The Burden of Hidradenitis Suppurativa Signs and Symptoms in Quality of Life: Systematic Review and Meta-Analysis

International Journal of Environmental Research and Public Health Systematic Review The Burden of Hidradenitis Suppurativa Signs and Symptoms in Quality of Life: Systematic Review and Meta-Analysis Trinidad Montero-Vilchez 1,2 , Pablo Diaz-Calvillo 1, Juan-Angel Rodriguez-Pozo 1, Carlos Cuenca-Barrales 1,2 , Antonio Martinez-Lopez 1,2, Salvador Arias-Santiago 1,2,3,* and Alejandro Molina-Leyva 1,2   Citation: Montero-Vilchez, T.; Diaz-Calvillo, P.; Rodriguez-Pozo, J.-A.; Cuenca-Barrales, C.; MartinezLopez, A.; Arias-Santiago, S.; MolinaLeyva, A. The Burden of Hidradenitis Suppurativa Signs and Symptoms in Quality of Life: Systematic Review and Meta-Analysis. Int. J. Environ. Res. Public Health 2021,18, 6709. https:// doi.org/10.3390/ijerph18136709 Academic Editor: Paul B. Tchounwou Received: 21 May 2021 Accepted: 21 June 2021 Published: 22 June 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1Dermatology Department, Hospital Universitario Virgen de las Nieves, Avenida de Madrid, 15, 18012 Granada, Spain; [email protected] (T.M.-V.); [email protected] (P.D.-C.); [email protected] (J.-A.R.-P.); [email protected] (C.C.-B.); [email protected] (A.M.-L.); [email protected] (A.M.-L.) 2Instituto de Investigación Biosanitaria GRANADA, 18012 Granada, Spain 3Dermatology Department, Faculty of Medicine, University of Granada, 18001 Granada, Spain *Correspondence: [email protected]; Tel.: +34-958-023-422 Abstract: Hidradenitis suppurativa (HS) is a chronic, recurrent and debilitating inflammatory skin disease of the hair follicle that usually presents as painful, deep-seated inflamed lesions in the apocrine gland-bearing areas of the body. HS patients suffer from uncomfortable signs and symptoms, such as pain, pruritus, malodour and suppuration, which may impair patients’ quality of life (QoL). Although HS patients frequently experience these signs and symptoms, they are only occasionally assessed by clinicians and, unexpectedly, the scientific evidence available is limited and heterogeneous. The aim of this study is to summarize the evidence regarding the impact of HS signs and symptoms on QoL to serve as a basis for future research and help clinicians to consider them in the daily care of HS patients. A systematic review and meta-analysis were conducted following PRISMA Guidelines. The following search algorithm was used: (hidradenitis or “acne inversa”) and (pain or itch or odour or malodour or suppuration or oozing or drainage) and (“quality of life”). The literature search identified 836 references, 17 of them met the eligible criteria and were included for analysis, representing 4929 HS patients. Mean age of the participants was 36.28 years and there was a predominance of female sex among study participants. The BMI of the population was in the range of over-weight and about two out five patients were active smokers. Studies included patients with mild to moderate HS, with a mean disease duration of 13.69 years. The HS signs and symptoms assessed were pain, pruritus, malodour and suppuration. Overall, the higher intensity of a sign or symptom correlated with poorer general QoL or specific QoL dimensions including sexual distress, anxiety, depression and sleep. The most frequently employed tool to assess QoL was the Dermatology Life Quality Index (DLQI). DLQI was used in 52.9% of the studies (9/17) with a mean value of 10.70 (2.16 SD). The scores employed to assess signs and symptoms severity were subjective and varied between studies, being the numerical rating scale (NRS) for each of the most used symptoms. The mean NRS value for pain was 3.99 and the mean NRS for pruritus was 4.99. In conclusion, we have summarized, categorized and analyzed the scientific evidence regarding signs and symptoms in HS patients and their impairment in QoL. Their assessment should be thorough and included during routine evaluation of HS patients to motivate therapeutic modifications and increase patients’ health. Keywords: acne inversa; dermatology; hidradenitis suppurativa; quality of life; pain; pruritus 1. Introduction Hidradenitis suppurativa (HS) is a chronic, recurrent and debilitating inflammatory skin disease of the hair follicle that usually presents after puberty with painful, deep-seated inflamed lesions in the apocrine gland-bearing areas of the body, most commonly the axillae, inguinal and anogenital regions [ 1 , 2 ]. It has an estimated prevalence rate in the Int. J. Environ. Res. Public Health 2021,18, 6709. https://doi.org/10.3390/ijerph18136709 https://www.mdpi.com/journal/ijerph Int. J. Environ. Res. Public Health 2021,18, 6709 2 of 17 general population of 1% [ 3 ] and is associated with several comorbidities, such as metabolic syndrome, cardiovascular risk, diabetes or inflammatory bowel disease [4]. HS is one of the dermatological diseases with the greatest impact on patients’ quality of life (QoL) [ 5 ]. Its impairment is similar to other conditions, such as cardiovascular disease, cancer, diabetes mellitus and chronic obstructive pulmonary disease [ 6 ]. In fact, the mean Dermatology Life Quality Index scores for HS (8.3–12.7) are typical for severe dermatoses [ 7 ]. The disease severity, the number of flares and the lesion location are major factors impairing QoL [ 7 , 8 ]. HS not only impairs the physical health but also mental and psychosocial health. Poor self-esteem and body image [ 9 , 10 ] and increased risk of anxiety and depression [ 11 , 12 ] are also factors associated with HS that worsen patients’ life. Moreover, HS has a negative effect on sexual function [13]. The tool used most frequently to assess patients’ QoL is the DLQI. Recently, disease specific instruments to assess quality of life in HS have been developed [ 14 ], such as the HSQoL-24 validated in the Spanish population [ 15 ]. Other questionnaires also employed to evaluate psychosocial and physical functioning in HS are Skindex, the EuroQol 5 Dimensions questionnaire (EQ-5D) and the Short Form 36 questionnaire (SF-36). The Hospital Anxiety and Depression Scale (HADS), Beck Depression Inventory (BDI) and Major Depression Inventory (MDI) have been used to assess the impact on psychological QoL [ 7 ]. The influence of sexual function on patients’ life has also been evaluated using different questionnaires, such as the six-item Female Sexual Function Index (FSFI-6) and the Five-Item International Index of Erectile Function (IIEF-5) [13]. The great impact on QoL might be in part due to its uncomfortable signs and symptoms. HS lesions produce pain, pruritus, malodour and suppuration, which make life difficult for patients [ 16 , 17 ]. Pain seems the most common and bothersome symptom of HS and it is usually linked to the inflammatory nodules or abscesses, reported by more than 95% of patients [ 7 ]. The pain reported in HS patients is higher than other skin diseases [ 18 ]. The pain is not specific to any location on the body and it is mainly described as shooting, itchy and blinding [ 19 ]. Regarding other HS symptoms, pruritus is the other one most overlooked in the literature, although HS is not usually considered a pruritic disease [ 20 ]. The most common tools used to evaluate the severity of HS symptoms are the visual analogue scale (VAS) and the numerical rating scale (NRS) [7]. Pain, pruritus, malodour and suppuration are signs and symptoms frequently experienced by patients, but they are only occasionally assessed by clinicians [ 21 ]. Signs and symptoms might be the main burden of patients with HS, producing a great impairment in quality of life. Unexpectedly, the scientific evidence available is limited and heterogeneous. The aim of this study is to summarize the evidence regarding the impact of HS signs and symptoms on QoL to serve as a basis for future research and help clinicians to consider them in the daily care of HS patients. 2. Materials and Methods A systematic review and meta-analysis were conducted. A literature search was performed using Medline, Scopus and Embase databases from conception to 4 May 2021, following PRISMA Guidelines (Supplementary Material). The following search algorithm was used: (hidradenitis or “acne inversa”) and (pain or itch or odour or malodour or suppuration or oozing or drainage) and (“quality of life”). Symptoms included in the literature search were selected by a dermatologist expert in HS (AML) following the most recent evidence in HS clinical presentation [1]. The search was limited to: (i) human data, (ii) articles correlating HS symptoms with quality-of-life impairment in HS patients, (iii) articles written in English. All types of epidemiological studies (clinical trials, cohort studies, case-control studies and crosssectional studies) were included and analyzed. Reviews, guidelines, protocols, case series, case reports and conference abstracts were excluded. Two researchers (TMV and AML) independently reviewed the titles and abstracts of the articles obtained in the first search to assess relevant studies. The full texts of all Int. J. Environ. Res. Public Health 2021,18, 6709 3 of 17 articles meeting the inclusion criteria were reviewed, and their bibliographic references were checked for additional sources. The articles considered relevant by both researchers were included in the analysis. Disagreements about inclusion or exclusion of articles were subjected to discussion until a consensus was reached. If not reached, resolution was achieved by discussion with a third researcher (SAS). The variables assessed were study design, author, country, level of scientific evidence according to the Centre for Evidence-Based Medicine, number of participants, age, sex, BMI (kg/m 2 ), smoking habit, disease duration, disease severity (Hurley stage), HS symptoms and aspects of QoL evaluated, QoL and symptoms assessment tools and scores, correlation between symptoms and QoL. The mean DLQI and NRS for symptoms was calculated by a random effect metaanalysis weighted by the study sample size. To estimate absolute mean effect of DLQI and NRS for each symptom, the mean, standard deviation and sample size were extracted from the studies. Research with unclear or incomplete reporting was excluded from the meta-analysis. To generate valid estimates, studies were weighed according to their sample size. Forest plots were constructed to assess the distribution of the data and summarize the effect size and their 95% CIs. Quantifying of Heterogeneity was evaluated using Cochrane Q statistic, an intermediary statistic employed to obtain a more useful measure of heterogeneity, the I2. Assuming a high heterogenicity between studies, we used a random effects model to calculate the outcome. Microsoft Excel version 2016, Redmond, Washington, The USA, was used to run this data [22]. The quality of the design was critically appraised using the National Institutes of Health quality assessment tool to evaluate risk of bias (Table S1) [ 23 ]. This tool is based on the key concepts for evaluating the internal validity of a study and is divided into a set of 14 set questions. Studies are classified depending on the rate: good quality (>9 criteria met), fair quality (5–9 criteria met) and poor quality (<5 criteria met). 3. Results The literature search identified 836 references, 523 after removing duplicated papers. After reviewing the title and abstract, 92 records underwent full-text review. A total of 75 records were excluded because they did not investigate the impact of HS symptoms on QoL. Other reasons for exclusion along with the flow chart are shown in Figure 1. Finally, 17 studies, representing 4929 patients with HS, met the eligible criteria and were included and fully reviewed [24–40]. The main characteristics of the studies included are summarized in Table 1. All studies had a cross-sectional design and were classified as scientific level of evidence 4. Samples were recruited from outpatient clinics or through focused electronic, postal or telephone surveys. Study participants were predominantly female. Mean age of the participants was 36.28 years. The BMI of the population was in the range of overweight, about two out five patients were active smokers. Studies included patients with mild to moderate HS, with a mean disease duration of 13.69 years. The body regions more frequently affected by HS were axilla and groins. The HS signs and symptoms assessed were pain, pruritus, malodour and suppuration. Overall, the higher intensity of a sign or symptom correlated with poorer general QoL or specific QoL dimensions including sexual distress, anxiety, depression and sleep. The most frequently employed tool to assess QoL was the DLQI. DLQI was used in 52.9% of the studies (9/17) with a mean value of 10.70 (2.16 SD) after conducting a random effect meta-analysis weighted by the study sample size (Figure 2). Int. J. Environ. Res. Public Health 2021,18, 6709 4 of 17 Int. J. Environ. Res. Public Health 2021, 18, x FOR PEER REVIEW 4 of 16 Figure 1. Flow chart of the studies included. Figure 2. Meta-analysis of the mean Dermatology Life Quality Index reported in the studies. Figure 1. Flow chart of the studies included. 3.1. Pain Thirteen studies evaluated the impact of pain in the QoL of HS patients, including 4216 participants with a mean age of 35.62 years (Table 2) [24–36]. The incidence of pain was reported in two studies, ranging from 65.24% [ 33 ] to 77.5% [ 32 ]. NRS was the scale most used to assess pain (53.85%, 7/13) [ 24 , 25 , 30 – 34 ]. The mean NRS value was 3.99 (SD 0.95) after conducting a random effect meta-analysis weighted by the study sample size (Figure 3). VAS was the second most employed tool for pain but was scored in different ways [ 26 , 27 , 29 , 32 , 35 ]. PainDETECT [ 27 ], boil-associated pain score [ 28 ] and self-reported number of painful lesions [ 36 ] were other ways of pain severity assessment. The most frequently employed tool to assess QoL was the DLQI [ 26 – 29 , 31 – 33 , 35 ]. Skindex-29 [ 26 ], patient global assessment (PtGA) of QoL [ 30 ] and Skindex-17 [ 35 ] were also employed to assess overall QoL in HS patients. The Hospital Anxiety and Depression Scale (HADs)-Anxiety was used to assess anxiety [ 26 ] and HADS-depression [ 26 ], Beck’s Depression Inventory [ 27 ] and Major Depression Inventory (MID) [ 34 ] were employed to evaluate depression. Sexual distress was assessed by NRS for HS impact on sex life, six-item Female Sexual Function Index (FSFI-6) and five-item International Index of Erectile Function (IIEF-5) [ 24 , 25 ]. The impairment of sleep was assessed by using the Athens Insomnia Scale (AIS) and the Pittsburgh Sleep Quality Index (PSQI) [29]. Int. J. Environ. Res. Public Health 2021,18, 6709 5 of 17 Table 1. Main characteristics of the studies regarding HS symptoms impact on QoL. Study, Site and Year Design CEBM Participants Age (Years) Sex (Female:Male Ratio) BMI (kg/m2) Smoking Habit (Yes) Disease Duration (Years) Disease Severity (Hurley I/II/III) HS Symptom Evaluated Main Aspects Od QoL Evaluated Alavi et al. Canada 2017 [37] Crosssectional 4 51 32.50 ±10.76 2.47:1 NS NS 11.10 ±8.57 13.7% (7)/45.1% (23)/41.2% (21) Malodour Overall QoL Cuenca-Barrales et al. Spain. 2019 [25] Crosssectional 4 386 37.81 ±9.26 3.83:1 29.35 ±6.71 42.2% (163) 17.77 ±9.62 17.6% (68)/45.1% (174)/37.3% (144) Pain, pruritus, malodour, suppuration Sexual distress Cuenca-Barrales and Molina-Leyva. Spain. 2020 [24] Crosssectional 4 386 37.81 ±9.26 3.83:1 29.35 ±6.71 42.2% (163) 17.77 ±9.62 17.6% (68)/45.1% (174)/37.3% (144) Pain, pruritus, malodour, suppuration Sexual dysfunction Frings et al. Germany. 2019 [26] Crosssectional 4 110 38 ±12 1.24:1 30.5 ±6.9 37% (41) NS 7% (8)/30% (33)/63% (69) Pain Overall QoL, anxiety and depression Huilaja et al. Finland. 2020 [27] Crosssectional 4 92 NS * NS * NS * NS * NS * NS * Pain Overall QoL and depression Jørgensenet al. Germany. 2020 [28] Crosssectional 4 339 39.4 ±13.5 1.80:1 29 ±7.6 75.2% (255) 13.8 ±11.5 28.3% (96)/ 57.5% (195)/14.2% (48) Pain Overall QoL Kaaz et al. Poland. 2018 [29] Crosssectional 4 108 36.3 ±12.1 0.89:1 28.8 ±5.4 18% (60) 9.1 ±8.3 46.3% (50)/45.4% (49)/ 8.3% (9) Pain and pruritus Sleep and insomnia Kirby et al. Denmark and USA. 2021 [30] Crosssectional 4 224 39.6 (19-77) 6.72:1 NS NS NS NS Pain Overall QoL Krajewski et al. Germany and Poland. 2021 [31] Crosssectional 4 1795 40.0 ±11.8 1.79:1 28.1 ±6.2 55.6% (998) NS NS Pain Overall QoL Machado et al. Canada. 2021 [38] Crosssectional 4 30 40.87 ±2.55 2.33:1 NS NS NS NS Malodour and drainage Overall QoL Matusiak et al. Poland 2018. [32] Crosssectional 4 103 35.6 ±13.2 0.94:1 29.4 ±5.7 54.4% (56) 8.9 ±7.5 40.8% (42)/45.6% (47)/13.6% (14) Pain and pruritus Overall QoL Molina-Leyva and Cuenca-Barrales. Spain. 2019 [33] Crosssectional 4 233 40.14 ±13.46 1.14:1 30.68 ±7.05 NS 13.99 ±10.59 30.04% (70); 41.63% (97); 28.33% (66) Pruritus, malodour Overall QoL Onderdijk et al. Netherlands. 2013 [34] Crosssectional 4 211 43.0 ±11.8 NS NS NS 16.8 ±11.6 30.1% (64)/56.4% (119)/13.5% (28) Pain and pruritus Overall QoL and depression Riis et al. Denmark. 2016 [39] Crosssectional 4 421 42.4 (19-77) 3.74:1 NS NS NS NS Pain, pruritus and malodour Health-realted overall utility Sampogna et al. Italy 2019 [35] Crosssectional 4 69 34.5 ±12.5 1.16:1 NS NS NS 27.5% (19)/43.5% (30)/29.0% (20) Pain Overaal QoL Int. J. Environ. Res. Public Health 2021,18, 6709 6 of 17 Table 1. Cont. Study, Site and Year Design CEBM Participants Age (Years) Sex (Female:Male Ratio) BMI (kg/m2) Smoking Habit (Yes) Disease Duration (Years) Disease Severity (Hurley I/II/III) HS Symptom Evaluated Main Aspects Od QoL Evaluated von der Werth et al. Denmark. 2001 [36] Crosssectional 4 160 40.9 ±11.7 6.13:1 NS NS NS NS Pain Overall QoL Vossen et al. Netherlands. 2017 [40] Crosssectional 4 211 38.0 (29–49) 1.78:1 28.5 ±5.9 19.9% (62) 14.0 (7–25) 15% (32)/66% (140)/19% (39) Pruritus Activities of daily living and sleep BMI, body mass index; CEBM, level of scientific evidence according to the Centre for Evidence-Based Medicine (24); DLQI, Dermatology Life Quality Index; HADS, Hospital Anxiety and Depression Scale; HS, hidradenitis suppurativa; HSS, Hidradenitis Suppurativa Score; IHS4, International Hidradenitis Suppurativa Severity Index; NRS, Numeric Rating Scale; NS, not specified; QoL, quality of life, VAS, visual analogue scale. Continuous data is expressed as media ± SD or median (interquartile range) and categorical data are presented as n or n/N (%). * The article contains this information in the Supplementary Material but it is not accessible (broken link). Int. J. Environ. Res. Public Health 2021,18, 6709 7 of 17 Int. J. Environ. Res. Public Health 2021, 18, x FOR PEER REVIEW 4 of 16 Figure 1. Flow chart of the studies included. Figure 2. Meta-analysis of the mean Dermatology Life Quality Index reported in the studies. Figure 2. Meta-analysis of the mean Dermatology Life Quality Index reported in the studies. Pain was related to the overall impact on QoL, assessed by DLQI independently of the tool used for assessing QoL and pain severity [ 26 – 28 , 30 , 32 , 33 , 35 , 36 ]. High NRS for pain was associated with high DLQI [ 31 – 34 ] (r = 0.581, p< 0.001 [ 31 ]; r = 0.48, p< 0.001 [ 32 ]; β = 0.91 ± 0.12, R2 = 0.36, p< 0.001 [ 33 ]; r = 0.60, p< 0.05 [ 34 ]) and PtGA of QoL (r = 0.66, 0.6–0.71 95% CI) [ 30 ]. High VAS for pain values were also linked to higher DLQI (r = 0.457, p< 0.001 [ 26 ]; r = 0.48, p< 0.001 [ 32 ]), Skindex-29 [ 26 ] and Skindex-17 [ 35 ]. Matusiak et al. showed that the presence of pain was a more important factor for worsening QoL (p= 0.002) than disease severity (p= 0.04). They also observed that pain severity was related to increased sweating, heat and physical activity [32]. Two studies showed that HS pain worsened psychological QoL [ 27 , 34 ]. Nevertheless, Frings et al. showed that pain impairs patients’ anxiety (r = 0.304, p= 0.009) but not depression (r = 0.193, p= 0.105) [ 26 ]. Kaaz et al. also found that HS pain was related to poor sleep quality [ 29 ]. Moreover, it was observed that NRS for pain was related to impact on sex life ( β = 0.15, p= 0.049) [ 25 ] and was a risk factor for sexual dysfunction in females (β= 0.1, p< 0.05) [24]. 3.2. Pruritus Eight studies evaluated the impact of pruritus on HS patients’ QoL, including 2059 participants with a mean age of 38.88 years (Table 3) [24,25,29,32–34,39,40]. The incidence of pruritus was reported in three studies (41.7% [ 32 ] vs. 57.3% [ 40 ] vs. 61.8% [ 33 ]). The NRS for pruritus was the scale most used to assess pruritus severity [ 24 , 25 , 32 – 34 , 39 , 40 ]. The mean NRS was 4.99 (0.96 SD), after conducting a random effect meta-analysis weighted by the study sample size, Figure 4. VAS for pruritus [ 29 ], 4-item itch questionnaire [32] and 5-D itch scale [40]. Int. J. Environ. Res. Public Health 2021,18, 6709 8 of 17 Table 2. Studies regarding pain impact on QoL. Study Pain QoL Correlation between Pain and QoL Assessment Tool Score Assessment Tool Score Cuenca-Barrales et al. Spain. 2019 [25]NRS 6.54 ±2.95 NRS for HS impact on sex life 7.24 ±2.77 in women 6.39 ±3.44 in men β= 0.15, p= 0.049 ** Cuenca-Barrales and Molina-Leyva. Spain. 2020 [24] NRS Women: 6.52 ±2.98 Prevalence of sexual dysfunction FSFI-6 ≤19 51% (156) β= 0.1, p< 0.05 ** Men: 6.64 ±2.81 IIEF-5 ≤21 60% (48) β= NS, p= 0.97 ** Frings et al. Germany. 2019 [26]VAS NS DLQI 12 ±7 r = 0.457, p< 0.001 HADS-Depression 6 ±4 r = 0.193, p= 0.105 HADS-Anxiety 7 ±4 r = 0.304, p= 0.009 Skindex-29 symptom score NS r = 0.547, p< 0.001 Skindex-29 function score r = 0.459, p< 0.001 Skindex-29 emotion score r = 0.399, p< 0.001 Huilaja et al. Finland. 2020 [27] VAS: -No pain (0–4 mm)/ -Mild pain (5–44 mm)/ -Moderate to severe pain (45–100 mm) 37% (34)/ 45.7% (42)/ 17.4% (16)/ DLQI 3.03 (0–9) vs. 8.76 (0–23) vs. 13.69 (4–29) p< 0.001 ¶ Beck’s Depression Inventory 6.68 (0–4.0) vs. 9.26 (0–30) vs. 13.06 (1–32) p= 0.019 ¶ PainDETECT: -Pain negative (0–12)/ -Unclear (13–18)/ -Pain positive (19–38) 41.3% (38)/ 27.2% (25)/ 31.5% (29) DLQI 4.53 (0–16) vs. 8.84 (1–23) vs. 10.55 (0–29) p< 0.001 ¶ Beck’s Depression Inventory 6.84 (0–20) vs. 7.68 (0–19) vs. 12.86 (0–32) p= 0.003 ¶ Jørgensen et al. Germany. 2020 [28] Boil-associated pain score (0–10) ≤5 boils/ >5 boils 8.6 ±7.4/ 15 ±7.4 DLQI 11.9 ±7.6 Mean difference: 6.3 ±1.85, p< 0.001 Ü Kaaz et al. Poland. 2018 [29]VAS 4.9 ±2.9 DLQI 13.0 ±8.0 NS AIS 5.4 ±4.3 p< 0.05 ˆ PSQI 6.5 ±3.6 p< 0.05 ˆ Kirby et al. Denmark and USA. 2021 [30]NRS 3.29 ±2.83 DLQI 12.97 ±8.33 NS PtGA of QoL (0–4) 2.09 ±1.34 r = 0.66 (0.6–0.71 95% CI) # Krajewski et al. Germany and Poland. 2021 [31] NRS NS DLQI 13.2 ±8.1 r = 0.581; p< 0.001 ˆ Matusiak et al. Poland. 2018 [32] Prevalence of pain 77.5% (80) DLQI 13.3 ±7.8 NS VAS 4.6 ±2.5 r = 0.48, p< 0.001 ˆˆ NRS 4.9 ±2.4 r = 0.48, p< 0.001 ˆˆ Molina-Leyva and Cuenca-Barrales. Spain. 2019 [33] NRS 4.64 ±3.43 DLQI 10.93 ±7.3 β= 0.91 ±0.12, R2 = 0.36, p< 0.001 * Onderdijk et al. Netherlands. 2013 [34]NRS 3.6 ±3.2 DLQI 8.4 ±7.5 r = 0.60, p< 0.05 Ü MDI 4.3 ±5.6 r = 0.36, p< 0.05 Ü Sampogna et al. Italy. 2019 [35] VAS: <5/ 5–6/ ≥7 25.9% (11)/ 29% (20)/ 55.1% (38) Skindex-17 Symptoms 53.6 vs. 72.0 vs. 72.6, p= 0.068 ¶ Skindex-17 psychosocial 39.4 vs. 54.6 vs. 61.7 p= 0.088 ¶ Int. J. Environ. Res. Public Health 2021,18, 6709 9 of 17 Table 2. Cont. Study Pain QoL Correlation between Pain and QoL Assessment Tool Score Assessment Tool Score von der Werthet al. Denmark. 2001 [36] Self-reported number of painful lesions 2 DLQI 8.9 ±8.3 r = 0.384, p< 0.01 Ü AIS, Athens Insomnia Scale; DLQI, Dermatology Life Quality Index; FSFI-6, six-item Female Sexual Function Index; HADS, Hospital Anxiety and Depression Scale; HS, hidradenitis suppurativa; IIEF-5, five-item International Index of Erectile Function; MDI, Major Depression Inventory; NRS, Numeric Rating Scale; NS, not specified; PSQI, Pittsburgh Sleep Quality Index; PtGA, patient global assessment; QoL, quality of life. * Simple linear regression analysis; ** Multivariate linear regression analysis; Analysis of variance; # Student’s t-test for independent samples; ¶ Multivariate analysis of variance; Ü Spearman correlation; ˆ Pearson correlation; ˆˆ Pearson’s correlation coefficient or Spearman’s correlation analysis with reference to the distribution of evaluated variables. Int. J. Environ. Res. Public Health 2021, 18, x FOR PEER REVIEW 6 of 16 3.1. Pain Thirteen studies evaluated the impact of pain in the QoL of HS patients, including 4216 participants with a mean age of 35.62 years (Table 2) [24–36]. The incidence of pain was reported in two studies, ranging from 65.24% [33] to 77.5% [32]. NRS was the scale most used to assess pain (53.85%, 7/13) [24,25,30–34]. The mean NRS value was 3.99 (SD 0.95) after conducting a random effect meta-analysis weighted by the study sample size (Figure 3). VAS was the second most employed tool for pain but was scored in different ways [26,27,29,32,35]. PainDETECT [27], boil-associated pain score [28] and self-reported number of painful lesions [36] were other ways of pain severity assessment. Figure 3. Meta-analysis of the mean Numerical Rating Scale for pain reported in the studies. The most frequently employed tool to assess QoL was the DLQI [26–29,31–33,35]. Skindex-29 [26], patient global assessment (PtGA) of QoL [30] and Skindex-17 [35] were also employed to assess overall QoL in HS patients. The Hospital Anxiety and Depression Scale (HADs)-Anxiety was used to assess anxiety [26] and HADS-depression [26], Beck’s Depression Inventory [27] and Major Depression Inventory (MID) [34] were employed to evaluate depression. Sexual distress was assessed by NRS for HS impact on sex life, sixitem Female Sexual Function Index (FSFI-6) and five-item International Index of Erectile Function (IIEF-5) [24,25]. The impairment of sleep was assessed by using the Athens Insomnia Scale (AIS) and the Pittsburgh Sleep Quality Index (PSQI) [29]. Pain was related to the overall impact on QoL, assessed by DLQI independently of the tool used for assessing QoL and pain severity [26–28,30,32,33,35,36]. High NRS for pain was associated with high DLQI [31–34] (r = 0.581, p < 0.001 [31]; r = 0.48, p < 0.001 [32]; β = 0.91 ± 0.12, R2 = 0.36, p < 0.001 [33]; r = 0.60, p < 0.05 [34]) and PtGA of QoL (r = 0.66, 0.6–0.71 95% CI) [30]. High VAS for pain values were also linked to higher DLQI (r = 0.457, p < 0.001 [26]; r = 0.48, p < 0.001 [32]), Skindex-29 [26] and Skindex-17 [35]. Matusiak et al. showed that the presence of pain was a more important factor for worsening QoL (p = 0.002) than disease severity (p = 0.04). They also observed that pain severity was related to increased sweating, heat and physical activity [32]. Figure 3. Meta-analysis of the mean Numerical Rating Scale for pain reported in the studies. Matusiak et al. observed that the presence of pruritus did not have an impact on QoL [ 32 ], while Molina-Leyva et al. observed that the presence of NRS for pruritus > 3 was related with higher rates in DLQI score ( β = 0.42 ± 0.11, R2 = 0.20, p< 0.001) [ 33 ]. Moreover, higher rates in VAS and NRS for pruritus were positively correlated with DLQI [ 32 , 34 ]. The impact of pruritus in overall QoL was also reflected by Riis et al. showing that higher NRS for pruritus were related to lower values in the EQ-5D (β=−0.017, p< 0.05) [39]. It was found that HS pruritus impaired sleep quality [ 29 , 40 ] and it was linked to poor mental health assessed by MDI [ 34 ]. Nevertheless, it was observed that NRS for pruritus did not have an impact on sex life ( β = 0.03, p= 0.615) [ 25 ], neither in men nor in women [24]. Factors associated with increased risk of pruritus were Hurley III, higher number of regions affected, the female sex, being an active smoker, the intensity of suppuration and pain, having Crohn’s disease and not using statins [32,33,40]. 3.3. Malodour Six studies evaluated the impact of pain in the QoL of HS patients, including 1507 participants with a mean age of 38.59 years [24,25,33,37–39], Table 4. Int. J. Environ. Res. 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