Title: Comparative responsiveness of cutaneous lupus erythematosus patients to methotrexate and mycophenolate mofetil: A cohort study
Abstract: To the Editor: For patients with antimalarial-refractory cutaneous lupus erythematosus (CLE), methotrexate (MTX) and mycophenolate mofetil (MMF) are frequently used.1Kuhn A. Aberer E. Bata-Csörgő Z. et al.S2k guideline for treatment of cutaneous lupus erythematosus - guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV).J Eur Acad Dermatol Venereol. 2017; 31: 389-404Crossref PubMed Scopus (83) Google Scholar Although surveys show that providers have medication preference by CLE subtype, which includes acute, subacute (SCLE), and discoid (DLE), there is a lack of evidence-based research comparing responses between these medications across subtypes.2Reich A. Werth V.P. Furukawa F. et al.Treatment of cutaneous lupus erythematosus: current practice variations.Lupus. 2016; 25: 964-972Crossref PubMed Scopus (11) Google Scholar,3Kreuter A. Tomi N.S. Weiner S.M. Huger M. Altmeyer P. Gambichler T. Mycophenolate sodium for subacute cutaneous lupus erythematosus resistant to standard therapy.Br J Dermatol. 2007; 156: 1321-1327Crossref PubMed Scopus (76) Google Scholar We retrospectively reviewed our institutional review board–approved prospective longitudinal CLE database. The CLE subtype was determined by clinical evidence and expert opinion of VPW according to the Gilliam classification.4Gilliam J.N. Sontheimer R.D. Distinctive cutaneous subsets in the spectrum of lupus erythematosus.J Am Acad Dermatol. 1981; 4: 471-475Abstract Full Text PDF PubMed Scopus (384) Google Scholar The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) has been established as a responsive outcome measure, with an improvement in the activity (CLASI-A) score by 50% indicating a clinically significant and meaningful improvement.5Chakka S. Krain R.L. Ahmed S. et al.Evaluating change in disease activity needed to reflect meaningful improvement in quality of life for clinical trials in cutaneous lupus erythematosus.J Am Acad Dermatol. 2021; 84: 1562-1567Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar We thus defined a medication response or nonresponse as a reduction in the CLASI-A score by ≥50% or <50% after starting the medication scored at the time of the visit, or chart documentation of response or nonresponse as evaluated by VPW. Discontinuations due to side effects were analyzed separately (Table I).Table IRates of discontinuation of medications due to side effectsMedicationSCLEMost common SE causing discontinuation in SCLEDLEMost common SE causing discontinuation in DLEMTX7/25 (28%)∗Percentages are for the rate of discontinuation due to SEs from all instances of that medication use within the population subset.Nausea/diarrhea3/16 (19%)Increased transaminasesMMF6/13 (46%)Nausea/diarrhea5/32 (16%)Nausea/diarrheaDLE, Discoid lupus erythematosus; MTX, methotrexate; MMF, mycophenolate mofetil; SCLE, subacute cutaneous lupus erythematosus; SE, side effect.∗ Percentages are for the rate of discontinuation due to SEs from all instances of that medication use within the population subset. Open table in a new tab DLE, Discoid lupus erythematosus; MTX, methotrexate; MMF, mycophenolate mofetil; SCLE, subacute cutaneous lupus erythematosus; SE, side effect. A total of 191 patients with SCLE and DLE were identified in the database. Of these, 73 took MTX and/or MMF, with at least 1 visit after the initiation of MTX or MMF, at least 2 months apart, to determine the response. This included 34 patients with concomitant systemic lupus erythematosus. The other subtypes and other systemic immunosuppressive medications were not powered for analysis and were excluded. Forty-four (60%) patients had CLASI-A data available. The responses for the remaining patients were determined by chart abstraction. The mean response rate was 64.8% (95% CI, 54.2%-75.4%). No statistically significant difference was found in the rate of response to MTX or MMF when comparing SCLE with DLE (P > .05) (Table II). Results suggest that MMF may be more effective in DLE than MTX, but our sample was not powered to show this (P = .175). The difference in response rate for MTX versus MMF for combined subtypes was not significantly different (P = .446), suggesting comparable response rates overall. Two patients with SCLE and none of the patients with DLE who previously failed MMF subsequently responded to MTX. Alternatively, 2 patients with SCLE and 3 patients with DLE who previously failed MTX responded to MMF.Table IIComparison of response rates for each medication between SCLE and DLEMedicationResponse typeSCLEDLEP value from Fisher exact test∗Statistical analysis was performed using Fisher exact test 2 × 2 tables using GraphPad Prism version 8.4.3.MTXn = 18†The n values do not include patients who discontinued each medication due to side effects.n = 13.262Responders13 (72%)6 (46%)Nonresponders5 (27%)7 (54%)MMFn = 7n = 27>.999Responders5 (71%)19 (70%)Nonresponders2 (29%)8 (30%)DLE, Discoid lupus erythematosus; MTX, methotrexate; MMF, mycophenolate mofetil; SCLE, subacute cutaneous lupus erythematosus.∗ Statistical analysis was performed using Fisher exact test 2 × 2 tables using GraphPad Prism version 8.4.3.† The n values do not include patients who discontinued each medication due to side effects. Open table in a new tab DLE, Discoid lupus erythematosus; MTX, methotrexate; MMF, mycophenolate mofetil; SCLE, subacute cutaneous lupus erythematosus. We compared response rates to MTX and MMF within and between SCLE and DLE and did not find substantial differences. This suggests similar efficacy for these medications between subtypes. Other factors such as side effect profiles, disease course, and comorbid conditions may influence medication selection. Limitations include that this was a refractory university cohort with a high proportion of concomitant systemic lupus erythematosus. Additionally, approximately 40% of patients did not have objective CLASI-A data to demonstrate response; thus, some subjectivity was introduced using VPW's expert opinion and chart abstraction. There were no differences in the populations of patients with or without CLASI-A data. Additionally, VPW's assessments always concurred with CLASI-A response. Together, these support that the chart abstraction was reliable when CLASI-A scores were unavailable. European guidelines list MTX as second line and MMF as third line. Our results suggest comparable response rates between MTX and MMF. However, other considerations such as immunosuppression level were considered while creating the guidelines.1Kuhn A. Aberer E. Bata-Csörgő Z. et al.S2k guideline for treatment of cutaneous lupus erythematosus - guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV).J Eur Acad Dermatol Venereol. 2017; 31: 389-404Crossref PubMed Scopus (83) Google Scholar Further randomized controlled studies are needed to assess whether MMF may work better than MTX in DLE and to further characterize and compare the effectiveness of immunosuppressive medications within and between subtypes. Authors Keyes, Jobanputra, Grinnell, Vazquez, and Diaz and Drs Feng and Werth do not have any conflicts of interest to disclose. The University of Pennsylvania owns the copyright for the CLASI.