Pulsed High-Dose Corticosteroids Combined with Low-Dose Methotrexate in Severe Localized Scleroderma

STUDY Pulsed High-Dose Corticosteroids Combined With Low-Dose Methotrexate in Severe Localized Scleroderma

Alexander Kreuter, MD; Thilo Gambichler, MD; Frank Breuckmann, MD; Sebastian Rotterdam, MD; Marcus Freitag, MD; Markus Stuecker, MD; Klaus Hoffmann, MD; Peter Altmeyer, MD

Objective: To evaluate the efficacy of pulsed high- ment included the monitoring of adverse effects and clini- dose corticosteroids combined with orally administered cal laboratory parameters. low-dose methotrexate therapy in patients with severe localized scleroderma (LS). Results: One patient discontinued therapy. In most of the remaining 14 patients, significant elimination of all Design: A prospective, nonrandomized, open pilot study. signs of active disease (inflammation) and remarkable softening of formerly affected sclerotic skin that resulted in a decrease of the mean±SD clinical score from 10.9±5.3 Setting: Dermatology department at a university hos- at the beginning to 5.5±2.5 at the end of therapy was ob- pital in Bochum, Germany. served (PϽ.001). Clinical improvement was confirmed by histologic and ultrasonographic assessments. No se- Patients: Fifteen patients with histologically con- rious adverse effects were noted. firmed severe LS. Conclusions: These data suggest that pulsed high-dose Interventions: Oral methotrexate (15 mg/wk) com- corticosteroids combined with orally administered low- bined with pulsed intravenous methylprednisolone (1000 dose methotrexate therapy is beneficial and safe in the mg for 3 days monthly) for at least 6 months. treatment of patients with LS. This treatment regimen should especially be considered for severe forms of LS Main Outcome Measures: Treatment outcome was in which conventional treatments have failed. evaluated by means of a clinical score, 20-MHz ultrasonography, and histopathologic analysis. Safety assess- Arch Dermatol. 2005;141:847-852

OCALIZED SCLERODERMA (LS) toimmune, genetic, infectious, and envi- or morphea denotes a spec- ronmental factors have been implicated. trum of disorders character- To date, no proven effective therapy for ized by hardening and thick- LS has been implemented. Numerous ening of different levels of treatments, such as penicillamine, anti- theL dermis, subcutis, and sometimes un- malarial drugs, retinoids, calcitriol, cyclo- derlying soft tissue and bone. Localized sporine, and interferon gamma, have re- scleroderma has been classified into portedly been used for the treatment of LS, plaque, generalized, bullous, linear in- with varying degrees of success.2-4 cluding scleroderma en coup de sabre, and The first encouraging results in the deep forms such as morphea profunda.1 treatment of LS were obtained with UV-A Hence, the clinical spectrum of LS ranges irradiation therapy (bath psoralen–UV-A from discrete, circumscribed sclerotic and low-dose UV-A1 phototherapy) alone or in combination with calcipotriene oint- CME course available at ment.5-8 However, the effects of UV-A are mainly restricted to the epidermis and der- www.archdermatol.com mis and may limit its use in deep generalized forms of LS. Both low-dose metho- plaques of cosmetic importance only to trexate and oral corticosteroid treatment Author Affiliations: more severe variants that may have dev- are reportedly effective in severe forms of Department of Dermatology 9,10 and Allergology, astating effects, such as growth retarda- LS in adults and children. In the pres- Ruhr-University Bochum, tion, muscle atrophy, flexion contrac- ent study, we examined the effects of Bochum, Germany. tures, and psychological disability. The pulsed high-dose corticosteroids com- Financial Disclosure: None. etiology of LS remains unknown, but au- bined with orally administered low-dose

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 (REPRINTED WITH CORRECTIONS) Table 1. Characteristics of Patients With Severe Localized Scleroderma Treated With PCMT

VAS Score for MSS Tightness VAS Score for Itching Patient Type of No./Sex/ Localized Duration of Duration of Before After Before After Before After Age, y Scleroderma Disease, y Treatment, mo Pretreatment Treatment Treatment Treatment Treatment Treatment Treatment 1/M/73 GM 3 18 . . . 12 4 80 10 90 15 2/F/69 GM 3 18 . . . 17 10 100 20 80 30 3/M/59 GM 8 18 Penicillin 19 8 70 30 50 0 4/F/61 GM 4 25 Penicillin, SS 17 7 70 30 60 5 5/F/18 LS 4 9 PU 6 3 70 35 30 0 6/F/39 GM 31 6 Penicillin, TS, SS 17 9 70 20 50 50 7/F/24 LS 7 6 Penicillin 4 2 20 10 0 0 8/F/23 LS 20 6 . . . 6 4 0 0 0 0 9/M/62 GM 1 9 SS 12 5 100 40 95 40 10/F/63 CS 36 6 Penicillin, TS, SS, PU 3 3 0 0 0 0 11/M/67 GM 1 8 PU 13 6 90 50 60 50 12/M/48 LS 6 6 Penicillin, PU 9 4 80 60 85 20 13/F/46 GM 4 6 Penicillin, TS, PU 13 9 80 20 90 15 14/F/51 GM 1 NA PU 4 NA 50 NA 50 NA 15/M/58 GM 1 6 . . . 11 5 100 60 45 5 Mean ± SD . . . 8.7 9.8 . . . 10.9 ± 5.3 5.5 ± 2.5 65.3 ± 33.6 27.5 ± 19.9 52.3 ± 33.2 14.4 ± 19.3

Abbreviations: CS, scleroderma en coup de sabre; GM, generalized morphea; LS, linear scleroderma; MSS, modified skin score; NA, not applicable; PCMT, pulsed high-dose corticosteroids combined with orally administered low-dose methotrexate therapy; PU, PUVA bath; SS, systemic steroids; TS, topical steroids; VAS, visual analog scale.

methotrexate therapy (PCMT) in 15 consecutive pa- features.1 Pretherapeutic histopathologic examination re- tients with severe LS. vealed dermal and subcutaneous sclerosis with thickened collagen bundles, a lymphoplasmacytic infiltrate, and endothe- lial cell swelling consistent with LS. Duration of disease METHODS ranged from 1 to 36 years. In 11 patients, conventional treatment did not result in significant improvement and did not PATIENTS stop progression of LS. Four patients had not previously been treated before entering this study (Table 1). No other sys- From 2000 to 2003, 15 consecutive patients (inpatient and out- temic or topical treatment was given for at least 4 weeks be- patient settings) with severe LS were included in this open, fore the initiation of therapy. prospective nonrandomized trial. The study followed the principles outlined in the Declaration of Helsinki. All patients gave informed oral consent. The presence of a severe form of TREATMENT PROTOCOL LS had to be characterized by 1 of the following criteria: (1) generalized or deep morphea that involved more than 2 ana- A treatment algorithm is provided in Figure 1. Patients who tomical body sites, resulting in restricted mobility or constric- qualified for this trial received an oral dose of 15 mg/wk of tion of the thorax with respiratory difficulties; (2) linear methotrexate. Additionally, high-dose intravenous methyl- scleroderma lesions with the involvement of fat, fascia, prednisolone sodium succinate, 1000 mg for 3 consecutive muscle, or bone, resulting in flexion contractures of the days monthly, was administered. Therapy was finished after 6 joints; or (3) linear scleroderma, including disfiguring en months in case of a reduction of the clinical score by one coup de sabre lesions with ophthalmologic or neurologic third. It was continued in case of insufficient response within changes. Additionally, inclusion criteria included signs of ac- this interval and finished if the primary end point (reduction tive disease manifested by growing of lesions, appearance of of the clinical score by more than one third) was achieved. new lesions, or clinical signs of inflammation within the last 3 Methotrexate dosage adjustments were performed according months. For each patient, a complete disease history was ob- to a protocol as reported previously.10 In case of leukopenia tained before starting therapy, and signs of systemic involve- (Ͻ3000/µL), increase in levels of liver enzymes (3ϫ the upper ment were ruled out. The initial laboratory evaluation was limit) or serum creatinine (Ͼ1.5 mg/dL), or clinical adverse composed of the most common serologic parameters (eg, an- events, methotrexate could be reduced to 7.5 mg/wk. Metho- tinuclear antibodies, anti–single-stranded DNA, extractable trexate could be increased to 25 mg/wk if softening of sclero- nuclear antigens, circulating immune complexes, C3 and C4 sis was not sufficient after 3 months of therapy. In case of per- levels, rheumatoid factor, antihistone antibodies, eosinophil sistent signs of active inflammation, low-dose prednisolone, 5 count, and IgG levels) besides complete blood cell count and mg/d, was added for a maximum of 2 months. Follow-up vis- routine blood chemistry testing. Patients younger than 18 its were performed every 4 weeks. On the initial and fol- years, women with childbearing potential without an accept- low-up visits, a complete blood cell count, serum chemical able means of contraception, concomitant chronic or malig- analysis including glucose and electrolytes measurement, and nant disease, any relevant abnormality in the laboratory as- urinalysis were performed. Additional therapy was restricted sessment at baseline, or serologic evidence of Borrelia to the use of emollients. All patients were evaluated by 2 der- burgdorferi infection were excluded. In all patients (9 women matologists at baseline and follow-up visits (A.K. and M.F.). and 6 men; age range, 18-73 years), the diagnosis of LS was In case of disagreement regarding the clinical score, a com- established according to accepted clinical and histopathologic promise was achieved.

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 (REPRINTED WITH CORRECTIONS) CLINICAL EVALUATION Severe Localized Scleroderma (See Inclusion Criteria) For assessment of skin involvement before and after treatment, a modified skin score (MSS) was used as described else- where.10,11 In brief, the body is divided into 7 regions (head and High-Dose Intravenous Methylprednisolone, 1000 mg for 3 Consecutive Days Monthly, neck, trunk, arms, hands, fingers, legs, and feet), skin thick- and 15 mg/wk of Methotrexate ness is assessed on a 0- to 3-point scale (0, normal skin; 1, thickened skin; 2, decreased ability to pinch or move skin; and 3, Initiation of Therapy unable to pinch or move skin), and involvement of each body area is assessed on a 0- to 3-point scale (0, no involvement; 1, Ͻ Ͼ Good Response Leukopenia Softening Persistent 33%; 2, 33%-67%; and 3, 67%). The sum of numerical units (Reduction of MSS Increase of Liver of Sclerosis Signs for thickness and involvement equals the MSS with a maxi- of One Third) Enzymes Not Sufficient of Active No Adverse Clinical Adverse Events After Inflammation mum score of 42. Patients’ estimates of pretherapeutic and post- Effects (See Treatment Protocol) 3 Months therapeutic tightness and itching were evaluated by means of a visual analog scale (VAS) on a 100-mm scale with 0 as the absence and 100 as the maximum of symptoms.10 Continue Reduce Increase Add 5 mg/d of Oral Methotrexate Methotrexate Methotrexate Prednisolone for With 15 mg/wk to 7.5 mg/wk to 25 mg/wk a Maximum of 2 mo ULTRASONOGRAPHY

Initially and at study end, ultrasonography was performed with Sufficient Response After 6 mo Insufficient Response After 6 mo a digital 20-MHz ultrasound scanner (DUB 20, Taberna Pro Medicum, Lüneburg, Germany), measuring both structure and thickness of a representative area (total thickness, upper sur- End of Therapy Continue Therapy Until face to the inner border of the subcutaneous tissue; usable depth Reduction of MSS of One Third of signal penetration, 8 mm). Additionally, pretherapeutic and posttherapeutic differences of mean cutaneous densitometric Follow-up Follow-up values were evaluated by the same investigator (S.R.).

HISTOPATHOLOGIC ANALYSIS Figure 1. Treatment algorithm. MSS indicates modified skin score.

Skin biopsy specimens were obtained from a representative af- Reduction of dosage was not performed in any case. Clini- fected skin area to confirm the clinical diagnosis of LS by a dif- cally, the results obtained were satisfactory for both the ferent investigator (M.S.). Posttreatment specimens were ob- patients and the physicians. In all patients except 1 (pa- tained from previously affected areas next to the sides of the first specimen. Each biopsy specimen was stained with hema- tient 10, with scleroderma en coup de sabre; no change toxylin-eosin. To avoid sampling error, many sections were as- was observed) who completed PCMT, palpation and in- sessed by a blinded second investigator (P.A.). spection showed an elimination of all signs of active disease (inflammation) and remarkable softening of for- STATISTICAL ANALYSIS merly affected sclerotic skin that resulted in a decrease in the MSS from 10.9±5.3 at the beginning to 5.5±2.5 Data of clinical scores and values of biometrical assessment at the end of therapy (Figure 2A and Table 2). This are given as mean±SD. After performing descriptive and difference was statistically significant (PϽ.001). In most explorative data analysis, pretherapeutic and posttherapeutic patients, early signs of improvement were noted after the evaluations were performed using the t test for paired first 2 months of PCMT. No correlation existed be- Ͻ samples (normal distribution). P .05 was considered statis- tween duration of disease and response to treatment. tically significant. The VAS score for tightness improved in 12 patients. Two patients had no sensation of tightness, and their score RESULTS was 0. In general, the VAS score for tightness significantly decreased from 65.3±33.6 to 27.5±19.9 (PϽ.001). Fifteen consecutive patients with severe LS were treated Similar results could be obtained for the VAS for itch- with PCMT. Ten had generalized morphea and 5 had lin- ing, in which 10 patients reported a decrease in itching ear scleroderma, including 1 with disfiguring sclero- after PCMT, 1 patient recognized no improvement, and derma en coup de sabre. The relevant clinical and bio- 3 patients had no itching before therapy. A statistically logical characteristics of the patients are summarized in significant (PϽ.001) change in VAS score for itching from Table 1. Most of them had previously been treated with 52.3±33.2 to 14.4±19.3 could be evaluated. a variety of agents without clinical benefit. All except 1 The clinical improvement was confirmed by 20-MHz (patient 14 discontinued therapy because of personal rea- ultrasonographic examination. Corium thickness was in- sons) completed this study. The PCMT was given for at creased before and significantly decreased toward an al- least 6 months. However, the clinical improvement was most normal range after PCMT (Figure 3A and Table 3) not sufficient in 6 patients and therapy was continued. (PϽ.001). Additionally, there was a significant increase Mean duration of treatment was 9.8 months. The metho- in dermal density after PCMT (PϽ.001). Similar results trexate dose was increased to 25 mg/wk in 1 patient (pa- were obtained by the histologic assessment of posttreat- tient 3) to improve clinical outcome. In patients 4 and ment biopsy specimens. The structure of the dermal col- 8, oral methylprednisolone sodium succinate, 5 mg/d, was lagen returned to normal or almost normal human skin added for 2 months because of persistent inflammation. architecture.

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Figure 2. Pulsed high-dose corticosteroids combined with low-dose methotrexate in severe localized scleroderma. A, Clinical aspects of patient 4 before therapy. Extensive sclerosis on the chest causing constriction of the thorax and resulting in respiratory difficulty. B, Impressive clearance of sclerosis after pulsed high-dose corticosteroids combined with orally administered low-dose methotrexate therapy.

Table 2. Modified Skin Scores Before and After Therapy

Total Clinical Head and Neck Trunk Arms Hands Fingers Legs Feet Score Patient No. Before After Before After Before After Before After Before After Before After Before After Before After 1 ...... - 6 2 ...... 6 2 ...... 12 4 2...... 5363...... 64...... 17 10 3423262...... 62...... 19 8 4415231...... 53...... 17 7 5 ...... - ...... 6 3 ...... 63 6323253...... 1...421...17 9 7 ...... 2 1 ...... 2 1 ...... 42 8112111...... 21...... 64 9 ...... 6 2 ...... 6 3 ...... 12 5 102211...... 33 11...... 1162...... 63...... 13 6 12 ...... 4 2 ...... 5 2 ...... 94 13...... 323243...... 32...... 13 9 14 ...... 3 ...... 1 ...... 4 ... 15 ...... 5 2 ...... 6 3 ...... 11 5

A B

Figure 3. Ultrasonography in a patient treated with pulsed high-dose corticosteroids combined with low-dose methotrexate. A, A 20-MHz ultrasonographic assessment of a representative sclerotic area before therapy. B, A 20-MHz ultrasonographic assessment after therapy. Improvement of sclerotic skin correlates with a decrease in corium thickness. The increase in echogenic structures indicates a normalization of skin structure.

Adverse effects of PCMT were moderate. Three pa- in weight (10 kg; patient 4) most likely related to meth- tients reported mild nausea and headache the day after ylprednisolone. These effects returned to normal after the methotrexate administration. Two patients developed dia- end of treatment. Apart from serum glucose level eleva- betes mellitus (patients 3 and 4), and 1 had an increase tion in 2 patients, no significant laboratory abnormali-

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 (REPRINTED WITH CORRECTIONS) ties have been detected during therapy. During follow-up for at least half a year, none of the patients Table 3. Results of 20-MHz Ultrasonographic Measurements experienced a relapse of LS. Before and After Treatment

Skin Thickness, µm Skin Density COMMENT Patient No. Before After Before After 1 1733 1422 43 37 Clinical and ultrasonographic evaluation revealed that 2 1797 1382 21 43 most patients markedly improved during PCMT. Be- 3 2488 2330 19 31 cause no universally effective causative treatment ex- 4 1639 1441 24 46 ists, management of LS varies in its different subtypes.12 5 1975 1402 27 47 In the treatment of mild singular en plaque lesions, topi- 6 849 671 27 65 7 2014 1602 25 60 cal steroids, calcipotriene ointment, or even observa- 8 888 869 71 123 tion might be considered because of a tendency toward 9 1896 1679 37 43 spontaneous resolution.13 Many systemic treatments, in- 10 2014 1995 24 45 cluding some with potentially severe adverse effects such 11 2804 2093 17 37 as penicillamine, calcitriol, cyclosporine, and interferon 12 1441 1224 44 67 gamma, have been reported, but none of them have be- 13 ...... 2-4 14 ...... come generally accepted. 15 2054 2014 33 40 UV-A irradiation was recently shown to be effective Mean ± SD 1847 ± 545 1432 ± 479 26 ± 15 46 ± 24 even in patients with long-standing LS and therefore has been added to the therapeutic armamentarium.5-8 Ac- cording to our experience, bath psoralen–UV-A is indi- cated for the early inflammatory stage, whereas UV-A1 appears to be more beneficial in the fibrotic stage of LS. with LS. All patients improved with this combination The optimal dose of UV-A1 phototherapy in LS remains therapy. Unfortunately, the authors did not use a clini- unclear, but a low-dose regimen (20-30 J/cm2) seems to cal scoring system or biometrical measurements to con- be sufficient. However, UV-A1 phototherapy usually fails firm the clinical improvement observed. Therefore, com- in rapid, severe courses of disease that involve the sub- parison with other studies might be difficult. cutaneous tissue and muscle, which generally require sys- Because of its favorable profile of safety and toler- temic therapy. ability, methotrexate is the most frequent choice of In the last decade, methotrexate has gained attention disease-modifying antirheumatic therapy for rheuma- as a new approach for sclerotic skin diseases. The benefi- toid arthritis. The moderate and reversible adverse cial effects of methotrexate have been reported in a double- effects observed in our study correspond to the fre- blind, placebo-controlled study14 of 29 patients with sys- quently occurring adverse reactions of low-dose temic sclerosis. Seyger et al10 reported their experience with methotrexate and/or pulsed high-dose corticosteroids 9 patients with widespread morphea treated with 15 mg/wk that have previously been reported in the litera- of methotrexate. All of them responded, resulting in a sig- ture.10,14,17,20 Nevertheless, sudden death after high- nificant decrease of MSS and durometer score. Methotrex- dose intravenous methylprednisolone therapy has ate’s mechanism of action seems to be based on an inhi- rarely been observed in patients with renal insuffi- bition of various cytokines (eg, interleukins 2, 4, 6, and ciency, electrolyte imbalances, or diuretic applica- 8) that were shown to be increased in LS and parallel with tion.21 Therefore, it is recommended that patients with the degree of skin sclerosis.15,16 a history of cardiac and/or renal diseases should be Beneficial effects of oral corticosteroids were re- monitored carefully during therapy. Uncommon but ported by Joly et al9 in a follow-up study that included more severe adverse effects of pulsed high-dose corti- 17 patients with severe LS.9 Although mean duration of costeroid therapy may also include aseptic bone necro- treatment was 18 months (0.5-1 mg/kg of oral predni- sis, osteoporosis, anaphylaxis, and exacerbation of sone per day, followed by a decrease in dose), 6 patients preexisting diseases such as gastric ulcer.22 However, experienced a relapse after discontinuation of therapy. similar to low-dose methotrexate treatment, pulsed Recently, pulsed high-dose corticosteroid therapy has high-dose corticosteroid therapy is characterized by a been considered an effective treatment regimen in dif- markedly favorable risk-benefit ratio in the treatment ferent skin diseases, including pemphigus vulgaris and of otherwise healthy patients.17 pyoderma gangrenosum.17-19 Administering pulsed high- Serologically, assessment of the therapeutic efficacy in dose corticosteroids fully exhibits anti-inflammatory and LS remains a problem. Various immunologic phenoma and immunomodulatory effects without occurrence of well- abnormalities such as antinuclear antibodies, antihistone known adverse effects associated with long-term corti- and anti–single-stranded DNA antibodies, eosinophilia, hy- costeroid treatment.17 To combine the early anti- pergammaglobulinemia, and rheumatoid factor have been inflammatory effects of corticosteroids and the antifibrotic detected in up to 80% of patients with severe generalized action of methotrexate, Uziel et al20 initiated a com- or linear LS, and a correlation with the clinical activity of bined methotrexate (0.3-0.6 mg/kg weekly) and pulsed disease has been hypothesized.23 Elevated levels of IgG and intravenous high-dose methylprednisolone (3 consecu- IgM have been reported in up to 50% of patients with se- tive days monthly for 3 months) therapy in 10 children vere LS. In this context, Falanga et al24 demonstrated higher

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 (REPRINTED WITH CORRECTIONS) levels of IgG in patients with LS and joint contractures. 7. Kerscher M, Volkenandt M, Gruss C, et al. Low-dose UVA1 phototherapy for treat- Sequential studies are necessary to assess the relative use ment of localized scleroderma. J Am Acad Dermatol. 1998;38:21-26. 8. Kreuter A, Gambichler T, Avermaete A, et al. Combined treatment with calcipo- of these markers over time. Serum aminoterminal pro- triol ointment and low-dose ultraviolet A1 phototherapy in childhood morphea. peptide of type III procollagen (PHINP), a marker for type Pediatr Dermatol. 2001;18:241-245. III collagen synthesis, has been recommended for moni- 9. Joly P, Bamberger N, Crickx B, Belaich S. Treatment of severe forms of localized toring the extent of sclerosis in patients with systemic scle- scleroderma with oral corticosteroids: follow-up study on 17 patients. Arch rosis and LS.25 Because no significant change in PIIINP was Dermatol. 1994;130:664-665. 10. Seyger MMB, van der Hoogen FHJ, de Boo T, de Jong EMGJ. Low-dose metho- observed with therapy in 2 recent trials, we refrained from trexate in the treatment of widespread morphea. J Am Acad Dermatol. 1998; 26 determination of PIIINP in our patients. 39:220-225. In conclusion, most patients included in this trial 11. Zachariae H, Bjerring P, Halkier Sorensen L, Heickendorff L, Sondergaard K. showed excellent response to PCMT without any major Skin scoring in systemic sclerosis: a modification—relations to subtypes and adverse effects. Response was sustained in all cases, ex- the aminoterminal propeptide of type III procollagen (PIIINP). Acta Derm Venereol. cept for one, and resulted in a significant decrease of MSS, 1994;74:444-446. 12. Vierra E, Cunningham BB. Morphea and localized scleroderma in children. Se- VAS score, and 20-MHz ultrasonographic measure- min Cutan Med Surg. 1999;18:210-225. ment. Important limitations of trials such as this in- 13. Cunningham BB, Landells ID, Langman C, Sailer DE, Paller AS. Topical calcipotri- clude the small numbers of patients, absence of any se- ene for morphea/linear scleroderma. J Am Acad Dermatol. 1998;39:211-215. rologic disease activity markers, and a study design that 14. Van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de is not double blinded and placebo controlled. Taking our Putte LB. Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomised double-blind trial, followed by a 24 week data into account, patients with widespread lesions of LS, observation trial. Br J Rheumatol. 1996;35:364-372. especially therapy-resistant, severe, and persistent ac- 15. Ihn H, Sato S, Fujimoto M, Kikuchi K, Takehara K. Demonstration of interleukin tive forms, should be selected for PCMT and have to be 8 in serum samples of patients with localized scleroderma. Arch Dermatol. 1994; carefully monitored. Nevertheless, because we assessed 130:1327-1328. only minimal adverse effects, PCMT application in less 16. 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 severe cases might also be considered. Even though pla- scleroderma. Arch Dermatol Res. 1995;287:193-197. cebo-controlled trials are difficult to perform in rare dis- 17. Reinhold U, Buttgereit F. High dosage steroid pulse therapy: is there an indica- eases, further studies are now needed to evaluate the op- tion in dermatology [in German]? Hautarzt. 2000;51:738-745. timal effective dosage and safety of PCMT in severe LS. 18. Prystowsky JH, Kahn SN, Lazarus GS. Present status of pyoderma gangrenosum. Arch Dermatol. 1989;125:57-64. 19. Werth VP. Treatment of pemphigus vulgaris with brief, high-dose intravenous Accepted for Publication: March 10, 2005. glucocorticoids. Arch Dermatol. 1996;132:1435-1439. Correspondence: Alexander Kreuter, MD, Department 20. Uziel Y, Feldman BM, Krafchik BR, Yeung RSM, Laxer RM. Methotrexate and cor- of Dermatology and Allergology, Ruhr-University Bo- ticosteroid therapy for pediatric localized scleroderma. J Pediatr. 2000;136: chum, Gudrunstrasse 56, D-44791 Bochum, Germany 91-95. ([email protected]). 21. Thompson JF, Chalmers DH, Wood RF, Kirkham SR, Morris PJ. Sudden death following high-dose intravenous methylprednisolone. Transplantation. 1983; 36:594-596. REFERENCES 22. Haugeberg G, Griffiths B, Sokoll KB, Emery P. Bone loss in patients treated with pulses of methylprednisolone is not negligible: a short term prospective obser- 1. Peterson LS, Nelson AM, Su WP. Classification of morphea. Mayo Clin Proc. 1995; vational study. Ann Rheum Dis. 2004;63:940-944. 70:1068-1076. 23. Sato S, Fujimoto M, Kikuchi K, Ihn H, Tamaki K, Takehara K. Soluble CD4 and 2. Falanga V, Medsger TA. D-penicillamine in the treatment of localized scleroderma. CD8 in serum from patients with localized scleroderma. Arch Dermatol Res. 1996; Arch Dermatol. 1990;126:609-612. 288:358-362. 3. Dutz J. Treatment options for localized scleroderma. Skin Therapy Lett. 2000;5: 24. Falanga V, Medsger TA Jr, Reichlin M, Rodnan GP. Linear scleroderma: clinical 3-5. spectrum, prognosis, and laboratory abnormalities. Ann Intern Med. 1986; 4. Hunzelmann N, Anders S, Fierlbeck G, Hein R, Hermann K, Albrecht M. Double 104:849-857. blind, placebo-controlled study of intralesional interferon gamma for the treat- 25. Heickendorff L, Zachariae H, Bjerring P, Halkier-Sorensen L, Sondergaard K. ment of localized scleroderma. J Am Acad Dermatol. 1997;36:433-435. The use of serologic markers for collagen synthesis and degradation in sys- 5. Kerscher M, Volkenandt M, Meurer M, et al. Treatment of localised scleroderma temic sclerosis. J Am Acad Dermatol. 1995;32:584-588. with PUVA bath photochemotherapy [letter]. Lancet. 1994;343:1233. 26. Hulshof MM, Bouwes Bavinck JN, Bergman W, et al. Double-blind, placebo- 6. Kerscher M, Dirschka T, Volkenandt M. Treatment of localised scleroderma by controlled study of oral calcitriol for the treatment of localized and systemic UVA1 phototherapy [letter]. Lancet. 1995;346:1166. scleroderma. J Am Acad Dermatol. 2000;43:1017-1023.

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