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REVIEW ARTICLE
Year : 2022 | Volume
: 23
| Issue : 3 | Page : 204-213
A comprehensive review of immunosuppressive drugs in pediatric dermatoses: Part II – methotrexate and mycophenolate mofetil
Shiti Bose1, Bhushan Madke2
1 Department of Dermatology, Venereology and Leprosy, City Hospital, Ernakulam, Kerala, India
2 Department of Dermatology, Venereology and Leprosy, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
Correspondence Address:
Shiti Bose
G 378, Panampilly Nagar, Ernakulam - 682 036, Kerala
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ijpd.ijpd_84_21
Immunosuppressants are required for an array of pediatric dermatoses. Certain dermatological conditions require long-term use of immunomodulators such as methotrexate and mycophenolate mofetil. All immunosuppressants have varying toxicity profiles and long-term use of these in the pediatric age group may lead to significant adverse effects. This concise review focuses on the immunosuppressants commonly used for dermatoses in children and gives a comprehensive list of the various indications for use in each and associated adverse effects on long-term use. An English language search was done on studies published till date on immunosuppressant use in pediatric dermatoses. A documented review was prepared, analyzed, and presented in a narrative fashion to highlight the important pediatric indications for the use of the respective immunosuppressant, with special emphasis on the adverse effects on prolonged usage.
Keywords: Adverse effects, immunosuppressants, indications, methotrexate, mycophenolate mofetil
Various steroid-sparing agents have been used in pediatric dermatoses. These immunomodulatory agents are essential for suppressing the debilitating skin conditions which affect the quality of life and restrict daily activities. Corticosteroids (CS) have been used often to tide-over widespread cutaneous inflammatory conditions, but prolonged use of CS may lead to various metabolic derangements and growth stunting in the pediatric age group, hence the need for safer immune modulators. This part of the review article discusses the safety and toxicity profile of commonly used immunosuppressants such as methotrexate (MTX) and mycophenolate mofetil (MMF) in pediatric dermatoses.
MethodologyA comprehensive English language literature search was done using multiple search engines-PubMed, EMBASE, Cochrane, and MEDLINE. MeSH terms (MTX, MMF, systemic, immunosuppressants, immunosuppressive therapy, pediatric dermatoses, children, psoriasis, atopic dermatitis (AD), chronic eczema, collagen vascular diseases, vasculitis, immunobullous disorders, indications, and adverse drug reactions) alone and in combination were considered. Studies done in the years from 1984 to 2021 were considered and particular emphasis was put on studies done on long-term adverse effects.
Clinical as well as randomized double-blinded or single-blinded controlled trials, open-label studies, retrospective studies, case series, reviews, and case reports on the use of immunosuppressants in pediatric age group, including their long-term adverse effects were screened. Only English-language articles were considered. Twenty-five articles were found, of which 18 were selected after removing duplication and articles having no relevant information. Evidence was prepared, analyzed, and presented in a narrative fashion to highlight the important pediatric indications for the use of the respective immunosuppressant, with special emphasis on the adverse effects on prolonged usage.
MethotrexateMTX is a stable analog of aminopterin, also known as amethopterin and was Food and Drug Administration (FDA) approved for use in Psoriasis in 1971.
Pharmacology and mechanism of action
MTX is a folic acid antagonist and it acts by competitively inhibiting dihydrofolate reductase, thus inhibiting the production of reduced folates, which leads to decreased amounts of purines, ultimately impairing DNA, RNA, and protein synthesis. The maximum cytotoxic effects are S-phase specific.[1],[2],[3],[4]
MTX has a greater effect on lymphoid tissue than keratinocytes hence its immunosuppressive effect is more than the anti-proliferative activity.
MTX also inhibits neutrophil chemotaxis, and secretion of pro-inflammatory cytokines, hence it has significant anti-inflammatory activity as well.[5]
Pediatric indications
FDA approved indications
Psoriasis: Methotrexate is indicated for use in the following conditions
Extensive plaque psoriasis (body surface area involvement >20%, or psoriasis area severity index score >10%)Erythrodermic psoriasisGeneralized or localized palmoplantar psoriasisModerate-to-severe psoriatic arthritis, not responding to conventional treatmentSevere nail psoriasisPsoriasis not responding to topical treatment/photo (chemo) therapy/systemic retinoids.In 2017, there was a retrospective study conducted across centers in America and Europe, to assess the safety of systemic agents in pediatric psoriasis, it was found that MTX and tumor necrosis factor inhibitors were the most frequently used agents.[6]
Multiple studies have concluded that MTX is effective in moderate-to-severe pediatric psoriasis (including generalized pustular psoriasis) and had a reasonable safety profile with nausea and vomiting being the most common side effect.[7]
In a study by Collin et al., in 13 children suffering from psoriasis treated with MTX, transient rise in serum transaminases were noted in nine children, mouth ulcers, easy bruising, transient nocturnal cough, and pain in the legs were noted in one child each.[8]
Sezary syndrome
Although extremely rare in the pediatric population, low dose (10–15 mg/week) MTX has been useful in the treatment of Sezary syndrome in two cases involving an 11 and 13-year-old girls.[9],[10]
Other off label indications
Proliferative dermatoses
Pityriasis rubra pilaris (PRP), pityriasis lichenoides et varioliformis acuta, Reiter's disease and extensive lichen planus.
Oral retinoids (isotretinoin and acitretin) are most commonly prescribed for the treatment of PRP in both children and adults. One of the severe side effects of retinoids in children is premature epiphyseal closure, especially when administered for a prolonged duration. Hence, MTX can be given as an alternative. Only a few case reports and case studies have reported successful use of MTX for PRP in children.[11],[12],[13]
MTX is administered for severe ulcero-necrotic forms of pityriasis lichenoides along with systemic steroids or cyclosporine and antibiotics. This therapy has induced remission even in severe life-threatening cases.[14],[15],[16]
Immunobullous disorders
Pemphigus vulgaris, bullous pemphigoid (BP), linear IgA disease.
In a case report by Peck et al., MTX was an effective alternative to corticosteroids in a child with pemphigus vulgaris who had developed cataract secondary to steroid therapy. Although MTX is not the first-line therapy for immunobullous disorders, it is a safer alternative with minimal adverse effects and can be effectively used as a steroid-sparing agent.[17]
In a case of linear IgA disease unresponsive to dapsone, MTX was effective and resulted in remission within nine months of treatment. The child continued to be in remission even after stopping MTX.[18]
Autoimmune connective tissue disorders
Juvenile dermatomyositis (JDM), systemic lupus erythematosus (SLE), systemic sclerosis and morphea.[5]
In systemic sclerosis, MTX and MMF are considered to be beneficial.[19] MTX at a dose of 25 mg/m2/week in children orally or subcutaneously is well tolerated.[20]
In progressive linear scleroderma and pansclerotic morphea in children, a weekly regimen of MTX at 15 mg/m2 as a single oral or subcutaneous dose is effective. During the initial three months of treatment, oral prednisone can be added as a “bridge therapy.” When treated for more than two years, a prolonged remission can be achieved.[21]
In a study by Christen-Zaech et al. including 136 children with localized scleroderma, out of 39 who received MTX, most of these children responded well to MTX with a significant reduction in the induration.[22]
Multiple studies concluded that the use of MTX along with prednisone, while tapering off the steroid was as effective as long-term corticosteroid therapy for children with JDM, with the added benefit of minimal adverse effects, such as those associated with long term steroid use.[23],[24],[25]
Vasculitis
MTX has been effectively used in the treatment of leukocytoclastic vasculitis (such as nonrenal chronic Henoch–Schonlein purpura), cutaneous polyarteritis nodosa, pediatric Wegener's granulomatosis, Kawasaki disease, and neutrophilic dermatoses.[26]
Atopic dermatitis and eczemas (actinic dermatitis, refractory pompholyx)
To date, seven studies have published reports of MTX treatment for childhood AD and discoid eczema and all studies report support low-dose MTX being safe, effective, and well-tolerated.[27]
Purvis et al. suggested that the sustained anti-inflammatory action of MTX helped improve and protect the skin barrier function for a prolonged period, hence preventing relapse and resulting in a long-lasting disease-free period. Furthermore, as AD even affects clinically normal-looking skin, prolonged response to MTX may be attributed to the treatment of the entire skin and not just localized areas, as seen with the use of topical steroids.[27]
In a study done at Children's Hospital, Philadelphia, 55 children suffering from severe AD were treated with MTX. Forty-two patients (76.4%) showed improvement with MTX whereas the rest showed no significant improvement.[28]
Autoimmune disorders like alopecia areata
MTX has been used alone or in combination with topical, oral, or intralesional CS in cases with extensive alopecia areata. It has been noted that the response to therapy was best when MTX was used along with CS rather than as monotherapy.[29]
In a study by Royer et al. in 14 children (aged 8–18 years) with severe alopecia areata treated with MTX (15–25 mg/week), five out of 14 children had >50% hair re-growth.[30]
Other cutaneous conditions
MTX has been used in Sarcoidosis, lymphomatoid papulosis, and chronic idiopathic urticaria.[5]
MTX is the drug of choice as a second-line treatment for sarcoidosis both in adults and children. It is given in cases refractory to steroids or in those who developed severe adverse effects to steroids. Although there is good improvement in the skin lesions, relapses have been known to occur soon after stopping the therapy, giving an indication that MTX can control the disease but is not effective in curing the disease.[27]
[Table 1] enumerates a few studies carried out in the pediatric age group for various indications.
Table 1: Studies on immunosuppressants: Methotrexate, mycophenolate mofetil in the paediatric age groupAdverse effects
MTX in children has been reported to be efficacious, and well-tolerated, with minimal side effects. The rate of adverse effects was minimal, out of which a majority (96%) were non-serious.[27] The earliest adverse effects noted are mucositis and burning and erythema over existing lesions of psoriasis.[5]
[Table 2] enlists the adverse drug reactions seen with the use of MTX.
Hematological
Cytopenia in the form of leucopenia, thrombocytopenia, or pancytopenia may occur in 10%–20% of cases. It is often seen within 4–6 weeks of starting MTX or with a change in dose.[34] Concomitant use of certain drugs (nonsteroidal anti-inflammatory drugs [NSAIDS] or trimethoprim-sulfamethoxazole) or pre-existing renal disease may lead to increased risk of developing cytopenia. The use of folic acid (5 mg/day) reduces the risk of cytopenia.
Gastrointestinal
In a study of a German registry with 411 children with juvenile arthritis, the most common adverse effects seen were gastrointestinal (22% cases).[40]
Nausea and vomiting are seen most commonly. Folic acid intake and dose-splitting are helpful in reducing the symptoms. Hepatotoxicity may occur which can be dose and duration dependant. MTX can be detected in the liver for up to 116 days after intake of the last dose.[31] Long-term use of MTX may lead to hepatic fibrosis.
In children, the role of liver biopsy is controversial. It is considered that in the absence of any preexisting risk factors, a liver biopsy may not be required.[27] Serum PIIINP (type I11 procollagen aminopeptide) is a noninvasive test for detecting early fibrinogenesis.[1] Prior to initiating therapy, baseline liver enzymes and PIIINP levels are tested; and if elevated, a liver ultrasound scan using transient elastography (Fibroscan) may be considered.[41] In a study of patients with psoriasis, by Raaby et al., Fibroscan correctly identified 88% of the patients to have no significant liver fibrosis who had a similar result on their liver biopsy.[41] Another noninvasive test is Fibrotest which can predict the presence of clinically significant liver fibrosis whereas Fibroscan predicts the absence of the same.[42] Liver fibrosis due to MTX use is potentially reversible. Even extensive liver fibrosis of histological grade 4, can revert to normal if MTX is avoided for 6–12 months.[31] As psoriasis has a seasonal variation, this permits discontinuation of the drug in the summer season in most cases, hence reversing the side effects.
Opportunistic infections
Methicillin-sensitive staphylococcal aureus (MSSA) infection, molluscum contagiosum, tinea, verrucae, and eczema herpeticum, are commonly encountered in patients on high dose, long term treatment.
Other adverse effects
A drug rash can develop in some patients. In a study by Roberts et al., one child on treatment for discoid eczema developed a generalized exanthematous rash which disappeared as soon as MTX was withdrawn.[34] Pulmonary (pneumonitis, fibrosis), renal toxicity, and neurological adverse effects maybe encountered rarely in pediatric doses and dermatological therapy.[5]
Accelerated nodulosis has been observed in children on MTX therapy for juvenile rheumatoid arthritis.[43]
In a study by Anderson et al., 50.9% of cases with AD on treatment with MTX, had at least one adverse effect during therapy. The most common was GI discomfort, experienced in 17 (30.9%) children. Few developed anemia and nearly 50% of cases developed skin infections. MSSA infection was the most common skin infection.[28]
Dosage
[Table 3] mentions the dosage and special considerations while prescribing MTX in dermatological practice.
Table 3: Drug dosage and special considerations while prescribing methotrexate and mycophenolate mofetilMTX can be administered orally or in parenteral form (subcutaneous, intramuscular, or intravenous). The oral route is preferred unless the patient has severe gastritis. The oral bioavailability is low (31%) whereas, bioavailability by parenteral route is 76%. Children should avoid concurrent food intake, especially milk and milk-containing meals as it interferes with MTX absorption.[46]
Schedules of administration
Single weekly dose
A 5 mg test dose (or 10-15 mg/m2) is given. A complete blood count (CBC) and liver functions tests are assessed after one week, if reports are normal then the dose is increased by 2.5 mg/week to an optimal dose between 7.5 and 30 mg/week.
Once the lesions have cleared by 80% the dosage is reduced by 2.5 mg/week every 2-4 weeks. In severe pustular or erythrodermic psoriasis, it is better to start with the maximal optimal dose rather than the test dose.
The effect is seen within 1 to 7 weeks (average of four weeks). Maximal effect seen in 8-12 weeks.
Triple-dose regimen (Weinstein and Frost regimen)
In this regimen, MTX is given once weekly as three divided doses 12 hours apart. The efficacy is similar to the single weekly dose but this regimen has a greater risk of hepatic fibrosis.[47] A daily folic acid supplementation (except on the days MTX is taken) reduces nausea/vomiting and mitigates the risk of developing anemia.
Monitoring
Monitoring guidelines are mentioned in [Table 4]. According to Weinblatt et al., macrocytosis, evident by elevated mean corpuscular volume (MCV), prior to the onset of anemia may be considered a predictor of impending hematologic toxicity.[48]
Table 4: Monitoring of methotrexate and mycophenolate mofetil in paediatric skin disordersDrug interactions
Dose reduction/alterations would be needed in patients on medications such as:
NSAIDS, phenytoin, doxycycline, minocycline, and tetracycline: When co-administered, these drugs increase the levels of MTX in the circulation.
Dapsone and sulfonamides and trimethoprim: When given along with MTX levels of dapsone, trimethoprim and sulfonamides can increase therefore increasing the risk of myelotoxicity.
Systemic retinoids: Added risk of hepatotoxicity is there when administered along with MTX.
Mycophenolate MofetilMMF is a pro-drug of mycophenolic acid (MPA) and has higher bioavailability, more efficacy, and lesser gastrointestinal (GI) side effects.[49] MPA was isolated from Penicillium stoloniferum by Gosio in 1896. MPA was used as an antibiotic till 1970s, when the antiviral, antitumor, and immunosuppressive properties were discovered.
Pharmacokinetics and mechanism of action
Following ingestion, MMF is hydrolyzed to MPA (its active metabolite). MMF non-competitively binds to inosine monophosphate dehydrogenase, which is a key enzyme in de novo pathway of purine biosynthesis; this, in turn, arrests purine biosynthesis. The B and T lymphocytes lack purine salvage pathway and are dependent solely on de novo pathway, hence the proliferation of B and T lymphocytes is affected preferentially.[39]
Pediatric indications
Food and Drug Administration approved indications
MMF has been approved for use in the prevention of renal transplant rejection in the pediatric population.[50] Because of the concern for risk of malignancy with long-term immunosuppression, therapy should be attempted to be tapered until discontinued after remission has been obtained.[49] In children, MMF therapy has been found to be safer as compared to the other immune suppressants in the treatment of pediatric AD and immuno-bullous disorders, lupus nephritis, and nephritic syndrome.[35],[39],[51],[52]
Table 1 shows some of the studies carried out using MMF in pediatric dermatoses.
Immunobullous dermatoses
A 27-month-old girl with linear IgA bullous disease of childhood was successfully treated by Farley-Li and Mancini by combining 100 mg of MMF with 25 mg of dapsone.[53]
Semanario-Vidal et al. reported a case of recalcitrant BP treated successfully with MMF.[35]
In another case report, successful treatment of mucous membrane pemphigoid was attained with MMF alone after tapering steroids.[54]
Although azathioprine has the maximum steroid-sparing effect, MMF was found to have comparable steroid-sparing effects and efficacy, but with a higher safety profile in the treatment of autoimmune bullous disorders as it is less myelosuppressive and hepatotoxic as compared to azathioprine. Hence, MMF could replace azathioprine as an immunosuppressant adjuvant of choice for pediatric autoimmune and inflammatory disorders such as severe pemphigus vulgaris and other immune bullous disorders.[35],[55]
Atopic dermatitis
MMF may be considered as an alternative to MTX for treating refractory AD, not responding to MTX therapy, or in children intolerant to MTX, (strength of recommendation C, and level of recommendation III).[27]
MMF is considered to have a better safety profile than cyclosporine or systemic steroids for long-term treatment of AD.[56]
Graft-Versus-host-disease
MMF in combination with UVA-1 has shown beneficial results in the treatment of pediatric graft-versus-host-disease.[57],[58]
Collagen vascular disorders
Approximately 20% of SLE patients are diagnosed in childhood.[59] The average age of onset of pediatric SLE is between 12 and 14 years and rarely before the age of 5 years.[60] Childhood-onset SLE is associated with greater lifetime morbidity and mortality than adult-onset SLE.[61]
In a study done by Kizawa et al., on 17 children with SLE, who were on treatment with MMF as a maintenance therapy (600–1200 mg/m2/day), there was a marked improvement in the SLE Disease Activity Score after 12 months of therapy.[62]
MMF has been shown to have lesser infection rates and adverse effects as compared to cyclophosphamide in patients with lupus nephritis.[63]
MMF has been presented as another potential option for the treatment of juvenile localized scleroderma. According to the multicenter audit conducted in the UK, MMF was the most commonly used second-line treatment in clinical practice and was used in 89.5% of cases.[37]
In juvenile systemic sclerosis (JSSc), with the involvement of skin, subcutaneous tissues, and joints, MMF may be a good alternative to MTX, in cases refractory to MTX.[21]
In the treatment of JDM, MMF may be a useful in the treatment of muscle and skin disease (including calcinosis) (level of evidence 3, strength of recommendation C).[64]
Papulosquamous disorders
Multiple studies have shown the efficacy of MMF in the treatment of psoriasis and lichen planus in adults, but studies in the pediatric population are lacking.[65]
Adverse effects
Table 2 enlists the various adverse effects seen with the use of MMF in dermatological practice.
Gastrointestinal side effects
Nausea, vomiting, diarrhea and abdominal discomfort, anal tenderness, soft and frequent stools, and in some cases, constipation are the most frequent side-effects of MMF, seen in 10%–30% of patients. A divided dose regimen helps reduce the gastrointestinal side effects. These side effects are also dose-dependent, with higher doses leading to more side effects. Mild reversible elevation of serum transaminases is also seen at times.[39],[49]
In those developing diarrhea several months after therapy, it is postulated that villous atrophy due to inhibition of mitosis of the intestinal epithelium is the possible cause of diarrhea.[66]
Hematologic side effects
These are seen in <5% of patients. Anemia, leucopenia, and thrombocytopenia are most common, and normalize once the dose is reduced or discontinued.[67],[68] Significant bone marrow suppression can be seen, although uncommon.
Genitourinary symptoms
These are often encountered in the first year of therapy with MMF. These include increased frequency, burning micturition, sterile pyuria, and urinary tract infection.
Infections
Viral infections such as cytomegalovirus infections, human herpesvirus type 6, herpes simplex virus, herpes zoster, viral warts, and pediatric disseminated varicella have been encountered when treated for a prolonged period. Bacterial infections such as streptococcus B septic shock, staphylococcal septicemia, and recurrent Escherichia More Details coli epididymitis may be seen. Fungal infections associated with MMF include candidiasis, mucormycosis, cryptococcosis, and pneumocystis jirovecii.[39],[49]
Malignancies
Both lymphomas and lymphoproliferative disorders have been reported in children on MMF monotherapy whereas lymphoproliferative disorders alone have been reported in children following organ transplant, and on a combination therapy of MMF with other immunosuppressants.[39],[69]
Dosage
The usual dose, given in adults, is 2–3 g/day (which is 30 mg/kg/day). The biologically equivalent dose for the pediatric age group would be children is 1200 mg/m2 daily, given in two divided doses, equivalent to 30–60 mg/kg/day.[70]
Due to rapid clearance of the drug because of faster metabolism of MMF by the liver, a higher dose maybe required in younger children (40–50 mg/kg/day) as compared to adolescents who show a good response to 30–40 mg/kg/day.[70] According to some authors, very high doses of up to 3.5 g/day (50–60 mg/kg/day) may be needed for some dermatological conditions such as recalcitrant AD in children for attaining disease remission.[71],[72]
There is a racial variation associated with the metabolism of MMF as African Americans may require higher doses of MMF due to increased clearance of the drug.[73]
According to a review by Narla et al., a dose of 20–50 mg/kg/day can be started in children with an increment of 500 mg every 2–4 weeks. It can be safely used up to a year.[6] MMF should be tapered slowly to prevent any flares. Special consideration should be given to children with severe renal impairments, necessitating the need for dose reduction.[65] According to Li et al., the following doses of MMF to be given with or without CS: for <1.25 m2: 600 mg/m2 twice a day, for 40–50 kg or 1.25–1.5 m2 = 750 mg twice a day, or those >50 kg or >1.5 m2 = 1000 mg twice a day.[74]
The dosage of MMF and special consideration while giving MMF are mentioned in [Table 3].
Drug monitoring guidelines are mentioned in [Table 4].
ConclusionThe use of immunosuppressants in the pediatric age group is limited to severe recalcitrant skin conditions not responding to the conventional therapy or in those with contraindications to the safer alternatives. Hence, short-term, <1 year use of immunosuppressants has been proven to be of great benefit in controlling the active phase of the disease and in reducing the psychosocial impact of skin diseases in the children and improving the quality of life. Long-term adverse effects of the immunosuppressants still need to be evaluated and hence, continuous monitoring is required in children requiring a longer duration of immunosuppressant therapy.
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Conflicts of interest
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References
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