Immunosuppressants are immunomodulatory agents used for the treatment of serious or recalcitrant inflammatory skin conditions. Corticosteroids (CS) are often the first-line systemic anti-inflammatory drug, but owing to serious adverse effects, especially in children, which are dose and duration dependent, other “steroid sparing” immunomodulatory drugs needed to control disease activity, especially when long-term treatment is required.
A comprehensive English language literature search was done using multiple search engines-PubMed, Google, EMBASE, Cochrane, and MEDLINE. MeSH terms (corticosteroids, azathioprine, cyclosporine A, systemic, immunosuppressive therapy, pediatric dermatoses, children, psoriasis, atopic dermatitis, chronic eczema, collagen vascular diseases, vasculitis, immunobullous disorders, indications, adverse drug reactions) alone, and in combination were considered. Studies done in the years from 1984 to 2021 were considered with particular emphasis 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. Thirty-eight articles were found, but only 28 were selected after removing duplication and articles having no relevant information. Using the selected articles, a 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 due to prolonged usage.
Pharmacology, pharmacokinetics, and mechanism of action
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor. Systemic CSs are broadly divided into short acting, intermediate acting, and long acting, as shown in Table 1.
Systemic CS have immunomodulatory (suppress T-lymphocyte activation and synthesis of acute-phase reactants) as well as nonimmunomodulatory actions (glucocorticoid effect, leading to gluconeogenesis and mineralocorticoid effects, leading to water retention and hypokalemia).
Pediatric indications of corticosteroids
Various indications for the use of oral CS in children are enlisted in Table 2.
According to the International Eczema Council, the use of systemic CS in children should be solely reserved for severe flares of atopic dermatitis, as a bridge to other immunosuppressive therapies or phototherapy, or if there are specific contraindications to the use of other forms of therapies. CS should be used for a short period to mitigate their adverse effects in children such as growth retardation, obesity, and risk of infections.
Systemic CS in childhood lichen planus (LP) are used in cases of recalcitrant eruptive LP, LP pemphigoides (LPP) and extensive oral LP at a dose of 0.5–1 mg/kg/day for 2–6 weeks. A review by Merhy et al. showed that most cases of pediatric LP were reported from India, and systemic CS were the second most commonly prescribed agent after topical CS. LPP responded well to CS and the incidence of postinflammatory hyperpigmentation was much less in children with darker skin treated with CS.
In juvenile dermatomyositis (JDM), high oral doses of CS (1.5–2 mg/day/day) or pulse intravenous methylprednisolone (IVMP) at a dose of 30 mg/kg given over two hours, three days a month in the early stage of the disease help in rapid control of muscle inflammation and calcinosis which may follow.
Table 3 enumerates few studies carried out in the pediatric age group for various indications.
Although methotrexate is considered first-line therapy for morphea profunda, adjuvant CS therapy at a dose of 1–2 mg/kg/day for up to three months leads to rapid control of the disease progression and resolution of joint contractures. Pulse intravenous CS using IVMP along with low weekly dose of methotrexate is effective and well tolerated in children suffering from severe forms of cutaneous scleroderma.
Henoch Schonlein Purpura is the most common self-limiting systemic vasculitis in children aged 17 years or less. Although CS was previously prophylactically administered to prevent nephritis, recent trials and meta-analyses suggest that it has no significant role in preventing the onset of renal disease or even abdominal complications. However, CS are effective in the symptomatic treatment of abdominal pain, arthralgia, and purpura. The Single Hub and Access point for pediatric Rheumatology in Europe guidelines state that CS are indicated in IgA associated vasculitis in case of orchitis, cerebral vasculitis, pulmonary hemorrhage or other life-threatening manifestations and the use of prophylactic CS treatment to prevent the development of IgA-associated nephritis is not indicated.
Systemic prednisolone (1–3 mg/kg/day) can be administered for weeks to months in complicated hemangiomas or where beta blockers are contraindicated (beta blockers have supplanted the use of CS in the treatment of complicated and large hemangiomas in most cases) In a meta-analysis by Bennette et al., systemic prednisone given at 2.9 mg/kg/day for a mean period of 1.8 months followed by tapering showed a positive response in 84% cases with infantile hemangiomas. Few other studies have also shown CS to be effective. In a study by Bauman et al., both CS and propranolol seemed to be equally efficacious, with CS showing a faster response, while propranolol being better tolerated with lesser side effects. Rebound growth was more often seen with CS usage.
Common indications for pulse steroid therapy are as follows:
- Pemphigus vulgaris: IVMP at a dose of 20–30 mg/kg (500–1000 mg/m2) per pulse or dexamethasone pulse (DP) therapy at a dose of 4–5 mg/kg (100–200 mg) per pulse can be given. Dexamethasone Cyclophosphamide pulse should be administered with caution and the doses reduced to half for children below the age of 12 years
- Autoimmune skin conditions like vitiligo, alopecia areata, LP: Oral mini pulse has been used using betamethasone 5 mg once a day, on two consecutive days of the week
- Connective tissue disorders
- Urticarial vasculitis.
The advantage of pulse therapy over conventional high dose treatment is that an immediate and profound anti-inflammatory action is achieved without the adverse effects of the latter such as hypothalamic–pituitary axis suppression. The clinical improvement appears faster and lasts up to three weeks after a single pulse.
Adverse effects of corticosteroid therapy
Table 4 enumerates the common adverse effects of CS, azathioprine and Cyclosporine or Cyclosporine A (CsA).
Hypothalamus-pituitary-adrenal axis suppression
It is both dose and duration dependent. Children receiving high doses of steroids, such as 1–2 mg/kg per day of prednisone, for three months or more eventually suffer significant adverse effects.
Sudden withdrawal of prolonged and high-dose CS therapy may result in fatal adrenal insufficiency.
Organ system-related and related to metabolic derangements
- Hyperglycemia (due to glucocorticoid induced-gluconeogenesis), hypertension and congestive heart failure (secondary to mineralocorticoid induced sodium retention), hyperlipidemia (GC effect). While giving pulse therapy, rapid flux of electrolytes can lead to seizures, hence children need to be monitored
- Musculoskeletal–Myopathy, avascular necrosis and osteoporosis:Children on high doses of steroids (1 mg/kg per day or 30 mg/d) for prolonged periods may develop steroid induced myopathy. In steroid myopathy there is an insidious onset of painless proximal muscle weakness (especially lower limbs), albeit acute myopathy may develop within a day of initiation of treatment. Respiratory muscle weakness and bulbar muscle weakness may also occur. Withdrawal of CS results in complete recovery of steroid myopathy in a few weeks' time, whereas myopathy due to worsening JDM/polymyositis would not show any improvement.
Prolonged (up to 6 months) and continuous high oral doses (2 mg/kg/day) or high intravenous pulse doses (10–30 mg/kg per pulse) may result in avascular necrosis, mainly involving the femoral head, resulting in asymmetrical limb shortening.
Osteopenia is not usually seen in children on short term CS. In contrast to adults both trabecular and cortical bones are affected in children (only trabecular bone affected in adults).
A bone densitometry done within 6–12 months of initiation of CS therapy helps predict significant bone loss as maximum bone loss occurs within this period.
- Cushingoid changes consisting of moon facies, buffalo hump, and obesity (melon-on-stick appearance) due to altered fat distribution and are common among children receiving prolonged moderate-to high-dose steroid therapy
- Immune related– There is an increased risk for bacterial and mycobacterial (tuberculosis), and viral infections (especially herpes zoster and herpes simplex), due to reduced immunoglobulin production and Pneumocystis carinii infections and candidiasis, due to T lymphocyte suppression
- Gastro-intestinal -Peptic ulcer, pancreatitis and intestinal perforations can occur in patients on CS therapy
- Ophthalmologic–Children on steroid therapy can develop cataract and glaucoma and the risk of developing posterior sub-capsular cataracts is higher when the steroid dose is 0.3 mg/kg per day (9 mg/m2 per day) or more administered for durations over one year. Children have a higher propensity of developing cataracts as compared to adults even with shorter durations or lower doses
- Neuropsychiatric–Mood changes, depression, psychosis, pseudotumor cerebri and sleep disturbances can occur. These effects can be seen with pulse therapy in 10 percent of the cases
- Dermatologic–Acne, fragile skin and easy bruising, hirsutism and poor wound healing maybe seen when on prolonged therapy
- Growth stunting-Prolonged therapy (>6 months) with doses up to ≥3 mg/day of prednisone in children may result in stunting due to suppression of cell growth and division and inhibition of somatomedin C (insulin-like-growth factor I) production and reduction in growth hormone levels. An alternate day regimen of prednisolone ≤10-15 mg/kg may not affect the growth of the child. A catch-up growth may be observed in the steroid-free period or when the dose is reduced, even in children on high doses of steroids. Dexamethasone is 18 times more potent in causing growth suppression as compared to prednisolone.
Anaphylactic shock associated with intravenous methylprednisolone can be a result of allergy to the succinate ester of methylprednisolone.
To summarize, a higher propensity to develop cataract, osteopenia with involvement of both the trabecular and the cortical bones and growth stunting are the features are features in the adverse effect profile in the pediatric age group distinct from adults.
The physiological replacement CS therapy is 5–7.5 mg of prednisone (or 20–30 mg of cortisol). Short courses (up to 3 weeks) may not require tapering of the drug, although tapering is beneficial in preventing relapses and symptoms of steroid withdrawal.
The basis of alternate day therapy lies in the fact that anti-inflammatory actions of CS persist longer than the duration of hypothalamus-pituitary-adrenal axis suppression when intermediate acting steroids are used.
Table 5 enumerates the corticosteroid drug dosing for various indications and special considerations while giving the therapy.
Monitoring of therapy
The baseline investigations and follow-up investigations are tabulated in Table 6.
Pharmacology and pharmacokinetics
The prodrug of azathioprine and 6-mercaptopurine (6-MP) was produced in the laboratory by Hitchings and Elion. Azathioprine, unlike 6-MP, is resistant to immediate catabolism and is selectively activated in target cells.
Azathioprine is absorbed almost completely from the intestine. Peak serum levels are attained in 2 hours and it does not cross the blood − brain barrier. The metabolism of azathioprine is shown in Figure 1.
Mechanism of action
The structural similarity of 6-Thioguanine (active metabolite) to endogenous purines allows it to be incorporated into the nucleic materials (DNA and RNA) of actively dividing cells, leading to inhibition of purine metabolism and cell division. The inhibition at the primary level may explain its delay of action, as it usually takes at least 1–2 months before clinical effects are seen.
Azathioprine selectively inhibits T-lymphocytes more than B-cells. The reduced antibody production due to B-cell inhibition is useful in treating immunobullous dermatoses like pemphigus vulgaris.
Indications for use in pediatric age group
Azathioprine is FDA approved for use in organ transplantation and severe rheumatoid arthritis only. The use of azathioprine in dermatological conditions, albeit off-label, has shown excellent response in immune bullous disorders, psoriasis, eczematous conditions, and photodermatoses. Few of these studies are enumerated in Table 3.
- Immunobullous disorders: Over the last five decades, azathioprine has proven to be safe and effective as an adjuvant or when substituting CS for long-term therapy. Azathioprine is considered the first-line adjuvant therapy for use with oral steroids in the treatment of pemphigus vulgaris, according to the British Association of Dermatologists (BAD) guidelines and the European Dermatology Forum. It has been used successfully as an adjuvant therapy in children with linear IgA dermatoses, pemphigus vulgaris, bullous pemphigoid, and bullous SLE. It also has the maximum CS sparing effect when compared to other immunosuppressants used as adjuvants.
- Dermatitis and papulosquamous disorders: Azathioprine has been used most often in recalcitrant cases of atopic dermatitis, hand eczemas and contact dermatitis, LP
- Photodermatoses: It has been often used in the treatment of recalcitrant polymorphic light eruptions.
- Neutrophilic dermatoses: Although commonly prescribed in adult Behcet's disease and pyoderma gangrenosum, there is a scarcity of studies in the pediatric age group
- Autoimmune connective tissue disorder: Azathioprine has been used to treat lupus erythematosus, polymyositis, and dermatomyositis
- Other uses: Azathioprine has been used to treat pityriasis rubra pilaris, erythema multiforme, graft-versus-host disease, and acne fulminans
Adverse drug reactions
Some of the significant adverse drug reactions are as follows:
- Gastrointestinal: Nausea, vomiting, and diarrhea can occur and is usually seen within the first 10 days of therapy. Dose reduction, divided doses, and intake of the drug along with food reduces these effects
- Myelosuppression: Seen most often in children having low thiopurine methyltransferase (TPMT) levels. Pretreatment TPMT levels and regular monitoring of complete blood count is required.Cytopenia can occur even in the presence of normal TPMT activity; therefore, blood monitoring is required in all patients. Dose reduction or alternative treatments can be considered where an abnormal TPMT status is identified.
The drug should be stopped if reduced blood counts occur (total lymphocyte count <3500–4000, hemoglobin <10 g/dl, and platelet count <100,000/mm3).
- Immunosuppression carcinogenesis: Acute lymphocytic leukemia, non-Hodgkin's lymphoma is common, and in those over 15 years of age, tumors of the central nervous system have been noted. No studies so far have shown these carcinomas occurring secondary to the treatment for dermatological indications
- Hypersensitivity: Manifest as cutaneous rash, fever, leukocytosis, arthralgia, and fatal presentations as a cardiovascular collapse, often within 1–4 weeks of starting therapy
- Cutaneous side effects: Common skin problems include alopecia, warts, and herpes zoster can occur while on treatment.
The adverse drug reactions due to azathioprine are summarized in Table 4.
Dosage and monitoring guidelines
The drug dosage and special considerations to be taken for a child on azathioprine are mentioned in Table 5.
Baseline monitoring and thorough follow-up evaluation are necessary [Table 6].
CsA was discovered in 1970, by Borel at the Sandoz laboratories in Switzerland from the soil fungus Tolypocladium inflatum gams.
Pharmacology and mechanism of action
Cyclosporine is a lipophilic cyclic polypeptide which causes a calcium-dependent inhibition of the intracellular enzyme calcineurin by forming a complex with cyclophilin leading to inhibition of IL-2 activity, which in turn leads to diminished T-cells in the epidermis.
The drug is poorly absorbed after oral administration and has a bioavailability of about 30% (range 5%–70%). Cyclosporine does not cross the blood-brain barrier. Cyclosporine metabolism is age dependent and children may require higher doses due to an increased clearance (up to four times that of adults above the age of 40 years) and decreased elimination half-life.
Indication for use and dosage in dermatological conditions in pediatric age group
Cyclosporine is a rapid acting drug which is very effective in controlling severe disease. Table 3 enumerates few studies on CsA being used in pediatric dermatoses.
According to expert consensus, systemic therapeutic agents should be considered in cases of severe, disabling psoriasis, severe flare-ups, and resistance/inadequate response or contraindications to topical or UV therapy. There are not many studies documenting the proper dose, safety or efficacy of anti-psoriatic systemic therapies in children and most of these agents are not licensed for use in pediatric age group.
Pediatric patients with active disease might need either maintenance therapy or long-term (up to two years) continuous cyclosporine therapy. In a study by Fernandes et al., as a maintenance therapy in adults, weekend cyclosporine at dose of 5 mg/kg/day for two consecutive days per week for 20 weeks was found to be just as effective to a daily dose of 3 mg/kg/day with the added advantages of having lesser adverse effects and lesser mean daily dose. Due to the property of being lipid soluble, it gets stored in the adipose tissue and hence can be discontinued for 3–5 days. Cyclosporine is also effective in nail psoriasis, alone, or along with topical calcipotriol or dithranol.
CsA has often been used as a “crisis buster” (used for short periods of 12–16 weeks) and often in the form of sequential therapy with methotrexate and acitretin separately.
Cyclosporine is very effective for the treatment of severe childhood atopic dermatitis not responding to the conventional topical therapies. It has been approved for use in Europe, the United Kingdom, and the United States at a dose 5 mg/kg/day for two weeks for induction and then depending on the clinical response, gradually tapering to a dose of 1.5 mg/kg/day in a span of three months. Patients treated with higher initial dose had better response and clearance at two weeks than those treated with lower starting dose, although the risk of adverse effects were higher on the first group. Maximal benefit is usually seen at 10 weeks of therapy. Some studies stated that despite pharmacokinetic differences in adults and children, CsA has similar efficacy at 2.5–5.0 mg/kg/day dose in both. On withdrawal of the drug, nearly 50% of the patients relapse within two weeks and about 80% in the following 6 weeks, although the patients are symptomatically better than the first presentation. Oral CsA is effective in controlling severe flares of atopic dermatitis, but when recurrences are frequent, continuous long-term therapy at lowest effective dose can be initiated and carried on for a maximum period of two years.
The British Association of Dermatologists (BAD) has recommended the use of cyclosporine for the treatment of severe chronic idiopathic urticaria not responding to antihistamines or short-term CS (strength of recommendation A).
The most effective dosage and duration suggested so far is 3 mg/kg/day, given in divided doses for six weeks, followed by 2 mg/kg/day for three weeks, followed by 1 mg/kg/day for three weeks, followed by discontinuation of treatment.
Other off-label uses
In pediatric Stevens − Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) CsA at a dose of 3 mg/kg/day for seven days followed by 1.5 mg/kg/day has been known to improve reepithelization, prevent occurrence of new lesions, reduce length of hospitalization, relatively lower side effect profile and reduce mortality, both in children and adults when compared to high dose IVIG. For connective tissue disorders such as juvenile dermatomyositis and scleroderma, CsA has been proposed as a second-line agent. When given as an adjuvant with systemic CS, it has been proven to be effective in controlling esophageal and lung involvement. In scleroderma, it has been effective in resolving digital infarcts and in reducing the skin thickness, but special caution needs to be taken as it can worsen the renal disease and hypertension associated with systemic sclerosis.
Oral CsA can be the considered as the treatment of choice in disseminated LP not responding to CS or retinoids, erosive LP, and in lichen planopilaris before severe follicular damage sets in. A case series on adult patients showed high efficacy of CsA in managing severe generalized LP at a dose ranging from 2.5 to 5 mg/kg per day.
When used in patients with prurigo nodularis, it has led to significant decrease in pruritus and healing of nodules within 2 weeks of therapy.
Cyclosporine has been used with some benefit in the treatment of bullous pemphigoid, Hailey–Hailey disease, and epidermolysis bullosa acquisita. According to the BAD guidelines (2018) CsA has not shown much benefit in the treatment of pemphigus vulgaris and pemphigus foliaceus (strength of recommendation D).
Few conditions in which CsA has not shown benefit include discoid lupus erythematosus. According to the BAD guidelines (2018), CsA is also not recommended for alopecia areata (AA), as it is associated with high risks of toxicity owing to high doses and long-term treatment (strength of recommendation D). In a case report, in a child of Down's syndrome with extensive AA, CsA was given at a dose of 3 mg/kg/day for six months. Although hair regrowth was attained, there was a relapse within three months. Cyclosporine although has been effective in treating alopecia universalis when used in combination with oral prednisolone, but it relapsed soon after stopping the treatment.
Adverse drug reactions
The most common adverse effects of CsA are nephrotoxicity and hypertension, hence, it is contraindicated in patients with uncontrolled hypertension and severe renal disease (except nephrotic syndrome). Renal function variations are dose and duration dependent, whereas hypertension is not preferentially dose dependent. It is therefore advisable that the maximum dose should be limited to 5 mg/kg/day and used not more than one year (level IV of evidence).
The common adverse drug reactions due to CsA are enlisted in Table 4.
Acute renal damage leading to increased serum creatinine occurs due to renal vascular or tubular changes. It is reversible on discontinuation of cyclosporine. Intermittent short-term therapy allows reversal of renal dysfunction, provided the dose is not exceeded beyond 5 mg/kg/day. Continuous treatment exceeding one year leads to vasculopathy, tubulopathy, and structural changes which are not reversible.
Cyclosporine-induced hypertension is rarely seen in children on CsA therapy for dermatological conditions. It is mainly due to vasoconstrictive effect of CsA on the vascular smooth muscle of the kidneys. Hypertension, although may also develop secondary to renal dysfunction. It is usually not dose-dependent and should be ideally be managed by antihypertensive, rather by dose reduction. The antihypertensive of choice is calcium channel blockers such as amlodipine or isradipine. If dose reduction is preferred, a dose reduction of 25%−50% is advisable.
Risk of non-melanoma skin cancers and lymphomas is more in psoriatic patients treated with psoralens and ultraviolet radiation or other immunosuppressant along with CsA. This has not been noted yet in children. Patients treated for over 2 years have a higher risk.
Cutaneous adverse effects
Cutaneous adverse effects of CsA are hypertrichosis, gingival hyperplasia, keratosis pilaris, acne, folliculitis, and sebaceous hyperplasia.
Neurological adverse effects like tremors, paraesthesia, headache, and hyperesthesia may occur. Tetracyclines should not be used concomitantly even to treat cyclosporine-induced acne because of the risk of pseudotumor cerebri.
Table 5 mentions the dosage and special considerations to be taken when prescribing CsA.
Short-term intermittent therapy (12–16 weeks) is the most frequently used mode of therapy in children. Treatment is administered till clinical improvement, following which it is discontinued. In case of relapse, CsA is restarted at the same starting dose.
Long-term therapy is given in case of frequent recurrence of severe forms of psoriasis or atopic dermatitis, wherein CsA is given at a lowest possible dose to control the disease. Due to a higher risk of adverse effects, CsA is discontinued within 1 year (followed in the US) or 2 years (followed in Europe) of starting therapy.
CsA can also be given in rotation with methotrexate, mycophenolate mofetil, and fumaric acid esters. This helps in minimizing the duration and toxicity of CsA.
The baseline evaluation and follow-up evaluation for a child on CsA are mentioned in Table 6. Monitoring the blood pressure and renal functions are important before and after initiating therapy.
Making decisions regarding medications in treating chronic pediatric skin disorders can be arduous for the treating physician as it may require long-term therapy which increases the risk of adverse effects as well. A thorough knowledge of the drugs and a tailored approach to treatment with regular monitoring will prevent adverse effects on long-term use.
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Conflicts of interest
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