Off-label indications

This review, which is not exhaustive, covers the main dermatoses for which there is a relatively large literature on the effect of anti-TNF drugs. Biological treatments seem to be an interesting alternative in the management of many inflammatory dermatological pathologies that are refractory to usual treatments. Indeed, the results of currently available studies are encouraging, but include a limited number of patients for the most part. Moreover, for some pathologies, we only have cases described; it is thus possible that there is a bias, by publishing only cases with a favorable response. Randomized double-blind studies are therefore necessary. Interestingly, ustekinumab has also been used successfully in some cases. In the coming years, the arrival of new molecules, such as anti-IL-17, should further increase our therapeutic possibilities.

In recent years, advances in immunological research have led to the development of therapeutic alternatives that more specifically target key stages of the pathogenesis of certain inflammatory diseases. In dermatology, we have seen the emergence of new treatments for psoriasis, targeted at the level of cytokine signaling involved in the genesis of the disease. Currently, there are several tumor necrosis factor (TNF)-α inhibitors approved in Switzerland for psoriasis: Etanercept, Infliximab and Adalimumab. More recently, a monoclonal antibody directed against the p40 subunit of interleukin (IL)-12 and IL-23, Ustekinumab, has also been launched.

There are many conditions for which these biologic therapies are effective, although they are not yet approved for use in these indications. Indeed, there is a growing body of literature that supports their use in many diseases, including dermatological.

Granulomatous diseases

TNF-α secreted by macrophages plays a central role in granuloma formation. Indeed, it has been shown that the use of anti-TNF drugs can induce the reactivation of latent tuberculosis. In addition, their effectiveness has been demonstrated in other granulomatous diseases, such as Crohn’s disease. It was therefore assumed that TNF antagonists could be useful in the treatment of certain cutaneous granulomatous diseases, refractory to conventional treatments.

Sarcoidosis is an inflammatory disease, characterized by the formation of non-caseating granulomas, which can affect many organs, most commonly the lungs and skin. There are several reports of systemic sarcoidosis with skin involvement treated with Infliximab [1–4]. In addition, two randomized, placebo-controlled studies have shown Infliximab to be effective in the treatment of extra-pulmonary involvement in sarcoidosis, including skin involvement [5,6]. In an analysis including 54 patients with lupus pernio, near complete resolution of lesions was seen in 77% of patients on Infliximab, compared with 19% of patients treated with systemic steroids [7]. There are also cases of sarcoidosis successfully treated with Adalimumab [8–10].

A recent randomized, double-blind, placebo-controlled study of 16 patients showed a significant decrease in lesion size in patients with cutaneous sarcoidosis treated with Adalimumab (initial dose 80 mg, then 40 mg/week) [11]. In the event of an inadequate response to the usual psoriasis dosage regimen, dose escalation can achieve a favorable outcome in patients with refractory chronic cutaneous sarcoidosis [12].

Etanercept appears to be less effective in this indication. Indeed, there is only one reported case [13]. This difference could be explained by the fact that, unlike Etanercept, Adalimumab and Infliximab induce apoptosis of cells that have the bound form of TNF-α on their surface, resulting in destruction of granulomas [12].
There are very few data on the prescription of Ustekinumab in sarcoidosis. It has been shown that there is increased production of IL-12 in sarcoidosis granulomas. IL-12 plays an important role in T-cell differentiation in this disease. Yet, in a recent study, which was conducted in a randomized, double-blind, placebo-controlled manner, including 173 patients, patients with pulmonary and/or cutaneous sarcoidosis did not respond to Ustekinumab 180 mg, then 90 mg at weeks eight, 16 and 24 [14].

Other rarer cutaneous granulomatous diseases have also shown a favorable evolution under biological treatments. This is notably the case of necrobiosis lipoidica. Although no studies are currently available, several cases that have responded to treatment with Adalimumab, Etanercept or Infliximab are described [15–19]. To increase bioavailability locally and reduce the risk of systemic side effects, some patients were treated with intra-lesional injections of Etanercept or Infliximab, with partial response in all patients [20,21].

Granuloma annulare is a common granulomatous dermatosis that is usually asymptomatic and regresses spontaneously after one to two years. However, there are disseminated cases that can be disabling and recalcitrant, and for which anti-TNF treatment may be an interesting alternative. There have been no randomized studies to date, but a few cases of granuloma annulare that regressed on anti-TNF have also been described [22–24].

Suppurative hidradenitis, dissecting cellulitis of the scalp

Hidradenitis suppurativa or Verneuil’s disease is a disabling disease, characterized by the presence of painful, abscessing lesions, leading to scarring in areas rich in apocrine glands, justifying the use of systemic treatments. Some studies evaluating the efficacy of anti-TNF in Crohn’s disease have shown concomitant improvement in this dermatosis.

Promising results with anti-TNF have been described in recent years. Numerous cases and case series have been published with a favourable outcome with all three anti-TNF agents. However, the response rate appears to be higher with Infliximab compared to Adalimumab and Etanercept (82, 76 and 68%, respectively) [25]. A double-blind, placebo-controlled study showed that Infliximab improved pain, disease severity, and quality of life, as well as decreased inflammatory markers in these patients [26]. A second prospective open-label study, including ten patients, also showed a significant decrease in the number of flare-ups and affected sites [27]. Adalimumab has also been shown to be effective, improving quality of life and decreasing the number of lesions and sites affected after one month of treatment in six patients [28]. A prospective open-label study showed that weekly treatment with Adalimumab resulted in significant improvement of lesions in 15 patients [29]. However, the results for Etanercept are less encouraging, as a randomized double-blind placebo-controlled study did not show significant improvement in 20 patients treated for 12 weeks (50 mg 2×/week) compared to the placebo group [30].

Given the response to anti-TNF drugs, it is possible that Ustekinumab is also effective, as it reduces the expression of Th1-type cytokines, such as TNF-α. Of the six cases described in the literature, five had a partial or complete response to treatment, while one case did not respond [31–34]. Finally, the use of interleukin-1 inhibitors such as Anakinra may also be of interest, as reported in a series of six patients [35].

Dissecting cellulitis can be an isolated disease or associated with Verneuil’s disease and acne conglobata as part of the triad of follicular occlusion syndrome. It is characterized by the presence of sterile follicular pustules, also leading to the formation of abscesses and scarring. Treatment is often disappointing. In view of the positive results of anti-TNF agents on hidradenitis suppurativa, some patients with severe dissecting cellulitis have been treated with Infliximab or Adalimumab, with good effect [36–38].

Pityriasis rubra pilaris (PRP)

It is a rare disease, characterized by the presence of hyperkeratotic follicular papules, evolving into orange erythematous plaques with reserved spaces of healthy skin. Although the pathogenesis of PRP is not known, it shares some clinical and histological features with psoriasis.

A recent review of the literature on type I PRP treatment with anti-TNF drugs, including 15 cases, found a complete response in twelve patients (80%), a partial response in two cases and no response in one patient [39]. All three anti-TNF agents have been used successfully, although Infliximab is the most commonly used agent. These treatments were prescribed as monotherapy in 40% of cases, and in combination with methotrexate or acitretin in 60% of cases. Rapid responses were also observed with Ustekinumab [40–42]. These observations suggest that biological therapies may be useful in the treatment of PRP refractory to conventional therapies. Nevertheless, it should be noted that in 80% of cases, PRP regresses spontaneously within three years of diagnosis. Prospective randomized studies are therefore needed to clearly establish the effectiveness of these treatments.

Neutrophilic diseases

Pyoderma gangrenosum (PG) is a chronic dermatosis characterized by the presence of ulcers with undermined borders, most often on the lower limbs. More than half of the cases occur in association with another pathology, most often an inflammatory bowel disease. Despite the paucity of controlled studies evaluating the treatment of PG and the absence of a standardized algorithm, prednisone and cyclosporine are usually prescribed for severe forms.

The first positive results of biologics in PG were described in patients with Crohn’s disease with associated PG. In 2001, Tan MH et al. reported two patients with Crohn’s disease and one PG treated with Infliximab for their digestive disease with improvement in both conditions [43]. Infliximab is the most widely used anti-TNF agent in this indication, but positive results have also been described with Adalimumab and Etanercept [44–45]. There is only one randomized, double-blind, placebo-controlled study involving 30 patients that has evaluated the efficacy of Infliximab in PG. Two weeks after a first injection of Infliximab 5 mg/kg, patients in the treatment group had a statistically significant greater response rate than in the placebo group. After one to two infusions, 69% of patients (20/29) had responded favorably, and 21% were in complete remission. There was no difference according to the coexistence of an associated digestive disease [46]. According to a recent review of the literature, anti-TNF drugs appear to be the most effective treatment with a 92% response rate [47].

In case of failure of anti-TNF, Ustekinumab could also be an alternative, as a few cases have been successfully treated [48–50] In one of these patients, IL-23 expression was shown to be increased in PG lesions [50].

Sweet’s syndrome is a neutrophilic dermatosis characterized by an abrupt onset of fever, neutrophilia, and painful lesions most often on the head, neck, and upper extremities. Many cases are idiopathic, but this dermatosis can be associated with neoplasia, inflammatory pathology or pregnancy. In general, the evolution is rapidly favorable under systemic corticosteroids, but there are recurrent forms. There are also a few cases of Sweet’s syndrome that have regressed with anti-TNF. The cases described are all associated with another inflammatory pathology, notably rheumatoid arthritis and Crohn’s disease [51–55]. However, it should be noted that there is an increased risk of developing tumor pathology with anti-TNF. These treatments should therefore be prescribed with caution in this indication, which may in some cases be associated with underlying neoplasia.

Conclusion

Biological treatments are an interesting alternative in many dermatological pathologies refractory to conventional treatments. In these situations, it is important to refer these patients to a dermatologist to evaluate the indication for this type of treatment.

TO REMEMBER

Biological treatments seem to be an interesting alternative in the management of many refractory inflammatory dermatological pathologies.
The results of currently available studies are encouraging, but include a limited number of patients for the most part. For some pathologies, we have only described cases. Randomized double-blind studies are therefore necessary.
In the coming years, the arrival of new molecules, such as anti-IL-17, should further increase our therapeutic possibilities.

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