10.5826/dpc.1202a99
Introduction: Pain is experienced by most patients with hidradenitis suppurativa (HS) and has a severe impact on their quality of life. Its management still presents a challenge. Adalimumab, a TNF-a antagonist, has shown promising results in HS-related pain reduction.
Objectives: To aggregate and synthesize all existing evidence regarding the effect of adalimumab on HS-associated skin pain.
Methods: We identified original controlled and uncontrolled studies with participants receiving adalimumab, which included change in pain score post-treatment comparing to baseline as an endpoint. We searched MEDLINE, ScienceDirect, the Cochrane Library, ClinicalTrials.gov and International Clinical Trials Registry Platform. The primary endpoint of our study was mean change (continuous variable) of pain scores at week 12 comparing to baseline.
Results: We performed a meta-analysis of four randomized controlled trials (282 patients in the intervention group and 266 patients in the control group). Adalimumab brought about a 0.418 reduction in mean pain score at its worst with 95%CI [-0.588, -0.248] and p = 0.000 at 12 weeks after treatment commencement. Four more studies were included in a qualitative synthesis, two of which reported statistically significant reduction in pain scores at week 12. Conclusions: Adalimumab could be prescribed more readily in cases of hidradenitis associated with significant skin pain.
 
 
text/xml
2160-9381
1996
en
Efstratios Vakirlis
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
NRS30
Adalimumab effect on pain in hidradenitis suppurativa patients: systematic review and meta-analysis
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2022-05-02
2021-08-26
2022-05-02
2022-05-24
e2022099
Dermatol Pract Concept
Introduction: Pain is experienced by most patients with hidradenitis suppurativa (HS) and has a severe impact on their quality of life. Its management still presents a challenge. Adalimumab, a TNF-a antagonist, has shown promising results in HS-related pain reduction.
Objectives: To aggregate and synthesize all existing evidence regarding the effect of adalimumab on HS-associated skin pain.
Methods: We identified original controlled and uncontrolled studies with participants receiving adalimumab, which included change in pain score post-treatment comparing to baseline as an endpoint. We searched MEDLINE, ScienceDirect, the Cochrane Library, ClinicalTrials.gov and International Clinical Trials Registry Platform. The primary endpoint of our study was mean change (continuous variable) of pain scores at week 12 comparing to baseline.
Results: We performed a meta-analysis of four randomized controlled trials (282 patients in the intervention group and 266 patients in the control group). Adalimumab brought about a 0.418 reduction in mean pain score at its worst with 95%CI [-0.588, -0.248] and p = 0.000 at 12 weeks after treatment commencement. Four more studies were included in a qualitative synthesis, two of which reported statistically significant reduction in pain scores at week 12. Conclusions: Adalimumab could be prescribed more readily in cases of hidradenitis associated with significant skin pain.
 
 
Efstratios Vakirlis
2022/05/02
10.5826/dpc.1202a99
e2022099
First Department of Dermatology and Venereology, School of Medicine, Aristotle University, Thessaloniki, Greece
2160-9381
NRS30
en
e2022099
Adalimumab effect on pain in hidradenitis suppurativa patients: systematic review and meta-analysis
https://dpcj.org/index.php/dpc/article/download/1996/1551
            Adalimumab Effect on Pain in Hidradenitis
             Suppurativa Patients: Systematic Review
                       and Meta-Analysis
    Aikaterini Tsentemeidou1, Elena Sotiriou1, Nikolaos Sideris1, Alexandra Kourouklidou1,
                   Aimilios Lallas1, Dimitrios Ioannides1, Efstratios Vakirlis1


1 First Department of Dermatology and Venereology, School of Medicine, Aristotle University, Thessaloniki, Greece



Keywords: hidradenitis suppurativa, adalimumab, pain, VAS, NRS30
Citation: Tsentemeidou A, Sotiriou E, Sideris N, et al. Adalimumab effect on pain in hidradenitis suppurativa patients: systematic review
and meta-analysis. Dermatol Pract Concept. 2022;12(2):e2022099. DOI: https://doi.org/10.5826/dpc.1202a99
Accepted: October 30, 2021; Published: April 2022
Copyright: ©2022 Tsentemeidou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Authorship: All authors have contributed significantly to this publication
Corresponding author: Elena Sotiriou, PhD, First Department of Dermatology and Venereology, School of Medicine, Aristotle University,
Thessaloniki, Greece. Email: elenasotiriou@yahoo.gr




  ABSTRACT             Introduction: Pain is experienced by most patients with hidradenitis suppurativa (HS) and has a se-
                       vere impact on their quality of life. Its management still presents a challenge. Adalimumab, a TNF-a
                       ­antagonist, has shown promising results in HS-related pain reduction.
                       Objectives: To aggregate and synthesize all existing evidence regarding the effect of adalimumab on
                       HS-associated pain.
                       Methods: We identified original controlled and uncontrolled studies with participants receiving
                       ­adalimumab, which included change in pain score post-treatment compared to baseline as an end-
                        point. We searched MEDLINE, ScienceDirect, the Cochrane Library, ClinicalTrials.gov and Interna-
                        tional Clinical Trials Registry Platform. The primary endpoint of our study was the mean change
                        (continuous variable) of pain scores at week 12 compared to baseline.
                       Results: We performed a meta-analysis of 4 randomized controlled trials (282 patients in the inter-
                       vention group and 266 patients in the control group). Adalimumab brought about a 0.418 reduction
                       in mean pain score at its worst with 95%CI [–0.588, –0.248] and P = 0.000 at 12 weeks after treat-
                       ment commencement. Four more studies were included in a qualitative synthesis, 2 of which reported
                       ­statistically significant reduction in pain scores at week 12.
                       Conclusions: Adalimumab could be prescribed more readily in cases of HS associated with significant
                       pain.




Review | Dermatol Pract Concept. 2022;12(2):e2022099                                                                                        1
Introduction                                                         and meta-analysis to aggregate and synthesize all existing data
                                                                     concerning adalimumab efficacy in alleviating HS-related pain.
Hidradenitis suppurativa (HS) is a chronic, inflammatory, re-
current, debilitating skin disease (of the terminal hair follicle)
that usually presents after puberty with painful, deep-seated,
                                                                     Methods
inflamed lesions in the apocrine gland-bearing areas of the          Study Design
body, most commonly in the axillary, inguinal, and anogenital
                                                                     This systematic review aimed at examining the effect of adali-
regions [1]. Pain is experienced by the majority of HS patients
                                                                     mumab on HS-related pain. It was conducted in accordance
[2–4]. HS-related pain is greater than the one associated with
                                                                     with the Preferred Reporting Items for Systematic Reviews
other skin diseases, such as eczema, psoriasis, skin tumors and
                                                                     and Meta‐analysis (PRISMA) Statement and was registered
acne, and constitutes one of the major reasons for the seriously
                                                                     with PROSPERO (ID: CRD42021229190).
impaired patient quality of life [4,5]. Among other things, pain
is responsible for the poor sleep quality, impaired general ac-
                                                                     Eligibility Criteria
tivity, negatively affected inter-personal relationships and re-
                                                                     To answer the research question, we identified original stud-
duced life enjoyment of this population [2,6]. Perception of
                                                                     ies with participants receiving adalimumab, which included
HS pain is influenced by depression and anxiety, which are
                                                                     change in pain scores compared to baseline as an endpoint.
frequent comorbidities, as well as by gender and age [3].
                                                                     We imposed no restrictions on adalimumab dose, language
    HS-related pain derives from deep-seated skin lesions and
                                                                     and year of publication and publication status. We included
is of two types: acute/episodic, attributed to disease flares
                                                                     both clinical trials and controlled and uncontrolled observa-
(newly formed and/or old recurring nodules and abscesses),
                                                                     tional studies in our review.
and chronic, which is the result of longstanding inflamed le-
sions such as sinuses, dermal nodules and contracted scars
[7–9]. Acute-pain relief is usually facilitated through abscess
                                                                     Literature Search
rupture or acute surgical interventions [7,9]. HS pain is most       A comprehensive electronic search of 5 databases was con-
commonly described as “shooting” (83%), “itchy” (79%)                ducted, namely MEDLINE, ScienceDirect, the Cochrane
and “blinding” (75%) and is more intense when more an-               Library, ClinicalTrials.gov and International Clinical Trials
atomic areas are involved or when disease is more severe             Registry Platform, from November 5–20, 2020, to source
(Hurley stage III) [3]. The 3 most common self-reported              studies pertaining to the research question. We also searched
pain aggravators are friction from tight clothing (47%), heat        Google Scholar and the archives of the major recent der-
(40%) and stress (13%) [10].                                         matology conferences to identify gray literature. Finally, we
    According to Ring et al HS patients tend to desperately          contacted AbbVie, the major sponsor of adalimumab trial
seek for ways to alleviate their pain [10]. The majority of them     projects, requesting unpublished material. The “Reference”
make use of analgesics (77%) [11]. Common pain relief strat-         section of manuscripts relevant to the research question was
egies include non-steroidal anti-inflammatory drugs (NSAIDs)         hand-searched, to maximize the sensitivity of our search. As
and paracetamol received either topically or systemically, as        this study was a review of existing research projects, neither
well as cold baths and wraps [9,10,12]. It is worth noting that      informed consent nor ethics approval was required.
this data has originated from European studies. When pain is            The comprehensive database search was performed in-
very severe, careful administration of opioids in collaboration      dependently by 2 authors (A.T. and E.S.). We used the fol-
with a pain specialist should be considered [9,13]. Self-­reported   lowing free-text terms for the MEDLINE database search:
use of tramadol was 37% in a 2016 study and opioids were             (hidradenitis suppurativa) OR (acne inversa) AND (adali-
reported the most efficient in offering relief [11]. Other op-       mumab) OR (biologic) OR (Humira®) OR (anti-TNF) OR
tions may include antidepressants, anticonvulsants, specialist       (monoclonal antibody) AND (pain) OR (skin pain) OR
psychological support and patient support groups [9,12].             (ache). Appropriate modifications were applied to the above
    Only a small number of studies have looked into the prev-        search strategy, so that it would comply with the search rules
alence and impact of pain or strategies for its alleviation in       of the rest of used databases.
HS populations [5,14]. What is more, it seems that the an-
algesics most commonly used by HS patients are inadequate            Study Selection
[10]. Adalimumab, a tumor necrosis factor antagonist, has            After removing duplicates, A.T. and E.S. initially, inde-
been approved for the treatment of moderate-to-severe HS,            pendently, read titles and abstracts to eliminate records out
based on the results of 2 clinical trials (PIONEER I and II)         of the scope of this review. They subsequently went through
[15,16]. A number of studies have reported that adalimumab           the full details of each record and settled disputes through
can effectively reduce pain. This is the first systematic review     consensus, having a set of predetermined inclusion and



2                                                                               Review | Dermatol Pract Concept. 2022;12(2):e2022099
exclusion criteria as a guide. Studies adhering to the follow-        of patients achieving NRS30 (dichotomous variable) at week
ing criteria were considered for inclusion: 1) trial or obser-        12. The 12-week timeframe was chosen, as it is a sensible
vational study, controlled or not, 2) recruited patients with         and widely used milestone regarding assessment of biologics’
a clinical diagnosis of HS, 3) patients (all of them or inter-        efficacy both in research and clinical practice.
vention arm) received adalimumab subcutaneously, 4) pain
intensity was assessed with a validated pain measuring scale          Risk of Bias Assessment
at baseline and 12 weeks after commencing treatment, 5)
change in pain scores and/or proportion of patients achiev-           Two researchers (A.T. and E.S) independently used the Co-
ing a certain reduction in such scores was documented, 6)             chrane risk-of-bias tool [18] to assess the risk of bias for
included patients were adults of any age, gender and back-            included randomized controlled clinical trials. Any disagree-
ground population. A study was excluded if it included: 1)            ments were resolved through consensus. Seven items were
non-human subjects, 2) pregnant or lactating females. All             rated as “high risk,” “low risk,” or “unclear risk” of bias:
selected studies were included in the qualitative synthesis,          (1) random sequence generation; (2) allocation concealment;
but only controlled ones were included in the quantitative            (3) blinding of participants and personnel; (4) blinding of
synthesis.                                                            outcome assessment; (5) incomplete outcome data; (6) se-
                                                                      lective outcome reporting; and (7) other sources of bias.
Data Extraction                                                       Non-randomized and/or uncontrolled studies were assessed
Eligible studies were subjected to data extraction using a            through the Methodological Index for Non-randomized
pre-formulated extraction sheet. This process was performed           studies (MINORS) [19]. Studies were considered low risk if
independently by two researchers (A.T. and E.S) and any dis-          all items were reported and adequate. Observational stud-
crepancies were settled through discussion and agreement. The         ies were evaluated through the National Institutes of Health
following data was retrieved from each one of the selected            (NIH) quality assessment tool for observational cohort and
studies: general characteristics (study identifier, ClinicalTrials.   cross-sectional studies. Fourteen individual points were thus
gov identifier, study design, phase, number of study sites, coun-     examined and an overall quality rating of good, fair, or poor
tries included, study period, funding, inclusion criteria, exclu-     was allocated to each study [20].
sion criteria, intervention, comparator, follow-up duration,
primary endpoint(s), secondary endpoints) and outcome data.           Statistical analysis
                                                                      We performed all statistical analyses with Comprehensive
Data Items                                                            Meta Analysis software (Comprehensive Meta-Analysis
Pain intensity is measured with scales assigning increasing           Version 3, Borenstein M, Hedges L, Higgins J, Rothstein H.
value to increasing pain intensity. In dermatology, both ge-          Biostat). Confidence intervals, P values, standard deviations
neric visual analogue scales (VAS) and specific tools, such           (SD) and other statistical measures were mentioned, if avail-
as the Patient's Global Assessment of Skin Pain Numeric               able. In the opposite case, authors were contacted and if they
Rating Scale (NRS), are commonly used [17]. The former                did not respond, results were described only narratively. The
represents a 100 mm-long scale, with 0 corresponding to “no           primary goal of this systematic review was to culminate in a
pain” and 100 to “worst possible pain” [17]. NRS consists             meta-analysis – quantitative synthesis – of the main outcome
of successive numbers (the actual length of the scale is not          measure. The principal summary measure used for the anal-
important), usually presented on a horizontal linear configu-         ysis of the primary endpoint was the mean difference in pain
ration, from 0 (no pain) to 5 or 10 (worst possible pain) [17].       scores between baseline and week 12. A decrease in the mean
The patient is asked to mark the point/length that best corre-        of pain scores meant that adalimumab had a positive effect
sponds to his/her pain intensity and this value is documented         on pain. Associated 95% confidence intervals (CI) were es-
[17]. Mean change and the proportion of patients achieving            timated and differences were considered significant when P
a certain score reduction are common efficacy endpoints.              ≤ 0.05 (two-tailed). The secondary endpoint was analyzed
NRS30 is a 30% and at least 1 unit reduction in the PGA               through descriptive statistics (frequencies). The presence of
skin pain NRS score compared to baseline. We imposed no               heterogeneity across studies was examined through the I2
restrictions to our search regarding the pain measuring tools         statistic (0% to 40%: might not be important; 30% to 60%:
used, on the basis that VAS data can be turned into NRS               may represent moderate heterogeneity; 50% to 90%: may
data through dividing by ten. The primary endpoint of our             represent substantial heterogeneity; 75% to 100%: consider-
study was mean change (continuous variable) of pain scores            able heterogeneity). In case heterogeneity was substantial or
at week 12 compared to baseline. In the absence of pub-               considerable (≥50%), the random effects model was used. In
lished statistical measures needed, we contacted authors and          the opposite case, the fixed effects model was used. A funnel
requested said data. Secondary endpoint was the percentage            plot was created to check for publication bias.



Review | Dermatol Pract Concept. 2022;12(2):e2022099                                                                              3
Results                                                            dosing of adalimumab was not consistent across all 8 studies
                                                                   or all study arms. Three studies [14,24,25] examined the effi-
Study Selection and Characteristics                                cacy of 40 mg of adalimumab administered every other week
Our search and screening process (Figure 1) culminated in 8        and 4 studies [14, 23, 26–28] evaluated the efficacy of 40 mg
studies eligible for inclusion. Basic study characteristics are    of adalimumab administered weekly. Alternate weekly dosing
presented in Table 1. All studies were published in English.       was also investigated in the second period of the 2 main phase
More than 1 publication was identified for 3 studies [14,21–       III RCTs (PIONEER I and II), on which drug approval was
23], in which case, one of those was chosen as the study iden-     based [23]. In the second period of a recent phase III study,
tifier based on its relevance to this review’s primary endpoint.   alternate weekly administration of 80 mg of adalimumab was
Four of the included studies were randomized controlled tri-       also assessed [26]. In most studies [14, 23,26–28] an introduc-
als (RCTs)[14,23,24], 2 were prospective open-label uncon-         tory dosage of 160 mg at week 0, 80 mg at week 2, and 40 mg
trolled trials [25,26], 1 was a retrospective cross-sectional      at week 4 was administered prior to maintenance treatment.
study [27] and one was a post-marketing observational study        A different introductory regimen was employed in 2 studies
[28,29]. A total of 863 participants with a mean age of 36.51      [24,25] (160 mg at week 0, 80 mg at week 1, 40 mg at week 4,
(SD = 11.59) years received either adalimumab subcutaneous         and 80 mg at week 0 respectively). Baseline characteristics of
injection (489 participants) or placebo (374 participants). The    participants are presented in Table 2.




Figure 1. Flow diagram of study selection based on the 2009 PRISMA statement format.



4                                                                              Review | Dermatol Pract Concept. 2022;12(2):e2022099
                                                                                                                                   Table 1. Study Characteristics
                                                       Study identifier          Scheinfeld et al 2016 [14,21]                Amano et al 2010 [25]                     PIONEER I 2016 [22, 23]                     PIONEER II 2016 [22, 23]
                                                       ClinicalTrials.gov   NCT00918255                                 NCT00827996                             NCT01468207                                 NCT01468233
                                                       Study design         Clinical Trial                              Clinical Trial                          Clinical Trial                              Clinical Trial
                                                       Phase                II                                          II                                      III                                         III
                                                       Study sites          26                                          1                                       48                                          101 in PIONEER I & II
                                                       Countries            Denmark, Germany, Netherlands,              United States                           Australia, Canada, Czech Republic,          Australia, Canada, Denmark, France,
                                                       included             United States                                                                       Germany, Hungary, United States             Greece, Netherlands, Puerto Rico, Swe-
                                                                                                                                                                                                            den, Switzerland, Turkey, United States
                                                       Study period         April 2009 – November 2010                  February 2007 – August 2008             November 2011 – January 2014                November 2011 – April 2014
                                                       Funding              Abbott                                      Florida Academic Dermatology            AbbVie (prior sponsor, Abbott)              AbbVie (prior sponsor, Abbott)
                                                                                                                        Centers, Abbott
                                                       Inclusion criteria   Healthy adults, able to administer          ≥18 years, moderate to severe HS        18-99 years, HS for at least 1 year and     18-99 years, HS for at least 1 year and




Review | Dermatol Pract Concept. 2022;12(2):e2022099
                                                                            subcutaneous injections, negative chest     and ≥1 of: ≥1year duration, mul-        stable for at least 2 months, at least      stable for at least 2 months, at least
                                                                            X-ray and PPD test or completed an-         tiple ER or doctor visits, >5/year      2 anatomic areas, one at least Hurley       2 anatomic areas, one at least Hurley
                                                                            ti-tuberculosis therapy                     triamcinolone injections, failed        Stage II or III, AN count ≥3, inadequate    Stage II or III, AN count ≥3, inadequate
                                                                                                                        retinoids and antibiotics, recon-       response to at least 90 days of antibiot-   response to at least 90 days of antibiot-
                                                                                                                        structive surgery, normal laboratory    ics for HS                                  ics for HS
                                                                                                                        values
                                                       Exclusion criteria   Prior anti-TNF treatment, unstable          Pregnancy, lactation, planning          Prior adalimumab or other anti-TNF          Prior adalimumab or other anti-TNF
                                                                            antibiotic therapy for HS, required         pregnancy, adalimumab allergy,          treatment, antibiotics for HS within        treatment, non-stable dose of permit-
                                                                            medication washouts for other HS            ­systemic anti-inflammatory medi-       previous 28 days, oral analgesics for       ted antibiotics for HS within previous
                                                                            treatments, prior exposure to Tysabri®       cation except NSAID and low-dose       HS within past 14 days, oral opioid or      28 days, oral analgesics for HS within
                                                                            (natalizumab), recent infection requiring    systemic steroids, HIV, HBV or         non-stable dose of non-opioid analge-       past 14 days, oral opioid or non-stable
                                                                            treatment, significant medical events or     HCV seropositive, serious infec-       sics for reason unrelated with HS within    dose of non-opioid analgesics for rea-
                                                                            conditions, pregnancy or breast-feed-        tions in previous 3 months, myco-      past 14 days                                son unrelated with HS within past
                                                                            ing or considering becoming pregnant         bacterial or opportunistic infection                                               14 days
                                                                            during the study, history of cancer,         within prior 6 months, lymphopro-
                                                                            except successfully treated skin cancer,     liferative disease, lymphadenopathy
                                                                            recent history of drug or alcohol abuse      or splenomegaly, malignancy within
                                                                                                                         5 years except fully excised BCC,
                                                                                                                         severe organ failure, solid organ
                                                                                                                         transplant, granulomatous infection

                                                                                                                                                                                                                                          (continued)




5
6
                                                                                                                              Table 1. Study Characteristics (Continued)
                                                        Study identifier           Scheinfeld et al 2016 [14,21]                  Amano et al 2010 [25]                      PIONEER I 2016 [22, 23]                      PIONEER II 2016 [22, 23]
                                                        Intervention         Period 1: Adalimumab, subcutaneous            Adalimumab subcutaneοus injec-           Period 1: Adalimumab, subcutaneous            Period 1: Adalimumab, subcutaneous
                                                                             injection, 160 mg at week 0, 80 mg at         tion, 160 mg at Week 0, followed         injection, 160 mg at Week 0, 80 mg at         injection, 160 mg at Week 0, 80 mg at
                                                                             Week 2, and 40 mg weekly starting at          by 80 mg at Week 1, and 40 mg at         Week 2, 40 mg every week from Week 4          Week 2, 40 mg every week from Week
                                                                             Week 4 through Week 15.                       alternate weeks until Week 12            to Week 12                                    4 to Week 12
                                                                             Or                                                                                     Period 2: prior placebo -> adalimumab         Period 2: prior placebo -> adalimumab
                                                                             80 mg at Week 0 and 40 mg every other                                                  40 mg every week until week 35, prior         40 mg every week until week 35, prior
                                                                             week starting at Week 1 through Week 15                                                adalimumab -> placebo every week,             adalimumab -> placebo every week,
                                                                             Period 2: 36 weeks, open label, adalim-                                                adalimumab 40mg every week or adali-          adalimumab 40mg every week or adali-
                                                                             umab 40 mg every other week                                                            mumab 40mg every other week                   mumab 40mg every other week
                                                        Comparator           Placebo weekly starting at week 0             Not applicable                           Placebo                                       Placebo
                                                                             through week 15
                                                        Follow-up            16 weeks                                      12 weeks                                 36 weeks                                      36 weeks
                                                        duration
                                                        Primary              Proportion of patients achieving an HS-       Proportion of patients achieving         Percentage of participants achieving          Percentage of participants achieving
                                                        endpoint(s)          PGA score of clear,                           decrease of 50% from baseline in         HiSCR at Week 12                              HiSCR at Week 12
                                                                             minimal, or mild with at least a 2-grade      the HSSI score after 12 weeks of
                                                                             improvement relative to baseline at           treatment
                                                                             Week 16
                                                        Secondary            Proportion of patients achieving clinical     Difference from baseline at          Percentage of participants achieving AN           Percentage of participants achieving AN
                                                        endpoints            response at Weeks 2, 4, 8, and 12 and         12 weeks in pain measured by a Vi- count 0, 1 or 2, NRS30 – At worst at                count 0, 1 or 2, NRS30 – At worst at
                                                                             all visits (period 2), HS-PGA score of        sual Analog Scale, DLQI, and PGA week 12, change of MSS at week 12                     week 12, change of MSS at week 12
                                                                             clear, minimal, or mild, mean change          of disease severity, number of pa-
                                                                             in MSS, mean percentage of improve-           tients with a >30 and >50% disease
                                                                             ment in abscesses, draining fistulas, or      activity at 12 weeks, adverse events
                                                                             inflammatory nodules, mean change in
                                                                             C-reactive protein levels, mean change
                                                                             in DLQIl score, total work productivity
                                                                             impairment at Week 16. Post hoc anal-
                                                                             ysis: proportion of patients achieving
                                                                             30% or greater reduction and a 10-mm
                                                                             or greater absolute reduction in pain
                                                                             Visual Analogue Scale score
                                                       HS = hidradenitis suppurativa; ER = emergency room; AN count = abscess and inflammatory nodule count; NSAID = non-steroidal anti-inflammatory drug; HIV = human immunodeficiency virus; HBV = ­hepatitis
                                                       B virus; HCV = hepatitis C virus; HS-PGA = Hidradenitis suppurativa – Physician’s Global Assessment; HSSI = Hidradenitis Suppurativa Severity Index; HiSCR = Hidradenitis Suppurativa Clinical Response;
                                                       MSS: Modified Sartorius Score; DLQI = Dermatology Life Quality Index; NRS30 = at least 30% and 1 unit reduction in pain numeric rating scale score.




Review | Dermatol Pract Concept. 2022;12(2):e2022099
                                                                                                                   Table 1. Study Characteristics (Continued)
                                                       Study title          Morita et al. 2019 [26]               HOPE 2019 [28]                                 Miller et al. 2011 [24]                 Caposiena Caro et al. 2020 [27]
                                                       ClinicalTrials.gov   NCT02904902                           NCT02739828                                    Not applicable                          Not applicable
                                                       Study design         Clinical Trial                        Observational                                  Clinical Trial                          Cross-sectional
                                                       Phase                III                                   Not applicable                                 Not reported                            Not applicable
                                                       Study sites          8                                     11                                             2                                       Not reported
                                                       Countries included   Japan                                 Sweden                                         Denmark                                 Not reported
                                                       Study period         September 2016 – May 2019             April 2016 – March 2018                        2007 – July 2010                        Not reported
                                                       Funding              AbbVie                                AbbVie                                         Abbott                                  Not reported
                                                       Inclusion criteria   18–99 years, HS for at least 6        18–99 years, HS diagnosis, receiving           ≥18 years, Hurley stage II or III        ≥ 18 years, diagnosis of HS, AN
                                                                            months & stable for at least 2        Adalimumab according to the Summary of         HS for at least 6 months, at least      count ≥ 3 at baseline, ≥ 1 year of
                                                                            months, ≥2 anatomic areas, one        Product Characteristics, willingness to sign   4 weeks of wash-out for previous        treatment with adalimumab
                                                                            at least Hurley Stage II or III, AN   informed consent                               treatments, females instructed to




Review | Dermatol Pract Concept. 2022;12(2):e2022099
                                                                            count ≥3                                                                             use contraception
                                                       Exclusion criteria   Prior adalimumab or other an-         Prior biologic treatment discontinued <6       Prior biologic treatment, conven-       Not reported
                                                                            ti-TNF treatment, other skin con-     months before the baseline visit               tional HS treatment within past 4
                                                                            dition impeding HS assessment,        Patient not able to understand the lan-        weeks, chronic or recurrent infec-
                                                                            antibiotics for HS other than a       guage of provided patient questionnaires,      tions, allergy to study drug, serious
                                                                            stable dose of doxycycline or mi-     history of non-compliance with medication      health problems, pregnancy and
                                                                            nocycline for past 28 days, topical   or a medical history that could enhance        breastfeeding, untreated or latent
                                                                            treatments or oral analgesics for     non-compliance with medication                 tuberculosis, cancer history, drug
                                                                            HS within past 14 days, systemic                                                     or alcohol abuse
                                                                            treatment for HS within past
                                                                            28 days
                                                       Intervention         Adalimumab 160 mg subcutane-          Adalimumab according to Summary of             Adalimumab, 80 mg subcutane-            Adalimumab 40 mg every week
                                                                            ous injection Week 0, 80 mg Week      Product characteristics                        ously at week 0 followed by 40 mg
                                                                            2, and 40 mg every week starting                                                     every other week for 12 weeks
                                                                            Week 4. After Week 52 switch
                                                                            to 80 mg every other week after
                                                                            consent
                                                       Comparator           Not applicable                        Not applicable                                 Placebo every other week for 12         Not applicable
                                                                                                                                                                 weeks
                                                       Follow-up duration   Up to 12 weeks                        Up to 24 weeks                                 24 weeks                                108 weeks

                                                                                                                                                                                                                                    (continued)




7
8
                                                                                                                                  Table 1. Study Characteristics (Continued)
                                                        Study title                    Morita et al. 2019 [26]                   HOPE 2019 [28]                                      Miller et al. 2011 [24]                   Caposiena Caro et al. 2020 [27]
                                                        Primary endpoint(s)            Percentage of participants achiev-        Change in DLQI score from baseline at               Change in Sartorius and Hurley            No outcome defined as primary
                                                                                       ing HiSCR at Week 12                      Week 12                                             scores at Weeks 12 and 24
                                                        Secondary endpoints            Percentage of participants achiev-        Change from baseline: of pain Numeric               Change in VAS pain score at Weeks         Every 12 weeks: number of pa-
                                                                                       ing AN count 0, 1 or 2 at Week            Raring Scale – at worst and on average at           12 and 24, self-reported days with        tients achieving HiSCR of ≥ 50%
                                                                                       12, NRS30 – At Worst at Week              Weeks 4, 12 and 24, of DLQI at Weeks                lesions between visits, DLQI and          reduction in inflammatory lesion
                                                                                       2, change of MSSf at Weeks 2,4,8          4 and 24, of EQ-5DgQuestionnaire re-                evaluation of scarring [Manchester        count, number of flares, mean time
                                                                                       & 12                                      sponses, EQ-5D VAS Score, HSIA Overall              post-inflammatory scar scoring            between flares, Hidradenitis Suppu-
                                                                                                                                 Score, WPAI-SHP score at Weeks 4, 12 &              and Physician Global Assessment           rativa IHS4##, pain VAS and lesion
                                                                                                                                 24, achievement of HiSCR at Weeks 4, 12             scar scoring], documentation of           count. Additionally, DLQI was
                                                                                                                                 & 24                                                adverse events                            assessed to measure quality of life
                                                                                                                                                                                                                               (QoL) every 24 weeks.
                                                       HS = hidradenitis suppurativa; AN count = abscess and inflammatory nodule count; HiSCR = Hidradenitis Suppurativa Clinical Response; DLQI = Dermatology Life Quality Index; NRS30 = at least 30% and 1
                                                       unit reduction in pain numeric rating scale score; MSS = Modified Sartorius Score; EQ-5D= instrument for evaluation of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression; VAS = Visual
                                                       Analogue Scale; HSIA = Hidradenitis Suppurativa Impact Assessment; WPAI-SHP = Work Productivity and Activity Impairment – Specific Health Problem; HiSCR: Hidradenitis Suppurativa Clinical Response;
                                                       IHS4 = International Hidradenitis Suppurativa Severity Score System.




Review | Dermatol Pract Concept. 2022;12(2):e2022099
                                                                                                                Table 2. Baseline Characteristics of Participants
                                                                              Scheinfeld et     Amano et al                                            Morita et al                                      Caposiena-Caro
                                                         Study identifier        al 2016          2010         PIONEER I 2016      PIONEER II 2016       2019         HOPE 2019      Miller et al.2011     et al.2020
                                                       Number of                    154              10               307              326                  15            10                21                 20
                                                       participants
                                                       Adalimumab (Ada)         103 (66.88)       10 (100)        153 (49.84)       163 (50)             15 (100)      10 (100)         15 (71.43)          20 (100)
                                                       (n, %)
                                                       Placebo (Pbo) (n, %)     51 (33.12)            0           154 (50.16)       163 (50)                 0             0             6 (28.57)              0
                                                       Gender (%)
                                                       Adalimumab              f: 74 (48.05)     f: 7 (70.0)     f: 91 (29.64)      f: 108 (33.13)      f: 2 (13.3)    f: 7 (70)       f: 12 (57.14)        f: 14 (70)
                                                                               m: 29 (18.83)    m: 3 (30.0)     m: 62 (20.20)       m: 55 (16.87)      m: 13 (86.7)    m: 3 (30)       m: 3 (14.29)         m: 6 (30)
                                                       Placebo                 f: 36 (23.38)          0         f: 105 (34.20)      f: 113 (34.67)           0             0            f: 5 (23.81)            0
                                                                               m: 15 (9.74)                     m: 49 (15.96)       m: 50 (15.34)                                       m: 1 (4.76)




Review | Dermatol Pract Concept. 2022;12(2):e2022099
                                                       Age (years, mean,        Ada: 35.6       32.6 (11.14)   Ada: 36.2 (10.83)   Ada: 34.9 (9.96)    42.1 (6.94)    42.7 (11.47)      Ada: 38.7           35.1 (12)
                                                       SD/95%CI)                 (11.6)                                                                                                (30.9–46.4)
                                                                                Pbo: 37.8                      Pbo: 37.8 (11.33)   Pbo: 36.1 (12.18)                                    Pbo: 40.2
                                                                                 (12.1)                                                                                                (25.8–54.5)
                                                       Race/ethnicity
                                                       (n, %)
                                                       White                  Ada: 73 (47.4)       5 (50)      Ada: 116 (37.79)    Ada: 143 (43.87)          0            NR                NR                 NR
                                                                              Pbo: 37 (24.03)                  Pbo: 118 (38.44)    Pbo: 130 (39.88)
                                                       Black                  Ada: 21 (13.64)      3 (30)      Ada: 33 (10.75)       Ada: 9 (2.76)           0            NR                NR                 NR
                                                                               Pbo: 8 (5.19)                    Pbo: 29 (9.45)      Pbo: 20 (6.13)
                                                       Other                       NR              2 (20)        Ada: 4 (1.3)       Ada: 11 (3.37)       15 (100)         NR                NR                 NR
                                                                                                                 Pbo: 7 (2.28)      Pbo: 13 (3.98)
                                                       Weight (kg, mean,        Ada: 97.62          NR         Ada: 97.1 (24.90)   Ada: 90.2 (21.74)       NR             NR                NR                 NR
                                                       SD)                       (24.92)
                                                                                Pbo: 96.5                      Pbo: 99.3 (25.13)   Pbo: 95.7 (25.87)
                                                                                 (24.8)
                                                       BMI (kg/m2, n)                                                                                                                 mean (95%CI)         mean (SD)
                                                       <25                    Ada: 15 (9.74)                    Ada: 24 (7.82)     Ada: 36 (11.04)       7 (46.7)          0          Ada: 32 (25.7          28.4 (6)
                                                                               Pbo: 9 (5.84)                    Pbo: 13 (4.23)      Pbo: 26 (7.98)                                      – 38.4)

                                                                                                                                                                                                               (continued)




9
                                                                                                                Table 2. Baseline Characteristics of Participants (continued)




10
                                                                                Scheinfeld et       Amano et al                                                      Morita et al                                                Caposiena-Caro
                                                          Study identifier         al 2016            2010             PIONEER I 2016         PIONEER II 2016          2019               HOPE 2019         Miller et al.2011      et al.2020
                                                        25 to <30              Ada: 23 (14.94)           NR             Ada: 31 (10.10)       Ada: 42 (12.88)          4 (26.7)              2 (20)          Pbo: 32.4 (24.7
                                                                                 Pbo: 6 (3.90)                          Pbo: 38 (12.38)       Pbo: 36 (11.04)                                                    – 40.2)
                                                        >30                    Ada: 65 (42.21)                          Ada: 97 (31.60)       Ada: 85 (26.07)          4 (26.7)              8 (80)
                                                                               Pbo: 36 (23.38)                         Pbo: 103 (33.55)       Pbo: 117 (35.89)
                                                        Disease duration        Ada: 11.1 (9.0)          NR           Ada: 8.8 [1.1, 40.4]   Ada: 9.0 [1.0,43.5]     14.1 (10.58)             NR                   NR                15.8 (10)
                                                        (years, mean/median,       Pbo: 13.4                          Pbo: 9.4 [1.0, 43.0]   Pbo: 9.9 [1.2,68.5]
                                                        SD/range)                   (10.4)
                                                        Smoking                Ada: 56 (36.36)           NR             Ada: 81 (52.60)      Ada: 105 (32.20)           12 (80)              4 (40)          Ada: 10 (47.62)          12 (70)
                                                                               Pbo: 29 (18.83)                          Pbo: 92 (59.74)       Pbo: 109 (33.44)                                               Pbo: 5 (23.81)
                                                        Hurley stage
                                                        I or II                Ada: 73 (47.40)           NR             Ada: 80 (51.95)       Ada: 86 (26.38)           9 (60)               2 (20)                NR                 11 (55)
                                                                               Pbo: 36 (23.38)                          Pbo: 81 (52.6)        Pbo: 89 (27.30)
                                                        III                    Ada: 30 (19.48)           NR             Ada: 73 (47.40)       Ada: 77 (23.62)           6 (40)               8 (80)                NR                  9 (45)
                                                                                Pbo: 15 (9.74)                          Pbo: 73 (47.40)       Pbo: 74 (22.70)
                                                        Baseline pain score       Ada: 52.5                             Ada: 5.1 (2.51)       Ada: 4.3 (2.62)         4.6 (0.60)           5.9 (2.59)           Ada: 58              4.8 (NR)
                                                        (VAS or NRS, mean,         (25.36)                                                                                                                   (40.63–75.37)
                                                        SD/95%CI)                  Pbo: 57.8                            Pbo: 4.8 (2.68)        Pbo: 4.8 (2.73)                                                 Pbo: 36.17
                                                                                    (28.5)                                                                                                                    (5.97–66.37)
                                                       N = number of participants; f = female; m = male; SD = standard deviation; 95%CI = 95% confidence interval; NR = not reported; VAS = visual analogue scale; NRS = pain numerical rating scale;
                                                       BMI = body mass index.




Review | Dermatol Pract Concept. 2022;12(2):e2022099
Methodological Quality Assessment                                        deemed fair (Table 4). According to the funnel plot no publi-
The methodological quality of the 4 included RCTs                        cation bias was detected (Figure 3).
[14,23,24] was assessed through the Cochrane Risk of Bias
tool (Figure 2). The overall risk for these studies was found to         Outcomes
be low. The 2 open-label uncontrolled studies were assessed              Quantitative synthesis of the 4 controlled studies was pos-
through the MINORS tool (Table 3) and were found to be                   sible for the primary outcome (data available for a total
high risk. The observational studies were assessed through               of 282 patients in the intervention group and 266 patients
the Quality assessment tool for observational cohort and                 in the control group) (Figure 4). VAS values [14,24] were
cross-sectional studies and their methodological quality was             converted to PGA-NRS values through dividing by 10. The


 A
                   RANDOM SEQUENCE GENERATION (SELECTION BIAS)

                         ALLOCATION CONCEALMENT (SELECTION BIAS)

     BLINDING OF PARTICIPANTS AND PERSONNEL (PERFORMANCE BIAS)

               BLINDING OF OUTCOME ASSESSMENT (DETECTION BIAS)

                         INCOMPLETE OUTCOME DATA (ATTRITION BIAS)

                               SELECTIVE REPORTING (REPORTING BIAS)

                                                              OTHER BIAS


                                                                            0%            25%             50%            75%        100%

        LOW RISK OF BIAS                            UNCLEAR RISK OF BIAS                        HIGH RISK OF BIAS


 B




Figure 2. A Overall risk of bias of randomized controlled trials, calculated with the Cochrane Risk of Bias tool. B Risk of bias of individual
randomized controlled trials, calculated with the Cochrane Risk of Bias tool.



Review | Dermatol Pract Concept. 2022;12(2):e2022099                                                                                      11
                    Table 3. Methodological Index for Non-randomized Studies (MINORS)
 Assessed items                                                                        Amano et al 2010               Morita et al 2019
 1. A clearly stated aim                                                                           2                              2
 2. Inclusion of consecutive patients                                                              0                              0
 3. Prospective collection of data                                                                 2                              2
 4. Endpoints appropriate to the aim of the study                                                  2                              2
 5. Unbiased assessment of the study endpoint                                                      0                              0
 6. Follow-up period appropriate to the aim of the study                                           2                              2
 7. Loss to follow up less than 5%                                                                 1                              1
 8. Prospective calculation of the study size                                                      0                              2
 9. An adequate control group                                                                     N/A                            N/A
 10. Contemporary groups                                                                          N/A                            N/A
 11. Baseline equivalence of groups                                                               N/A                            N/A
 12. Adequate statistical analyses                                                                N/A                            N/A
 Total score                                                                                       9                             11
 Judgement                                                                                     High risk                     High risk
Methodological Index for Non-randomized studies (MINORS) scale contains 8 assessment points for non-comparative studies and 4 extra
points for comparative studies[19]. Each item receives 0, 1 or 2 points, if it is not reported, reported but inadequate or reported and adequate
respectively, with an ideal overall score of 16 for non-comparative and 24 for comparative studies.

N/A = not applicable or not available?Please explain




         Table 4. Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies
                                                                                                                           Caposiena Caro
 Assessed Items                                                                                         HOPE 2019            et al 2020
 1. Was the research question or objective in this paper clearly stated?                               Yes                Yes
 2. Was the study population clearly specified and defined?                                            Yes                Yes
 3. Was the participation rate of eligible persons at least 50%?                                       Yes                Not reported
 4. Were all the subjects selected or recruited from the same or similar populations                   Yes                Yes
 (including the same time period)? Were inclusion and exclusion criteria for being in
 the study prespecified and applied uniformly to all participants?
 5. Was a sample size justification, power description, or variance and effect estimates               No                 No
 provided?
 6. For the analyses in this paper, were the exposure(s) of interest measured prior to                 Yes                Yes
 the outcome(s) being measured?
 7. Was the timeframe sufficient so that one could reasonably expect to see an associa- Yes                               Yes
 tion between exposure and outcome if it existed?
 8. For exposures that can vary in amount or level, did the study examine different                    Not applicable Not applicable
 levels of the exposure as related to the outcome (eg, categories of exposure, or expo-
 sure measured as continuous variable)?
 9. Were the exposure measures (independent variables) clearly defined, valid, reliable,               Yes                Yes
 and implemented consistently across all study participants?
 10. Was the exposure(s) assessed more than once over time?                                            Yes                Yes
 11. Were the outcome measures (dependent variables) clearly defined, valid, reliable,                 Yes                Yes
 and implemented consistently across all study participants?
 12. Were the outcome assessors blinded to the exposure status of participants?                        No                 No
 13. Was loss to follow-up after baseline 20% or less?                                                 No                 Yes
 14. Were key potential confounding variables measured and adjusted statistically for                  No                 No
 their impact on the relationship between exposure(s) and outcome(s)?
 Overall rating (good, fair, poor)                                                                     Fair               Fair



12                                                                                     Review | Dermatol Pract Concept. 2022;12(2):e2022099
                                                                                                                                 BLINDING OF PARITCIPANTS AND PERSONNEL (PERFORMANCE BIAS)


                                                                                                                                                                                             BLINDING OF OUTCOME ASSESSMENT (DETECTION BIAS)
                                       RANDOM SEQUENCE GENERATION (SELECTION BIAS)




                                                                                                                                                                                                                                               INCOMPLETE OUTCOME DATA (ATTRITION BIAS)
                                                                                     ALLOCATION CONCEALMENT (SELECTION BIAS)




                                                                                                                                                                                                                                                                                           SELECTIVE REPORTIVE (REPORTING BIAS)


                      MILLER 2011             +                                                 ?                                            +                                                         +                                                –                                        +                                 OTHER BIAS
                                                                                                                                                                                                                                                                                                                                     –


                           PIONEER I            ?                                             +                                              +                                                         +                                               +                                         +                                   +


                       PIONEER II               ?                                             +                                              +                                                         +                                                –                                        +                                   +


                 SCHEINFELD 2016              +                                               +                                              +                                                         +                                               +                                         +                                   +


                                                                                                                               FUNNEL PLOT OF STANDARD ERROR BY STD DIFF IN MEANS
                     0.0


                     0.1
    STANDARD ERROR




                     0.2


                     0.3


                     0.4


                     0.5

                       -2.0            -1.5                                                                                     -1.0                                                                                                           -0.5                                                                                0.0                0.5         1.0          1.5          2.0

                                                                                                                                                                                                                                                                                          STD DIFF IN MEANS
Figure 3. Funnel plot for the assessment of publication bias, designed with Comprehensive Meta Analysis software.


meta-analysis performed showed that adalimumab admin-                                                                                                                                                                                                                                                                             regarding the “adalimumab every other week” arm was
istered for 12 weeks significantly decreased pain compared                                                                                                                                                                                                                                                                        missing. We contacted authors via email in an effort to ac-
to placebo (-0.418 reduction in mean pain score [95% CI                                                                                                                                                                                                                                                                           quire this data, but they did not respond.
–0.588, –0.248] and P = 0.000). There was very little het-                                                                                                                                                                                                                                                                                  No quantitative synthesis of controlled studies was pos-
erogeneity across studies based on the I2 statistic (2.985).                                                                                                                                                                                                                                                                      sible for the secondary outcome, due to missing data (email
Only the “adalimumab every week” arm of Scheinfeld et                                                                                                                                                                                                                                                                             communication with authors was fruitless). According to
al [14] was included in the meta-analysis, as statistical data                                                                                                                                                                                                                                                                    Scheinfeld et al [14], 63% (P < 0.001) and 43% of patients



Review | Dermatol Pract Concept. 2022;12(2):e2022099                                                                                                                                                                                                                                                                                                                                              13
Figure 4. Forest plot of comparison between adalimumab and placebo regarding skin pain reduction: adalimumab significantly reduced
mean pain score at week 12 comparing to placebo. Standard mean difference = –0.418 (95% Confidence Interval –0.588, –0.248), P = 0.000


receiving adalimumab every week and every other week re-             patients’ quality of life and the established under-treatment
spectively achieved minimum clinically important difference          or difficult treatment of HS-related pain, the key finding
in pain at week 12 (defined as half of standard deviation            of this study suggests that dermatologists should consider
of baseline pain score) comparing to 26% of patients re-             adalimumab when pain is a primary concern of a HS patient
ceiving placebo [30]. The same study revealed that 52.1%             (in terms of severity, frequency and or perception).
(P < 0.001) and 27.7% of patients receiving adalimumab                  The limitations of our study are the small number of
every week and every other week, respectively, achieved              studies included in the quantitative synthesis, which, how-
≥50% reduction in baseline VAS score at week 12, contrary            ever, reflects the actual paucity of evidence regarding the ef-
to 18.8% of patients receiving placebo [14]. According to            fect of adalimumab on HS-associated pain. What is more,
PIONEER I, 27.9% of patients receiving adalimumab and                the main body of evidence included in this review and analy-
24.8% of patients receiving placebo achieved NRS30 at                sis came from pre-drug-approval RCTs, which, though solid
week 12 (P = 0.628) [23]. According to PIONEER II, 45.7%             methodologically, may not accurately simulate real-life con-
of patients receiving adalimumab and 20.7% of patients re-           ditions eg strict inclusion and exclusion criteria, higher treat-
ceiving placebo achieved NRS30 at week 12 (P < 0.001).               ment compliance, more frequent doctor visits, etc. Another
     Amano et al found that the median VAS pain score de-            limitation of our study is th that we did not check for con-
creased from 60.0 to 57.5 at week 12 (P = 0.55) [25]. Morita         founding factors such as the impact of mood improvement
et al found that 66.7% (95%CI 29.9, 92.5) of participants            on pain perception.
achieved NRS30 at week 12. According to the Swedish                     Pain is the principal determinant of life quality in HS pa-
post-marketing study, pain score decreased by 3.5 (95% CI            tients [31]. A recent (2020) cross-sectional study included
1.04, 5.96) after 12 weeks of adalimumab (P = 0.0147) (data          1,795 HS patients, 83.6% of whom experienced pain [32].
available for 6 patients) [28]. Caposiena Caro et al measured        Pain intensity correlated positively with female gender,
a 1.3 reduction in VAS score after 12 weeks of adalimumab            smoking, multiple affected areas and more severe disease
(no variance or significance data reported) [27].                    [32]. Commonly employed HS treatments offer inadequate
                                                                     pain relief and, on top of this, dermatologists tend to be

Conclusions                                                          insufficiently trained in clinical pain management [31]. As
                                                                     a result, patients frequently self-medicate and may expose
We performed a meta-analysis of 4 good-quality RCTs as-              themselves to the dangers of opioid or other substance mis-
sessing the efficacy of adalimumab in reducing HS-related            use [31]. On another note, 82% of 110 HS patients tried to
pain. Adalimumab was found significantly superior to pla-            alleviate their pain through manually draining pus from their
cebo regarding pain score reduction after 3 months of treat-         own lesions [33]. According to the European guidelines for
ment. Our systematic review yielded 4 more open-label                the treatment of HS [34] a holistic approach is mandatory,
uncontrolled studies, 2 of which [26,28] showed that mean            when deciding how to manage HS patients. Aside from the
pain scores reduced significantly after 12 weeks of adalim-          principal pharmaceutical therapy, a plan should be made,
umab treatment. In light of the severe impact of pain on HS          among other things, for handling pain. There is, however,




14                                                                               Review | Dermatol Pract Concept. 2022;12(2):e2022099
only low-strength evidence (D) for the administration of                      in hidradenitis suppurativa. Curr Pain Headache Rep.
common mild (nonsteroidal anti-inflammatory drugs) and                        2017;21(12):49. DOI:10.1007/s11916-017-0647-3. PMID:
                                                                              29094219. PMCID: PMC5784845.
strong (opioids) analgesics [34]. Therefore, well-studied
                                                                         6.   Chernyshov PV, Zouboulis CC, Tomas-Aragones L, et al. Qual-
drugs against HS with an established pain-reducing action,
                                                                              ity of life measurement in hidradenitis suppurativa: position
like adalimumab, are most precious weapons in the derma-                      statement of the European Academy of Dermatology and Ve-
tologist’s arsenal.                                                           nereology task forces on Quality of Life and Patient-Oriented
    Increased TNF-a levels in HS patients, and improvement                    Outcomes and Acne, Rosacea and Hidradenitis Suppurativa. J
of HS in patients with Crohn disease receiving adalimumab,                    Eur Acad Dermatology Venereol. 2019;33(9):1633–1643. DOI:
                                                                              10.1111/jdv.15519. PMID: 31037773.
led to adalimumab being tried as a primary treatment for
                                                                         7.   Zouboulis CC, Desai N, Emtestam L, et al. European S1 guide-
moderate-to-severe HS [35]. Trials showed that the drug
                                                                              line for the treatment of hidradenitis suppurativa/acne inversa.
is both efficacious and easily tolerated, while positively af-                J Eur Acad Dermatol Venereol. 2015;29(4):619–644. DOI:
fecting important secondary endpoints, like quality of life                   10.1111/jdv.12966. PMID: 25640693.
and pain [35]. Secukinumab reduced VAS pain score in a                   8.   Puza CJ, Wolfe SA, Jaleel T. Pain management in patients
reported case of recalcitrant HS and its efficacy against HS is               with hidradenitis suppurativa requiring surgery. Derma-
                                                                              tologic Surg. 2019;45(10):1327–1330. DOI: 10.1097/
currently being examined in clinical trials [36]. Ustekinumab
                                                                              DSS.0000000000001693. MID: 30570515.
brought about significant reduction in VAS pain score in a
                                                                         9.   Horváth B, Janse IC, Sibbald GR. Pain management in patients
phase II open-label trial of patients with moderate-to-severe                 with hidradenitis suppurativa. J Am Acad Dermatol. 2015; 73(5
HS [37]. Apremilast was also found to significantly reduce                    Suppl 1): S47–S51. DOI: 10.1016/j.jaad.2015.07.046. PMID:
VAS pain score in a case-series of 9 patients (P = 0.026) [38].               26470616.
    It has been undoubtedly established, that pain should               10.   Ring HC, Theut Riis P, Miller IM, Saunte DM, Jemec GB.
                                                                              Self-reported pain management in hidradenitis suppurativa. Br
be brought into focus as far as HS-related research is con-
                                                                              J Dermatol. 2016;174(4):909–911. DOI: 10.1111/bjd.14266.
cerned. Existing and potential new anti-HS drugs should be
                                                                              Epub 2016 Jan 6. PMID: 26521975.
studied more rigorously in terms of their ability to mitigate           11.   Ring HC, Sørensen H, Miller IM, List EK, Saunte DM, Jemec
acute and chronic HS pain, while standardized pain out-                       GB. Pain in Hidradenitis Suppurativa: A Pilot Study. Acta Derm
come measures, such as the newly introduced pain index,                       Venereol. 2016;96(4):554–556. DOI 10.2340/00015555–2308.
should be consistently used across such studies [39]. On the                  PMID: 26631388.
                                                                        12.   Jemec G. Quality of life considerations and pain manage-
other hand, high-quality large-scale studies testing the effi-
                                                                              ment in hidradenitis suppurativa. Semin Cutan Med Surg.
cacy and safety of various analgesics in HS patients should
                                                                              2017;36(2):75–78. DOI: 10.12788/j.sder.2017.016. PMID:
be designed and conducted soon. This evidence will act as                     28538748
the basis for the issuing of pain-specific treatment guidelines         13.   Enamandram M, Rathmell JP, Kimball AB. Chronic pain
that will support dermatologists in their difficult role and                  management in dermatology. Pharmacotherapy and ther-
improve the life-quality of HS patients.                                      apeutic monitoring with opioid analgesia. J Am Acad
                                                                              Dermatol.       2015;3(4):575–582;quiz       583–584.      DOI:
                                                                              10.1016/j. aad.2014.11.038. PMID: 26369841.
                                                                        14.   Scheinfeld N, Sundaram M, Teixeira H, Gu Y, Okun M. Reduc-
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