Risankizumab shows high efficacy and maintenance in improvement of response until week 52

Abstract Risankizumab has been recently approved for moderate‐to‐severe plaque psoriasis; however, real‐life studies are scarce. Analysis of possible predictor factors of treatment response are limited to body mass index (BMI) and previous biologic experience. Our objectives were to evaluate the effectiveness and safety of Risankizumab and to investigate on possible predictor factors response. We retrospectively analyzed 166 patients from two centers in Italy who undergone Risankizumab for psoriasis. The proportion of patients achieving a 100%, 90%, 75% of improvement in Psoriasis Area Severity Index (PASI) and PASI <3 were collected at weeks 16, 28, 40, and 52. Study population was analyzed in subgroups to investigate possible predictors of response to Risankizumab since week 40. At the time of analysis 165, 103, 30, and 11 patients had completed 16, 28, 40, and 52 weeks of treatment, respectively. The mean PASI score decreased from 12.5 ± 5.1 at baseline to 1.9 ± 2.4 at week 16. Similar reductions were observed when considering PASI <3, PASI 75, PASI 90, and PASI 100. Previous biologics failure, different smoking habits, obesity, and joint involvement resulted in a lower response to risankizumab. In particular, significant differences in mean PASI at any time‐points was observed between psoriatic arthritis (PSA) and non‐PSA patients: 2.7 versus 1.7 (p = 0.036), 1.9 versus 0.4 (p = 0.006), and 4.1 versus 0.5 (p = 0.016) at 16, 28, and 40 weeks, respectively. No difference in response to risankizumab occurred in the case of involvement of difficult‐to‐treat areas. In this population, Risankizumab was effective and safe. Smoking habits, joint involvement, obese status, and previous biologic experience may negatively affect treatment response, while difficult body sites involvement have minor impact.


| INTRODUCTION
Risankizumab is the latest biologic treatment approved by Food and Drug Administration and European Medical Agency for moderate-tosevere plaque psoriasis. 1,2 This new biologic, a humanized IgG1 monoclonal antibody, targets the p19 subunit of IL-23. 3 High levels of efficacy and safety have been demonstrated in different clinical trials (UltIMMA-1 and -2, IMMerge, IMMvent, SustaIMM). [4][5][6][7] In these studies, a great percentage of patients reached PASI 90 (>70%) and complete remission at 16 weeks. This result was supported by real-world evidence available in the literature since now. 2,3,[8][9][10] Real-life studies were scarce and with small sample size and short follow-up, due to the novelty of the drug, most of the studies are limited to the 16th week and in the following weeks the sample drops significantly. 2,3,10 The analysis of possible response factors to treatment with risankizumab is limited in clinical trials and real-life studies to body mass index (BMI) and the use of previous biologic therapy. 2,9 Realworld data show good responses in difficult-to-treat areas such as the nails and the palm-plantar area. 3,10 Although new systemic treatments and recent literature reviews have reduced the weight of these difficult locations (scalp, nails, folds, genital sites, and palms and soles of the feet) in the course of psoriatic disease, these sites may still show a slower response to the new biologics. 3,10,11 Lifestyle habits, such as smoking, negatively impact the course of psoriasis through the production of free radicals that activate the tumor necrosis factor (TNF)alfa and Janus kinase (JAK) pathways. 12,13 No data on the impact of smoking habits on risankizumab response are available in literature.
The presence of joint involvement, psoriatic arthritis (PSA), shares the same inflammatory pathways as the cutaneous form, however, the greater resistance to treatment and the deeper systemic involvement suggests the role of further molecular and genetic factors, not yet well defined. The impact on the quality of life of PSA is often greater than its skin counterpart and therapeutic options lead to more modest results. 14 The high impact on quality of life of PsA and involvement of difficult sites justifies the prescription of biologic drugs even in patients with a limited extent of disease [i.e., low Psoriasis Area Severity Index (PASI)]. 3,14 The purpose of our study was to assess the effectiveness and safety of risankizumab and possible prognostic factors as the use of previous biological therapies, obese status, the involvement of difficult sites, the habit of smoking, and joint involvement in real life setting.

| METHODS
This was a retrospective multicenter study with the aim of analyzing data and possible demographic markers of prognostic response in adult patients treated with Risankizumab for moderate-to-severe psoriasis in two tertiary centers in Italy, the Dermatology Clinic of the

| RESULTS
Since September 2020, a total of 166 patients were treated at the two centers with risankizumab for moderate-to-severe psoriasis and enrolled in this study. Of these 166 patients, 66% were male (n = 108), the mean age of the patients was 65.1 (SD 18.6), the mean age of onset of psoriasis was 32.1 (ds 16.6). At baseline, the mean BMI was 27 (SD 6) and 36 (22%) patients were obese (BMI > 30).
66% of patients reported at least one comorbidity, cardiovascular and metabolic diseases were present in 28% and 8% of patients, respectively. Regarding concomitant infectious diseases, 5 patients had a history of HCV, 2 of HBV, 1 of HIV, at a young age one patient had viral encephalitis and another reported a history of tuberculosis 43 years previously, 1 patient tested positive for Quantiferon-TB screening without subsequent prophylactic therapy. During the weeks of follow-up, there was no reactivation of the disease and no further infection. Of note, three patients had experienced low-grade bladder carcinoma more than 5 years previously and 1 patient had experienced osteosarcoma with lung metastases more than 20 years previously. Thirty-eight percent of patients were active smokers, 23% reported quitting smoking and 39% had never smoked. Twenty-one (13%) patients also suffered from PsA and 72 (43%) patients had at least one complicated site involved (i.e., nails, folds, palms and soles, and genitals).
Baseline features of the study population are depicted in Table 1.

| RISANKIZUMAB TREATMENT
During the study period, only 7 adverse events were observed, To identify possible predictors of response to treatment, we compared various subpopulations of patients with each other. In agreement with previous studies, we compared patients based on their previous-biologic status and BMI, in particular the obese versus nonobese population (BMI <30). We also analyzed concerning the habit of smoking which, as mentioned, is a recognized disadvantage F I G U R E 2 Graphic reduction in mPASI and in the achievement of PASI 100, 90, 75, and <3 in general population during weeks 16, 28, and 40 according to previous biologic status, BMI status, difficult sites involvement, smoking habits and joint involvement response factor to treatments in the psoriatic patient, compared patients with difficult/special sites involved to non-difficult, and concerning the presence or absence of PsA.
Significant differences were found between bio-naive and bio- In conclusion, a previous history of using biological drugs may reduce response to risankizumab.
The scalp, folds, palms, nails, and genitals have traditionally been considered difficult sites in the treatment of psoriasis due to the reduced efficacy or difficult application of topical treatment. Systemic treatment including biological treatment should lead to better results in these sites. 11  Recently brodalumab, guselkumab and tildrakizumab have demonstrated safety and efficacy in patients with this type of disease. [22][23][24] There is currently no study demonstrating the superiority of one biologic over another for the treatment of PsA. Existing studies have can assume a lower efficacy of risankizumab in psoriatic arthritis.
The safety of risankizumab over 52 weeks was good, with only one side effect-related discontinuation (0.6% of the total population), a result similar to that reported by phase III and same nature studies. 2,4 No new safety signals were observed. These results were recently underlined by a study on the safety of risankizumab and other anti IL23 in frail, elderly patients with numerous comorbidities. 25 In our population, one event of peri-malleolar edema leading to treatment discontinuation occurred, this event was not previously reported. One patient died before week 16. Death was correlated to the patient's previous general condition and not to the treatment. No recurrence or new neoplasia were observed. Only 8 patients (4.8%) stopped the treatment, mainly due to primary inefficacy. Indeed, adverse events led to treatment discontinuation in only 1 patients (0.6%), further supporting risankizumab high safety profile.
Our study shares the usual limitations of real-life studies, retrospective design, and absence of a control group. The number of patients is relatively low, although higher than the real-life studies currently present in the literature. The sample, also tend to reduce during the following time-points analyzed, making it impossible to perform statistical analysis at week 52.

| CONCLUSIONS
In our study, risankizumab showed efficacy and optimal safety profile.
Our data support what was previously highlighted by clinical trials and previous real-life studies, addressing outcomes not analyzed in previous studies such as PASI <3. The efficacy was slightly slower than that reported in trials at all the outcomes analyzed, with PASI outcomes being inferior at week 16 but equaling the data of clinical trials and other real-life at later time-points. The high operatordependence of PASI as an efficacy measure may have critically plagued our results.
This slow and progressively greater effect could be associated with a persisting response over time, and longer studies are needed to confirm this hypothesis. The lower number of administrations required by Risankizumab is not to be overlooked in those patients whose extent of disease does not justify repeated and close administration but whose burden of disease makes biological treatment necessary.
Our data show that obesity, previous biologic experience and above all joint involvement determine a lower response to treatment. Less pronounced differences were found with respect to smoking habits and difficult site involvement in our study only affects PASI 90 outcome at 16 weeks, generally we can say that Risankizumab did not show different among smoking habits, and classic and difficult sites. Real-life studies with higher numbers especially at higher time-points and with longer follow-up could better estimate the efficacy of risankizumab in the clinical setting.
Proof-of-concept studies are needed to better evaluate the weight of possible prognostic factors in the psoriasis response to risankizumab.