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Clinical trial

A prospective open-label clinical trial of adalimumab for the


treatment of hidradenitis suppurativa
Masahiro Amano, MD, PhD, Annika Grant, RN, MBA, and Francisco A. Kerdel, BSc, MBBS

Department of Dermatology and Summary


Cutaneous Surgery, University of Miami Objective To evaluate the safety and efficacy of adalimumab for the management of
School of Medicine, Miami, FL, USA
hidradenitis suppurativa (HS).
Methods In a prospective open-label phase II study, adalimumab was administered
Correspondence
Francisco A. Kerdel, BSc, MBBS subcutaneously in a dose of 160 mg induction regimen at week 0, followed by 80 mg at
Director of Dermatology Inpatient week 1, and 40 mg at alternate weeks for 12 weeks in 10 patients. The patients were
Service and Chief of Staff followed up to 13 weeks and their disease activity was assessed using the HS Severity
University of Miami Hospital
Index (HSSI) as well as with the numbers of daily dressing changes, the Visual Analogue
1400 NW 12th Avenue, Suite 4
Scale (VAS), Dermatologic Life Quality Index (DLQI), and Physicians Global Assessment
Miami
FL 33136 of disease severity (PGA).
USA Results Ten patients were enrolled in this study. Of these, six patients completed the
E-mail: dr.Kerdel@fadcenter.com 12-week treatment period. A 50% decrease of HSSI score was not found in any of the
patients at week 2, 4, 8, and 12. None of the 10 patients was classified as a responder at
week 12 compared with baseline. Statistically significant difference in HSSI score was
found between baseline and week 8 (P < 0.05) only but no significant differences were
found between baseline and week 2, 4, and 12. Comparison of baseline with week 12 VAS
and DLQI scores failed to show statistically significant improvement. Adalimumab was well
tolerated and there were no serious adverse events reported.
Conclusions Our study demonstrated statistically clinical improvement is not observed in
the treatment of HS with adalimumab. Future studies using higher doses of adalimumab
are warranted.

effective in the treatment of psoriasis and psoriatic arthri-


Introduction
tis. While speculative, TNF-a potentially may play a cen-
Hidradenitis suppurativa (HS) is a condition characterized tral role in the pathologic inflammatory response
by the formation of multiple abscesses and sinus tracts in associated with HS. In fact, diseases such as Crohns dis-
apocrine gland-bearing areas.1 The etiology and patho- ease and pyoderma gangrenous which are currently trea-
genesis of HS are unknown, however, apocrine glands ted with anti-TNF agents have been associated with HS.
play a central role in the disease. Interestingly, apocrine Moreover, a number of case reports document improve-
gland involvement histologically is seen in only a minority ment in the symptoms of HS with anti-TNF therapy using
of cases, with the most characteristic finding being follicu- infliximab.38 Similarly, etanercept and adalimumab have
lar occlusion.2 Together with acne, dissecting cellulitis of also been shown to be efficacious in HS.9,10
the scalp and pilonidal cyst, HS is believed to be a follicu- This report relates to a study to assess the efficacy and
lar occlusion disease. safety of adalimumab in subjects with moderate to severe
Treatment is notoriously difficult. In severe involve- HS. The dose employed was that used for Crohns dis-
ment, wide local excision and healing by secondary inten- ease, namely 160 mg at week 0, 80 mg at week 1, and
sion is up to now, the treatment of choice. Surgery 40 mg every other week. Efficacy was evaluated using the
however, when undertaken, is often disfiguring and not Hidradenitis Suppurativa Severity Index (HSSI). Other
always curative.1 TNF-a is known to induce proinflam- parameters evaluated included individual components of
matory cytokines and may play an important role in a the HSSI (pain/drainage) as well as Dermatology Life
number of separate inflammatory disorders. In Dermatol- Quality Index (DLQI) and Physicians Global Assessment
950 ogy, TNF-a inhibition has already been shown to be (PGA).

International Journal of Dermatology 2010, 49, 950955 2010 The International Society of Dermatology
Amano, Grant, and Kerdel Adalimumab for treating hidradenitis suppurativa Clinical trial 951

after the last injection. (2) Known allergy against ada-


Patients and methods
limumab. (3) Use of other systemic anti-inflammatory
A prospective, open-label, phase II study was conducted medication except NSAID and low-dose systemic steroids.
during the period FebruaryNovember 2007. Twelve (4) Documentation of seropositive for human immunode-
patients with HS were screened of which 10 patients were ficiency virus (HIV). (5) A positive test for hepatitis B sur-
enrolled in the study. Two patients screened failed because face antigen or hepatitis C. (6) Have a known history of
of a positive Purified Protein Derivative (PPD) and on serious infections in the previous 3 months, or (7) have
Methicillin Resistant Staphylococcus Aureus (MRSA) cul- or have had an opportunistic infection within 6 months
ture result from a wound. The protocol for the study was prior to screening. (8) Have a history of lymphoprolifera-
approved by a local institutional review board (Western tive disease, including lymphoma or signs suggestive of
IRB). The protocol was given the number HIDRI2006 and possible lymphoproliferative disease such as lymphade-
registered in clinical trials.gov (NCT: 00827996). nopathy of usual size or location, or splenomegaly. (9)
The diagnosis of HS was made by clinical criteria1,9,10 Any known malignancy or have a history of malignancy
comprising (1) the presence of subcutaneous nodules in within the previous 5 years, with the exception of basal
area of skin rich in apocrine glands and (2) compatible cell or squamous cell carcinoma of the skin that had been
history of recurrent drainage from the affected areas. fully excised with no evidence of recurrence. (10) Have
The inclusion criteria was applied to subjects with current signs or symptoms of severe, progressive or
moderate to severe HS as defined by HSSI 8 (Table 1) uncontrolled renal, hepatic, hematologic, gastrointestinal,
and at least one of the following: (1) HS 1 year duration endocrine, pulmonary, cardiac, neurologic, or cerebral
with multiple ER or doctors visits related to HS, (2) int- disease. (11) Presence of transplanted solid organ. (12)
ralesional triamcinolone injection >5/year, however, none Have a concomitant diagnosis or history of congestive
within 2 weeks of entry, (3) failed systemic retinoids, but heart failure. (13) Have a history of latent or active gran-
not within 3 months of entry, (4) failed at least one prior ulomatous infection, including TB, histoplasmosis, or coc-
course of antibiotic therapy, which must not have been cidiodomycosis, prior to screening. (14) Have had a
administered within 2 weeks of entry to the study nontuberculous mycobacterial infection or opportunistic
(excluding the recommended antibiotic regimen given for infection within 6 months prior to screening.
evidence of active infection immediately before randomi- All patients were administered adalimumab subcutane-
zation), (5) history of surgery (reconstructive), but not ously. The dose of adalimumab employed was 160 mg
within 3 months of entry, (6) gender: male or female, given at week 0, followed by 80 mg at week 1, and
patients >18 years of age, (7) the screening laboratory test 40 mg at alternate weeks. The maintenance regimen of
results had to meet the following criteria: (i) normal 40 mg was continued every other week until week 12.
WBC, (ii) normal absolute neutrophil count (ANC), (iii) At each visit, all patients had a thorough clinical exam-
hemoglobin: >10 mg/dl, (iv) with normal platelet counts, ination by two physicians. The physicians measured the
(v) normal serum urea and creatinine, (vi) SGOT (AST- diameter of all involved areas using the palm of the hand
aspartate aminotransferase): <2 times upper normal limit, to represent approximately 1% of BSA. The other compo-
(vii) SGPT (ALT-alanine aminotransferase): <2 times nents of the HSSI were also assessed, namely; number of
upper normal limit, (viii) normal Alkaline phosphatase, painful erythematous lesions, drainages, and pain. HSSI
and (ix) unremarkable urinalysis. score was assessed both for the baseline visits and the fol-
The exclusion criteria were: (1) women who were preg- low-up visits at week 2, 4, 8, 12, and 13 (Table 1).
nant, nursing, or planning pregnancy within 6 months Apart from HSSI, the patients were asked to complete
the DLQI questionnaire and the physicians rated the
Table 1 Hidradenitis Suppurativa Severity Index (HSSI)
items of the criteria using a PGA scale. The static PGA 7
point scale assesses extent of skin involvement and
Body surface Lesions Drainage (dressing
area (%) (erythematous, changes/working Pain
reports symptoms as cleared (100% improvement), excel-
Index [palm(s)] painful) hours) (VAS) lent (7599% improvement), good (5074% improve-
ment), fair (2549% improvement), slight (124%
0 0 0 0 01 improvement), unchanged (0%), and worse.
1 1 12 12
PPD and Chest X-ray (CXR) were performed during
2 23 23 1 24
3 45 45 >1 57 screening. A complete blood count (CBC) was performed
4 >5 >5 810 on screening and at week 12. Complete clinical chemistry
was also performed at screening.
Composite scoring (019). The primary endpoint was the proportion of subjects
Mild = 07, moderate = 812, Severe 13. responding to study treatment. Response was defined as a

2010 The International Society of Dermatology International Journal of Dermatology 2010, 49, 950955
952 Clinical trial Adalimumab for treating hidradenitis suppurativa Amano, Grant, and Kerdel

decrease of 50% from baseline in the HSSI score after


12 weeks of treatment. Secondary endpoints were Pain
measured by a Visual Analog Scale (VAS), DLQI, and
PGA of disease severity. Difference compared with base-
line were evaluated with Wilcoxons ranked sum test
(P < 0.05). The number of patients with a > 30 and
>50% disease activity was also calculated.
All adverse events occurring during or over follow-up
period were documented and reported to the IRB.

Results
Ten patients were enrolled in this study. Of these, six
patients completed the 12-week study and four patients
Figure 1 Changes of disease activity (HSSI) score during the
withdrew during the treatment period. Four patients with- 12-week treatment period
drew because of disease worsening and lack of efficacy. Of
the six patients who completed the treatment period, four
completed the post-treatment assessment at 13 weeks.
Two patients were lost to follow-up after the week 12 One patient reported a decrease in the number of daily
visit. Although patients were allowed to use nonsteroidal dressing changes at week 2. Three patients reported a
anti-inflammatory drugs and or low-dose prednisone, none decrease of the number of daily dressing changes at week
of the patients received any concomitant therapy during 4 and two patients reported a decrease of the number of
the trial. The characteristics of patients enrolled in this daily dressing changes at week 8. One patient reported a
study and their affected skin areas are shown in Table 2. decrease of the number of daily dressing changes at week
Changes in disease activity as measured by the HSSI score 12 but the rest of the patients reported no change of the
during the 12-week treatment period for each of the number of daily dressing changes at each week (data not
enrolled patients is shown in Fig. 1. A 50% decrease of shown).
that score was not found in any of the patients at week 2, Changes in pain scales using VAS during therapy and
4, 8, or 12. None of the 10 patients was classified as a at follow-up for each of the enrolled patients are shown
responder at week 12 compared with baseline. A 30% in Fig. 2. The median VAS scores were diminished from
decrease of that score was found in one patient at week 2; 60.0 to 20.0 at week 2 (P = 0.17), and from 60.0 to 20.0
in two patients at week 4; in one patient at week 8; and at week 4 (P = 0.42), from 60.0 to 30.0 at week 8
no patients at week 12. The median baseline HSSI score (P = 0.29), from 60.0 to 57.5 at week 12 (P = 0.55). No
was 17.0 and this score decreased slightly after 12 weeks significant differences were found between baseline and
of treatment to 14.5 (P = 0.40). Statistically significant dif- week 2, 4, 8, and 12.
ference was found between baseline and week 8 (P < 0.05) Changes of the DLQI score over the 12-week treatment
only, but no significant differences were found between period for each of the enrolled patients are shown in
baseline and week 2, 4, and 12. Fig. 3. The median DLQI scores were diminished from

Table 2 Demographic characteristics of ten patients with hidradenitis suppurativa enrolled in the study

Gender HSSI at
Patient Age (M/F) Ethnicity screening Involved skin areas

1 23 F Hispanic 14 Left submammary area, groin, buttocks


2 34 F Black 17 Both axillae, both submammary areas, groin, buttocks, genitalia
3 26 M White 18 Scalp, neck, both axillae, groin, buttocks
4 18 F Black 17 Both axillae, both submammary areas, groin, buttocks, genitalia
5 25 F White 13 Both submammary areas, groin, buttocks, genitalia
6 47 F Hispanic 12 Both submammary areas, groin, buttocks
7 52 M White 18 Neck, both axillae, abdomen, groin, buttocks, genitalia
8 40 F White 18 Both axillae, both submammary areas, groin, buttocks, genitalia
9 36 M White 18 Neck, both axillae, groin, buttocks, genitalia, inner thighs
10 25 F Black 13 Both axillae, both submammary areas, groin, buttocks, genitalia

International Journal of Dermatology 2010, 49, 950955 2010 The International Society of Dermatology
Amano, Grant, and Kerdel Adalimumab for treating hidradenitis suppurativa Clinical trial 953

Figure 2 Changes in pain scales (VAS) during the 12-week


treatment period

Figure 4 Changes of the PGA scale over the 12-week treat-


13.0 to 7.0 at week 2 (P = 0.03), and from 13.0 to 12.0 ment period
at week 4 (P = 0.57), from 13.0 to 7.0 at week 8
(P = 0.37), from 13.0 to 12.0 at week 12 (P = 0.65).
Statistically significant difference was found between patients who failed to complete the treatment period, two
baseline and week 2 (P < 0.05) only but no significant stopped because of the lack of efficacy, once transitioned
differences were found between baseline and week 4, 8, to the lower dosing (40 mg EOW), and two stopped
and 12. because of worsening of disease.
Changes of the PGA scale over the 12-week treatment
period for each of the enrolled patients are shown in
Discussion
Fig. 4. At week 2, two patients were good, one patient
was fair and five patients were slightly improved. At week This is not the first study to examine the beneficial effect
4, two patients were good and three patients were fair, of adalimumab in HS. Former case-report studies enrolled
two patients were slightly improved, one patient was a small number of patients. In 2006, Moul and Korman
unchanged and one patient was worse. At week 8, one reported a first case of HS being successfully treated with
patient was good, two patients were fair, two patients adalimumab. In this case, a 67-year-old man with a his-
were slightly improved, and one patient was unchanged. tory of inflammatory bowel disease received adalimumab
At week 12, three patients were slightly improved, one at a dose of 40 mg subcutaneously. His condition
patient was unchanged, and two patients were worse. improved significantly after the first injection and further
Adalimumab was well tolerated and there were no seri- improved throughout treatment.10 Scheinfeld reported a
ous adverse events reported and no infectious complica- case of coincident seronegative arthritis and HS treated
tions were observed during the study period. Of the with adalimumab. The patient began receiving ada-
limumab 40 mg every other week, and after 2 months his
condition improved significantly. However, 1 month later
the patient stated that his condition was worsening, and
the adalimumab was increased to 40 mg weekly. Over the
following months, pain and edema decreased13 (Table 3).
Yamauchi and Mau reported three patients who experi-
enced the resolution of skin lesions associated with HS
after treatment with adalimumab. The patients found this
treatment to be convenient, as they could administer the
therapy at home, and one patient was able to avoid surgi-
cal intervention through use of TNF-antagonist therapy.14
Blanco et al. evaluated the adalimumab efficacy in six
patients with refractory HS. Adalimumab was prescribed
in a dose of 40 mg every other week. The dosage was
Figure 3 Changes of the DLQI score over the 12-week treat- increased to 40 mg/week when the disease was inade-
ment period quately controlled and gradually decreased to 40 mg

2010 The International Society of Dermatology International Journal of Dermatology 2010, 49, 950955
954 Clinical trial Adalimumab for treating hidradenitis suppurativa Amano, Grant, and Kerdel

Table 3 Description of reported cases of moderate to severe HS treated with adalimumab

Reference (No. of
patients treated) Medication regimen and dose Outcome

Moul and Korman10 (1) 40 mg EOW Improved significantly


Scheinfeld13 (1) 40 mg EOW, increased to 40 mg weekly because of worsening Improved
Yamauchi and Mau14 (3) 40 mg EOW, increased to 40 mg weekly because of relapse Improved 80% from baseline
40 mg EOW Improved 70% from baseline
40 mg EOW, increased to 40 mg weekly Occasional flare-ups but HS remained controlled
Blanco et al.15 (6) 40 mg EOW, increased to 40 mg weekly because relapse Improved significantly, adalimumab was well
Decrease to 40 mg E3W in of clinical remission Tolerated

IBD, inflammatory bowel disease; EOW, every other week; HS, hidradenitis suppurativa; E3W, every three weeks.

every 3 weeks if HS was in clinical remission. Significant dose as a favorable trend occurred after the induction
improvements after 1 month of treatment were seen in phase with a high dose. Therefore, in the treatment of HS
the DLQI, in the number of affected regions, nodules, fis- a higher dose may be required, particularly after the
tulas, and in the basic laboratory findings. Improvements induction phase.
were maintained and the medication was well tolerated.15 In regards to effects as pain as measured by VAS, no
The present study is the fifth report of HS cases treated significant differences were found between baseline and
with adalimumab. The results of our study demonstrate week 2, 4, 8, 12. The DLQI score over the 12-week treat-
that adalimumab is well tolerated in patients with HS but ment found a statistically significant difference between
had minimal clinical significant efficacy. baseline and week 2 (P < 0.05), but no significant differ-
The existing prospective studies of TNF-a inhibitors for ences were found between baseline and week 4, 8, 12.
HS have varied in their outcome assessment, population The DLQI score was positively correlated with the pain
studied, and dose and type of TNF-a inhibitor used. In scale using VAS.
particular, these studies tended to find higher responses In conclusion, results of the present prospective open-
when using the Sartorius score compared with using glo- label phase II trial showed minimal evidence of clinically
bal assessment tools.16 Our study used the HSSI score significant efficacy of adalimumab in the treatment of HS.
which is a comprehensive instrument that assesses clinical The patients in this study were on the severe spectrum of
severity of HS and takes into account the number of disease and this could have affected the results. Neverthe-
lesions, pain, and impact on daily activities. Other instru- less a trend toward a beneficial response was observed.
ments proposed for the assessment of HS include Hurleys Future studies using higher doses of adalimumab are war-
Clinical Staging18 and the recently validated Sartorius ranted. Ultimately, a double-blind, placebo-controlled
score.17 The former allows for staging of the disease with trial will be necessary to demonstrate the efficacy of ada-
suggestions on treatment for patients at each stage but is limumab in the management of HS.
not suitable to report treatment effects, whereas the latter
fails to evaluate the main features of the disease such as
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International Journal of Dermatology 2010, 49, 950955 2010 The International Society of Dermatology
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2010 The International Society of Dermatology International Journal of Dermatology 2010, 49, 950955

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