Pediatric Dermatology Vol. 25 No.

2 184–188, 2008

Systemic Methotrexate Treatment in Childhood

Psoriasis: Further Experience in 24 Children
from India
Inderjeet Kaur, M.D., Sunil Dogra, M.D., D.N.B., Dipankar De, M.D.,
and Amrinder Jit Kanwar, M.D.
Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and
Research, Chandigarh, India

Abstract: Well-designed studies on systemic therapeutic modalities for

severe psoriasis in children are rare. Children with severe disease are treated
with the support of data extrapolated from that in adult, although manage-
ment in them differs from adults in several important aspects. Like other
systemic modalities, data regarding the use of methotrexate in the treatment
of childhood psoriasis is meager. This study aims to analyze the efficacy and
safety of methotrexate in severe or disabling childhood psoriasis. The
records of all the patients <18 years of age treated with systemic metho-
trexate at the psoriasis clinic of our institute from January 1993 to December
2006 were retrieved. Information regarding demographic profile, disease
characteristics, response to treatment, side effects, etc. was noted from
predesigned clinic proforma. Indications of methotrexate use were baseline
psoriasis area and severity index (PASI) >10, disease refractory to conven-
tional therapies and disabling psoriasis even though the psoriasis area and
severity index was <10. Clinical status of patients was assessed at weekly
intervals for the first 2 weeks, fortnightly during next month and then
monthly. Response to therapy was graded as good (50–75% decrease in
PASI) and excellent (>75% decrease in PASI). Laboratory investigations to
detect methotrexate induced toxicity were performed at regular intervals. Of
the 29 patients treated with methotrexate, 24 were eligible for the final
data analysis. Indication for the institution of methotrexate therapy was
severe disease, viz., extensive recalcitrant plaque type psoriasis in 17
patients, erythroderma and generalized pustular psoriasis of von-
Zumbusch type in three patients each and severe disabling palmo-plantar
involvement along with chronic plaque lesions in one patient. Response to
therapy was excellent (>75% decrease in PASI) in all but two patients. The
mean time to control the disease, i.e., 50% reduction in PASI was 5.1 weeks.
Mean total cumulative dose of methotrexate in the first episode was 215 mg.
The duration of remission could be calculated in nine patients only, varying

Address correspondence to Dr. Inderjeet Kaur, Department of

Dermatology, Venereology and Leprology, Postgraduate Institute
of Medical Education and Research, Chandigarh-160012, India, or
e-mail: sundogra@hotmail.com.

DOI: 10.1111/j.1525-1470.2008.00629.x

184  2008 The Authors. Journal compilation  2008 Blackwell Publishing, Inc.
 Kaur et al: Systemic Methotrexate in Childhood Psoriasis 185

from 1.5 months to 3 years. Side effects were mild, observed in nine chil-
dren, which included nausea, vomiting, and loss of appetite. Methotrexate is
an effective, cheap, easily available, and reasonably safe drug to be used in
severe childhood psoriasis under an expert supervision and laboratory
monitoring.

Psoriasis is a chronic disease of variable severity that Indications of institution of MTX were baseline PASI
affects 1% to 2% of the general population and con- >10, disease refractory to conventional therapies and
tributes about 4% of the childhood dermatoses. disabling psoriasis even though the PASI was <10.
Although all the clinical types of psoriasis occur in chil- Methotrexate was administered as once weekly oral dose
dren, the severe forms like pustular or erythrodermic of 0.2–0.4 mg ⁄ kg. Folic acid supplementation to ame-
psoriasis are rare. On the contrary, guttate and flexural liorate MTX-associated side effects and toxicities was
psoriasis occur commonly (1,2). given in a dose of 5 mg ⁄ day on three consecutive days in
Although majority of the childhood psoriasis cases a week, the middle day falling on the day of MTX con-
can be managed with various topical therapies, a pro- sumption. Treatment was continued till 75% decline in
portion of patients need systemic treatment at some point PASI compared with baseline score was obtained.
for severe disease during the disease course. Well- Thereafter, the dose was decreased at the rate of
designed studies on systemic therapeutic modalities for 2.5 mg ⁄ week, wherever applicable and then stopped. A
psoriasis in pediatric age group are meager and children record of number of episodes requiring MTX therapy
are treated with the support of data extrapolated from culminating into total cumulative dose of MTX and
that in adults (2). Various systemic treatment options disease free interval between each episode of MTX was
tried for psoriasis in children include narrow band taken. Control of disease was defined as 50% or more
ultraviolet B, acitretin, methotrexate (MTX), cyclo- decrease in PASI. Response to therapy was graded as
sporine (CYA), and biological agents (tumor necrosis good (50–75% decrease in PASI) and excellent (>75%
factor antagonist) (2–4). However, systemic toxicity and decrease). Relapse of disease was defined as increase in
long-term safety of these agents are the serious concerns PASI by 50% compared with that at the time of stopping
in children. MTX.
Like other systemic modalities, data regarding the use Methotrexate was started preferably on inpatient
of MTX in the treatment of childhood psoriasis is scarce. basis. Patients were called for follow-up weekly for the
In children, this drug is administered routinely in various first 2 weeks, fortnightly for next month and then
conditions like in autoimmune disorders, leukemias, monthly. Side effects, if any, related to MTX use were
lymphomas, histiocytosis, and few other malignancies. enquired about and noted. Complete blood cell counts
We report herein, our experience of efficacy and safety of were advised before each follow-up visit. Liver function
MTX in 24 patients of childhood psoriasis. tests were repeated once every 2 months and renal
function tests once every 3 months.
PATIENTS AND METHODS
RESULTS
We retrospectively analyzed the records of all the pa-
tients <18 years of age treated with systemic MTX at Demographics and disease parameters and particulars
psoriasis clinic of our institute from January 1993 to regarding MTX therapy are depicted in Table 1. Of the
December 2006. Apart from demographic characteris- total 395 patients treated with MTX at our psoriasis
tics, other relevant data including duration of disease clinic over this period, 29 were below 18 years of age.
before starting MTX, clinical type of psoriasis, body Five patients were excluded from the study as the follow-
surface area involvement, psoriasis area and severity up was inadequate. Of the 24 remaining patients, 20 were
index (PASI) and response to treatment were noted. boys and four were girls. Mean age of patients at the
Laboratory investigations including complete blood commencement of MTX therapy was 11.3 years, rang-
counts, liver and renal function tests, chest radiograph, ing from 2.5 to 14 years. Duration of disease before
serological tests for HIV and hepatitis B were carried starting MTX varied form 1 month to 4 years with mean
out, as a routine in every patient before initiating MTX. of 10 months. Body surface area (BSA) involvement
Patients with liver disease, active infections or any other ranged from 25% to 100% (mean 60%). Initial PASI
known contraindication for MTX were not prescribed ranged from 8.6 to 31.2 (mean 18.4). Most common
this treatment (3). indication for institution of MTX therapy was extensive
186 Pediatric Dermatology Vol. 25 No. 2 March ⁄ April 2008

TABLE 1. Demographics, Disease Parameters, and Particulars DISCUSSION

Regarding Methotrexate Therapy
Methotrexate is an antimetabolite agent, a synthetic
Total patients (n) 24 analogue of folate, used in the treatment of various
Age (yrs) 11.3 (2.5–14)
Sex malignancies and autoimmune diseases. It is a compet-
Male 20 itive inhibitor of the enzyme di-hydro folate reductase
Female 4 responsible for the conversion of folic acid to reduced
Duration of disease before 10 mos (1 mo–4 yrs)
starting MTX folate cofactors, i.e., tetrahydrofolate which are required
Clinical type of psoriasis for metabolic transfer of 1-carbon units as in DNA
Plaque 17 synthesis. Inhibition of thymydilate synthesis is the most
Erythroderma 3
Generalized pustular psoriasis 3 important effect exerted by MTX which results in DNA
Chronic plaque psoriasis with 1 synthesis, thus inhibiting replication and function of
disabling palmo-plantar T and B lymphocytes. Similarly, it inhibits epidermal
involvement
Body surface area involvement (%) 60 (25–100) hyperproliferation. However, proliferating macrophag-
PASI 18.4 (8.6–31.2) es and T-cells in vitro are 100-fold more sensitive to the
Response to therapy cytotoxic effects of MTX than keratinocytes. Recent
Excellent 75–100% decrease
in PASI investigations have suggested that MTX possesses both
Good 50–75% decrease immunomodulatory and profound antiinflammatory
in PASI properties. There is accumulating evidence that these
Time to clearance (wks) 5.1 (3–10)
Total duration of MTX 4.97 (2–16) effects are mediated through the release of adenosine at
therapy (mos) the sites of inflammation by fibroblasts and endothelial
Total cumulative dose of 215 (65–675) cells (5). Suppression of epidermal proliferation and
MTX use (mg)
Side effects 9 (nausea, vomiting, inflammatory cell chemotaxis, inhibition of mono-
and loss of appetite) cyte ⁄ macrophage activation, and inhibition of hista-
Values are expressed as mean (range) or n (%). mine release from basophils are other potential
MTX, methotrexate; PASI, psoriasis area and severity index. mechanisms of MTX activity in skin diseases including
psoriasis (6).
recalcitrant plaque type psoriasis in 17 patients. Other Limited treatment options and compliance to therapy
indications included erythroderma and generalized pus- are constrains to psoriasis management in pediatric age
tular psoriasis of von-Zumbusch type in three patients group. The side effect profile of MTX is not favorable for
each and severe disabling palmo-plantar involvement its use in children as an antipsoriatic agent except in select
along with chronic plaque lesions in one patient. situations such as generalized pustular psoriasis, psori-
Response to therapy was excellent (>75% decrease in atic erythroderma, psoriatic arthropathy, or recalcitrant
PASI) in all the patients except in two who exhibited 50– severe plaque type psoriasis, as in adults. Since late 1950s,
75% decline in PASI score (good response). The mean MTX is the gold standard therapy in psoriasis and in era
time to the control of disease, i.e., 50% reduction in PASI of biological treatments, it continues to be an agent with
was 5.1 weeks in an average, ranging from 3 to 10 weeks. which other systemic psoriasis medications are com-
Maximum dose of MTX use per week ranged from 7.5 to pared. However, there are no guidelines or consensus on
20 mg. The mean duration of MTX use was 4.97 months the use of systemic therapies in childhood psoriasis and
(range 2–16 months). Total cumulative dose of MTX in are used mostly empirically. The major limitation of oral
the first episode was noted to be 65 to 675 mg with mean retinoids (acitretin) in children is the risk of growth
of 215 mg. Follow-up periods calculated from the first retardation because of premature closure of epiphyses on
visit varied from 2 months to 3.5 years. The duration of long-term use (2). The drawback of CYA is its cost and
remission of disease could be calculated in nine patients renal toxicity. Although there are reports of favorable
only. This period varied from 1.5 months to 3 years. response with CYA in childhood psoriasis, Mahe et al
However, in all, relapses were not severe enough to (7) reported four cases, in none of whom it was found to
warrant repeat courses of MTX and could be managed be effective. CYA is generally effective in doses of 2.5–
with topical therapies. 5 mg ⁄ kg ⁄ day in adults. Pharmacokinetics of CYA
Side effects such as nausea, vomiting, and loss of including intestinal absorption, distribution in body flu-
appetite were observed in 9 (37.5%) children. These ids and tissues, metabolism and elimination is different in
complaints were mild and well controlled with the use of children, thus requiring higher doses for similar thera-
antiemetics. No significant alteration in the laboratory peutic effects with potential risk of dose-dependent tox-
parameters was detected in any of the patients. icity (8). Experience regarding use of hydroxyurea as
 Kaur et al: Systemic Methotrexate in Childhood Psoriasis 187

systemic agent in the treatment of childhood psoriasis is monitoring hepatotoxicity, while there is no longer a
limited (9). Psoralen + ultraviolet A (PUVA) therapy is significant role for routine recording of cumulative MTX
contraindicated in children, although if needed may be dose (16). However, need for more specific noninvasive
used in adolescents. Narrow band ultraviolet B is better markers remains, particularly in those patients who have
choice among phototherapeutic modalities, although it is raised PIII NP levels but do not have hepatic fibrosis. The
associated with problems like school absenteeism in direct markers of hepatic fibrosis in addition to PIIINP
children and loss of work for parents because of frequent include procollagen 1, type 4 collagen, laminin, hya-
visits to the phototherapy unit. Etanercept, a TNF-a luronic acid, tissue metalloproteinases and their inhibi-
antagonist is a recently introduced treatment modality tors (15). Sensitivity and specificity, however, vary
for psoriasis, but experience of its use in childhood pso- depending on the cause of fibrosis.
riasis is limited (4). In none of our patients, MTX was discontinued
The tolerability and efficacy of MTX in the treat- because of intolerable side effects. In a recent systematic
ment of childhood psoriasis is not yet established. The review by Dadlani and Orlow (17), it was observed that
available evidence in this age group comes largely from when MTX used in children in rheumatologic and
a few studies involving small number of patients. In a dermatologic dosing levels, the major side effects noted
previous report from our centre, Kumar et al (10) used were elevated liver enzymes, stomatitis, nausea, and
MTX successfully in seven children (3–16 years of age) vomiting. These side effects generally responded to
having severe disease without any significant side temporary cessation of MTX, decreasing the dose or
effects or biochemical and hematological alterations. were otherwise treatable. Overall review showed little or
Kumar et al (10) has used MTX successfully in a child no side effect on pulmonary, cardiac, renal, develop-
as young as 3.5 years and Dogra et al (11), in a 2-year- mental, and dermatologic systems. Lahdenne et al (18)
old child with generalized pustular psoriasis (not in- recently evaluated hepatotoxicity caused by high-dose
cluded in this series). Our experience with MTX use in MTX (20–30 mg ⁄ m2) given for long term (>2.4 years)
children with severe psoriasis is encouraging as the in juvenile idiopathic arthritis (JIA). The authors con-
results of our study indicate. Response to therapy was cluded that aggressive medical treatment of JIA by
excellent in 22 patients, with mean time to achieve 50% MTX along with concomitant disease modifying anti-
decrease in PASI being 5.1 weeks. In all patients except rheumatic drugs and corticosteroids may contribute to
one, MTX could be discontinued in a mean period of minimize the liver abnormalities that seem to be
4.97 months. reversible. In the light of these studies and our obser-
The long-term use of MTX with attendant risk of liver vation, MTX appears to be a well-tolerated drug in
fibrosis is the main concern while using it in children with children as used in dermatologic and rheumatologic
a chronic disease like psoriasis. However, the natural doses. Meticulous use of MTX may avert the long-term
course of psoriasis and the pharmacokinetics of MTX or serious side effects.
may prove to be reprieve to it. As psoriasis in general is Our study had some limitations such as small sample
more severe in winters, MTX can be used and tapered to size and short follow-up. However, we can conclude that
complete withdrawal when disease is controlled with MTX is a cheap, easily available, reasonably safe drug
seasonal change and manageable with topical medica- having convenient once weekly dose to be used in severe
tions. Methotrexate has been detected in liver for up to childhood psoriasis with success in resource-poor
116 days after the last dose (12). Thus intermittent drug settings and will continue to be a paradigm in the
free intervals can allow the liver to recover from drug approaching exciting new era of biologic treatment
induced toxicities. The fibrotic changes observed in the options. Considering the long-term safety concerns
liver after MTX use is potentially reversible. It has been in children, use of systemic agents such as MTX and
considered that even histological grade 4 liver fibrosis acitretin should be undertaken only by experienced
may return towards normal if MTX is avoided for 6 to dermatologists with adequate facilities for monitoring.
preferably 12 months (13). Advances in the noninvasive
assessment of liver fibrogenesis may eventually further
REFERENCES
reduce the need for liver biopsy to detect extent of MTX
induced liver fibrosis (14). Indirect markers of liver 1. Nyfors A, Lemholt K. Psoriasis in children. A short review
fibrosis such as a2-macroglobulin, a2-globulin, c-globu- and a survey of 245 cases. Br J Dermatol 1975;92:437–442.
2. Burden AD. Management of psoriasis in childhood. Clin
lin, apolipoprotein A1, c-glutamyl transferase, and total Exp Dermatol 1999;24:341–345.
bilirubin has been investigated in other diseases, partic- 3. Roenigk HH Jr., Auerbach R, Maibach H et al. Metho-
ularly hepatitis C infection (15). Recent studies highlight trexate in psoriasis: consensus conference. J Am Acad
procollagen III propeptide (P3NP) as a valuable agent for Dermatol 1998;38:478–485.
188 Pediatric Dermatology Vol. 25 No. 2 March ⁄ April 2008

4. Hawrot AC, Metry DW, Theos AJ et al. Etanercept for 12. Charache S, Condit PT, Humphreys SR. Studies on the
psoriasis in the pediatric population: experience in nine folic acid vitamins. IV. The persistence of amethopterin in
patients. Pediatr Dermatol 2006;23:67–71. mammalian tissues. Cancer 1960;13:236–240.
5. Chan ES, Cronstein B. Molecular action of methotrexate 13. Newman M, Auerbach R, Feiner H et al. The role of liver
in inflammatory diseases. Arthritis Res 2002;4:266–273. biopsies in psoriatic patients receiving long-term metho-
6. Cassetty CT, Shupack JL, Washenik K. Cytotoxic and trexate treatment. Improvement in liver abnormalities after
antimetabolite agents. In: Freedberg IM, Eisen AZ, Wolff cessation of treatment. Arch Dermatol 1989;125:1218–
K, Austen KF, Goldsmith LA, Katz SI, eds. Fitzpatrick’s 1224.
dermatology in general medicine, 6th ed. New York: 14. MacDonald A, Burden AD. Noninvasive monitoring for
McGraw-Hill, 2003:2398–2408. methotrexate hepatotoxicity. Br J Dermatol 2005;152:405–
7. Mahe E, Bodemer C, Pruszkowski A et al. Cyclosporine in 408.
childhood psoriasis. Arch Dermatol 2001;137:1532–1533. 15. Afdhal NH, Nunes D. Evaluation of liver fibrosis: a concise
8. Cooney GF, Habucky K, Hoppu K. Cyclosporine phar- review. Am J Gastroenterol 2004;99:1160–1174.
macokinetics in pediatric transplant recipients. Clin Phar- 16. Grills C, Burge S. Methotrexate: improving safety profile.
macokinet 1997;32:481–495. Australas J Dermatol 2006;47:178–181.
9. Juanqin G, Zhiqiang C, Zijia H. Evaluation of the 17. Dadlani C, Orlow SJ. Treatment of children and adoles-
effectiveness of childhood generalized pustular psoriasis cents with methotrexate, cyclosporine, and etanercept:
treatment in 30 cases. Pediatr Dermatol 1998;15:144–146. review of the dermatologic and rheumatologic literature.
10. Kumar B, Dhar S, Handa S et al. Methotrexate in J Am Acad Dermatol 2005;52:316–340.
childhood psoriasis. Pediatr Dermatol 1994;11:271–273. 18. Lahdenne P, Rapola J, Ylijoki H et al. Hepatotoxicity in
11. Dogra S, Kumaran MS, Handa S et al. Methotrexate for patients with juvenile idiopathic arthritis receiving long-
generalized pustular psoriasis in a 2-year-old child. Pediatr term methotrexate therapy. J Rheumatol 2002;29:2442–
Dermatol 2005;22:85–86. 2445.