Effectiveness of adalimumab combined with adjuvant surgery versus adalimumab monotherapy in the treatment of hidradenitis suppurativa.

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic,
recurrent, inflammatory and debilitating skin disease that usually presents
after puberty. HS is characterised by painful, deep-seated, and inflamed boils
most commonly in the axillary, inguinal, and anogenital regions. HS is a common
disease with an average prevalence of 1% in Europe. It*s association with a
variety of concomitant and secondary diseases such as obesity, metabolic
syndrome, diabetes, inflammatory bowel disease (e.g. Crohn*s disease), and
spondyloarthropathy is currently under investigation. Moreover HS is a highly
associated with smoking.

HS has the greatest impact on quality of life (QoL) of patients compared to
other dermatological diseases, this is mostly due to the symptoms of pain and
foul discharge. It has been reported that patients with severe HS have a work
absence rate of on average 34 days per year due to their disease. Some patients
even lost their job. Despite this profound impact on patients QoL, HS has
suffered from a lack of interest of dermatologists. It was long considered
difficult to manage with virtually no effective therapy for the more severe
phenotypes of HS. The disease originates form keratinous plugging of the upper
part of the hair follicle, resulting in dilatation and subsequent rupturing.
The exposure of the dermis to the hair follicles contents leads to a foreign
body-like inflammatory response, resulting in abscesses. Aberrant healing leads
to sinus tract formation and scarring. The sinus tracts and fistulas are most
likely the origin of the recurrent nature of the disease.

In 2015 treatment guidelines have been published in the *European S1 guideline
for the treatment of hidradenitis suppurativa/acne inversa*. This guideline
suggests that moderate and severe HS should be treated with a combination of
antibiotics (e.g. clindamycin plus rifampicin or tetracyclines), vitamin A
derivatives (acetretin) and anti-tumour necrosis factor-α (anti-TNF-α)
biologicals (e.g. adalimumab). The recent registration of adalimumab for the
treatment of HS in Europe (including the Netherlands) is seen as a huge step
forward in the management of HS. Not only does it improve HS symptoms it might
also impact conditions associated with HS such as metabolic syndrome and
insulin resistance and sensitivty. However, the dose of adalimumab needed to
maintain a good clinical response in HS patients is twice as high as the dose
needed in other diseases such as rheumatoid arthritis (RA) and Crohn*s disease
(CD). This results in the accumulation of costs as maintenance treatment will
be necessary to supress the disease activity. Even though all of the before
mentioned treatments can significantly reduce inflammation and provide
symptomatic relief, none resolves the fistula*s and therefore these treatments
cannot cure the disease. Although there is no high level evidence, expert
opinion recommends a combination of the above treatments with en bloc excision
of the affected areas to remove the fistulas. Additionally repeated surgery (en
bloc excision) should be preceded by systemic treatment to reduce inflammation
and thereby reduce the area in need of surgery and to reduce the recurrence
rate of HS after surgery. However, en bloc excision is associated with a
hospital stay of at least two days and a secondary intention healing phase with
extensive wound care at home. The surgery and after care may have an impact on
patients quality of life, but is likely to recover after the healing is
achieved.

Remarkably there are currently no published reports evaluating the effect of
the addition of adjuvant surgery to anti-TNF-α therapy in HS. Therefore, this
study aims to evaluate the effectiveness of the addition of adjuvant en bloc
excision to adalimumab therapy in patients with moderate to severe HS. As
adalimumab therapy does not cure the disease, our working hypothesis is that
combining this treatment with adjuvant surgery will be more effective.

The primary objective of this prospective study is to assess the clinical
efficacy of the combination of adalimumab and surgery compared to adalimumab
monotherapy after one year of treatment in adult patients with moderate to
severe HS at the last visit (12 months or the last visit before dropout) using
the International Hidradenitis Suppurativa Severity Score System (delta IHS4)

This is a randomized, controlled clinical trial in a real life setting with a
12 month follow-up. The inclusion period will span two years. Potentially
eligible patients will be informed about the study procedures and will be given
ample time to consider their decision. After obtaining informed consent patient
will be screened for eligibility. Eligible subjects will be randomised to one
of the two study arms, treated and followed for 1 year (V0 up to and including
V4). Patients in group A will be treated with adalimumab monotherapy according
to normal clinical practice. Patients in group B will receive adalimumab
combined with adjuvant en bloc excision of active lesions (under general
anesthesia or procedural sedation and analgesia), both according to routine
clinical practice. Patients from Group A will be offered the possibility to
cross over to Group B when they do not achieve HiSCR after 6 months of
treatment. Additionally they will be offered to start infliximab treatment
during this period until the last surgery.

This study consists of two treatment arms. The intervention consists of a
combination of adalimumab and adjuvant surgery. The patients in this group will
receive adalimumab treatment and additional surgery to remove HS lesions, with
a maximum of two surgical interventions. Surgery will take place at 3 months
(V1) and 6 months (V2). The adalimumab treatment will continue continued until
the end of the study.

This treatment strategy will be compared with adalimumab monotherapy.
Adalimumab will be administered through subcutaneous injections in weekly dose
of 40mg from week 4 up to 12 months (V4), after an initial dose of 160mg at
week 0 and a 80mg dose at week 2.

Patients will visit the hospital every three months for a duration of 12
months. On all visits blood samples will be collected, in accordance with
routine clinical practice. Patients from the intervention group will undergo
surgery followed by three hospital visits to evaluate wound healing.

In both groups biopsies will be taken at baseline and three months from
lesional skin. A skin biopsy is generally safe, however there is a small risk
of bleeding and infection. Patients will complete multiple questionnaires at
baseline and every visit thereafter. Filling out these questionnaires at
baseline and every even visit thereafter will take approximately 15 minutes, at
every even visit approximately 10 minutes. During the adalimumab treatment
patients will fill out a weekly diary, this will take approximately 5 minutes
per week.

Risks for participating patients consists of the occurrence of treatment
related side effects and adverse events, including an increased risk of
infection, anaemia, abnormalities in liver parameters, and injection site
reactions when treated with adalimumab. Complications arising from surgical
intervention include post-operative bleeding, wound infections and local
hypoesthesia.The additional risks in this study on top of the aforementioned
risks of the standard treatments consits of the risks associated with the
biopsies.