Use of methotrexate in patients with scleroderma and mixed connective tissue disease O. Kowal-Bielecka1 and O. Distler2 1Department of Rheumatology and Internal ABSTRACT cal trials. Methotrexate (MTX), which Medicine, Medical University of Bialystok, Systemic sclerosis (scleroderma, SSc) proved effective in rheumatoid arthritis Poland; and mixed connective tissue disease (3 and reviewed in other chapters of 2Department of Rheumatology, University (MCTD) are chronic autoimmune dis- this issue), is also considered an op- Hospital Zurich, Switzerland. eases characterised by a broad spec- tion in treating SSc and MCTD. In the Otylia Kowal-Bielecka, MD trum of clinical manifestations includ- present review we discuss the available Oliver Distler, MD ing different forms of musculoskeletal evidence concerning usage of MTX in Please address correspondence involvement, skin and vascular chang- and reprint requests to: SSc and MCTD. Oliver Distler, MD, es, as well as internal organ complica- Department of Rheumatology, tions. Clinical course and outcomes Use of methotrexate in University Hospital Zurich, might vary from mild forms with good systemic sclerosis Gloriastrasse 25, clinical prognosis to severe rapidly Background 8091 Zurich, Switzerland. progressive life-threatening diseases. Systemic sclerosis (scleroderma, SSc) is E-mail: [email protected] At present, immunosuppressive thera- a multisystem connective tissue disease Received and accepted on July 24, 2010. pies are considered a cornerstone in characterised by widespread vasculop- Clin Exp Rheumatol 2010; 28 (Suppl. 61): the treatment of MCTD, and are fre- athy and profound fibrosis of the skin S160-S163. quently used in clinical practice in SSc and internal organs. Involvement of in- © Copyright CLINICAL AND despite limited evidence from clinical ternal organs, such as the lungs, heart, EXPERIMENTAL RHEUMATOLOGY 2010. trials. The aim of the present review is gastrointestinal tract and/or the kidneys to discuss available data concerning results in high morbidity and mortality Key words: Methotrexate, systemic efficacy of methotrexate therapy in SSc in SSc patients. At present, pulmonary sclerosis, mixed connective tissue and MCTD. complications including interstitial disease. lung disease (pulmonary fibrosis) and Introduction pulmonary arterial hypertension are Systemic sclerosis (scleroderma, SSc) the leading causes of death accounting and mixed connective tissue disease together for almost 60% of disease-re- (MCTD) are autoimmune diseases lated mortality in SSc patients (4). characterised by a broad spectrum of The natural clinical course of dis- clinical manifestations including dif- ease might vary. There are two major ferent forms of musculoskeletal in- forms of the disease: limited cutaneous volvement, skin changes, as well as in- SSc (lSSc) and diffuse cutaneous SSc ternal organ complications (1, 2). The (dSSc), which differ with respect to natural history of the disease and clini- extent and progression of skin thicken- cal outcome are highly variable in both ing, but also with respect to a pattern SSc and MCTD. Some patients have a of internal organ involvement and life mild, slowly progressive or self-lim- expectancy (5). ited disease, whereas others develop In patients with lSSc skin changes are major organ involvement that requires limited to face and distal parts of the aggressive treatment. No universal extremities, the disease progress is slow disease-modifying drugs are available and severe internal organ involvement for SSc and MCTD, and it is generally (usually interstitial lung disease or pul- agreed that treatment depends on each monary arterial hypertension) develop patient’s clinical involvement (organ- at later stages, often after several years targeted therapy). Clinical heteroge- from first symptoms attributable to SSc. neity is one of the main obstacles in In patients with dSSc skin thickening performing clinical trials in SSc and is much more extensive spreading from MCTD and for these reasons only a the distal parts to the arms, thighs and few therapies have proved effective the trunk, the pace of skin changes is Competing interests: none declared. in disease-specific randomised clini- much more rapid, especially in the first S-160 Use of methotrexate in patients with SSc and MCTD / O. Kowal-Bielecka & O. Distler years of the disease, and severe inter- Patients were evaluated in a double- temporary MTX withdrawal and did nal organ involvement (usually inter- blind manner and clinical response to not increase after resuming MTX. stitial lung disease, renal failure, heart treatment was defined as improvement Another larger multicenter double- or gastrointestinal involvement) might by at least 30% in total skin score, by at blind randomised trial included 71 develop early. least 15% in DLCO or by at least 50% patients with early dSSc of less than 3 Although destructive arthritis is uncom- in visual analogue scale (VAS) of well years duration, 35 of whom received mon in SSc, musculoskeletal involve- being, provided that such improve- MTX (orally 15mg-17.5mg/d) and 36 ment is frequent in SSc and includes ment was not accompanied by persist- received placebo (8). After 12 months, joint pain, joint contractures due to skin ing digital ulcerations or decrease in an intent-to-treat analysis showed im- changes, non-erosive arthritis, tendon DLCO by at least 15%. Twenty-five provement in skin scores in the MTX friction rub, myopathy and myositis out of 29 patients completed 24 weeks group (p<0.04 for the University of (1). SSc can also occur co-existing with of treatment. In the completers, fa- California Los Angeles (UCLA) skin other fully developed autoimmune dis- vourable response to treatment/clini- score and p<0.09 for the modified Rod- eases such as rheumatoid arthritis or cal improvement was seen more fre- nan skin score (mRSS)) versus pla- polymyositis; this situation is often re- quently in patients receiving MTX cebo. The mean changes in skin scores ferred to as overlap syndromes (2). (eight out of 15=53%) when compared were rather small (-1.2 for UCLA and Factors triggering SSc are not known. with the placebo-treated group (one -4.3 for mRSS in the MTX group com- Although the pathogenesis of SSc is not out of ten=10%, p=0.03). The favour- pared with 1.2 and 1.8 in the placebo fully clarified, clinical and experimental able response to treatment was due to group, respectively, p<0.05 for both evidence indicates that autoimmunity, skin score improvement in 3 patients, UCLA and mRSS), and the difference vascular injury and excessive produc- VAS improvement in 4 patients, and in the UCLA score lost its significance tion of connective tissue play key roles both skin and VAS improvement in 1 after adjustment for use of steroids and in the development and progression of patient. An intent-to-treat analysis of sex differences (p<0.07). MTX ap- the disease (6). Understanding of the single variables revealed a trend to- peared also to better preserve diffusing processes involved in SSc pathogenesis wards improvement of skin score and capacity of the lungs (DLCO) (p<0.03 led to design of treatment strategies. creatinine clearance in the MTX group for between group comparison at 12 Accordingly, recognition of the pres- at week 24 (p=-0.06 and p=0.07 versus months), however, the mean DLCO ence of autoimmune phenomenon in placebo, respectively). changes were small and did not differ SSc, such as the presence of autoanti- An extension study of another 24 significantly (-3.7% in MTX group vs. bodies, associations between specific weeks, during which MTX was given at -7.7% in placebo group, p<0.14). autoantibodies and particular disease 15mg/week in 9 MTX responders and No significant effect could be seen with patterns/outcomes and the presence of in 9 patients from the placebo group, or regard to other outcome measures, in- perivascular inflammatory mononuclear increased up to 25mg/week in 6 MTX cluding oral opening, grip strength, cell infiltration in the skin and internal non-responders, revealed improvement flexion index, functional index, HAQ or organs in early diffuse rapidly progres- in skin score and/or VAS in 15 out of patient global assessment. sive SSc, have led to the usage of im- 23 (68%) patients who completed 48 Thirteen (37%) patients withdraw from munosuppressive therapies in SSc. weeks. No significant differences in the MTX group and 11 (31%) patients clinical variables could, however, be from the placebo group, mainly due Clinical studies of methotrexate identified at week 48 when compared to treatment inefficacy. Only 1 patient in SSc with baseline values. Laboratory evalu- dropped out because of adverse event So far, the results of two multicentre ation revealed significant decrease in (oral ulcers on MTX treatment). randomised clinical trials investigating haemoglobin, white blood cells, plate- In summary, the results of the two ran- the efficacy and safety of MTX in SSc lets and IgG levels, when compared domised controlled trials (RCTs) indi- have been published (7, 8). with baseline values. cate that MTX improves skin changes The first trial involved 29 SSc patients Six patients (21%) withdrew from the in early dSSc. However, its clinical with early disease, defined as disease study during 48 weeks: four due to SSc- effect is of borderline value. No sig- duration shorter than 3 years from first related causes (death or renal crisis), 1 nificant improvement in internal organ signs of skin thickening. Patients with due to sudden death and 1 due to side manifestations could be demonstrated longer disease duration were also in- effects of treatment (persistent, severe with MTX therapy. The withdrawal cluded if they had experienced progres- headache after each injection). One rate was high in both trials, mainly due sion of skin thickening, persistent digital patient, who subsequently died due to treatment inefficacy or SSc-related ulcerations, or deterioration in pulmo- to severe interstitial lung disease, had complications. Toxicity of MTX was nary function during the last 6 months.