on prolonged courses of corticosteroids ¾ regardless of the steroid preparation used.

Etanercept in Wegener's Granulomatosis
Abstract #577 Phase I/II Trial Of Etanercept In Wegeners Granulomatosis (WG): Safety And Preliminary Experience C Langford, C Talar-Williams, K Barron, K McCabe, M Sneller

Overview of study: Preliminary results from a randomized but unblinded trial of etanercept in WG, designed to investigate the safety of this agent in this disease and determine if the drug has a steroid-sparing effect and if it decreases the rate of relapse. Only patients with non-life threatening ("limited") WG are eligible to enroll, since methotrexate is used as standard therapy in both treatment groups (rather than cyclophosphamide). In an unusual study design, all patients in the trial initiate therapy with both etanercept and methotrexate, as well as corticosteroids. Steroids are tapered off after 3 months. At 6 months, patients in remission are randomized (in an unblinded fashion) either to continue etanercept or to discontinue this medication.

Summary of findings: Over 18 months, 24 patients have been enrolled, of whom 11 have been randomized after reaching 6 months of therapy and achieving disease remissions. Disease flares have occurred in several patients in the trial to date, several before the time of randomization. Among those randomized, disease flares have occurred in both groups (slightly more in the no etanercept group, but the numbers are too small to discern reliable patterns). To date there have been no indications of increased numbers of infections in this group of WG patients receiving both etanercept and methotrexate, nor have the etanercept-patients demonstrated a propensity to form ANA or anti-dsDNA antibodies.

Editorial Comment: This study will provide some useful data on the safety, pharmacokinetic, and immunologic effects of etanercept combined with methotrexate in WG. The unblinded nature of the trial may complicate interpretation of the results related to the efficacy of etanercept.

Abstract #2024 Etanercept in Wegeners Granulomatosis: A Six month Open-Label Trial To Evaluate Safety J Stone, M Uhlfelder, D Hellmann, S Crook, N Bedocs, G Hoffman

Overview of study: This was a two-center study conducted at Johns Hopkins and the Cleveland Clinic, designed to investigate the safety of etanercept when used in conjunction with conventional treatments for WG. Twenty WG patients with histories of refractory disease and active disease at enrollment received 25 mg of etanercept, added to their conventional treatment regimens. Conventional treatment regimens were prescribed according to disease severity. Thus, most patients were on prednisone and an additional immunosuppressive agent: e.g., cyclophosphamide (n=6), methotrexate (n=8), or azathioprine (n=4). Although the primary purpose of the trial was to investigate safety, disease activity was measured by the Birmingham Vasculitis Activity Score for WG (BVAS/WG).

Summary of findings: Injection site reactions (ISRs) were the most common adverse event related to etanercept (8 episodes in 5 patients [25%]; <1% of all injections). There were a total of 5 hospitalizations (1 patient had 4), but none were attributable solely to etanercept-related adverse events. Nineteen patients (95%) remained on treatment at 6 months, the single exception being a patient who developed progression of orbital (retro-bulbar) disease at 4 months. There were no deaths.

The mean BVAS/WG at entry was 3.6 (range: 1-8). At 6 months, the mean BVAS/WG score decreased 3.0 points, to 0.6 (P < 0.001; 95% C.I.: -4.0, -2.1). Among the 14 patients in whom etanercept was the only new treatment variable, the mean daily prednisone dose decreased from 12.9 mg at entry to 6.4 mg at 6 months. This comparison did not achieve statistical significance (difference: - 6.5; P = 0.19; C.I.: -16.6, +3.6). Sixteen of the patients (80%) achieved BVAS/WG scores of 0 at some point. However, intermittently active disease was observed in 15 patients (75%).

Editorial Comments: The combination of etanercept and conventional therapies appeared safe in this relatively small trial of short duration. Data on efficacy was encouraging, but persistently active disease was observed in a number of patients. Further data on the efficacy of etanercept in WG will come from an ongoing randomized, double-blind, placebo-controlled trial currently under way at 8 American medical centers, funded by NIAMS and the FDA and coordinated by Johns Hopkins.

15-Deoxyspergualin in ANCA-Associated Vasculitis
Abstract #1804 Successful Treatment Of Refractory ANCA-Associated Vasculitis (Mostly Wegeners Granulomatosis) With 15-Deoxyspergualin R Birck, K Warnatz, H Lorenz, Mira Choi, M Haubitz, M Grunke, H Peter, J Kalden, J Drexler, R Nowack, F van der Woude. Germany.

Overview of study: This trial was a multi-center, open-label pilot trial of 15-deoxyspergualin (DSG) in patients with WG. The study drug has been employed to date primarily in investigative settings, particularly in organ transplantation. The patients included (n=20) were patients with active disease who were either unresponsive to cyclophosphamide (CYC) (n=7) or who had various contraindications to standard immunosuppressive approaches. Corticosteroids were the only form of therapy permitted in this trial. DSG was administered in a cyclical fashion according to the induction of neutropenia: patients received 0.5 mg/kg/day until the peripheral white blood cell count declined to less than 3,000/ml (generally 2-3 weeks), at which time the medication was withheld until WBC recovery. The patients underwent a total of 6 cycles. The study outcomes, which included disease activity, achievement of remission, and disease flares, were determined by clinical judgement. Among the patients enrolled, 7 (35%) had elements of disease that were resistant to CYC.

Summary of findings: Despite the refractory nature of most enrolled patients WG, 6 (30%) were regarded as achieving complete remissions. Nine patients (45%) had stable disease (no new disease manifestations), of whom 5 had improvement. WG clearly progressed in 2 patients, and 3 patients dropped out of the trial, 2 because of infection and 1 because of thrombocytopenia.

Editorial Comment: DSG is a promising agent for the treatment of WG. The myelotoxicity of this agent requires short-term monitoring. The long-term implications of such predictable bone marrow suppression and the potential complications when used in tandem with other immunosuppressive agents require further investigation.

Inrerferon-alpha in Churg-Strauss Syndrome
Abstract #1818 Long-Term Treatment of Churg-Strauss Syndrome With Interferon-alpha C Metzler, E Tatsis, A Gause, W Gross. Germany.

Overview of study: Interferon-alpha (IFN) is a rational choice of therapy for Churg-Strauss syndrome (CSS) because of its known efficacy in the hypereosinophil syndrome. The study reported in this abstract is an expansion of a smaller series of patients (n=4) reported in the Annals of Internal Medicine in the late 1990s. The dose of INF used began at 9 million units/week and was titrated to patients disease activity and white blood cell counts.

Summary of findings: At a median of 13 months, 10 of the 12 patients remained on treatment. One patient entered a complete remission; the other was required to stop because of the development of epilepsy. Blood eosinophil counts were reduced effectively from a median at entry of 812/mm3 (range: 76-5633) to 260/mm3 (range: 19-1044) at follow-up. The decrease in eosinophil count appeared to be dose-dependent. There appeared to be a modest decrease in prednisone requirement at follow-up compared to trial entry (decline in the median prednisone dose from 5 mg/day to 4 mg/day).

Editorial Comment: IFN may be a useful adjunct to therapy in patients with CSS who require excessive doses of corticosteroids. The dose of IFN may be limited by the induction of neutropenia.

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