Systemic Immunosuppressive Medications for the Treatment of Moderate-to-Severe Atopic Dermatitis
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
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:
- 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.
- 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 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 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
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
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
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
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 ¼ 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
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.
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
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
- August PJ. Azathioprine in the treatment of eczema and actinic
reticuloid. Br J Dermatol. 1982;107(suppl. 22):23.
- 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.
- Buckley DA, Baldwin P, Rogers S. The use of azathioprine in
severe adult atopic eczema. J Eur Acad Dermatol.
- Chu AC. The role of systemic therapy in atopic eczema. CME
Bull Dermatol. London: Rila Publications Ltd;
- Meggitt SJ, Reynolds NJ. Azathioprine for atopic dermatitis.
Clin Exp Dermatol. 2001;26:369-375.
- 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.
- 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;
- 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.
- 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.
- Grundmann-Kollmann M, Kortin HC, Behrens S, et al.
Successful treatment of severe refractory atopic dermatitis with
mycophenolate mofetil. Br J Dermatol.
- Benez A, Fierlbeck G. Successful long-term treatment of severe
atopic dermatitis with mycophenolate mofetil. Br J
- Neuber K, Schwartz I, Itschert G, Dieck AT. Treatment of atopic
eczema with oral mycophenolate mofetil. Br J Dermatol.
- 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.
- Satchell AC, Barnetson R. Staphylococcal septicaemia
complicating treatment of atopic dermatitis with mycophenolate.
Br J Dermatol. 2000; 143:198-233.
- Morrison JGL, Shultz EJ. Treatment of eczema with
cyclophosphamide and azothioprine. Br J Dermatol. 1978;