Fumarates and vitamin A derivatives advance and latest insights in non-biologic systemic therapeutic agents in psoriasis and atopic dermatitis

Prof. Peter van de Kerkhof (Radboud University Medical Center, the Netherlands) presented situations where dimethyl fumarate might be considered as a first-line treatment for psoriasis. Acitretin (synthesised retinoic acid) has a potent activity in pustular psoriasis and erythrodermic psoriasis as monotherapy. In chronic plaque psoriasis, it has a strong therapeutic activity, particularly in combination with phototherapy/UVB. Dimethyl fumarate and acitretin have a unique profile; in patients with contraindications for immunosuppressive therapies, both therapies may provide a solution [1].

Dimethyl fumarate has a very long history, particularly in German-speaking countries and the Netherlands. EMA registration has now been filed, after which regulated pharmacovigilance will be enforced and active research will be extended to enhance the proper use of this drug. The European Guidelines on the systemic treatment of psoriasis vulgaris recommends fumaric acid esters for the induction and long-term treatment of psoriasis, applying a slow increased step-by-step dose regimen [2]. Prof. van de Kerkhof stressed that patient selection is key to decide whether a patient will benefit from dimethyl fumarate. It should be noted that dimethyl fumarate is not appropriate when you are going for the “quick fix”, and that is not indicated for arthritis; so psoriatic arthritis patients should not be considered candidates for this alternative.

The advancement in the uses of drugs like dimethyl fumarate and acitretin comes down to the personalised treatment selection. For example, if you have a patient who requires systemic treatment because of unstable disease, consider the triggering factors of the patient. If there are underlying conditions that make a patient susceptible to infections, a systemic biologic treatment may not be the best choice. If there is no urgent need for rapid a resolution, and the patient is happy with a gradual improvement but wants a definite improvement without use of topicals, dimethyl fumarate may be an option. The patient may have chronic asthmatic bronchitis and needs antibiotics at times, so no immunosuppressive treatments would be indicated, or the patient may travel frequently to areas with endemic tuberculosis. Some patients should not receive strong immunosuppressive therapy.

However, if systemic therapy is indicated for such a patient, “my first choice would be dimethyl fumarate; the second choice would be acitretin (although there are some side effects), which has modest efficacy as monotherapy,” said Prof. van de Kerkhof. Presuming that (1) a gradual improvement is requested/acceptable; (2) there is no arthritis; (3) in case of active infections, dimethyl fumarate can be continued; and (4) there are no concerns that the patient travels to areas with endemic tuberculosis. The dosage needs to be incrementally increased to avoid nausea. Once PASI-75 has been achieved, the dose could be incrementally and slowly reduced, and later increased again upon relapse. What is unique about this approach is the flexible dosing, which can be important for some patients.

Some notable side effects observed with dimethyl fumarate include gastrointestinal complaints, flushing, and lymphopenia. What is important to realise is that the efficacy increases with time and the maximal efficacy is observed after 12 months of treatment. This means that timely and appropriate management of toxicities is especially important for this therapeutic approach. In a series of patients receiving long-term care (max. 24 months), 41% patients developed lymphopenia and 12% had leucopenia. These conditions are important to recognise, but if the attending physician follows the clear lymphopenia protocol, assesses lymphocyte counts every 3 months, and intervenes when the counts get near <0.7 x109 cells/L, this side effect can be managed adequately. One practical consideration regarding dimethyl fumarate is that the indication is not limited by a threshold PASI and can be first-line systemic therapy. It only mildly modulates the immune system and is therefore appropriate for cancer patients or can be used in patients at risk for infections. It can be used in combination with phototherapy or even in patients overtreated with phototherapy. If you follow the guidelines with respect to safety monitoring, this is an effective and safe treatment. Vitamin A derivatives/retinoids do not have sufficient available evidence to generate an evidence-based recommendation for or against the use of acitretin as a monotherapy [3]. Based on clinical experience and depending on the opinion and the most important outcome for the individual patient, we suggest a low dose (10-30 mg daily) with respect to tolerability and a high dose (>30 mg daily) with respect to efficacy. For pustular psoriasis, the preferred dosage is 60 mg daily, and for erythrodermic psoriasis, the dosage is preferably 25 mg daily. Acitretin is not used often, but when biologics are not available, the combination therapy of acitretin and phototherapy may be an appropriate alternative for cases where systemic therapy is required, and an immunosuppressive therapy is contraindicated.

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   1. Van de Kerkhof P. SPIN 2019, 25-27 April, Paris, France.
   2. Mrowietz U, et al. Br J Dermatol. 2017; 176(3): 615-623.
   3. Nast A, et al. J Eur Acad Dermatol Venereol. 2015;29(12):2227-2294.

Posted on 21 June 201924 March 2021