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Immunosuppressive Therapy in Hidradenitis Suppurativa
Hanne Nybæk, Gregor B.E. Jemec
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Key points
Q Immunosuppression is a possible therapeutic strategy in the treatment of hidradenitis suppurativa (HS)
Q Immunosuppressive or anti-inflamma- tory drugs are generally safe in HS
Q The use of immunosuppression in the absence of bacterial infection often brings rapid relief to patients
Q Immunosuppressive drugs can be used to control flares, and prepare the patient for surgery, for example
Q Longer term immunosuppression may help the patient gain better control of their disease for a period
Q Immunosuppressive therapy alone is unlikely to be curative
#ONTENTS
18.1 Introduction . . . .136 18.2 What Can We Achieve With Therapy? . . . 137 18.3 Immunosuppressive Therapies . . . 137 18.3.1 Prednisolone and Other Corticosteroids 138 18.3.2 Ciclosporin . . . .138 18.3.3 Dapsone . . . .138 18.3.4 Methotrexate . . . .138 18.4 Hidradenitis Suppurativa as a Side-
Effect of Immunosuppressive Drugs . . . . 139 18.5 Practical Use of Immuno-
suppressive Therapy . . . 139 References . . . 140
18.1 Introduction
Hidradenitis suppurativa (HS) is an inflamma- tory skin disease. The clinical presentation and historical concept of the disease have tradition- ally been interpreted to indicate that bacteria have a pathogenic role, but specific microbio- logical investigations have suggested that the role of bacteria is generally not that of a simple infection. Routine cultures are more often than not found to be sterile, and recognized patho- gens such as Staphylococcus aureus can be found mainly in rapidly evolving lesions [1, 2]. Heavy bacterial overgrowth of known pathogens is therefore not a main feature of the disease, and the pathogenic role of bacteria may be an im- munological one. Bacteria may only be the anti- gen that starts an immunological disease. Simi- lar mechanisms have been described in guttate psoriasis and atopic dermatitis. In acne, bacte- rial antigens have also been shown to elicit an immunological response, suggesting a similar mechanism.
Similarly scarring is a prominent feature of more advanced disease [3]. Whereas scarring is currently not amenable to medical therapy, pre- ventive medical therapy may be of clinical inter- est. Since the primary pathogenic event in HS is not known, treatment directed at minimizing scar formation is of independent interest to all involved. Immunosuppressive therapy has a po- tential in reducing the inflammatory phase of the disease, which may result in subsequent scar formation. Accepting the possibility of such a mechanism, a different range of therapeutic op- tions becomes available to the dermatologist.
18.2 What Can We Achieve With Therapy?
The obvious goal of therapy in HS is to heal ex- isting lesions and prevent the development of new lesions. This is potentially possible in early lesions (Hurley stage I), where scarring does not dominate the clinical picture, although this form of treatment is more likely to alleviate symptoms than to cure patients. Therapy may furthermore not influence established fibrosis, although intralesional steroids, for example, are commonly used to treat hypertrophic scars.
Immunosuppression however has immediate benefits for patients. The main symptom for most patients with HS is pain, which in turn is due to inflammation. By offering patients immunosuppressive therapies inflammation is reduced and pain alleviated. Immunosuppres- sive therapy therefore has both immediate and potential long-term benefits for patients.
18.3 Immunosuppressive Therapies
A limited body of data exists to describe the therapeutic experience of using immunosup- pressants in HS. It is not clear whether it is the immunosuppressive or the anti-inflammatory effect of these drugs which is the stronger when used for HS, although it may be speculated that long-term results stem from immunosuppres- sion rather than anti-inflammatory therapy.
The therapies are however at best described through small case series, and the evidence base of these therapies therefore needs to be expand- ed. Dose-finding or testing observations are both necessary and interesting, and any positive findings have to be confirmed in actual ran- domized controlled trials (see Table 18.1).
Table 18.1. Immunosupressive treatment of HS
Drug Author Number
of patients
Location Dosage and duration
Outcome
Ciclosporin Gupta et al. [8] 1 (male, 60 years)
6 mg/kg for 6 weeks Moderate response
Buckley and Rogers [9]
1 4.5 mg/kg Good response
Rose et al. [5] 2 a. Female
38 yearsa b. Male
31 years
a. Groin b. Axillae and groin
a. 4 mg/kg (3 months) then tapered to 2 mg/kg for continuous therapy b. 3 mg/kg
for 3 months
a. Continuous therapy with good effect b. Remission
for 4 months after 3 months of treatment
Dapson Hofer
and Itin [11]
5 Axillae
and groin
25–100 mg/day Effect within 2–4 weeks, described as very good by 2 and good by 3 patients Methotrexate Jemec [12] 3 Axillae
and groin
12.5–15 mg per week for 6 weeks
to 6 months
No effect on primary lesions or recurrence rates, but slight weakening of flare intensity
aPatients previously treated with corticosteroids.
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18.3.1 Prednisolone
and Other Corticosteroids
Early studies of adrenocorticotrophic hormone (ACTH) and corticosteroids suggested that gen- eral immunosuppression was beneficial to the well-being of HS patients [4]. These studies however do not conform to current require- ments for evidence as they are anecdotal rather than randomized and controlled. Relief is how- ever regularly offered to patients with flares of HS by treating with prednisolone, either as monotherapy or in combination with other therapies. In this manner systemic corticoste- roids may be used in a manner analogous to their use in acne fulminans. Usually doses of 0.5–0.7 mg/kg are sufficient to achieve control of the inflammation. Initial doses can then be tapered over weeks to control the disease. How- ever, in some cases tapering is not possible due to rapid flares and alternative therapies must therefore be instituted. The patients reported by Rose et al. [5] are examples of such cases. Sys- temic corticosteroids are therefore often used in conjunction with other therapies such as antibi- otics [6, 7].
Careful swabbing and biochemical control are necessary to identify ongoing clinically sig- nificant infections when prednisolone therapy is instituted. Similarly patients must be in- formed of possible side-effects of the treatment.
Intralesional steroids are also an important tool for HS management, although their use is again unsupported by formal studies. Intrale- sional steroids are most often used to treat recal- citrant nodules in HS (see Chap. 21). Triamcino- lone (10 mg/ml) is the most commonly used drug, but other drugs may be as efficient. The effect of the injection occurs after a few days, either as the disappearance of the lesion, or spontaneous rupture. Pain is generally reduced significantly in a short space of time. The long- term effect of using intralesional corticosteroids is not known. In our experience complications, with for example superinfection, are rare, and can be monitored through more aggressive microbiological sampling with regular swabs from lesions that do not react in the described manner but persist or develop in spite of treat- ment.
18.3.2 Ciclosporin
Single cases have been presented showing the beneficial effects of ciclosporin (CsA) in the management of HS [8, 9]. CsA has been used successfully where patients’ responses to sys- temic corticosteroids were found to be unsatis- factory because of rapid relapses [5]. One case found that a 4-month remission was induced by CsA therapy, and that subsequent flares were milder, but CsA has also been used as a low- dose, long-term suppressive therapy.
A beneficial effect of CsA would be in accor- dance with the described early changes of HS, where a perifollicular lymphocytic infiltrate has been found [10]. In other diseases the use of CsA has furthermore been characterized by a rapid onset of effect, which may be of particular inter- est to HS patients because of the associated pain reduction. No long-term results (years) or larger case series have been reported.
18.3.3 Dapsone
This traditional drug has been widely used in the treatment of acne conglobata. A case series has been published suggesting its efficacy in HS as well [11]. Potentially this drug may have anti- bacterial effects as well, but the main effect is immunosuppressive. Any effect in HS should be suspected as being due to general immunosup- pression rather than a specific effect on neutro- philic granulocytes, which are not common in HS lesions.
18.3.4 Methotrexate
The histological similarities and co-occurrence of HS and Crohn’s disease have led to specula- tion that treatments used for Crohn’s disease may have a role in the management of HS as well. This is further supported by the beneficial effects of biologics in HS (see Chap. 20). Metho- trexate is another drug used in Crohn’s disease that has been evaluated in a small open case se- ries. The results were variable, and although in- dividual patients experienced some relief from symptoms, an overall evaluation suggested only
a weak effect on the severity of HS flares and no apparent effect on the recurrence rate [12]. It is possible that a higher dose of methotrexate than the one examined could influence the results positively.
18.4 Hidradenitis Suppurativa as a Side-Effect of Immuno- suppressive Drugs
HS has also been described as a side-effect of immunosuppression associated with rapamycin (Sirolimus®) treatment [13]. This drug has been reported to be associated with acne-like and other follicular inflammation in renal trans- plant patients. The study was carried out with stringent dermatological evaluation of patients, and an incorrect diagnosis of HS is therefore relatively unlikely. Specific immunosuppressive mechanisms may therefore play a role and not all immunosuppressants may be suitable for use in HS. In addition, bacterial infections may sim- ulate HS to non-dermatologists and cause addi- tional confusion.
18.5 Practical Use of Immuno- suppressive Therapy
Immunosuppressive therapy can be used at all stages of the disease for the benefit of the pa- tient. Essentially it may be directed at two dif- ferent aspects of the disease: disease progression and flares.
When used to treat disease progression it is a long-term therapy aimed at controlling the in- flammation-induced fibrosis of the tissue, and helping the patient to take more control of their disease. The treatment should be continued for at least 3 months with monitoring of the effect as well as possible side-effects specific to the drug chosen. Very often patients have experi- enced a relentless progression of their disease and are therefore highly encouraged by the al- leviation provided by these drugs. The clinical impression is therefore generally favorable, al-
though proper randomized controlled trials are lacking. By viewing HS as any other inflamma- tory skin disease, parallel conclusions may however be drawn about the benefits of such a therapeutic strategy. It may be speculated that long-term immunosuppression and a subse- quent reduction of the inflammatory processes may stop or delay the subsequent fibrosis which forms a major factor in the perpetuation of this disease.
In contrast, treatment of flares is a short-term treatment, in which the immunosuppression is aimed at easing the patients’ problems, but most often it is used in conjunction with other thera- pies that may be perceived as being more cura- tive. Particularly in the early stages of the disease immunosuppression may help gain sufficient control of a lesion to allow more curative surgery, as this is made easier if the tissue is not highly inflamed at the time of the operation.
Intralesional therapy may be used to achieve this (see Chap. 21). Similarly, immunosuppres- sion at later stages may be combined with, for example, antibiotics to treat the combined effects of long-standing HS and superinfection more effectively.
Just as for most other forms of therapy, the data on which these treatments are used are very limited. Publication of additional, larger case series is therefore strongly encouraged, particu- larly if the observations are structured so as to provide information about possible dose–effects relationships, which may help determine the optimum dosage of a given drug for use in a subsequent randomized controlled trial.
In general, immunosuppressive therapy is of- ten perceived to be in conflict with the clinical presentation of HS. This is however a view with a limited understanding of the disease process, which involves considerable, sterile inflamma- tion. Therefore, as with many other dermato- logical conditions it may often be treated with anti-inflammatory or immunosuppressive ther- apies. In addition, these therapies offer the ad- vantage of alleviating patient suffering effec- tively, if not permanently.
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