- Email: [email protected]
Low-dose methotrexate in the treatment of widespread morphea
Low-dose methotrexate in the treatment of widespread morphea Marieke M. B. Seyger, MD,a Frank H. J. van den Hoogen, MD,b Theo de Boo, MSc,c and Elke M. G. J. de Jong, MDa Nijmegen, The Netherlands Background: Low-dose methotrexate (MTX) has been shown to be effective in the treatment of systemic sclerosis. Objective: We evaluated the effect of low-dose MTX on widespread morphea in a 24-week trial. Methods: Oral MTX, 15 mg/week, was administered to nine patients. Clinical records (modified skin score [MSS], durometer score, and the scores on a visual analogue scale (VAS) of feelings of tightness and itching), as well as laboratory data were examined. Serum aminoterminal propeptide of type III procollagen (PIIINP) was determined at weeks 0, 12, and 24. Results: At the end of the 24-week treatment period, significant improvement was observed in MSS (P = .01) and the VAS score for tightness (P < .01), whereas the durometer score (P = .07) and the VAS for itching (P = .07) showed a tendency toward improvement. PIIINP level did not alter. No serious adverse events were noted. Conclusion: These results suggest a beneficial effect of MTX on widespread morphea. Because spontaneous improvements are not uncommon, prospective double-blind, placebo-controlled studies are necessary to determine the usefulness of MTX in this disease. (J Am Acad Dermatol 1998;39:220-5.)
Morphea or localized scleroderma can manifest in various forms. Greenberg and Falanga1 distinguished the following main types: morphea, linear scleroderma, and generalized morphea. Sclerosis is the hallmark and is usually confined to cutis and direct underlying tissue, resulting in tightness of the skin. Tightness and itching are the major complaints. The disease is often self-limiting; however, widespread or generalized morphea is often complicated by contractures and is cosmetically disabling. Several treatments have been described for widespread morphea, but with varying degrees of success. Successful treatment has been reported with D-penicillamine, antimalarial drugs, sulfasalazine, or plasmapheresis, and more recently retinoids, calcitriol, PUVA, bath-PUVA, cyclosporine, tranilast, and prednisone.2-11 The efficacy From the Departments of Dermatology,a Rheumatology,b and Medical Statistics,c University Hospital Nijmegen. Reprint requests: Marieke M. B. Seyger, MD, Dept. of Dermatology, University Hospital Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/1/90797
220
of these drugs has never been proved in doubleblind placebo-controlled trials. Recently, in a double-blind, placebo controlled study of 29 patients with systemic sclerosis, beneficial effects of treatment with methotrexate (MTX) on the skin lesions has been reported.12 Because of the similarities between the skin lesions in patients with systemic sclerosis and morphea, we decided to examine the effects of low-dose MTX on the skin lesions of patients with widespread morphea. For assessing skin involvement, the modified skin score (MSS), first described by Zachariae13 and the durometer score were used.14 Both methods have recently been validated and proven reliable, especially when used together.15 By means of a visual analogue scale (VAS) the patients’ evaluations of tightness and itching were determined. In addition, the level of serum aminoterminal propeptide of type III procollagen (PIIINP), which is a serologic marker for type III collagen synthesis16 was measured before and after treatment. The PIIINP concentration has been shown to be elevated in patients with localized scleroderma and systemic sclerosis13,17 and correlates with the extent
Journal of the American Academy of Dermatology Volume 39, Number 2, Part 1
of skin involvement as measured by means of the MSS.
Seyger et al. 221 chemistry (creatinine, alkaline phosphatase, AST, ALT, lactate dehydrogenase, bilirubin) and adverse events were assessed.
MATERIAL AND METHODS
Patients
PIIINP
After approval of the protocol by the local Ethical Committee and written informed consent, nine patients were enrolled in this study. All patients had widespread morphea, without any signs of systemic involvement. The disease duration had to be less than 6 months, or, if longer, patients had to experience active spread of the skin lesions. In all patients histologic confirmation of the diagnosis was obtained. Any systemic treatment with known or suspected effect on morphea had to be discontinued for at least 4 weeks before the start of the study, and topical treatment for at least 2 weeks. The following exclusion criteria were applied: age less than 18 years; the presence of acute or chronic infection; pregnancy or childbearing potential without an acceptable means of contraception; the presence of liver disease, defined as a value exceeding twice the upper limit of normal for a hepatic function test or the presence of a known liver disease; serum creatinine level > 130 µmol/L or a creatinine clearance rate < 50 mL/min as estimated by the method of Cockcroft and Gault18; known pulmonary disease; a leukocyte count of < 3.5 × 109/L or a platelet count < 150 × 109/L; the presence of concurrent neoplastic disease; the presence of active peptic ulcer disease; the presence of insulin-dependent diabetes mellitus; alcohol abuse; and the use of an antifolate drug other than MTX such as sulfonamide derivatives, allopurinol, or probenecid. Patients with concomitant diseases (arthritis, hyperthyroidism) that can affect the serum level of PIIINP were also excluded.
At study entry, after 12 weeks and after 24 weeks of treatment with MTX, the level of PIIINP, which is a serologic marker for type III collagen synthesis,16 was determined. Sera were collected and stored at –20°C until analysis. PIIINP concentrations were measured with a radioimmunoassay based upon the human propeptide (FARMOS Diagnostica, Espoo, Finland).16 The reference range for adults (based on healthy Finnish blood donors) as provided by the manufacturer is 1.7 to 4.2 µg/L.
Study design The study was designed as an open prospective trial. During a period of 24 weeks, patients were treated with an oral dose of 15 mg MTX weekly. If the clinical response was not sufficient after 12 weeks of treatment, the dose was increased to 25 mg/week. Response to treatment was defined as stabilization or improvement of the MSS, or more than 25% improvement of the durometer score. In case of a favorable response, the initial dose was maintained (see Dosage adjustments). Patients were evaluated every 4 weeks. Initial assessment included concurrent medication, chest x-ray, detection of circulating autoantibodies (by counter immunoelectrophoresis and immunoblotting) and complete physical examination, which was repeated at the end of the study. Every 4 weeks, clinical evaluation, hematologic findings (hemoglobin, hematocrit, platelets, white blood cell count, differentiation), blood
Clinical evaluation Clinical evaluation of the skin was assessed by the MSS, and the durometer score.14 The MSS is a clinical skin score in which the body is divided into seven regions (R): head and neck region, trunk, arms, hands, fingers, legs, and feet. The degree of thickening and pliability (T) was assessed on a 0 to 3 scale: 0, normal skin; 1, thickened skin; 2, decreased ability to pinch or move skin; and 3, skin that is unable to be pinched or moved (hide-bound). The most affected part of the region determined the score. In addition, involvement in each area (A) was determined by estimation and given the following scores: 0, no involvement; 1, less than 33%; 2, 33% to 67%; and 3, more than 67%. The sum of the numerical units for thickening and the percentage of area surface involved is the MSS. Thus the MSS is Σ(T + A)R1-R7. The possible minimum score is 0, representing no affected skin, and the maximum score is 42, for extreme involvement in all areas.13 The hardness of the morphea lesions was examined by means of a hand-held type durometer with an affixed weight of approximately 400 g. In this way, the measurements were carried out with a constant weight, not allowing additional pressure (model 1600-OO, Rex Gauge Co., Glenview, Ill.).14,19 The durometer is fitted with a calibrated gauge that registers linearly divided units present on a scale from 0 to 100. The durometer readings were taken at the intersection of two imaginary lines drawn through the largest horizontal and vertical diameter of the most indurated lesions in each of the seven regions, used for the determination of the MSS. Four consecutive readings were taken at the same site. The patient was lying flat, and contraction and muscle tension were avoided by putting a pillow under the extremities. The total durometer score is the sum of the means of the four determinations at each site. By means of a VAS the patients’ estimate of tight-
Journal of the American Academy of Dermatology August 1998
222 Seyger et al. Table I. Patient characteristics Total
Patient No.
1 2 3 4 5 6 7 8 9
Age (y)
Duration of treatment (wk)
MSS
durometer score
VAS tightness
Before
After
Before
After
Before
50 38 63 71 49 53 34 35 37
12 24 24 24 24 24 20 8 24
12 8 7 6 3 4 3 4 2
10 6 5 3 3 3 3 3 2
138 172 119 118 57 87 109 42 67
133 134 97 92 45 72 101 55 78
66 82 73 64 50 48 0 100 0
VAS itching
After
Before
After
3 35 9 0 15 0 0 23 0
5 74 78 32 22 0 0 100 7
20 21 3 0 5 0 10 18 18
N.D., Not done. *Normal range < 25 U/L. †Normal range < 30 U/L.
ness and itching were assessed. Both VAS scores were determined by the patient on a 100 mm scale, on which 0 mm represents the absence of itch or tightness and 100 mm represent maximal itching or tightness.
Dosage adjustments All patients started with an initial dosage of 15 mg MTX per week. The trial medication was reduced by 50% if white blood cell count was less than 3.0 × 109/L, if platelet count was less than 150 × 109/L, if liver enzyme levels exceeded three times the upper limit of normal, if serum creatinine levels exceeded 160 µmol/L for two consecutive measurements, or in case of severe clinical deterioration or adverse events. When these conditions persisted or recurred after reduction of the dosage, the patient was permanently withdrawn from the study. An increase in dosage of MTX to 25 mg/week was administered after 12 weeks in those patients who did not respond according to the predefined study criteria and who did not show any adverse events.
Statistical analysis Main analysis is based on intention to treat; the differences between the initial and the last recorded values of the patients who have at least one value after t = 0 were examined by means of the Student paired t test. In correlation analysis the Spearman correlation coefficient was used. The level of significance was 0.05. RESULTS
Patients Detailed patient characteristics are summarized in Table I. Nine patients were enrolled in the study: Two men and seven women with a mean age of
47.8 ± 4.4 (SEM). Seven patients (1 through 7) had multiple plaques from 5 up to 10 cm on their trunk, arms and legs (Table I). The low MSS in patients (5 to 7) was not because of a small area of involvement, but because of a low degree of thickening. Patient 8 had a large lesion on her neck, indurated in such an extent that she was not able to bend her head completely, and suffered from a constant headache. Patient 9 had three large plaques on the trunk, involving her breast. Of the nine patients, three failed to complete the study. Two patients were withdrawn (one at 12, and the other at 20 weeks) because of elevated liver function tests and fatigue. One patient was withdrawn at 8 weeks because of stomatitis and substantial weight loss. In two of the six who completed the study, the dosage was reduced after 12 weeks to 7.5 mg weekly because of nausea and raised liver enzyme levels. With the dosage of 7.5 mg weekly the liver enzymes returned to normal and the nausea disappeared. At 12 weeks, the dose of MTX had to be raised because of an unfavorable response to 25 mg/week in one patient. No other adverse events occurred during the study. Clinical evaluation An improvement in MSS was found in six patients, whereas the MSS remained the same in the other three. The difference in MSS score before (5.4 ± 1.1; mean ± SEM) and after treatment (4.2 ± 0.8) of the patients who completed the study is significant (P = .01). The durometer scores decreased in seven
Journal of the American Academy of Dermatology Volume 39, Number 2, Part 1
Seyger et al. 223
Liver enzymes (U/L) AST*
PIIINP (µg/L)
ALT†
Before
After
Before
After
Before
After
3.81 2.61 3.5 2.4 2.75 2.32 3.41 2.8 3.17
4.59 1.94 3.78 3.18 N.D. 2.09 2.56 N.D. 2.71
5 8 15 10 10 12 15 6 6
31 10 19 20 14 19 45 12 9
9 20 17 13 11 15 19 8 9
84 20 29 40 15 37 95 14 15
patients. Two patients showed an increase in the durometer score; patient 9 did not show any improvement despite an increase in MTX dose to 25 mg/week, whereas patient 8 was withdrawn from the study at 8 weeks. An improvement in durometer score before (101 ± 13.9) and after (89.7 ± 10.3) treatment was found (P = .07). A division of the total durometer score in the different regions showed the greatest improvement in the arm region (P = .03). The VAS for tightness improved in seven patients. Two patients did not have complaints of tightness of their lesions before the start of the study. Their VAS score for tightness remained zero. The change in VAS score for tightness before (53.7 ± 11.4) and after (9.4 ± 4.2) treatment was significant (P < .01). In five patients the VAS score for itching diminished, in three patients it increased, and in one patient it remained zero. The VAS score for itching showed a tendency toward improvement (P = .07). The mean values before and after treatment were 35.3 ± 12.9 and 10.6 ± 2.9, respectively. PIIINP All PIIINP values were within the reference range for healthy persons. Patient 1 showed values of PIIINP above the upper range after 12 weeks of treatment and was withdrawn at 12 weeks because of raised liver enzyme levels. In three patients the level of PIIINP increased, whereas it decreased in four patients. The serum PIIINP of patient 5 was not determined at 24 weeks. No difference in PII-
INP levels before (3.0 ± 0.26) and after (3.0 ± 0.42) treatment was found. No correlation was found between PIIINP levels and the MSS r = 0.14, P = .71) and between PIIINP and the durometer score r = 0.2, P = .61). DISCUSSION
The mechanism of action of MTX is based on its resemblance to folic acid; it inhibits folate dependent enzymes involved in DNA, RNA, and protein synthesis.20 The mechanism through which MTX acts in morphea has yet to be established. Direct inhibition of extracellular matrix production by fibroblasts is unlikely: MTX enhances glycosaminoglycan production by fibroblasts from patients with systemic sclerosis in culture.21 Anti-inflammatory effects have been hypothesized as the mechanism through which MTX acts in rheumatoid arthritis. It has crucial effects on the cascade of events initiated by some cytokines (interleukins 1 and 6 [IL-1 and IL-6], tumor necrosis factor).22 In 48 patients with morphea, an increase in serum levels of IL-2, IL-4, and IL-6 were demonstrated by Ihn et al.,23 and a decrease in these levels paralleled improvement in cutaneous sclerosis. In addition, IL-8 was present in serum of patients with localized scleroderma.24 Decreases in circulating IL-6 and soluble IL-2 have been reported with MTX.25 In patients with psoriasis, and in patients with rheumatoid arthritis, MTX induced inhibition of IL-8 production by peripheral blood monocytes. In addition, a decrease of IL-8 production was associated with clinical improvement in both diseases, and levels of IL-8 were closely related to the clinical severity of psoriasis and to the response to treatment.26,27 These pathways might account for the beneficial effect of MTX on patients with widespread morphea. Various studies have described an increase in serum PIIINP levels in patients with systemic sclerosis and localized scleroderma.13,17 In addition, a correlation was found between PIIINP and the extent of sclerosis of the skin.13,28,29 In the present investigation, a decrease in serum levels of PIIINP could be expected as the induration of morphea lesions diminished. On the other hand, PIIINP is known to be increased in patients with liver cirrhosis treated with MTX for their psoriasis.30,31 Although our group of patients who completed the study did not have any disturbances of liver func-
Journal of the American Academy of Dermatology August 1998
224 Seyger et al. tion tests at the end of the trial, and showed a decrease of clinical scores for morphea, no significant changes in PIIINP levels were detected. These findings are in line with the results of Hein et al.,32 who also found unchanged levels of PIIINP in patients with systemic sclerosis after treatment with interferon gamma despite clinical improvement. In contrast to Zachariae et al.,13 we, therefore, could not confirm a correlation between serum PIIINP levels and the extent of skin involvement. This study demonstrates that patients with morphea respond to low dose MTX. Prospective double-blind placebo controlled trials will be needed to determine the position of MTX therapy in the treatment of widespread morphea.
14. 15.
16.
17.
18. 19.
REFERENCES 1. Greenberg AS, Falanga V. Localized cutaneous sclerosis. In: Sontheimer RD, Provost TT, editors. Cutaneous manifestations of rheumatic diseases. Baltimore: Williams & Wilkins; 1996. p. 141-55. 2. Falanga V, Medsger TA Jr. D-Penicillamine in the treatment of localized scleroderma. Arch Dermatol 1990;126:609-12. 3. Cribier B, Faradji T, Le Coz C, Oberling F, Grosshans E. Extracorporeal photochemotherapy in systemic sclerosis and severe morphea. Dermatology 1995;191:25-31. 4. Hulshof MM, Pavel S, Breedveld FC, Dijkmans BA, Vermeer BJ. Oral calcitriol as a new therapeutic modality for generalized morphea. Arch Dermatol 1994;130: 1290-3. 5. Peter RU, Ruzicka T, Eckert F. Low-dose cyclosporine A in the treatment of disabling morphea. Arch Dermatol 1991;127:1420-1. 6. Joly P, Bamberger N, Crickx B, Belaich S. Treatment of severe forms of localized scleroderma with oral corticosteroids: follow-up study on 17 patients. Arch Dermatol 1994;130:663-4. 7. Kanekura T, Fukumaru S, Matsushita S, Terasaki K, Mizoguchi S, Kanzaki T. Successful treatment of scleroderma with PUVA therapy. J Dermatol 1996;23:455-9. 8. Kerscher M, Volkenandt M, Meurer M, Lehmann P, Plewig G, Rocken M. Treatment of localised scleroderma with PUVA bath photochemotherapy [letter]. Lancet 1994;343:1233. 9. Falanga V. Fibrosing conditions in childhood. Adv Dermatol 1991;6:145-58. 10. Czarnecki DB, Taft EH. Generalized morphoea successfully treated with salazopyrine. Acta Derm Venereol (Stockh) 1982;62:81-2. 11. Neuhofer J, Fritsch P. Treatment of localized scleroderma and lichen sclerosus with etretinate. Acta Derm Venereol (Stockh) 1984;64:171-4. 12. van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB. Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. Br J Rheumatol 1996;35:364-72. 13. Zachariae H, Bjerring P, Halkier Sorensen L,
20. 21.
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Heickendorff L, Sondergaard K. Skin scoring in systemic sclerosis: a modification—relations to subtypes and the aminoterminal propeptide of type III procollagen (PIIINP). Acta Derm Venereol (Stockh) 1994;74:444-6. Falanga V, Bucalo B. Use of a durometer to assess skin hardness. J Am Acad Dermatol 1993;29:47-51. Seyger MMB, van den Hoogen FHJ, de Boo T, De Jong EMGJ. Reliability of two methods to assess morphea: skin scoring and the use of a durometer. J Am Acad Dermatol 1997;37:793-6. Risteli J, Niemi S, Trivedi P, Maentausta O, Mowat AP, Risteli L. Rapid equilibrium radioimmunoassay for the aminoterminal propeptide of human type III procollagen. Clin Chem 1988;34:715-8. Zachariae H, Halkier Sorensen L, Heickendorff L. Serum aminoterminal propeptide of type III procollagen in progressive systemic sclerosis and localized scleroderma. Acta Derm Venereol (Stockh) 1989;69:66-70. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41. Aghassi D, Monoson T, Braverman I. Reproducible measurements to quantify cutaneous involvement in scleroderma. Arch Dermatol 1995;131:1160-6. Jolivet J, Cowan KH, Curt GA, Clendeninn NJ, Chabner BA. The pharmacology and clinical use of methotrexate. N Engl J Med 1983;309:1094-104. van den Hoogen FH, van der Kraan PM, Boerbooms AM, van den Berg WB, van Lier HJ, van de Putte LB. Effects of methotrexate on glycosaminoglycan production by scleroderma fibroblasts in culture. Ann Rheum Dis 1993;52:758-61. Segal R, Yaron M, Tartakovsky B. Methotrexate: mechanism of action in rheumatoid arthritis. Semin Arthritis Rheum 1990;20:190-200. Ihn H, Sato S, Fujimoto M, Kikuchi K, Takehara K. Demonstration of interleukin-2, interleukin-4 and interleukin-6 in sera from patients with localized scleroderma. Arch Dermatol Res 1995;287:193-7. Ihn H, Sato S, Fujimoto M, Kikuchi K, Takehara K. Demonstration of interleukin 8 in serum samples of patients with localized scleroderma. Arch Dermatol 1994;130:1327-8. Barrera P, Haagsma CJ, Boerbooms AM, van Riel PL, Borm GF, van de Putte LB, et al. Effect of methotrexate alone or in combination with sulphasalazine on the production and circulating concentrations of cytokines and their antagonists: longitudinal evaluation in patients with rheumatoid arthritis. Br J Rheumatol 1995;34:747-55. Teranishi Y, Mizutani H, Murata M, Shimizu M, Matsushima K. Increased spontaneous production of IL8 in peripheral blood monocytes from the psoriatic patient: relation to focal infection and response to treatments. J Dermatol Sci 1995;10:8-15. Seitz M, Loetscher P, Dewald B, Towbin H, Rordorf C, Gallati H, et al. Methotrexate action in rheumatoid arthritis: stimulation of cytokine inhibitor and inhibition of chemokine production by peripheral blood mononuclear cells. Br J Rheumatol 1995;34:602-9. Krieg T, Langer I, Gerstmeier H, Keller J, Mensing H, Goerz G, et al. Type III collagen aminopropeptide levels in serum of patients with progressive systemic scleroderma. J Invest Dermatol 1986;87:788-91. Gerstmeier H, Gabrielli A, Meurer M, Brocks D, Braun Falco O, Krieg T. Levels of type IV collagen and laminin fragments in serum from patients with progressive systemic sclerosis. J Rheumatol 1988;15:969-72.
Journal of the American Academy of Dermatology Volume 39, Number 2, Part 1
Seyger et al. 225
30. Boffa MJ, Smith A, Chalmers RJ, Mitchell DM, Rowan B, Warnes TW, et al. Serum type III procollagen aminopeptide for assessing liver damage in methotrexate-treated psoriatic patients. Br J Dermatol 1996;135: 538-44. 31. Zachariae H, Sogaard H, Heickendorff L. Serum aminoterminal propeptide of type III procollagen: a non-
O
invasive test for liver fibrogenesis in methotrexate-treated psoriatics. Acta Derm Venereol (Stockh) 1989;69: 241-4. 32. Hein R, Behr J, Hundgen M, Hunzelmann N, Meurer M, Braun Falco O, et al. Treatment of systemic sclerosis with gamma-interferon. Br J Dermatol 1992;126:496501.
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Morphea or localized scleroderma can manifest in various forms. Greenberg and Falanga1 distinguished the following main types: morphea, linear scleroderma, and generalized morphea. Sclerosis is the hallmark and is usually confined to cutis and direct underlying tissue, resulting in tightness of the skin. Tightness and itching are the major complaints. The disease is often self-limiting; however, widespread or generalized morphea is often complicated by contractures and is cosmetically disabling. Several treatments have been described for widespread morphea, but with varying degrees of success. Successful treatment has been reported with D-penicillamine, antimalarial drugs, sulfasalazine, or plasmapheresis, and more recently retinoids, calcitriol, PUVA, bath-PUVA, cyclosporine, tranilast, and prednisone.2-11 The efficacy From the Departments of Dermatology,a Rheumatology,b and Medical Statistics,c University Hospital Nijmegen. Reprint requests: Marieke M. B. Seyger, MD, Dept. of Dermatology, University Hospital Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/1/90797
220
of these drugs has never been proved in doubleblind placebo-controlled trials. Recently, in a double-blind, placebo controlled study of 29 patients with systemic sclerosis, beneficial effects of treatment with methotrexate (MTX) on the skin lesions has been reported.12 Because of the similarities between the skin lesions in patients with systemic sclerosis and morphea, we decided to examine the effects of low-dose MTX on the skin lesions of patients with widespread morphea. For assessing skin involvement, the modified skin score (MSS), first described by Zachariae13 and the durometer score were used.14 Both methods have recently been validated and proven reliable, especially when used together.15 By means of a visual analogue scale (VAS) the patients’ evaluations of tightness and itching were determined. In addition, the level of serum aminoterminal propeptide of type III procollagen (PIIINP), which is a serologic marker for type III collagen synthesis16 was measured before and after treatment. The PIIINP concentration has been shown to be elevated in patients with localized scleroderma and systemic sclerosis13,17 and correlates with the extent
Journal of the American Academy of Dermatology Volume 39, Number 2, Part 1
of skin involvement as measured by means of the MSS.
Seyger et al. 221 chemistry (creatinine, alkaline phosphatase, AST, ALT, lactate dehydrogenase, bilirubin) and adverse events were assessed.
MATERIAL AND METHODS
Patients
PIIINP
After approval of the protocol by the local Ethical Committee and written informed consent, nine patients were enrolled in this study. All patients had widespread morphea, without any signs of systemic involvement. The disease duration had to be less than 6 months, or, if longer, patients had to experience active spread of the skin lesions. In all patients histologic confirmation of the diagnosis was obtained. Any systemic treatment with known or suspected effect on morphea had to be discontinued for at least 4 weeks before the start of the study, and topical treatment for at least 2 weeks. The following exclusion criteria were applied: age less than 18 years; the presence of acute or chronic infection; pregnancy or childbearing potential without an acceptable means of contraception; the presence of liver disease, defined as a value exceeding twice the upper limit of normal for a hepatic function test or the presence of a known liver disease; serum creatinine level > 130 µmol/L or a creatinine clearance rate < 50 mL/min as estimated by the method of Cockcroft and Gault18; known pulmonary disease; a leukocyte count of < 3.5 × 109/L or a platelet count < 150 × 109/L; the presence of concurrent neoplastic disease; the presence of active peptic ulcer disease; the presence of insulin-dependent diabetes mellitus; alcohol abuse; and the use of an antifolate drug other than MTX such as sulfonamide derivatives, allopurinol, or probenecid. Patients with concomitant diseases (arthritis, hyperthyroidism) that can affect the serum level of PIIINP were also excluded.
At study entry, after 12 weeks and after 24 weeks of treatment with MTX, the level of PIIINP, which is a serologic marker for type III collagen synthesis,16 was determined. Sera were collected and stored at –20°C until analysis. PIIINP concentrations were measured with a radioimmunoassay based upon the human propeptide (FARMOS Diagnostica, Espoo, Finland).16 The reference range for adults (based on healthy Finnish blood donors) as provided by the manufacturer is 1.7 to 4.2 µg/L.
Study design The study was designed as an open prospective trial. During a period of 24 weeks, patients were treated with an oral dose of 15 mg MTX weekly. If the clinical response was not sufficient after 12 weeks of treatment, the dose was increased to 25 mg/week. Response to treatment was defined as stabilization or improvement of the MSS, or more than 25% improvement of the durometer score. In case of a favorable response, the initial dose was maintained (see Dosage adjustments). Patients were evaluated every 4 weeks. Initial assessment included concurrent medication, chest x-ray, detection of circulating autoantibodies (by counter immunoelectrophoresis and immunoblotting) and complete physical examination, which was repeated at the end of the study. Every 4 weeks, clinical evaluation, hematologic findings (hemoglobin, hematocrit, platelets, white blood cell count, differentiation), blood
Clinical evaluation Clinical evaluation of the skin was assessed by the MSS, and the durometer score.14 The MSS is a clinical skin score in which the body is divided into seven regions (R): head and neck region, trunk, arms, hands, fingers, legs, and feet. The degree of thickening and pliability (T) was assessed on a 0 to 3 scale: 0, normal skin; 1, thickened skin; 2, decreased ability to pinch or move skin; and 3, skin that is unable to be pinched or moved (hide-bound). The most affected part of the region determined the score. In addition, involvement in each area (A) was determined by estimation and given the following scores: 0, no involvement; 1, less than 33%; 2, 33% to 67%; and 3, more than 67%. The sum of the numerical units for thickening and the percentage of area surface involved is the MSS. Thus the MSS is Σ(T + A)R1-R7. The possible minimum score is 0, representing no affected skin, and the maximum score is 42, for extreme involvement in all areas.13 The hardness of the morphea lesions was examined by means of a hand-held type durometer with an affixed weight of approximately 400 g. In this way, the measurements were carried out with a constant weight, not allowing additional pressure (model 1600-OO, Rex Gauge Co., Glenview, Ill.).14,19 The durometer is fitted with a calibrated gauge that registers linearly divided units present on a scale from 0 to 100. The durometer readings were taken at the intersection of two imaginary lines drawn through the largest horizontal and vertical diameter of the most indurated lesions in each of the seven regions, used for the determination of the MSS. Four consecutive readings were taken at the same site. The patient was lying flat, and contraction and muscle tension were avoided by putting a pillow under the extremities. The total durometer score is the sum of the means of the four determinations at each site. By means of a VAS the patients’ estimate of tight-
Journal of the American Academy of Dermatology August 1998
222 Seyger et al. Table I. Patient characteristics Total
Patient No.
1 2 3 4 5 6 7 8 9
Age (y)
Duration of treatment (wk)
MSS
durometer score
VAS tightness
Before
After
Before
After
Before
50 38 63 71 49 53 34 35 37
12 24 24 24 24 24 20 8 24
12 8 7 6 3 4 3 4 2
10 6 5 3 3 3 3 3 2
138 172 119 118 57 87 109 42 67
133 134 97 92 45 72 101 55 78
66 82 73 64 50 48 0 100 0
VAS itching
After
Before
After
3 35 9 0 15 0 0 23 0
5 74 78 32 22 0 0 100 7
20 21 3 0 5 0 10 18 18
N.D., Not done. *Normal range < 25 U/L. †Normal range < 30 U/L.
ness and itching were assessed. Both VAS scores were determined by the patient on a 100 mm scale, on which 0 mm represents the absence of itch or tightness and 100 mm represent maximal itching or tightness.
Dosage adjustments All patients started with an initial dosage of 15 mg MTX per week. The trial medication was reduced by 50% if white blood cell count was less than 3.0 × 109/L, if platelet count was less than 150 × 109/L, if liver enzyme levels exceeded three times the upper limit of normal, if serum creatinine levels exceeded 160 µmol/L for two consecutive measurements, or in case of severe clinical deterioration or adverse events. When these conditions persisted or recurred after reduction of the dosage, the patient was permanently withdrawn from the study. An increase in dosage of MTX to 25 mg/week was administered after 12 weeks in those patients who did not respond according to the predefined study criteria and who did not show any adverse events.
Statistical analysis Main analysis is based on intention to treat; the differences between the initial and the last recorded values of the patients who have at least one value after t = 0 were examined by means of the Student paired t test. In correlation analysis the Spearman correlation coefficient was used. The level of significance was 0.05. RESULTS
Patients Detailed patient characteristics are summarized in Table I. Nine patients were enrolled in the study: Two men and seven women with a mean age of
47.8 ± 4.4 (SEM). Seven patients (1 through 7) had multiple plaques from 5 up to 10 cm on their trunk, arms and legs (Table I). The low MSS in patients (5 to 7) was not because of a small area of involvement, but because of a low degree of thickening. Patient 8 had a large lesion on her neck, indurated in such an extent that she was not able to bend her head completely, and suffered from a constant headache. Patient 9 had three large plaques on the trunk, involving her breast. Of the nine patients, three failed to complete the study. Two patients were withdrawn (one at 12, and the other at 20 weeks) because of elevated liver function tests and fatigue. One patient was withdrawn at 8 weeks because of stomatitis and substantial weight loss. In two of the six who completed the study, the dosage was reduced after 12 weeks to 7.5 mg weekly because of nausea and raised liver enzyme levels. With the dosage of 7.5 mg weekly the liver enzymes returned to normal and the nausea disappeared. At 12 weeks, the dose of MTX had to be raised because of an unfavorable response to 25 mg/week in one patient. No other adverse events occurred during the study. Clinical evaluation An improvement in MSS was found in six patients, whereas the MSS remained the same in the other three. The difference in MSS score before (5.4 ± 1.1; mean ± SEM) and after treatment (4.2 ± 0.8) of the patients who completed the study is significant (P = .01). The durometer scores decreased in seven
Journal of the American Academy of Dermatology Volume 39, Number 2, Part 1
Seyger et al. 223
Liver enzymes (U/L) AST*
PIIINP (µg/L)
ALT†
Before
After
Before
After
Before
After
3.81 2.61 3.5 2.4 2.75 2.32 3.41 2.8 3.17
4.59 1.94 3.78 3.18 N.D. 2.09 2.56 N.D. 2.71
5 8 15 10 10 12 15 6 6
31 10 19 20 14 19 45 12 9
9 20 17 13 11 15 19 8 9
84 20 29 40 15 37 95 14 15
patients. Two patients showed an increase in the durometer score; patient 9 did not show any improvement despite an increase in MTX dose to 25 mg/week, whereas patient 8 was withdrawn from the study at 8 weeks. An improvement in durometer score before (101 ± 13.9) and after (89.7 ± 10.3) treatment was found (P = .07). A division of the total durometer score in the different regions showed the greatest improvement in the arm region (P = .03). The VAS for tightness improved in seven patients. Two patients did not have complaints of tightness of their lesions before the start of the study. Their VAS score for tightness remained zero. The change in VAS score for tightness before (53.7 ± 11.4) and after (9.4 ± 4.2) treatment was significant (P < .01). In five patients the VAS score for itching diminished, in three patients it increased, and in one patient it remained zero. The VAS score for itching showed a tendency toward improvement (P = .07). The mean values before and after treatment were 35.3 ± 12.9 and 10.6 ± 2.9, respectively. PIIINP All PIIINP values were within the reference range for healthy persons. Patient 1 showed values of PIIINP above the upper range after 12 weeks of treatment and was withdrawn at 12 weeks because of raised liver enzyme levels. In three patients the level of PIIINP increased, whereas it decreased in four patients. The serum PIIINP of patient 5 was not determined at 24 weeks. No difference in PII-
INP levels before (3.0 ± 0.26) and after (3.0 ± 0.42) treatment was found. No correlation was found between PIIINP levels and the MSS r = 0.14, P = .71) and between PIIINP and the durometer score r = 0.2, P = .61). DISCUSSION
The mechanism of action of MTX is based on its resemblance to folic acid; it inhibits folate dependent enzymes involved in DNA, RNA, and protein synthesis.20 The mechanism through which MTX acts in morphea has yet to be established. Direct inhibition of extracellular matrix production by fibroblasts is unlikely: MTX enhances glycosaminoglycan production by fibroblasts from patients with systemic sclerosis in culture.21 Anti-inflammatory effects have been hypothesized as the mechanism through which MTX acts in rheumatoid arthritis. It has crucial effects on the cascade of events initiated by some cytokines (interleukins 1 and 6 [IL-1 and IL-6], tumor necrosis factor).22 In 48 patients with morphea, an increase in serum levels of IL-2, IL-4, and IL-6 were demonstrated by Ihn et al.,23 and a decrease in these levels paralleled improvement in cutaneous sclerosis. In addition, IL-8 was present in serum of patients with localized scleroderma.24 Decreases in circulating IL-6 and soluble IL-2 have been reported with MTX.25 In patients with psoriasis, and in patients with rheumatoid arthritis, MTX induced inhibition of IL-8 production by peripheral blood monocytes. In addition, a decrease of IL-8 production was associated with clinical improvement in both diseases, and levels of IL-8 were closely related to the clinical severity of psoriasis and to the response to treatment.26,27 These pathways might account for the beneficial effect of MTX on patients with widespread morphea. Various studies have described an increase in serum PIIINP levels in patients with systemic sclerosis and localized scleroderma.13,17 In addition, a correlation was found between PIIINP and the extent of sclerosis of the skin.13,28,29 In the present investigation, a decrease in serum levels of PIIINP could be expected as the induration of morphea lesions diminished. On the other hand, PIIINP is known to be increased in patients with liver cirrhosis treated with MTX for their psoriasis.30,31 Although our group of patients who completed the study did not have any disturbances of liver func-
Journal of the American Academy of Dermatology August 1998
224 Seyger et al. tion tests at the end of the trial, and showed a decrease of clinical scores for morphea, no significant changes in PIIINP levels were detected. These findings are in line with the results of Hein et al.,32 who also found unchanged levels of PIIINP in patients with systemic sclerosis after treatment with interferon gamma despite clinical improvement. In contrast to Zachariae et al.,13 we, therefore, could not confirm a correlation between serum PIIINP levels and the extent of skin involvement. This study demonstrates that patients with morphea respond to low dose MTX. Prospective double-blind placebo controlled trials will be needed to determine the position of MTX therapy in the treatment of widespread morphea.
14. 15.
16.
17.
18. 19.
REFERENCES 1. Greenberg AS, Falanga V. Localized cutaneous sclerosis. In: Sontheimer RD, Provost TT, editors. Cutaneous manifestations of rheumatic diseases. Baltimore: Williams & Wilkins; 1996. p. 141-55. 2. Falanga V, Medsger TA Jr. D-Penicillamine in the treatment of localized scleroderma. Arch Dermatol 1990;126:609-12. 3. Cribier B, Faradji T, Le Coz C, Oberling F, Grosshans E. Extracorporeal photochemotherapy in systemic sclerosis and severe morphea. Dermatology 1995;191:25-31. 4. Hulshof MM, Pavel S, Breedveld FC, Dijkmans BA, Vermeer BJ. Oral calcitriol as a new therapeutic modality for generalized morphea. Arch Dermatol 1994;130: 1290-3. 5. Peter RU, Ruzicka T, Eckert F. Low-dose cyclosporine A in the treatment of disabling morphea. Arch Dermatol 1991;127:1420-1. 6. Joly P, Bamberger N, Crickx B, Belaich S. Treatment of severe forms of localized scleroderma with oral corticosteroids: follow-up study on 17 patients. Arch Dermatol 1994;130:663-4. 7. Kanekura T, Fukumaru S, Matsushita S, Terasaki K, Mizoguchi S, Kanzaki T. Successful treatment of scleroderma with PUVA therapy. J Dermatol 1996;23:455-9. 8. Kerscher M, Volkenandt M, Meurer M, Lehmann P, Plewig G, Rocken M. Treatment of localised scleroderma with PUVA bath photochemotherapy [letter]. Lancet 1994;343:1233. 9. Falanga V. Fibrosing conditions in childhood. Adv Dermatol 1991;6:145-58. 10. Czarnecki DB, Taft EH. Generalized morphoea successfully treated with salazopyrine. Acta Derm Venereol (Stockh) 1982;62:81-2. 11. Neuhofer J, Fritsch P. Treatment of localized scleroderma and lichen sclerosus with etretinate. Acta Derm Venereol (Stockh) 1984;64:171-4. 12. van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB. Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. Br J Rheumatol 1996;35:364-72. 13. Zachariae H, Bjerring P, Halkier Sorensen L,
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30. Boffa MJ, Smith A, Chalmers RJ, Mitchell DM, Rowan B, Warnes TW, et al. Serum type III procollagen aminopeptide for assessing liver damage in methotrexate-treated psoriatic patients. Br J Dermatol 1996;135: 538-44. 31. Zachariae H, Sogaard H, Heickendorff L. Serum aminoterminal propeptide of type III procollagen: a non-
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