Practice-oriented recommendations for system therapy

Fortunately, developments in recent years have led to the effective treatment of many patients with moderate to severe psoriasis. In addition to classical immunosuppressants, several biologics and a small molecule inhibitorare currently available. Increasingly, the goal is to provide individualized therapy that takes into account comorbidities/co-occurring conditions as well as patient preferences in therapy selection.

In recent years, it has become widely recognized that psoriasis not only affects the skin, but is an immune-mediated inflammatory systemic disease. “That’s why we absolutely need systemic therapies to support our patients in the best possible way,” emphasized PD Dr. Dr. Ahmad Jalili, head of the Dermatology & Skin Care Clinic, Buochs [1]. In the Global Report on Psoriasis, the World Health Organization (WHO) stated that psoriasis is associated with a variety of trigger factors and possible comorbidities [2] (box). According to the WHO, there is an urgent need for early evidence-based psoriasis treatment to prevent disease progression and an increase in cumulative disability over the life course.

Severity classification and history and prescreening.

The Rule of Ten states that if body surface area (BSA)≥10, psoriasis area and severity index (PASI)≥10, and dermatology life quality index (DLQI)≥10, psoriasis is moderate to severe, so by definition, the indication for systemic treatment is given [3]. According to recent findings, however, psoriasis can be classified as moderate to severe even at values below this if lesions in certain localizations or severe itching are predominant (box, upgrade criteria) [3].

“It is very important that we take the history accurately,” Dr. Jalili emphasized [1]. Pre-screening is due for conventional systemic therapeutics (csDMARDs), as well as for synthetic small molecule inhibitors(sDMARDs), and for biological agents/biologics (bDMARDs) prior to initiation of therapy [1]. For this purpose, the speaker recommends a large blood count; in particular, the liver and kidney values, as well as the inflammatory parameters should be recorded and, if necessary (depending on the therapy option), monitored. In addition, a hepatitis and HIV serology, as well as a clarification for latent or manifest tuberculosis must be performed. In addition, the vaccination status should be checked and it is advisable to perform necessary vaccinations or boosters, especially with live vaccines, before starting therapy.

Important criteria for therapy selection include patient characteristics and any comorbidities. A particularly common concomitant of psoriasis is psoriatic arthritis (PsA). If there is evidence of joint involvement in patients, they can be put on a treatment that is also effective against PsA – the latter is true for more than 80% of systemic therapies, Dr. Jalili explained [1]. Nail involvement is a known risk factor for developing PsA at some point in the disease course.

Which system therapy to start with?

In Switzerland, it is regulated that one must first start with csDMARD (methotrexate, ciclosporin A, acitretin, dimethyl fumarate, phototherapy) or explain why this therapy is contraindicated in the respective patient and a bDMARD or an sDMARD (currently only apremilast is approved) should be used directly [1]. Compared with biologics and apremilast, the goals that can realistically be achieved with conventional systemic therapeutics are more modest:

• Dimethyl fumarate (DMF): In Germany, this is one of the most frequently prescribed conventional systemic therapeutics, according to Dr. Jalili. The PASI-75 response rate at week 12 was 43%, but interestingly, a response rate of 87.7% was achieved at week 52. With DMF, one should watch out for a drop in the lymphocyte count (=risk of opportunistic infections) and gastrointestinal complaints may occur as a side effect.
• Methotrexate (MTX): At week 16, a PASI-75 response rate of 41% was achieved. MTX is available in oral and subcutaneous (s.c.) dosage forms, with s.c. MTX in particular generally being very well tolerated. Studies showed no severe side effects and no increased risk of malignancy.
• Ciclosporin A (CsA): In one study, approximately 40% of psoriasis patients treated with CsA reported a satisfactory response. Because of known side effect risks (e.g., renal function, arterial hypertension), avoid long-term treatment with CsA whenever possible.
• Acitretin: In a study with different doses, the best response was achieved under 35 mg/d – at week 12, a proportion of 69% achieved a PASI-75. The most important (dose-dependent) side effect is considered to be mucocutaneous infections.

If a reduction in PASI of ≥75% is achieved in the induction phase with a systemic therapeutic agent, the treatment can be considered successful. In contrast, a PASI reduction of <50% would be equivalent to treatment failure. If the PASI is in the range of ≥50 and <75%, this is a moderate success – if the Dermatology Life Quality Index (DLQI) is <5, therapy can be continued, otherwise a switch is advisable [1].

bDMARD and sDMARD: highly effective against systemic inflammation

In Switzerland, apremilast (sDMARD) is included in the list of specialties with a limitation. Whether a cost approval is required must be assessed on a case-by-case basis [1]. Biologics (bDMARDs) are genetically engineered drugs and specifically interfere with the immune system’s dysfunction, blocking certain pro-inflammatory cytokines. Therefore, Dr. Jalili [1] explained, one can select the respective active ingredient adapted to the patient characteristics. The first biologics were TNF-α inhibitors, and the spectrum of biologic agents has since expanded to include an anti-IL-12/23 antibody (Ak), several anti-IL-17-Aks, and three anti-IL-23-Aks. For the choice of therapy, not only the skin symptoms are relevant, but also comorbidities and concomitant diseases. Especially with the modern substance classes of IL-17 and IL-23 inhibitors, ambitious therapy goals, such as a PASI-90 or freedom from manifestations, are achievable.

• TNF-α inhibitors (etanercept, adalimumab, infliximab, certolizumab pegol) [1,4]: Etanercept is almost no longer used, whereas adalimumab still plays an important role and is approved not only for psoriasis but also for inflammatory bowel disease (IBD), acne inversa and arthritis. Infliximab is only a third-line therapy in dermatology, Dr. Jalili said [1]. If infliximab is re-administered after interruption of therapy, there is an increased risk of an anaphylactic reaction. Certolizumab is the only TNF-α inhibitor that can be safely administered during pregnancy and lactation [1].
• IL (interleukin)-12/23p40 blockade (ustekinumab) [1,4]: The monoclonal antibody ^Stelara® directed against IL-12 and IL-23 was the first biologic with an application interval of three months, a great advance at that time, Dr. Jalili reported [1].
• IL-17 blockade (ixekizumab, secukinumab, bimekizumab) [1,4]: In addition to the IL-17-A inhibitors ixekizumab (^Taltz®) and secukinumab (^Cosentyx®), which have been available for several years, the dual IL-17A/F inhibitor bimekizumab (^Bimzelx®) was recently approved in Switzerland [1,4]. Not approved in Switzerland, however, is brodalumab – a highly potent IL-17 receptor inhibitor, with rapid worsening or relapse of psoriasis often occurring after discontinuation, Dr. Jalili explained [1]. Studies are currently underway on sonelokimab – this is a bispecific anti-IL-17A/F nanobody that inhibits both IL-17A and IL-17F. Nanobodies are significantly smaller than conventional antibodies, which is why they can probably penetrate the tissue better, which may have a favorable effect on efficacy.
• IL-23p19 blockade (guselkumab, risankizumab, tildrakizumab) [1,4]: “Blocking IL-23 seems to be significantly more important than blocking both cytokines IL-23 and IL-12,” Dr. Jalili reported, adding, “The efficacy of guselkumab, risankizumab, and tildrakizumab is significantly better compared with ustekinumab” [1]. Guselkumab (^Tremfya®), risankizumab (^Skyrizi®), and tildrakizumab (^Ilumetri®) differ in binding affinity to IL-23 and half-life [1,4]. The dosing interval after the induction phase is 8 weeks for guselkumab and 12 weeks for both risankizumab and tildrakizumab.

While all the biologics mentioned are administered subcutaneously or intravenously, apremilast – currently the only approved small molecule inhibitor in the indication area psoriasis – is available in oral dosage form. The treatment algorithm (Fig. 1) also mentions deucravacitinib, as approval is expected soon, Dr. Jalili elaborated [1].

• Apremilast [1,4]: This is an oral PDE-4 inhibitor. Laboratory monitoring is not required for therapy with apremilast (^Otezla®), the speaker said [1,4]. Apremilast achieves lower PASI response rates than modern biologics, but in certain locations (e.g., scalp or nail involvement, genital psoriasis, palmoplantar psoriasis) and for severe pruritus, it is a treatment option that has demonstrated high patient satisfaction.
• Deucravacitinib [1]: This is an orally available tyrosine kinase (TYK)-2 inhibitor that inhibits the signaling cascade of IL-12 and IL-23 as well as that of type 1 interferon. Deucravacitinib is expected to be approved in Switzerland soon. Promising results have been achieved in the Phase III trials (POETYK PSO-1 and -2). “We don’t have approval in Switzerland yet, but it’s potentially a good drug,” Dr. Jalili summarized [1].

Subgroup-specific criteria for therapy selection

In general, therapy selection should be tailored to patient characteristics or psoriasis manifestations, but situational factors may also play a role. Dr. Jalili gave some examples which are frequently encountered in clinical practice (more detailed information on the individual agents can be found in the current S3 guideline) [1,3]: With regard to the fastest possible onset of action, for example, the IL-17 and IL-23 inhibitors are ahead of the field and are superior to TNF-α-i. In nail psoriasis, almost all biologics work well, but anti-IL-17-Ak and anti-TNFα-Ak work better and faster. In obesity, IL-17 and IL-23 inhibitors do well. However, if there is evidence of inflammatory bowel disease (IBD) in patients, therapy with anti-IL-17-Ak is not advisable, and if there is a history of arterial hypertension or thrombosis, one must be cautious about TYK-2 inhibition (deucravacitinib is currently being studied in pivotal trials). In patients with malignancies, the use of anti-IL-23-Ak or anti-IL-17-Ak may need to be considered in collaboration with oncologists. If patients have multiple sclerosis (MS), DMF may be considered, as this therapeutic also has approval for MS. If latent tuberculosis has been identified in prescreening, IL-23 or IL-17 inhibitors are possible. There are no restrictions for HIV patients on antiretroviral therapy (HAART), he said. And children and adolescents can also be treated with some of the biologics: Etanercept, adalimumab, ustekinumab, secukinumab, and ixekizumab have approval in Switzerland from 6 years of age, and other bDMARDs are being evaluated for indication expansion. There is also a lot going on with the sDMARD and it will be interesting to see what happens next.

Literature:

1. “Systemic therapies in psoriasis: why, when, and with which?”, PD Dr. Dr. Ahmad Jalili, continuing education event (online), University Hospital Basel, May 30, 2023.
2. WHO: Global report on Psoriasis 2016, www.who.int/publications,(last accessed 16.06.2023).
3. Nast A, et al: German S3 guideline for the therapy of psoriasis vulgaris, adapted from EuroGuiDerm – Part 1: Therapy goals and therapy recommendations. JDDG 2021; 19(6): 934-951.
4. Drug Information, www.swissmedicinfo.ch,(last accessed 06/16/2023).
5. Nast A, et al: German S3-guidelines on the treatment of psoriasis vulgaris (short version). Arch Dermatol Res 2012; 304(2): 87-113.

DERMATOLOGIE PRAXIS 2023; 33(4): 21-24 (published 8/27-23, ahead of print).