A long-term follow-up study of methotrexate injuvenile localized scleroderma (morphea)

Francesco Zulian, MD,a Cristina Vallongo, MD,a Annalisa Patrizi, MD,b Anna Belloni-Fortina, MD, PhD,a

Mario Cutrone, MD,c Maria Alessio, MD,d Silvana Martino, MD, PhD,e Valeria Gerloni, MD,f

Fabio Vittadello, MSc, DrPH,a and Giorgia Martini, MD, PhDa

Padua, Bologna, Mestre, Naples, Turin, and Milan, Italy

From

m

U

U

U

ta

Fund

Conf

Background: Recent studies report that methotrexate (MTX) is beneficial in the treatment of juvenilelocalized scleroderma (JLS) but little is known about its long-term effectiveness.

Objective: We assessed the therapeutic role of MTX in children with JLS who were followed up for aprolonged period.

Methods: A cohort of patients with JLS, previously enrolled in a double-blind, randomized controlled trialand treated with oral MTX (15 mg/m2/wk) and prednisone (1 mg/kg/d, maximum 50 mg) for the first 3months, were prospectively followed up. Lesions were evaluated clinically, with infrared thermography,and by a computerized skin score. Response to treatment was defined as: (1) no new lesions; (2) skin scorerate less than 1; and (3) decrease in lesion temperature by at least 10% compared with baseline. Clinicalremission (CR) on medication was defined when response was maintained, on treatment, for at least 6months, and complete CR when response was maintained, without treatment, for at least 6 months.

Results: Of 65 patients treated with MTX, 48 (73.8%) were responders, 10 (15.4%) relapsed by 24 monthssince MTX start, and 7 (10.8%) were lost to follow-up. Among the responders, 35 (72.9%) maintained CR fora mean of 25 months and 13 (27.1%) were in CR on medication. Adverse effects seen in 28 patients (48.3%)were generally mild and never required treatment discontinuation.

Limitations: The use of objective measures not widely available, such as infrared thermography andcomputerized skin score, makes it difficult to compare data from previous studies.

Conclusions: Long-term MTX therapy is beneficial and well tolerated for JLS. ( J Am Acad Dermatol2012;67:1151-6.)

Key words: localized scleroderma; methotrexate; morphea; outcome; prednisone; safety; thermography.

Several uncontrolled studies1-6 have reportedbenefit from methotrexate (MTX), with orwithout systemic corticosteroids, in the treat-

ment of juvenile localized scleroderma (JLS)(morphea).

In a recent double-blind, placebo-controlledstudy in which oral MTX (15 mg/m2/wk) and pred-nisone (1 mg/kg/d, maximum 50 mg) for the first 3months was compared to treatment with oral

the Department of Pediatrics, University of Paduaa; Depart-

ent of Dermatology, University of Bolognab; Dermatology

nit, Children Hospital of Mestrec; Department of Pediatrics,

niversity Federico II of Naplesd; Department of Pediatrics,

niversity of Turine; and Department of Rheumatology, Hospi-

l G. Pini, Milan.f

ing sources: None.

licts of interest: None declared.

prednisone alone, we found a response in 67.4% oftheMTX-treated patients comparedwith 29.2% in thecontrol group (P \ .005).7 During the 12-monthstudy period, new scleroderma lesions appeared in6.5% of the patients on MTX compared with 16.7% ofthose treated with prednisone alone.

The purpose of this open-label extension studywas to assess the long-term benefit of MTX in thesame cohort of patients with JLS.

Accepted for publication March 8, 2012.

Reprint requests: Francesco Zulian, MD, Department of Pediatrics,

University of Padua, Via Giustiniani 3, 35128 Padua, Italy. E-mail:

zulian@pediatria.unipd.it.

Published online June 1, 2012.

0190-9622/$36.00

� 2012 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2012.03.036

1151

J AM ACAD DERMATOL

DECEMBER 20121152 Zulian et al

METHODSThe cohort consisted of patients who were ran-

domized to the MTX arm in the blinded phase of thedouble-blind, randomized controlled trial7 and thoseinitially randomized to the placebo arm who weretreated with MTX in the open extension phase (Fig1). The follow-up period lasted from June 2006

CAPSULE SUMMARY

d Little is known about the long-termtherapeutic role and tolerability ofmethotrexate in juvenile localizedscleroderma (morphea).

d This prospective study shows that oralmethotrexate therapy, with prednisoneadministered concurrently during thefirst 3 months, is an effective treatmentfor juvenile localized scleroderma withonly minor side effects.

d Methotrexate should be used early injuvenile localized scleroderma, especiallyin linear, generalized, pansclerotic, andmixed subtypes.

through December 2010.All patientsmet the follow-

ing inclusion criteria: diagno-sis of JLS (linear, generalized,and mixed subtypes)8; dis-ease in the activephase; onsetbefore 16 years of age; andabsence of immunosuppres-sive treatment during the 6months before enrollment.Active disease was definedby the appearance of newlesions or increased size ofpre-existing lesions, withsigns of active inflammationsuch as erythema and/or pos-itive thermography.

Patients with active JLSwere treated with a singleweekly dose of oral MTX at

15 mg/m2 (maximum 20 mg/wk). Once remissionwas achieved, MTX treatment was maintained for atleast 12 months and then gradually stopped. Folicacid supplementation (2.5 mg/wk, 48 hours afterMTX) was administered to each patient. Oral pred-nisone (1 mg/kg/d, maximum 50 mg/d), as a singlemorning dose for 3 months and then graduallytapered over 1 month, was added initially as bridgingtreatment.

Clinical assessment, performed at least every 3months, included evaluation of the shape and size ofthe scleroderma skin lesions and documentation ofnew lesions. The degree of inflammation wasassessed by infrared thermography, according to astandardized procedure.9 A lesion was consideredpositive to thermography (active lesion) when asubstantial area more than 0.58C warmer than thematching opposite limb or body area site was visible.When comparing serial evaluations of the samelesion, we considered the percentage thermalchange from the baseline value (DTh%) accordingto the formula (tn e t0/t0) 3 100, where tn is thetemperature value at the time of evaluation and t0 isthe value at baseline. A negative DTh% value indi-cated improvement, and a positive DTh% valuemeant an increase in inflammation of the targetlesion. A single lesion judged as active by both

clinical evaluation and thermography was selectedas a ‘‘target’’ and its size was measured by thecomputerized skin score (CSS) system.10

To analyze progression or regression of the skinlesions we used the ratio between the area of thelesion and the body surface area, expressed as apercentage (standardized CSS). The values obtained

at baseline (t0) and at thefollowing visits (tn) allowedus to calculate the skin scorerate (SSR), ie, the ratio tn stan-dardized CSS/t0 standardizedCSS. SSR less than 1 indicatedregression of the lesion, andSSR greater than 1 indicatedan increase in size.

Responders were definedas those patients who satis-fied all the following 3 crite-ria: SSR less than 1; a decreasein DTh% value of at least 10%with respect to baseline; andabsence of new lesions.

Disease flare was definedas when at least 1 of thefollowing 3 conditions waspresent: SSR greater than 1;

less than 10% improvement or positive DTh% value;and appearance of new lesions.

Clinical remission (CR) was defined as mainte-nance of responder status after stopping treatmentfor at least 6 months.

CR on medication (CRM) was defined as mainte-nance of responder status while maintained on MTXtreatment for at least 6 months.

Potential predictors of good outcome assessedwere sex, age, disease duration, JLS subtype antinu-clear antibodies, and rheumatoid factor.

Statistical analysisQuantitative variables were expressed as the

mean and SD, and qualitative variables as numbersand percentages. The MTX responder groups werecompared with respect to baseline demographic,clinical, and disease characteristics using the Studentt test, x2 test, and Fisher exact test, whereappropriate.

Kaplan-Meier survival curves were used to esti-mate the proportion of patients in CR or CRM duringthe follow-up period. Data were analyzed withstatistical software (SPSS, Version 14.0, SPSS Inc,Chicago, IL). A P value of .05 or less was consideredsignificant.

Abbreviations used:

CR: clinical remissionCRM: clinical remission on medicationCSS: computerized skin scoreJLS: juvenile localized sclerodermaMTX: methotrexateSSR: skin score ratet0: value obtained at baselinetn: value obtained at following visitsDTh%: percentage thermal change from baseline

value

J AM ACAD DERMATOL

VOLUME 67, NUMBER 6Zulian et al 1153

RESULTSA total of 65 patients treated with MTX during the

open-label phase of the original double-blind studyentered the follow-up study. In all, 58 patients(89.2%) were followed up for a mean of 40.3 months(range 3-72), and 7 (10.8%) were lost to follow-up.Table I summarizes the demographic and clinicalcharacteristics of the patients with information onoutcome.

The cohort of 65 patients was composed of 31patients who, in the previous study, were respondersafter 12 months’ follow-up, 15 patients who relapsedon MTX but responded to a brief course of oralprednisone (1 mg/kg/d for 2 months then taperedand discontinued over 1 month) in the open-labelphase, 17 patients in the placebo arm who relapsedduring the first 12 months of treatment, and 2patients in the placebo arm who were respondersat 12 months but who relapsed at 18 and 36 months,respectively (Fig 1). The majority of patients werefemale (72.4%) with a mean age of 9.4 years atdisease onset and disease duration of 2.4 years atinitiation of MTX therapy.

The JLS subtype was linear scleroderma in 37patients (63.8%), generalized morphea in 13 (22.4%),and mixed subtype (linear/circumscribed morphea)in 8 (13.8%). In all, 26 patients (44.8%) had positiveantinuclear autoantibodies whereas rheumatoid fac-tor was positive only in 2 (3.4%) at low titers (55 and89 IU/L, respectively).

At the last follow-up visit, 48 patients (82.8%)were responders and 10 (17.2%) relapsed within 24months of initiation of MTX therapy (Fig 1). Theresponders were evaluated every 3 to 4 months for amean of 43 months (median 48; range 6-72).

Fig 2 summarizes the overall response to MTXtreatment according to the length of follow-up. Mostpatients who relapsed did so in the first 12 months oftreatment. Only 1 of 39 patients in CRM at 24 monthsrelapsed later. Of patients, 50% remained in CR for aslong as 5 years.

Among the 48 responders, 35 (72.9%), who re-ceived a mean of 27.5 months of MTX treatment

(median 24, range 18-30), remained in CR for 25.6 ormore months (median 24, range 6-48) after stoppingtreatment. The remaining 13 patients (27.1%), after amean follow-up of 20.5 months (median 15.5, range6-45), were still on MTX treatment (CRM). In 5 of 13patients, the disease relapsed soon after gradualtapering of MTX was tried after 12 months of clinicalresponse, and MTX was restarted. The other 8patients in the CRM group had not yet reached theminimum follow-up period of 12 months.

In Fig 3, the Kaplan-Meier survival curve showsthe remission probability of the group of patients onMTX treatment (CRM) and of those in CR. After 12months of treatment the remission probability is verysimilar in the 2 groups, being 100% in the CR groupand 85% in the CRM group. At 24 and 36 months, thisprobability remains high in the CR group whereas itdecreases to 55% and 41%, respectively, in the CRMgroup. This means that a good response to treatmentby 24 months indicates a high probability ofsustained long-term remission. Conversely, aremitting-relapsing course during the first 2 years ishighly predictive of treatment failure.

Ten patients were MTX refractory: 4 had a linearJLS subtype (2 limb, 2 face), 4 had amixed subtype (2linear-circumscribed, 2 linear-pansclerotic), and 2had generalized morphea. The clinical characteris-tics of this group of patients were not significantlydifferent from the responders, except for a longerlength of follow-up in the responders (Table I).

MTX-related side effects, observed in 28 patients(48.3%), were generally mild and did not requiretreatment discontinuation (Table I). The most fre-quent symptom was nausea, reported in 25% ofpatients. Seven patients (12.1%) had headache and 3had transitory elevation of serum liver transaminasesthat never exceeded 3-fold the upper normal level.Symptoms receded or the enzyme levels normalizedwith either an extra weekly dose of folic acid or byreducing the MTX dose to 10 mg/m2/wk. Transitoryhair loss and fatigue were reported in 2 patients,respectively, but did not require a treatment change.

DISCUSSIONThis prospective study provides evidence that

long-term MTX maintenance therapy halts diseaseprogression and improves the clinical manifestationsof many patients with JLS (morphea).

Of patients, 74% experienced a prolonged clinicalimprovement that, in more than 50%, persisted longafter MTX was discontinued. The prospective natureof the study allowed us to determine the rate ofcomplete CR after MTX discontinuation (53.8%), therate of CRM (20%), and rate of treatment failure(15.4%). MTX efficacy in previous studies ranged

Fig 1. Methotrexate (MTX) in juvenile localized scleroderma (JLS). Disposition of patients withJLS enrolled in study. Cohort of 65 patients who entered open-label phase was composed of 31patients who, in previous double-blind study,7 were responders at 12 months’ follow-up; 15patients on MTX who partially relapsed but responded to brief course of oral prednisone; and19 patients who relapsed on placebo and started MTX in open-label fashion. Diagram reflectsall available information through December 28, 2010.

J AM ACAD DERMATOL

DECEMBER 20121154 Zulian et al

between 71% and 90%2-5 and this has been con-firmed also in adult patients, where it ranged be-tween 67% and 86.7%.11,12 Complete CR was definedin only 1 study and was reported in just 26.5% of thepatients.4 In that study, the rate of relapse was 43.7%,which is higher than in others (37.5% and 28%)5,13

and more than 3 times the rate we observed (12.5%).The difference may be related to the longer diseaseduration at initiation of treatment4 and to the diverseand/or less homogeneous treatment protocols4,5,13

as compared with ours.Duration of MTX treatment proved to be another

important predictor of disease relapse.We found that

relapsers tended to have had a shorter MTX coursethan nonrelapsers, suggesting that longer treatmentduration may help reduce the occurrence of relapse.In our study, MTX treatment was maintained for amean of 27.5 months before considering discontin-uation. In previous pediatric studies, MTX was con-tinued for less than 24 months4,5 and a relapse rate of28.6% was reported in a cohort of adult patientstreated for just 15 months.12

A longerMTXcoursemayalso reduce the incidenceof disease flare after MTX tapering. We noted a 12.5%relapse rate in the small group of patients treated forless than 24 months and no relapse for those treated

Table I. Methotrexate in juvenile localized scleroderma: patient demographics and disease characteristicsaccording to methotrexate response

Overall

(n = 58)

Methotrexate responders

(n = 48)

Methotrexate refractory

(n = 10) Significance P

Female gender 42 (72.4%) 35 (72.9%) 7 (70.0%) n.s.Age, y 9.4 (4.6) 9.2 (4.7) 10.1 (4.5) n.s.Age at disease onset, y 6.9 (3.7) 6.7 (3.8) 7.8 (3.4) n.s.Disease duration, y 2.4 (2.4) 2.5 (2.3) 2.2 (2.6) n.s.Juvenile localized scleroderma subtypeLinear 37 (63.8%) 28 (58.3%) 6 (60.0%) n.s.Generalized 13 (27.1%) 11 (22.9%) 2 (20.0%) n.s.Mixed 8 (13.8%) 6 (12.5%) 2 (20.0%) n.s.

Follow-up duration, moMean 40.3 43.0 11.1 \.01Median 30 48 12 \.01Range 3-72 12-72 3-24

AutoantibodiesRheumatoid factor 2 (3.4%) 2 (4.2%) 0 (0.0%) n.s.Antinuclear antibodies 26 (44.8%) 21 (43.8%) 5 (50.0%) n.s.

Methotrexate-related side effects 28 (48.3%) 23 (47.9%) 5 (50.0%) n.s.Alopecia 2 (3.4%) 2 (4.2%) 0 (0.0%) n.s.Nausea 14 (24.1%) 11 (22.9%) 3 (30.0%) n.s.Headache 7 (12.1%) 5 (10.4%) 2 (20.0%) n.s.Fatigue 2 (3.4%) 1 (2.1%) 1 (10.0%) n.s.Hepatotoxicity 3 (5.2%) 2 (4.2%) 1 (10.0%) n.s.

Data are number (%) or mean (SD) unless otherwise indicated.

n.s., Not significant.

Fig 2. Methotrexate (MTX ) in juvenile localized sclero-derma. Response to MTX treatment during long-termfollow-up period. CR, Clinical remission; CRM, clinicalremission on medication. Fig 3. Kaplan-Meier survival curve showing remission

probability of patients with juvenile localized sclerodermaon methotrexate treatment (clinical remission on medica-tion [CRM]) and of those in complete clinical remissionwithout any treatment (CR). After 12 months of treatment,remission probability is similar in 2 groups, being 100% inCR group and 85% in CRM group. At 24 and 36 months,probability remains still high in CR group whereas itdecreases to 55% and 41%, respectively, in CRM group.

J AM ACAD DERMATOL

VOLUME 67, NUMBER 6Zulian et al 1155

for longer. Similar findings have been reported byChristen-Zaech et al6 but not by other authors.13

We were unable to identify early predictors oftreatment response and other studies have reportedcontradictory results. In 1 study, the linear limbsubtype and older age at disease onset were foundto be related to a high relapse rate.13 On the contrary,other authors showed that a younger age at diseaseonset and longer follow-up were the main negativepredictors.4 The retrospective nature of these studiesmay explain, at least in part, these discrepancies.

MTX was generally well tolerated. There weremild adverse events in almost 50% of the patients butthey did not require treatment discontinuation. Our

J AM ACAD DERMATOL

DECEMBER 20121156 Zulian et al

study confirms the existing data from the literaturereporting mild adverse events in 30% to 76% ofpediatric patients2-5 and in 43% to 53% of adults.11,12

The innovative aspect of this study is the applica-tion of well-defined criteria to judge the response totreatment and CR. The introduction of restrictive andobjective criteria may explain the discrepancy be-tween our and other results where response totreatment was based on clinical assessment,2,4-6,13

telephone questionnaire,3 and semiquantitative ther-mography evaluation.4

This study is subject to some limitations. Objectivemeasures such as infrared thermography and CSS arenot widely available, and this makes it difficult tocompare data. The introduction to clinical practice ofvalidated clinical measures, such as the LocalizedScleroderma Severity Index and the modified sys-temic sclerosis score,14,15 and a wider use of moreobjective methods for measuring outcome, such asthermography and CSS, may help improve diseaseassessment and allow treatment comparison in thefuture.

In conclusion, long-term maintenance MTX treat-ment is beneficial for localized scleroderma (mor-phea) in young patients and is generally welltolerated with rare occurrence of significant adverseevents. We recommend an initial 3 months of com-bined MTX-corticosteroid therapy and MTX treat-ment duration of at least 24 months to ensure aprolonged and sustained disease remission for themajority of patients.

We thank C. Borgna from Ferrara, R. Barcellona fromPalermo, L. Breda from Chieti, A. Stabile and M. Paradisifrom Rome, F. Falcini from Florence, F. La Torre from Bari,and R. Podda from Cagliari (Italy) for having enrolledpatients at the current study.

REFERENCES

1. Zulian F, Athreya BH, Laxer RM, Nelson AM, de Oliveira SKF,

Punaro MG, et al. Juvenile localized scleroderma: clinical and

epidemiological features in 750 children; an international

study. Rheumatology (Oxford) 2006;45:614-20.

2. Uziel Y, Feldman B, Krafchik B, Yeung R, Laxer RL. Methotrex-

ate and corticosteroid therapy for pediatric localized sclero-

derma. J Pediatr 2000;136:91-5.

3. Fitch P, Rettig P, Burnham J, Finkel T, Yan A, Akin E, et al.

Treatment of pediatric localized scleroderma with methotrex-

ate. J Rheumatol 2006;33:609-14.

4. Weibel L, Sampaio M, Visentin MT, Howell K, Woo P, Harper J.

Evaluation of methotrexate and corticosteroids for the treat-

ment of localized scleroderma (morphea) in children. Br J

Dermatol 2006;155:1013-20.

5. Cox D, O’Regan G, Collins S, Byrne A, Irvine A, Watson R.

Juvenile localized scleroderma: a retrospective review of

response to systemic treatment. Ir J Med Sci 2008;177:343-6.

6. Christen-Zaech S, Hakim MD, Afsar FS, Paller AS. Pediatric

morphea (localized scleroderma): review of 136 patients. J Am

Acad Dermatol 2008;59:385-96.

7. Zulian F, Martini G, Vallongo C, Vittadello F, Falcini F, Patrizi A,

et al. Methotrexate in juvenile localized scleroderma: a ran-

domized, double-blind, placebo-controlled trial. Arthritis

Rheum 2011;63:1998-2006.

8. Laxer R, Zulian F. Localized scleroderma. Curr Opin Rheumatol

2006;18:606-13.

9. Martini G, Murray KJ, Howell KJ, Harper J, Atherton D, Woo P,

et al. Juvenile-onset localized scleroderma activity detection

by infrared thermography. Rheumatology (Oxford) 2002;41:

1178-82.

10. Zulian F, Meneghesso D, Grisan E, Vittadello F, Belloni Fortina

A, Pigozzi B, et al. A new computerized method for the

assessment of skin lesions in localized scleroderma. Rheuma-

tology (Oxford) 2007;46:856-60.

11. Kreuter A, Gambichler T, Breuckmann F, Rotterdam S, Freitag

M, Stuecker M, et al. Pulsed high-dose corticosteroids com-

bined with low-dose methotrexate in severe localized sclero-

derma. Arch Dermatol 2005;141:847-52.

12. Kroft EBM, Creemers MCW, van den Hoogen FHJ, Boezeman

JBM, de Jong EMGJ. Effectiveness, side-effects and period of

remission after treatment with methotrexate in localized

scleroderma related sclerotic skin diseases: an inception

cohort study. Br J Dermatol 2009;160:1075-82.

13. Mirsky L, Chakkittakandiyil A, Laxer RM, O’Brien C, Pope E.

Relapse after systemic treatment in pediatric morphea. Br J

Dermatol 2012;166:443-5.

14. Arkachaisri T, Pino S. Localized scleroderma severity index and

global assessments: a pilot study of outcome instruments.

J Rheumatol 2008;35:650-7.

15. Zachariae H, Bjerring P, Halkier Sorensen L, Heickendorff L,

Sondergaard K. Skin scoring in systemic sclerosis: a modifica-

tionerelations to subtypes and the aminoterminal propeptide

of type III procollagen (PIIINP). Acta Derm Venereol 1994;74:

444-6.