Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2022;12(2):e2022099 1 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. 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 2 Review | Dermatol Pract Concept. 2022;12(2):e2022099 Introduction 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, inflamed lesions in the apocrine gland-bearing areas of the body, most commonly in the axillary, inguinal, and anogenital regions [1]. Pain is experienced by the majority of HS patients [2–4]. HS-related pain is greater than the one associated with other skin diseases, such as eczema, psoriasis, skin tumors and acne, and constitutes one of the major reasons for the seriously impaired patient quality of life [4,5]. Among other things, pain is responsible for the poor sleep quality, impaired general ac- tivity, negatively affected inter-personal relationships and re- duced life enjoyment of this population [2,6]. Perception of HS pain is influenced by depression and anxiety, which are frequent comorbidities, as well as by gender and age [3]. HS-related pain derives from deep-seated skin lesions and is of two types: acute/episodic, attributed to disease flares (newly formed and/or old recurring nodules and abscesses), 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 rupture or acute surgical interventions [7,9]. HS pain is most commonly described as “shooting” (83%), “itchy” (79%) and “blinding” (75%) and is more intense when more an- atomic areas are involved or when disease is more severe (Hurley stage III) [3]. The 3 most common self-reported pain aggravators are friction from tight clothing (47%), heat (40%) and stress (13%) [10]. According to Ring et al HS patients tend to desperately seek for ways to alleviate their pain [10]. The majority of them make use of analgesics (77%) [11]. Common pain relief strat- egies include non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol received either topically or systemically, as well as cold baths and wraps [9,10,12]. It is worth noting that this data has originated from European studies. When pain is very severe, careful administration of opioids in collaboration with a pain specialist should be considered [9,13]. Self- reported use of tramadol was 37% in a 2016 study and opioids were reported the most efficient in offering relief [11]. Other op- tions may include antidepressants, anticonvulsants, specialist psychological support and patient support groups [9,12]. Only a small number of studies have looked into the prev- alence and impact of pain or strategies for its alleviation in HS populations [5,14]. What is more, it seems that the an- algesics most commonly used by HS patients are inadequate [10]. Adalimumab, a tumor necrosis factor antagonist, has been approved for the treatment of moderate-to-severe HS, based on the results of 2 clinical trials (PIONEER I and II) [15,16]. A number of studies have reported that adalimumab can effectively reduce pain. This is the first systematic review and meta-analysis to aggregate and synthesize all existing data concerning adalimumab efficacy in alleviating HS-related pain. Methods Study Design This systematic review aimed at examining the effect of adali- mumab on HS-related pain. It was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐analysis (PRISMA) Statement and was registered with PROSPERO (ID: CRD42021229190). Eligibility Criteria To answer the research question, we identified original stud- ies with participants receiving adalimumab, which included change in pain scores compared to baseline as an endpoint. We imposed no restrictions on adalimumab dose, language and year of publication and publication status. We included both clinical trials and controlled and uncontrolled observa- tional studies in our review. Literature Search A comprehensive electronic search of 5 databases was con- ducted, namely MEDLINE, ScienceDirect, the Cochrane Library, ClinicalTrials.gov and International Clinical Trials Registry Platform, from November 5–20, 2020, to source studies pertaining to the research question. We also searched Google Scholar and the archives of the major recent der- matology conferences to identify gray literature. Finally, we contacted AbbVie, the major sponsor of adalimumab trial projects, requesting unpublished material. The “Reference” section of manuscripts relevant to the research question was hand-searched, to maximize the sensitivity of our search. As this study was a review of existing research projects, neither informed consent nor ethics approval was required. The comprehensive database search was performed in- dependently by 2 authors (A.T. and E.S.). We used the fol- lowing free-text terms for the MEDLINE database search: (hidradenitis suppurativa) OR (acne inversa) AND (adali- mumab) OR (biologic) OR (Humira®) OR (anti-TNF) OR (monoclonal antibody) AND (pain) OR (skin pain) OR (ache). Appropriate modifications were applied to the above search strategy, so that it would comply with the search rules of the rest of used databases. Study Selection After removing duplicates, A.T. and E.S. initially, inde- pendently, read titles and abstracts to eliminate records out of the scope of this review. They subsequently went through the full details of each record and settled disputes through consensus, having a set of predetermined inclusion and Review | Dermatol Pract Concept. 2022;12(2):e2022099 3 exclusion criteria as a guide. Studies adhering to the follow- ing criteria were considered for inclusion: 1) trial or obser- vational study, controlled or not, 2) recruited patients with a clinical diagnosis of HS, 3) patients (all of them or inter- vention arm) received adalimumab subcutaneously, 4) pain intensity was assessed with a validated pain measuring scale at baseline and 12 weeks after commencing treatment, 5) change in pain scores and/or proportion of patients achiev- ing a certain reduction in such scores was documented, 6) included patients were adults of any age, gender and back- ground population. A study was excluded if it included: 1) non-human subjects, 2) pregnant or lactating females. All selected studies were included in the qualitative synthesis, but only controlled ones were included in the quantitative synthesis. Data Extraction Eligible studies were subjected to data extraction using a pre-formulated extraction sheet. This process was performed independently by two researchers (A.T. and E.S) and any dis- crepancies were settled through discussion and agreement. The following data was retrieved from each one of the selected studies: general characteristics (study identifier, ClinicalTrials. gov identifier, study design, phase, number of study sites, coun- tries included, study period, funding, inclusion criteria, exclu- sion criteria, intervention, comparator, follow-up duration, primary endpoint(s), secondary endpoints) and outcome data. Data Items Pain intensity is measured with scales assigning increasing value to increasing pain intensity. In dermatology, both ge- neric visual analogue scales (VAS) and specific tools, such as the Patient's Global Assessment of Skin Pain Numeric Rating Scale (NRS), are commonly used [17]. The former represents a 100 mm-long scale, with 0 corresponding to “no pain” and 100 to “worst possible pain” [17]. NRS consists of successive numbers (the actual length of the scale is not important), usually presented on a horizontal linear configu- ration, from 0 (no pain) to 5 or 10 (worst possible pain) [17]. The patient is asked to mark the point/length that best corre- sponds to his/her pain intensity and this value is documented [17]. Mean change and the proportion of patients achieving a certain score reduction are common efficacy endpoints. NRS30 is a 30% and at least 1 unit reduction in the PGA skin pain NRS score compared to baseline. We imposed no restrictions to our search regarding the pain measuring tools used, on the basis that VAS data can be turned into NRS data through dividing by ten. The primary endpoint of our study was mean change (continuous variable) of pain scores at week 12 compared to baseline. In the absence of pub- lished statistical measures needed, we contacted authors and requested said data. Secondary endpoint was the percentage of patients achieving NRS30 (dichotomous variable) at week 12. The 12-week timeframe was chosen, as it is a sensible and widely used milestone regarding assessment of biologics’ efficacy both in research and clinical practice. Risk of Bias Assessment Two researchers (A.T. and E.S) independently used the Co- chrane risk-of-bias tool [18] to assess the risk of bias for included randomized controlled clinical trials. Any disagree- ments were resolved through consensus. Seven items were rated as “high risk,” “low risk,” or “unclear risk” of bias: (1) random sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; (6) se- lective outcome reporting; and (7) other sources of bias. Non-randomized and/or uncontrolled studies were assessed through the Methodological Index for Non-randomized studies (MINORS) [19]. Studies were considered low risk if all items were reported and adequate. Observational stud- ies were evaluated through the National Institutes of Health (NIH) quality assessment tool for observational cohort and cross-sectional studies. Fourteen individual points were thus examined and an overall quality rating of good, fair, or poor was allocated to each study [20]. Statistical analysis We performed all statistical analyses with Comprehensive Meta Analysis software (Comprehensive Meta-Analysis Version 3, Borenstein M, Hedges L, Higgins J, Rothstein H. Biostat). Confidence intervals, P values, standard deviations (SD) and other statistical measures were mentioned, if avail- able. In the opposite case, authors were contacted and if they did not respond, results were described only narratively. The primary goal of this systematic review was to culminate in a meta-analysis – quantitative synthesis – of the main outcome measure. The principal summary measure used for the anal- ysis of the primary endpoint was the mean difference in pain scores between baseline and week 12. A decrease in the mean of pain scores meant that adalimumab had a positive effect on pain. Associated 95% confidence intervals (CI) were es- timated and differences were considered significant when P ≤ 0.05 (two-tailed). The secondary endpoint was analyzed through descriptive statistics (frequencies). The presence of heterogeneity across studies was examined through the I2 statistic (0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: consider- able heterogeneity). In case heterogeneity was substantial or considerable (≥50%), the random effects model was used. In the opposite case, the fixed effects model was used. A funnel plot was created to check for publication bias. 4 Review | Dermatol Pract Concept. 2022;12(2):e2022099 dosing of adalimumab was not consistent across all 8 studies or all study arms. Three studies [14,24,25] examined the effi- cacy of 40 mg of adalimumab administered every other week and 4 studies [14, 23, 26–28] evaluated the efficacy of 40 mg of adalimumab administered weekly. Alternate weekly dosing was also investigated in the second period of the 2 main phase III RCTs (PIONEER I and II), on which drug approval was based [23]. In the second period of a recent phase III study, alternate weekly administration of 80 mg of adalimumab was also assessed [26]. In most studies [14, 23,26–28] an introduc- tory dosage of 160 mg at week 0, 80 mg at week 2, and 40 mg at week 4 was administered prior to maintenance treatment. A different introductory regimen was employed in 2 studies [24,25] (160 mg at week 0, 80 mg at week 1, 40 mg at week 4, and 80 mg at week 0 respectively). Baseline characteristics of participants are presented in Table 2. Results Study Selection and Characteristics Our search and screening process (Figure 1) culminated in 8 studies eligible for inclusion. Basic study characteristics are presented in Table 1. All studies were published in English. More than 1 publication was identified for 3 studies [14,21– 23], in which case, one of those was chosen as the study iden- tifier based on its relevance to this review’s primary endpoint. Four of the included studies were randomized controlled tri- als (RCTs)[14,23,24], 2 were prospective open-label uncon- trolled trials [25,26], 1 was a retrospective cross-sectional study [27] and one was a post-marketing observational study [28,29]. A total of 863 participants with a mean age of 36.51 (SD = 11.59) years received either adalimumab subcutaneous injection (489 participants) or placebo (374 participants). The Figure 1. Flow diagram of study selection based on the 2009 PRISMA statement format. Review | Dermatol Pract Concept. 2022;12(2):e2022099 5 Ta b le 1 . St u dy C h ar ac te ri st ic s S tu d y i d e n ti fi e r S ch e in fe ld e t a l 2 0 1 6 [ 1 4 ,2 1 ] A m a n o e t a l 2 0 1 0 [ 2 5 ] P IO N E E R I 2 0 1 6 [ 2 2 , 2 3 ] P IO N E E R I I 2 0 1 6 [ 2 2 , 2 3 ] C li n ic al T ri al s. go v N C T 0 0 9 1 8 2 5 5 N C T 0 0 8 2 7 9 9 6 N C T 0 1 4 6 8 2 0 7 N C T 0 1 4 6 8 2 3 3 St u dy d es ig n C li n ic al T ri al C li n ic al T ri al C li n ic al T ri al C li n ic al T ri al P h as e II II II I II I St u dy s it es 2 6 1 4 8 1 0 1 i n P IO N E E R I & I I C o u n tr ie s in cl u d ed D en m ar k , G er m an y, N et h er la n d s, U n it ed S ta te s U n it ed S ta te s A u st ra li a, C an ad a, C ze ch R ep u b li c, G er m an y, H u n ga ry , U n it ed S ta te s A u st ra li a, C an ad a, D en m ar k , F ra n ce , G re ec e, N et h er la n d s, P u er to R ic o , S w e- d en , S w it ze rl an d , T u rk ey , U n it ed S ta te s St u dy p er io d A p ri l 2 0 0 9 – N o ve m b er 2 0 1 0 F eb ru ar y 2 0 0 7 – A u gu st 2 0 0 8 N o ve m b er 2 0 1 1 – J an u ar y 2 0 1 4 N o ve m b er 2 0 1 1 – A p ri l 2 0 1 4 F u n d in g A b b o tt F lo ri d a A ca d em ic D er m at o lo gy C en te rs , A b b o tt A b b V ie ( p ri o r sp o n so r, A b b o tt ) A b b V ie ( p ri o r sp o n so r, A b b o tt ) In cl u si o n c ri te ri a H ea lt h y ad u lt s, a b le t o a d m in is te r su b cu ta n eo u s in je ct io n s, n eg at iv e ch es t X -r ay a n d P P D t es t o r co m p le te d a n - ti -t u b er cu lo si s th er ap y ≥1 8 y ea rs , m o d er at e to s ev er e H S an d ≥ 1 o f: ≥ 1 ye ar d u ra ti o n , m u l- ti p le E R o r d o ct o r vi si ts , > 5 /y ea r tr ia m ci n o lo n e in je ct io n s, f ai le d re ti n o id s an d a n ti b io ti cs , r ec o n - st ru ct iv e su rg er y, n o rm al l ab o ra to ry va lu es 1 8 -9 9 y ea rs , H S fo r at l ea st 1 y ea r an d st ab le f o r at l ea st 2 m o n th s, a t le as t 2 a n at o m ic a re as , o n e at l ea st H u rl ey St ag e II o r II I, A N c o u n t ≥3 , i n ad eq u at e re sp o n se t o a t le as t 9 0 d ay s o f an ti b io t- ic s fo r H S 1 8 -9 9 y ea rs , H S fo r at l ea st 1 y ea r an d st ab le f o r at l ea st 2 m o n th s, a t le as t 2 a n at o m ic a re as , o n e at l ea st H u rl ey St ag e II o r II I, A N c o u n t ≥3 , i n ad eq u at e re sp o n se t o a t le as t 9 0 d ay s o f an ti b io t- ic s fo r H S E x cl u si o n c ri te ri a P ri o r an ti -T N F t re at m en t, u n st ab le an ti b io ti c th er ap y fo r H S, r eq u ir ed m ed ic at io n w as h o u ts f o r o th er H S tr ea tm en ts , p ri o r ex p o su re t o T ys ab ri ® (n at al iz u m ab ), r ec en t in fe ct io n r eq u ir in g tr ea tm en t, s ig n ifi ca n t m ed ic al e ve n ts o r co n d it io n s, p re gn an cy o r b re as t- fe ed - in g o r co n si d er in g b ec o m in g p re gn an t d u ri n g th e st u d y, h is to ry o f ca n ce r, ex ce p t su cc es sf u ll y tr ea te d s k in c an ce r, re ce n t h is to ry o f d ru g o r al co h o l ab u se P re gn an cy , l ac ta ti o n , p la n n in g p re gn an cy , a d al im u m ab a ll er gy , sy st em ic a n ti -i n fl am m at o ry m ed i- ca ti o n e x ce p t N SA ID a n d l o w -d o se sy st em ic s te ro id s, H IV , H B V o r H C V s er o p o si ti ve , s er io u s in fe c- ti o n s in p re vi o u s 3 m o n th s, m yc o - b ac te ri al o r o p p o rt u n is ti c in fe ct io n w it h in p ri o r 6 m o n th s, l ym p h o p ro - li fe ra ti ve d is ea se , l ym p h ad en o p at h y o r sp le n o m eg al y, m al ig n an cy w it h in 5 y ea rs e x ce p t fu ll y ex ci se d B C C , se ve re o rg an f ai lu re , s o li d o rg an tr an sp la n t, g ra n u lo m at o u s in fe ct io n P ri o r ad al im u m ab o r o th er a n ti -T N F tr ea tm en t, a n ti b io ti cs f o r H S w it h in p re vi o u s 2 8 d ay s, o ra l an al ge si cs f o r H S w it h in p as t 1 4 d ay s, o ra l o p io id o r n o n -s ta b le d o se o f n o n -o p io id a n al ge - si cs f o r re as o n u n re la te d w it h H S w it h in p as t 1 4 d ay s P ri o r ad al im u m ab o r o th er a n ti -T N F tr ea tm en t, n o n -s ta b le d o se o f p er m it - te d a n ti b io ti cs f o r H S w it h in p re vi o u s 2 8  d ay s, o ra l an al ge si cs f o r H S w it h in p as t 1 4 d ay s, o ra l o p io id o r n o n -s ta b le d o se o f n o n -o p io id a n al ge si cs f o r re a- so n u n re la te d w it h H S w it h in p as t 1 4 d ay s (c o n ti n u ed ) 6 Review | Dermatol Pract Concept. 2022;12(2):e2022099 S tu d y i d e n ti fi e r S ch e in fe ld e t a l 2 0 1 6 [ 1 4 ,2 1 ] A m a n o e t a l 2 0 1 0 [ 2 5 ] P IO N E E R I 2 0 1 6 [ 2 2 , 2 3 ] P IO N E E R I I 2 0 1 6 [ 2 2 , 2 3 ] In te rv en ti o n P er io d 1 : A d al im u m ab , s u b cu ta n eo u s in je ct io n , 1 6 0 m g at w ee k 0 , 8 0 m g at W ee k 2 , a n d 4 0 m g w ee k ly s ta rt in g at W ee k 4 t h ro u gh W ee k 1 5 . O r 8 0 m g at W ee k 0 a n d 4 0 m g ev er y o th er w ee k s ta rt in g at W ee k 1 t h ro u gh W ee k 1 5 P er io d 2 : 3 6 w ee k s, o p en l ab el , a d al im - u m ab 4 0 m g ev er y o th er w ee k A d al im u m ab s u b cu ta n eο u s in je c- ti o n , 1 6 0 m g at W ee k 0 , f o ll o w ed b y 8 0 m g at W ee k 1 , a n d 4 0 m g at al te rn at e w ee k s u n ti l W ee k 1 2 P er io d 1 : A d al im u m ab , s u b cu ta n eo u s in je ct io n , 1 6 0 m g at W ee k 0 , 8 0 m g at W ee k 2 , 4 0 m g ev er y w ee k f ro m W ee k 4 to W ee k 1 2 P er io d 2 : p ri o r p la ce b o - > a d al im u m ab 4 0 m g ev er y w ee k u n ti l w ee k 3 5 , p ri o r ad al im u m ab - > p la ce b o e ve ry w ee k , ad al im u m ab 4 0 m g ev er y w ee k o r ad al i- m u m ab 4 0 m g ev er y o th er w ee k P er io d 1 : A d al im u m ab , s u b cu ta n eo u s in je ct io n , 1 6 0 m g at W ee k 0 , 8 0 m g at W ee k 2 , 4 0 m g ev er y w ee k f ro m W ee k 4 t o W ee k 1 2 P er io d 2 : p ri o r p la ce b o - > a d al im u m ab 4 0 m g ev er y w ee k u n ti l w ee k 3 5 , p ri o r ad al im u m ab - > p la ce b o e ve ry w ee k , ad al im u m ab 4 0 m g ev er y w ee k o r ad al i- m u m ab 4 0 m g ev er y o th er w ee k C o m p ar at o r P la ce b o w ee k ly s ta rt in g at w ee k 0 th ro u gh w ee k 1 5 N o t ap p li ca b le P la ce b o P la ce b o Fo ll ow -u p d u ra ti o n 1 6 w ee k s 1 2 w ee k s 3 6 w ee k s 3 6 w ee k s P ri m ar y en d p o in t( s) P ro p o rt io n o f p at ie n ts a ch ie vi n g an H S- P G A s co re o f cl ea r, m in im al , o r m il d w it h a t le as t a 2 -g ra d e im p ro ve m en t re la ti ve t o b as el in e at W ee k 1 6 P ro p o rt io n o f p at ie n ts a ch ie vi n g d ec re as e o f 5 0 % f ro m b as el in e in th e H SS I s co re a ft er 1 2 w ee k s o f tr ea tm en t P er ce n ta ge o f p ar ti ci p an ts a ch ie vi n g H iS C R a t W ee k 1 2 P er ce n ta ge o f p ar ti ci p an ts a ch ie vi n g H iS C R a t W ee k 1 2 Se co n d ar y en d p o in ts P ro p o rt io n o f p at ie n ts a ch ie vi n g cl in ic al re sp o n se a t W ee k s 2 , 4 , 8 , a n d 1 2 a n d al l vi si ts ( p er io d 2 ), H S- P G A s co re o f cl ea r, m in im al , o r m il d , m ea n c h an ge in M SS , m ea n p er ce n ta ge o f im p ro ve - m en t in a b sc es se s, d ra in in g fi st u la s, o r in fl am m at o ry n o d u le s, m ea n c h an ge i n C -r ea ct iv e p ro te in l ev el s, m ea n c h an ge in D L Q Il sc o re , t o ta l w o rk p ro d u ct iv it y im p ai rm en t at W ee k 1 6 . P o st h o c an al - ys is : p ro p o rt io n o f p at ie n ts a ch ie vi n g 3 0 % o r gr ea te r re d u ct io n a n d a 1 0 -m m o r gr ea te r ab so lu te r ed u ct io n i n p ai n V is u al A n al o gu e Sc al e sc o re D if fe re n ce f ro m b as el in e at 1 2  w ee k s in p ai n m ea su re d b y a V i- su al A n al o g Sc al e, D L Q I, a n d P G A o f d is ea se s ev er it y, n u m b er o f p a- ti en ts w it h a > 3 0 a n d > 5 0 % d is ea se ac ti vi ty a t 1 2 w ee k s, a d ve rs e ev en ts P er ce n ta ge o f p ar ti ci p an ts a ch ie vi n g A N co u n t 0 , 1 o r 2 , N R S3 0 – A t w o rs t at w ee k 1 2 , c h an ge o f M SS a t w ee k 1 2 P er ce n ta ge o f p ar ti ci p an ts a ch ie vi n g A N co u n t 0 , 1 o r 2 , N R S3 0 – A t w o rs t at w ee k 1 2 , c h an ge o f M SS a t w ee k 1 2 H S = h id ra d en it is s u p p u ra ti va ; E R = e m er ge n cy r o o m ; A N c o u n t = a b sc es s an d in fl am m at o ry n o d u le c o u n t; N SA ID = n o n -s te ro id al a n ti -i n fl am m at o ry d ru g; H IV = h u m an im m u n o d ef ic ie n cy v ir u s; H B V  =   h ep at it is B v ir u s; H C V = h ep at it is C v ir u s; H S- P G A = H id ra d en it is s u p p u ra ti va – P h ys ic ia n ’s G lo b al A ss es sm en t; H SS I = H id ra d en it is S u p p u ra ti va S ev er it y In d ex ; H iS C R = H id ra d en it is S u p p u ra ti va C li n ic al R es p o n se ; M SS : M o d if ie d S ar to ri u s Sc o re ; D L Q I = D er m at o lo gy L if e Q u al it y In d ex ; N R S3 0 = a t le as t 3 0 % a n d 1 u n it r ed u ct io n i n p ai n n u m er ic r at in g sc al e sc o re . Ta b le 1 . St u dy C h ar ac te ri st ic s (C o n ti n u ed ) Review | Dermatol Pract Concept. 2022;12(2):e2022099 7 Ta b le 1 . St u dy C h ar ac te ri st ic s (C o n ti n u ed ) S tu d y t it le M o ri ta e t a l. 2 0 1 9 [ 2 6 ] H O P E 2 0 1 9 [ 2 8 ] M il le r e t a l. 2 0 1 1 [ 2 4 ] C a p o si e n a C a ro e t a l. 2 0 2 0 [ 2 7 ] C li n ic al T ri al s. go v N C T 0 2 9 0 4 9 0 2 N C T 0 2 7 3 9 8 2 8 N o t ap p li ca b le N o t ap p li ca b le St u dy d es ig n C li n ic al T ri al O b se rv at io n al C li n ic al T ri al C ro ss -s ec ti o n al P h as e II I N o t ap p li ca b le N o t re p o rt ed N o t ap p li ca b le St u dy s it es 8 1 1 2 N o t re p o rt ed C o u n tr ie s in cl u d ed Ja p an Sw ed en D en m ar k N o t re p o rt ed St u dy p er io d Se p te m b er 2 0 1 6 – M ay 2 0 1 9 A p ri l 2 0 1 6 – M ar ch 2 0 1 8 2 0 0 7 – J u ly 2 0 1 0 N o t re p o rt ed F u n d in g A b b V ie A b b V ie A b b o tt N o t re p o rt ed In cl u si o n c ri te ri a 1 8 –9 9 y ea rs , H S fo r at l ea st 6 m o n th s & s ta b le f o r at l ea st 2 m o n th s, ≥ 2 a n at o m ic a re as , o n e at l ea st H u rl ey S ta ge I I o r II I, A N co u n t ≥3 1 8 –9 9 y ea rs , H S d ia gn o si s, r ec ei vi n g A d al im u m ab a cc o rd in g to t h e Su m m ar y o f P ro d u ct C h ar ac te ri st ic s, w il li n gn es s to s ig n in fo rm ed c o n se n t ≥1 8 y ea rs , H u rl ey s ta ge I I o r II I H S fo r at l ea st 6 m o n th s, a t le as t 4 w ee k s o f w as h -o u t fo r p re vi o u s tr ea tm en ts , f em al es i n st ru ct ed t o u se c o n tr ac ep ti o n ≥ 1 8 y ea rs , d ia gn o si s o f H S, A N co u n t ≥ 3 a t b as el in e, ≥ 1 y ea r o f tr ea tm en t w it h a d al im u m ab E x cl u si o n c ri te ri a P ri o r ad al im u m ab o r o th er a n - ti -T N F t re at m en t, o th er s k in c o n - d it io n i m p ed in g H S as se ss m en t, an ti b io ti cs f o r H S o th er t h an a st ab le d o se o f d o x yc yc li n e o r m i- n o cy cl in e fo r p as t 2 8 d ay s, t o p ic al tr ea tm en ts o r o ra l an al ge si cs f o r H S w it h in p as t 1 4 d ay s, s ys te m ic tr ea tm en t fo r H S w it h in p as t 2 8 d ay s P ri o r b io lo gi c tr ea tm en t d is co n ti n u ed < 6 m o n th s b ef o re t h e b as el in e vi si t P at ie n t n o t ab le t o u n d er st an d t h e la n - gu ag e o f p ro vi d ed p at ie n t q u es ti o n n ai re s, h is to ry o f n o n -c o m p li an ce w it h m ed ic at io n o r a m ed ic al h is to ry t h at c o u ld e n h an ce n o n -c o m p li an ce w it h m ed ic at io n P ri o r b io lo gi c tr ea tm en t, c o n ve n - ti o n al H S tr ea tm en t w it h in p as t 4 w ee k s, c h ro n ic o r re cu rr en t in fe c- ti o n s, a ll er gy t o s tu d y d ru g, s er io u s h ea lt h p ro b le m s, p re gn an cy a n d b re as tf ee d in g, u n tr ea te d o r la te n t tu b er cu lo si s, c an ce r h is to ry , d ru g o r al co h o l ab u se N o t re p o rt ed In te rv en ti o n A d al im u m ab 1 6 0 m g su b cu ta n e- o u s in je ct io n W ee k 0 , 8 0 m g W ee k 2 , a n d 4 0 m g ev er y w ee k s ta rt in g W ee k 4 . A ft er W ee k 5 2 s w it ch to 8 0 m g ev er y o th er w ee k a ft er co n se n t A d al im u m ab a cc o rd in g to S u m m ar y o f P ro d u ct c h ar ac te ri st ic s A d al im u m ab , 8 0 m g su b cu ta n e- o u sl y at w ee k 0 f o ll o w ed b y 4 0 m g ev er y o th er w ee k f o r 1 2 w ee k s A d al im u m ab 4 0 m g ev er y w ee k C o m p ar at o r N o t ap p li ca b le N o t ap p li ca b le P la ce b o e ve ry o th er w ee k f o r 1 2 w ee k s N o t ap p li ca b le Fo ll ow -u p d u ra ti o n U p t o 1 2 w ee k s U p t o 2 4 w ee k s 2 4 w ee k s 1 0 8 w ee k s (c o n ti n u ed ) 8 Review | Dermatol Pract Concept. 2022;12(2):e2022099 S tu d y t it le M o ri ta e t a l. 2 0 1 9 [ 2 6 ] H O P E 2 0 1 9 [ 2 8 ] M il le r e t a l. 2 0 1 1 [ 2 4 ] C a p o si e n a C a ro e t a l. 2 0 2 0 [ 2 7 ] P ri m ar y en d p o in t( s) P er ce n ta ge o f p ar ti ci p an ts a ch ie v- in g H iS C R a t W ee k 1 2 C h an ge i n D L Q I sc o re f ro m b as el in e at W ee k 1 2 C h an ge i n S ar to ri u s an d H u rl ey sc o re s at W ee k s 1 2 a n d 2 4 N o o u tc o m e d efi n ed a s p ri m ar y Se co n d ar y en d p o in ts P er ce n ta ge o f p ar ti ci p an ts a ch ie v- in g A N c o u n t 0 , 1 o r 2 a t W ee k 1 2 , N R S3 0 – A t W o rs t at W ee k 2 , c h an ge o f M SS f a t W ee k s 2 ,4 ,8 & 1 2 C h an ge f ro m b as el in e: o f p ai n N u m er ic R ar in g Sc al e – at w o rs t an d o n a ve ra ge a t W ee k s 4 , 1 2 a n d 2 4 , o f D L Q I at W ee k s 4 a n d 2 4 , o f E Q -5 D g Q u es ti o n n ai re r e- sp o n se s, E Q -5 D V A S Sc o re , H SI A O ve ra ll Sc o re , W PA I- SH P s co re a t W ee k s 4 , 1 2 & 2 4 , a ch ie ve m en t o f H iS C R a t W ee k s 4 , 1 2 & 2 4 C h an ge i n V A S p ai n s co re a t W ee k s 1 2 a n d 2 4 , s el f- re p o rt ed d ay s w it h le si o n s b et w ee n v is it s, D L Q I an d ev al u at io n o f sc ar ri n g [M an ch es te r p o st -i n fl am m at o ry s ca r sc o ri n g an d P h ys ic ia n G lo b al A ss es sm en t sc ar s co ri n g] , d o cu m en ta ti o n o f ad ve rs e ev en ts E ve ry 1 2 w ee k s: n u m b er o f p a- ti en ts a ch ie vi n g H iS C R o f ≥ 5 0 % re d u ct io n i n i n fl am m at o ry l es io n co u n t, n u m b er o f fl ar es , m ea n t im e b et w ee n fl ar es , H id ra d en it is S u p p u - ra ti va I H S4 # # , p ai n V A S an d l es io n co u n t. A d d it io n al ly , D L Q I w as as se ss ed t o m ea su re q u al it y o f li fe (Q o L ) ev er y 2 4 w ee k s. H S = h id ra d en it is s u p p u ra ti va ; A N c o u n t = a b sc es s an d i n fl am m at o ry n o d u le c o u n t; H iS C R = H id ra d en it is S u p p u ra ti va C li n ic al R es p o n se ; D L Q I = D er m at o lo gy L if e Q u al it y In d ex ; N R S3 0 = a t le as t 3 0 % a n d 1 u n it r ed u ct io n i n p ai n n u m er ic r at in g sc al e sc o re ; M SS = M o d if ie d S ar to ri u s Sc o re ; E Q -5 D = i n st ru m en t fo r ev al u at io n o f m o b il it y, s el f- ca re , u su al a ct iv it ie s, p ai n /d is co m fo rt , a n d a n x ie ty /d ep re ss io n ; V A S = V is u al A n al o gu e Sc al e; H SI A = H id ra d en it is S u p p u ra ti va I m p ac t A ss es sm en t; W PA I- SH P = W o rk P ro d u ct iv it y an d A ct iv it y Im p ai rm en t – Sp ec if ic H ea lt h P ro b le m ; H iS C R : H id ra d en it is S u p p u ra ti va C li n ic al R es p o n se ; IH S4 = I n te rn at io n al H id ra d en it is S u p p u ra ti va S ev er it y Sc o re S ys te m . Ta b le 1 . St u dy C h ar ac te ri st ic s (C o n ti n u ed ) Review | Dermatol Pract Concept. 2022;12(2):e2022099 9 Ta b le 2 . B as el in e C h ar ac te ri st ic s o f Pa rt ic ip an ts S tu d y i d e n ti fi e r S ch e in fe ld e t a l 2 0 1 6 A m a n o e t a l 2 0 1 0 P IO N E E R I 2 0 1 6 P IO N E E R I I 2 0 1 6 M o ri ta e t a l 2 0 1 9 H O P E 2 0 1 9 M il le r e t a l. 2 0 1 1 C a p o si e n a -C a ro e t a l. 2 0 2 0 N u m b er o f p ar ti ci p an ts 1 5 4 1 0 3 0 7 3 2 6 1 5 1 0 2 1 2 0 A d al im u m ab ( A d a) (n , % ) 1 0 3 ( 6 6 .8 8 ) 1 0 ( 1 0 0 ) 1 5 3 ( 4 9 .8 4 ) 1 6 3 ( 5 0 ) 1 5 ( 1 0 0 ) 1 0 ( 1 0 0 ) 1 5 ( 7 1 .4 3 ) 2 0 ( 1 0 0 ) P la ce b o ( P b o ) (n , % ) 5 1 ( 3 3 .1 2 ) 0 1 5 4 ( 5 0 .1 6 ) 1 6 3 ( 5 0 ) 0 0 6 ( 2 8 .5 7 ) 0 G en d er ( % ) A d al im u m ab f: 7 4 ( 4 8 .0 5 ) f: 7 ( 7 0 .0 ) f: 9 1 ( 2 9 .6 4 ) f: 1 0 8 ( 3 3 .1 3 ) f: 2 ( 1 3 .3 ) f: 7 ( 7 0 ) f: 1 2 ( 5 7 .1 4 ) f: 1 4 ( 7 0 ) m : 2 9 ( 1 8 .8 3 ) m : 3 ( 3 0 .0 ) m : 6 2 ( 2 0 .2 0 ) m : 5 5 ( 1 6 .8 7 ) m : 1 3 ( 8 6 .7 ) m : 3 ( 3 0 ) m : 3 ( 1 4 .2 9 ) m : 6 ( 3 0 ) P la ce b o f: 3 6 ( 2 3 .3 8 ) 0 f: 1 0 5 ( 3 4 .2 0 ) f: 1 1 3 ( 3 4 .6 7 ) 0 0 f: 5 ( 2 3 .8 1 ) 0 m : 1 5 ( 9 .7 4 ) m : 4 9 ( 1 5 .9 6 ) m : 5 0 ( 1 5 .3 4 ) m : 1 ( 4 .7 6 ) A ge ( ye ar s, m ea n , SD /9 5 % C I) A d a: 3 5 .6 (1 1 .6 ) 3 2 .6 ( 1 1 .1 4 ) A d a: 3 6 .2 ( 1 0 .8 3 ) A d a: 3 4 .9 ( 9 .9 6 ) 4 2 .1 ( 6 .9 4 ) 4 2 .7 ( 1 1 .4 7 ) A d a: 3 8 .7 (3 0 .9 –4 6 .4 ) 3 5 .1 ( 1 2 ) P b o : 3 7 .8 (1 2 .1 ) P b o : 3 7 .8 ( 1 1 .3 3 ) P b o : 3 6 .1 ( 1 2 .1 8 ) P b o : 4 0 .2 (2 5 .8 –5 4 .5 ) R ac e/ et h n ic it y (n , % ) W h it e A d a: 7 3 ( 4 7 .4 ) 5 ( 5 0 ) A d a: 1 1 6 ( 3 7 .7 9 ) A d a: 1 4 3 ( 4 3 .8 7 ) 0 N R N R N R P b o : 3 7 ( 2 4 .0 3 ) P b o : 1 1 8 ( 3 8 .4 4 ) P b o : 1 3 0 ( 3 9 .8 8 ) B la ck A d a: 2 1 ( 1 3 .6 4 ) 3 ( 3 0 ) A d a: 3 3 ( 1 0 .7 5 ) A d a: 9 ( 2 .7 6 ) 0 N R N R N R P b o : 8 ( 5 .1 9 ) P b o : 2 9 ( 9 .4 5 ) P b o : 2 0 ( 6 .1 3 ) O th er N R 2 ( 2 0 ) A d a: 4 ( 1 .3 ) A d a: 1 1 ( 3 .3 7 ) 1 5 ( 1 0 0 ) N R N R N R P b o : 7 ( 2 .2 8 ) P b o : 1 3 ( 3 .9 8 ) W ei gh t (k g, m ea n , SD ) A d a: 9 7 .6 2 (2 4 .9 2 ) N R A d a: 9 7 .1 ( 2 4 .9 0 ) A d a: 9 0 .2 ( 2 1 .7 4 ) N R N R N R N R P b o : 9 6 .5 (2 4 .8 ) P b o : 9 9 .3 ( 2 5 .1 3 ) P b o : 9 5 .7 ( 2 5 .8 7 ) B M I (k g/ m 2 , n ) m ea n ( 9 5 % C I) m ea n ( SD ) < 2 5 A d a: 1 5 ( 9 .7 4 ) A d a: 2 4 ( 7 .8 2 ) A d a: 3 6 ( 1 1 .0 4 ) 7 ( 4 6 .7 ) 0 A d a: 3 2 ( 2 5 .7 – 3 8 .4 ) 2 8 .4 ( 6 ) P b o : 9 ( 5 .8 4 ) P b o : 1 3 ( 4 .2 3 ) P b o : 2 6 ( 7 .9 8 ) (c o n ti n u ed ) 10 Review | Dermatol Pract Concept. 2022;12(2):e2022099 S tu d y i d e n ti fi e r S ch e in fe ld e t a l 2 0 1 6 A m a n o e t a l 2 0 1 0 P IO N E E R I 2 0 1 6 P IO N E E R I I 2 0 1 6 M o ri ta e t a l 2 0 1 9 H O P E 2 0 1 9 M il le r e t a l. 2 0 1 1 C a p o si e n a -C a ro e t a l. 2 0 2 0 2 5 t o < 3 0 A d a: 2 3 ( 1 4 .9 4 ) N R A d a: 3 1 ( 1 0 .1 0 ) A d a: 4 2 ( 1 2 .8 8 ) 4 ( 2 6 .7 ) 2 ( 2 0 ) P b o : 3 2 .4 ( 2 4 .7 – 4 0 .2 ) P b o : 6 ( 3 .9 0 ) P b o : 3 8 ( 1 2 .3 8 ) P b o : 3 6 ( 1 1 .0 4 ) > 3 0 A d a: 6 5 ( 4 2 .2 1 ) A d a: 9 7 ( 3 1 .6 0 ) A d a: 8 5 ( 2 6 .0 7 ) 4 ( 2 6 .7 ) 8 ( 8 0 ) P b o : 3 6 ( 2 3 .3 8 ) P b o : 1 0 3 ( 3 3 .5 5 ) P b o : 1 1 7 ( 3 5 .8 9 ) D is ea se d u ra ti o n (y ea rs , m ea n /m ed ia n , SD /r an ge ) A d a: 1 1 .1 ( 9 .0 ) N R A d a: 8 .8 [ 1 .1 , 4 0 .4 ] A d a: 9 .0 [ 1 .0 ,4 3 .5 ] 1 4 .1 ( 1 0 .5 8 ) N R N R 1 5 .8 ( 1 0 ) P b o : 1 3 .4 (1 0 .4 ) P b o : 9 .4 [ 1 .0 , 4 3 .0 ] P b o : 9 .9 [ 1 .2 ,6 8 .5 ] Sm o k in g A d a: 5 6 ( 3 6 .3 6 ) N R A d a: 8 1 ( 5 2 .6 0 ) A d a: 1 0 5 ( 3 2 .2 0 ) 1 2 ( 8 0 ) 4 ( 4 0 ) A d a: 1 0 ( 4 7 .6 2 ) 1 2 ( 7 0 ) P b o : 2 9 ( 1 8 .8 3 ) P b o : 9 2 ( 5 9 .7 4 ) P b o : 1 0 9 ( 3 3 .4 4 ) P b o : 5 ( 2 3 .8 1 ) H u rl ey s ta ge I o r II A d a: 7 3 ( 4 7 .4 0 ) N R A d a: 8 0 ( 5 1 .9 5 ) A d a: 8 6 ( 2 6 .3 8 ) 9 ( 6 0 ) 2 ( 2 0 ) N R 1 1 ( 5 5 ) P b o : 3 6 ( 2 3 .3 8 ) P b o : 8 1 ( 5 2 .6 ) P b o : 8 9 ( 2 7 .3 0 ) II I A d a: 3 0 ( 1 9 .4 8 ) N R A d a: 7 3 ( 4 7 .4 0 ) A d a: 7 7 ( 2 3 .6 2 ) 6 ( 4 0 ) 8 ( 8 0 ) N R 9 ( 4 5 ) P b o : 1 5 ( 9 .7 4 ) P b o : 7 3 ( 4 7 .4 0 ) P b o : 7 4 ( 2 2 .7 0 ) B as el in e p ai n s co re (V A S o r N R S, m ea n , SD /9 5 % C I) A d a: 5 2 .5 (2 5 .3 6 ) A d a: 5 .1 ( 2 .5 1 ) A d a: 4 .3 ( 2 .6 2 ) 4 .6 ( 0 .6 0 ) 5 .9 ( 2 .5 9 ) A d a: 5 8 (4 0 .6 3 –7 5 .3 7 ) 4 .8 ( N R ) P b o : 5 7 .8 (2 8 .5 ) P b o : 4 .8 ( 2 .6 8 ) P b o : 4 .8 ( 2 .7 3 ) P b o : 3 6 .1 7 (5 .9 7 –6 6 .3 7 ) N = n u m b er o f p ar ti ci p an ts ; f = f em al e; m = m al e; S D = s ta n d ar d d ev ia ti o n ; 9 5 % C I = 9 5 % c o n fi d en ce i n te rv al ; N R = n o t re p o rt ed ; V A S = v is u al a n al o gu e sc al e; N R S = p ai n n u m er ic al r at in g sc al e; B M I = b o d y m as s in d ex . Ta b le 2 . B as el in e C h ar ac te ri st ic s o f Pa rt ic ip an ts ( co n ti n u ed ) Review | Dermatol Pract Concept. 2022;12(2):e2022099 11 Methodological Quality Assessment The methodological quality of the 4 included RCTs [14,23,24] was assessed through the Cochrane Risk of Bias tool (Figure 2). The overall risk for these studies was found to be low. The 2 open-label uncontrolled studies were assessed through the MINORS tool (Table 3) and were found to be high risk. The observational studies were assessed through the Quality assessment tool for observational cohort and cross-sectional studies and their methodological quality was deemed fair (Table 4). According to the funnel plot no publi- cation bias was detected (Figure 3). Outcomes Quantitative synthesis of the 4 controlled studies was pos- sible for the primary outcome (data available for a total of 282 patients in the intervention group and 266 patients in the control group) (Figure 4). VAS values [14,24] were converted to PGA-NRS values through dividing by 10. The 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. 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 HIGH RISK OF BIASUNCLEAR RISK OF BIASLOW RISK OF BIAS 0% 25% 50% 75% 100% A B 12 Review | Dermatol Pract Concept. 2022;12(2):e2022099 Table 4. Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies Assessed Items HOPE 2019 Caposiena Caro 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 (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? Yes Yes 5. Was a sample size justification, power description, or variance and effect estimates provided? No No 6. For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured? Yes Yes 7. Was the timeframe sufficient so that one could reasonably expect to see an associa- tion between exposure and outcome if it existed? Yes Yes 8. For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (eg, categories of exposure, or expo- sure measured as continuous variable)? Not applicable Not applicable 9. Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? Yes Yes 10. Was the exposure(s) assessed more than once over time? Yes Yes 11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? Yes Yes 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 their impact on the relationship between exposure(s) and outcome(s)? No No Overall rating (good, fair, poor) Fair Fair 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 Review | Dermatol Pract Concept. 2022;12(2):e2022099 13 MILLER 2011 + ? ? ? + + – – –+ + + + +++ + + + ++ + + + + +++ R A N D O M S EQ U EN C E G EN ER A TI O N (S EL EC TI O N B IA S) A LL O C A TI O N C O N C EA LM EN T (S EL EC TI O N B IA S) B LI N D IN G O F PA R IT C IP A N TS A N D P ER SO N N EL (P ER FO R M A N C E B IA S) B LI N D IN G O F O U TC O M E A SS ES SM EN T (D ET EC TI O N B IA S) IN C O M P LE TE O U TC O M E D A TA (A T TR IT IO N B IA S) SE LE C TI V E R EP O R TI V E (R EP O R TI N G B IA S) O TH ER B IA S PIONEER I PIONEER II SCHEINFELD 2016 0.0 FUNNEL PLOT OF STANDARD ERROR BY STD DIFF IN MEANS 0.1 0.2 ST A N D A R D E R R O R 0.3 0.4 0.5 -2.0 -1.5 -1.0 -0.5 0.0 STD DIFF IN MEANS 0.5 1.0 1.5 2.0 Figure 3. Funnel plot for the assessment of publication bias, designed with Comprehensive Meta Analysis software. meta-analysis performed showed that adalimumab admin- istered for 12 weeks significantly decreased pain compared to placebo (-0.418 reduction in mean pain score [95% CI –0.588, –0.248] and P = 0.000). There was very little het- erogeneity across studies based on the I2 statistic (2.985). Only the “adalimumab every week” arm of Scheinfeld et al [14] was included in the meta-analysis, as statistical data regarding the “adalimumab every other week” arm was missing. We contacted authors via email in an effort to ac- quire this data, but they did not respond. No quantitative synthesis of controlled studies was pos- sible for the secondary outcome, due to missing data (email communication with authors was fruitless). According to Scheinfeld et al [14], 63% (P < 0.001) and 43% of patients 14 Review | Dermatol Pract Concept. 2022;12(2):e2022099 patients’ quality of life and the established under-treatment or difficult treatment of HS-related pain, the key finding of this study suggests that dermatologists should consider adalimumab when pain is a primary concern of a HS patient (in terms of severity, frequency and or perception). The limitations of our study are the small number of studies included in the quantitative synthesis, which, how- ever, reflects the actual paucity of evidence regarding the ef- fect of adalimumab on HS-associated pain. What is more, the main body of evidence included in this review and analy- sis came from pre-drug-approval RCTs, which, though solid methodologically, may not accurately simulate real-life con- ditions eg strict inclusion and exclusion criteria, higher treat- ment compliance, more frequent doctor visits, etc. Another limitation of our study is th that we did not check for con- founding factors such as the impact of mood improvement on pain perception. Pain is the principal determinant of life quality in HS pa- tients [31]. A recent (2020) cross-sectional study included 1,795 HS patients, 83.6% of whom experienced pain [32]. Pain intensity correlated positively with female gender, smoking, multiple affected areas and more severe disease [32]. Commonly employed HS treatments offer inadequate pain relief and, on top of this, dermatologists tend to be insufficiently trained in clinical pain management [31]. As a result, patients frequently self-medicate and may expose themselves to the dangers of opioid or other substance mis- use [31]. On another note, 82% of 110 HS patients tried to alleviate their pain through manually draining pus from their own lesions [33]. According to the European guidelines for the treatment of HS [34] a holistic approach is mandatory, when deciding how to manage HS patients. Aside from the principal pharmaceutical therapy, a plan should be made, among other things, for handling pain. There is, however, receiving adalimumab every week and every other week re- spectively achieved minimum clinically important difference in pain at week 12 (defined as half of standard deviation of baseline pain score) comparing to 26% of patients re- ceiving placebo [30]. The same study revealed that 52.1% (P  <  0.001) and 27.7% of patients receiving adalimumab every week and every other week, respectively, achieved ≥50% reduction in baseline VAS score at week 12, contrary to 18.8% of patients receiving placebo [14]. According to PIONEER I, 27.9% of patients receiving adalimumab and 24.8% of patients receiving placebo achieved NRS30 at week 12 (P = 0.628) [23]. According to PIONEER II, 45.7% of patients receiving adalimumab and 20.7% of patients re- ceiving placebo achieved NRS30 at week 12 (P < 0.001). Amano et al found that the median VAS pain score de- creased from 60.0 to 57.5 at week 12 (P = 0.55) [25]. Morita et al found that 66.7% (95%CI 29.9, 92.5) of participants achieved NRS30 at week 12. According to the Swedish post-marketing study, pain score decreased by 3.5 (95% CI 1.04, 5.96) after 12 weeks of adalimumab (P = 0.0147) (data available for 6 patients) [28]. Caposiena Caro et al measured a 1.3 reduction in VAS score after 12 weeks of adalimumab (no variance or significance data reported) [27]. Conclusions We performed a meta-analysis of 4 good-quality RCTs as- sessing the efficacy of adalimumab in reducing HS-related pain. Adalimumab was found significantly superior to pla- cebo regarding pain score reduction after 3 months of treat- ment. Our systematic review yielded 4 more open-label uncontrolled studies, 2 of which [26,28] showed that mean pain scores reduced significantly after 12 weeks of adalim- umab treatment. In light of the severe impact of pain on HS 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 Review | Dermatol Pract Concept. 2022;12(2):e2022099 15 in hidradenitis suppurativa. Curr Pain Headache Rep. 2017;21(12):49. DOI:10.1007/s11916-017-0647-3. PMID: 29094219. PMCID: PMC5784845. 6. Chernyshov PV, Zouboulis CC, Tomas-Aragones L, et al. Qual- ity of life measurement in hidradenitis suppurativa: position statement of the European Academy of Dermatology and Ve- nereology task forces on Quality of Life and Patient-Oriented Outcomes and Acne, Rosacea and Hidradenitis Suppurativa. J Eur Acad Dermatology Venereol. 2019;33(9):1633–1643. DOI: 10.1111/jdv.15519. PMID: 31037773. 7. Zouboulis CC, Desai N, Emtestam L, et al. European S1 guide- line for the treatment of hidradenitis suppurativa/acne inversa. J Eur Acad Dermatol Venereol. 2015;29(4):619–644. DOI: 10.1111/jdv.12966. PMID: 25640693. 8. Puza CJ, Wolfe SA, Jaleel T. Pain management in patients with hidradenitis suppurativa requiring surgery. Derma- tologic Surg. 2019;45(10):1327–1330. DOI: 10.1097/ DSS.0000000000001693. MID: 30570515. 9. Horváth B, Janse IC, Sibbald GR. Pain management in patients with hidradenitis suppurativa. J Am Acad Dermatol. 2015; 73(5 Suppl 1): S47–S51. DOI: 10.1016/j.jaad.2015.07.046. PMID: 26470616. 10. Ring HC, Theut Riis P, Miller IM, Saunte DM, Jemec GB. Self-reported pain management in hidradenitis suppurativa. Br J Dermatol. 2016;174(4):909–911. DOI: 10.1111/bjd.14266. Epub 2016 Jan 6. PMID: 26521975. 11. Ring HC, Sørensen H, Miller IM, List EK, Saunte DM, Jemec GB. Pain in Hidradenitis Suppurativa: A Pilot Study. Acta Derm Venereol. 2016;96(4):554–556. DOI 10.2340/00015555–2308. PMID: 26631388. 12. Jemec G. Quality of life considerations and pain manage- ment in hidradenitis suppurativa. Semin Cutan Med Surg. 2017;36(2):75–78. DOI: 10.12788/j.sder.2017.016. PMID: 28538748 13. Enamandram M, Rathmell JP, Kimball AB. Chronic pain management in dermatology. Pharmacotherapy and ther- 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- tion in pain scores and improvement in depressive symptoms in patients with hidradenitis suppurativa treated with adalimumab in a phase 2, randomized, placebo-controlled trial. Dermatol Online J. 2016;22(3):13030/qt38x5922j. PMID: 27136622. 15. Kimball AB, Sundaram M, Shields AL, et al. Adalimumab alle- viates skin pain in patients with moderate-to-severe hidradenitis suppurativa: secondary efficacy results from the PIONEER I and PIONEER II randomized controlled trials. J Am Acad Derma- tol. 2018; 79(6):1141-1143. DOI: 10.1016/j.jaad.2018.05.015. PMID: 29787843. 16. Gupta AK, Studholme C. Adalimumab (Humira) for the treat- ment of hidradenitis suppurativa. Skin Therapy Lett. 2016; 21(4):1–4. PMID: 27388530. 17. Haefeli M, Elfering A. Pain assessment. Eur Spine J. 2006; 15 Suppl 1(Suppl 1):S17–S24. DOI: 10.1007/s00586-005-1044-x. PMID: 16320034. PMCID: PMC3454549. 18. Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. DOI:10.1136/bmj.d5928. PMID: 22008217. PMCID: PMC3196245. only low-strength evidence (D) for the administration of common mild (nonsteroidal anti-inflammatory drugs) and strong (opioids) analgesics [34]. Therefore, well-studied drugs against HS with an established pain-reducing action, like adalimumab, are most precious weapons in the derma- tologist’s arsenal. Increased TNF-a levels in HS patients, and improvement of HS in patients with Crohn disease receiving adalimumab, led to adalimumab being tried as a primary treatment for moderate-to-severe HS [35]. Trials showed that the drug is both efficacious and easily tolerated, while positively af- fecting important secondary endpoints, like quality of life and pain [35]. Secukinumab reduced VAS pain score in a reported case of recalcitrant HS and its efficacy against HS is currently being examined in clinical trials [36]. Ustekinumab brought about significant reduction in VAS pain score in a phase II open-label trial of patients with moderate-to-severe HS [37]. Apremilast was also found to significantly reduce VAS pain score in a case-series of 9 patients (P = 0.026) [38]. It has been undoubtedly established, that pain should be brought into focus as far as HS-related research is con- cerned. Existing and potential new anti-HS drugs should be studied more rigorously in terms of their ability to mitigate acute and chronic HS pain, while standardized pain out- come measures, such as the newly introduced pain index, should be consistently used across such studies [39]. On the other hand, high-quality large-scale studies testing the effi- cacy and safety of various analgesics in HS patients should be designed and conducted soon. 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