By Abby Van Voorhees, MD, April 02, 2012
In this month’s Acta Eruditorum column, Physician Editor Abby S. Van Voorhees, MD, talks with M.E. Schram, MD, PhD, about her recent Journal of Clinical Allergy and Immunology article, “A randomized trial of methotrexate vs. azathioprine for severe atopic eczema.”
Dr. Van Voorhees: Let’s start by having you tell us a little bit about how you came to start studying severe atopic dermatitis? Aren’t there alternative therapies for these patients? Why did you choose to study methotrexate and azathioprine?
Dr. Schram: My PhD research was primarily directed at atopic dermatitis (AD), a chronic inflammatory skin disorder with an increasing (high) prevalence. Some patients are severely affected, which means that they do not respond to intensive topical treatment or phototherapy. AD can result in impairment of skin function and poor sleep and it has a high social burden.
Frequently used options for systemic treatment of AD include cyclosporine and systemic corticosteroids. Although these have proven efficacy, many patients have contraindications for cyclosporine or discontinue treatment because of ineffectiveness or side effects (Acta Derm Venereol 2007; 87:100-11). Moreover, long-term use of cyclosporine raises concerns of nephrotoxicity. Systemic corticosteroids are used frequently to suppress exacerbations, although high-level evidence is lacking. Medium- to long-term treatment with prednisolone is relatively contraindicated because of the cumulative effect of the side effects. Additionally, both treatments may cause a rebound effect.
In our perspective, more treatment options for severe AD are needed. Long-existing and relatively cheap disease-modifying anti-rheumatic drugs have been shown to be of some benefit in part of the patients with AD. Two of those drugs are methotrexate and azathioprine.
Two randomized controlled trials (RCTs) comparing azathioprine with placebo showed that azathioprine was significantly superior to placebo in the treatment of AD with mean improvements of 26 and 37 percent on clinical outcome scales after three months (Br J Dermatol 2002; 147: 324-30, Lancet 2006; 367: 839-46, Arch Dermatol 2011; 147: 474-88). Several case series and open-label studies for methotrexate have supported a role for methotrexate in the management of severe AD (Br J Dermatol 2007; 156: 346-51, Isr Med Assoc J 2008; 10:413-4, Eur J Dermatol 2006;16: 155-8, J Am Acad Dermatol 2003; 48: 417-9). No RCT level of evidence for methotrexate was available and a comparison study with azathioprine versus methotrexate was missing.[pagebreak]
Dr. Van Voorhees: Let’s begin with your study design. How many patients were studied? How did you dose these medications in the study?
Dr. Schram: This study was an investigator-initiated, single-blind, parallel-group (ratio 1:1), randomized controlled trial evaluating efficacy, safety, and quality of life with methotrexate versus azathioprine over a 12-week period and a 12-week follow-up period.
Randomization, efficacy assessment, and statistical analysis were blinded. Forty-five adult patients with severe AD were screened and 42 patients were randomized to receive either methotrexate or azathioprine. In total, 52 percent of the patients were male, the mean age was 40 years, and the mean duration of eczema was 36 years.
Treatment with methotrexate was initiated at 10 mg/wk in a single oral dose. Dose escalation with 2.5 to 5 mg per scheduled visit was allowed with a maximum of 22.5 mg/wk. Patients also received 5 mg of folate one day after methotrexate intake. Azathioprine was initiated at 1.5 mg/kg/day in a single dose, and the dosage could be escalated at each visit with 0.5 mg/kg/day until a maximum of 2.5 mg/kg/day was reached. The dosages could be decreased according to protocol in case of abnormal findings on physical examination, laboratory markers, and/or adverse events. After the first 12 weeks, dosages in responders were reduced to find the optimum dosage. To illustrate this, mean dose of methotrexate at week 12 was 20 mg/wk and 17.5 mg/wk at week 24. Mean dosage of azathioprine was 2.2 mg/kg/d at week 12 and 2.1 mg/kg/d at week 24.
Dr. Van Voorhees: How did the two drugs compare in terms of their efficacy in treating severe adult atopic dermatitis? What percentage improvement was seen with methotrexate versus azathioprine?
Dr. Schram: There were no significant differences between methotrexate and azothioprine in all the efficacy outcome parameters we measured at week 12 and 24.
At week 12, mean SCORing Atopic Dermatitis index (SCORAD) in the patients in the methotrexate group showed a relative reduction of 42 percent (P < 0.001). SCORAD scores in patients randomized to the azathioprine group showed a relative reduction of 39 percent (P < 0.001). The P value for the absolute difference between the groups is 0.89.[pagebreak]
Dr. Van Voorhees: Was there a difference in percentage of patients in the two groups who achieved mild disease or improvement in quality of life scores?
Dr. Schram: No, there was no statistically significant difference between the groups for the percentage of patients achieving at least mild disease on the physician global assessment; 75.0 percent in the methotrexate group versus 68.2 percent in the azathioprine group.
For measuring quality of life, the mean Skindex-17 score was used. Patients in the methotrexate group experienced a relative reduction on the Skindex-17 of 26 percent, in the azathioprine group of 20 percent. There was no statistically significant difference (P= 0.65).
Dr. Van Voorhees: Was there a difference in adverse events in those treated with either agent?
Dr. Schram: Infections, gastrointestinal adverse events, and increased liver enzyme levels occurred in equal proportion in both groups (P= 0.66). Abnormalities in blood count (mostly lymphocytopenia) were statistically significantly more frequent in the azathioprine group (P= 0.002). Three (15 percent) patients in the methotrexate group had an exacerbation of their eczema during the study compared with two (9 percent) patients in the azathioprine group. No severe and serious adverse events occurred.
Dr. Van Voorhees: Your pilot study suggests that these drugs may come to play a more significant role in the treatment of severe atopic dermatitis. Have you planned additional larger studies to further clarify this?
Dr. Schram: A five-year follow up study is currently being undertaken to address long-term safety in this patient group. The two-year data will be analyzed soon.
Dr. Mandy Schram is a dermatology resident in the department of dermatology at the University of Amsterdam. Her article, co-written with Evelien Roekevisch, MD, Mariska M.G. Leeflang, PhD, Jan D. Bos, MD, PhD, Jochen Schmitt, MD, and Phyllis I. Spuls, MD, PhD, was published in the Journal of Clinical Allergy and Immunology, 128(2):353-9 (August 2011). doi:10.1016/j.jaci.2011.03.024.