Focus on Research will be a permanent feature on our front page under CSSA News and Information.

This is the second of a series of articles entitled “Focus on Research”. The purpose of this section is threefold: to let CSS patients know about research pertaining to CSS, to introduce the researchers engaged in such research, and hopefully, to stimulate a greater awareness and interest in Churg Strauss Syndrome. One of the researcher profiled in this news feature, Dr. Bernhard Hellmich, has been very supportive of the formation of the CSS Association and serves on our Medical Advisory Board.

Summary of: Churg Strauss-Syndrome –Successful Induction of Remission with Methotrexate and Unexpected High Cardiac and Pulmonary Relapse Ratio During Maintenance Treatment

Claudia Metzler, Bernhard Hellmich

Introduction:
Studies of treatment regiments in Churg-Strauss-Syndrome (CSS) are rare, due to the low incidence of CSS (1-3.4 /million inhabitants per year in Western Europe) [1, 2]. Therefore there are no larger patient cohorts including solely CSS that have been prospectively subjected to uniform and standardized treatment regimens.

Prednisolone (PRD) alone is considered to be effective to control the disease in most patients. Howevereven doses of PRD above the Cushing threshold partly in conjunction with cytotoxic agents like azathioprine and cyclophosphamide (CYC) for the first year after treatment initiation [3] cannot reliably prevent relapses, which still occur in 10-30% of the patients [3, 4, 5]. Furthermore, deaths from uncontrollable disease despite high dose steroids with and without cytotoxics occur in up to 10% of patients with CSS [3, 5]. Moreover, there is a considerable morbidity from steroid-related adverse events with hypercortisolism, steroid-induced diabetes mellitus, osteoporotic fractures and avascular necrosis [3, 4, 5]. Thus, the need for steroid-sparing agents in CSS in evident. CYC, the gold standard drug for induction of remissison in ANCA-associated vasculitis [6, 7] should be confined to induction of remission in disease courses with critical organ involvement because of its toxicity [6, 8, 9]. In CSS there is only scarce experience with regimens for remission induction in less severe disease courses and especially for maintenance of remission.

In Wegener's Granulomatosis (WG) – a clinically and histopathologically related disorder - low-dose methotrexate (MTX) has proven safe and effective for induction and maintenance of remission in patients with non-life-threatening manifestations and without renal involvement [10-15]. Thus, its use in CSS seems reasonable. This study assesses the efficacy and safety of MTX for induction and maintenance of remission in CSS.

Patients and Methods:
In an open-label study 11 patients were treated with MTX for induction of remission at initial diagnosis and relapse. Twenty-five patients received MTX for maintenance of remission. MTX was administered at 0.3 mg/kg bodyweight (BW) i.v. once weekly, in accordance to the regimen used in WG [11]. An equivalent dose of folinic acid was given on the day following MTX to avoid long-term toxicity. Primary end points were the achievement of remission and the incidence of relapses, respectively. Doses of concomitant prednisolone (PRD) and side effects were secondary endpoints.

Results:
Induction of remission was achieved in 8/11 patients with MTX/PRD. Median time to remission was five months (range 2 – 9). Remission was maintained in 12 of 23 with available long-term follow-up (median 48 months). Eleven patients experienced eight major and three minor relapses with median time from remission to first relapse of 9 months. Eight relapses were classified as major, presenting as follows: Three patients had new ECG changes suggestive of cardiac ischemia, two with elevated cardiac enzymes additionally, one with progressive cardiac failure with ejection fraction of 11%. Five patients showed pulmonary activity, two with infiltrations on the chest x-ray, two with eosinophilic pneumonia in the bronchoalveolar lavage, one with bronchial granuloma on CT-scan, all with correlating raise in CRP and eosinophil counts. Three relapses were minor ones (one with ENT involvement, one with constitutional symptoms, one with arthritis). With MTX, the median cumulative PRD dose during the induction phase was 6.2 g. In the maintenance phase PRD could be reduced by 53 % in responders. Apart from one MTX-induced pneumonitis adverse events were confined to mild/moderate episodes of infections and leucopenia. No opportunistic infections occurred, neither did steroid-specific adverse events

Discussion:
In this study, combined treatment with MTX and PRD resulted in successful induction of remission in 8 of 11 CSS patients (72%). The concomitant PRD dose could be reduced significantly during the induction phase. The remission rate obtained and median time to remission are in line with those in Wegener’s granulomatosis [6, 10, 11].

The remission rate we achieved with MTX plus low-dose PRD was slightly lower than the findings in two previous studies: In a Spanish cohort of 32 patients using a variety of treatments including azathioprin in two and CYC in 17 patients a remission rate of 81% [5] was observed. A long-term follow-up of 96 French CSS patients revealed an overall remission rate of 91.5% [3], again applying different treatment protocols including azathioprine, cyclophosphamide and plasmapheresis, all using high dose concomitant steroids above the Cushing threshold for more than 1 year.

In the Spanish protocol the elevated PRD-dosage led to hypercortisolism in 25%, diabetes mellitus in 12,5%, osteoporotic fractures in 6,3% and avascular necrosis of the femoral head 3,1% of the 32 treated patients [5].

When MTX was used for maintenance of remission, nearly 50% of the patients experienced a relapse, after a median time of 9 months with a substantial number of critical cardiac and severe pulmonary manifestations with subsequent fatality in one patient. The French-Vasculitis-Study-Group described 64 CSS patients within a group of 278 patients with different vasculitic disease entities [4]. After a median follow-up of 88 months, a relapse rate of 20.3% was found in the CSS subgroup irrespective of the treatment allocation. Mean time to relapse was comparable to our cohort (21 vs. 24.6 months). Solans found in his cohort of 32 CSS patients a relapse rate of 28% [5]. In none of the above mentioned trials patients were placed on a specifically designed maintenance regimen, and largely there are no data available of their immunosuppression at the time of their relapse. This renders the outcomes of the different trials not directly comparable. The high relapse rate in our cohort with a rather short median time of 9 months from remission to relapse may indicate that steroid taper occurred too vigorously and/or too early during the maintenance phase, despite concomitant cytotoxic treatment with MTX. Demasking of CSS disease activity by reduction of antiasthmatic drugs including PRD may contribute to an elevated relapse rate [16]

Our remission induction and maintenance regimen with MTX shows considerably few treatment-related adverse events comprising one MTX-associated pneumopathy, altogether 10 airway- or urinary tract infections and some epidsodes of cytopenia, the latter in CYC-pre-treated patients only. All adverse events were of mild or moderate severity. This is in contrast to the profile of side effects reported in immunosuppressive regimens other than MTX and low-dose PRD [3, 4, 5]. Remarkably, we have observed hardly any clearly steroid-associated severe adverse event. This may be a clear advantage of our protocol, as a great proportion of the side effects [3, 4, 5] can be ascribed to use of cyclophosphamide and high-dose PRD, which renders long-term or repeated usage of both drugs difficult. The optimal concomitant steroid regimen for treatment of CSS remains to be studied.

In conclusion, MTX with concomitant low-dose PRD is a quite safe and successful regimen for induction of remission in non life-threatening CSS and has a significant steroid sparing potential. For maintenance of remission, however, our MTX/PRD regimen was not convincing, despite its excellent long-term tolerability, due to the unsatisfactorily high relapse rate with critical organ manifestations. If MTX is used for maintenance of remission, close surveillance of the patients is mandatory and PRD should be tapered more slowly than in our protocol. Further work on maintenance regimens in CSS includes the identification of an optimal steroid regimen in conjunction with a well tolerated cytotoxic and of potential predictors of relapse. In view of the low incidence of the disease this should be a subject of a multicenter effort.

Original article published in Clinical and Experimental Rheumatology 2004; 22(6) (suppl.36):S52-S61

References:
1. Watts RA, Carruthers DM, Scott DG. Epidemiology of systemic vasculitis: changing incidence or definition? Semin Arthritis Rheum. 1995 Aug;25(1):28-34.

2. Haugeberg G, Bie R, Bendvold A, Larsen AS, Johnsen V.
Primary vasculitis in a Norwegian community hospital: a retrospective study. Clin Rheumatol. 1998;17(5):364-8.

3. Guillevin L, Cohen P, Gayraud M, Lhote F, Jarrousse B, Casassus P. Churg-Strauss syndrome. Clinical study and long-term follow-up of 96 patients. Medicine (Baltimore) 1999; 78:(1):26-37.

4. Solans R, Bosch JA, Perez-Bocanegra C, Selva A, Huguet P, Alijotas J, et al. Churg-Strauss syndrome: outcome and long-term follow-up of 32 patients. Rheumatology (Oxford) 2001; 40:(7):763-71.

5 Gayraud M, Guillevin L, le Toumelin P, Cohen P, Lhote F, Casassus P, et al. Long-term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients. Arthritis Rheum 2001; 44:(3):666-75.

6. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD et al. Wegener's granulomatosis: an analysis of 158 patients. Ann. Intern. Med. 1992; 116:(6):488 - 498.

7. European therapeutic trials in ANCA-associated systemic vasculitis: disease scoring, consensus regimens and proposed clinical trials. European Community Study Group on Clinical Trials in Systemic Vasculitis ECSYSVASTRIAL. Clin Exp Immunol. 1995 Jul;101 Suppl 1:29-34

8. Reinhold-Keller E, Beuge N, Latza U, de Groot K, Rudert H, Nölle B, et al. An interdisciplinary approach to the care of patients with Wegener's granulomatosis. Long term outcome in 155 patients. Arthritis Rheum. 2000; 43:(5):1021-1032.

9. Talar-Williams C, Hijazi YM, Walther MM, Linehan WM, Hallahan CW, Lubensky I, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener's granulomatosis. Ann. Intern. Med. 1996; 124:477-484.

10. Sneller MC, Hoffman GS, Talar-Williams C, Kerr GS, Hallahan CW, Fauci AS. An analysis of forty-two Wegener's granulomatosis patients treated with methotrexate and prednisone. Arthritis Rheum 1995; 38:(5):608-613.

11. de Groot K, Mühler M, Reinhold-Keller E, Paulsen J, Gross WL. Induction of remission in Wegener's granulomatosis with low-dose methotrexate. J. Rheumatol. 1998; 25:492-495.

12. de Groot K, Reinhold-Keller E, Tatsis E, Paulsen J, Heller M, Gross WL. Therapy for the maintenance of remission in sixty-five patients with generalized Wegener's granulomatosis. Methotrexate versus Trimethoprim/Sulfamethoxazole. Arthritis Rheum 1996; 39:(12):2052-2061.

13. Langford CA. Treatment of ANCA-associated vasculitis. N Engl J Med. 2003 Jul 3;349(1):3-4

14. Reinhold-Keller E, Fink CO, Herlyn K, Gross WL, De Groot K. High rate of renal relapse in 71 patients with Wegener's granulomatosis under maintenance of remission with low-dose methotrexate. Arthritis Rheum 2002; 47:(3):326-32.

15. de Groot K, Rasmussen N, Bacon PA, Cohen Tervaert JW, Feighery C, Gregorini G, et al. Randomized Trial of Cyclophosphamide Versus Methotrexate for Induction of Remission in "non-renal" ANCA-associated Vasculitis Arthritis Rheum. 2003, 48 (9) (suppl): 660 (1726)

16. Hellmich B, Gross WL. Recent Progress in the Pharmacotherapy in Churg-Strauss-syndrome. Exp Opin Pharmacotherap 2004; 5: 25-35