The efficacy and tolerability of tetracyclines and clindamycin plus rifampicin for the treatment of hidradenitis suppurativa: Results of a prospective European cohort study Kelsey R. van Straalen, MD, PhD,a Thrasyvoulos Tzellos, MD, PhD,b Phillipe Guillem, MD, PhD,c,d,e Farida Benhadou, MD, PhD,f Carlos Cuenca-Barrales, MD,g,h Mathilde Daxhelet, MD,f Mathieu Daoud, MD,f Ourania Efthymiou, MD,i Evangelos J. Giamarellos-Bourboulis, MD, PhD,j Gregor B. E. Jemec, MD, DMSci,k Alexandros C. Katoulis, MD,i Anke Koenig, MD, PhD,l Elizabeth Lazaridou, MD, PhD,m Angelo V. Marzano, MD,n,o qucas Matusiak, MD, PhD,p Alejandro Molina-Leyva, MD, PhD,g,h Chiara Moltrasio, MRes,n,q Andreas Pinter, MD, PhD,l Concetta Potenza, MD,r Jorge Romanı, MD, PhD,s Ditte M. Saunte, MD, PhD,k Nevena Skroza, MD,r Dimitra Stergianou, MD,j Jacek Szepietowski, MD, PhD, FRCP,p Anastasia Trigoni, MD, PhD,m Eva Vilarrasa, MD,t and Hessel H. van der Zee, MD, PhDa Rotterdam, the Netherlands; Bodø, Norway; Lyon and Paris, France; Brussels, Belgium; Granada, Spain; Athens, Greece; Copenhagen, Denmark; Frankfurt am Main, Germany; Thessaloniki, Greece; Milan, Trieste, and Polo Pontino-Latina, Italy; Wroclaw, Poland; and Sabadell and Barcelona, Spain Background: Tetracyclines and clindamycin plus rifampicin combination therapy are both considered first-line therapy in current hidradenitis suppurativa guidelines. However, evidence for their efficacy is drawn from small studies, often without validated outcomes. Objective: To assess the 12-week efficacy of oral tetracyclines and a combination of clindamycin and rifampicin. From the Erasmus MC, University Medical Center Rotterdam, Wroclawp; Department of Medical Surgical and Health Sciences, Department of Dermatology, Rotterdama; Department of University of Trieste, Triesteq; Dermatology Unit ‘Daniele Dermatology, Nordland Hospital Trust, Bodøb; Department of Innocenzi,’ Department of Medical-Surgical Sciences and Bio- Surgery, Clinique du Val d’Ouest, Lyonc; ResoVerneuil, Parisd; technologies, Sapienza University of Rome, Polo Pontino-Lati- Groupe de Recherche en Proctologie de la Societe Nationale nar; Department of Dermatology, Corporaci o Sanitaria Parc Française de ColoProctologie, Parise; Department of Derma- Taulı, Sabadells; and Department of Dermatology, Hospital de la tology, Universite Libre de Bruxelles, Erasme Hospital, Brusselsf; Santa Creu i Sant Pau, Universitat Aut onoma de Barcelona, Department of Dermatology, Hospital Universitario Virgen de Barcelona.t las Nieves, Granadag; TECe19-Clinical and Translational Derma- Drs van Straalen and Tzellos contributed equally to this article. tology Investigation Group Instituto de Investigaci on Bio- Funding sources: None. sanitaria, Granadah; Second Department of Dermatology and IRB approval status: The study was performed within daily practice Venereology, National and Kapodistrian University of Athens, and in accordance with current guidelines; therefore, it was Medical School, ‘‘Attikon’’ General University Hospital, Athensi; deemed exempt from IRB review. Fourth Department of Internal Medicine, National and Kapodis- Accepted for publication December 29, 2020. trian University of Athens, Medical School, Athensj; Department Reprints not available from the authors. of Dermatology, Zealand University Hospital, Roskilde and Correspondence to: Hessel H. van der Zee, MD, PhD, Department Health Sciences Faculty, University of Copenhagenk; Depart- of Dermatology, Erasmus University Medical Center, dr. ment of Dermatology, Venereology and Allergology, University Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. Hospital Frankfurt am Mainl; Second Department of Derma- E-mail: h.vanderzee@erasmusmc.nl. tology and Venereology, Aristotle University of Thessaloniki, Published online January 20, 2021. General Hospital Papageorgiou, Thessalonikim; Dermatology 0190-9622 Unit, Fondazione Istituto di Ricovero e Cura a Carattere Ó 2021 by the American Academy of Dermatology, Inc. Published Scientifico Ca’ Granda Ospedale Maggiore Policlinico, Milann; by Elsevier Inc. This is an open access article under the CC BY Department of Pathophysiology and Transplantation, Uni- license (http://creativecommons.org/licenses/by/4.0/). versita degli Studi di Milano, Milano; Department of Derma- https://doi.org/10.1016/j.jaad.2020.12.089 tology, Venereology and Allergology, Medical University, 369 370 van Straalen et al J AM ACAD DERMATOL AUGUST 2021 Methods: A prospective, international cohort study performed between October 2018 and August 2019. Results: In total, 63.6% of the included 283 patients received oral tetracyclines, and 36.4% were treated with clindamycin and rifampicin. Both groups showed a significant decrease in International Hidradenitis Suppurativa Severity Score System from baseline (both P \ .001). The Hidradenitis Suppurativa Clinical Response (HiSCR) was achieved in 40.1% and 48.2% of patients, respectively (P = .26). Patient characteristics or disease severity were not associated with the attainment of HiSCR or the minimal clinically important differences for the Dermatology Life Quality Index and pain. Limitations: Cohort study. Respectively, 23.9% and 19.4% of patients had to be excluded from the HiSCR analysis for the tetracycline and combination therapy group because of a low abscess and nodule count at baseline. Conclusion: This study shows significant efficacy of both tetracycline treatment and clindamycin and rifampicin combination therapy after 12 weeks in patients with hidradenitis suppurativa. No significant differences in efficacy were observed between the 2 treatments, regardless of disease severity. ( J Am Acad Dermatol 2021;85:369-78.) Key words: acne inversa; antibiotics; clindamycin; doxycycline; efficacy; guideline; minocycline; outcome; rifampicin; tetracycline; therapy; treatment. Hidradenitis suppurativa CAPSULE SUMMARY clindamycin and rifampicin (HS) is a chronic, auto- using validated and clini- inflammatory skin disease d Evidence for the efficacy of tetracyclines cally meaningful physician characterized by painful, and clindamycin plus rifampicin in and patient reported out- deep-seated, highly inflamed hidradenitis suppurativa is drawn from comes in patients with nodules and draining tunnels small studies, often without validated HS. In addition, we aimed in the intertriginous areas of outcomes. to identify factors associated the body.1-3 Traditionally, HS with treatment response. has been treated with systemic d Both treatment with tetracyclines and antibiotics, which remain the clindamycin combined with rifampicin MATERIALS AND first-line medical therapy to show significant efficacy in patients with METHODS date. Current guidelines and hidradenitis suppurativa. No significant Study design consensus statements on the differences in efficacy were observed, A detailed protocol treatment of HS consistently regardless of disease severity. including study design, recommend 2 types of anti- inclusion and exclusion biotic therapy as the first-line criteria, HS treatment guide- treatment.4-11 Oral tetracyclines, such as doxycycline lines, assessment schedule, and timeline was sent out and minocycline, are recommended as a first-line in October 2018 to all centers that previously therapy for mild to moderate HS.4-11 The combina- participated in an European Hidradenitis tion of clindamycin and rifampicin is favored as a Suppurativa Foundation consortium study.5,11 first-line therapy for moderate to severe HS but is also recommended as a second-line therapy for Participants mild to moderate disease unresponsive to oral Following this protocol, patients who were tetracyclines before biologic treatment.4-11 treated according to the current international guide- Even though these treatments are considered first- lines with either oral tetracyclines (tetracycline line therapy, the evidence to support their efficacy is 500 mg twice daily, doxycycline 100 mg once daily, weak. Oral tetracycline has been studied in an small minocycline 100 mg once daily) or clindamycin randomized controlled trial, showing similar efficacy 300 mg twice daily in combination with rifampicin to topical clindamycin.12 The efficacy of clindamycin 600 mg a day in daily practice were included from and rifampicin combination therapy is derived from 15 European centers between October 2018 and several small retrospective and prospective case August 2019. Patients were included in a real-life series.13-22 Therefore, the aim of this multicenter, clinical practice setting without blinding or random- international study was to assess the 12-week effi- ization. Exclusion criteria were concomitant systemic cacy of oral tetracyclines and a combination of therapy or invasive treatment (deroofing, excision, J AM ACAD DERMATOL van Straalen et al 371 VOLUME 85, NUMBER 2 groups were assessed by using independent Student Abbreviations used: t tests or Mann-Whitney U tests for continuous BMI: body mass index variables and chi-square tests or the Fisher exact CI: confidence interval DLQI: Dermatology Life Quality Index test for categorical variables, where appropriate. HiSCR: Hidradenitis Suppurativa Clinical Change from baseline after 12 weeks of treatment Response was assessed by using paired t tests or Wilcoxon’s HS: hidradenitis suppurativa IHS4: International Hidradenitis Suppurativa signed rank test for continuous variables. Univariate Severity Score System logistic regression models were constructed to MCID: minimal clinical important difference assess the association of antibiotic treatment and NRS: Numerical Rating Scale OR: odds ratio HiSCR, MCID DLQI, and MCID NRS Pain attainment PROM: patient-reported outcome measure and to identify factors associated with treatment response. laser therapy, incision and drainage procedure, or RESULTS In total, 283 patients were included; 63.6% (180/ intralesional corticosteroids) during the 12 weeks 283) patients received tetracycline treatment (tetra- and missing lesion counts at either baseline or cycline, n = 42; doxycycline, n = 121; minocycline, follow-up. Patient characteristics (age, sex, body n = 17) and 36.4% (103/283) patients received mass index [BMI], disease duration, first or second treatment with a combination of clindamycin plus degree family history) were collected at baseline. rifampicin. There were no significant differences Patient-reported outcome measures (PROMs) between these 2 treatment groups regarding sex, (Numerical Rating Scale [NRS] pain, NRS Pruritus, age, age at onset, disease duration, BMI, smoking and Dermatology Life Quality Index [DLQI]), and status, family history of HS, or previous surgical physician scores (inflammatory nodule count, ab- treatment (Table I). Patients treated with clindamycin scess count, draining sinus tract count, International and rifampicin had significantly more severe disease Hidradenitis Suppurativa Severity Score System reflected in a significantly higher number of inflam- [IHS4], modified Sartorius score, Hurley and refined matory nodules (P = .029) and draining sinus tracts Hurley staging) were assessed at baseline and after (P = .003), higher IHS4 score (P = .019), Hurley stage 12 weeks of treatment.23-25 Hidradenitis Suppurativa (P = .004), modified Sartorius (P = .001), and NRS Clinical Response (HiSCR), (50% or greater reduction Pain score (P = .005) compared with patients treated in inflammatory lesion count [abscesses plus inflam- with tetracycline. matory nodules] and no increase in abscesses or Both groups showed a significant decrease in draining fistulas compared with baseline) was calcu- IHS4 from baseline; from a median (interquartile lated at 12 weeks.26 range) of 9.0 (5.0-18.5) to 5.0 (2.0-12.0) (P \.001) in The minimal clinical important difference (MCID) the tetracycline group and from 13.0 (6.0-27.0) to 6.0 was calculated for the DLQI score ($4 point reduc- (1.0-17.0) (P \ .001) in the combination therapy tion from baseline) and for NRS Pain ($30% and $1 (Table II and Fig 1). Reductions in all lesion counts point reduction from baseline).27,28 MCIDs were were observed (inflammatory nodules, abscesses, considered missing when a patient did not meet and draining tunnels). There was no significant the baseline requirements for MCID calculationsd difference in the percentage of patients achieving that is, DLQI score of less than 4 and NRS Pain score HiSCR between the tetracycline group (40.1%) and of less than 3. HiSCR was calculated for patients with the clindamycin and rifampicin group (48.2%; a baseline abscess and nodule count of 3 or greater.26 P = .263) (Table II). HiSCR attainment was not Patients who discontinued treatment were deemed related to Hurley stage or IHS4 category for either to have not achieved HiSCR, MCID DLQI, and MCID tetracyclines (P = .920 and P = .495) and clindamycin NRS Pain. and rifampicin (P = .807 and P = .796); see Tables III and IV. Statistical analyses Patients in both groups reported a significant Patient characteristics are presented as number decrease in DLQI, NRS Pain, and NRS pruritus after (percentage) for categorical variables and as 12 weeks of treatment (Table II and Fig 1). There was mean 6 standard deviation or median (interquartile no significant difference between the treatment range), where appropriate for continuous variables. groups regarding the percentage of patients who Normality was assessed by using the Kolmogorov- achieved either the MCID for NRS Pain or the MCID Smirnov test. Differences in patient characteristics, for the DLQI (P = .643 and P = .084, respectively). PROMs, and physician scores between treatment MCID pain was significantly more often achieved by 372 van Straalen et al J AM ACAD DERMATOL AUGUST 2021 Table I. Baseline characteristics Patient characteristics Tetracyclines (n = 180) Clindamycin and rifampicin (n = 103) P value Female sex, n (%) 106 (58.9) 56 (54.4) .533 Age, y, median (IQR) 37 (26-46) 36 (27-45) .917 Missing, n 0 1 Age at onset, y, median (IQR) 21 (15-30) 21 (16-28) .854 Missing, n 3 0 Disease duration, median (IQR) 10 (6-19) 10 (5-17) .415 Missing, n 3 1 BMI, kg/m2, mean (SD) 29.81 (6.1) 29.21 (6.2) .428 Missing, n 6 0 Current smoker, n (%) 110 (61.8) 56 (56.6) .443 Missing, n 2 4 Family history of HS, n (%) 58 (34.3) 34 (35.1) 1.000 Missing, n 11 6 Previous surgical treatment, n (%) 69 (38.3) 39 (38.6) 1.000 Missing, n 0 2 Patient-reported outcomes DLQI, mean (SD) 13.3 (7.5) 15.1 (7.9) .071 Missing, n 8 7 NRS Pain, median (IQR) 6 (4-8) 7 (5-8) .005 Missing, n 7 3 NRS Pruritus, median (IQR) 3 (0-6) 4 (0-7) .204 Missing, n 13 8 Physician scores Inflammatory nodules, median 3.5 (1.0-6.0) 4 (2-9) .029 (IQR) Abscesses, median (IQR) 0.0 (0.0-2.0) 0 (0-2) .975 Draining sinus tracts, median (IQR) 1.0 (0.0-2.0) 1 (0-4) .003 Hurley stage Stage I, n (%) 54 (30.2) 14 (13.6) .004 Stage II, n (%) 90 (50.3) 58 (56.3) Stage III, n (%) 35 (19.5) 31 (30.1) Missing, n 1 0 Refined Hurley stage Stage Ia, n (%) 22 (12.3) 2 (1.9) .004 Stage Ib, n (%) 24 (13.4) 9 (8.7) Stage Ic, n (%) 17 (9.5) 11 (10.7) Stage IIa, n (%) 22 (12.3) 6 (5.8) Stage IIb, n (%) 42 (23.5) 25 (24.3) Stage IIc, n (%) 29 (16.2) 28 (27.2) Stage III, n (%) 23 (12.8) 22 (21.4) Missing, n 1 0 IHS4, median (IQR) 9.0 (5.0-18.5) 13.0 (6.0-27.0) .019 Mild, n (%) 29 (16.1) 8 (7.8) .032 Moderate, n (%) 77 (42.8) 38 (36.9) Severe, n (%) 74 (41.1) 57 (55.3) Modified Sartorius, median (IQR) 25.5 (17.0-44.0) 40.0 (26.0-59.0) <.001 Missing, n 38 46 Bold indicates significant P value # .05. BMI, Body mass index; DLQI, Dermatology Quality of Life Index; HS, hidradenitis suppurativa; IHS4, International Hidradenitis Suppurativa Scoring System; IQR, interquartile range; NRS, Numerical Rating Scale; SD, standard deviation. patients in Hurley stage III or IHS4 severe category Univariate regression analysis showed no signif- (respectively, P = .028 and P = .001) in the tetracy- icant difference between treatment with tetracycline cline group. No significant difference for MCID pain or clindamycin and rifampicin regarding attainment attainment was found in the clindamycin and rifam- of either HiSCR, MCID NRS Pain, or MCID DLQI: picin group. respectively, odds ratio [OR], 1.39 (95% confidence J AM ACAD DERMATOL van Straalen et al 373 VOLUME 85, NUMBER 2 Table II. Response to treatment after 12 weeks Clindamycin and rifampicin Outcomes Tetracyclines (n = 180) P value* (n = 103) P value* P valuey Patient-reported outcomes DLQI, mean (SD) 10.2 (8.2) <.001 9.8 (7.6) <.001 Missing, n 7 3 DLQI MCID achieved, n (%) 58 (36.3) 44 (47.3) .084 Missing, n 20 10 NRS Pain, median (IQR) 4.0 (1.5-7.0) <.001 3 (0.0-5.5) <.001 Missing, n 4 3 NRS Pain MCID achieved 58 (59.8) 51 (63.8) .643 Missing, n 83 23 NRS Pruritus, median (IQR) 1.0 (0.0-5.0) <.001 1.0 (0.0-5.0) <.001 Missing, n 12 8 Physician scores Inflammatory nodule count, 2.0 (0.0-4.0) <.001 2.0 (0.0-4.0) <.001 median (IQR) Abscess count, median (IQR) 0.0 (0.0-1.0) <.001 0.0 (0.0-1.0) .001 Draining sinus tract count, 0.0 (0.0-2.0) <.001 1.0 (0.0-2.0) <.001 median (IQR) IHS4, median (IQR) 5.0 (2.0-12.0) <.001 6.0 (1.0-17.0) <.001 Mild, n (%) 58 (32.2) 34 (33.0) Moderate, n (%) 70 (38.9) 29 (28.2) Severe, n (%) 52 (28.9) 40 (38.8) Modified Sartorius, median 17.0 (10.0-35.0) <.001 25.0 (13.0-44.0) <.001 (IQR) Missing, n 41 45 HiSCR achieved 55 (40.1) 40 (48.2) .263 Missing because of base- 43 20 line count \3, n Discontinuation and side effects Discontinuation 19 (10.7) 16 (15.8) .260 Missing, n 3 2 Gastrointestinal adverse ef- 24 (16.4) 10 (11.8) .346 fects not leading to discontinuation Missing 34 18 Bold indicates significant P values. DLQI, Dermatology Quality of Life Index; HiSCR, Hidradenitis Suppurativa Clinical Response; IHS4, International Hidradenitis Suppurativa Scoring System; IQR, interquartile range; MCID, minimal clinically important difference; NRS, numerical rating scale; SD, standard deviation. *Compared with baseline scores. y Comparison of tetracycline and clindamycin plus rifampicin groups. interval (CI), 0.80-2.40; P = .243); OR, 1.58 (95% CI, 1.15 (95% CI, 1.02-1.30; P = .023) and OR, 1.11 (95% 0.94-2.65; P = .085); and OR, 1.18 (95% CI, 0.64-2.18; CI, 1.01-1.23; P = .034); see Supplemental Tables I P = .590); see Table III. HiSCR attainment was and II. not associated with specific patient characteristics, Gastrointestinal adverse effects, not leading to baseline PROMs, or physician scores for either treatment discontinuation, were reported by 16.4% tetracycline or clindamycin and rifampicin of patients in the tetracycline group compared with treatment (Supplemental Tables I and II; available 11.8% of patients in the combination treatment via Mendeley at https://doi.org/10.17632/xkz8rfy group (P = .346). The percentage of participants vdp.1). Baseline inflammatory nodule count discontinuing either tetracycline treatment (10.7%) was significantly associated with MCID NRS or clindamycin and rifampicin treatment (15.8%) Pain attainment in both the tetracycline and because of effects did not differ significantly the combination treatment group: respectively, OR, (P = .260). 374 van Straalen et al J AM ACAD DERMATOL AUGUST 2021 Fig 1. Response after 12 weeks of treatment. A, DLQI. B, IHS4. C, NRS Pain. D, NRS Pruritus. DLQI, Dermatology Quality of Life Index; IHS4, International Hidradenitis Suppurativa Scoring System; NRS, Numerical Rating Scale. *P \ .05, **P \ .01, ***P \ .001. Table III. Response to treatment per disease severity category Hurley Hurley Hurley IHS4 IHS4 IHS4 stage I stage II stage III P value mild moderate severe P value Tetracyclines, n 54* 90* 35* 29 77 74 HiSCR achieved, n (%) 15 (39.5) 30 (41.7) 10 (37.0) .920 5 (41.7) 20 (34.5) 30 (44.8) .495 Missing, n 16 18 8 17 19 7 MCID DLQI achieved, n (%) 20 (41.7) 28 (35.4) 10 (31.3) .629 9 (31.0) 25 (32.5) 24 (34.3) .901 Missing, n 6 11 3 6 10 4 MCID Pain achieved, n (%) 13 (41.9) 29 (64.4) 16 (76.2) .028 3 (23.1) 19 (51.4) 36 (76.6) .001 Missing, n 23 45 14 16 40 27 Clindamycin plus rifampicin, n 14 58 31 8 38 57 HiSCR achieved, n (%) 3 (37.5) 24 (51.1) 13 (46.4) .807 1 (25.0) 12 (48.0) 27 (50.0) .796 Missing, n 6 11 3 4 13 3 MCID DLQI achieved, n (%) 6 (54.5) 25 (49.0) 13 (41.9) .763 2 (33.3) 16 (47.1) 26 (49.1) .843 Missing, n 3 7 0 2 4 4 MCID Pain achieved, n (%) 5 (62.5) 28 (62.2) 18 (66.7) .941 2 (40.0) 17 (58.6) 32 (69.6) .357 Missing, n 6 13 4 3 9 11 Bold indicates significant P values. DLQI, Dermatology Quality of Life Index; HiSCR, Hidradenitis Suppurativa Clinical Response; IHS4, International Hidradenitis Suppurativa Scoring System; MCID, minimal clinically important difference. *Hurley stage missing for 1 patient on tetracyclines. No significant associations were found for BMI, association was found for treatment with clindamy- age, smoking status, discontinuation of treatment, or cin and rifampicin. gastrointestinal adverse effects for either tetracycline or combination treatment, (data not shown). Women DISCUSSION more often reported gastrointestinal adverse effects This multicenter, prospective study shows signif- compared with men when treated with tetracyclines: icant reduction in IHS4, pain, and DLQI scores after OR, 2.81 (95% CI, 1.04-7.56; P = .041). No such 12 weeks of treatment with both tetracyclines J AM ACAD DERMATOL van Straalen et al 375 VOLUME 85, NUMBER 2 Table IV. Regression analysis of validated outcomes HiSCR MCID DLQI MCID pain n OR (95% CI) P value n OR (95% CI) P value n OR (95% CI) P value Antibiotic treatment 220 1.39 (0.80-2.40) .243 253 1.58 (0.94-2.65) .085 177 1.18 (0.64-2.18) .590 Patient characteristics Sex* 220 1.03 (0.60-1.77) .910 253 0.98 (0.59-1.62) .928 177 0.97 (0.52-1.79) .915 Age 219 1.02 (1.00-1.04) .051 252 1.00 (0.99-1.03) .395 177 1.03 (1.00-1.05) .042 Age at onset 218 1.02 (0.99-1.05) .126 250 1.00 (0.98-1.03) .855 176 1.03 (1.00-1.07) .051 Disease duration 217 1.02 (0.99-1.05) .291 249 1.01 (0.99-1.04) .257 176 1.00 (0.98-1.03) .782 BMI 215 0.99 (0.95-1.04) .786 247 0.96 (0.96-1.04) .799 173 1.00 (0.94-1.05) .858 Smoking status* 218 1.35 (0.78-2.36) .286 250 1.34 (0.80-2.27) .271 174 2.03 (1.09-3.80) .026 Family history of HS* 208 1.02 (0.57-1.81) .955 238 1.07 (0.62-1.83) .820 165 1.15 (0.60-2.22) .673 Previous surgical treatment* 219 1.14 (0.66-1.96) .644 251 1.21 (0.72-2.02) .468 175 1.63 (0.86-3.09) .138 Patient-reported outcome measures at baseline DLQI 211 1.04 (1.00-1.07) .053 251 1.11 (1.07-1.16) \.001 170 1.02 (0.98-1.07) .305 NRS Pain 216 1.03 (0.93-1.14) .601 250 1.06 (0.97-1.17) .215 176 1.01 (0.88-1.16) .867 NRS Pruritus 208 1.07 (0.98-1.16) .131 240 1.11 (1.03-1.20) .009 169 1.07 (0.97-1.18) .154 Physician scores at baseline Inflammatory nodule count 220 1.06 (1.00-1.12) .044 253 1.03 (0.98-1.08) .299 177 1.13 (1.05-1.22) .002 Abscess count 220 0.96 (0.87-1.07) .473 253 1.06 (0.96-1.17) .271 177 1.18 (1.02-1.37) .026 Draining sinus tract count 220 0.96 (0.87-1.04) .340 253 0.92 (0.84-1.00) .054 177 1.06 (0.94-1.19) .328 Presence of sinus tracts 220 0.90 (0.52-1.54) .690 253 0.78 (0.47-1.31) .352 177 1.36 (0.73-2.54) .332 Hurley stage Hurley stage I Reference Reference Reference Hurley stage II 220 1.22 (0.71-2.08) .475 252 1.03 (0.62-1.70) .922 177 1.16 (0.63-2.13) .626 Hurley stage III 220 0.93 (0.50-1.72) .814 252 0.80 (0.44-1.44) .459 177 1.75 (0.86-3.57) .125 IHS4 220 1.00 (0.98-1.01) .677 253 0.99 (0.98-1.01) .331 177 1.03 (1.01-1.05) .017 Mild Reference Reference Reference Moderate 220 0.74 (0.42-1.28) .281 253 1.02 (0.61-1.70) .941 177 0.63 (0.34-1.17) .139 Severe 220 1.43 (0.83-2.45) .194 253 1.03 (0.62-1.70) .916 177 2.85 (1.52-5.34) .001 Modified Sartorius 161 0.99 (0.98-1.00) .100 183 0.99 (0.98-1.00) .054 122 1.00 (0.98-1.01) .603 Bold indicates significant P values. BMI, Body mass index; CI, confidence interval; DLQI, Dermatology Quality of Life Index; HiSCR, Hidradenitis Suppurativa Clinical Response; HS, hidradenitis suppurativa; IHS4, International Hidradenitis Suppurativa Scoring System; MCID, minimal clinically important difference; NRS, Numerical Rating Scale; OR, odds ratio. *Reference categories: female, nonsmokers, no family history, no previous surgical treatment. treatment and clindamycin and rifampicin combina- inflammatory lesions in patients with moderate to tion therapy. The use of tetracyclines in HS is derived severe acne vulgaris.29 Because the same mecha- from a small randomized controlled trial showing nisms of the effect of tetracyclines (antibacterial and equal efficacy of oral tetracyclines and topical anti-inflammatory) are assumed in acne and HS, a clindamycin in patients with mild to moderate HS similar dose-response effect in HS is conceivable. using a nonvalidated outcome.12 More recently, Current guidelines advise the use of clindamycin HiSCR response was assessed in a retrospective 300 mg twice daily and rifampicin 300 mg twice daily case series of patients treated with systemic doxycy- or 600 mg once daily for a duration of 10 to 12 weeks cline 100 mg twice daily, with 60% of patients for moderate to severe HS.30 Treatment with clinda- achieving HiSCR after 12 weeks of treatment.14 This mycin and rifampicin has been previously assessed is markedly higher than the 40.1% HiSCR attainment in 1 prospective and several smaller retrospective found in the tetracycline group in our study. trials with differing types of administration (intrave- However, no baseline abscess and nodule count nous or oral), dosage (eg, 4 times 125 mg of was reported by Vural et al,14 which is known to clindamycin or 300 mg twice daily), and timing of influence HiSCR attainment, and the included pop- the primary endpoint (ranging from 8 to ulation may not be comparable to that of our study. 12 weeks).13-22 Overall, HiSCR was achieved by Nonetheless, doxycycline has previously been 33.3% to 56.7% of patients treated with clindamycin shown to have a dose-response effect in reducing plus rifampicin. Even though some of these studies 376 van Straalen et al J AM ACAD DERMATOL AUGUST 2021 report excluding patients lost to follow-up from the more treatment discontinuation was seen in the efficacy analysis, potentially inflating response rates, clindamycin and rifampicin group. our study found HiSCR attainment in the higher end In the current HS treatment guidelines and of this range (48.2%). Severe HS might represent a consensus statements, tetracyclines are considered specific subtype.31 Contradictory results regarding the first-line treatment for mild to moderate HS, an association between disease severity and clinical whereas the combination of clindamycin and rifam- response have been reported. Caposiena Caro et al15 picin is favored for moderate to severe HS.4-11 found that HiSCR attainment on clindamycin plus Interestingly, our study showed no significant differ- rifampicin therapy was significantly more common ences between the 2 antibiotic strategies for the in patients with mild and moderate disease, validated outcomes HiSCR, MCID Pain, or MCID measured with both the Hurley stage and IHS4 DLQI, even in patients with moderate to severe HS. (respectively, P \ .001 and P = .02).15 Our results These results suggest that tetracyclines could be show no association between disease severity and considered as the first-line treatment in patients HiSCR attainment, similar to the results from with moderate to severe disease. This could prove Dessinioti et al.18 especially valuable in countries with endemic tuber- Current guidelines advise the use of a combina- culosis, where rifampicin is preferably reserved for tion of clindamycin and rifampicin.4-11 However, the treatment of tuberculosis or in patients with rifampicin has been shown to dramatically reduce relative contraindications because of potential drug plasma concentrations of clindamycin, making a interaction, such as, for example, oral contracep- meaningful contribution of clindamycin to either tives.36 Moreover, guidelines advise that biologics bacterial resistance or reduction of inflammation in (adalimumab) can be initiated after failure of con- this combination unlikely.32 A retrospective study ventional treatment, often clindamycin and rifam- found similar rates of HiSCR attainment between picin combination therapy.4-11 However, because treatment with clindamycin and rifampicin our study suggests that this treatment is similar to compared with clindamycin alone after 8 weeks of treatment with tetracyclines, failure of tetracycline treatment: 56.7% versus 63.3% (P = .598), excluding treatment could be a sufficient indication for biologic patients who were lost to follow-up from the efficacy eligibility. Nonetheless, a head-to-head randomized, analysis.19 blinded, controlled trial comparing tetracycline treat- Even though there are validated MCID values for ment with clindamycin and rifampicin combination both the NRS Pain and the DLQI, only 1 registry therapy is needed to increase the evidence to a level study has published MCID results to date, with where firmer conclusions can be drawn. these lacking in the large randomized controlled A limitation of this study is inherent to the trials.26-28,33 Achieving the MCID, defined as the calculation of the HiSCR. In accordance with its smallest change that a patient would identify as original publication, HiSCR can be calculated only in clinically meaningful, could be more informative and patients with 3 or more inflammatory lesions (ab- clinically relevant than the mean reductions in DLQI scesses and nodules) at baseline.26 Overall, respec- or pain scores frequently reported in HS clinical tively, 23.9% and 19.4% of patients had to be trials. Overall, in our study, approximately 60% of excluded from the HiSCR analysis for the tetracycline patients attained a clinically meaningful difference in and combination therapy group based on low NRS Pain, and between 36% and 47% achieved a abscess and nodule counts at baseline. However, meaningful improvement in DLQI score, with no this is not representative of real life and hampers the significant differences between treatment groups. extrapolation of HiSCR results to routine clinical Gastrointestinal adverse effects are a main settings. This issue could potentially be overcome by concern because they often lead to discontinuation a dichotomous version of the IHS4 score. of treatment.34,35 The frequency of gastrointestinal In conclusion, this study shows no significant adverse effects in our study (11.8%) was lightly lower difference between patients treated with tetracy- than those previously reported in a large retrospec- clines or with a combination of clindamycin and tive study and the only prospective study on clinda- rifampicin in the validated outcomes HiSCR, IHS4, mycin and rifampicin to date at, respectively, 14% MCID DLQI, and MCID Pain after 12 weeks, regard- and 19.2%.17,18 However, the discontinuation rate less of disease severity. These results might suggest (15.8%) in our study was slightly higher than that that tetracyclines could be considered as the first- seen in these studies, at 11.4% and 11.5% respec- line treatment in patients with moderate to severe tively. Interestingly, more gastrointestinal adverse disease, and failure of tetracyclines may be a effects, not leading to treatment discontinuation, sufficient indication for the initiation of biologic were noted in the tetracycline group, whereas therapy. J AM ACAD DERMATOL van Straalen et al 377 VOLUME 85, NUMBER 2 Conflicts of interest Efthymiou, Marzano, Molina-Leyva, Moltrasio, Potenza, Dr Tzellos has reported relationships with AbbVie, Skroza, Stergianou, and Vilarrasa have no conflicts of UCB, and Sanofi Genzyme. Dr Guillem has received interest to declare. honoraria from AbbVie and Novartis as a consultant and has given nonpaid lectures for AbbVie, Brothier, Cicaplus, REFERENCES Coloplast, Inresa, and Novartis. Dr Giamarellos-Bourboulis 1. Tricarico PM, Boniotto M, Genovese G, et al. An integrated has received honoraria from Abbott CH, Angelini Italy, approach to unravel hidradenitis suppurativa etiopathogene- bioMerieux Inc, InflaRx GmbH, MSD Greece, and sis. 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