Metformin for the treatment of hidradenitis suppurativa: a little help along the way

Authors


  • Conflict of Interest
    None declared.

  • Funding Sources
    None declared.

N. Clayton. E-mail:drnicky.clayton@doctors.uk; rverdolini@hotmail.com

Abstract

Background  Despite recent insights into its aetiology, hidradenitis suppurativa (HS) remains an intractable and debilitating condition for its sufferers, affecting an estimated 2% of the population. It is characterized by chronic, relapsing abscesses, with accompanying fistula formation within the apocrine glandbearing skin, such as the axillae, ano-genital areas and breasts. Standard treatments remain ineffectual and the disease often runs a chronic relapsing course associated with significant psychosocial trauma for its sufferers.

Objective  To evaluate the clinical efficacy of Metformin in treating cases of HS which have not responded to standard therapies.

Methods  Twenty-five patients were treated with Metformin over a period of 24 weeks. Clinical severity of the disease was assessed at time 0, then after 12 weeks and finally after 24 weeks. Results were evaluated using Sartorius and DLQI scores.

Results  Eighteen patients clinically improved with a significant average reduction in their Sartorius score of 12.7 and number of monthly work days lost reduced from 1.5 to 0.4. Dermatology life quality index (DLQI) also showed a significant improvement in 16 cases, with a drop in DLQI score of 7.6.

Conclusion  Metformin helps control HS with minimal side effects and good patient compliance and can represent a further agent in the spectrum of treatments available in the treatment of this disease.

Introduction

Hidradenitis suppurativa (HS) is a stubborn inflammatory disorder affecting an estimated 2% of the population. Females are significantly more affected than males.

HS is insidious and develops typically in the second or third decade in otherwise healthy individuals. It should be strongly suspected in post pubertal adults presenting with recurrent, deep furuncular lesions in flexural sites, especially if such lesions respond poorly to antibiotic treatment.

It is characterized initially by the development of deep tender subcutaneous nodules primarily affecting the apocrine gland bearing areas, including the axillae, perineum, and sub and infra-mammary regions.

Over time these nodules may spontaneously rupture forming chronic, relapsing, deep-seated dermal abscesses. Eventually, these become complicated by fibrosis and formation of extensive sinus tracts, which can coalesce and potentially dissect into deep structures including muscle, lymph nodes, and even urethra and bowels. They extrude foul smelling purulent discharge. Subsequent repair with scarring, dermal contractures and in duration of the skin follows.

There is considerable physical pain from these disfiguring lesions as well as the immense social embarrassment. The enormity of its psychological impact on patients’ social, personal, work and familial spheres of life has been well documented.1,2

Spontaneous resolution is unlikely, and progressive disability is commonly experienced by sufferers. It is primarily for this reason that this condition is associated with a high degree of morbidity.

Potential complications from HS include increased risk of squamous cell carcinoma developing in 2–4% of sufferers.3,4 Other long term sequelae are contractures, which can affect limb mobility, serious infections and anaemia.5

The aetiology of HS is still not completely understood.6 It was long thought to have an infective aetiology, being a suppurative disorder, but bacterial colonization has now been shown to be a secondary event and even very potent antibiotic treatments remain unsuccessful, at least in the long term. Staphylococci eradicating combination therapy with Clindamycin and Rifampicin may sometimes be effective,7,8 but improvement is temporary and recurrences common after discontinuation of the treatment.

The peculiarity of distribution within the apocrine glands led it to be considered a disease of the apocrine glands. However, histo-pathology studies have confirmed it to be mostly a disorder of the pilosebaceous unit with the central aspect of this pathological process being follicular structural abnormality and consequent inflammation with apocrine sweat gland involvement remaining a secondary aspect.9–12 A genetic predisposition leading to a specific alteration of the terminal follicular epithelium with a possible dilatation and distortion of the upper infundibular tract seems to be the initial causative factor.13 This would lead to the occlusion of the affected hair follicles with subsequent bacterial infection, pustula formation, fistulization and scarring.

This represents a sequence of events similar in certain aspects to acne vulgaris. It has therefore been strongly suggested that the name of ‘acne inversa’ is a more accurate representation of its pathology.14

Complementing the sequence of events described above is the recent observation of the alteration of sebaceous gland tissue mass in HS sufferers. Recent studies raised suspicion of the possibility of the primary involvement of sebaceous glands in the aetiology of HS, with a generalized reduction of Sebaceous gland tissue mass being demonstrated in perilesional tissue. Sebaceous glands contribute to the local homeostasis of the skin with their antibacterial, antifriction, endocrine and inflammation modulatory functions and it has been speculated that a reduction in their volume or possibly loss of one or more of their specific functions may represent one of the primary changes leading to the cascade of events that lead to HS.15

A further theory about HS having an immunological aetiology with an upregulation of toll-like receptors has also been suggested and immunological disregulation might represent another co-factor.16,17 In particular an exaggerated expression of Toll-like receptor 2 has been found in the macrophages and dendritic cells infiltrating the dermis in HS affected areas. Toll-like receptor 2 is known to have a pivotal role in the innate immune response, and its overexpression had been suspected to represent a possible contributory factor in the pathogenesis of HS.18 Also neutrophilic cells isolated from HS patients had been found to be responsible for an exaggerated release of free oxygen radicals, suggesting that dysfunctionality of neutrophils might play a role in the pathogenesis and progression of this disease.17The use of immunosuppressants, and biologic inhibitors of TNF-α, although promising in some cases,19–22 have however given conflicting results in other cases,23 leaving immunological disregulation as a theory of uncertain significance.

The notable female preponderance, the association with polycistic ovary syndrome (PCOS) and the observation that HS may decline significantly following menopause has suggested a possible hormonal influence.24 Past studies, having observed the association of HS with irregular menstruation, hirsutism, premenstrual HS flares and acne vulgaris, suspected high total testosterone concentrations and higher free androgen index as possible factors.25 Although some studies have argued against Hyperandrogenism as a possible cause, as androgen levels were found normal in a significant proportion of HS patients,26,27 more recent studies seem to have definitely confirmed a hormonal influence, with a statistically significant association with obesity, hyper-androgenism, and PCOS (calculated as 38% of analyzed cases). Gene mapping of familial cases seem to have identified a genetic link13 and further studies suggested a hormonal influence on gene expression.

In terms of treatment, an effective standalone therapy for HS has not yet been established. Traditional treatments have included retinoids, antibiotics (including eradication treatment with Clyndamycin and Rifampicin,7,8) and Dapsone, both systemic and topical.28–30 Clinical and histological similarities of HS to acne vulgaris have led to treatment attempts with Isotretinoin. This medication, which is very effective for acne, is, however, almost redundant for HS. There is only anecdotal evidence substantiating any successful outcomes with its use. Acitretin has been more successful, however, its use is restricted to male patients (who are less commonly affected than females), and females of non-child bearing age (not frequently sufferers of this condition).31,32

As a result of the possible hormonal influence, there have been several trials conducted using anti-androgen therapies, such as cyproterone acetate33and finestride,34 with some documented improvement in disease activity.

Anecdotal reports of improvements obtained with other various treatment options have also been published over the years: radiation therapy,35,36 Botulinum toxin,37 anti TNF-α antagonists19 and PDT,38,39 have been used with variable success.

Carbon dioxide laser therapy has been successfully used to ablate tissue, producing results similar to standard surgery at its endpoint.40

Early definitive surgical intervention has been regarded as one of the most effective treatments for intractable HS. Surgical removal of the entire follicular sweat gland apparatus with generous excision margins is currently being advocated as the gold standard.4,41,42

However poor surgical outcomes, often with results unacceptable to patients, have frequently been cited with surgery; the most commonplace complications being high recurrence rates, scarring, or skin graft failure.

This frustrating scenario led us to begin a systematic analysis of cases under our care and an analysis of the data collected was begun in an attempt to improve and optimize outcomes or at least contribute to broadening the spectrum of treatment strategies.

As the vast majority of our patients were females with a relatively high BMI, it suggested that sex hormone balance could represent a possible treatment target, confirming the data found in specialized literature. Further findings from our analysis demonstrated that a number of subjects suffered from low glucose tolerance and that some cases were also affected by PCOS. These observations provided the rationale for considering Metforminas a novel potential treatment option.

Aim

To evaluate the clinical efficacy of Metformin in treating cases of HS, which have not responded to standard therapies.

Material and methods

Twenty-five patients with HS were identified and recruited from amongst a set of dermatology outpatientswith no past medical history of previous Metformin use. Twenty-four of them were already diagnosed with the condition and had already received numerous and protracted courses of antibiotics with poor or very minimal results. Twenty-two were females, three males (See Tables 1 and 4). In two cases the disease affected both mother and daughter.

Table 1. Sartorious Score
PtInitialsSexAgeLocationSartorius baselineSartorius 12 weeksSartorius 24 weeks
 1MMF25Groins, vulva, perianal584136
 2NQF30Groins, vulva, perianal402326
 3MNF19Groins, axillae271419
 4JTF45Perianal, groins, vulva, breasts554021
 5SMF29Axillae, groins311717
 6NNLF46Armpits, groins, vulva404240
 7FAF24Axillae171414
 8SAF51Axillae, breasts, groins512017
 9SAF20Axillae181811
10MMF42Axillae353536
11JHF45Breasts, axillae, groins492427
12ATF22Groins, perianal262213
13IPDTF46Axillae, breasts363313
14IDF19Axillae, groins272726
15MHM49Perianal, groins545155
16BSAM19Axillae272117
17THYM17Axillae221711
18LSMF47Breasts323822
19CGF44Axillae343633
20HSF23Axillae, breasts292416
21GWMF19Axillae, perianal, groins534329
22MUMF45Axillae, breasts281415
23GBDIF23Groins, breasts261812
24BASAF17Axillae282728
25GSMF21Axillae17108
Table 2. T-test for dependent samples (Sartorious score)
VariableMeanMinimumMaximumStandard deviationDifferenceStandard deviation difference P
Time 034.4017.0058.0012.460.00000.00001.0000
Time 12 Weeks26.7610.0051.0011.227.64008.845340.0055
Time 24 weeks22.3918.0055.0011.3012.782610.09300.0001
Table 3. Sartorius Score's trend at 0, 12 and 24 weeksThumbnail image of
Table 4. DLQI Scores
PatientInitialsSexAgeLocationDLQI – baselineDLQI – 12 weeksDLQI – 24 weeks
 1MMF25Groins, vulva, perianal241311
 2NQF30Groins, vulva, perianal1657
 3MNF19Groins, axillae701
 4JTF45Perianal, groins, vulva, breasts1782
 5SMF29Axillae, groins823
 6NNLF46Armpits, groins, vulva242123
 7FAF24Axillae1188
 8SAF51Axillae, breasts, groins1441
 9SAF20Axillae9104
10MMF42Axillae201820
11JHF45Breasts, axillae, groins1034
12ATF22Groins, perianal13104
13IPDTF46Axillae, breasts19127
14IDF19Axillae, groins12138
15MHM49Perianal, groins252225
16BSAM19Axillae171010
17THYM17Axillae18147
18LSMF47Breasts11146
19CGF44Axillae131412
20HSF23Axillae, breasts1262
21GWMF19Axillae, perianal, groins1472
22MUMF45Axillae, breasts1194
23GBDIF23Groins, breasts14105
24BASAF17Axillae181818
25GSMF21Axillae1812

The diagnosis of HS was made on clinical grounds by two clinicians, and in two cases, biopsies were taken so as to rule out a possible cancerous transformation (Marjolin ulcer).

All the patients were extremely frustrated with their condition, and a few had even expressed suicidality as a direct consequence. Eleven patients had been sufficiently depressed to have been managed on anti-depressants.

All the patients had already received orthodox treatments, with both long term Augmentin, Erythromycin, Doxycycline or Rifampicin in combination with Clindamycin. Eleven had also received Isotretinoin and one man had received both Isotretinoin and Acitretin. Another seven had been hospitalized on several occasions to be treated surgically with excision of the affected areas, or drainage, with disappointing outcomes.

Possible side effects were discussed and informed consent was obtained as per protocol.

Metformin was up-titrated from a starting dose of 500 mg once/day (OD) in the first week, to 500 mg twice/day (BD) in the second week, with a maximum dose of 500 mg three times/day (TDS) introduced from the third week onwards.

The maximum Metformin dose that nine patients in the series could tolerate (due to gastrointestinal discomfort or lifestyle compromise) was 500 mg BD. The Metformin dose for another patient with a particularly high BMI was suitably adjusted to 850 mg BD.

Patients who suffered from both diabetes and HS, and had been started on Metformin in the past by other clinicians or GPs managing their care were not included in this study.

In one instance, a newly diagnosed patient asked to be started on Metformin immediately, as her mother was responding successfully to this treatment.

Prior to starting treatment, patients were assessed by both Dermatology life quality index (DLQI) and Sartorius score43 and then again at 12 and 24 weeks (Tables 1 and 2).

Statistical analysis was then performed by using Student’s t-test.

Results

Six patients remained unresponsive to treatment. However comparison of the results at time 0 and at subsequent follow up appointments (after 12 weeks from the first appointment, then after a further 12 weeks), showed a steady improvement in the majority of the patients (Figs 1–3).

Figure 1.

 This lady suffered with recurrent boils under the armpit for over 20 years. The use of Metformin determined a consistent improvement (Fig. 1b).

Figure 2.

 This young man was refractory to any type of antibiotic treatment. After Metformin was initiated, the condition subsided and after 24 weeks no inflamed spots were present (Fig. 2b).

Figure 3.

 This patient suffered with Hidradenitis Suppurativa for 22 years. Fig. 3b Shows the clinical picture at week 12.

Severity, calculated by Sartorious score, dropped from severe to mild/moderate in 48% of the cases (12 out of 25) with a reduction of the average score from 40.7 to 21. In another 7 cases there had been only marginal improvements which however were clearly notable when compared with previous photographs, with a drop from an average of 12.7 to 7.3. In general Sartorious score improved in 19 patients (76%) with a reduction of the Sartorious score from an average of 33.8 to 18.1. The inability to attend work or social events also fell: in particular the number of work days lost dropped from an average of 1.5 per month to almost zero (0.4). DLQI also dropped significantly (more than 50%) in 16 out of 25 cases (64%), with a reduction from an average of 14 to 4.1 and the patients seemed not to be as troubled by the disease as much as before. In three patients the DLQI only improved marginally (reduction from 13.3 to 8) and in six remained at the same level.

Depression, which had been a major issue for 11 patients, became a non severe issue for the whole group but four patients. Unfortunately, one of the patients in whom suicidality had been a persistent issue, failed to respond to treatment with Metformin, and severe depression and an inability to cope with life and work remained.

Sartorius score (See Tables 1–3)

Eighteen patients had clinically improved with an average reduction in Sartorius score of 12.7. In seven patients the improvement was significant, with reduction of the Sartorius Score of 50% or more.

Seven patients (28%) had no response.

DLQI (See Tables 4–6)

Table 5. T-test for dependent samples (DLQI)
VariableMeanMinimumMaximumStandard deviationDifferenceStandard deviation difference P
  1. Marked differences are significant at P < 0.05000.

Time 015.00007.00025.0004.95810.000000.0000001.000000
Time 12 Weeks10.08000.00022.0005.95764.920004.6180800.0017
Time 24 Weeks7.652171.00025.0007.11987.608704.7743550.000009
Table 6. DLQI trend at time 0, week 12 and week 24.Thumbnail image of

Nineteen patients improved, with an average reduction in DLQI = 7.6.

The improvement was quite significant in sixteen patients (64%).

Number of work days lost reduced from 1.5 to virtually zero (0.4).

Depression, previously ranked as ‘severe’ for 11 patients, became non-severe for all except four patients.

Discussion

HS is a chronic disease which impacts on patients both physically and psychologically. Current treatment options, both medical and surgical, do not assure complete recovery, and relapse is common. In early 2004 we began analyzing cases under our care in order to improve treatment. The patients were almost entirely female with the majority of them being overweight, which suggested to us that the sex hormone balance could have been a possible treatment target.

Further observations from this series indicated that there were a disproportionate number of patients suffering from low glucose tolerance, frank diabetes and PCOS.

The link between HS and PCOS has been well established, with some authors even supporting the view that all female patients presenting with HS should be evaluated for underlying PCOS and insulin resistance. Recent literature also advocates that hormonal manipulation should be attempted in all women presenting with PCOS. After it was demonstrated that hyperinsulinaemia is a fundamental disturbance in PCOS, the use of insulin-sensitizing drugs such as Metformin was introduced, and is now considered the first choice of drug for patients affected with this condition, either alone or as an adjunct to other treatments.44–46

A literature search also showed that antiandrogen therapy was superior to oral antibiotic therapy (55% vs. 26%)8,47 in treating HS. Cyproterone acetate has had a degree of success in some cases but in our experience however, even with some notable successes, the results of Cyproterone acetate therapy were invariably below expectations.

In light of these considerations, we thought it very likely that Metformin could have a role to play in the treatment of HS: Metformin improves glucose utilization, both in lowering its level and by increasing receptor sensitivity. The anti-androgenic properties of Metformin have long been established, and androgens imbalance have been found to be a contributory factor to HS (see ante).

Metformin is now the first line treatment for restoring cyclicity and ovulation in women with polycystic ovarian syndrome,48,49 the accompanying improvement in glucose utilization may also play a part in ameliorating the symptoms in HS.

In our view Metformin provides a new option for the treatment of HS that may represent a new approach. The mechanism as to how Metformin operates in the treatment of HS is not entirely clear and studies are still needed, but it may be that it works through two pathways. The first is through its anti-androgenic effect, thus influencing expression of the genes possibly involved in this condition and the second might be through lowering the insulin resistance that is usually present in some patients with HS.

Metformin induced a remission of the disease in the sense that if pustules were still present, they were less numerous, less severe and less debilitating. The disease was also not as painful with improvement to quality of life and the majority of patients continued on the treatment well past the time of the trial. The majority of the patients reported that, although the condition was still present, it was more tolerable, and not as debilitating as before.

Very importantly no significant adverse effects were recorded and blood tests regularly taken during the trial period have remained within the normal range for all patients. Only minor gastrointestinal disturbances at the beginning of treatment were recorded. Even patients who did not enroll in the study because of their difficulties in attending appointments (and who remained inconsistent with their follow-up attendances) continued using Metformin which was prescribed by their GPs.

Conclusion

Metformin helps control HS with minimal or null side effects and good patient compliance. Based on our results we think that this treatment is a good alternative to current treatments such as high dose, long term antibiotics. Larger trials to further evaluate the benefits are indicated.

Ancillary