ORIGINAL ARTICLES

An open-label study of anakinra for the treatmentof moderate to severe hidradenitis suppurativa

Kieron S. Leslie, DTM&H, FRCP, Shivani V. Tripathi, MD, Tien V. Nguyen, MD, Mariela Pauli, MS,and Michael D. Rosenblum, MD, PhD

San Francisco, California

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Background: Hidradenitis suppurativa (HS) is a chronic inflammatory disorder characterized by sterileabscesses and fistulae predominantly affecting the axillae and groin. Various biologic agents have beenattempted for HS, but there is still no definitive treatment.

Objectives: We sought to evaluate the efficacy, safety, and tolerability of anakinra in the treatment ofmoderate to severe HS.

Methods: Six patients with moderate to severe HS were enrolled in an open-label study with all patientsreceiving active treatment for 8 weeks with an additional 8 weeks of follow-up off therapy.

Results: The 5 patients who completed the 8-week therapy showed a significant mean decrease in theirmodified Sartorius score of 34.8 points. The physician and patient global assessment of overall activityshowed significant reductions between baseline and 8 weeks of therapy: 45.8 points and 35.6 points,respectively. The Dermatology Life Quality Index showed a significant reduction after 8 weeks of treatmentwith anakinra. Functional T-cell analysis revealed that patients had increased percentages of CD31 T cellsin lesional skin compared with nonlesional skin before therapy.

Limitations: The limited number of patients and lack of control group are limitations.

Conclusions: Anakinra demonstrated decreased HS disease activity by both objective and subjectivemeasures. ( J Am Acad Dermatol 2014;70:243-51.)

Key words: anakinra; inflammation; interleukin-1; hidradenitis suppurativa; T cells; treatment.

Abbreviations used:

CI: confidence intervalDLQI: Dermatology Life Quality IndexHS: hidradenitis suppurativaIL: interleukinTh: helper T cellTNF: tumor necrosis factorVAS: visual analog scale

Hidradenitis suppurativa (HS) is a chronicinflammatory disorder characterized bysterile abscesses and fistulae predominantly

affecting the axillae and groin. It causes significantmorbidity from pain and drainage and is associatedwith significantly compromised quality of life.1 Thereare few epidemiologic data but prevalence rates havebeen reported from 0.05% in North America2 to 4% inDenmark.3

There is increasing evidence that the immunesystem plays a crucial role in the development andpersistence of HS. Overproduction of cytokines

the Department of Dermatology, University of California, San

ancisco.

ish Orphan Biovitrum AB provided study drug but all other

nding was from internal research funds.

osure: Dr Leslie has served as a consultant and is on the

eaker’s bureau for Novartis Pharmaceuticals. Drs Tripathi,

guyen, and Rosenblum, and Ms Pauli have no conflicts of

terest to declare.

pted for publication September 19, 2013.

associated with innate immunity (including interleu-kin [IL]-1b and tumor necrosis factor [TNF]-alfa) have

Reprint requests: Kieron S. Leslie, DTM&H, FRCP, Department of

Dermatology, University of California, San Francisco, 1701

Divisadero St, San Francisco, CA 94115. E-mail: lesliek@derm.

ucsf.edu.

Published online December 5, 2013.

0190-9622/$36.00

� 2013 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2013.09.044

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been observed from HS skin cultures.4 In addition,expression of cytokines that directly modulate theadaptive immune system (including IL-10, IL-12,IL-17, and IL-23) are observed in HS skin.4,5

Although these studies have implicated variouscytokines and inflammatory pathways in initiatingand maintaining inflammation in patients with

CAPSULE SUMMARY

d Effects of anakinra therapy onhidradenitis suppurativa were evaluatedin this open-label clinical trial.

d Anakinra resulted in significantreductions in the modified Sartoriusscore and improvement in quality of life.

d Anakinra has potential as a treatment forhidradenitis suppurativa.

HS, the dominant cytokine(s)that drive this disease haveyet to be determined.Understanding the dominantcytokines that CD41 helperT cells (Th) produce in theskin is critical in attemptsto better define the patho-genesis of HS. Th differenti-ation (ie, Th1, Th2, Th17)dictates the type of cutane-ous inflammation and pro-vides a rationale approachfor therapies that target

specific cytokines and immune pathways.

Therapy with biologic agents that inhibit specificcytokines have been increasingly attempted forpatients with severe and refractory disease.TNF-alfa blockade with infliximab has been reportedin a randomized double-blind crossover study todecrease the severity score of HS in the majority ofpatients as compared with placebo.6 Initialreports suggested etanercept as an useful agent7,8

although subsequent trials showed little to noefficacy.9,10 More recently, a large multicenterstudy11 demonstrated that after 16 weeks of therapy,adalimumab achieves a clinical response in 17.6% ofpatients as compared with 9.6% in patients dosedevery over week and 3.9% in the placebo group.Clinical improvements in patients treated withthe p40 inhibitor, ustekinumab, have also beenreported.12-14 Despite these encouraging results,highly efficacious therapy for patients with HS andsevere disease has yet to be elucidated.

We recently reported a marked reduction indisease activity in a patient with HS and concom-itant pyoderma gangrenosum who was treatedwith anakinra, an IL-1 receptor antagonist,15 afterfailing multiple other therapies. Both HS andthe autoinflammatory syndromes are characterizedby recurrent noninfectious inflammatory episodeswithout autoantibodies or antigen-specific Tcells.16 Indeed, most autoinflammatory syndromeshave been shown to be remarkably responsiveto IL-1 blockade such as cryopyrin-associatedperiodic syndrome,17 TNF receptoreassociatedperiodic syndrome,18 and familial Mediterraneanfever.19

The objective of this study was to evaluate theefficacy, safety, and tolerability of anakinra in thetreatment of moderate to severe HS. The study’sdesign was open-label, with all patients receivingactive treatment for 8 weeks with an additional8 weeks of follow-up off therapy. In addition tomeasuring clinical disease, we functionally defined

skin-infiltrating T cells andT-cell cytokine productionin these patients to deter-mine the nature of theadaptive immune responsein HS and the influence ofIL-1 blockade.

METHODSStudy patients

This was an investigator-initiated clinical trial thatwas approved by the localinstitutional review board

and was registered with ClinicalTrials.gov(NCT01516749). Patients aged 18 years or olderwith moderate to severe HS were recruited from anacademic dermatology practice in San Francisco, CA.Informed consent was obtained before study entry.Patients were included if they had minimummodified Sartorius score20 of 25 or greater and activedisease in at least 2 anatomic regions. Patients wereallowed oral or topical antibiotic therapy for their HSas long as they were receiving a stable dose for atleast 4 weeks before baseline visit and were willingto remain on a stable dose for the full duration of thestudy. Exclusion criteria included concurrent activeinfections such as HIV, hepatitis B, hepatitis C, andtuberculosis; history of malignancy; and use of otherimmunosuppressive therapies within 12 weeks ofthe baseline visit.

Study designThis was an open-label pilot study, where all

patients received active therapy of anakinra(Kineret) for 8 weeks, followed by an additional8 weeks of follow-up off therapy.

Treatment and assessmentsAll study patients were treated with self-

administered daily anakinra (100 mg) via subcuta-neous injection. At each study visit, the samephysician examined patients, and the modifiedSartorius score was calculated. In addition, thephysician assessed disease activity on visualanalog scale (VAS) ranging from 0 mm (absent) to100 mm (worst imaginable) as a physicians globalassessment. Similarly, the patients reported overall

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(global) disease activity of HS, in addition to focusedsubjective measures of pain, drainage, and odor withappropriate VAS. Patient were asked, ‘‘What is theoverall activity (pain, discharge, odor, and presenceof new lesions) of hidradenitis at this visit?’’ with ascale of 0 = no activity to maximal activity = 100. TheDermatology Life Quality Index (DLQI) wascompleted at every visit in addition to the ShortForm (36) Health Survey; these questionnaires wereboth self-administered. Clinical photographs weretaken of all affected body sites.

Skin digestion and flow cytometrySkin biopsies of lesional and unaffected skin were

performed at the baseline visit and after completing8 weeks of therapy. Skin was minced finely withdissection scissors and digested overnight in bufferconsisting of 0.8 mg/mL collagenase type 4(Worthington 4188, Biochemical Corp, Lakewood,NJ), 0.02 mg/mL deoxyribonuclease (Sigma DN25-1G, St Louis, MO), 10% fetal bovine serum, 1%hydroxyethyl piperazineethanesulfonic acid, and 1%penicillin/streptavidin in Roswell Park MemorialInstitute medium. For detection of intracellular cyto-kine production, punch biopsy specimens were stim-ulated with 1 �g/mL lipopolysaccharide (Sigma) for 6hours, 70 ng/mL of phorbol myristate acetate, and 700ng/mL of ionomycin in the presence of BrefeldinA (Sigma) for 4 to 5 hours. Data were acquired by anLSRFortessa (BD Biosciences, San Jose, CA) and ana-lyzed using FlowJo software (Tree Star, Ashland, OR).

SafetyVital signs and physical examination were

undertaken at every visit. The investigators assessedadverse events throughout the study by directpatient query, observation by study personnel, andspontaneous patient reporting. Blood chemistrywas assessed at baseline, week 4 (on therapy), andweek 12 (off therapy). No Formal adverse eventquestionnaire was used in this study.

Study end pointsThe primary end point measure was the

proportion of patients who had a significantreduction in modified Sartorius score at the end ofthe treatment period, week 8 compared with week 0.Secondary end points included VAS scores for thephysician’s global assessment and subjective patientratings of overall disease activity, pain discharge,and odor. Other measures included quality-of-lifeevaluation with DLQI and SF36. Acute phaseresponse, with C-reactive protein levels, was alsoevaluated throughout the trial.

Statistical analysisDescriptive statistics (SD, mean, minimum, and

maximum) by visit were computed for the outcomevariables. Parametric tests (paired t test) were usedto analyze efficacy of the treatment. Significancewas accepted at P less than .05. Analysis softwarewas Stata, Version 12.0 (StataCorp LP, CollegeStation, TX).

RESULTSEleven patients were screened for this study, and 6

fit the criteria and were enrolled. Baseline character-istics are depicted in Table I. Five patients completedthe treatment phase of the studywith anakinra; oneofthese patients was subsequently lost to follow-upbecause of difficult socioeconomic factors prevent-ing attendance at follow-up study visits. The sixthpatient received treatment for 2weekswith anakinra,at which point, he had shown improvement in allstudy outcomes (modified Sartorius score, physicianglobal assessment, and all patient subjective mea-sures). He did not report any treatment side effects.Subsequent to this visit he was lost to follow-up. Theonly side effect reported by patients globally was theinjection site reaction that subsided for all patients byweek 2 of treatment. No adverse events were seen inany of the study participants in either the treatmentphase or follow-up phase of the study.

The 5 patients who completed the 8-week therapyshowed a significant mean decrease in theirmodified Sartorius score of 34.8 points (P = .024,95% confidence interval [CI] 7.56-62.05). The meanvalue for the modified Sartorius scores showedprogressive improvement during the treatmentperiod, and rebound during the follow-up post-treatment period (Fig 1, A and Fig 2).

The physician global assessment and patientglobal assessment of overall activity using VAS(maximum score 100) showed significant reductionsin mean values between baseline and 8 weeks oftherapy: 45.8 points (P = .006, 95% CI 22.1-69.5) and35.6 points (P = .019, 95% CI 9.83-61.4), respectively(Fig 1, B). Rebound in these values was appreciatedin the follow-up phase of the study. Other subjectivepatient assessments that showed a significant changefrom baseline to end of treatment phase includedpain, which showed a mean reduction of 35.2(P = .033, 95% CI 4.66-65.74) and discharge severity(mean change 27.4, P = .019, 95% CI 0.07-54.11).Odor severity mean showed a 30.0-point reductionalthough was not significant for the 5 patients(P = .079, 95% CI e5.53 to 65.53) (Fig 1, C ).

The DLQI, measuring the extent to which diseaseaffects quality of life with higher score (maximum 30)reflecting a larger negative effect of disease onquality

Table I. Hidradenitis suppurativa: baseline demographic and clinical characteristics of patients

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6

Age, y 39 41 41 37 27 36

Sex Female Male Female Female Female Male

Race Black Hispanic White White Black Hispanic

Weight, kg 85 173.7 116.95 92.75 87.1 134.7

BMI* 28.7 53 38.6 30.6 29.8 41.4

Smoker No No No No Yes No

Family history ofhidradenitissuppurativa

Father Mother Sister, aunt Father Aunt Mother

Prior antibiotic Minocycline,doxycycline,clindamycin

Doxycycline,clindamycin

Doxycycline,tetracycline,clindamycin

Doxycycline,minocycline,tetracycline,clindamycin

Doxycycline,tetracycline

Doxycycline

Prior surgery Groin (r, l) Axilla (r, l), groin (r, l),scrotum, buttock (r, l)

Axilla (r, l),groin (r)

Axilla (r, l) No Axilla (r, l),thigh (r)

Prior systemicor biologic

Methotrexate Prednisone Prednisone,isotretinoin

Prednisone Prednisone Prednisone

Initial modifiedSartorius scorey

88 94 59 42 93 95

Initial C-reactiveprotein, mg/L

31.5 56.9 2.6 9.5 57.2 25.8

Initial DLQI score 26 9 27 15 28 11

BMI, Body mass index; DLQI, Dermatology Life Quality Index; l, left; r, right.

*Underweight\18.5, normal weight 18.5-24.9, overweight 25-29.9, obesity $ 30.ySee Sartorius et al20 for modified Sartorius scoring.

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Fig 2. Hidradenitis suppurativa, patient 1: left axilla atweeks 0 (baseline), 8 (on treatment), and 16 (off treatment).

Fig 1. Hidradenitis suppurativa.A, Modified Sartorius scorefor patients 1 to 6 at weeks 0 (premedication); 2, 4, and 8(treatment period); and 12 and 16 (follow-up). B, Meanphysician versus patient global assessments of diseaseactivity; visual analog scale (VAS ) (0-100). C, Mean patientVAS scores for pain, discharge, and odor. D, Mean Derma-tology Life Quality Index (DLQI ) for patients at each visit.

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of life, showed a significant reduction in mean scoresafter 8 weeks of treatment with anakinra, a meandecreaseof 8.4 points (P= .046, 95%CI 0.23-16.57). Atfollow-up DLQI scores worsened and reflected thepretreatment scores (Fig 1, D).

Baseline C-reactive protein levels varied tremen-dously from 2.6 to 57.2 mg/L (normal \3.1 mg/L)

Fig 3. A, Immunoflow cytometry on nonlesional and lesional skin from patients withhidradenitis suppurativa (HS) before and after treatment (tx) with anakinra. Percentages ofCD3-, interleukin (IL)-17-, or interferon-g (IFNg)-secreting cells in nonlesional and lesional skinof patients with HS before tx with anakinra. B, Flow cytometry of patient 1 before and after txwith anakinra. Plots are pregated on viable CD31CD41 cells.

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with a mean of 30.6 (SD 23.03) (n = 6). C-reactiveprotein levels showed a mean reduction of16.7 points from baseline to end of treatment phase.This change was not significant (P = .076, 95% CIe2.784 to 36.14) although suggests a trend forreduction in acute phase response.

Functional T-cell analysis of the patients revealedthat all patients had increased percentages of CD31 Tcells in lesional skin compared with nonlesional skinbefore therapy (Fig 3, A). All patients had skewingaway from Th17 differentiation in lesional skin com-pared with nonlesional skin (ie, T cells from HS skinproduced less IL-17 comparedwith clinically normal-appearing skin harvested from the same patient) (Fig3, A, bottom left). Interestingly, the patient with the

best clinical response (patient 1) had a predominantTh1 skew in lesional skin comparedwith nonlesionalskin, with marked increased in interferon-g produc-tion from T cells infiltrating diseased skin in thispatient (Fig 3,A, bottom right). In addition, treatmentwith anakinra completely reversed the Th1 skewobserved in this patient (Fig 3, B).

DISCUSSIONTo our knowledge, this clinical trial is the first to

prospectively address the efficacy and safety ofanakinra, an IL-1 receptor antagonist for thetreatment of moderate to severe HS. Previous casereports have had conflicting results with both areduction in disease activity15 or no response to

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IL-1 inhibition.21 In this open-label study, anakinraappeared to be well tolerated and demonstrated astatistically significant decrease in disease activity ofHS by both objective and subjective measures.The 8-week observation period enabled us toidentify potential rebound. Limitations of this studyinclude the lack of a control group and a smallnumber of participants.

The modified Sartorius score is a validatedinstrument that assesses disease activity in HS andhas been used in other therapeutic studies.11 In the 5patients who completed the treatment phase of thestudy, a significant and clinically meaningfulreduction of score by a mean of 34.8 points wasrecorded. This was evident at all time points from 2weeks onward but was maximal at 8 weeks. Ourresults compare favorably with a large blindedrandomized study comparing adalimumab, weeklyversus every other week dosing against placebo,11

which also used the modified Sartorius score as anend point. This study found a median 30-pointreduction in score at 16 weeks of treatment withadalimumab 40 mg weekly versus 16-pointreduction in the every other week group versus7.5-point reduction in the placebo group. Inaddition, we saw a significant rebound in the scoreduring the follow-up phase for the 4 patients whoremained in the study with a mean increase of 52.5points at 16 weeks compared with 8 weeks.

The quality of life in patients with HS is severelyimpacted with considerable pain,22 emotional dis-tress,23 and sexual health.24 The minimal clinicallymeaningful reduction in DLQI score is considered tobe between �6.96 and �4.05.25 Clinical trials usingTNF-alfa-blocking agents have reported reductionsin DLQI scores ranging from �6.911 to no significantchange26,27 with adalimumab, �106 to �9.128 withinfliximab, and variable results with etanercept from�11.6,7 �4,10 to no change.9 Our study showed amean reduction in DLQI score of �8.4 after 8 weeksof therapy (P = .047). This improvement in meanDLQI score is similar to that reported by Kimballet al11 of �6.3 in patients treated with weeklyadalimumab. Again rebound back to baseline scoreswere seen in the DLQI for the 4 remaining patients inour study during the follow-up (observation) phase.

Anakinra was well tolerated in this study with 5of the 6 enrolled patients completing treatment.There were no adverse events. Daily injections arerequired because of its short half-life of 6 hours,which may limit its acceptability as a treatment forpatients. All of our patients reported painfulinjection site reactions, which decreased inseverity after a few weeks of treatment. Injectionsite reactions with anakinra have been commonly

reported.29 Otherwise anakinra has a favorableside-effect profile when compared with otherbiologics. Increased risk of infection30 andneutropenia are the most commonly reported. Noassociation with an increased risk of malignancyhas been reported.31

Clinically, we show that IL-1 blockade isefficacious in treating HS. On a cellular andmolecular level, we show that HS is associated withskewing away from Th17 differentiation, and thepatient with the best response to anakinra haddisease that was dominated by Th1 cytokineproduction. IL-1a and IL-1b are pleiotropiccytokines with multiple effects on the immunesystem.32 IL-1a is produced by many cell types,including endothelial cells and keratinocytes, and isthought to act locally. In contrast, expression of IL-1bappears to be relatively restricted to monocytes andmacrophages and can act systemically. Thebiologicalactivities of IL-1a and IL-1b are mediated by bindingto IL-1 receptor type I, which is expressed on widevariety of cell types.33 The IL-1 pathway is one of themost potent proinflammatory pathways and IL-1-mediated inflammation has been shown to induceand enhance both Th17- and Th1-type T-cell re-sponses.34 It has been proposed that IL-1 signalingmay promote Th1 immunity through increasedsurvival and expansion of interferon-g-producingT cells, possibly through augmentation of thenuclear factor kappa B pathway.34-36 Here, weshow that HS is not associated with Th17-typeinflammation, suggesting that IL-1 does not contrib-ute to HS pathogenesis by augmenting Th17responses. Instead, we speculate that in the settingof diminished Th17 disease, the dominant role of IL-1is to increase the survival and expansion of Th1. Thisis supported by the observation that blocking IL-1signaling in a patient with HS and predominant Th1disease led to a complete reversal of Th1 cytokineproduction and near complete disease resolution.Thus, we speculate that biologic therapy that prefer-entially inhibits Th1 differentiation and/or Th1 cyto-kine production will most likely be more efficaciousin treating HS than those that target Th2 or Th17cytokines. Of course, a larger study with morepatients is needed to definitively test this.

In conclusion, our study demonstrated that dailyanakinra is an effective treatment in patients with HSwith significant reduction in subjective andobjective measurements of disease activity.However HS disease activity rebounded rapidlywhen off therapy. The current cost of anakinraas listed by Epocrates (https://online.epocrates.com/home) is $22,516 (annual cost) compared withweekly adalimumab, which costs $50,700 (annual

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cost). Future research should address whether theseresults are replicated in a larger randomizedblinded placebo-controlled study. Ultimately, aclinical trial comparing IL-1 inhibition with thecurrent gold standard of biological therapy of TNFblockers is warranted in moderate to severe HS.

The authors are very grateful to Charles McCulloch,PhD, Department of Epidemiology, University ofCalifornia, San Francisco, for his advice regarding statisticalanalysis, and to the patients for their participation in thisstudy.

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