Key Points
Question
Is thalidomide potentially effective for continuous treatment for chronic erythema multiforme?
Findings
In this retrospective cohort including 35 patients with chronic erythema multiforme, after 6 months of thalidomide treatment, 23 patients did not have any flare of erythema multiforme, 7 experienced at least 1 flare, and 5 stopped taking thalidomide. Twenty-five patients stopped taking thalidomide by 12 months.
Meaning
Thalidomide may be an alternative therapy for chronic erythema multiforme.
This cohort study examines use of thalidomide as continuous treatment for patients with chronic erythema multiforme in French hospital dermatology departments.
Abstract
Importance
Erythema multiforme (EM) may become long term, with a recurrent or persistent course. First-line treatment for chronic EM is valaciclovir. There is no consensus for selection of second-line treatment of chronic EM.
Objective
The aim of this study was to assess the effectiveness of treatment with thalidomide for patients with chronic EM.
Design, Setting, and Participants
In this retrospective national multicenter cohort study, among 68 French hospital dermatology departments contacted by e-mail, 10 reported having eligible cases. All adults aged 18 years or older under dermatology care for chronic EM (including recurrent and persistent forms) who had received thalidomide between 2010 and 2018 were included. Analyses were conducted from June 24, 2019, to December 31, 2019.
Main Outcomes and Measures
The primary outcome was the proportion of patients who did not experience an EM flare within 6 months of initiating thalidomide treatment for recurrent EM or with complete clearance at 6 months for persistent EM (complete remission).
Results
Overall, 35 patients with chronic EM (median [range] age, 33 [15-65] years; 20 [57%] female) experienced failure of at least 1 previous treatment prior to initiating treatment with thalidomide. After 6 months of continuous thalidomide treatment, 23 (66%) were in complete remission, 5 (14%) had stopped the treatment, and 7 (20%) experienced at least 1 flare. The median (IQR) initial dose followed by remission was 50 (50-100) mg/d. Main adverse effects were asthenia (16 [46%]) and neuropathy (14 [40%]). Twenty-five (71%) of patients stopped thalidomide treatment after a median (IQR) of 12 (8-20) months owing to lack of effect (7/25 [28%]), neuropathy or another adverse effect (14/25 [56%]), or long-term complete remission (4/25 [16%]). Low-dose thalidomide, less than 50 mg every other day was sufficient in 9 of 23 (39%) of responders and was associated with less neuropathy and longer treatment duration.
Conclusions and Relevance
In this cohort study, second-line therapy with thalidomide was associated with complete remission in two-thirds of the 35 patients with chronic EM. However, adverse events were a common cause of thalidomide withdrawal. In the long term, dose reduction when possible may allow for continuation by improving tolerance.
Introduction
Erythema multiforme (EM) is a rare disorder characterized by typical target lesions and mucosal erosions.1 Common triggers are infections, including herpes simplex virus and Mycoplasma pneumoniae.2,3,4 Erythema multiforme may become chronic in 30% of cases, with a recurrent or persistent course, causing food intake impairment, hospitalization, and negatively affecting quality of life.5
A recent systematic review6 highlighted the lack of evidence for treatment of chronic EM. One randomized clinical trial7 assessed aciclovir vs placebo in patients with chronic EM. In this study, 15 of 20 patients had postherpetic EM, and after 6 months of treatment, 7 of 11 patients in the aciclovir group had no EM attack vs 0 of 9 in the placebo group.7 No trial has assessed interventions following failure with antiviral treatment. Six retrospective case series of low methodological quality reported partial or complete remission with various off-label continuous treatments including dapsone, azathioprine, intravenous immunoglobulin, or thalidomide.6,8 Patients with uncontrolled disease often use systemic corticosteroids, with risk of dependence or long-term use.9
The aim of our study was to evaluate thalidomide as continuous treatment for chronic EM.
Methods
In this retrospective multicenter cohort study, all French hospital dermatology departments were contacted by email on June 24, 2019. In France, thalidomide is only dispensed by hospital pharmacies, with traced prescriptions. For all departments reporting thalidomide use for chronic EM, all cases were identified from hospital pharmacy databases.
Adults aged 18 years or older with a diagnosis of chronic EM and who received thalidomide initiated between January 1, 2010, and December 31, 2018, were included in the study. The diagnosis of EM was clinically assessed by a dermatologist based on typical skin target lesions and mucosal erosions. Patients with mucosal-only involvement were also included only if confirmed by histologic findings and negative direct immunofluorescence and antibody testing results ruled out other chronic mucous oral diseases including autoimmune bullous dermatoses. Recurrent EM was defined as having at least 1 flare per year. Persistent EM was defined as having continuous disease or flares separated by fewer than 15 days.10 Patient data were extracted from medical records with a data collection form.
The primary outcome was the proportion of patients achieving complete remission (CR) within 6 months of initiating treatment with thalidomide (ie, complete absence of relapse during the 6 months for recurrent EM and complete regression without relapse for persistent EM). Secondary outcomes were the proportion of patients achieving CR at 3 and 12 months, number of relapses during the period covered by thalidomide prescription, corticosteroid consumption, factors associated with lack of relapse, doses, treatment duration, adverse events, and withdrawals.
We calculated the proportion of patients without EM relapse at 3, 6, and 12 months and 95% CIs. We used intent-to-treat analyses for primary and secondary outcomes: patients who stopped treatment before the end point analysis, for whatever reason, were considered to have experienced treatment failure. Medians and interquartile ranges (IQRs) were calculated for quantitative data. Clinical factors associated with lack of relapse were investigated by univariate analyses with χ2 or Fisher exact test. The study was approved by the institutional review board of Henri Mondor Hospital (00011558 May 28, 2020), and patients gave written informed consent.
Results
Among the 68 French dermatology departments contacted, 10 reported 41 cases; the other centers had no eligible patients. Six patients were excluded because of age younger than 18 years (n = 1), thalidomide initiation before 2010 (n = 2), and insufficient medical records (n = 3). We included 35 patients: 22 had recurrent EM and 13 had persistent EM. Patient characteristics are presented in Table 1. All female patients were on effective contraception with monthly pregnancy testing as is legally required for thalidomide treatment.
Table 1. Baseline Characteristics of Patients With Chronic Erythema Multiforme (EM) Treated With Thalidomide.
| Characteristic | No. (%) |
|---|---|
| No. | 35 |
| Sex | |
| Male | 15 (43) |
| Female | 20 (57) |
| Age at diagnosis of EM, median (range), y | 30 (12-63) |
| Age at thalidomide initiation, median (range), y | 33 (15-65) |
| Duration of the EM course at the thalidomide introduction, median (range), y | 2 (0.25-17) |
| Follow-up duration, median (IQR), moa | 48 (31-88) |
| Cutaneous involvement | 30 (86) |
| Mucous membrane involvement | |
| 1 | 13 (37) |
| ≥2 | 22 (63) |
| Pure mucosal forms | 5 (14) |
| Identified triggers | |
| Herpes simplex virus infection | 10 (29) |
| Mycoplasma pneumoniae infection | 2 (6) |
| Perimenstrual pattern of flaring | 0 |
| Drug | 0 |
| None | 24 (69) |
| EM flares per year for recurrent EM, median (IQR) | 6 (4-6) |
| Patients with persistent EM | 13 (37) |
| Treatments received before thalidomide | |
| Valaciclovir | 33 (94) |
| Systemic corticosteroids | 24 (69) |
| Other (dapsone, hydroxychloroquine, rituximab, colchicine, methotrexate, clarithromycin) | 15 (43) |
| Treatment lines before thalidomide initiation, median (range) | 2 (1-6) |
| Specific treatments still in use at the initiation of thalidomide | |
| Systemic corticosteroid therapy | 7 (20) |
| Valaciclovir | 9 (26) |
| HSV serology | |
| Positive | 11 (31) |
| Negative | 9 (26) |
| Not performed | 15 (43) |
| Antiplakine antibodies (immunoblotting) | |
| Positive | 7 (20) |
| Negative | 6 (17) |
| Not performed | 22 (63) |
Abbreviations: EM, Erythema multiforme; HSV, herpes simplex virus.
Follow-up duration from EM diagnosis to the discontinuation of thalidomide or to date of last assessment if thalidomide was still being used at the end of the study.
After 6 months of thalidomide, 23 of 35 patients (66%; 95% CI, 50%-81%) achieved CR, and 7 of 35 (20%) experienced at least 1 flare. At 3 and 12 months, 29 of 35 (83%; 95% CI, 70%-95%) and 14 of 35 (40%; 95% CI, 24%-56%) achieved CR. Among the patients with persistent EM, 8 of 13 (62%) achieved CR at 6 months. For patients with recurrent EM who did not achieve CR after 12 months of thalidomide (n = 7), the median number of relapses decreased by 67%, from 6 per year (IQR, 5-8) before initiation vs 2 per year (IQR, 1.5-2) under treatment. Four of the 7 patients previously dependent taking corticosteroids were able to stop systemic corticosteroids therapy, and 3 of the 9 patients still on valaciclovir discontinued it after thalidomide initiation (2 continued, 4 missing data).
Thalidomide treatment was stopped in 25 (71%) patients because of failure (n = 7, 28%, after a median of 8 [IQR, 8-19] months), adverse events (n = 14, 56%, after a median of 12 [IQR, 7-23] months), or long-term remission (n = 4, 16%, after a median of 13 [IQR, 10-20] months). Ten patients (29%) were still receiving treatment at the time of the study for a median treatment duration of 32 (IQR, 23-50) months. Overall, 28 (80%) patients had at least 1 adverse event. The main adverse effects were fatigue in 16 (46%) patients and neuropathy in 14 patients (40%) (Table 2). No patients experienced severe adverse effects or events including thrombosis.
Table 2. Main Adverse Events With Thalidomide.
| Adverse events | No. (%) |
|---|---|
| No. | 35 |
| Fatigue | 16 (46) |
| Neuropathy | 14 (40) |
| Constipation | 4 (11) |
| Weight gain | 3 (9) |
| Headache | 3 (9) |
| Amenorrhea | 1 (3) |
| Amnesia episode | 1 (3) |
| Diarrhea | 1 (3) |
| Psychotic episode | 1 (3) |
| Tremors | 1 (3) |
| Erectile dysfunction | 1 (3) |
| Thrombosis | 0 |
The median initial dose followed by remission was 50 mg/d (IQR, 50-100). For the 23 patients with CR at 6 months, the maintenance dose was 50 mg/d or more for 8, 50 mg every other day for 6, and less than 50 mg every other day for 9 (minimum dose, 50 mg every 7 days). For patients receiving low-dose thalidomide (<50 mg daily), maintenance of thalidomide over time was longer, with fewer instances of neuropathy (Figure). Among patients treated with less than 50 mg every other day, none discontinued thalidomide because of an adverse event.
Figure. Tolerance Data According to Minimum Effective Doses of Thalidomide Over the Long Term in Patients in Complete Remission at 6 Months.
At 6 months, CR was significantly more frequent in patients with fewer than 6 EM flares per year prior to thalidomide therapy vs those with 6 or more flares per year (9/9 [100%] vs 6/13 [46%]; P = .02). Univariable analyses did not identify other factors associated with absence of relapse. In particular, pure mucosal forms and other forms did not differ in response (eAppendix in the Supplement).
Discussion
Findings from this cohort study show that continuous thalidomide was associated with CR in 66% of patients with chronic EM at 6 months and a decrease from a median of 6 to 2 flares per year in patients without CR. The duration of disease prior to thalidomide therapy and failure of previous treatments suggest the clinical benefit of thalidomide rather than the spontaneous evolution of the disease. The previous retrospective series reporting the effect of thalidomide included only 6 patients with continuous treatment.8 Our study is significant because it expands the available data on continuous thalidomide treatment in patients with chronic EM.
Limitations
Study limitations include the retrospective and single-country setting and a small number of patients included, but chronic EM is rare. Postherpetic EM may be underrepresented in our study population, which may limit the generalizability of these findings to all patients with chronic or recurrent EM. Indeed, 33 patients experienced failure of antiviral agents before thalidomide, and among the 20 patients with herpes simplex virus serologic analysis performed, 9 had negative results (Table 1).
A considerable proportion (71%) of patients discontinued the medication in the first year of continuous treatment for various reasons. As previously published,11 we describe many adverse effects, thus potentially limiting the prolonged use of thalidomide. The rate of neuropathy (40%) in this study population was comparable to that reported in other studies describing thalidomide therapy for other skin diseases.12 Because neuropathy recovers in only half of cases after cessation of thalidomide, stopping the drug is essential when clinical signs of neuropathy appear.13 Of note, a thalidomide dose less than 50 mg every other day was effective in 39% of responders and associated with longer duration of treatment and reduced rate of neuropathy, a dose-dependent adverse effect.12 Whether lenalidomide, a similar medication to thalidomide with less neurotoxic effects, is effective in chronic EM would be an important future direction.14
Conclusions
The findings of this cohort study suggest that thalidomide may be a useful alternative therapy for chronic EM. Because of the long-term adverse effects, the search for a minimal maintenance dose is essential in patients with good response.
Univariable Analysis
References
- 1.Samim F, Auluck A, Zed C, Williams PM. Erythema multiforme: a review of epidemiology, pathogenesis, clinical features, and treatment. Dent Clin North Am. 2013;57(4):583-596. doi: 10.1016/j.cden.2013.07.001 [DOI] [PubMed] [Google Scholar]
- 2.Schofield JK, Tatnall FM, Leigh IM. Recurrent erythema multiforme: clinical features and treatment in a large series of patients. Br J Dermatol. 1993;128(5):542-545. doi: 10.1111/j.1365-2133.1993.tb00232.x [DOI] [PubMed] [Google Scholar]
- 3.Wetter DA, Davis MDP. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol. 2010;62(1):45-53. doi: 10.1016/j.jaad.2009.06.046 [DOI] [PubMed] [Google Scholar]
- 4.Amode R, Ingen-Housz-Oro S, Ortonne N, et al. Clinical and histologic features of Mycoplasma pneumoniae-related erythema multiforme: a single-center series of 33 cases compared with 100 cases induced by other causes. J Am Acad Dermatol. 2018;79(1):110-117. doi: 10.1016/j.jaad.2018.03.013 [DOI] [PubMed] [Google Scholar]
- 5.Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schröder W, Roujeau J-C; SCAR Study Group. Severe Cutaneous Adverse Reactions . Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol. 2002;138(8):1019-1024. doi: 10.1001/archderm.138.8.1019 [DOI] [PubMed] [Google Scholar]
- 6.de Risi-Pugliese T, Sbidian E, Ingen-Housz-Oro S, Le Cleach L. Interventions for erythema multiforme: a systematic review. J Eur Acad Dermatol Venereol. 2019;33(5):842-849. doi: 10.1111/jdv.15447 [DOI] [PubMed] [Google Scholar]
- 7.Tatnall FM, Schofield JK, Leigh IM. A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol. 1995;132(2):267-270. doi: 10.1111/j.1365-2133.1995.tb05024.x [DOI] [PubMed] [Google Scholar]
- 8.Cherouati K, Claudy A, Souteyrand P, et al. [Treatment by thalidomide of chronic multiforme erythema: its recurrent and continuous variants. a retrospective study of 26 patients]. Ann Dermatol Venereol. 1996;123(6-7):375-377. [PubMed] [Google Scholar]
- 9.Ting HC, Adam BA. Erythema multiforme—response to corticosteroid. Dermatologica. 1984;169(4):175-178. doi: 10.1159/000249598 [DOI] [PubMed] [Google Scholar]
- 10.Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129(1):92-96. doi: 10.1001/archderm.1993.01680220104023 [DOI] [PubMed] [Google Scholar]
- 11.Franks ME, Macpherson GR, Figg WD. Thalidomide. Lancet. 2004;363(9423):1802-1811. doi: 10.1016/S0140-6736(04)16308-3 [DOI] [PubMed] [Google Scholar]
- 12.Bastuji-Garin S, Ochonisky S, Bouche P, et al. ; Thalidomide Neuropathy Study Group . Incidence and risk factors for thalidomide neuropathy: a prospective study of 135 dermatologic patients. J Invest Dermatol. 2002;119(5):1020-1026. doi: 10.1046/j.1523-1747.2002.19502.x [DOI] [PubMed] [Google Scholar]
- 13.Fullerton PM, O’Sullivan DJ. Thalidomide neuropathy: a clinical electrophysiological, and histological follow-up study. J Neurol Neurosurg Psychiatry. 1968;31(6):543-551. doi: 10.1136/jnnp.31.6.543 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Drahy F, Ingen-Housz-Oro S, Grootenboer-Mignot S, Wolkenstein P, Chosidow O. Lenalidomide as an alternative to thalidomide for treatment of recurrent erythema multiforme. JAMA Dermatol. 2018;154(4):487-489. doi: 10.1001/jamadermatol.2017.5889 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Univariable Analysis