Dear Editor:
Fumaric acid derivatives (FADs) including dimethyl fumarate (DMF) are small molecular based systemic treatments that have therapeutic effects in adult patients with psoriasis. Among FADs, DMF was found to be an active ingredient with immunomodulatory, anti-proliferative, anti-inflammatory, and apoptotic effects1. The BRIDGE study, a double-blinded, randomized, and placebo-controlled trial, evaluated the efficacy of DMF, which can be adjusted to doses ranging from 30 to 720mg/day depending on the treatment effect and safety, and showed no inferior efficiency compared to fumaric acid esters, which were previously prescribed clinically2,3. Several studies have evaluated the efficacy and safety of DMF for moderate-to-severe psoriasis under real-life conditions in European patients. Recently, DMF has been approved for psoriasis treatment in Korea. However, the safety and efficacy of DMF in real-life clinical practice have not been investigated in Asian populations, including Koreans1,2,4. In this case series, the short-term safety of DMF in Korean patients with psoriasis was evaluated in a real-life clinical setting.
We retrospectively reviewed the medical records of 20 consecutive patients with psoriasis treated with DMF at Seoul National University Hospital from March 2022 to October 2022 and collected the following clinical information: age, sex, body mass index, comorbidities, previous treatment history, prescription period and dose of DMF, occurrence of adverse events (AEs), and severity of psoriasis before and after DMF treatment with Psoriasis Area and Severity Index (PASI). AEs occurred within 16 weeks after the start of DMF treatment were analyzed to evaluate the short-term safety of DMF5. This study was conducted with the approval of the Institutional Review Board (IRB) of Seoul National University Hospital (IRB No. 2211-040-1375). The requirement for the informed consent was waived by the board.
The demographic information and summary of the treatment outcomes of the patients are shown in Table 1. All patients were adults (median, 51.5 years; range, 26–67 years) and 14 (70%) were females. Ten patients underwent conventional systemic therapy including cyclosporine or methotrexate. Fourteen patients (70%) had comorbidities such as hypertension, diabetes, hyperlipidemia, and liver dysfunction, and none of the patients had previously received biologics.
Table 1. Clinical characteristics of 20 patients with psoriasis treated with dimethyl fumarate.
| Cases | Age (yr)/sex | BMI (kg/m2) | Comorbidity | DMF duration (wk) | Efficacy | AEs | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| Baseline PASI | PASI after DMF medication (wk*) | AEs | Time to onset (wk) | Dosage at AE (mg/day) | DMF management status | |||||
| 1 | 60/F | 18.6 | HTN | 11 | 7.0 | 6.2 (11) | LFT abnormality | 11 | 240 | Discontinuation |
| 2 | 54/M | 26.2 | DM | 10 | N/A | N/A | - | - | - | - |
| 3 | 63/F | 30.0 | HTN, DM, HIVD | 21 | 3.8 | 0.5 (7) | Diarrhea | 11 | 240 | Dose reduction |
| 4 | 50/F | 28.1 | DM, epilepsy | 23 | N/A | N/A | Aggravation of epilepsy | 11 | 360 | Dose reduction |
| 5 | 46/M | 24.1 | - | 26 | 8.6 | 8.6 (20) | Dyspepsia, Abdominal distention | 10 | 360 | Dose reduction |
| 6 | 58/F | 22.9 | DM, DL | 2 | 6.1 | 6.1 (2) | Dyspnea | 2 | 60 | Discontinuation |
| 7 | 66/M | 27.8 | CKD | 17 | N/A | N/A | Flusing | 13 | 480 | Dose reduction |
| 8 | 62/M | 26.3 | HTN, DL | 19 | 11.0 | 12.2 (4) | Blurred vision | 10 | 360 | Dose reduction |
| 9 | 53/F | 28.9 | HTN, DM, Fatty liver | 26 | 11.0 | 4.1 (17) | - | - | - | |
| 10 | 64/F | 27.3 | - | 6 | N/A | N/A | - | - | - | |
| 11 | 67/M | 32.7 | Fatty Liver | 20 | N/A | N/A | Dyspepsia | 7 | 240 | Dose reduction |
| 12 | 26/F | 23.3 | - | 22 | 16.4 | 4.8 (30) | - | - | - | |
| 13 | 50/F | 27.2 | Depression | 4 | 4.6 | 2.8 (5) | Abdominal pain | 4 | 120 | Discontinuation |
| 14 | 43/F | 33.6 | - | 33 | 5.4 | 2.3 (25) | Diarrhea | 9 | 360 | Dose reduction |
| 15 | 28/F | 23.7 | - | 25 | N/A | N/A | - | - | - | |
| 16 | 50/F | 15.8 | DL | 19 | 3.0 | 2.2 (26) | Abdominal pain, Nausea | 8 | 240 | Dose reduction |
| 17 | 47/M | 26.1 | - | 18 | 7.4 | 4.5 (12) | - | - | - | |
| 18 | 42/F | 29.7 | - | 17 | N/A | N/A | - | - | ||
| 19 | 62/F | 21.2 | HTN | 15 | 5.5 | 7.9 (15) | - | - | - | - |
| 20 | 26/F | 30.3 | DM, HTN, Subclinical hypothyroidism | 9 | N/A | N/A | Abdominal pain | 9 | 240 | Discontinuation |
BMI: body mass index, DMF: dimethyl fumarate, PASI: Psoriasis Area and Severity Index, AE: adverse event; F: female, M: male, HTN: hypertension, DM: diabetes mellitus, HIVD: hernia of intervertebral disc, DL: dyslipidemia, CKD: chronic kidney disease, LFT: liver function test, N/A: not available (missing data).
*Number of weeks that PASI evaluation have been performed since the start of DMF treatment.
In all patients, DMF was started at 30 mg/day and increased by 30 mg/day every week, reaching a total of 120 mg/day at week 4 (induction phase), and then increased or reduced by 120 mg/day at every visit after considering the treatment effect, AEs, and patient compliance (maintenance phase). All patients received a fixed-dose combination of calcipotriol/betamethasone dipropionate together with DMF in the form of a gel, foam, or ointment, and no patient received phototherapy concurrently. Patients regularly underwent blood tests, including liver function test and lymphocyte count, every 3–6 weeks before and after DMF treatment.
The median treatment duration was 18.5 weeks (range, 2–33 weeks). Records of PASI scores were available for 12 patients, of whom eight (67%) showed a reduction in PASI score after DMF treatment. In these 12 patients, the median PASI score decreased from 6.6 (range, 3.0–16.4) to 4.6 (range, 0.5–12.2) during treatment, and PASI50 was achieved in four (33%) patients (cases 3, 9, 12, and 14). Of the 20 patients, three patients (cases 8, 10, and 19) switched to other systemic agents because of insufficient response to DMF.
Within 16 weeks of treatment, AEs occurred in 12 patients (60%), of which four patients (20%) stopped DMF due to AEs, and the other eight (40%) continued treatment by reducing the dose. Gastrointestinal problems (n=7, 35%), including abdominal pain (n=3), dyspepsia (n=2), and diarrhea (n=2), were the most frequent. Four patients (20%) discontinued DMF treatment due to the following: increased transaminase (case 1), dyspnea (case 6), and abdominal pain (cases 13 and 20). Ten patients experienced AEs during the maintenance phase, while the other two experienced them during the induction phase. The median time interval from the start of medication to the occurrence of AEs was 10 weeks (range, 2–15 weeks). The median drug dosage at the time of AEs occurrence was 240 mg/day (range, 60–480 mg/day). All AEs resolved during follow-up observation after DMF dose reduction or discontinuation. DMF treatment was discontinued in all patients who experienced AEs within 4 weeks of DMF treatment (induction phase), whereas only 2 of 10 patients with AEs that occurred after 4 weeks of treatment (maintenance phase) were discontinued (Table 2). Early-onset AEs may cause treatment discontinuation considering the risk-benefit of efficacy and AEs because the response to DMF is usually insignificant in the early period. However, the number of patients were small and thus further studies are necessary.
Table 2. Profile of DMF treatment discontinuation rate by time of AEs occurrence.
| Time to onset of AEs (wk) | Number of patients treated with DMF | Number of AEs occurred | Number of treatment discontinuation (d/t AE) | Number of discontinuation (not d/t AE) | Proportion of treatment discontinuation d/t AE (%) |
|---|---|---|---|---|---|
| 0–4 | 20 | 2 | 2 | 0 | 100.0 |
| 4–8 | 18 | 2 | 0 | 1* | 0.0 |
| 8–12 | 17 | 7 | 2 | 1† | 28.6 |
| 12–16 | 14 | 1 | 0 | 1* | 0.0 |
AE: adverse event, DMF: dimethyl fumarate, d/t: due to.
*Discontinuation d/t low efficacy; †Discontinuation d/t opthalmologic treatment.
This study is the first to investigate the short-term safety of DMF in Korean patients with psoriasis. The incidence of AEs for the first 16 weeks was found to be 60% after taking DMF, which was included in the range of 42.9%–84% as reported in previous studies surveyed in Europeans1,2,6,7,8. In line with the literature, the main AEs are mild gastrointestinal symptoms, including diarrhea, abdominal pain, and dyspepsia. In terms of the short-term efficacy of DMF combined with topical calcipotriol/betamethasone dipropionate, 33% of the patients reached PASI50 between 10 and 24weeks. In previous studies of European patients, DMF efficacy was investigated from 6 to 36 months, and a lack of treatment effects was reported in 39%–51.4% of patients2,6,8. Lymphopenia and hyper-eosinophilia reported in previous studies were not reported in this study, and the incidence of laboratory adverse effects was 5%, which was lower than that reported in previous studies9. In previous studies of European patients, AEs could be alleviated by reducing the doses, and all AEs investigated in the current study were resolved through dose reduction or discontinuation2,10.
In conclusion, this study showed that the incidence of short-term AEs due to DMF in Korean patients was high, but the AEs were not severe, and no patient experienced any permanent AE. Although DMF treatment for psoriasis is thought to be a tolerable and fair alternative, dermatologists are recommended to pay attention to the risk of AEs through appropriate interviews and laboratory monitoring for safe and compliant treatment.
Footnotes
FUNDING SOURCE: None.
CONFLICTS OF INTEREST: The authors have nothing to disclose.
DATA SHARING STATEMENT: The data that support the findings of this study are available on request from the corresponding author.
References
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