Letters to the Editor Is methotrexate plus cyclosporine cy / t o l e rability rat i o , the patients re c e ive d the other hand 19 patients (34%) experi- A a useful salvage therapy for MTX intravenously and the dose was ad- enced a definitive benefit from this treat- rheumatoid arthritis patients justed individually. This resulted in a medi- ment, with the arrest of further radiological unresponsive to other types of an 22.5 mg/week [22.5-25]. Doses we re progression and regression of inflammatory 2000 mg/day [2000-2000] for SSZ and 400 activity. MTX+CSA is thus a viable option methotrexate combination treat- mg/day [400-400] for HCO. At inclusion in in patients refractory to other MTX combi- ment ? this study, MTX remained unchanged, and na tions and should be included in future stu- SSZ and HCO were terminated. CSA was dies aimed at devising a rational approach Sirs, initiated with 2.5 mg/kg/ day and escalated to this highly selected patient subset. Methotrexate (MTX) is considered to be the to 3.5 and 4.5 mg/kg/day, if necessary. Con- agent of first choice for rheumatoid arthritis t ra i n d i c ations for CSA confo rmed with C. LERIN-LOZANO, PhD, MD of moderate or high activity (1). But accept- established guidelines (9). Arterial hyper- A. SCHNABEL, MD able suppression of disease activity is tension was required to be controlled with B. ERBSLÖH-MÖLLER, MD achieved in no more than 70% of patients no more than two drugs. Newly developing W.L. GROSS, MD, Professor on MTX monotherapy and the percentage is or exacerbating hypertension was met by:1. even lower at the severe end of the disease reduction of CSA dose by 30-50%; 2. sin- Poliklinik für Rheumatologie, Medizinische spectrum (1). Combination regimens con- Universität Lübeck, and Rheumaklinik Bad gle-agent antihypertensive treatment; and, sisting of methotrexate (MTX), salazosul- Bramstedt, Germany. if the hypertension persisted, by 3. with- fapy ridine (SSZ) and/or hy d rox y ch l o ro- Address correspondence and reprint requests drawal of CSA. An increase in serum creati- quine (HCO) are being increasingly used in to: Prof.Dr. W.L. Gross, Rheumaklinik Bad nine by 30% or above the upper limit of these poor responders, but a sizable propor- Bramstedt, Oskar-Alexander-Strasse 26, normal was addressed by reduction of CSA D-24576 Bad Bramstedt, Germany. tion of the patients remain still active (2, 3). by 30-50%. If levels remained elevat e d, E-mail: [email protected] MTX plus cyclosporin A (CSA) is a further CSA was withdrawn. Prednisolone was ta- combination regimen with a proven addi- pered to the lowest effective dose. No non- References tive effect (4-6). We therefore examined, in s t e roidal antiinfl a m m at o ry agents we re 1. PINCUS T, O’DELL JR, KREMER JM: Combi- an observational study, whether MTX+CSA nation therapy with multiple disease-modify- allowed. can serve as salvage therapy for patients ing antirheumatic drugs in rheumatoid arthri- Eighteen patients (33%) terminated MTX + unresponsive to other MTX combinations. t i s : A preve n t ive strat egy. Ann Intern Med CSA during the first year (Fig. 1). Four 1999; 131: 768-74. From 1997 through 1998, we recruited 55 patients had a severe disease exacerbation. 2. O ’DELL JR, HAIRE CE, ERIKSON N, et al. : consecutive patients with RA (7) and per- Seven patients developed hypertension pro- Tre at m e n to fr h e u m at o i d art h ri t i s with metho- sistent disease activity despite combination trexate alone, sulfasalazine and hydroxychlor- hibiting further CSA tre atment. Th re e t re atment with either MTX+SSZ+HCO oquine, or a combination of all three medica- patients developed renal insufficiency and 4 (n=26), MTX+SSZ (n=13) or MTX+HCO tions. N Engl J Med 1996; 334: 1287-91. patients terminated CSA because of either 3. HAAGSMA CJ, VAN RIEL PL, DE POOIJ DJ, et (n=16). These we re 37 females and 18 nausea, gingival hyperplasia or a rash. De- al.: Combination of methotrexate and sulfa- males, median age 58.7 years [interquartile teriorating renal function and newly devel- salazine ve rsus methotrex ate alone: A ra n- range 55.2-64.01 years], disease duration d o m i zed open clinical trial in rheumat o i d oping or exacerbating arterial hypertension 8.1 years [4.0-14.7], and Larsen grade 3 [2- a rt h ritis patients resistant to sulfa s a l a z i n e were thus the main limiting side effects. 4]; 41 were rheumatoid factor positive (8). theapy. Br J Rheumatol 1994; 33: 1049-55. These occurred in 5 of the 12 patients with, 4. TUGWELL P, PINCUS T, YO C U M D, et al. : For maximal efficacy and an optimal effica- but in only 7 of the 43 patients without, pre- Combination therapy with cyclosporine and existing hypertension (p = 0.030). m e t h o t rex ate in seve re rheumatoid art h ri t i s . The Methotrexate-Cyclosporine Combination Thirty-seven patients stayed on MTX+CSA St u d y Group. N Engl J Med 1995; 333: 13 7 - for at least 12 months, the median CSA 14 1 . dose being 3.2 mg/kg/day [2.5-4.0]. Th e 5. SALAFFI F, CAROTTI M,CERVINI C: Combina- prednisolone requirement dropped from 7.5 tion therapy of cyclosporine A with metho- mg/day [5.0-10.0] to 4.0 mg/day [3.0-5.5] t rex ate or hy d rox y ch l o roquine in re f ra c t o ry rheumatoid arthritis. Scand J Rheumatol 1996; (p < 0.001). Since this was a cohort with 25: 16-23. p a rt i c u l a rly aggre s s ive disease, our mini- 6. STEIN CM,PINCUS T, YOCUM D, et al.: Com- mum requirement for a sufficient treatment bination treatment of severe rheumatoid arthri- response was the arrest of radiologic pro- tis with cy cl o s p o rine and methotrex ate fo r gression together with regression of the fo rty-eight we e k s : an open-label ex t e n s i o n study. The Methotrexate-Cyclosporine Com- joint count and the C-reactive protein by at bination Study Group. Arthritis Rheum 1997; least 30%. This was attained in 19 of the 55 40: 1843-51. p atients (34%), wh e reas MTX+CSA wa s 7. ARNETT FC, EDWORTHY SM, BLOCH DA et either only marginally superior or equiva- al.: The American Rheumatism Association lent to combinations of MTX, SSZ and HQ 1987 revised criteria for the classification of r h e u m atoid art h ritis. Art h r itis Rheum 1 9 8 8 ; in the remaining 18 patients (33%). 31: 315-24. In conclusion, these patients with RA re- 8. LARSEN A , DALE K, E E K M: R a d i ograp h i c fractory to combinations of MTX,SSZ and/ evaluation of rheumatoid arthritis and related or HQ experienced a substantial number of conditions by standard reference films. Acta CSA side effects. Hyperte n s i ve patients wer e Radiol 1977; 18: 481-91. 9. CUSH JJ, TUGWELL P, W E I N B L ATT M, YO- particularly poor candidates for the combi- Fi g. 1 . Outcome of methotrex ate plus cy cl o - CUM D: US consensus guidelines for the use nation of MTX+CSA, even if their blood sporin A treatment. of cy cl o s p o rin A in rheumatoid art h ritis. J pressure was previously well controlled. On Rheumatol 1999; 26: 1176-86.

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