Clinical and Epidemiological Characteristics of Hidradenitis Suppurativa Patients with Paradoxical Psoriasiform Reactions following Treatment with Adalimumab

Abstract

Introduction

Immunomodulation using TNF-α inhibitors (anti-TNF-a), especially adalimumab, is highly effective in the treatment of hidradenitis suppurativa (HS) in cases that are poorly controlled by conventional treatments. However, paradoxical psoriasis represents a peculiar type of psoriasis that may occur de novo or as the worsening of pre-existent psoriatic lesions during treatment with adalimumab.

Case Presentation

We reported 4 cases of patients suffering from HS, who developed paradoxical psoriasis after treatment with adalimumab for their HS, analyzing their clinical and epidemiological characteristics. All 4 cases were middle aged, smokers, overweight or obese. Half of the patients were males (50%). All of them were classified as Hurley stage III, with a mean duration of HS of 20 years. Two patients had a family history of psoriasis. All 4 patients had been on at least 5 months of successful treatment with adalimumab before the onset of the lesions.

Conclusions

Paradoxical psoriasis emerged in 4 patients who received at least 5-month regimen of adalimumab for long-lasting HS. Although different mechanisms have been hypothesized for such events, the exact underlying pathogenetic pathway remains unclear. Consistent reporting of such rare cases, and on a larger scale, is encouraged in order to enrich the available literature.

Established Facts

• Genetic predisposition for psoriasis of patients with HS may be a responsible factor for the development of paradoxical psoriasiform lesions.

• Although classical and paradoxical psoriasis clinically share common clinical characteristics, they likely represent two different entities with different pathophysiological pathways.

• The clinical manifestations of paradoxical psoriasis include typical psoriasiform lesions, palmoplantar pustulosis, and severe involvement of the scalp leading to alopecia.

Novel Insights

• Consistent reporting of such events in the future is needed to establish a clearer clinical and pathogenetic association between these two entities.

• Paradoxical psoriasiform reaction may be controlled by the addition of calcipotriol/betamethasone foam.

Introduction/Literature Review

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease, also called acne inversus, with a characteristic clinical presentation of recurrent or chronic painful, suppurating lesions including deep-seated nodules and abscesses, draining tracts, and fibrotic scars, especially in the intertriginous areas [1, 2]. The prevalence of HS is between 0.05% and 4.10% [3]. This estimated prevalence may be underestimated due to under-reporting and misdiagnosis of the disease, resulting in a delay of the correct diagnosis by approximately 7 years [1]. The age of onset is between 20 and 40 years. Women are more commonly affected than men. The exact pathogenetic mechanism remains unclear [4]. However, several genetic, anatomical, immunological, and behavioral factors have been associated with the course of this cutaneous disease. Hereditary factors, obesity, metabolic syndrome, smoking, hormonal influence, and mechanical stress have also been reported as contributing factors to the development or exacerbation of HS [5]. HS has a negative psychological impact on patients' quality of life. Diagnosis is mainly based on clinical presentation [4, 5]. The Hurley staging system is a widely used grading system in patients with HS that takes into account the extent and severity of the disease and classifies them into three severity groups [6]. HS can be treated with medicines and surgical interventions. Biologic agents can be a therapeutic weapon for patients suffering from moderate to severe HS [7]. In particular, adalimumab is the only TNF-a inhibitor (anti-TNF-a) indicated for the treatment of moderate to severe HS [8]. However, anti-TNF-a is associated with adverse reactions. Paradoxical psoriasis represents a peculiar type of psoriasis that may occur de novo or as the worsening of pre-existent psoriatic lesions during treatment with anti-TNF-a [2]. The pathogenetic mechanisms underlying the induction of these events are not clear yet. Therefore, it is crucial to fully understand the pathogenesis of these reactions, as well as the genetic susceptibility of patients suffering from PPR (paradoxical psoriasiform reaction) after treatment with adalimumab for HS. Herein, we report 4 cases of patients suffering from HS, who developed PPR after treatment with adalimumab for their initial diagnosis.

Case Presentation

Case 1

A 47-year-old overweight and smoker male with a 23-year history of HS (Hurley stage III) presented with a PPR following 5 months treatment with adalimumab. The patient reported a family history of psoriasis and HS. The anatomical sites of lesions included elbows, back, and thighs and the extent of body surface area (BSA) was 1%. The morphology of psoriasiform lesions was that of psoriasis vulgaris (chronic plaque type). Continuation of adalimumab did not improve the course of PPR, despite addition of calcipotriol/betamethasone foam. Furthermore, HS got worse; hence, adalimumab was discontinued and replaced with secukinumab; the latter yielded satisfactory results, and the psoriasiform lesions were finally improved.

Case 2

A 58-year-old obese and smoker male patient with a 9-year history of HS (Hurley stage III) presented with a psoriasiform rash affecting 1% of his BSA. Duration of treatment with adalimumab before PPR onset was 6 months. The target lesion was located on the right elbow, presenting as chronic plaque psoriasis. The lesion was kept under observation during his treatment with adalimu­mab for HS. Patient had had no family medical history of psoriasis or HS. The course of PPR remained stable during adalimumab treatment; clinical improvement was observed when calcipotriol/betamethasone foam was added.

Case 3

A 47-year-old overweight and smoker female, with a positive family medical history of psoriasis and HS, presented with psoriasiform lesions on her elbows after treatment with adalimumab for HS. The patient had a 22-year history of HS (Hurley stage III). Approximately 1% of her BSA was involved, presenting with chronic plaque psoriasis. The duration of administration of adalimumab before the development of psoriasiform eruptions was 7 years. Topical treatment with calcipotriol/betamethasone foam failed to improve PPRs; considering also the worsening of HS, we were led to discontinue adalimumab and switch to secukinumab. This resulted in improvement of PPRs.

Case 4

A 44-year-old overweight and smoker female with a 26-year history of HS (Hurley stage III) presented with a PPR following 14-month treatment with adalimumab for HS. The lesions appeared on soles as pustular psoriasis and the extent of BSA was 2%. Patient had had no family medical history of psoriasis. Course of psoriasiform eruptions remained stable during adalimumab treatment. PPRs were improved and finally controlled by the addition of calcipotriol/betamethasone foam.

Discussion

The unpredictable manifestation of the so-called paradoxical eruptions during treatment with adalimumab in patients with HS has emerged as a type of drug-related adverse event with complicated pathophysiology. In our case series study (Table 1), we investigated the clinical and epidemiological characteristics of patients with moderate to severe HS, who developed PPR following standard treatment with adalimumab. All 4 cases were middle aged (mean value 49 years old, range 44–58 years old), smokers, overweight or obese. Half of the patients were males (50%). All of them classified as Hurley stage III, with a mean duration of HS of 20 years (range 9–26 years). Two patients have had a family history of psoriasis. Although it would be desirable to conduct a biopsy, the lesions were typical psoriatic and therefore the diagnosis was based on history and clinical examination. All 4 patients had been on successful treatment with adalimumab for at least 5 months before the onset of PPR (range from 5 months to 7 years). In all 4 cases, the extent of PPR was very limited (1–2%) affecting specific psoriasis-prone sites (extensor surfaces, i.e., elbows, back, soles), while morphology was that of psoriasis vulgaris in 3 out of 4 patients and pustular psoriasis in the remaining 1 patient. Two patients improved with the addition of calcipotriol/betamethasone foam. In the remaining two patients, we decided to discontinue adalimumab because of failure of topical treatment for PPR combined with HS worsening. Switching to secukinumab led to PPR improvement (Table 1).

Table 1.

Clinical and epidemiological characteristics of four HS patients with PPRs following treatment with adalimumab

	Pt#1	Pt#2	Pt#3	Pt#4
Gender	Male	Male	Female	Female
Age, years	47	58	47	44
Smoking	Yes	Yes	Yes	Yes
Hurley stage	III	III	III	III
Duration of HS, years	23	9	22	26
Family history of Ps/Hs	+/+	−/–	+/+	−/+
Duration of adalimumab before PPR onset	5 months	6 months	7 years	14 months
Response of HS to adalimumab	No	Yes	No	Yes
BSA with PPR, %	1	1	1	2
Anatomical sites with PPR	Elbows, back, and thighs	Right elbow	Elbows	Soles
Morphology of PPR	Chronic plaque psoriasis	Chronic plaque psoriasis	Chronic plaque psoriasis	Pustular psoriasis
Course of PPR with regard to treatment	Worse after adalimumab discontinuation − improvement with secukinumab	Stable during adalimumab treatment − improved after addition of calcipotriol/betamethasone foam	Worse after adalimumab discontinuation − improvement with secukinumab	Stable during adalimumab treatment − improved after addition of calcipotriol/betamethasone foam

Psoriasiform lesions have been described as a well-established complication of anti-TNF-a treatment in immune-mediated inflammatory diseases, including HS [8]. PPRs have been reported to occur in up to 19.5% of patients suffering from HS when they are treated with anti-TNF-a agents [9]. Their clinical manifestations include typical psoriasiform lesions, palmoplantar pustulosis, and severe involvement of the scalp leading to alopecia [9, 10]. These PPRs are probably related to the depletion of TNF and represent an ongoing type-I interferon-driven innate inflammatory process [11]. In PPRs, the blockade of TNF-α results in an excess of IFN which induces T-cell migration to the skin [11]. Although classical and paradoxical psoriasis clinically may share common clinical characteristics, there is some evidence that they likely represent two different entities with different pathophysiological pathways [12, 13]. Furthermore, the genetic predisposition for psoriasis of patients with HS may be a responsible factor for the development of these lesions [2]. Psoriasis and HS are also likely to share a common genetic predisposition [2]. According to Ikeya et al. [11], MEFV mutations might be potential predisposing factors for the paradoxical reactions, but there are no evidence data for this hypothesis up to date. It is interesting to note that all our patients were smokers and overweight/obese, which are also common risk factors for HS. Smoking and obesity have an important association with the severity of HS [4]. In accordance with our case series, adalimumab and other anti-TNF-a agents were discontinued and replaced in almost 50% of patients with PPR reported in the literature due to the severity of the lesions [9, 10]. Although paradoxical reactions may have disease-specific features, scarce data are available in the literature concerning the extent, anatomical sites, as well as the morphology of PPR to compare with our results. Although similar cases have been previously reported in the literature, they remain worth of further exploration, especially when considering their rarity and the fact that factors other than genetic may predispose to their appearance, as found in 2 out of our 4 cases.

Conclusion

In conclusion, we report 4 cases of patients suffering from HS, who developed PPR after treatment with adalimumab for their HS. Scarce data are available regarding these rare reactions in HS patients. Although we can hypothesize several different pathogenetic mechanisms, there is not a clear explanation for this rear entity. Consistent reporting of cases on a larger sample is encouraged in order to enhance available literature regarding the etiology, the incidence, and the disease-specific genetic and clinical predisposition of patients presenting with PPR during adalimumab treatment.

Statement of Ethics

Ethics approval was not required. This was decided by the Ethics Committee of University Hospital “ATTIKON.” Written informed consent was obtained from all participants for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors declare that there were no funding sources supporting this study.

Author Contributions

All authors have contributed significantly and seen and approved the final version of the submitted manuscript. Antonios Kanelleas: conceptualization, data curation, supervision, writing − original draft, and writing − review and editing. Ourania Efthymiou: conceptualization, data curation, supervision, writing − original draft, and writing − review and editing. Eleni Routsi: data curation, formal analysis, writing − original draft, and writing − review and editing. Dimitrios Sgouros: writing − original draft and writing − review and editing. Georgia Pappa: data collection and writing − review and editing. Evridiki Tsoureli Nikita: data collection and writing − review and editing. Evangelia Bozi: data collection and writing − review and editing. Alexandros Katoulis: conceptualization, supervision, and writing − review and editing.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.