7
Hidradenitis Suppurativa and Crohn’s Disease
Philippe Seksik, Jean-François Contou, Anne Cosnes and Jacques Cosnes
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Key points
Q An association between hidradenitis suppurativa (HS) and Crohn’s disease (CD) appears to be well established
Q Recognizing HS in a patient with CD, or vice versa, has no immediate major therapeutic implications but may lead to the choice of a more aggressive medical strategy
Q One can expect that a genetic link between the two diseases will be demonstrated and may lead to the development of specific targeted therapies
#ONTENTS
7.1 Definition and Course
of Crohn’s Disease . . . .50
7.1.1 Pathophysiology . . . .50
7.1.1.1 Genetic Factors . . . 51
7.1.1.2 Enteric Microflora . . . 51
7.1.1.3 Immune-Mediated Tissue Injury . . . 51
7.2 Pathology . . . 51
7.3 Clinical Aspects . . . 52
7.3.1 Disease Location . . . 52
7.3.2 Clinical Presentation . . . 52
7.4 Therapeutic Aspects and Prognosis . . . 52
7.5 Cutaneous Crohn’s Disease . . . 52
7.5.1 Clinical Presentation of Cutaneous Lesions . . . 53
7.5.2 Therapeutic Aspects and Prognosis . . . 53
7.6 Crohn’s Disease and Hidradenitis Suppurativa . . . 53
7.6.1 Differential Diagnosis . . . 53
7.7 Co-Existence of HS and CD . . . 55
7.8 Treatment of Perianal Co-existent CD and HS . . . 55
References . . . 55
Crohn’s disease (CD) is a chronic granuloma- tous inflammatory bowel disease that may in- volve the anus and the perianal region. About 50% of patients with CD develop perianal le- sions during the course of their disease. In some of these patients, perianal cutaneous lesions may mimic those of HS. Moreover, the occur- rence of both HS and CD in the same individual has been reported in quite a large number of cases. This paper reviews the main pathophysi- ological and clinical aspects of CD, describes the perianal lesions of CD, comparing them to those of HS, and discusses the links between the two diseases.
7.1 Definition and Course of Crohn’s Disease 7.1.1 Pathophysiology
The cause of CD remains unknown. Recent ad- vances in the pathogenesis of CD involve inter- actions of three elements: genetic factors, enteric microflora and immune-mediated tissue injury.
Furthermore cigarette smoking has been de-
scribed as the main risk factor for relapse and
poor evolution of the disease [1].
7.1.1.1 Genetic Factors
CD appears to have a genetic tendency, with multiple susceptibility genes. The first suscepti- bility locus for CD, which was found in replica- tive studies worldwide [2, 3], is on the pericen- tromeric region of chromosome 16 (IBD1 locus).
Mutations of the NOD2 gene in this region have been conclusively associated with CD. Homo- zygosity and compound heterozogosity increase the relative risk of developing CD by 20- to 40-fold compared to non-NOD2-mutated sub- jects. Nods proteins are thought to be cytosolic receptors for pathogenic bacterial signals. Nod2 recognizes muramyl dipeptide (MDP) [4], a conserved structure in bacterial peptidoglycan.
Nod2 is expressed in monocytes and activates nuclear factor kappa B (NF-KB), which is a key transcriptional factor involved in the initiation of the inflammatory response [5]. Since NOD2 variants seem to account for less than 20% of CD, other candidate susceptibility genes need to be investigated.
7.1.1.2 Enteric Microflora
The absence of evidence for transmission of either CD or ulcerative colitis argues against a transmissible infectious etiology. However, there are several pieces of indirect evidence that commensal microflora contribute to the patho- genesis of CD, such as:
1. The failure of induction of colitis in germ-free animals [6]
2. The occurrence of inflammatory bowel disease (IBD) lesions in areas of greatest bacterial exposure
3. The induction of relapse in ileal CD by the fecal stream [7]
4. The difference of fecal and mucosal flora composition between patients with CD and healthy subjects [8]
5. The loss of tolerance to the compo- nents of endogenous flora in patients with CD [9]
6. The influence of antibiotics and probiot- ics in experimental animals and in some clinical situations (postoperative relapse of CD) [10].
7.1.1.3 Immune-Mediated Tissue Injury Host–microbial interactions involve commen- sal species that reside permanently within the gastrointestinal tract and this adaptation active- ly contributes to immunological tolerance and homoeostasis within the healthy gut. Molecular mechanisms of this prokaryote/eukaryote cross- talk involve different bacterial signals and pat- tern recognition receptors (PPRs) such as toll- like receptors (TLRs) and NODs [11]. The bacterial stimuli represent a cluster of various signals called pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), peptidoglycans and bacterial nucleic ac- ids (CpG DNA). TLR are key regulators of the innate immune response, and different changes in selective epithelial expression of TLRs have been reported to occur in CD [12]. In CD tissue damage arises from excessive TH1 cytokine re- sponses or a failure to turn off such responses after pathogenic infection in genetically suscep- tible individuals. Additionally, cytokines act on local microvasculature, upregulate adhesion molecules and facilitate the recruitment of neu- trophils and phagocytes, which contribute to the amplification of the inflammatory response and further tissue damage. In healthy individu- als, activated mucosal T cells are controlled through regulatory T cells and apoptosis path- ways, both of which seem to be defective in pa- tients with CD [13].
7.2 Pathology
The elementary intestinal lesion consists of fo- cal infiltration of mononuclear cells, eosino- phils, and polymorphonuclear cells in the lami- na propria, small vessels, and epithelium [7].
Lesions tend to become chronic and deeper, in-
volving in some places all the width of the intes-
tinal wall. Important characteristics are the
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patchy distribution of the lesions, the epitheli- oid granulomas which are observed in up to 60% of patients, and the formation of strictures and fistulas.
7.3 Clinical Aspects
CD is usually diagnosed during the third de- cade of life, but is not exceptional in childhood and after 60 years.
7.3.1 Disease Location
CD may involve any part of the digestive tract, but is located most commonly to the ileum and/
or the colon [14]. Most frequently, the disease location remains the same, namely ileocolonic, ileal, or colonic, throughout the course of the disease, although some patients (fewer than 10%–20%) may develop new lesions in another part of the intestine.
7.3.2 Clinical Presentation
Symptoms depend on disease location (colonic lesions being more expressive) and anatomical severity. Patients usually present with diarrhea, mucous and blood discharges, abdominal pain, and weight loss. Other features of flares are fatigue, fever, articular, cutaneous and ocular manifestations, and biological inflammatory response (elevated C-reactive protein and eryth- rocyte sedimentation rate, ESR). In some cases, the disease is latent until the development of a complication, a stricture causing an intestinal obstruction or a perforation (peritonitis, or more commonly internal fistula with abscess formation). The course of CD is poorly predict- able. Most patients have flares separated by re- mission phases of variable duration; others (about 10%–15%) have a chronic active disease.
The disease has a protracted benign course in fewer than 15% of patients.
7.4 Therapeutic Aspects and Prognosis
Flare-up episodes are usually treated with ami- nosalicylates or prednisolone, according to their clinical severity. When steroid therapy fails (10%–30% of patients), the anti-tumor necrosis factor-alpha antibody infliximab 5 mg/kg is usually active.
Maintenance treatment prescribed with the goal of preventing flare-ups uses aminosalicy- lates and, in more severe forms, immunosup- pressive drugs (azathioprine or methotrexate).
Immunosuppressants are very effective as main- tenance treatment, achieving and maintaining remission, sparing steroids, leading in some cases to mucosal healing, and improving quality of life [15]. Accordingly, there is a clear tendency over time to initiate immunosuppressants ear- lier and in a larger proportion of patients [16].
Nowadays about two-thirds of patients receive immunosuppressants. Repeated perfusions of infliximab may be used in the few patients who are non-responders to classical immuno- suppressants. Surgery is reserved for stenotic and extra-parietal complications, or intractable forms after a well-conducted medical manage- ment. The cumulative risk of intestinal surgery is 82% after 20 years.
CD is an all-life chronic disease with no ten- dency to burn out over time. However, most pa- tients are able to have an almost normal life.
Mortality is slightly increased when compared to the general population [17].
7.5 Cutaneous Crohn’s Disease At the time of diagnosis of intestinal CD, ex- amination of the anus shows anal or perianal lesions in about one-quarter of patients. Later on, up to half of patients eventually develop perianal lesions. Those lesions are more fre- quent when CD involves the distal part of the colon and rectum, but may be associated with ileal disease without colonic involvement, and also may precede for years the development of intestinal lesions. Recent data identified a new variant gene OCTN (organic cation transporter) associated with perianal and fistulizing CD.
This gene is located on the locus of IBD-5.
7.5.1 Clinical Presentation of Cutaneous Lesions
The primary lesions of CD are confined largely to the endoanal skin, the transitional epithelium of the anal canal, and the contiguous 1–2 cm of rectal mucosa. The primary lesion is a painless, midline fissure of the anal canal, which usually remains symptomless and benign. Edematous skin tags arise from the distal margin of super- ficial fissures. They may be voluminous, with no tendency to decrease. A second and more destructive lesion is a penetrating ulcer which gives rise to fistulas [18]. Fistulous tracts may be low, superficial, or high, long and tortuous, de- pending on the location of their primary open- ing in relation to the anal canal. They may form cavities and lead to abscess formation. They may extend to the anal sphincter and have an impact on continence. Finally, anal lesions may lead to stricture formation [19]. Over one-quarter of patients with CD will present with or develop perianal fistula.
Aggressive ulceration is an uncommon form that extends rapidly beyond the perianal skin to involve the perineum and often the vulva [18]. It is usually associated with cavitating endoanal ulcers. Involvement of skin distant to the gas- trointestinal tract (metastatic CD) is uncom- mon, but CD affecting penile and scrotal skin has been described.
Perianal lesions should be carefully assessed and classified (ulceration, fistula, stricture) by physical examination. However examination under anesthesia and modern imaging tech- niques (endoanal sonography, magnetic reso- nance imaging) improve the detection and characterization of fistulas and abscesses, and are necessary before defining a therapeutic strategy.
7.5.2 Therapeutic Aspects and Prognosis
The overall strategy facing perianal CD is con- servative [20, 21]. The control of sepsis is the first objective. Antibiotics (metronidazole, cip- rofloxacin, and clofazimine) are used for self- limited complications (small abscesses, acute
exacerbations without abscess formation), but not as a maintenance therapy. Surgical inter- vention is required for drainage of an abscess, non-cutting seton drainage of complex fistulas with deep pus collection [22, 23], and dilatation of a symptomatic anal stenosis.
The effect of immunosuppressants is not as favorable as it is on the intestinal disease. In children, purine analogs have been shown to improve perianal tenderness and induration in most patients and to achieve fistula closure in some [24]. In adults, although purine analogs may induce the closure of perianal fistulas [25], only one-third of patients with perianal lesions clearly improve. Patients aged 40 years or more, with recent perianal lesions, and without fistula are the best responders [26].
The management of perianal fistulizing dis- ease resistant to standard treatment has greatly improved with the introduction of infliximab [27]. The complete arrest of the drainage of fis- tulas is obtained in 46% of patients 10 weeks af- ter the administration of 5–10 mg/kg of inflix- imab at weeks 0, 2 and 6 and lasts on average for 12 weeks. However, fistula closure is often in- complete or superficial, fistulous tracts can per- sist despite closure of the external opening, and relapses are common. This may lead to a re- sumption of infliximab and to its being admin- istered on a chronic basis (5–10 mg/kg every 2 months), with a tendency to a loss of efficacy with time. In cases of incontinence or when the lesions are severely disabling, proctectomy may become necessary (10%–38% of patients).
7.6 Crohn’s Disease
and Hidradenitis Suppurativa 7.6.1 Differential Diagnosis
In a patient with perianal disease, the differen-
tial diagnosis between CD and HS is usually
easy, as in HS other disease sites (axillae, groin)
have been involved and anal examination does
not demonstrate endoanal lesions or primary
ulcerations with fistula formation. Fistulas to
the anal canal may occur in HS, however they
do not extend more than the extreme location of
the apocrine glands [28, 29]. In contrast, in CD
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anal lesions may be absent or have healed. The aspect of the perianal lesions also differs. In CD the lesions are more ulcerative, scars are retrac- tile, and the skin is involved only around the anus (Figs. 7.1–7.3), whereas in HS, there are cu- taneous scarring, comedones, skin bridges and sinuses (Figs. 7.4, 7.5). From a pathological point of view, lesions may be very similar. Attanoos et al. [30] specifically looked at the granuloma in 101 HS patients. They found that although for- eign-body-type granulomas are a common fea- ture of HS (25%), the presence of discrete epi- thelioid granulomas in the dermis away from the site of active inflammation is unusual and should alert one to the possibility of granuloma- tous disease such as CD [30].
Fig. 7.1. The elementary lesions of perianal Crohn’s dis- ease (CD, posterior fissure, skin tags, and fistulas)
Fig. 7.2. A CD fissure merging on the perianal skin
Fig. 7.3. A suppurative form of perianal CD with mul- tiple fistulas
Fig. 7.4. HS lesions in a patient with operated perianal CD
Fig. 7.5. HS lesions in a patient with CD
7.7 Co-Existence of HS and CD
A clinical association between HS and CD has been described in some cases reports [31–33]
and in one case series [34]. Gower-Rousseau et al. reported the occurrence of HS in two first- degree relatives of patients with CD [35]. This finding suggests a common genetic susceptibil- ity for the two diseases. In the study by Church et al. [34], CD lesions were found in 24 out of 61 patients with HS. In our series of 2926 patients with CD, 18 (0.6%) have such an association.
This figure should be considered as minimal, as a systematic search for HS was not made. Of note, the proportion of active smokers was 78%
in our patients with both diseases. Clinical characteristics of patients with HS and CD in the two latter studies are given in Table 7.1. CD patients with HS differ from other CD patients by a higher frequency of colonic and perianal involvement, an increased need for immuno- suppressants, and, more importantly, a very un- usual need for proctectomy and definitive ileos- tomy. Finally, the evolution of the two diseases is not parallel, with possible exacerbations of HS while the intestinal disease is burning out.
From a practical point of view, the occur- rence of digestive symptoms or unexplained biological abnormalities (anemia, hypoferri- tinemia, elevated C-reactive protein) in one pa- tient with HS should alert the physician and
lead to colonoscopy, as the presence of gastroin- testinal endoscopic lesions and granulomas on biopsy establishes the diagnosis of CD. Con- versely, there is a need for a systematic search for acne, folliculitis, and HS skin lesions in CD patients, particularly when a steroid treatment is planned.
7.8 Treatment of Perianal Co-existent CD and HS
The use of steroids should probably be discour- aged in the acute phases because of their poor efficacy and the risk of septic complications.
Immunosuppressants need to be evaluated once sepsis has been completely controlled. Inflix- imab has been proven to be efficient in the treat- ment of cutaneous CD manifestations such as pyoderma gangrenosum [36]. This led some authors to use infliximab in patients with both HS and CD [37–42]. Infliximab was introduced when conventional medical treatment and sur- gical drainage failed. Various infliximab regi- mens of one to three perfusions have been re- ported with prolonged efficacy. Improvement was noted in both the perineal CD course and axillary or perineal HS lesions. These observa- tions reinforce the link between the two diseases and suggest a shared inflammation pathway.
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Table 7.1. Characteristics of Crohn’s disease (CD) in two series of CD associated with hidradenitis suppurativa (HS)
Cleveland Clinic
St. Antoine
Males/females 11/13 7/11
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sis of CD (years) 39 (18–75) 26 (11–50) CD location (small
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