J Clin Aesthet Dermatol. 2024;17(11):45–49.
by Martina Burlando, MD; Adelaide Algeri, MD; Ilaria Salvi, MD; Emanuele Cozzani, PhD; and Aurora Parodi, MD
All authors are with the Section of Dermatology, DISSAL, at the University of Genoa, Ospedale-Policlinico San Martino, IRCCS in Genova, Italy and IRCCS Ospedale Policlinico San Martino in Genova, Italy.
FUNDING: No funding was provided for this article.
DISCLOSURES: Drs. Burlando and Parodi have served as speakers for AbbVie, Amgen, Almirall, Eli Lilly, Janssen, Novartis, and UCB.
ABSTRACT: Background. Dimethyl fumarate (DMF) is an oral treatment approved by the European Medicines Agency (EMA) to treat moderate-to-severe plaque psoriasis among adult patients.
Objective. This study aims to evaluate sociodemographic, anthropometric, and medical characteristics in patients with psoriasis without previous history of traditional systemic therapy and to observe if the efficacy or AEs of dimethyl fumarate correlate to any of the patients’ characteristics.
Methods. Ninety-two patients with mild-to-moderate psoriasis were enrolled. Each patient was reviewed at 4, 12, 24 and 36 weeks. The PASI score and any clinical side effects or blood count abnormalities were recorded.
Results. After 4 weeks, a decrease in the median value of PASI index was already noticeable (p<0.001). After 12 weeks of treatment, 43.9% of patients reached PASI-50, 12.3% PASI-75. The patients achieving PASI-75 after 12 weeks of treatment were significantly younger than those who did not. Age, BMI index, gender and gastroprotection used were not significantly related to the occurrence of side effects.
Conclusion. Profiling of patients could be useful in predicting the response to treatment. In our study, younger patients were found to respond better to dimethyl fumarate.
Keywords: Dimethyl fumarate, age, efficacy, adverse events, psoriasis
Introduction
Dimethyl fumarate (DMF), a fumaric acid ester, is an oral formulation approved by the European Medicines Agency (EMA) to treat moderate-to-severe plaque psoriasis among adult patients requiring systemic therapy.1 DMF has been approved since 2017, and data on its safety and efficacy are being published in Germany and other European countries.2,3,4 As a result of its widespread use and safety profile, European guidelines consider DMF as the first systemic drug to be considered in chronic treatment, rather than methotrexate or cyclosporine, that are immunosuppressive.1,5
A significant limitation of DMF is adverse events (AEs). The most frequent AEs are gastrointestinal disorders, mainly diarrhea and abdominal pain in 50.0 percent and 35.1 percent of patients, respectively, flushing (28.0%), and lymphopenia (31.2%), primarily mild/moderate.6 Fortunately, they tend to improve over time, but the first weeks of treatment can pose a challenge to patients, who often discontinue it during this time.1
It is unclear which patients are at heightened risk of developing these AEs, and which would benefit the most from treatment with DMF. In clinical practice, patient characteristics, including sex, disease severity, body weight, comorbidities, and concomitant medications may impact safety or the patient’s therapeutic response to pharmacological treatments.7 Information on patient demographics and baseline characteristics that have the potential to affect the clinical response in real-world practice is scarce, aside from a multivariable regression analysis from the German Psoriasis Registry PsoBest.8
Therefore, the aim of the present study was to evaluate the sociodemographic, anthropometric, and medical characteristics of patients with psoriasis who have never been treated with traditional systemic therapy and to observe if the efficacy or AEs of dimethyl fumarate correlate to any of the patients’ characteristics.
Methods
Between January and December 2021, patients with mild-to-moderate psoriasis were enrolled at the Dermatology Clinic of Policlinico San Martino Hospital in Genoa, Italy. The inclusion criteria were as follows: Patients with mild-to-moderate psoriasis according to the Psoriasis Area and Severity Index (PASI); naïve to traditional systemic therapy; older than 18 years; not intolerant to dimethyl fumarate; and agreeance to sign informed consent. Exclusion criteria were as follows: pregnant or lactating patients and/or patients who refused systemic therapy with DMF.
For each patient, the following data were recorded: sex, age, types of psoriasis (plaque, genital, palmoplantar, or nail psoriasis), disease duration expressed in years, body mass Index (BMI), comorbidities, concomitant therapies and PASI at baseline.
Some patients took the drug following the classical titration (30mg daily for one week, followed by 30mg twice daily [BID] for one week, followed by 30mg thrice daily [TID] for one week, followed by 120mg daily); others followed a diluted titration scheme. Therefore, they took 30mg daily for the first two weeks, 30mg BID for the next two weeks, and then 30mg BID for an additional two weeks before switching to 120mg as those who did the classical titration therapy. These dosing schedules were assigned at the discretion of the attending dermatologist. A total of 38/92 (41.3%) patients followed the diluted titration.
Each patient was evaluated at 4, 12, 24 and 36 weeks, and PASI and any side effects were recorded. Any changes in the full blood count, treatment discontinuation, and drug dose administered were recorded. If the drug was well tolerated and the skin improvement was not satisfactory, the dosage of DMF could be increased from 120mg daily up to 720mg daily. On the contrary, the patients were advised to mantain the minimum effective dosage and, in case of AEs, they could reduce the dosage of the drug.
Statistical analysis. Data were summarized by descriptive analysis. Means, median, and standard deviations (SDs) were calculated for continuous variables, while absolute values and frequency (percentage) were calculated for categorical variables. Comparison of mean values between groups was performed by a Student’s t-test, comparison of mean values within group was performed by a paired t-test and comparison of proportions by the Chi-square test. Analyses were performed using MedCalc® Statistical Software version 20.111 (MedCalc Software Ltd, Ostend, Belgium; https://www.medcalc.org; 2022).
Results
Demographic characteristics. Ninety-two patients (N=92) were enrolled in the study (Table 1). Thirty-eight (41.3%) participants were female versus 54 male participants (58.7%). The median age was 55.7 (±17.8).
The BMI was recorded for 65 of the 92 patients and was 26±4.0. The majority of the patients (85.9%) had plaque psoriasis, three out of 92 (3.3%) had psoriasis of the folds, and 12 of 92 (13%) had palmoplantar psoriasis. The disease duration was recorded for 81 patients and was 17.3±16.2.
Forty-eight patients (52.2%) had at least one comorbidity (Figure 1): six (6.5%) had infectious diseases (HCV; QuantiFERON positivity); 13 (14.1%) had neoplastic diseases; 23 (25%) had hypertension; nine (9.8%) had heart disease; six (6.6%) had diabetes; 10 (10.9%) had dyslipidemia; and 32 (34.8%) other (eg, benign prostatic hyperplasia, thyroiditis, chronic obstructive pulmonary disease, etc.).
In our study, 46 patients (50%) were on concomitant therapies. The mean number of drugs taken concomitantly was 1.7 (± 2.8), median value 0.5, min–max 0–14 (Figure 2). Thirty (33.7%) patients were taking medication for hypertension; 17 (19.1%) for dyslipidemia; 6 (6.6%) for diabetes; 4 (4.3%) for heart disease; 13 (14.6%) for gastroprotection; and 24 (27.0%) of patients were using other therapies (e.g. hormonal contraceptives, bronchodilators, antidepressants, etc).
Trend of PASI score. After four weeks, a decrease in the median value of PASI index was noticeable (p<0.001) (Figure 3). After 12 weeks of treatment, 25 out of 57 (43.9%) patients achieved PASI-50, 7 (12.3%) PASI-75. The patients achieving PASI-75 after 12 weeks of treatment were significantly younger than those who did not (41±16 years versus 58±18 years). Fifteen patients were under 40 years old, and 4 (27%) of these 15 patients achieved PASI-75 after 12 weeks; 42 patients were over 40 years old and 3 (7%) achieved PASI-75 index after 12 weeks. The proportion of patients younger than 40 years old reaching PASI-75 index was significantly higher than that of older patients (p=0.049) (Figure 4).
The patient BMI did not significantly differ between patients who achieved PASI-75 and those who did not achieve PASI-75 after 12 weeks. There was no significant difference between the male and female sex in terms of PASI-75 after 12 weeks.
The rate of PASI-50 achievement after 12 weeks did not significantly correlate with sex, age, and BMI. PASI-50 after 12 weeks was achieved by 21 (46%) patients with psoriasis vulgaris, 1 (50%) patient with inverse psoriasis, and 3 (33%) patients with palmoplantar psoriasis (p=0.781). PASI-75 was achieved after 12 weeks by 6 (13%) patients with psoriasis vulgaris ,1 (50%) patient with inverse psoriasis, and zero patients with palmoplantar psoriasis (p=0.425).
Adverse events. Thirty-three out of 92 patients (35.9%) reported side effects and 17 of the 92 patients (18.5%) discontinued the study due to adverse reactions (Table 2). Fourteen patients showed blood count abnormalities and 7 out of the 14 (50%) dropped out of the study. Age, BMI, sex, and gastroprotection used were not significantly related to the occurrence of side effects. Patients who dropped out of the study were older than those who did not, although no statistical significance was reached (64±18 years vs. 57±18 years, p=0.073).
Eight out of twenty patients (40%) who manifested gastrointestinal side effects and 4/9 (44%) of patients who manifested flushing episodes dropped out of the study (p=0.825). Fourteen out of 36 patients (39%) on “full dosing” and 14/38 (37%) of patients on “diluted dosing” experienced adverse reactions (p=0.857).
There was no statistically significant difference (p=0.162) regarding the proportion of gastrointestinal side effects between female (n=11/38, 41%) and male subjects (n=9/54, 17%), nor regarding the proportion of flushing episodes in female (n=6/38, 16%) and male participants (n=3/54,6%), p=0.106. There was no statistically significant difference (p=0.966) relative to the age of patients who manifested gastrointestinal side effects (56±19 years) and those who did not (56±18 years). There was no statistically significant difference (p=0.139) regarding the age of patients who manifested flushing episodes (47±23 years) and those who did not (57±17 years).
Drug dosage. There was no significant correlation between drug dose and PASI score after four weeks of treatment (p=0.100). There was no significant correlation between medication dose and PASI score after 8, 12, 18, and 24 weeks of treatment (p=0.405); (p=0.140); (p=0.169); (p=0.274) (Table 3).
The dose of DMF did not significantly correlate with the type of psoriasis, since a different response in terms of dosage related to different psoriasis types was not seen. The most used dosage was 120mg daily and it was maintained for a mean of 6.8 weeks (± 3.6 weeks).
Patients lost at follow up. For analyses of patients lost to follow-up, only the first 63 patients are considered (other patients have a shorter follow-up period). After 12 weeks, 13 out of 63 patients (21%) were lost to follow-up. There was no significant difference relative to age between patients lost and not lost to follow-up (52 [± 18] years vs. 59 [± 17] years, p=0.147). There was no relevant difference relative to BMI between patients lost and not lost at follow-up (25 [±5] vs. 26 [±4] years, p=0.536). There was no relevant difference relative to sex between patients lost and not lost to follow-up (6/29 females [21%] vs. 7/34 males [21%], p=0.992).
Discussion
Fumarates are a group of small molecules often used as first-line treatment for systemic psoriasis, showing an acceptable efficacy and safety profile for long-term therapy.9 The numerous side effects of DMF that usually resolve after the first weeks of treatment are well-known in the literature.10 Unfortunately, they lead to drug discontinuation when they appear, reducing the patient’s therapeutic options. Knowing which patient can be the ideal candidate for DMF and is less likely to develop AEs could greatly help psoriasis management.
Reich et al8 recently published a multivariable regression. They observed the patient characteristics enrolled in the PsoBest registry, looking for potential treatment effect modifiers. They did not find any. They observed that patients with a PASI less than 10 had four times higher odds of achieving a response than those with severe psoriasis (PASI>20).
Based on data collected from a single center, our study focused on patients with different baseline characteristics: lower PASI at the time of enrollment, lower BMI, and any previous systemic therapy except topical, reflecting the typical psoriatic patient that in Italy is considered eligible for DMF.
Our data show that a patient younger than 40 years with moderate psoriasis responds faster than patients older than 40 years in terms of PASI 75 at 12 weeks.
There seems to be no sex predilection, nor does BMI affect the response to therapy, in line with other studies in the literature.11
Comorbidities and related therapies did not appear to influence the efficacy of DMF in our study, much less its tolerability. Therefore, DMF can be considered a viable therapeutic option in patients with comorbidities and those taking other treatments, unlike cyclosporine and methotrexate.1,12
In our study, 35.9 percent of patients developed adverse events, but only 18.5 percent discontinued the drug. This data is more favorable than that seen in the PSOBEST registry.8 One possible explanation could be the drug dosage, which in our patients is around 120mg/day, while the average daily dosage of our German colleagues is around 240/360mg. Nevertheless, our data suggest no relationship between the two dosing regimens and the development of adverse events and efficacy.
As other studies show, flexibility and dose customization make dimethyl fumarate a welcome option for the patient and physician.13 Tolerability of the drug seems to depend on neither sex, age, or BMI. Although, in general, older patients tolerated the drug less, we must remember that the type of excretion via CO2 does not interfere with cytochrome P450 and therefore does not interact with any therapy usually taken by the elderly.11 In any case, this is not statistically significant p=0.073.
The different types of side effects, too, seem to have no sex nor age predilection, so as might have been expected, women did not report more flushing and men more gastrointestinal side effects.
In particular, our study found that women had gastrointestinal complaints in 41 percent of cases, versus 17 percent of men; as for flushing, the incidence was 16 percent in women and 6 percent in men, but statistically, these differences were not considered significant (p=0.162 and p=0.106).
At the discretion of the attending dermatologist, some patients had a diluted titration. According to the datasheet, DMF should be administered one time daily at a dose of 30mg for the first week and then increased by 30mg daily per week up to a dose of 120mg daily. Once 120mg daily is reached, from week to week, it can be increased by 120mg/day until a maximum of 720mg daily is reached.
In case of diluted therapy, the dosage was increased every two weeks. This type of titration, suggested by Malara et al,13 is an excellent choice to avoid adverse events. However, from our data, adverse events were not less common in the group receiving diluted dosing, and no threshold dose for the developement of adverse events was found. Each patient is, therefore, different from another. In more detail, our study found adverse reactions in 39 percent of patients on standard dosing and in 37 percent of patients on diluted dosing.
Also, in terms of ideal dose, at the various follow-ups, no dosing was observed to be significantly related to the PASI achieved. This is also observed in other real-life data where patients respond to very low dosages while others only at higher ones.14,15
Among the treated patients, three had inverse psoriasis, and 12 had palmoplantar psoriasis. No difference in efficacy was seen in terms of PASI50 or PASI75 in patients with different forms of psoriasis. However, patients with palmoplantar psoriasis took longer to achieve PASI75 compared to patients with plaque psoriasis.
Sixty-three out of 92 patients were evaluated up to Week 12; 21 percent were lost to follow-up. There was no correlation with sex, age or BMI. The percentage includes patients who developed adverse events and those who were lost at follow-up regardless of side effects or drug efficacy.
Conclusion
The drugs used for psoriasis are numerous, and thanks to the new biologic therapies, also very safe and effective. According to Italian Medicines Agency (AIFA), however, only the patient with moderate-to-severe psoriasis who has already undergone traditional systemic therapy is eligible for biologic therapies.
Among the traditional systemic therapies: cyclosporine and methotrexate are immunosuppressive; acitretin is more indicated for the palmoplantar form and is not prescribed in childbearing women; PUVA therapy is often not feasible, as it is time-consuming. Therefore, the possibility of having a safe, non-immunosuppressive therapy such as DMF has provided an extra therapeutic chance for the psoriatic patient. However, it is common practice to observe the drug’s efficacy in some patients and complete ineffectiveness in others, who often develop side effects. Profiling of DMF-responsive patients is, therefore, mandatory.
What was observed in our study is that younger patients are those who respond better to the drug. Associated comorbidities or any concomitant therapies do not affect tolerability.
Therefore, we can consider DMF a systemic therapy in young patients with moderate-severe psoriasis to whom we do not want to prescribe immunosuppressive therapies such as cyclosporine or methotrexate, but further studies involving a greater number of patients are necessary.
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