Employing Adalimumab in Treatment of Moderate-to-Severe Hidradenitis Suppurativa: Real-Life Multicenter Data from the Czech Republic

Adalimumab is the only approved biologic treatment for moderate-to-severe hidradenitis suppurativa, nonetheless, long-term data from real-life setting are still limited. Te objective of this observational multicenter study was to evaluate the efectiveness, safety, and drug survival of adalimumab in patients with hidradenitis suppurativa included in the BIOREP registry. A total of 299 patients who initiated adalimumab therapy for hidradenitis suppurativa from 2011 to November 2021 were included. Te Dermatology-Life-Quality-Index (DLQI), pain scale, the number of abscesses, infammatory nodules and draining tunnels, and International Hidradenitis Suppurativa Severity Score System (IHS4) were recorded in the 0 th , 3 rd , and 6 th months; then every 6 months during the ongoing adalimumab treatment. Studied patients underwent treatment for up to 48months, with the average duration of treatment lasting 2.3years. Te mean age of the patients was 44.9 years, 79% were smokers or ex-smokers, 54.8% were obese, and 26.4% were overweight, the mean BMI was 30.8. Te mean time from diagnosis to initiation adalimumab therapy was 9.1 years. Te number of patients with severe IHS4 dropped from the initial 249 (83.3%) to 65 (30.1%) after 12months and this trend was maintained up to the 48 th month. A decreasing number of infammatory lesions were rapid and sustained and correlated to the improvement of patients’ quality of life, the mean DLQI score dropped from 17.6 to 8.5 after 3months and to 5, 7 after 48 months. No unexpected risk signals were observed. Our long-term study demonstrates the efectiveness and safety of ada-limumab in a real-life setting.


Introduction
Hidradenitis suppurativa (HS) is a chronic infammatory skin disease that severely impairs patients' quality of life.It is characterized by recurrent painful nodules, abscesses, and draining sinus tracts most commonly in the axillary, inguinal, and anogenital regions Reference [1].Chronic infammation and dysregulated epithelial diferentiation, especially of hair follicle keratinocytes, which leads to follicular hyperkeratosis, dilatation, and rupture, have been involved in the pathogenesis of HS [2].Cardiovascular diseases risk factors including central obesity, history of smoking, metabolic syndrome, dyslipidemia, and hypertension are more prevalent among HS patients compared to the general population [3].At the same time, HS is associated with other immune-mediated diseases, such as infammatory bowel disease and spondyloarthropathy (Nguyen TV, Damiani G) and high rates of depression and anxiety have been reported in HS patients [4].
In a recent review, the prevalence of HS in the American and European populations varies from 0.7% to 1.2% [5].Te onset of the disease is usually shortly after puberty, and HS is more common in women compared to men (>2 : 1).It is not clear whether menopause induces remission [1,6].Delayed diagnosis led to irreversible scarring and signifcantly impacted patient's physical and mental health and his ability to integrate into everyday work and social life [7].In a recent multicenter study, the therapeutic delay correlated to lack of response to adalimumab [8].
According to the recommendations of the Czech State Institute for Drug Control, fully human monoclonal antibody blocking tumor necrosis alfa-adalimumab, is the only approved biological drug for the treatment of moderate-tosevere HS.Treatment is reimbursed only for adult patients and adolescents over 12 years of age who have active moderate-to-severe form of HS and not responded to or are intolerant to 3 months of oral antibiotic therapy [9].
Clinical trials demonstrated safety and efectiveness of adalimumab [10].However, comprehensive long-term data from the common clinical practice of HS are still limited [11][12][13].
Te aim of this observational, multicenter study was to describe the patient cohort of 299 patients from the Czech Republic treated for moderate-to-severe HS with adalimumab as well as data related to drug survival, efectiveness, and health-related quality using long-term data from the BIOREP registry.

Methods
In this retrospective multicenter study, data from the nationwide BIOREP registry (established in May 2005) were used.BIOREP is a web-based database of patients with psoriasis, hidradenitis suppurativa (2011), and atopic dermatitis (2018) treated with biologics or targeted therapy.In the Czech Republic, biological therapy is administered at 37 specialized centres, 35 of which are included in the BIOREP registry.Adalimumab for HS was administered in 18 centres at the time of the analysis.
Te study was conducted in accordance with the Helsinki Declaration of 1964 and all subsequent amendments, and all patients provided a written informed consent.Patient-level data used for this analysis were deidentifed, and Institutional Review Board approval was not required for this study.Permission to use data from the BIOREP registry was obtained.Patients with HS who received at least one dose of adalimumab were analyzed.Te cut-of date for our analysis was 15 th of November 2021.Patients were treated according to the standard treatment regimen of adalimumab: 160 mg at baseline and 80 mg at week 2, followed by 40 mg weekly from week 4 or 80 mg every other week in maintenance phase [14,15].
Patients' demographic and baseline clinical characteristics were collected including age, the age at onset of HS, gender, weight, height and body mass index (BMI), occupation, smoking status, alcohol consumption, family history of HS, patients' comorbidities, duration and severity of the disease, previous treatment, standardized measures of health status; Dermatology Life Quality Index (DLQI), pain according to visual analogue scale (VAS), number of abscesses, infammatory nodules and draining tunnels, and International Hidradenitis Suppurativa Severity Score System (IHS4).Tis validated scoring system was calculated by the number of nodules * 1 + number of abscesses * 2 + number of draining tunnels * 4 with a total score: ≤3-mild, 4-10-moderate, and ≥11-severe [16] Level of white blood cell count and C-reactive protein (CRP) was analysed when available.In addition, the age at onset of adalimumab treatment was recorded.
2.1.Treatment Assessment.Disease severity was assessed using IHS4 at baseline, month 3, 6, and then every 6 months.Te HS lesions were counted and included number of infammatory nodules, abscesses, and draining fstulas.
Te Dermatology Life Quality Index (DLQI) questionnaire and the Visual Analogue Scale for pain (VAS) which are instruments widely accepted to evaluate QoL in HS, were collected at baseline and month 3, 6, and then every 6 months.

Statistical Analysis.
Collected parameters were summarized using descriptive statistics.Categorical outcomes were evaluated by the number and percentage in each category and continuous outcomes were assessed by mean and standard deviation (SD).Te persistence on adalimumab was defned as the time from initiation of adalimumab treatment to the discontinuation, temporary termination, or switch of the treatment.Patients were censored in case they were lost to follow-up or in case no more follow-up visits were available.Te persistence was assessed using Kaplan-Meier survival curves, which take into account right-censored data.Diferences between survival curves were tested using the log-rank test at the signifcance level of 5.0%.Statistical analyses were performed using Stata software [17].

Demographics and Clinical Characteristics.
A total of 299 patients with moderate-to-severe HS were enrolled, 133 women (44.5%) and 166 men (55.5%) with a mean age of 44.9 years (SD 12.9).At baseline the HS status of patients was evaluated.Hurley stage I was shown in 1%, Hurley stage II in 37%, and Hurley stage III in 58%.Te mean age at the time of diagnosis of HS was 33.6 years (SD 13.1), the mean age at the initiation of adalimumab treatment was 42.7 years (SD 12.7).Te mean duration from diagnosis to the initiation of adalimumab was 9.1 years (SD 9.1).A total of 51 patients (17.1%) had a family history of HS.Almost 80% of patients were current smokers or ex-smokers with an average of 13.8 cigarettes smoked per day.More than half of the patients worked full-time, 22.4% were on disability pension, 6.7% were retired, 4.3% were studying, 4.3% worked half-time, 4.0% were unemployed, and 3.7% were on long-term incapacity for work (Tables 1 and 2).

Adalimumab Treatment.
Out of 299 patients, a total of 216 patients (72.2%) completed 12 months of treatment, 137 patients (45.8%) completed 24 months, and 46 patients (15.4%) completed 48 months of adalimumab treatment.In total, 96.0% of analysed patients received Humira and 4.0% of patients were treated by biosimilars of adalimumab.
Te mean VAS score was 5.2 (SD 2.7) at baseline.In terms of infammatory serum markers, the mean baseline level of white blood cell count was 10.6 × 10 9 (SD 2.9), and a total CRP serum level was 20.3 mg/ml (SD 22.3) (Table 2).
During the adalimumab treatment, there was a substantial reduction in number of abscesses, nodules and draining fstulas, IHS4, and DLQI scores (Figure 1).At baseline, the HS status was assessed as severe in 249 patients (83.3%) based on IHS4 scoring and moderate or mild in 37 patients (12.4%) (Table 2).Te proportion of patients with severe IHS4 score decreased from 83.3% to 39.6% after 3 months and to 30.1% patients after 12 months of adalimumab treatment and remained stable for the rest of followup (Figure 2).
Te improvement in IHS4 correlated with the number of active HS lesions.Te mean number of infammatory nodules at baseline was 8.2, the mean number of draining fstulas was 5.0, and the mean number of abscesses was 3.0.Te improvement was observed after only 3 months of treatment, mean values decreased to 3.5 of infammatory nodules, 1.9 fstulas, and 1.1 abscesses.After 12 months of treatment the mean values were as follows: infammatory nodules 2.8, draining fstulas 1.4, and abscesses 0.7.Te number of active lesions was stable at low levels during the patients´visits up to 48 months of treatment.A minor Dermatologic Terapy 3 increase in the number of draining tunnels (1.5 after 30 months and 1.6 after 48 months of treatment) could be observed (Figure 1).Decreasing number of infammatory lesions correlated to the improvement of patients' quality of life, refected in the DLQI questionnaire.A mean DLQI score was 17.6 (SD 7.3) at baseline, dropped to 8.5 (SD 6.5) after 3 months and to 6.1 (SD 6.0) after 12 months of treatment and remained stable during observation period (Table 2, Figure 1).Furthermore, we analysed the course of BMI level during the treatment, at baseline the mean BMI was 30.8 (SD 5.9), with a slightly decreasing trend to 30.2 (SD 5.0) at 24 months, 29.9 (SD 5.4) at 30 months, and 28.9 (SD 5.9) at 48 months.
Te mean duration of adalimumab treatment was 2.3 years (SD 1.7) for all analysed patients.In patients who discontinued the treatment, the mean duration was 1.7 years (SD 1.4).Te mean duration of treatment in treated patients was 2.4 years (SD 1.8).
Survival estimates were also analysed according to the smoking status: patients, who never smoked and those, who were currently smoking or previously smoked.No statistically signifcant diferences were observed between these two groups (P � 0.330) (Figure 4(b)).For nonsmokers the persistence rates were 91.2% after 12 months of treatment, 84.5% after 24 months, and 80.4% after 36 and 48 months of treatment.For smokers and ex-smokers, the persistence rates were 93.3%, 80.0%, 69.2%, and 64.0% after 12, 24, 36, and 48 months of treatment, respectively.
Te persistence on treatment was also analysed by the BMI category: patients with normal BMI (BMI ≤ 25) and patients with overweight or obese patients (BMI > 25).Te persistence rates using the Kaplan-Meier method showed lower survival in overweight or obese patients, although the diference was not statistically signifcant (P � 0.395) (Figure 4(c)).Te persistence rates were 95.9%, 85.7%, 75.0%, and 71.3% for patients with normal BMI after 12, 24, 36, and 48 months of treatment; and 91.8%, 79.4%, 70.2%, and 65.6% for patients with overweight or obese patients.

Discussion
Te results of this multicenter retrospective study demonstrate the efectiveness and safety of adalimumab in the realworld setting.
Te analysis of the demographic data showed higher percentage of male patients in our cohort (55%) similarly to other study confrming the fact, that men have increased disease severity [18].

Dermatologic Terapy
Te long duration of disease before initiation of biologic therapy (9.1 years) pose a problem in HS likewise to other chronic infammatory skin diseases, including psoriasis, moreover a common feature is diagnostic delay in HS and the average interval from self-reported onset of symptoms to diagnosis is 7.2 years [19].
In our cohort, approximately 80% of the patients were active smokers or ex-smokers, which is in accordance to the meta-analysis [20] reporting that patients with HS are about 4 times (OR, 4.26) more likely to be smokers.However, our cohort shows even higher percentage of smokers when compared to the other HS registries [21].Tis has proven to be unsurprising, as it correlates with the fact that the Czech Republic is among the 7 countries in the world with the highest amounts of cigarettes smoked per person [22].
Te IHS4 severity score is recognized as simple and practical validation system which was adapted for daily practice and has been used in several clinical trials  Dermatologic Terapy [16,23,24].We used this scoring system to assess therapeutical response in our cohort.
During the adalimumab treatment, there was a substantial reduction in number of abscesses, nodules and draining fstulas, IHS4 and DLQI scores.Te proportion of patients with severe IHS4 dropped from 249 (83.3%) at initial baseline to 65 (30.1%) after 12 months; this trend was maintained up to the 48 th month.Te results are comparable to the response observed in the SOLACE and OLE study, which also collected real-world data [12,25].To our knowledge, our study ofers real-world data with the longest mean duration of treatment of 2.3 years, and a maximum treatment period of 48 months.In most of patient cases, the clinical response to adalimumab has been sustained.Te long-term response in our cohort may be also explained by the slightly improvement of patients BMI levels during the treatment.It has been proven that elevated BMI in HS is associated with decreased response to adalimumab therapy [26].
Adalimumab persistence rates in our cohort were 92.5%, 80.5%, 71.0%, and 66.7% after 12, 24, 36, and 48 months of treatment, respectively, which was higher than in other one-center study with a median survival probability of 74.1% after one year [27].
Survival estimates were also analysed according to the smoking status and BMI.Although no statistically signifcant diferences were observed, there was observable better treatment persistence in patients who never smoked contrast to those who were smokers or ex-smokers.Te diference was also observed between obese and nonobese patients.
Adalimumab discontinuation occurred in 22.1% of patients, with the main reason being loss of treatment efcacy.
Te safety profle of adalimumab in the analysed group of patients was good and in accordance with other realworld data [28].A total of 8.0% AEs were reported.Te most frequent mild AEs were infections (4.7%) and skin disorders (1.3%); the serious AEs included severe infections (1%) and malignancies (0.3%).
Te limitations of our study include its retrospective design and the absence of a control group, which is typical in studies that use realworld data.Under discussion could also be the evaluation of efcacy with IHS4 only.IHS4 was recognized as validated and simple to use scoring system for clinical research and daily practice (14).In addition, the

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Dermatologic Terapy correlation between IHS4 and Hidradenitis Suppurativa Clinical Response (HiSCR) was described by Caposiena and Gulliver (12,27).Notwithstanding these limitations, our study is the long follow-up period with a large number of patients in a real-world and provide evidence that adalimumab achieves IHS4 and DLQI improvement with some sustainability of response.

Figure 3 :
Figure 3: Reasons for discontinuation of treatment.

Table 1 :
Demographic and clinical patients' characteristics.

Table 2 :
Baseline clinical characteristics, adalimumab treatment and adverse events.