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Clinical Updates

Jack B. Cohen, DO

Systemic Immunosuppressive Medications for the Treatment of Moderate-to-Severe Atopic Dermatitis

Jack Cohen

Wednesday, July 06, 2005

Atopic dermatitis (AD) is a severely pruritic, chronic, relapsing eczematous skin condition that affects 15% of children, but it can persist into or develop in adulthood. Most patients present with mild-to-moderate severity and are able to be controlled with combinations of emollients, topical corticosteroids, oral antihistamines, antibiotics, and the newer topical immunomodulators tacrolimus and pimecrolimus. Secondary infections can be treated with appropriate antimicrobial or antiviral medications. However, some patients progress to widespread involvement that is marked by severe lichenification, facial involvement, or erythroderma. Current treatment options for these patients include oral corticosteroids, UVB phototherapy, systemic or bath PUVA, and systemic immunosuppressive medications.

Oral Corticosteroids

Oral corticosteroids (most commonly, prednisone or prednisolone), cyclosporine, and azathioprine are common immunosuppressive medications that are used for moderate-to-severe AD. These are usually rapidly effective, starting at a 1 mg/kg/day dose; however, as the dose is decreased, often the disease will relapse. Intramuscularly administered triamcinolone suspension 40-80 mg, a long-acting corticosteroid suspension whose absorption is variable and lasts for 3-4 weeks, has also been used.

However, systemic corticosteroids have two main drawbacks:

  1. Relapses are very common, and moderate-to-high doses are required for continued disease control, which can lead to corticosteroid dependence. Among the multitude of well-recognized adverse effects resulting from long-term corticosteroid use are hypertension, diabetes, increased incidence of serious infections, striae, cataracts, myopathy, skin atrophy, and osteoporosis. Osteoporosis can occur even at low doses.
  2. A rebound effect, defined as a relapse with more widespread skin involvement than before beginning corticosteroids, can occur upon withdrawal. Many patients with severe AD began with mild-to-moderate disease that was repeatedly treated with short courses of systemic corticosteroids.

Because of these problems, clinicians have searched for alternative immunosuppressive agents that have a better side-effect profile than systemic corticosteroids.

Azathioprine

Azathioprine has been reported to be successful in treating severe AD in uncontrolled studies, mostly in adults.1-6 A common starting dose is 50 mg twice daily, with subsequent dose increases as tolerated. Berth-Jones et al.7 published the only double-blind, placebo-controlled crossover trial of azathioprine. This 12-week study used azathioprine at 2.5 mg/kg/day as a single dose from the onset. Significant improvement in the objective sign score, as measured by the six area, six sign AD (SASSAD) score, was seen in those who completed the study. There was a 27% reduction in the SASSAD score in those who completed the protocol compared with 2% with placebo.

Azathioprine was not well tolerated, however, with 12 of the 34 patients in the azathioprine arm withdrawing from the study, compared with only 4 of 29 in the placebo arm. Gastrointestinal side effects of nausea, vomiting, anorexia, abdominal pain, and bloating were seen in 14 patients and caused 4 patients to withdraw from the study. Transient elevations in liver enzymes were seen in 8 patients, and neutropenia with lymphopenia, as well as lymphopenia alone, occurred in 1 patient each.

Azathioprine may be effective for some patients; however, its usefulness is limited by the slow onset of improvement (usually 4-6 weeks, with peak efficacy at 3 months or longer), as well as by its side effects. It is safer to screen patients for a key enzyme, thiopurine methyl transferase (TMPT), which is important in the metabolism of azathioprine. One in 300 people are deficient,7 whereas others have low levels of this enzyme,6,7 which causes an increased risk of developing severe myelosuppression. Measuring this enzyme prior to initiating therapy allows azathioprine to be administered safely at the proper dose from the onset of therapy.

Cyclosporine

Cyclosporine at 3-5 mg/kg/day can be rapidly effective in controlling severe AD, with onset of symptomatic relief beginning 2 weeks after initiating therapy. In a double-blind, controlled crossover study in adults treated for 8 weeks, disease activity measured by the SASSAD score showed a 55% reduction at the 5 mg/kg/day dose and a 41% reduction at the 3 mg/kg/day dose.8 None of the 33 patients withdrew from the study, although 20 of the cyclosporine-treated patients reported side effects, compared to 8 of the placebo-treated patients.

Relapses after cessation of therapy did occur, but signs and symptoms still did not return to baseline at 8 weeks after discontinuing therapy. Hepatotoxicity, significant elevation of serum creatinine with cumulative renal toxicity, and the development of hypertension relegate this medication's role to only short-term usage. A 1-year randomized controlled study comparing cyclosporine with combined UVA and UVB phototherapy reported a significant increase in serum creatinine in 6% of patients and the development of mild-to-moderate hypertension in 19% of patients receiving cyclosporine.9

Mycophenolate Mofetil

In my experience, the new oral immunosuppressive medication mycophenolate mofetil (MMF) shows considerable promise. MMF selectively and reversibly inhibits inosine monophosphate dehydrogenase, which suppresses the de novo pathway of purine synthesis that is required by lymphocytes. Other inflammatory cells can use a salvage pathway for purine biosynthesis; thus, MMF suppresses lymphocyte function selectively.

MMF is usually started at 2 g/day and may be increased up to 3 g/day if there is insufficient response. There has yet to be a double-blind crossover study of MMF; however, there are several small retrospective studies.10,11 In prospective open-labeled studies,12,13 the severity scoring of atopic dermatitis (SCORAD) index was used to show a statistically significant reduction of AD in all patients (10 in each study) at 12 and 8 weeks, respectively. Patients who responded did so within 2-4 weeks.

MMF was well tolerated, and the most common side effects were nausea, gastric discomfort, mild headaches, and fatigue. Less commonly reported side effects have been liver enzyme elevations and serious skin infections with Staphylococcus aureus14 and herpes retinitis.13 Relapses can occur with decrease or withdrawal of the drug, but the dose can be increased to regain control. No rebound flares had been noted upon discontinuation.

In a retrospective review of my experience using MMF, 17 of 18 patients with AD improved within 4 weeks of starting therapy. Nine patients had disease remission and were subsequently able to discontinue MMF, whereas 8 patients attained satisfactory control of their AD with maintenance therapy for up to 3 years.

No patients discontinued MMF because of side effects, mostly gastrointestinal, but 4 patients developed uncomplicated herpes zoster that responded to oral antiviral therapy, and 2 patients were treated with oral antibiotics for superficial infections with S.  aureus.

Cyclophosphamide

Experience with cyclophosphamide is limited. Morrison and Shultz15 retrospectively reported success treating 3 adults with cyclophosphamide for severe atopic dermatitis. All patients were on oral corticosteroids. Cyclophosphamide was started at 100 mg daily and reduced according to the total white cell count. None developed neutropenia. Time to significant response averaged 3 ΒΌ months and the duration of treatment varied from 6 to 14 months. One patient had azospermia that resolved upon discontinuation of the drug. Relapses occurred in all patients, but only 1 patient restarted cyclophosphamide 3.5 years later. Only 1 patient was able to discontinue oral corticosteroids altogether.

Cyclophospahamide is a cytostatic agent that primarily affects B lymphocytes and antibody formation, but T lymphocytes are also affected. Well-known side effects include hemorrhagic cystitis, bone marrow suppression, sterility, and long-term use has a higher risk of developing secondary malignancies, including lymphoma, leukemia, and bladder carcinoma.

Conclusions

Therapy for severe AD has to be individualized and based on the patient's medical history, concomitant medications, and resources. Given the choices of immunosuppressive medications profiled in this article, MMF can be rapidly effective for severe AD and has a better safety profile than corticosteroids, azathioprine, or cyclosporinecyclosporine, or cyclophosphamide for long-term treatment.

Cyclosporine can also be effective as a rescue medication, but its toxicities prevent its safe use for long periods of time. Azathioprine appears to be slower in onset, less effective than MMF and cyclosporine, and less tolerated in short courses. Not enough published data on cyclophosphamide use in AD is available. Systemic corticosteroids, although inexpensive, hopefully will fall out of favor in treating AD, as their administration may contribute to the development of widespread dermatitis, steroid dependence, and side effects.

References

  1. August PJ. Azathioprine in the treatment of eczema and actinic reticuloid. Br J Dermatol. 1982;107(suppl. 22):23.
  2. Lear JT, English JSC, Jones P, Smith AG. Retrospective review of the use of azathioprine in severe atopic dermatitis. J Am Acad Dermatol. 1996;35:642-643.
  3. Buckley DA, Baldwin P, Rogers S. The use of azathioprine in severe adult atopic eczema. J Eur Acad Dermatol. 1998;11:137-140.
  4. Chu AC. The role of systemic therapy in atopic eczema. CME Bull Dermatol. London: Rila Publications Ltd; 1999;2:23-28.
  5. Meggitt SJ, Reynolds NJ. Azathioprine for atopic dermatitis. Clin Exp Dermatol. 2001;26:369-375.
  6. Murphy LA, Atherton DJ, Chir B. Azathioprine as a treatment for severe atopic eczema in children with partial thiopurine methyl transferase (TMPT) deficiency. Pediatr Dermatol. 2003;20:531-534.
  7. Berth-Jones J, Takwale A, Tan E, et al. Azathioprine in severe adult atopic dermatitis: a double-blind, placebo-controlled, crossover trial. Br J Dermatol 2002; 147: 324-330.
  8. Berth-Jones J, Graham-Brown RAC, Marks R, et al. Long-term efficacy and safety of cyclosporin in severe adult atopic dermatitis. Br J Dermatol. 1997;136:76-81.
  9. Granlund H, Erkko P, Remitz A, et al. Comparison of cyclosporin and UVAB phototherapy for intermittent one-year treatment of atopic dermatitis. Acta Derm. Venereol. 2001;81:22-27.
  10. Grundmann-Kollmann M, Kortin HC, Behrens S, et al. Successful treatment of severe refractory atopic dermatitis with mycophenolate mofetil. Br J Dermatol. 1999;141:175-176.
  11. Benez A, Fierlbeck G. Successful long-term treatment of severe atopic dermatitis with mycophenolate mofetil. Br J Dermatol. 2001;144:638-639.
  12. Neuber K, Schwartz I, Itschert G, Dieck AT. Treatment of atopic eczema with oral mycophenolate mofetil. Br J Dermatol. 2000;143:385-391.
  13. Grundmann-Kollmann M, Podda M, Ochsendorf F, Boehncke WH, Kaufmann R, Zollner TM. Mycophenolate mofetil is effective in the treatment of atopic dermatitis. Arch Dermatol. 2001;137:870-73.
  14. Satchell AC, Barnetson R. Staphylococcal septicaemia complicating treatment of atopic dermatitis with mycophenolate. Br J Dermatol. 2000; 143:198-233.
  15. Morrison JGL, Shultz EJ. Treatment of eczema with cyclophosphamide and azothioprine. Br J Dermatol. 1978; 98:203-207.
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