Use of methotrexate in patients with and mixed connective tissue disease O. Kowal-Bielecka1 and O. Distler2

1Department of 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 , joint 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, 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- ; 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. experienced transient pancytopenia, low, and included mainly transient ab- Seventeen patients received MTX at a which resolved after MTX withdrawal. normalities in liver enzymes or oral ul- dose of 15mg/week given as intramus- Transient elevation of liver enzymes cers, which are well-known side effects cular injections, while the remaining 12 was observed in 6 patients receiving of MTX therapy. received injections with placebo (7). MTX. Liver enzymes normalised after It should be noticed that these studies

S-161 Use of methotrexate in patients with SSc and MCTD / O. Kowal-Bielecka & O. Distler have several limitations. The number myositis overlap syndromes in whom disease stages (19). MTX might there- of patients included in the RTCs was musculoskeletal manifestations domi- fore mediate its effect through suppres- rather low and therefore could be un- nate in the clinical picture (14). Indeed, sion of profibrotic factors, although this derpowered to detect smaller effects, MTX is frequently used in clinical has not been analysed in great detail in particular for internal organ involve- practice despite its limited evidence for (20). It remains unclear whether MTX ment. Of interest, recent re-analysis efficacy (15). SSc patients who might might directly inhibit extracellular ma- of the data from the multicenter study particularly benefit from treatment trix synthesis, which is considered the using Bayesian analysis suggests that with MTX are patients suffering from key pathology in SSc. The limited evi- MTX has a high probability of benefi- polyarthritis or polymyositis, either as dence from experimental studies does cial effects in SSc for skin disease and part of the SSc disease spectrum, or as not support direct anti-fibrotic effects global assessment (9). The probability part of an In these of MTX. A recent report did not show that treatment with MTX results in bet- patients, MTX therapy might allow beneficial effects of MTX in bleomy- ter mean outcomes than placebo was spearing higher doses of steroids which cin-induced skin fibrosis in mice (21). 94% for mRSS, 96% for UCLA skin have been associated with risk of scle- On the other hand, some experimental score and 88% for physician global as- roderma renal crisis in retrospective studies suggest that MTX might even sessment. Moreover, the doses of MTX analyses, a life threatening complica- stimulate fibroblast function. In the used in both trials were also lower than tion of SSc (16). study by Van den Hoogen et al., MTX that used in current clinical practice. There are controversies regarding the stimulated in a dose-dependent manner This fact might by responsible for low potential role of MTX in inducing in- in vitro synthesis of glycosaminogly- efficacy but also low toxicity of MTX terstitial lung disease in SSc. MTX cans by normal and SSc fibroblasts observed in these RCTs. might induce lung injury through al- (22). Moreover, adenosine, a key mol- Notably, the mild positive effects of lergic, cytotoxic or immunologic reac- ecule in the anti-inflammatory action of MTX on skin fibrosis in early dSSc tions (17, 18). This effect is infrequent, MTX seems to have a pro-fibrotic effect are not unique for MTX, but have unpredictable and usually develops in some experimental models, thereby been demonstrated also with other im- in close relationship with the start of suggesting a mechanism through which munosuppressive regimens including MTX therapy. The limited data avail- MTX could lead to a fibrotic process oral cyclophosphamide (10). Some able from the two RCTs in SSc did not (23). Since the pathogenesis of SSc is other immunosuppressive treatments, however show worsening of lung func- complex, further studies are required to such as mycophenolate mophetil or tion in MTX-treated patients for up to clarify impact of MTX on development cyclosporine, which have not yet been 12 months (7, 8). Taking into account of fibrosis in SSc investigated in the setting of RCTs, the risk of development of disease-re- have also shown potentially beneficial lated lung fibrosis and possible MTX- Use of methotrexate in mixed effects on skin changes in open-label related pulmonary complications, reg- connective tissue disease or retrospective studies (11, 12). Over- ular monitoring including past medi- Mixed connective tissue disease all, it appears that the mild effects on cal history, physical examination and (MCTD) is an autoimmune systemic skin fibrosis of borderline clinical value pulmonary function tests, is advisable disease characterised by the presence might be shared between different im- to identify early potential pulmonary of high titers of anti-U1-RNP autoanti- munosuppressives. complications. bodies. Typical clinical features include However, as long as convincing al- puffy fingers, acrosclerosis, Raynaud’s ternatives for the treatment of fibrotic Mechanisms of action of MTX phenomenon, myositis and synovitis. manifestations are not available, it in fibrotic conditions Features common to other connective seems at present reasonable to consider The mechanisms of action of MTX in tissue diseases might also develop, in- MTX as a treatment option in SSc pa- SSc are not fully clarified. MTX, as cluding pulmonary arterial hyperten- tients with progressive diffuse SSc and an anti-inflammatory and immunosup- sion, while severe kidney and CNS-in- in whom the efficacy/risk ratio favours pressive agent, might act through de- volvement are rare in MCTD. MCTD MTX over other immunosuppressive creasing systemic immune and inflam- has been considered a “go-through drugs or who cannot tolerate other im- matory reactions as well as through state” by some authors, because as munosuppressive treatments. Accord- diminishing local inflammatory infil- much as 50% of patients with MCTD ingly, MTX has been recommended for trates which are found in the skin and fulfil the classification criteria for other treating skin changes in patients with internal organs in the early stages of connective tissue diseases during fol- early diffuse SSc (13). SSc. However, the inflammatory in- low-up, mostly SSc, SLE and RA. Despite the lack of specific randomised filtrates are usually sparse even in the However, several genetic, serologic and clinical trials, MTX, due to its anti- early stages and are limited in the skin clinical features support the concept of inflammatory actions and relatively to perivascular locations. In contrast, MCTD as its own disease entity (2). good safety profile, is also considered profibrotic cytokines are expressed by No controlled clinical trials have been the treatment of choice in patients with resident cells such as fibroblasts and published to guide therapy in MCTD, SSc/inflammatory arthritis and SSc/ endothelial cells throughout different and therefore treatment strategies

S-162 Use of methotrexate in patients with SSc and MCTD / O. Kowal-Bielecka & O. Distler largely rely upon conventional thera- formed with lower than optimal MTX 12. CLEMENTS PJ, LACHENBRUCH PA, STERZ pies that are used for similar problems dosage, making definite conclusions on M et al.: Cyclosporine in systemic sclerosis. Results of a forty-eight-week open safety in other rheumatic conditions. MTX the efficacy of MTX in SSc difficult. study in ten patients. Arthritis Rheum 1993; is therefore most often used in MCTD Regular follow-up of patients treated 36: 75-83. when polyarthritis or myositis is prom- with MTX for SSc or MCTD is of key 13. KOWAL-BIELECKA O, LANDEWÉ R, AVOU- inent and cannot be controlled by other importance for monitoring treatment ef- AC J et al.: EULAR recommendations for the treatment of systemic sclerosis: a report treatments. Indeed, musculoskeletal ficacy and safety in individual patients. from the EULAR Scleroderma Trials and symptoms are frequent in MCTD and Research group (EUSTAR). Ann Rheum Dis include non-specific arthralgias and References 2009; 68: 620-8. , arthritis and myositis. The 1. DISTLER O, GAY S: Scleroderma. Internist 14. QUILLINAN NP, DENTON CP: Disease- (Berl) 2010; 5: 30-8. modifying treatment in systemic sclerosis: joint involvement in MCTD tends to 2. DISTLER J, KALDEN JR, DISTLER O: Undif- current status. Curr Opin Rheumatol 2009; be more severe than in SLE and SSc. ferentiated connective tissue diseases, over- 21: 636-41. Inflammatory arthritis is often the pre- lap syndromes, and mixed connective tis- 15. HUNZELMANN N, MOINZADEH P, GENTH E et al.: High frequency of corticosteroid and senting symptom of MCTD and occurs sue disease. In: JWJ BIJLSMA EULAR (Ed.): Compendium on Rheumatic Diseases. Lon- immunosuppressive therapy in patients with in 60–100% of patients with MCTD. don: BMJ, 2009, p. 244-56. systemic sclerosis despite limited evidence The arthritis in MCTD can be erosive 3. GAUJOUX-VIALA C, SMOLEN JS, LANDEWÉ for efficacy. Arthritis Res Ther 2009; 11: in 30–70% of patients by x-ray. How- R et al.: Current evidence for the manage- R30. 16. STEEN VD, MEDSGER TA JR: Case-control ever, the course of MCTD associated ment of rheumatoid arthritis with synthetic disease-modifying antirheumatic drugs: a study of corticosteroids and other drugs that inflammatory joint disease is usually systematic literature review informing the either precipitate or protect from the devel- more benign than that of erosive RA. EULAR recommendations for the manage- opment of scleroderma renal crisis. Arthritis Arthritis mutilans can also occur in ment of rheumatoid arthritis. Ann Rheum Dis Rheum 1998; 41: 1613-9. 17. KIM YJ, SONG M, RYU JC: Mechanisms rare cases. The prevalence of myositis 2010; 69: 1004-9. 4. STEEN VD, MEDSGER TA: Changes in causes underlying methotrexate-induced pulmonary in MCTD varies from 15-75% in dif- of death in systemic sclerosis 1972-2003. toxicity. Expert Opin Drug Saf 2009; 8: 451- ferent studies. Myositis is often present Ann Rheum Dis 2007; 66: 940-4. 8. early in the course of the disease and 5. LEROY EC, MEDSGER TA JR: Criteria for the 18. ARAKAWA H, YAMASAKI M, KURIHARA Y, YAMADA H, NAKAJIMA Y: Methotrexate in- manifests as acute flares. Less often, classification of early systemic sclerosis. J Rheumatol 2001; 28: 1573-6. duced pulmonary injury: serial CT findings. myositis presents as a low grade and 6. ABRAHAM D, BEYER C, DISTLER JHW, DIS- J Thorac Imaging 2003; 18: 231-6 persistent manifestation (2). While TLER O: The pathogenesis of systemic sclero- 19. DISTLER O, PAP T, KOWAL-BIELECKA O et MTX is often used in clinical practice sis. In: O. DISTLER (Ed.): Scleroderma - mod- al.: Overexpression of monocyte chemoat- ern aspects of pathogenesis, diagnosis, and tractant protein 1 in systemic sclerosis: role for these patients, published evidence therapy. Unimed Bremen 2009, pp. 24-33. of platelet-derived growth factor and effects concerning the efficacy and safety of 7. VAN DEN HOOGEN FH, BOERBOOMS AM, on monocyte chemotaxis and collagen syn- MTX in MCTD is limited and consist SWAAK AJ, RASKER JJ, VAN LIER HJ, VAN DE thesis. Arthritis Rheum 2001; 44: 2665-78. mainly of single case reports and ex- PUTTE LB: Comparison of methotrexate with 20. YOZAI K, SHIKATA K, SASAKI M et al.: placebo in the treatment of systemic sclero- Methotrexate prevents renal injury in experi- pert opinions (24, 25). sis: a 24 week randomized double-blind trial, mental diabetic rats via anti-inflammatory followed by a 24 week observational trial. Br actions. J Am Soc Nephrol 2005; 16: 3326- Conclusions J Rheumatol 1996; 35: 364-72. 38. 21. 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MTX modestly improves skin changes 10. KOWAL-BIELECKA O, VEALE DJ: DMARDs Ann Rheum Dis 1993; 52: 758-61. in systemic sclerosis: Do they exist? In: O. 23. CHAN ES, CRONSTEIN BN: Adenosine in in early dSSc. However, its clinical ef- DISTLER (Ed.): Scleroderma - modern as- fibrosis. Mod Rheumatol 2010; 20: 114-22. fect is of borderline significance. At pects of pathogenesis, diagnosis, and thera- 24. ROZENBAUM M, SLOBODIN G, BOULMAN present, available evidence does not py. Unimed Bremen, 2009, p 90-7. N et al.: Therapeutic vignette: old and new support usage of MTX for treating in- 11. DERK CT, GRACE E, SHENIN M, NAIK M, drugs in mixed connective tissue disease. Isr SCHULZ S, XIONG W: A prospective open- Med Assoc J 2008; 10: 831-2. ternal organ involvement in SSc. How- label study of mycophenolate mofetil for 25. KIM P, GROSSMAN JM: Treatment of mixed ever, clinical trials evaluating efficacy the treatment of diffuse systemic sclerosis. connective tissue disease. 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