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The off-label use of biologic therapies in dermatology Natasha Lee, Laura Jane Savage

Biological agents or simply ‘biologics’, refer to systemic immunotherapies that are protein-derived and cultured from living material (human, animal or micro-organisms) in a laboratory. Unlike conventional immunosuppressant therapies, which modulate the immune system in a broad and non-specific manner, biologics target specific mediators of inflammation, and therefore have superior efficacy and an enhanced safety profile when compared to drugs such as methotrexate, ciclosporin and mycophenolate mofetil. In recent years, a number of biologic agents have been developed to treat advanced malignant melanoma and chronic spontaneous urticaria; however, it is within the inflammatory dermatoses where the biologic agents first came to the fore in dermatology and continue to generate most interest in terms of off-label use. Moderate-to-severe psoriasis is the only inflammatory skin disorder for which biologic agents are currently licensed in the UK. Four biologic agents are recommended by the National Institute for Health and Care Excellence (NICE), namely adalimumab (Humira®), etanercept (Enbrel®), infliximab (Remicade®) and ustekinumab (Stelara®)(NICE, 2012), with many more in development. Biologics have revolutionised the treatment of severe psoriasis and have heralded a shift in thinking for the treatment of other difficult-to-treat inflammatory skin conditions.This article will briefly outline the mechanism of action of the most commonly used biologic agents and their ‘off-label’ use in various dermatological conditions.

Key words Biologics Immunosuppressant therapies Psoriasis Inflammatory skin conditions Off-label Biologic therapies in dermatology — mechanism of action

Adalimumab, etanercept and infliximab (anti-TNF or TNF antagonists) Cytokines are small proteins that are important in cell signalling.They include interferons, interleukins, adipokines and growth factors, among others. Cytokines can be pro-inflammatory or anti-inflammatory; however it is the overexpression of these pro-inflammatory cytokines that are believed to be

Natasha Lee is a medical student at the School of Medicine, University of Leeds. Dr Laura Jane Savage is a Doctoral Research Fellow at Leeds Centre for Dermatology, Chapel Allerton Hospital, Leeds

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responsible for the initiation, persistence and recurrence of skin lesions such as the plaques found in psoriasis. The most well-studied and understood pro-inflammatory cytokine is tumour necrosis factor-alpha (TNF-α), an adipokine member of the TNF superfamily. It is a multifunctional cytokine with a wide spectrum of activity throughout the body, regulating diverse biological processes such as cell proliferation, lipid metabolism and coagulation. However, its key role is as a central protagonist in systemic inflammation; in addition to inflammatory skin disorders,TNF-α is implicated in other inflammatory diseases including cancer and many autoimmune conditions. TNF-α was the first biological target in psoriasis and, to date, there are three agents that suppress this key cytokine. Adalimumab, a fully human monoclonal antibody (mAb), functions in the same way as infliximab (chimeric mouse/ human antibody), binding both soluble and membrane bound TNF-α. In contrast, etanercept is a receptor fusion protein, and is composed of two human TNF-α receptors fused to the Fc portion of a

human antibody, which binds free TNF-α. Suppression of TNF-α subsequently down-regulates pro-inflammatory pathways in lesional skin and reduces epidermal hyperplasia. Ustekinumab (IL-12/23p40 antagonist) Ustekinumab, a fully human mAb, is targeted against the common p40 subunit of interleukin (IL)-12 (IL-12) and IL-23. Both cytokines are naturally occurring proteins that play a key role in immunemediated inflammatory disorders, including psoriasis. IL-12 induces a proinflammatory response by activating T helper 1 (Th1) cells, which in turn give rise to proinflammatory cytokines including TNF-α, IFN-γ and IL-2. However, more recently Th17 cells have been recognised as a distinct lineage of proinflammatory T helper cells essential for the pathogenesis of immune diseases (Blauvelt, 2008). IL-23 is required to activate, proliferate and maintain Th17 cells in the dermis. Many studies have demonstrated the key roles that IL-12 and IL-23 play in the development of psoriasis, due to their relation to both the stimulation of the innate and adaptive immune systems, and there is now interest in

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Rituximab Rituximab is a chimeric mouse/human monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes. As it eliminates mature circulating B-cells, it is used to treat diseases that are characterised by overactive, dysfunctional or excessive numbers of B cells. Licensed indications include rheumatoid arthritis, haematological malignancies (chronic lymphocytic leukaemia and non-Hodgkin’s lymphoma) and certain types of vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis). At present, it has no licensed indication within dermatology, but is being used with increasing confidence in some dermatoses including systemic lupus erythematosus and some autoimmune blistering conditions.

Dermatological conditions for which biologic agents are being used off-licence

Hidradenitis suppurativa Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder of apocrine gland-bearing intertriginous areas, such as the axillae, groins, perineum and sub-mammary folds. It is characterised by recurrent papules and pustules that form as a result of perifollicular apocrine occlusion and subsequent inflammation. For some, the condition may be mild, but for others, it can be extremely severe, with deep and painful abscesses, sinus tract formation and unsightly scarring leading to significant morbidity and psychological sequelae (Figure 1). HS is notoriously difficult to treat. The precise cause of HS is unknown, although there are some data to support the role of innate immune system dysregulation leading to the condition. Traditional methods of treating HS have included antiseptics, antibiotics, isotretinoin, dapsone, colchicine and acitretin, although response is very variable and not hugely successful in moderate-severe cases. Surgical excision and laser ablation of persistent sinus tracts are also used, although recurrence is common.

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the use of ustekinumab to treat other inflammatory diseases (both cutaneous and non-cutaneous) where Th17 cells are thought to play a role, such as pyoderma gangrenosum and Crohn’s disease.

Figure 1. Adalimumab and infliximab have shown to be effective in treating HS. A rationale for using TNF-α antagonists in HS emerged following data from The Netherlands, which demonstrated elevated levels of TNF-α in HS skin (van der Zee et al, 2011). A 2012 systematic review identified four subsequent randomised controlled trials (RCTs) that evaluated the use of TNF-α in severe (grade 3) HS in addition to several other case series and reports.The authors concluded that the greatest success was found with infliximab, although at higher doses adalimumab also showed promise (van Rappard et al, 2013). No benefit was found with etanercept. A lack of effect for etanercept, as compared to adalimumab and infliximab, was replicated in a further small study, where seven of 10 patients did not achieve remission (50mg once weekly for 12 weeks) and required a second course of therapy (Pelekanou et al, 2010). The efficacy of adalimumab (40mg once weekly, as compared to once a fortnight in psoriasis) in HS has been supported by two further clinical trials (Sotiriou et al, 2012; Kimball et al, 2012). In one of these studies (n=15), significant reductions were found in all three indices measured (the HS Sartorius score (a severity assessment tool for HS), a disease activity visual analogue score (VAS) and the Dermatology Life Quality Index (DLQI)). Promising results were seen with regard to time to recurrence of HS lesions, observed at 11 weeks after treatment cessation (Sotiriou et al, 2012). Even though there was recurrence, the primary outcome measure (final Sartorius score at week 48) was met, with significantly lower scores than at baseline. In the second study, patients were randomised to placebo, adalimumab 40mg every other week (EOW) or adalimumab 40mg weekly. Those in the latter group had the greatest

response, with 17.6% achieving a clear, almost clear or mild result after 16 weeks of therapy, compared with 3.9% of those in the placebo group and 9.6% in the EOW group, suggesting that adalimumab weekly does alleviate moderate to severe HS for some (Kimball et al, 2012). Based on these encouraging findings, a NICE single technology appraisal to assess the clinical and cost effectiveness of adalimumab in moderate and severe HS is proposed. While much focus has been on the potential for the use of TNF-α inhibitors for HS, Schlapbach et al investigated the role of the IL-23/Th17 pathway in skin biopsies taken from ten patients with HS. Both IL-12 and IL-23 were found to be abundantly expressed by macrophages infiltrating the dermis of lesional skin, providing a rationale for the trial of ustekinumab in recalcitrant disease (Schlapbach et al, 2011). However, clinical trials are needed to assess the efficacy and safety of ustekinumab in patients with severe HS. Similarly, while the data for the use of adalimumab and infliximab is encouraging, larger scale randomised control trials are needed to assess whether the benefits outweigh the risks and cost implications of these therapies in the longer term for HS. Autoimmune blistering disorders Autoimmune blistering disorders comprise a group of mucocutaneous disorders where the immune system generates an abnormal attack against healthy tissue. Pemphigus is a group of chronic bullous disorders, characterised histologically by intraepidermal blister formation and immunopathologically by the presence of bound and circulating immunoglobulin G (IgG) directed against the cell surface of keratinocytes.There are three primary subtypes of pemphigus: pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. Pemphigus vulgaris (PV) accounts for around 70% of all pemphigus cases, and patients present with tender, flaccid blisters arising on healthy-looking skin. Approximately 50-70% will also have mucosal erosions affecting the oral cavity. Antibodies in PV are directed against desmogleins 1 and 3, and destruction of this protein leads to an intraepidermal split between adjacent keratinocytes.Therapeutic strategies are

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or azathioprine.

Figure 2. Case studies have shown promise for infliximab and ustekinumab in treating PG lesions. broad and include systemic corticosteroids, tetracycline antibiotics, nicotinamide, conventional immunosuppressants, dapsone, gold, cyclophosphamide and intravenous immunoglobulins (IVIg). With limited success from conventional treatments, the search for a more efficacious therapy has led many to try rituximab (Ahmed et al, 2006; Joly et al, 2007; Cianchini et al, 2007; El Tal, et al, 2006; Schmidt et al, 2006). Its success was first noted in a patient with nonHodgkin’s lymphoma who had associated paraneoplastic pemphigus (Borradori et al, 2001) and subsequent studies have shown impressive results. Leshem et al used the rheumatoid arthritis licensed dose of rituximab (2x 1000mg infusions, two weeks apart) in 10 patients, and 9 achieved remission at six months.Twothirds of participants had relapsed after a mean follow-up of 22 months, suggesting that repeated cycles may be required (Leshem et al, 2014). Most studies have adopted the regimen used for lymphoma (375mg weekly for four weeks) (Maloney et al, 1997; Balighi et al, 2013), although several authors have investigated lower-dose regimens. In one prospective openlabel study, 15 patients with PV and pemphigus foliaceous were treated with two 500mg infusions of rituximab, 2 weeks apart (Arin, Hunzelmann, 2005). All 15 patients responded to rituximab; 8 had complete remission and 7 saw a partial improvement. Relapses were seen in 6 patients after a median interval of 97 weeks. Success at this lower dose is encouraging as this carries potential future economic savings for health providers. However, more work is needed to 54

support these small scale observations — in a retrospective study by Kim et al, patients with PV and pemphigus foliaceus all responded, but those who had received a lower dose were more likely to relapse than those receiving a higher dose of rituximab (Kim et al, 2011), which may reduce the economic benefits if a second cycle is required. Aside from rituximab, there are case reports that describe the success of both etanercept (Berookhim et al, 2004) and infliximab (Jacobi et al, 2005) in refractory pemphigus, although robust clinical trials are lacking. Pyoderma gangrenosum Pyoderma gangrenosum (PG) is an uncommon, ulcerative inflammatory neutrophilic dermatosis of uncertain aetiology. It is characterised by enlarging painful ulcers with a violaceous border that exhibit pathergy (Figure 2). 50% of cases are associated with systemic disease, including inflammatory bowel disease, rheumatoid arthritis, haematological malignancy, vasculitis and infection, with the remaining 50% being idiopathic. Dysregulation of the immune system, and specifically altered neutrophil chemotaxis (where too many neutrophils are attracted to a specific site) is believed to be responsible for generating the lesions of PG. Like many inflammatory dermatoses where the precise pathogenesis is not fully understood, therapeutic strategies for pyoderma are broad. In addition to local wound care, treatment includes ultrapotent topical corticosteroids or immune modifiers (such as tacrolimus), oral prednisolone, and in certain cases systemic immunosuppressant therapies such as ciclosporin, mycophenolate mofetil

The pathogenic role of TNF-α in many of the PG-associated conditions, especially rheumatoid arthritis (Choy, Panayi, 2001) and inflammatory bowel disease (Stokkers et al, 1995), suggests that this cytokine could be implicated in the aetiology of pyoderma and has generated interest as a potential therapeutic target. Several case series and reports have shown promise for infliximab to aid the resolution of PG lesions, and this has been supported by data from a small double-blind RCT (n=30). Patients in this trial received an infusion of either infliximab (5mg/kg) or placebo each week for six weeks. 69% demonstrated a clinical response, and 21% were clear at 6 weeks (Brooklyn et al, 2006). Data from a recent systematic review of patients with PG who had received biologic treatment for inflammatory bowel disease demonstrated that, of the 40 patients to receive infliximab (n=34), adalimumab (n=4) or both (n=2), 92% of lesions had responded (Agarwal, Andrews, 2013). Infliximab currently has the most data to support its use in PG, although, as this systematic review supports, there is some data for adalimumab in recalcitrant disease (Hinterberger et al, 2012; Heffernan et al, 2007; Fonder et al, 2006) in addition to a few case reports for etanercept (Pastor et al, 2006; Rogge et al, 2008; Goldenberg, Jorizzo, 2005; Charles et al, 2007). Ustekinumab has also been reported to be effective in cases of PG, though the data is largely in case report form (Fahmy et al, 2012; Goldminz et al, 2012; Guenova et al, 2011). Like TNF-α, IL-23 is involved in the pathogenesis of Crohn’s disease, and given the known association between the two conditions it is reasonable to suspect that PG may be driven by a pathogenic mechanism similar to that of inflammatory bowel disease. Analysis of lesional skin from a 37-year-old patient showed highly elevated expression of IL-23 in a recalcitrant PG lesion, and on the basis of this, ustekinumab was trialled (as per the licensed dose for psoriasis — 45mg at week 0 and week 4).This led to a significant decrease of tissue IL-23 expression and healing after 14 weeks of therapy, with no relapse within six months of follow-up (Guenova et al, 2011).

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significant improvement have also been published for etanercept (Tuchinda, Wong, 2006; Khanna et al, 2003). Adalimumab was recently investigated in a small RCT (n=16) and produced a significant reduction in lesion area after 24 weeks of therapy (Pariser et al, 2013).

Figure 3. TNF-alpha inhibitors may help those with cutaneous sarcoidosis. Overall, there is an increasing body of evidence to suggest that both TNF-α and IL-12/IL-23p40 antagonism may be effective for refractory PG, although further large-scale randomised controlled trials are needed to ascertain the long-term safety, efficacy and cost-effectiveness of these agents. Granulomatous diseases Sarcoidosis is a multisystem inflammatory disease of unknown aetiology, characterised by the formation of noncaseating granulomas in virtually any organ system (Figure 3). Around onethird of cases have skin involvement. TNF-α plays a defined role in the development and maintenance of noncaseating granulomas in a variety of disorders (Chensue et al, 1995) and an increasing number of reports suggest that antagonism with anti-TNF-α therapies may be effective. The majority of data is in the form of case reports and small case series; however, the response appears to be dramatic, especially for infliximab (Tuchinda et al, 2012). Hefferman and colleagues reported a case of recalcitrant cutaneous sarcoidosis with multiple papules and plaques, which achieved 90% clearance by week six of intravenous infliximab treatment (Heffernan, Anadkat, 2005). Similarly impressive results were seen in a case series of 10 patients, five of whom had disfiguring lupus pernio lesions (Doty et al, 2005) and in a series of 9 sarcoidosis patients (3 of whom had cutaneous disease) who were previously without response to corticosteroids, methotrexate or mycophenolate mofetil that resolved with infliximab (Sweiss et al, 2005). Isolated reports of clearance or

For patients with cutaneous sarcoidosis who are refractory to corticosteroids and/or systemic immunosuppressants, it does appear that TNF-α inhibitors may be effective. However, paradoxical sarcoidosis induced by TNF-α inhibitors has also been reported (Clementine et al, 2010), and therefore large prospective trials are now required to confirm the safety and efficacy of these therapies for this potentially disfiguring dermatosis.

Other dermatological conditions The conditions discussed in this article are those attracting the most attention in terms of off-label experimentation with biologic drugs.This is perhaps a reflection of the increased understanding of the pathological mechanisms that contribute to the aetiology of these conditions, leading to a clearer rationale for the use of biologic therapies. However, there is an increasing body of literature reporting the use of licensed biologic therapies for many more dermatological conditions other than those discussed, including rituximab for systemic lupus erythematosus and dermatomyositis, and the TNF-α inhibitors for a multitude of immune-mediated disorders including pityriasis rubra pilaris, Beçhet’s disease, scleroderma, toxic epidermal necrolysis, SAPHO syndrome, graft-versus-host disease, granuloma annulare, necrobiosis lipoidica and alopecia areata. For some dermatoses such as vitiligo, while there are reports to support the use of some biologics such as etanercept (Campanati et al, 2010; Rigopoulos et al, 2007), there are reports of the condition worsening on others (infliximab) (Alghamdi et al, 2011), highlighting the importance of treating each patient as an individual.

Conclusion After many decades of limited advancement in the management of many inflammatory dermatoses, we are now in an exciting era where new molecules are potentially available to treat disfiguring and

recalcitrant conditions. However, these drugs will remain off-label until robust, prospective clinical trials are undertaken to prove their safety, efficacy and costeffectiveness in the long term. Unlike psoriasis, which affects up to 2% of the UK population, many of the inflammatory dermatoses discussed in this article are comparatively rare, making recruitment to adequately powered studies very difficult.This also limits the wiliness of the pharmaceutical industry to invest in clinical trials, as they may view their economic return as too small to make investment worthwhile. Currently, health professionals must submit individual funding requests to enable biologic drugs to be prescribed ’off-label’ for their patients, which is timeconsuming and not always successful due to high drugs tariffs. However, from the perspective of healthcare funders, while the biologic therapies are relatively expensive, they may ultimately be more cost-effective when taking into account the cumulative costs associated with repeated flares of a condition such as pyoderma gangrenosum or hidradenitis suppurativa (dressings, multiple courses of conventional drugs, hospital stays, nursing, medical and surgical care, patient time away from employment, etc.). In addition, clinicians will continue to strive for the most effective therapies for their patients and collaborations between centres will help to answer some of the current questions surrounding safety and effective dosing regimens.The use of biologic therapies in dermatology looks set to continue to grow, even if their use remains off-label. DN

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