Adalimumab effect on pain in hidradenitis suppurativa patients: systematic review and meta-analysis

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 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.

Keywords : hidradenitis suppurativa, adalimumab, pain, VAS, NRS30

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Introduction

Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent, 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 activity, negatively affected inter-personal relationships and reduced 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 lesions 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 anatomic 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 strategies 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 options may include antidepressants, anticonvulsants, specialist psychological support and patient support groups [ 9 , 12 ] .

Only a small number of studies have looked into the prevalence and impact of pain or strategies for its alleviation in HS populations [ 5 , 14 ] . What is more, it seems that the analgesics 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 adalimumab 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 studies 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 observational studies in our review.

Literature Search

A comprehensive electronic search of 5 databases was conducted, namely MEDLINE, ScienceDirect, the Cochrane Library, 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 dermatology 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 independently by 2 authors ( A.T. and E.S. ). We used the following free-text terms for the MEDLINE database search: (hidradenitis suppurativa) OR (acne inversa) AND (adalimumab) 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, independently, 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 exclusion criteria as a guide. Studies adhering to the following criteria were considered for inclusion: 1) trial or observational study, controlled or not, 2) recruited patients with a clinical diagnosis of HS, 3) patients (all of them or intervention 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 achieving a certain reduction in such scores was documented, 6) included patients were adults of any age, gender and background 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 discrepancies were settled through discussion and agreement. The following data was retrieved from each one of the selected studies: general characteristics (study identifier, identifier, study design, phase, number of study sites, countries included, study period, funding, inclusion criteria, exclusion 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 generic 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 configuration, from 0 (no pain) to 5 or 10 (worst possible pain) [ 17 ] . The patient is asked to mark the point/length that best corresponds 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 published 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 Cochrane risk-of-bias tool [ 18 ] to assess the risk of bias for included randomized controlled clinical trials. Any disagreements 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) selective 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 studies 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 available. 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 analysis 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 estimated 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 I ² 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%: considerable 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.

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 identifier based on its relevance to this review’s primary endpoint. Four of the included studies were randomized controlled trials (RCTs) [ 14 , 23 , 24 ] , 2 were prospective open-label uncontrolled 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 dosing of adalimumab was not consistent across all 8 studies or all study arms. Three studies [ 14 , 24 , 25 ] examined the efficacy 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 introductory 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 .

Figure 1 .

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

Table 1

Study Characteristics

Table 2

Baseline Characteristics of Participants

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 publication bias was detected ( Figure 3 ).

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.

Figure 3 .

Funnel plot for the assessment of publication bias, designed with Comprehensive Meta Analysis software.

Table 3

Methodological Index for Non-randomized Studies (MINORS)

Table 4

Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies

Outcomes

Quantitative synthesis of the 4 controlled studies was possible 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 meta-analysis performed showed that adalimumab administered 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 heterogeneity across studies based on the I ² 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 acquire this data, but they did not respond.

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

No quantitative synthesis of controlled studies was possible 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 receiving adalimumab every week and every other week respectively 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 receiving 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 receiving placebo achieved NRS30 at week 12 (P < 0.001).

Amano et al found that the median VAS pain score decreased 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 assessing the efficacy of adalimumab in reducing HS-related pain. Adalimumab was found significantly superior to placebo regarding pain score reduction after 3 months of treatment. 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 adalimumab treatment. In light of the severe impact of pain on HS 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, however, reflects the actual paucity of evidence regarding the effect of adalimumab on HS-associated pain. What is more, the main body of evidence included in this review and analysis came from pre-drug-approval RCTs, which, though solid methodologically, may not accurately simulate real-life conditions eg strict inclusion and exclusion criteria, higher treatment compliance, more frequent doctor visits, etc. Another limitation of our study is th that we did not check for confounding factors such as the impact of mood improvement on pain perception.

Pain is the principal determinant of life quality in HS patients [ 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 misuse [ 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, 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 dermatologist’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 affecting 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 concerned. 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 outcome 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 efficacy and safety of various analgesics in HS patients should be designed and conducted soon. This evidence will act as the basis for the issuing of pain-specific treatment guidelines that will support dermatologists in their difficult role and improve the life-quality of HS patients.