Biologics For Hidradenitis Suppurativa
(Verneuil’s Disease in the Era of Biologics)
Sharon E. Jacob, Francisco A. Kerdel
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Key points
Q Hidradenitis suppurativa (HS) is resistant to current medical manage- ment options
Q The association with Crohn’s disease (CD) suggests an inflammatory etiology
Q Infliximab has been shown to induce durable remissions in patients with HS and HS/CD
Q The efficacy of infliximab suggests a role for tumor necrosis factor alpha (TNFA) in the etiology and pathogen- esis of HS
Q The efficacy of infliximab in HS suggests a role for broadening the therapeutic applications of TNFA inhibitors
#ONTENTS
20.1 Introduction . . . 145
20.2 Background . . . 145
20.2.1 Crohn’sDisease and Hidradenitis Suppurativa Co-Occurrence: A Rationale for Anti-TNF Therapy . . . 147
20.3 Anti-TNF Drugs in HS . . . 147
20.4 Future Prospects . . . 148
References . . . 149
20.1 Introduction
Verneuil’s disease, better known as hidradenitis suppurativa (HS), is a chronic inflammatory disease that is clinically hallmarked by multiple abscesses and sinus tracts distributed in areas densely populated with apocrine glands. Stage I HS is characterized by the presence of abscesses without scarring or sinus tracts. With progres- sion to Stage II, scarring and sinus tract forma- tion are seen. By definition, patients with Stage III disease have multiple interconnected sinus tracts and scarring, typically involving multiple regions [1]. The significant morbidity of this disease is important, and is emphasized further by the limited effectiveness of the currently available “standard” medical therapies, includ- ing antibiotics (Chap. 15), antiandrogens (Chap.
16), retinoids (Chap. 17), immunosuppressants (Chap. 18), and/or complementary and alterna- tive medicines (Chap. 19) [2].
20.2 Background
Similar to most chronic diseases in the current
medical milieu, there is a constant interplay be-
tween therapeutics and pathophysiology. With
the development of novel therapeutic agents
with specific mechanisms of action and the
knowledge of such mechanisms, new inroads
have been made into our understanding of the
pathophysiology of several diseases. This in
turn has spawned further development of medi-
cal pharmacological therapies. The closer we get
to understanding the molecular mechanisms of
a disease, and in particular of HS, the greater
our opportunity to pinpoint directed medical
management. Nowhere does this ring more true
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Table 20.1. Biologic therapy in HS [5, 8–11]. (CD Crohn’s disease, CR case report, CS case series, HS hidradenitis sup- purativa, PC personal communication, UC ulcerative colitis)
Author Case report no.
Year Strength of evi- dence
Age (years)/
sex
Disease dura- tion (years)
Bio- logic
Outcome measures
Outcomes
Martinez et al. [8]
1 2001 CR 30/F,
HS + CD
6 Inflixi-
mab
Resolution of refractory nod- ules
Remission 6 months after two infusions, maintained with azathio- prine (adverse reaction noted after 2nd dose) Katsanos
et al. [5]
2 2002 CR 39/M
HS + CD
Unknown Inflixi- mab
Remission Remission after 2 years of infusions Lebwohl and
Sapadin [9]
3 2003 CR 21/M
HS +/– CD
2 Inflixi-
mab
Complete re- epithelializa- tion
Disease resolution
Adams et al. [10]
4 2003 CR 17/M
HS + UC
3 Inflixi-
mab
Complete re- mission
Complete resolution of pain, tenderness, purulence, draining and odor Induc- tion of disease remission Adams et al.
[10] (K.B.G.)
5 2003 PC Unknown
HS
Unknown Inflixi- mab
Remission Successful remission Sullivan
et al. [11]
6–10 2003 CS 51/F
28/F 36/F 57/F 45/M All HS
20 10 20 44 25
Inflixi- mab
Patient report- ed disease activity scale Ability to decrease
“standard”
systemic medications (ciclosporin, prednisone)
Patients’
reported disease activity significantly decreased within 3–7 days (p=0.0001) paired t test Patients reported de- creased pain after 24 h Rosi et al.
[12]
11 2005 CR 30/F
HS + CD
1.5 Inflixi- mab
Improvement of symptoms
No evidence of active in- flammation 5 weeks into therapy
than for the new biologic therapies. This is par- ticularly important in HS, given that there is no universally effective medical therapy, and, fur- thermore, current medical management is mar- ginally beneficial even when claimed to work.
20.2.1 Crohn’s Disease and Hidradenitis Suppurativa Co-Occurrence:
A Rationale for Anti-TNF Therapy While the etiology and pathogenesis of HS re- main largely unknown, the disease has been shown to occur in association with other disor- ders of follicular occlusion, such as acne conglo- bata and dissecting cellulitis of the scalp. In these disorders, follicular occlusion leads to overgrowth of bacteria and subsequent neutro- philic inflammation. Many observations have been reported regarding the role of androgens/
hormones, obesity, and genetics, which may in addition influence the clinical picture [3, 4]. It is the reported association with Crohn’s disease (CD), however, which has led to speculation and opportunities for novel management. It has been postulated that the two conditions share similar pathological immune mechanisms, such as increased levels of tumor necrosis factor al- pha (TNFA) and neutrophilic chemotaxis [5].
This interesting co-occurrence of HS and CD highlights both the inflammatory nature of the disease and the rationale for using biologics known to be effective in CD [6].
There is evidence that infliximab is effica- cious at stopping fistula drainage when used as a maintenance agent in fistulizing CD [7]. It is reasonable to suppose that if a patient sees inf- liximab-induced improvement of their CD fis- tulization, they would also see the healing of any co-existing HS with skin fistulization. A re- view of the literature demonstrates that this is indeed the case. The first three cases of effective treatment of HS with infliximab were in pa- tients who had undergone the treatment for CD.
At the time of writing this chapter, 11 cases of HS treated with infliximab have been reported in the literature. Of the 11 reported cases, 4 (36%) had been patients with associated CD (see Table 20.1) [5, 8–12]. Nevertheless, these pre- liminary cases demonstrate both the high de-
gree of efficacy of infliximab therapy for long- standing HS and that in some cases improvement was observed in as little as 3 days.
20.3 Anti-TNF Drugs in HS
Infliximab is the only biologic with reported use in HS. It is a chimeric monoclonal antibody with high affinity for TNFA. The molecular structure encompasses the human IgG constant region spliced with a murine variable antigen- binding region. This therapeutic antibody scav- enges free TNFA, neutralizing its proinflamma- tory biological effects. Mitigation of the target immunological endpoints for TNFA include:
1. Induction of proinflammatory cytokines interleukin-1 (IL-1), IL-6, and IL-8 2. Activation of neutrophils, lymphocytes,
and eosinophils
3. Upregulation of adhesion molecule expression by endothelial cells [13, 14].
Additionally, infliximab binds mem- brane-bound and receptor-bound TNFA leading to complement-induced antibody- mediated CD4+ T cell cytotoxicity.
Infliximab is currently approved by the Food and Drug Administration (FDA) for the treat- ment of rheumatoid and psoriatic arthritis, Crohn’s disease and ankylosing spondylitis.
Many off-label uses of this agent have addition- ally been reported in the literature and not sur- prisingly many relate to inflammatory skin dis- ease.
The drawbacks to infliximab therapy are few.
Commonly reported side-effects include diar- rhea, headache, pharyngitis, upper respiratory tract infection, and urinary tract infection [15–
20]. Rare instances of re-activation of tubercu-
losis (TB), aseptic meningitis, systemic lupus
erythematosus and antibody-mediated anaphy-
lactic shock have also been reported. In the
147,000 cases throughout the world that have
received infliximab that Keane et al. [21] re-
viewed in 2001, there were 70 cases of TB, and
approximately 60% of these represented extra-
pulmonary disease. The current understanding
suggests that re-activation of TB is associated
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with disruption of the immune system’s ability to compartmentalize the bacilli in granulomas and inhibition of macrophage apoptosis. Thus the FDA requires that patients have a negative purified protein derivative (PPD) test prior to the onset of infliximab therapy. Infusion-asso- ciated anaphylactoid reactions, while rare, can be avoided by slowing the infusion rate and pre- treating the patients with antihistamines and steroids.
Antibody formation can be seen with long- term use and is inversely proportional to total infliximab dose. The concern regarding the de- velopment of antibodies to infliximab with long-term use follows the observation that 13%
of Crohn’s patients treated with repeated infu- sions had indeed formed antibodies [22]. As ex- pected, loss of clinical efficacy accompanies the antibody formation, as does the development of infusion-related chest pain, bronchospasm, and anaphylactic shock. The development of anti- bodies can be reduced by treating the patients on a scheduled, regular basis (i.e., every 8 weeks) and with the concomitant use of low-dose im- munosuppressants [16].
In the reported cases of HS treated with inf- liximab therapy, the demographics for ten pa- tients are known (one case was reported without specifications) (see Table 20.1) [5, 8–11]. Four
patients were reported to have had concurrent CD. Patients’ age ranged from 17 to 57 years with a mean age of 35.4 years. There were four men and six women. HS disease duration was reported as being between 1.5 and 44 years, with a mean duration of 14 years. As the majority of the reports are single case reports of successful therapy, long-term effects were not known or described. Importantly, 9 of the 11 patients re- ported a significant reduction in disease activity within 5 weeks of infliximab infusion therapy.
The five patients treated in a dermatological inpatient ward were observed to have marked or moderate improvement within 3–7 days after each infusion [11].
20.4 Future Prospects
While no specific reports exist regarding the other FDA-approved anti-TNF agents on the market, one of the authors (F.A.K.) has treated two patients with HS with etanercept. The pa- tients appeared to improve, however not as markedly as seen with infliximab. This is not surprising given that etanercept has not been found to be effective in CD. The other anti-TNF agent approved by the FDA, namely adalimum- ab, has not been reported in association with
Table 20.2. Biologics used in CD [22–24]. (AS Ankylosing spondylitis, CD Crohn’s disease, JRA juvenile rheumatoid arthritis, PsA psoriatic arthritis, Pso psoriasis, PsoA psoriatic arthritis, RA rheumatic arthritis, TNF tumor necrosis factor, UC ulcerative colitis)
Generic name
Company Subset Structure Target FDA indication
Infliximab Centocor IgG1 Chimeric: human Fc and murine Fab
TNFα, complement fixation, T cell apop- tosis
CD, RA, AS, PsA
Adalimumab Abbott IgG1 Fully human TNFα, complement fixation, T cell apop- tosis
RA CD Phase III
CDP571 Abbott IgG4 Humanized, murine
complementarity determining region
TNFα, decrease C reactive protein, no complement fix
CD failed Phase III UC Phase IIa
CDP 870 UCB – Humanized Fab,
linked to polyethylene glycol
TNFα,
no complement fix
CD Phase III
Etanercept Amgen/
Wyeth
Recep- tor IgG1
Human Fc backbone TNFα, TNFα RA, AS, JRA, Pso, PsoA CD failed Phase II
treatment of HS; additionally, CDP571 is in phase III trials for CD (see Table 20.2) [22–24].
If we are to follow the infliximab lead, it stands to reason that agents shown to be prom- ising in CD clinical trials, such as the fully hu- man IgG1 anti-TNF monoclonal antibody adali- mumab and the fully humanized anti-alpha4 integrin IgG4 antibody natalizumab, would of- fer opportunities for effective management of HS [7] (see Table 20.2) [22–24]. At this time, the efficacy of these agents in inflammatory disor- ders such as rheumatoid arthritis has proven impressive and the short-term side-effects have been minimal with regard to the risk/benefit ra- tio. As we proceed to develop our experience and monitor the long-term effects, we are pre- sented with determining the utility of each bio- logic therapy and ultimately finding the most appropriate disease–therapeutic pairing. Not all biologics are equally effective, but finding the optimal target disease may level the playing field.
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