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Summer 2014, Vol. 22 No. 2

Hong Kong J. Dermatol. Venereol. (2014) 22, 66-74


Paediatric Dermatology Column: Review Article

The use of systemic therapy in childhood eczema: a review and our Australian experience

系統性治療在兒童濕疹之應用:澳洲的經驗回顧

VM Palmer and D Orchard

Abstract

Topical therapies and patient education are the mainstays of treatment for atopic dermatitis, being effective for the majority of children who have limited disease of mild to moderate severity. More severe, widespread, or recalcitrant disease may necessitate systemic therapy. Treatment modalities may be divided into education, topical therapies, antihistamines, antimicrobials, systemic vitamin D, phototherapy, systemic steroids and systemic immunomodulatory agents. This review will focus mainly on the more commonly used systemic therapies in paediatric dermatology and also give advice based on our experience.

外用藥物治療和患者教育是治療異位性皮膚炎的基石,對大多數輕微至中度嚴重性的兒童異位性皮膚炎皆為有效。但更嚴重的、廣泛的或頑固的病情,便可能要考慮系統性治療。治療方法一般可分為病者教育、外用療法、抗組織胺、抗微生物藥物 、口服維生素D、光療、系統性類固醇激素和系統性免疫調節劑。本回顧文章將主要集中在小兒皮膚科中比較常用的系統性治療藥物,並根據我們的經驗提出用法建議。

Keywords: Atopic dermatitis, paediatric, systemic treatment

關鍵詞: 異位性皮膚炎、小兒科、系統性治療

Introduction

Atopic dermatitis (AD) affects 10-20% of children worldwide,1 with 28% of infants in Australia reported to suffer from eczema by 12 months of age.2 Atopic dermatitis places a significant burden on affected children and their families.

Atopic dermatitis is a cutaneous inflammatory reaction pattern, and individuals have varying thresholds dependent on the skin barrier function, susceptibility genes, immune function, and the environment, creating a broad range of clinical presentations. The two strongest associated risk factors for the development of AD are 1) family history of atopy and 2) loss of function mutations in the filaggrin (FLG) gene.3 There are many potential triggers, and most eczema presentations are multifactorial. Common triggers include dryness, heat, irritation, infection, allergy, intolerance or other immune stimuli.

Most patients respond well to the addressing of triggers and topical therapies including emollients, topical corticosteroids and topical calcineurin inhibitors, however a minority of children have resistant disease that requires a systemic approach. Safety of topical corticosteroid use has been extensively examined which is why they remain as the pivotal first line agent to settle eczema.4-6 Further review of topical therapies is beyond the scope of this article, which will focus on systemic therapies.

Treatment must be individually tailored, depending on age, site, morphology, extent, previous treatment and the presence or absence of secondary infection. Emollients form the basis of management, and should be used even when the skin is clear. Worsening of eczema is often due to bacterial super-infection and treatment with antibiotics (topical or systemic) is warranted. Educational programmes play a crucial role in eczema management for the patients and their families. An updated Cochrane review detailed potential gains of education programmes; although lacking rigorously designed studies, education may be especially important for parents of children under seven years old.7 The effectiveness is also directly linked to patient adherence to the application schedule, so the treatment must be acceptable to both the patient and caregiver.

Discoid, or nummular, eczema is of unknown aetiology, and starts with eczema at one site for any reason, usually in minimally atopic patients. The skin then breaks out in 'sympathy' patches, and becomes a vicious cycle. The rationale of therapy is to break the cycle, by preventing pruritus and maintaining a barrier function.

The aim of this paper is to review the systemic therapies.

Antihistamines

Although commonly prescribed for eczema-associated pruritus, a recent Cochrane review found no evidence to support the efficacy or safety of oral H1 antihistamines as monotherapy for children and adults with AD. A further review assessing efficacy as adjunct therapy is ongoing.8 In our experience antihistamines are useful in select patients with symptomatic dermographism.

Antimicrobials

Interventions to reduce Staphylococcus aureus in the management of AD were the subject of a recent Cochrane review and update.9,10 No convincing evidence for anti-staphylococcal interventions in patients with eczema that was not clinically infected was found. Of note the European TREatment of severe Atopic eczema in children Taskforce (TREAT) survey found that over half of the respondents routinely test and treat skin infection prior to initiation of systemic immunomodulatory agents, with the majority of clinicians opting for penicillins as the first-line.11 Certain individuals with eczema do seem to be particularly susceptible to secondary colonisation and infection. The use of bleach baths,12 and at times prophylactic oral antibiotic therapy for some individuals is important.

Systemic vitamin D

Vitamin D as therapy has been a popular topic of research in recent years, and stimulated much debate. Recent literature reviews have shown that replenishing deficient vitamin D levels in AD patients improves disease severity, with many studies showing an inverse relationship between AD severity and vitamin D levels.13 A Cochrane review in 2012, however, found no convincing evidence that dietary supplements were of benefit in established atopic eczema.14

Phototherapy / UV therapy

Narrowband UVB (nbUVB) (311 nm) is the preferred choice for full-body phototherapy in children as it is less erythemogenic and is the most efficient anti-inflammatory wavelength.15 It is also easier to deliver than psoralens and UVA (PUVA) which although proven to be efficacious in children, requires the strict use of protective eyewear for 24 hours. A comparative cohort study in children treated with twice weekly nbUVB for a total of 24 exposures (n=29) reported a 61% reduction in mean six area, six sign atopic dermatitis (SASSAD) score compared to a 6% increase in the unexposed cohort (n=26). This was associated with improved quality of life scores and maintained clinical effect for 6 months post treatment.16 A retrospective evaluation of nbUVB safety and efficacy in the treatment of psoriasis and AD in 129 paediatric patients found that 25% (9 of 36) of patients with AD cleared with the treatment, and 41% (16 of 36) had a partial response. Adverse effects in children with AD treated included six cases of mild erythema, one case of first-degree burn and three cases of pruritus. The authors advised annual follow-up for carcinoma surveillance.17 Narrowband UVB is an appropriate second-line therapy for eczema that requires much effort and copious topical corticosteroids to maintain, and may delay or prevent the need for immunomodulatory drugs. Contraindications include inability to attend for regular treatment, inability to stand in a confined space, fair skin or family history of skin cancer, and prolonged use with regard to the total UVB exposure. Long-term risk of skin cancer (particularly in Caucasian children) needs to be seriously considered, especially with children that may go on to receive systemic immunomodulatory treatment that further increases the risk of cutaneous malignancies.

Systemic treatments

Oral immunomodulatory treatments are indicated for chronic life-ruining eczema, and for AD patients whose families are in desperation. The aim of treatment is to provide respite and hopes to break the vicious cycle. Prior to initiating oral immunomodulatory treatments, it is important to rule out remediable reasons for the failure of first-line agents or exacerbating factors. It may also be prudent to have an observed hospital stay to ensure a failure in education or application techniques is not to blame for the treatment failure. There are no official prescribing guidelines for systemic agents in children with AD, and there is much variability between centres in monitoring recommendations. An update from our centre was published in 2008,18 and there have been other recent reviews on this topic.19,20

Prednisolone

Prednisolone, when necessary, is best used in very short bursts given the side effect profile of longer term use (see Table 1). It is useful for treating allergic reactions, especially severe type-1 or type-4 allergic reactions, in kick-starting therapy for severe eczema or discoid eczema, or to use at times when rapid clearance is important, such as for school examinations or camps. The usual starting dose is 1 mg/kg for 3 days, then weaned over 10 days. It is important to note that if oral prednisolone is taken at dosages of ≧20 mg/day, ≧2 mg/kg/day, for 14 days or longer, then live vaccinations are contraindicated during the subsequent three months.21 Children with concomitant asthma have often received previous courses of oral or inhaled corticosteroids, and clinicians should be wary of prescribing further courses in these patients due to cumulative risks.

Table 1 Indications, screening and monitoring advice for systemic agents in childhood atopic dermatitis18
Therapy Mechanism of action Advice/uses Screening Tests Monitoring Dose
nbUVB (311 nm) Immuno-modulatory via inhibition of Langerhan's cells and alters keratinocyte production
Also reduces Staphylococcus aureus colonisation
Eczema reasonably controlled but taking a lot of effort and topical steroids
Type IV or V skin
Full skin examination Clinic review
Ongoing annual full skin examination
Most common initial dose is 70% of minimal erythema dose (MED)
Usually 2-3 times a week for 12 week course or until clearance

MEDs >390 mJ/cm2 are more likely to clear
Prednisolone Anti-inflammatory effects via decreased production of cytokines and pro-inflammatory molecules and effects on specific inflammatory cells Allergic reactions
To 'kick start' therapy for severe eczema or discoid eczema
To use on school camps/examination times
Use in very short bursts
Usually none for short term use Usually none for short term use Usually 1 mg/kg for 3 days then wean down over 10 days
Cyclosporin A Calcineurin inhibitor(interleukin-2 inhibitor) For children who have a protracted flare and/or poor social situation, with a mild-moderate background eczema tendency
For severe combined chronic urticaria with eczema
Blood pressure

Blood tests at baseline: full blood count, renal and liver profiles
Blood pressure

2 hours post cyclosporin levels (aim for 400-1000 μg/L)

Blood tests (full blood count, renal and liver profile) at 1 month, then every 3 months
Maximum 5 mg/kg in divided doses

Wean down with control

Aim for 3-9 month course
Azathioprine Purine analogue
Anti-inflammatory and immune-suppressive effects
For chronic severe patients with massive IgE levels Blood tests at baseline:
Full blood count (note lymphocytes are sensitive, aim for range 1.0-1.5x103/μl)
Renal and liver profiles, IgE (very high >2000 units/mL usually with environmental allergies)
TPMT (1% of population have homozygous deficiency: have much higher risk of myelo-suppression)
Blood tests: Full blood count, renal and liver profile at 1 month and then every 3 months Aim for 2.5 mg/kg/day(dependent on TPMT level: TPMT <3 nmol/h/mL: contraindicated, TPMT 3-8nmol/h/mL: low dose 0.5-1mg/kg/day, TPMT 8-14.5 nmol/h/mL: 1-3 mg/kg/day allowed)Incremental dosage increase (start at 25% to 33% of full dose and increase to full dose over 6-8 weeks)
Methotrexate Inhibits dihydrofolate reductase
More anti-inflammatory than immuno-suppressive
Useful in recalcitrant discoid eczema and those not responding or intolerant to cyclosporin A and azathiaprine Blood tests at baseline:
Full blood count
Renal and liver profiles
Full blood count, renal and liver profiles at 1 month and then every 3 months At rheumatological doses:
0.3-0.6 mg/kg/week
MUST also take Folic Acid 5 mg weekly

Table 1 (Con't) Indications, screening and monitoring advice for systemic agents in childhood atopic dermatitis18
Advantages Contraindications/
considerations
Side effects
short term
Side effects long term
May delay or avoid the need for systemic immune-modulatory agents
Helps to decrease time-consuming topical regime
Logistics
Ability to stand in confined space
Fair skin
Family history of skin cancer
Prolonged use (consider total UVB exposure) and need for further immune-modulatory therapy in future
Erythema
Pruritus
Pain
Burn
Initial flare
Photosensitivity
Pigmentation
Hypertrichosis
Herpes simplex reactivation
Koebnerisation
Premature skin-aging
Cumulative risk of skin cancer unknown
Extremely effective
Rapid response
Short-term tolerability
Low cost
Availability
Consider previous corticosteroid use (topical, inhaled, previous oral prednisolone courses)
Long-term side effects unacceptable
Corticosteroid dependency
Hypothalamic-pituitary-adrenal axis
Steroid withdrawal syndrome
Addisonian crisis

Metabolic effects
Hyperglycaemia, hypertension
Congestive heart failure
Cushingoid changes
Increased appetite, excessive weight gain
Hypokalaemia, hypertriglyceridaemia
Hypocalcaemia
Menstrual irregularity
Osteoporosis, osteonecrosis
Myopathy
Growth impairment

Cutaneous
Flare of pustular psoriasis
Poor healing
Striae, atrophy, telangiectasia
Steroid acne, actinic purpura
Infection
Telogen effluvium, hirsutism
Acanthosis nigricans

Gastrointestinal
Nausea, vomiting, steato-hepatitis
Peptic ulcer disease
Gastro-oesophageal reflux
Bowel perforation

Ocular
Cataracts, glaucoma
Refraction error, infection

Psychiatric
Psychosis, personality change,
Depression, agitation
Pseudotumour cerebri
Epidural lipomatosis
Peripheral neuropathy

Infectious
Tuberculosis reactivation
Herpes virus
Opportunitistic infections

Malignancy
Non-Hodgkin's lymphoma
Kaposi's sarcoma
Squamous cell carcinoma
(skin, female genito-urinary tract)
Well-tolerated
Convenient syrup
Reasonably quick acting
Usually achieves adequate control
Children tend to tolerate better than adults
Renal impairment
Eczema will often flare upon weaning
Renal dysfunction
Hypertension
Headache
Tremor, paraesthesia and hyperaesthesia
Arthralgia and myalgia Hypertrichosis
Nausea and vomiting
Gingival hyperplasia
Hyperkalaemia
Hyperuricaemia
Hypomagnesaemia
Hyperlipidaemia
Lymphoma
Internal malignancy
Skin cancer Chronic renal disease (arteriolo-pathy and tubular interstitial disease)
Has continued effect even after cessation
Many patients are able to be weaned successfully
May not be as immunosuppressive as cyclosporin A
Delayed onset of action: up to 12 weeks after full dose reached Hypersensitivity reactions (within 1-4 weeks of initiation) including: fever, malaise, rigors, myalgia, cardiovascular collapse,pneumonitis cutaneous eruptions(maculopapular rash, urticaria, vasculitis, erythema multiforme, erythema nodosum)

Pancytopaenia
Nausea, vomiting Diarrhoea
Malignancy including
Non-Hodgkin
B-cell
lymphoma
Squamous cell carcinoma of skin

Opportunistic infections including
Herpes simplex
Herpes zoster
Human papilloma-virus
Molluscum contagiosum

Teratogenicity
Well-tolerated
Safer than other immuno-suppressants
Not as powerful Haematological toxicity: pancytopaenia
Nausea, Vomiting Stomatitis
Hepatotoxicity Idiosyncratic pulmonary toxicity(acute pneumonitis, pulmonary fibrosis)
Renal toxicity
Headache
Fatigue
Dizziness
Cutaneous effects including acral erythema, epidermal necrosis, vasculitis, alopecia and phototoxicity
Lymphoma
Teratogenicity
Methotrexate osteopathy

Cyclosporin A

Cyclosporin A is a calcineurin and IL-2 inhibitor, and potently inhibits T-lymphocyte dependent immune responses. Cyclosporin was recently found to be the most common systemic treatment for children with severe AD in the TREAT survey, followed by oral corticosteroids and then azathioprine.11 Recently, an unblended study compared the efficacy and safety of methotrexate (7.5 mg/week) and cyclosporin (2.5 mg/kg/day) over a 12-week period in 40 children with severe AD: both agents showed similar efficacy and were associated with mild and reversible side effects, none of which required dose reduction or cessation of the drug.22 Schmitt et al undertook a systematic review and meta-analysis of cyclosporin for AD treatment: three of their included studies involved only children, with doses ranging from 2.5 to 5 mg/kg/day for durations ranging from six weeks to one year. Pooled data from the meta-analysis including adults as well found that cyclosporin was similarly effective in adults and children, with a relative effectiveness of 55% after six to eight weeks.23

There are no published guidelines for dosing and monitoring in children. Flohr and Irvine have recently published their advice for adults and children on systemic therapies, and recommended starting cyclosporin at 2.5 mg/kg/day, increasing to 5 mg/kg/day if necessary.19 We start our patients on 5 mg/kg/day in divided doses, and measure cyclosporin levels two hours post dose, aiming for 400-1000 mg/L. We monitor blood pressure, full blood count, renal and liver profile pre-treatment, after one month, and subsequently every three months (see Table 1). The dose should be weaned as disease is controlled, and a total duration of therapy of 3-9 months is recommended. Cyclosporin is generally well-tolerated, especially in younger patients, and is available as a convenient syrup formulation. The onset of action is rapid, and it usually achieves adequate control, but prompt relapse after cessation is the rule. Long-term side effects include impaired renal function, immunosuppression, hypertension, hyperlipidaemia, hypertrichosis and gingival hyperplasia. We find it useful for children who experience a protracted flare and/or a poor social situation, on a background of not overly severe AD, and also for severe chronic urticaria combined with eczema.

Azathioprine

Azathioprine is a purine analogue with anti-inflammatory and immunosuppressive effects. A retrospective evaluation of azathioprine in 48 children with severe AD has shown it to be safe and effective, although in some cases a higher dosage than the usual adult dosage (2.5-3.5 mg/kg/day) was needed, possibly due to decreased drug absorption.24 The British Association of Dermatologists' guidelines for the safe use of azathioprine advise long-term follow-up, and advise on photoprotection when using the drug off-licensed for paediatric AD.25

Although not reported in AD patients treated with azathioprine, the risks of lymphoma or progressive multifocal leucoencephalopathy (PML) may be especially important when receiving azathioprine in the context of inflammatory bowel disease (lymphoma) or in combination immunosuppressive therapy or in autoimmune disease (PML).19

Thiopurine methyl-transferase (TPMT) metabolises azathioprine to an inactive metabolite, and activity of this enzyme must be tested prior to therapy to reduce the risk of toxicity. One percent of the population has a homozygous deficiency in TPMT and are therefore at higher risk of myelosuppression secondary to increased conversion to the active metabolite, mercaptopurine. Potential problems with azathioprine include tolerability (nausea, lethargy, tiredness), hypersensitivity (seen after two to three weeks of therapy), immunosuppression and bone marrow suppression.

The target dose should be 2.5 mg/kg/day, achieved with incremental increases: start at one quarter to one third of the calculated full dose, and increase gradually over six to eight weeks. Full blood count, renal and liver profile, IgE and TPMT levels should be checked pre-treatment, then a repeat full blood count, renal and liver profile should be checked after one and three months. Dosage increases should be accompanied by more frequent blood tests. Very high levels of IgE (greater than 2000 units/mL), are often associated with environmental allergies, this ratifies the decision to use immunosuppression but does not impact upon therapy. It is noteworthy that atopic dermatitis with other manifestations of atopy including IgE elevations was concluded to be a risk factor for childhood asthma occurrence, severity and persistence.26

Azathioprine has a delayed clinical effect taking up to eight to 12 weeks before improvement is seen after the full dose is reached. Lymphocyte count is the most sensitive biochemical marker of effect, and we aim for a range of 1.0 to 1.5x103/μl. Benefits of azathioprine include sustained efficacy, and most patients can be successfully weaned off treatment over many months. We recommend using azathioprine for patients with chronic, severe eczema with massive IgE levels.

Methotrexate

Methotrexate inhibits dihydrofolate reductase, and is more anti-inflammatory than immunosuppressive, and although the mechanism in AD is poorly understood, it is known to reduce allergen-specific T-cell activity. Rheumatological doses are 0.3-0.6 mg/kg/week and it is from the rheumatology literature that most information about this drug is derived. As previously discussed, a randomised controlled trial in 40 children found methotrexate (7.5 mg weekly) comparable in efficacy with cyclosporin (2.5 mg/kg/day).22 Methotrexate has a delayed clinical efficacy similar to azathioprine. We often use 10 mg/week, with the option to increase to 15 mg/week if it is well-tolerated. Folic acid 5 mg/week should be given. Full blood count and renal and liver profile should be checked pre-treatment, at one month, and then every three months. Methotrexate is generally well-tolerated, with occasional nausea, liver function abnormalities and bone marrow suppression. Subcutaneous administration may ameliorate gastrointestinal upset, and can be successful in those not responding to oral therapy. In our experience, it is safer than other immunosuppressants, though not as powerful. It is useful in recalcitrant discoid eczema and those not tolerating or responding to cyclosporin or azathioprine.

Other treatment options

The remaining systemic treatment options have insufficient evidence to guide clinical practice.27 Mycophenolate mofetil (MMF) is not funded in Australia, and may cause unwanted gastrointestinal side effects, and less commonly liver dysfunction and rarely bone marrow suppression. A retrospective chart analysis of 12 children with severe AD treated with MMF after failure to respond to, or intolerance of azathioprine reported 66% (8 of 12) of patients had significant clinical improvement, and lower rates of laboratory abnormalities when compared to children on azathioprine.28 A retrospective analysis of 14 children treated with MMF, at doses of 40-50 mg/kg/day for younger children and 30-40 mg/kg/day for adolescents, reported that 8 of 14 patients had >90% improvement within three months of therapy initiation. All patients tolerated the medication well, and 12 patients continued treatment for up to 24 months without adverse effects.29

Interferon gamma may be considered as a third-line therapy option for patients with severe AD unsuitable for, or resistant to, other systemic agents. Close monitoring is required, and moderate evidence for its short-term use in adults has been discussed in a review.30

Use of intravenous immunoglobulin (IVIg) is limited by a high cost and limited access, and in a recent review was not recommended for treatment of severe AD due to poorer efficacy compared to placebo or cyclosporin.30

Roekevisch et al conducted a systematic review of safety and efficacy of systemic therapy for moderate to severe AD in adults, and suggested pimecrolimus as a possible short-term option. They advised that montelukast, traditional Chinese herbal medicine, Mycobacterium vaccae (specifically reviewed in children), and thymopentin are currently not recommended for treatment of AD. Randomised controlled trials using these medications in children are lacking.

Omalizumab is an IgE monoclonal antibody that, until recently, had been sparsely reported as a treatment for children with AD. A letter reporting the use of omalizumab in seven children (aged 6-19 years) for severe AD, with doses dependent on patient's mass and baseline serum IgE titres found that all patients improved after three to six months, with IgE levels reduced by 60.5%. There were no adverse effects reported during the mean follow-up period of 30 months.31

The T-cell modulator, efalizumab, does not have robust enough evidence to recommend its off-label use in this population. Siegfried reported sustained efficacy in a child, though the patient developed acute autoimmune thrombocytopaenia and was forced to discontinue its use.32

In summary, it is important to prevent eczema from remaining severe, and be liberal with the use of topical corticosteroids, and to be aware of systemic agents for cases that require them.

References

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