Paradoxical Hidradenitis Suppurativa during Biologic Therapy

Paradoxical Hidradenitis Suppurativa during Biologic Therapy: History

Please note this is an old version of this entry, which may differ significantly from the current revision.

Subjects: Allergy

Contributor: Angelo Ruggiero

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease usually occurring after puberty with painful, deep-seated, inflammatory lesions in the apocrine gland-bearing areas of the body. Paradoxical reactions during biologic treatments may be defined as the appearance or exacerbation of a pathological condition that usually responds to this class of drug while treating a patient for another condition.

paradoxical hidradenitis
hidradenitis suppurativa
paradoxical reaction
biologics

1. Introduction

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic, inflammatory skin disease usually occurring after puberty with painful, deep-seated, inflammatory lesions in the apocrine gland-bearing areas of the body [1,2]. HS affects about 1% of the global population. HS typically occurs after puberty, with the average age of onset in the second or third decades of life, and with a female predominance [2]. Although HS pathogenesis is still unproven, recent major research advantages have increased our knowledge of the mechanisms behind HS lesions. Particularly, follicular occlusion followed by follicular rupture has been shown to be crucial to HS development, leading to immune response activation, and resulting in typical clinical HS lesions [2,3,4]. Moreover, an increased and imbalanced cytokine production—such as interleukin (IL) 17 and tumor necrosis factor (TNF) α—as well as an unopposed type I interferon production, and a change toward a helper T cell 1/helper T cell 2 profile, may all play a role in HS and psoriasis [4,5]. Furthermore, in the last few years, many studies have hypothesized that HS may be triggered by genetic and environmental factors, including drugs [3]. Moreover, the de novo onset of HS has been reported after the administration of biologic treatments for chronic inflammatory diseases. Indeed, patients treated with biologic therapies for chronic inflammatory disorders may experience the onset of new skin diseases as paradoxical reactions. These are defined as the occurrence, during treatment with biologics, of a disease that is usually responsive to this class of drug [6,7]. Psoriasiform reaction, HS, uveitis, inflammatory bowel diseases, and Pyoderma Gangrenosum were the most commonly described paradoxical reactions during biological treatment [8]. In particular, the most commonly reported was psoriasis, which is a paradoxical skin reaction since it may be both induced and treated with anti-TNF [6,7]. In recent years, even more paradoxical adverse events have been described during treatment [7,8,9]. Since the recent increased use of biologic treatments in HS, an increased number of paradoxical HS occurrences have been reported. To date, TNF inhibitors represent the only class of biologics used in HS, particularly, adalimumab is the only biologic agent formally approved for the management of moderate to severe HS [10,11,12]. Although the use IL 17 inhibitors in HS is still off-label, in the literature, data are growing regarding their efficacy (particularly for secukinumab and ixekizumab), linked with an increasing number of paradoxical HS reactions [5,10,11].

2. Paradoxical Hidradenitis Suppurativa during Biologic Therapy

3.1. Anti-TNF α

TNF α is considered as a primary driver of the inflammatory process behind HS [12]. Indeed, significantly higher TNF α concentration was found in lesional HS skin, perilesional HS skin and the serum of HS patients compared with healthy controls, although no significant correlation between TNF α levels and disease severity, including the intensity of inflammation, has been demonstrated [21,22]. Moreover, the blockage of TNF α showed significant improvements on HS. Hence, anti-TNF α represents the only approved biologic for moderate and severe forms of HS. Many cases of paradoxical skin reactions—especially psoriasis—secondary to the use of TNF α inhibitors have already been reported, as well as other immune-mediated inflammatory diseases. Moreover, anti-TNF also represents the most reported biologic class linked with paradoxical HS.

3.2. Adalimumab

Adalimumab, a fully human monoclonal IgG1 antibody directed toward membrane-bound TNF α is the only FDA-approved biologic therapy for moderate to severe HS [6,23,24]. The approved standard dosing regimen of adalimumab is 160 mg at baseline (week 0), and 80 mg at week 2, followed by 40 mg weekly from week 4 [16,25,26,27,28]. Some cases of paradoxical HS have been reported in patients suffering from chronic inflammatory bowel diseases treated with adalimumab who developed moderate to severe forms of paradoxical HS [20,29]. Indeed, in a retrospective study including 25 patients affected by autoimmune diseases, Faivre et al. reported 12 cases of paradoxical HS during adalimumab treatment, which showed improvements after adalimumab suspension and a HS relapse when restarting the treatment [6]. Furthermore, Delobeau et al. reported four cases of patients suffering from autoimmune diseases (such as Crohn’s Disease, juvenile idiopathic arthritis, severe plaque psoriasis and ankylosing spondylitis) developing paradoxical HS under adalimumab [13]. In all these studies, females were the dominant gender [6,13,14,15,20,29]. Regarding the need for adalimumab discontinuation or not, the recently proposed algorithm management of paradoxical HS proposed to continue adalimumab in mild forms and discontinue treatments only in the case of progressive worsening or in more severe forms. In all cases, additional treatment was required to improve HS outcomes.

3.3. Etanercept

Etanercept is a dimeric fusion protein that binds to the soluble and leukocyte membrane-bound TNF α receptor. FDA approved the use of etanercept to treat moderate to severe rheumatoid arthritis, moderate to severe polyarticular juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis. To date, fewer cases of paradoxical HS have been reported with etanercept than adalimumab [16,30]. Particularly, Pellegrino M. et al., reported the case of a 30-year-old male diagnosed with juvenile idiopathic arthritis who developed paradoxical HS lesions during etanercept treatment [30]. Only three other cases have been reported of paradoxical HS during etanercept in patients suffering from other autoimmune diseases [16]. In all cases, etanercept suspension lead to an improvement of HS lesions and a remission after the addition of other treatments [16,30].

3.4. Infliximab

Infliximab is a chimeric monoclonal antibody approved to treat a number of autoimmune and chronic inflammatory diseases, including CD, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, and Behçet’s disease. Even if adalimumab still represents the only FDA-approved biologic for HS, infliximab has been demonstrated to be an effective treatment for HS and, as confirmed from recent guidelines, it could be proposed as a second line biologic treatment for moderate to severe HS (recommendation grade B; evidence level: 2) [31]. Although lower than for adalimumab, some cases of paradoxical HS have been reported [31,32]. Particularly, Savaşan et al. [31] reported the case of a young patient suffering from CD who developed, for the first time, HS lesions as a paradoxical effect of infliximab treatment [33]. Similarly, cases of paradoxical HS were reported in patients suffering from CD treated with infliximab [32,33,34,35,36].

3.5. Other Biologic Classes

Although anti-TNF still represents the only FDA-approved class of biologic treatment for moderate to severe HS, new emergent treatments have been shown to be potentially effective therapies in the management of unresponsive HS forms [10,11,17]. Hence, with the progressively increased use of these new drugs, the cases of paradoxical HS reactions are slowly increasing in the literature.

3.6. Anti-IL-17

Increased IL 17 levels have recently been found in serum of HS patients linked with a significantly increased number of IL 17-producing cells in both affected and non-affected skin of HS patients [3]. Indeed, recent clinical trials with secukinumab have been performed to evaluate its efficacy and safety in moderate to severe HS. Although the use of anti-IL 17 is still off-label in HS, data are growing in the literature regarding their efficacy (particularly for secukinumab, a fully human IgG1 kappa monoclonal antibody targeting IL 17A) [5,10,11,17,37]. With regard to paradoxical HS, few cases have been reported with the use of secukinumab [13,17,18,37]. Particularly, Navarro et al. reported the case of a patient suffering from severe psoriasis unresponsive to anti-TNF, who developed paradoxical HS lesions after secukinumab treatment [17]. Moreover, a previously published article (Marasca et al., 2019 [38]) highlighted the immunological complexity behind HS, showing the potential double pathophysiological face of secukinumab in HS, describing a case of secukinumab-induced HS and a case of HS provoked by adalimumab treatment and controlled with secukinumab therapy [18]. Hence, the real role of secukinumab in the management of HS is still not well clarified, and it is a possible trigger for paradoxical HS lesions.

3.7. Anti-IL-12/23 and Anti-IL-23

Ustekinumab is a fully human monoclonal antibody against IL 12/23, acting on Th1 and Th17 pathways [39]. Although the use of anti-IL 12/23 in the management of moderate to severe HS is still off-label, several case series and studies have been reported about its possible efficacy in unresponsive and severe HS [40,41]. Indeed, in the literature, some case reports showed the possible role of ustekinumab in HS management [41,42]. However, a phase II open label study evaluating ustekinumab use in moderate to severe HS showed only limited benefits [42]. With regard to paradoxical HS, to date only one case has been described. Particularly, Gkini et al. reported the case of a 19-year-old female treated with ustekinumab for severe psoriasis, who developed HS lesions (Hurley stage II), requiring a surgical approach [19]. Anti-IL 23 drugs (guselkumab, risankizumab, tildrakizumab) represent the latest class of biologics approved for the treatment of moderate to severe psoriasis [43,44,45,46]. To date, the efficacy and safety of anti-IL 23 in the management of HS have been described only in some case series, showing contrasting results [47,48,49,50]. Indeed, the precise role of IL 23 in HS is not yet fully understood. However, previous findings suggest that the IL 23/Th17 pathways seem to be crucial in the pathogenesis of HS, including IL 23, suggesting a potential role of anti-IL 23 in HS management [50]. With regard to paradoxical HS during anti-IL 23 treatment, no cases have been reported to date.

3. Summary

TNF-α is a proinflammatory cytokine produced by innate and adaptive immune cells, has been shown to play a central role in HS [2,3,4]. These findings result in the approval of targeted therapy (anti-TNF) for the management of most severe forms of HS [3].

Typical examples of paradoxical adverse effect are: psoriasis (such as palmoplantar pustular), psoriasiform reactions, and HS. These reactions have been mainly reported in patients during biologic treatment for rheumatoid arthritis or inflammatory bowel disease [29]. However, the exact underlying physiopathologal mechanism behind these paradoxical reactions is unknown, although it has been showed that multiple immunological pathways may be involved. Particularly, one of the most important factors behind paradoxical reactions could be cytokine imbalance, which could play a key role in the development of these paradoxical reactions [6].

Although the pathogenesis of paradoxical HS induced by biologics is still unproven, it has been observed that, in genetically predisposed individuals, the introduction of biologics may induce a modulation of the innate immune system, leading to an alteration of the cytokine balance, and an increase in pro-inflammatory cytokines [38]. Nowadays, adalimumab represents the most commonly used biologic treatment involved in the onset of paradoxical HS. Particularly, a recently published multicenter retrospective study reported paradoxical HS under biological agents, with adalimumab being responsible for 48% of new HS onset cases [6]. TNF α inhibitors may cause modification of the local cytokine balance and activate alternate pathways, namely type 1 interferon and the IL 1-related family of inflammation mediators, in selected patients. The production of IL 1b is increased up to 54-fold in conventional HS skin, compared with healthy control skin, and IL 1 receptor antagonists have shown efficacy in HS. Individual susceptibility is required if further up-regulation of the IL 1 pathway is involved in TNF α inhibition, because adalimumab reduces IL 1b levels in conventional HS. It is also important to consider that, due to the larger use of this class in the management of HS, the paradoxical reactions after their use (particularly with adalimumab) are reported most frequently, without implying that there is a higher individual risk of causing paradoxical HS. As consequence, a challenging issue is whether or not to continue anti-TNF treatment after the onset of paradoxical HS. Indeed, a management algorithm for paradoxical HS has recently been proposed which suggested to continue anti-TNF treatment in mild paradoxical HS forms, suggesting a suspension in the case of a progressive worsening, or at the beginning in more severe forms [6].

In order to clarify the role of adalimumab and other anti-TNF involved in HS paradoxical reactions, including infliximab and etanercept, an imbalance has been supposed, induced by TNF blockage in the cytokine pool and a consequent activation of type I interferon or IL 1 beta, together with the possible role of occult infections [51,52]. Although adalimumab still represents the only FDA-approved biologic therapy in HS management, it has also been recently proposed that a key role is played by the IL 17 pathway in HS pathogenesis. Indeed, increased serum levels of IL 17 have been found in patients with HS, as well as a significantly increased quantities of IL 17-producing cells in both lesional and perilesional HS skin, compared with healthy subjects [2,3]. Indeed, anti-IL 17s, particularly secukinumab and ixekizumab, have been proposed as treatment options for moderate to severe HS, being also reported as possible effective therapies in some case reports [4,5,6,7]. Furthermore, secukinumab is being investigated in a phase III trial for HS treatment. Although only a few cases have been reported, anti-IL 17 has been linked to the development of paradoxical HS [5,10,11,17,18,37,38]. Indeed, HS and inflammatory bowel diseases, such as CD, share genetic susceptibility, common clinical manifestations at the gut and skin, and some immunologic features. Some genes, for example SULT1B1 (OMIM 608436) and SULT1E1 (OMIM 600043), have been associated with HS and inflammatory bowel disease. Emerging studies have shown that HS and inflammatory bowel disease are both diseases characterized by immune dysregulation. Cytokine abnormalities, such as the elevation of IL 1, IL 6, IL 17, IL 23 and the tumor necrosis factor, are involved in HS and inflammatory bowel disease. Alteration of the microbiota, resulting in immune dysregulation, also appears to play an important role in both diseases [53]. However, the exact mechanism linking paradoxical HS manifestation and CD is still unclear.

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10020455

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