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IJPD SYMPOSIUM
Year : 2018  |  Volume : 19  |  Issue : 2  |  Page : 108-115

Treatment guidelines for atopic dermatitis by ISPD task force 2016


1 Department of Pediatric Dermatology, Wadia Children Hospital, Mumbai, Maharashtra, India
2 Department of Pediatric Dermatology, Institute of Child Health, Kolkata, West Bengal, India
3 Consultant Pediatric Dermatologist, Kanchi Kamakoti Childs Trust Hospital, Chennai, Tamil Nadu, India
4 Consultant Pediatric Dermatologist, Indira Gandhi Institute of Child Health, Bangalore, Karnataka, India
5 Department of DVL-1, CMC, Vellore, Tamil Nadu, India
6 Department of Dermatology, Sri B M Patil Medical College, BLDE University, Bijapur, Karnataka, India
7 Hon. Pediatric Dermatologist, Wadia Hospital for Children, Mumbai, Maharashtra, India
8 Professor of Dermatology, Vivekananda Institute of Medical Science, Kolkata, West Bengal, India
9 Department of Dermatology, Sharda Hospital, Greater Noida, Uttar Pradesh, India
10 Department of Dermatology, Lady Hardinge Medical College, Delhi, India
11 Department of Dermatology, MAMC and Associated LNGP Hospital, New Delhi, India
12 Consultant, Dermatologist, S D M Hospital, Jaipur, Rajasthan, India

Date of Web Publication26-Mar-2018

Correspondence Address:
Sandipan Dhar
Flat 9C, Palazzo, 35, Panditia Road, Kolkata - 700 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.IJPD_28_18

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How to cite this article:
Parikh D, Dhar S, Ramamoorthy R, Srinivas S, Sarkar R, Inamadar A, Shah M, Banerjee R, Kanwar AJ, Mendiratta V, George R, Gulati R. Treatment guidelines for atopic dermatitis by ISPD task force 2016. Indian J Paediatr Dermatol 2018;19:108-15

How to cite this URL:
Parikh D, Dhar S, Ramamoorthy R, Srinivas S, Sarkar R, Inamadar A, Shah M, Banerjee R, Kanwar AJ, Mendiratta V, George R, Gulati R. Treatment guidelines for atopic dermatitis by ISPD task force 2016. Indian J Paediatr Dermatol [serial online] 2018 [cited 2018 Sep 22];19:108-15. Available from: http://www.ijpd.in/text.asp?2018/19/2/108/228348



Part-3: Systemic Therapies

These guidelines are prepared by ISPD task force. It reflects the groups' experience, opinion and recommendation on the current treatment of atopic dermatitis in Indian scenario.

Disclaimer

Adherence to these guidelines will not ensure successful treatment in every situation. Furthermore, these guidelines should not be interpreted as setting a standard of care, or be deemed inclusive of all proper methods of care nor exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific therapy must be made by the physician and the patient in light of all the circumstances presented by the individual patient, and the known variability and biological behavior of the disease. This guideline reflects the best available data at the time the guideline was prepared. The results of future studies may require revisions to the recommendations in this guideline to reflect new data.

Atopic dermatitis (AD) is a chronic pruritic inflammatory skin condition. This guideline outlines various treatment options.

When to Use Systemic Therapy and Oral Steroids

Recently there has been a comprehensive article on 'when to start systemic therapy on atopic dermatitis' by International Eczema Council (IEC).[1] This guideline addresses the use of systemic therapy including oral steroids in pediatric atopic dermatitis patients. We recommend systemic immunomodulatory agents for the following situations:

  • Severe recalcitrant AD (pediatric patients in whom topical regimens using emollients, topical anti-inflammatory therapies, adjunctive methods, and/or phototherapy do not adequately control the disease, and contact dermatitis and food allergy has been considered)[2]
  • Widespread atopic dermatitis including erythroderma due to AD
  • Steroid dependent atopic dermatitis
  • Patients whose medical, physical, and/or psychological states are affected immensely by their skin disease, and may include adverse impact on school performance or personal relationships [2]
  • Oral steroids are recommended only as short term bridging therapy while buying time for other immunosuppresssants to act. It should only be used if there is an affordability issue and there is no other option. Otherwise it is better to avoid. When used, it should be prednisolone 0.5 mg/kg/day tapering off in 2-3 weeks.[3]


There are few studies in the literature that compare different systemic therapies with one another in a randomized, controlled fashion.[4],[5],[6] It is therefore difficult to determine the relative efficacy of the available options for the pediatric population. Current literature suggests that cyclosporine (CsA), methotrexate (MTX), mycophenolate mofetil (MMF), and azathioprine (AZA) are used the most and are more efficacious in treating AD, whereas other agents (leukotriene inhibitors, oral calcineurin inhibitors) have limited data. Biologic drugs are relatively new and the lack of available data prevents a recommendation for use in AD at this time. The management of AD with systemic corticosteroids should generally be avoided because of short- and long-term adverse effects and an unfavourable benefit-risk profile,[7],[8],[9],[10] however we recommend short term bridging therapy when buying time for other immunosuppressants to take effect.

CsA is the only FDA-approved treatment of atopic dermatitis in children and is approved in Europe as a first-line systemic treatment for severe AD in children and adults.[6] Multiple RCTs support the use of CsA for recalcitrant AD.[11] It is very effective as a rescue treatment due to rapid onset of action. AZA is used primarily as a stabilizing therapy to control relapse rather than as a rescue treatment.[12] An extensive systematic review puts a strong clinical recommendation for AZA in atopic dermatitis while another case series shows safety in many children treated for more than 1 year.[13],[14],[15] MTX is recommended as a systemic agent for the treatment of refractory AD.[16] Considering the cost benefit ratio, MTX may be considered as a first line systemic treatment. MMF may be considered as an alternative, variably effective therapy for refractory AD.[6],[17] All systemic treatments need a thorough pre-evaluation including screening for infections like HIV, Hepatitis B, Hepatitis C and tuberculosis. Relapse after withdrawl of systemic treatment varies from drug to drug, and can be managed either on topical treatment or reintroduction of the same or different immunomodulatory as appropriate.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

  1. Simpson E L, Brui-Weller M, Flohr C, Arden-Jones MR, Barbarot S, Deleuran M, et al. When does atopic dermatitis warrant systemic therapy ? Recommendations from an expert panel of the International Eczema Council. J Am Acad Dermatol 2017;77:623-33.
  2. Sidbury R, Davis DM, Cohen DE, Cordoro KM, Berger TG, Bergman JN, et al. Guidelines of care for the management of atopic dermatitis Section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol 2014; 71:327-49.
  3. Drucker AM, Eyerich K, de Brin-Waller MS, Thyssen JP, Splus PI, Irvine AD, et al. Use of systemic corticosteroids for atopic dermatitis: International Eczema Council consensus statement. Br J Dermatol 2018 (in press).
  4. Schram ME, Roekevisch E, Leeflang MM, Bos JD, Schmitt J, Spuls PI. A randomized trial of methotrexate versus azathioprine for severe atopic eczema. J Allergy Clin Immunol 2011;128:353-9.
  5. Haeck IM, Knol MJ, Ten Berge O, van Velsen SG, de Bruin-Weller MS, Bruijnzeel-Koomen CA. Enteric-coated mycophenolate sodium versus cyclosporin A as long-term treatment in adult patients with severe atopic dermatitis: a randomized controlled trial. J Am Acad Dermatol 2011;64:1074-84.
  6. Schmitt J, Schakel K, Folster-Holst R, Bauer A, Oertel R, Augustin M, et al. Prednisolone vs cyclosporin for severe adult eczema: an investigator-initiated double-blind placebo-controlled multicenter trial. Br J Dermatol 2010;162:661-8.
  7. Slater NA, Morrell DS. Systemic therapy of childhood atopic dermatitis. Clin Dermatol 2015;33:289-99.
  8. Neves WC, Mayumi J, Gianini A, Liuson D, Tanaka E. Rebound phenomenon to systemic corticosteroid in atopic dermatitis. Allergol Immunopathol. 2005;33:307-11.
  9. Ricci G, Dondi A, Patrizi A, Masi M. Systemic therapy of atopic dermatitis in children. Drugs 2009;69:297-306.
  10. Tan AU, Gonzalez ME. Management of severe atopic dermatitis in children. J Drugs Dermatol 2012;11:1158-65.
  11. Roekevisch E, Spuls PI, Kuester D, Limpens J, Schmitt J. Efficacy and safety of systemic treatments for moderate-to-severe atopic dermatitis: A systematic review. J Allergy Clin Immunol. 2014;133:429-38.
  12. Garnacho-Saucedo G, Salido-Vallejo R, Moreno-Gimenez JC. Actualización en dermatitis atópica. Propuesta de algoritmo de actuación. Actas Dermosifiliogr 2013;104:4-16.
  13. Schram ME, Borgonjen RJ, Bik CM, van der Schroeff JG, van Everdingen JJ, Spuls Pl, et al. Off-label use of azathioprine in dermatology: A systematic review. Arch Dermatol 2011;147:474-88.
  14. Caufield M, Tom WL. Oral azathioprine for recalcitrant pediatric atopic dermatitis: Clinical response and thiopurine monitoring. J Am Acad Dermatol 2013;68:29-35.
  15. Waxweiler WT, Agans R, Morrell DS. Systemic treatment of pediatric atopic dermatitis with azathioprine and mycophenolate mofetil. Pediatr Dermatol 2011;28:689-94.
  16. El-Khalawany MA, Hassan H, Shaaban D, Ghonaim N, Eassa B. Methotrexate versus cyclosporine in the treatment of severe atopic dermatitis in children: A multicenter experience from Egypt. Eur J Pediatr 2013;172:351-6.
  17. Heller M, Shin HT, Orlow SJ, Schaffer JV. Mycophenolate mofetil for severe childhood atopic dermatitis: Experience in 14 patients. Br J Dermatol 2007;157:127-32.



  Cyclosporine Top


Cyclosporine (CsA) has been shown to be particularly useful for short term control of AD in children aged 2 to 16 years with good tolerability and a relative effectiveness of 55% after six to 8 weeks of therapy.[1],[2] An initial dosage of 5 mg/kg of CsA is clearly superior in terms of faster clinical efficacy in atopic dermatitis, when compared to 2.5 mg/kg/day.[3] Relapse of AD within 6 weeks of discontinuation of CsA has been noted in about 80% patients.[1],[4]

Continuous therapy of AD with CsA gives superior results in terms of better control of the disease.[2] Recently, longer course with low dose CsA was found to be associated with longer duration of remission of AD.[5],[6]

CsA has been used for prevention and treatment of transplant rejection in infants older than 6 months of age.[7] Renal toxicity of cyclosporine is associated with larger cumulative dose, longer treatment duration and higher daily dose of >5 mg/kg.[8] In general children show higher tolerability to Cs when compared to adults, with a lesser incidence adverse effects.[1],[9],[8],[10] However, in view of the lack of sufficient data on the long term safety with respect to kidney function during cyclosporine usage,[11] continuous therapy of AD with CsA for more than a year is not recommended. Longterm risk of malignancy in children treated with CsA is unknown and likely to be minimal.

Recommendations; Strength of recommendation A: level of evidence 1.

  • Cyclosporine is the only US FDA approved drug for systemic therapy of recalcitrant AD
  • The usually recommended dosage schedule of CsA for severe AD is 2.5 to 5mg/kg/day in divided doses. the dose of CsA is tapered after sufficient clinical response over the next two to three months months to a dose of 1.5 to 3 mg/kg/day.[12] Appropriate antibiotic therapy for skin infections should instituted before commencing on CsA
  • Insufficient clinical response within three weeks of treatment in spite of being on adequate dosage of CsA is an indication for discontinuation of CsA and a need to switch over to other therapeutic options for severe AD
  • Blood pressure measurements, urine analysis and creatinine levels should be checked regularly at intervals of two weeks for first eight weeks. Monitoring of lipid profile is also required. Sustained increase in level of creatinine by greater than 30% over baseline for more than two weeks requires reduction in dosage of CsA by 25 to 50% for a period of one month and then serum creatinine should be rechecked. If the creatinine level continues to remain elevated by more than 30% above the baseline, therapy with CsA should be discontinued. Therapy with CsA can be restarted at a lower dose if the creatinine level is within 10% of the baseline value.[13]
  • Continuous therapy for more than a year with CsA is not recommended
  • Concomitant usage of phototherapy or immunosuppressants is not recommended.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

  1. Schmitt J, Schmitt N, Meurer M. Cyclosporin in the treatment of patients with atopic eczema – A systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2007;21:606-19.
  2. J.I. Harper, I. Ahmed. G. Barclay, M. Lacour et al., Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy, Br J Dermatol. 2000:142:52-5.
  3. Roekevisch E, Spuls PI, Kuester D, Limpens J, Schmitt J. Efficacy and safety of systemic treatments for moderate-tosevere atopic dermatitis: a systematic review. J Allergy Clin Immunol 2014;133:429-38.
  4. McAleer M A, Flohr C, Irvine AD, Management of difficult and severe eczemain childhood. BMJ 2012;345:e 4770.
  5. Haw S, Shin Min-Kyung, Haw Choong-Rim. Ann Dermatol 2010;22:9-15. The Efficacy and Safety of Long-term Oral Cyclosporine Treatment for Patients with Atopic Dermatitis. Ann of Dermatol 2010;22:9-15.
  6. Cathryn Sibbald, Elena Pope, Nhung Ho Miriam Weinstein Retrospective Review of Relapse after Systemic Cyclosporine in Children with Atopic Dermatitis.pediatr dermatol. 2015;1:36-40.
  7. Cordoro KM. Systemic and Light Therapies for the Management of Childhood Psoriasis: Part II, skin therapy letter. 2008;13:1-3.
  8. G. Feutren and M. J. Mihatsch, Risk Factors for Cyclosporine-Induced Nephropathy in Patients with Autoimmune Diseases, N Engl J Med. 1992;326:1654-60.
  9. Jorien Van Der Schaft, Arjan D. Van Zulienz, Joukje Deinum, Carla A. F. M, de Bruin-Weller MS. Serum Creatinine Levels During and After Long-term Treatment with Cyclosporine A in Patients with Severe Atopic Dermatitis. Acta Derm Venereol 2015;95:963-7
  10. ZonneveldIM, DeRieMA, BeljaardsRC, VanDerRhee HJ, Wuite J, Zeegelaar J, et al. The long-term safety and efficacy of cyclosporin in severe refractory atopic dermatitis: a comparison of two dosage regimens. Br J Dermatol. 1996;135 Suppl 48:15-20.
  11. Eliza R. Notaro, Robert Sidbury, Systemic Agents for Severe Atopic Dermatitis in Children, Pediatr Drugs. 2015;17:449-7.
  12. Giampaolo Ricci, Arianna Dondi, Annalisa Patrizi and Massimo Masi. Systemic Therapy of Atopic Dermatitis in Children Drugs 2009;69:297-306.
  13. Ryan C, Amor K T, Mentor A. The use cyclosporine in dermatology: part 2, J Am Acad Dermatol 2010;63:949-72.



  Methotrexate Top


Methotrexate (MTX) is a useful therapeutic option often employed in the management of severe atopic dermatitis in adults.[1],[2],[3] MTX has been widely used in children in other chronic inflammatory diseases with a well established efficacy and safety data.[4],[5],[6],[7],[8],[9],[10],[11] Because of its favourable toxicity profile and efficacy, low dose MTX is increasingly used by many dermatologists world wide for AD. MTX commonly is used as first line therapy for the treatment of severe AD in our setting.

Clinical improvement may not be noticed until 12 weeks after intake of MTX. The efficacy of MTX in adult AD is comparable to that of azathioprine.[5] No statistically significant difference in clinical improvement of AD was seen between groups of children aged 7 to 14 yrs, who were on 7.5 mg/week of MTX and CsA at a dose of 2.5 mg/kg/day for 12 weeks. However remission of AD produced by MTX was long lasting when compared to CsA.[3] 75% of children diagnosed with AD responded to MTX in a recently published, retrospective uncontrolled study.[7] In another study, MTX was found to be effective in clearing refractory discoid eczema in children aged 3 to 15 years.[6] MTX is particularly effective in children who presented with psoriasis eczema overlap.[8]

Recommendations: Strength of recommendation B: level of evidence 2.

  • MTX is usually administered at 0.2 to 0.7 mg/kg/week until achievement of therapeutic response followed by slow tapering to maintanence dose
  • Co-administration of 5mg of Folic acid once weekly, 24 hours prior to the weekly dose of MTX or the day following the dose is recommended [11]
  • Routine laboratory investigations for monitoring hematologic, liver, renal parameters can be performed at longer intervals than those used in adults.[9]


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

  1. Weatherhead SC, Wahie S, Reynolds NJ, et al. An open-label, dose-ranging study of methotrexate for moderate-to-severe adult atopic eczema. Br J Dermatol 2007;156:346-1.
  2. Goujon C, Berard F, Dahel K, Guillot I, Hennino A, Nosbaum A et al. Methotrexate for the treatment of adult atopic dermatitis. Eur J Dermatol 2006;16:155-158. 59.
  3. Lyakhovitsky A, Barzilai A, Heyman R, Baum S, Amichai B, Solomon M et al. Low-dose methotrexate treatment for moderate-to-severe atopic dermatitis in adults. J Eur Acad Dermatol Venereol 2010;24:434-39.
  4. El-Khalawany MA, Hassan H, Shaaban D, Ghonaim N, Eassa B. Methotrexate versus cyclosporine in the treatment of severe atopic dermatitis in children: a multicenter experience from Egypt. Eur J Pediatr 2013;172:351-6.
  5. Schram ME, Roekevisch E, Leeflang MM, Bos JD, Schmitt J, Spuls PI. A randomized trial of methotrexate versus azathioprine for severe atopic eczema. J Allergy Clin Immunol 2011;128:353-59.
  6. Roberts H, Orchard D. Methotrexate is a safe and effective treatment for paediatric discoid (nummular) eczema: a case series of 25 children. Australas J Dermatol 2010;51:128-130.
  7. Deo M, Yung A, Hill S, Rademaker M. Methotrexate for treatment of atopic dermatitis in children and adolescents. Int J Dermatol. 2014;53(8):1037-41.
  8. Rahman SI, Siegfried E, Flanagan KH, et al. The methotrexate polyglutamate assay supports the efficacy of methotrexate for severe inflammatory skin disease in children. J Am Acad Dermatol. 2014;70:252-6.
  9. Tim Niehues and Petra Lankisch, Recommendations for the Use of Methotrexate in Juvenile Idiopathic Arthritis, Pediatr Drugs 2006;8(6):347-35.
  10. Hashkes PJ, Becker ML, Cabral DA, Laxer RM, Paller AS et al., Methotrexate: new uses for an old drug J Pediatr 2014;164(2):231-6.
  11. S.L. Morgan and J.E. Baggott, Folate supplementation during methotrexate therapy for rheumatoid arthritis, Clin Exp Rheumatol 2010; 28 (Suppl. 61): S102-S109.



  Azothioprine (AZT) Top


It is indicated in severe, recalcitrant atopic dermatitis (AD) not responding to topical therapy (off label use in AD). It is given in a small subset of children not responding to cyclosporine.[1] In a systematic review of off label use of oral AZT, high quality evidence (level A) was found for moderate thereuptic effect in severe atopic dermatitis.[2] AZT is a purine analog that blocks the synthesis of DNA and RNA, thus inhibiting the proliferation of T and B cells there by reducing the inflammation in AD.

Several studies have shown clinical efficacy of AZT between 2-4 mg/kg/day from a period of 12 weeks to 12 months.[3],[4],[5],[6] However we believe that in the Indian scenario of lower dose of 1-2mg/kg/day is better tolerated. Metabolism of AZT is based on individual TPMT levels (thiopurine methyltransferase). Genetic polymorphisms in TPMT activity are linked to individual susceptibility to AZT toxicity. Adverse effects include gastrointestinal disturbances, hepatotoxicity, leucopenia and myelosuppression.[3] There is risk of myelosuppression with low TPMT levels. Dose adjustment can be done to prevent myelosuppression. Normal or high TPMT levels include >15.4 U/ml and low TPMT include <5.9 U/ml. TPMT assay is not completely reliable as it is an inducible enzyme and the change of levels has been reported over time, and hence leucocyte count should be regularly monitered, but it is strongly recommended before starting AZT.[3]

In a recent cohort of adverse effects of long term (mean duration 2.14 years) AZT in 182 children there was no fatal reaction noted and majority of the children had mild adverse effect. Among them 11 children had low TPMT levels.[7] There are no published guidelines for monitoring adverse effects of AZT in children. Pre evaluation of complete blood count, liver enzymes, HIV, hepatitis B and C, mantoux test and TPMT levels is necessary. Blood tests should be repeated after 1, 3, 7 and 12 weeks.[7]

Level of evidence and strength of recommendation: 2, B

Recommendations

  • AZT is recommended if AD is not responding to cyclosporine or Methotrexate
  • Pre evaluation of complete blood counts, liver enzymes and mantoux test is necessary
  • Children should be screened for TPMT levels before starting AZT. Dosing should be based on TPMT levels
  • Children with normal TPMT levels can be started between 1-2 mg/kg/day and stepped up to 3 mg/kg/day depending upon the clinical response. Low TPMT levels can be started on low dose 1mg/kg body weight or avoided and monitored for side effects
  • If TPMT levels cannot be afforded, AZT can be started at lowest dose and monitored for adverse effects. Investigations should be repeated after every 4-5 days for 2 to 3 weeks and dosage can be increased by 0.5 mg every week accordingly to a maximum dosage based on clinical response
  • AZT can be given up to 6 months to 3 years with regular monitoring of complete blood counts and liver enzymes.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

  1. Sarkar R. Proceedings from “Clinical Dermatology Updates - Atopic dermatitis, 3-4March, 2012, Mumbai. Indian J Dermatol Venereol Leprol 2012;78:524-5.
  2. Schram ME, Borgonjen RJ, Bik CM, van der Schroeff JG, van Everdingen JJ, Spuls Pl, et al. Off-label use of azothioprine in dermatology: a systematic review. Arch Dermatol 2011;147:474-88.
  3. Caufield M, Tom WL. Oral azathioprine for recalcitrant pediatric atopic dermatitis: clinical response and thiopurine monitoring. J Am Acad Dermatol 2013;68:29-35.
  4. Murphy L.A, Atherton D. A retrospective evaluation of azathioprine in severe childhood atopic eczema, using thiopurine methyltransferase levels to exclude patients at high risk of myelosuppression. Br J Dermatol 2002;147:308–315
  5. Waxweiler W.T, Agans R, Morrell D.S. Systemic treatment of pediatric atopic dermatitis with azathioprine and mycophenolate mofetil. Pediatr Dermatol 2011;28:689–694.
  6. Hon KL, Ching GK, Leung TF, Chow CM, Lee KK, Ng PC. Efficacy and tolerability at 3 and 6 months following use of azathioprine for recalcitrant atopic dermatitis in children and young adults. J Dermatolog Treat 2009;20:141-5.
  7. Fuggle NR, Bragoli W, Mahto A, Glover M, Martinez AE, Kinsler VA. The adverse effect profile of oral azathioprine in pediatric atopic dermatitis, and recommendations for monitoring. J Am Acad Dermatol. 2015;72:108-14



  Mycophenolate Mofetil (MMF) Top


MMF is an off label indication for treatment of severe, recalcitrant AD not responding to other systemic agents.[1] There are insufficient studies regarding efficacy of MMF in children. MMF blocks purine biosynthesis pathway of T and B cells by inhibiting inosine monophosphate dehydrogenase and decreases inflammation. There are insufficient studies comparing the efficacy of MMF with other immunosuppressant as monotherapy.

MMF has been given for AD at a dose of 0.5g - 2g/day in adults with good clinical improvement upto 12 to 24 months with good safety profile.[2],[3] In an uncontrolled retrospective study of 14 children (age above 2 years) treated with MMF for recalcitrant AD, efficacy was present at dosage of 40-50 mg/kg/day in younger children, and 30-40 mg/kg/day in adolescents. Clinical improvement was seen at 8 to 12 weeks. Among the 14 children, 4 children showed complete clearance, 4 children had more than 90% improvement, 5 had 60-90% improvement and 1 had not responed to treatment.[4] There is paucity of data regarding long term MMF monotherapy.

MMF has a favourable long term side effect profile compared to cyclosporine, but cyclosporine has greater efficacy than MMF.[1] MMF is well tolerated in children. In the above study mentioned none of the children showed any adverse effect. Side effects known with MMF are gastrointestinal effects like nausea, diarrhea, anorexia, abdominal cramps, emesis, headache, hematological effects like anemia, leucopenia and thrombocytopenia. However newer derivative enteric coated mycophenolate sodium salt is better tolerated as it reduces gastrointestinal side effects.[5] Rarely cutaneous infections, genitourinary symptoms like frequent urination, dysuria, hematuria and malignancy can be associated. Baseline monitoring includes complete blood count, urine analysis, liver and renal function tests, HIV and Mantoux test.

Level of evidence and strength of recommendation: 3, C

Recommendations

  • MMF can be used for treatment of recalcitrant AD if cyclosporine or AZT is not effective, however there are not enough clinical data regarding its efficacy and safety profile in children
  • There is insufficient data in children to make recommendation regarding MMF dosing, duration and maintenance in children
  • However the dosing ranges from 30-50 mg/kg/day and can be given up to 1 to 2 years with good safety profile with regular monitoring of blood counts, liver and renal function tests.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

  1. Buell C, Koo J. Long term safety of mycophenolate and cyclosporine: A review. J Drugs Dermatol 2008;7:741-8.
  2. Murray ML, Cohen JB. Mycophenolate mofetil therapy for moderate to severe atopic dermatitis. Clin Exp Dermatol 2006;32:23-7.
  3. Grundmann-Kollman M, Podda M, Oschsendorf F, et al. Mycophenolate mofetil is effective in the treatment of atopic dermatitis. Arch Dermatol 2001;137:870-73.
  4. Heller M, Shin HT, Orlow SJ, Schaffer JV. Mycophenolate mofetil for severe childhood atopic dermatitis: experience in14 patients. Br J Dermatol 2007;157:127-32.
  5. Burg M, Saemann MD, Wieser C, Kramer S, Fischer W, Lhotta K. Enteric-coated mycophenolate sodium reduced gastrointestinal symptoms in renal patients. Transplant Proc 2009;4:4159-64.



  Antihistamines in Atopic Dermatitis Top


Pruritus is an indispensable component of atopic dermatitis in children which deteriorates the quality of life of patient. Histamine is by far, the most important pruritogen in atopic dermatitis.[1] Plasma levels of histamine are significantly higher in comparison to healthy individuals.[2]

Histamine receptor blockers

In clinical practice, commonly used Histamine 1(H1) receptor blockers include hydroxyzine, pheniramine, fexofenadine, cetirizine and levocetirizine.[3],[4] There are no randomized controlled trials supporting the use of H1R antagonists alone in AD. There is only one report in support of fexofenadine (60 mg twice daily for a week).[5] Besides, topical doxepin, diphenhydramine and loratidine are found to reduce the pruritus in a few cases of AD.[6],[7]

Recommendations and important key points

  • Evidence supporting the general use of systemic antihistamines in the management of atopic dermatitis is lacking
  • Sedating antihistamines (esp. hydroxyzine) may be used for a short duration, in patients where itching signficantly hampers sleep.[8],[9] (Strength of Recommendation: C Level of Evidence: III)
  • Non sedating antihistamines do not have any role in the treatment of atopic dermatitis, except in patients suffering from concomitant urticaria, allergic rhinitis, conjunctivitis.[10] (Strength of Recommendation: A Level of Evidence: II)
  • Olopatadine reduces nocturnal scratching behavior in atopic dermatitis patients [11]
  • When it comes to safety, cetirizine and levocetirizine have been found to extremely safe, as confirmed by two studies [ETAC and EPAAC][12],[13],[14],[15] Desloratidine is by far the safest drug in patients with hepatic dysfunction. When it comes to renal dysfunction, fexofenadine is the best option
  • Adverse effects of antihistamines should be kept in mind, whenever we prescribe them. Few of the important ones include CNS effects (sleepiness, loss of concentration, or malaise), anticholinergic effects (dry mouth, urinary retention etc.), gastrointestinal effects (nausea, vomiting, diarrhea, and abdominal pain).


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

  1. Jutel M, Akdis M, Akdis CA. Histamine, histamine receptors and their role in immune pathology. Clin Exp Allergy 2009;39:1786-800.
  2. Imaizumi A, Kawakami T, Murakami F, Soma Y, Mizoguchi M. Effective treatment of pruritus in atopic dermatitis using H1 antihistamines (second-generation antihistamines): Changes in blood histamine and tryptase levels. J Dermatol Sci 2003;33:23-9.
  3. Higashi M, Ohsawa I, Oda F, Yamada Y, Kawana S, Iida K, et al. Histamine H1-receptor antagonistic drug olopatadine suppresses TSLP in atopic dermatitis model mice. Allergol Int 2013;62:137-8.
  4. Akamatsu H, Makiura M, Yamamoto N, Yagami A, Shimizu Y, Matsunaga K. The effect of fexofenadine on pruritus in a mouse model (HR-ADf) of atopic dermatitis. J Int Med Res 2006;34:495-504.
  5. Kawashima M, Tango T, Noguchi T, Inagi M, Nakagawa H, Harada S. Addition of fexofenadine to a topical corticosteroid reduces the pruritus associated with atopic dermatitis in a 1-week randomized, multicentre, double-blind, placebo-controlled, parallel-group study. Br J Dermatol 2003;148:1212-21.
  6. Groene D, Martus P, Heyer G. Doxepin affects acetylcholine induced cutaneous reactions in atopic eczema. Exp Dermatol 2001;10:110-7.
  7. Weisshaar E, Forster C, Dotzer M. Heyer G. Experimentally induced pruritus and cutaneous reactions with topical antihistamine and local analgesics in atopic eczema. Skin Pharmacol 1997;10:183-90.
  8. Schlapbach C, Simon D. Update on skin allergy. Allergy 2014;69:1571-81.
  9. Rubel D, Thirumoorthy T, Soebaryo RW. et al. Consensus guidelines for the management of atopic dermatitis: an Asia-Pacific perspective. J Dermatol. 2013;40:160-71.
  10. Ring J, Alomar A, Bieber T, Deleuran M, Fink-Wagner A, Gelmetti C, et al. Guidelines for treatment of atopic eczema (atopic dermatitis). Part I. J Eur Acad Dermatol Venereol 2012; 26: 1045-60.
  11. Yamanaka K, Motomura E, Noro Y, Umeda K, Morikawa T, Umeda-Togami K. et al. Olopatadine, a non-sedating H1 antihistamine, decreases the nocturnal scratching without affecting sleep quality in atopic dermatitis. Exp Dermatol. 2015;24:227-9.
  12. La Rosa M, Ranno C, Musarra I, Guglielmo, F., Corrias, A., Bellanti, J.A. Double-blind study of cetirizine in atopic eczema in children. Ann Allergy 1994; 73: 117–122.
  13. Simons FE. Safety of levocetirizine treatment in young atopic children: an 18-month study. Pediatr Allergy Immunol 2007; 18: 535-42.
  14. Simons FE. Prospective long-term safety evaluation of the H1-receptor antagonist cetirizine in very young children with atopic dermatitis. J Allergy Clin Immunol 1999; 104: 433-40.
  15. Diepgen TL. Early Treatment of the Atopic Child Study Group. Long-term treatment with cetirizine in infants with atopic dermatitis: a multi-country, double-blind, randomized, placebo-controlled trial (the ETAC trial) over 18 months. Pediatr Allergy Immunol 2002;13:278–286.



  Antimicrobial Therapy in Atopic Dermatitis Top


Altered skin barrier function and lack of antimicrobial peptides in Atopic dermatitis (AD) predispose to enhanced susceptibility to infections by Staphylococcal aureus, Streptococcus pyogenes, Herpes simplex virus and Malassezia furfur.

Bacterial infections

The prevalence of colonization of the skin and/or nose by S. aureus varies from 60 to 100 % in AD, and from 5 to 30 % in controls.[1] Dhar and Kanwar reported correlation between bacterial colonization and severity of eczema in 1992.[2] Some toxins produced by S. aureus act as superantigens: induce massive activation of T cells, production of specific IgE, and activation of basophils, and the inflammatory cascade.[3] The staphylococcal colonization of skin decreases with anti-inflammatory agents (topical corticosteroid (TCS)/topical calcineurin inhibitor (TCI) however there are no prospective, controlled studies suggesting benefits of antiseptics like chlorhexidine/crystal violet or triclosan in AD.[4]

Short term topical antibiotic therapy is indicated only in localized, overt bacterial infection in AD. Prolonged use can promote bacterial resistance. Cream is preferable for treating exudative lesions, while ointment is used to treat dry lesions. Fusidic acid and mupirocin are used twice a day for 7-10 days.[5] Since mupirocin-resistant staphylococci strains have been isolated, treatment should not be prolonged over 10 days.[3]

Retapamulin ointment should be reserved for strains resistant to conventional treatments. Nasal colonization with S. aureus is associated with recurrences. If recurrences of bacterial infections are multiple and nasal swab is positive for S. aureus, nasal decolonization with mupirocin can be effective. Mupirocin is applied twice a day in both nostrils for 5 days per month for a variable period of 3-18 months .[3]

Recommendations

  • Routine use of topical antibiotics is not recommended in AD. Strength of recommendation A, Level of evidence 1[4]
  • Short-term treatment (7-10 days) with topical antibiotics (Fusidic acid/mupirocin) is recommended in overt, localized bacterial infection in AD. Strength of recommendation A, Level of evidence II (b)
  • For multiple episodes of recurrent infection in moderate to severe AD which show positive nasal swab for S. aureus, nasal decolonization with mupirocin is recommended.


Strength of recommendation B, Level of evidence II,[6]

Systemic Antibiotics

Systemic antibiotics are indciated only in the presence of a wide spread/generalized bacterial infection.[7],[8] Selection of antibiotic does not routinely require bacterial culture.[9]

Uncomplicated staphylococcal infections can be treated according to the regional antibiotic sensitivity patterns. Cephalosporins ( first and second generation)/Amoxycillin - clauvalinic acid combination/macrolides can be given for 7-14 days. If antibiotic therapy does not prove effective, compliance should be evaluated and cultures with antimicrobial sensitivity patterns should be obtained from both skin and nostrils. In case of failure of response to oral therapy or in hospitalized patients with severe infections, 2nd line antibiotics like vancomycin/linezolid can be administered parentrally.[9].

Methicillin resistant Staphylococcal (MRSA) prevalence rates are variable and range from 0.5% to 16% in AD.[10],[11] High methicillin resistance among S. aureus isolates can be worrying because these patients require aggressive antibiotic therapy. Children colonized by MRSA can be decolonized with topical mupirocin, except for those carrying mupirocin-resistant isolates. Community-acquired MRSA isolates are susceptible to trimethoprim/sulfamethoxazole hence, this drug can be an option in MRSA decolonization schemes.[12]

Recommendations

  • No systemic antibiotic is recommended if not infected. Strength of recommendation B, Level of evidence II [13],[14]
  • Recommended for infected AD in the presence of overt signs of infection (amoxy-clavulinic acid/cephalosporins (Strength of recommendation B, level of evidence II).[13],[14]


Eczema herpeticum

Infection with HSV occurs in 3% of patients. It can be localized infection characterized by umbilicated vesicles present over face and limbs. Wide spread infection is associated with fever, lymphadenopathy, and bacterial superinfection. Vesicles are often confluent and covered with yellowish crusts. Eczema herpeticum should be treated without delay using systemic antiviral therapy. Acyclovir is given orally in localized infection and intravenously if fever is present .[15]

Recommendations

  • It is recommended to give oral acyclovir in localized infection and parentral in wide spread eczema herpeticum where fever/systemic symptoms are present)
  • Acyclovir is given orally for localized infection in the dose of 25 mg/kg/day in 5 divided doses for 5-7 days
  • Itis administered intravenously (500mg/m 2/day, 8 hourly for 10 days), in the presence of fever or systemic symptoms.


(Strength of recommendation C, level of evidence II.[15]

Malassezia furfur

The possibility of Malassezia exacerbating AD during adolescence via an immunological mechanism has been described.[16],[17] Malassezia may be implicated in recalcitrant AD and head and neck atopic eczema. Treatment with oral itraconazole, ketoconazole or fluconazole has proven effective in this subset of AD.[17] Ketoconazole is no longer used due to its high risk profile.

Recommendations

  • Oral antifungal therapy may be efficacious in recalcitrant head and neck variant of AD.


(Strength of recommendation 2b, B).[17]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

  1. Park H-Y, Kim C-R, Huh I-S, et al. Staphylococcus aureus colonization in acute and chronic skin lesions of patients with atopic dermatitis. Ann Dermatol. 2013;25:410-6.
  2. Dhar S, Kanwar AJ, Kaur S, Sharma P, Ganguly NK. Role of bacterial flora in the pathogenesis and management of atopic dermatitis. Ind J Med Res 1992; 95:234-8.
  3. Spaulding AR, Salgado-Pabon W, Kohler PL, et al. Staphylococcical and Streptococcal superantigen exotoxin. Clin Microbiol Rev. 2013;26:422-46.
  4. Tang CS, Wang CC, Huang CF, et al. Antimicrobial susceptibility of Staphylococcus aureus in children with atopic dermatitis. Pediatr Inf. 2011;53:363-7.
  5. Bath-Hextall FJ, Birnie AJ, Ravenscroft JC, Williams HC. Interventions to reduce Staphylococcus aureus in the management of atopic eczema: an updated Cochrane review. Br J Dermatol. 2010;163:12-26.
  6. Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS. Treatment of Staphylococcus aureus colonization in atopicdermatitis decreases disease severity. Pediatrics 2009;123:e808-14.
  7. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71:327.
  8. Slater NA, Morrell DS. Systemic therapy of childhood atopic dermatitis. ClinDermatol. 2015;33(3):289-99.
  9. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:18-55.
  10. Balma-Mena A, Lara-Corrales I, Zeller J, Richardson S, McGavin MJ, Weinstein M, et al. Colonization with community-acquired methicillin-resistant Staphylococcus aureus in children with atopic dermatitis: a cross-sectional study. Int J Dermatol. 2011;50:682-8.
  11. 11 Pascolini C, Sinagra J, Pecetta S, Bordignon V, De Santis A, Cilli L, et al. Molecular and immunological characterization of Staphylococcus aureus in pediatric atopic dermatitis: implications for prophylaxis and clinical management. Clin Dev Immunol. 2011;2011:708-18.
  12. Cavalcante FS, Schuenck RP, Caboclo RM, Ferreira DC, Nouer SA, Santos KR. Tetracycline and trimethoprim/sulfamethoxazole at clinical laboratory: can they help to characterize Staphylococcus aureuscarrying different SCCmec types? Rev Soc Bras Med Trop. 2013;46:100-2.
  13. Boguniewicz N, Sampson A, Leung SB, Harbeck R, Leung DY. Effects of cefuraxime axetil on staph. aureus colonization and superantigen production in AD. J Allergy Clin Immunol. 2001; 108:651-2.
  14. Weinberg E, Fourie B, Allmann B, Toerien A. The use of cefadroxil in superinfected atopic dermatitis. Curr Ther Res. 1992;52:671-6.
  15. Aronson PL, Yan AC, Mittal MK. Delayed acyclovir and outcomes of children hospitalized with eczema herpeticum. Pediatrics. 2011;128:1161-7.
  16. Lange L, Alter N, Keller T, et al. Sensitization to Malassezia in infants and children with atopic dermatitis: prevalence and clinical characteristics. Allergy. 2008;63:486-7.
  17. Darabi K, Hostetler SG, Bechtel MA, et al. The role of Malassezia in atopic dermatitis affecting the head and neck of adults. J Am Acad Dermatol. 2009;60:125-36.





 

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