Cutaneous adverse effects of biological therapies for psoriasis

ARTICLE

Auteur(s) : Esther Roé, Lluís Puig, Francisca Corella, Xavier García-Navarro, Agustín Alomar

Department of Dermatology. Hospital de la Santa Creu i Sant Pau, Mas Casanovas 90 08025 Barcelona. Spain

accepté le 16 Juin 2008

Biological therapies for psoriasis, targeting molecular pathways of inflammation, are intended to provide long-term control of the disease with minimal organ-specific toxicity. Nevertheless, acute and chronic dermatological adverse effects are frequently observed, appearing during the course of treatment. Their inflammatory nature can be considered paradoxical, knowledge about them is limited and their potential pathogenic mechanisms have not been identified yet.

We describe cutaneous eruptions in 7 patients, illustrating the gamut of cutaneous adverse effects of biological agents in patients with psoriasis. Changes in the morphology of psoriasis lesions are commonly reported in patients under treatment with TNF-blockers, whereas transient papular exacerbations and rebounds with changes in morphology represent a worrisome occurrence in patients under treatment with efalizumab.

Case reports (table 1)

Case 2. Male, 40-year-old, previously treated with PUVA, cyclosporine and methotrexate, who developed palmoplantar sterile pustulosis after the sixth infusion of infliximab 5 mg/kg. Before initiating treatment, PASI was 17.8. Infliximab was stopped (PASI 0.8) and treatment with methotrexate for 2 months led to a partial improvement of pustulosis. Etanercept was later started but due to worsening of the psoriasis (PASI 13.1) infliximab 5 mg/kg in combination with methotrexate 5 mg/week was reinitiated with eventual resolution of the lesions.

Case 3. Female, 33-year-old with pustular psoriasis of the palms and soles previously treated with methotrexate, hand and feet PUVA and cyclosporine. Ten weeks after beginning treatment with etanercept 25 mg biw, she developed flexural psoriasis and suprapubic sterile pustulosis (figures 2 and 3) that improved with a dose increase. Eventually, the treatment had to be stopped because of the appearance of urticaria.

Case 4. Female, 47-year-old, with plaque psoriasis and two previous episodes of generalised pustular psoriasis. She had been treated with methotrexate, cyclosporine and PUVA. Since the start of treatment with efaluzimab (PASI 14.2) she had developed papular lesions on previously non-involved areas, reminiscent of psoriasis guttata and clinically and pathologically consistent with transient exacerbations after each injection for the first 4 months of treatment. After 8 months of treatment, PGA was 0. After 16 months of treatment she developed erythematous papules and plaques on the arms and back, with a skin biopsy that was consistent with Sweet-like neutrophilic dermatosis (figures 4 and 5).

Case 5. Male, 66-year-old, with non-arthropathic psoriasis vulgaris previously treated with acitretin, methotrexate, PUVA, cyclosporine and etanercept. After 3 months of treatment with efaluzimab he developed erythroderma with polyarthritis that prompted discontinuation of the drug and resolved following etanercept treatment. Before initiating treatment, PASI was 10, rising to 43 in the third month of treatment. A rheumatologist studied the episode of polyarthritis, excluding other forms of arthritis.

Case 6. Male, 58-year-old, with psoriasis vulgaris previously treated with cyclosporine and methotrexate. After two months of treatment with efaluzimab he suddenly developed erythroderma that prompted drug withdrawal and resolved with infliximab 5 mg/kg. Before treatment PASI was 20.3 and when efaluzimab was discontinued, PASI was 52.2.

Case 7. Male, 48-year-old, with psoriasis vulgaris previously treated with methotrexate and cyclosporine. The patient had no history of atopy. Before treatment with efaluzimab, PASI was 15.3. After one month of treatment with efalizumab eczematous lesions started to appear in areas not involved with psoriasis. A skin biopsy was consistent with eczema. After 4 months of treatment, the psoriasis had improved (PASI 2) but the eczematous lesions persisted.
Table 1 

Discussion

TNF-blockers

Previously reported cutaneous adverse effects of tumor necrosis factor antagonists have mostly been reported in extracutaneous indications. Some of these events are common to the group of TNF-α antagonists, and the pathogenic mechanism might be common, accounting for a class effect.

Infliximab

The cutaneous adverse events described can be divided into:

• – Acute infusion reactions: defined as events occurring at the time of the infusion and up to 24 hours after. They have a low incidence of occurrence (approx 5% of all infusions). Most of them are non-immune-mediated, being similar to those observed during a rapid infusion of vancomycin. The rest are IgE mediated and they include urticaria, Quincke edema and anaphylactoid shock [3, 5].
• – Delayed cutaneous reactions:
  • Maculo-papular urticarial rash, considered a delayed hypersensitivity reaction, appears several days after the infusion and it can be accompanied be systemic symptoms [3, 6].
  • New onset or worsening of a pre-existing psoriasis: The most common clinical presentations are palmoplantar (pustular) psoriasis and plaque psoriasis, even though cases of flexural and gutate psoriasis have also been reported [1-4, 7-9]. The pathogenic mechanisms accounting for this paradoxical adverse effect ares still unclear, but several possible explanations have been proposed, including an imbalance of the dynamic interplay between TNF and interferon α, or a change in T cell function following TNF-α inhibition [10-17].
  • Lupus erythematosus (LE): there is an increase in peripheral T-cell reactivity to self-antigens by blocking the TNF-α. Clinically, there have been cases reported of discoid LE, LE tumidus and systemic LE with absence of end-organ damage and reversible after treatment discontinuation [3, 18, 19].
  • Interface dermatitis (erythema multiforme and lichenoid eruptions): this is an unexpected reaction since TNF-α is an important cytokine for the development of this type of eruption. The pathogenic hypotheses are that there is a paradoxical overproduction of TNF-α, or the occurrence of new immunogenic sites by a complex formed by the antibody and the fixed TNF-α [3, 20, 21].
  • Bullous eruption: a large localized bullous eruption after the fourth perfusion in one patient has been described, which regressed after treatment with systemic steroids. The eruption was not compatible with pemphigus vulgaris, bullous pemphigoid or bullous lupus erythematosus [3, 22].
  • Vascular lesions: serum sickness is a type III hypersensitivity reaction. The incidence of this adverse reaction in a population of 500 patients with Crohn’s disease was 2.8%, but it has also been reported in patients with psoriasis. There is no consensus about treatment discontinuation or the prescription of concomitant immunosuppressive agents and premedication [3, 23]. Other vascular reactions: leucocytoclastic vasculitis and eczematid-like purpura perniosis [3, 20].
  • Eczematous eruption (atopic-dermatitis-like eruptions): It is considered a non-allergic reaction, probably induced by an impaired Th1-Th2 balance towards Th2. If the eruption can be controlled with topical corticosteroids it is not necessary to stop infusions [3, 24-27]. Nevertheless, Jacobi et al. [28] performed an open prospective study administering infliximab to nine patients with severe atopic dermatitis. Their hypothesis was based on significantly elevated serum and tissue concentratins of TNF-α. All the patients improved during the induction therapy but only two patients sustained the improvement during the maintenance therapy.
  • Interstitial granulomatous dermatitis: described in 2 patients with rheumatoid arthritis (RA) under treatment with infliximab. This entity has been more commonly associated with systemic diseases, such as RA, but these cases are attributed to medication because of the temporal relationship with drug initiation and the clearance of the lesions after drug discontinuation [29].
  • Superficial granuloma annulare: 1 case described. Treatment with topical corticosteroids allowed continuing infusions with infliximab [3, 20].
  • Infections: Several cases of acute dermatological infections have been reported: acute bacterial folliculitis, dermatophytosis, herpes simplex, and recurrent bilateral eyelid molluscum contagiosum [1, 3, 20, 30].
  • Cutaneous lymphoma: Several cases of systemic lymphoproliferative disease have been described in the literature. There is one CD30 T cell cutaneous lymphoma in a patient under treatment with infliximab and cyclosporine that regressed after treatment discontinuation [31], another patient with CD8+ atypical cutaneous lymphoproliferative disease [32], a patient with Sezary syndrome which partially remitted after treatment discontinuation [33] and finally a systemic anaplastic large cell lymphoma with cutaneous involvement [34]. The causal link between anti TNFα and lymphomas is uncertain, the overall incidence of lymphoma in anti-TNF-α treated patients as compared to appropriate control populations is still under study.
  • Non-melanoma skin cancer: the temporal relationship observed between the initiation of infliximab infusions and the acute appearance of skin tumours suggests that the immunosuppressive effect of this drug induces the rapid proliferation of these lesions. The pre-existence of photodamaged skin favours this situation, so a close dermatological follow-up is needed in this kind of patient [3, 35].

Etanercept

The cutaneous adverse effects described in the literature are:

• – Injection site reactions: Local erythema, itching, pain and edema occurring at the injection site (20-42%). Usually occurs in the first month of treatment and then decreases in frequency. It is not dose-limiting and it has been hypothesized that is a T-lymphocyte-mediated delayed-type hypersensitivity reaction and a subsequent induction of tolerance. This is supported by the “recall reactions” at previous sites of injection suffered by some patients [3, 36-38].
• – New onset or worsening of a pre-existing psoriasis: the appearance of palmoplantar pustular psoriasis or psoriasis vulgaris in patients under treatment with etanercept is mainly described in patients with rheumatic disease [3, 10-13, 17, 20, 39]. Lee et al. [1] found that chronic inflammatory diseases like psoriasis and infectious skin diseases were the cutaneous adverse effects most frequently found in these patients.
• – Lupus erythematosus (LE); in clinical trials the development of anti-etanercept antibodies has been described in less than 5% of patients. 11% of patients developed antinuclear antibodies and 15% developed anti-DNA native antibodies, which was significantly higher than the placebo group (4 and 5% respectively). The development of these antibodies did not increase the risk of development of clinical symptoms. Nevertheless, some case reports describe the appearance of subacute and systemic LE in patients under treatment with etanercept. The pathogenic mechanisms of the induction of LE in these patients is unclear [3, 36, 40-46].
• – Interface dermatitis (erythema multiforme): Described in a patient with rheumatoid arthritis after the second injection of etanercept. At the same time the patient developed anti-Ro antibodies. The patient had a medical history of toxic epidermal necrosis after leflunomide. The lesions disappeared with the drug discontinuation [3, 47].
• – Leucocytoclastic vasculitis: Mohan et al. described the development of vasculitis in 35 patients under anti TNF-α treatment, 15 of them under etanercept. The appearance of symptoms was at a mean time of 28 weeks and usually began in the limbs (3 of them began at the injection site). In some cases systemic symptoms were reported. In 22 out of 35 patients the symptoms regressed with the discontinuation of treatment [48].
• – Eczematous eruption (atopic-dermatitis-like eruptions): Several cases of eczematous eruption have been described [3, 49]. In the Lee et al. [1] series the skin lesions were located primarily on the extremities (antecubital and popliteal fossae), but also on the face or trunk area. The patients experienced moderate to severe itch. Buka et al. [50] treated two patients with atopic dermatitis with etanercept but the treatment was unsuccessful, differing from the results of Jacobi et al. [28] with infliximab.
• – Interstitial granulomatous dermatitis: described in a patient with rheumatoid arthritis under treatment with etanercept and methotrexate. The lesions persisted under follow-up since the treatment could not be discontinued [29].
• – Cutaneous sarcoidosis: A cutaneous and ocular sarcoidosis in a 7-year-old child with chronic juvenile arthritis has been described after a month of treatment with etanercpt. The symptoms disappeared after treatment discontinuation and systemic corticosteroid therapy [51].
• – Urticaria: Skytta et al. [52] described a series of urticaria in patients with juvenile idiopathic arthritis under treatment with etanercept.
• – Rheumatoid nodules: one case is reported [53].
• – Infections: Mainly described in patients under treatment with infliximab, but also some cases described with etanercept [1, 3].
• – Cutaneous lymphoma: A case of rapid onset and progression of Sezary syndrome in a patient treated with etanercept for 18 months for arthritic psoriasis is been described in the literature [34]. The authors believe that perhaps the patient had a pre-existing T-cell lymphoma kept in check by cellular immunity.
• – Non-melanoma skin cancer: There are several reports in the literature about the rapid onset of squamous cell carcinomas after treatment initiation. A high level of suspicion is needed in these patients [54, 55].

Efalizumab

There are two main cutaneous reactions described during treatment with this drug. The first one is the transient papular eruption that usually occurs at the beginning of treatment; 21% (7 out 33) of our patients treated with efalizumab developed this eruption during the course of their treatment. Efalizumab-associated papular eruption does not require discontinuation of therapy and occurs predominantly in responding patients; it is characterized by bouts of psoriasiform papules, which can be variable in number, widespread or grouped on flexural areas, and appear either sporadically or following each injection for a limited period of time. It is amenable to topical treatment or to short courses of combined systemic treatment (e.g. low doses of methotrexate) treatment. Even though the original reports described a neutrophilic dermatosis (which we have seen in a patient with several previous bouts of papular eruption), this eruption is now generally considered to be a variant of (guttate) psoriasis [56], with the development of lesions impaired by CD11a blockage [57]. Our patient 4 sequentially developed the two variants of this eruption. The second type of skin-related adverse effects in patients under treatment with efalizumab is the exacerbation of psoriasis (rebound) that in some cases is associated with arthritis, even in the absence of a previous history of articular symptoms [58], as in our case 5. It appears mostly in non-responders, peaks following the discontinuation of efalizumab and requires fast-acting and highly effective systemic treatment. Finally, the appearance of eczematous lesions during treatment with efaluzimab is uncommon [59]. Similar cases have been reported during the course of anti-TNF treatment [1, 3]. In our patient 7 treatment was not discontinued and his psoriasis continued improving but the eczematous lesions persisted.

Previously reported cutanous adverse events described in patients under treatment with efalizumab are the following:

During treatment:

• – Non-specific/urticarial rashes have been observed in a very low percentage of the patients treated, and the relation to efaluzimab treatment has not been clearly established. The urticarial rash manifestations disappear, it not being necessary to discontinue treatment. No events of anaphylactic shock have been observed to date [3, 60].
• – Injection site reactions: 1% of patients under treatment with efaluzimab develop injection site reactions versus 0.4% in the placebo group. After the first 3 injections these are no more frequent than placebo [3, 60].

Transient neutrophilic dermatosis/Eruptive papules/Localized mild breakthrough

• – Dermatitis: Groot et al. [59] described the appearance of pruritic dermatitis lesions in the 9^th week of treatment with efalizumab in a patient with psoriasis.On the other hand, there are some reports in the literature of succesfully treated atopic dermatitis patients with efalizumab. The role of T cell mediated inflammation in atopic dermatitis and the efalizumab prevention of the migration and activation of T cells supported the choice of this treatment [61-63].
• – Lupus erythematosus: A case of subacute LE is described in a patient enrolled in a clinical trial studying efaluzimab for treatment of oral erosive lichen planus. Symptoms disappeared after treatment discontinuation [64].
• – Exacerbation: Widespread worsening of psoriasis with inflammatory component, estimated to occur in 1 to 3% of patients. Usually occurs in non-responders within 6 to 10 weeks after the initiation of treatment [3, 58, 60].
• – Change of psoriasis morphology: Described in 6 patients (4 plaque psoriasis, 1 generalized pustular psoriasis and 1 erythrodermic psoriasis) between 15 days and 18 months after beginning treatment. All the patients developed guttate psoriasis in areas of the body that were free of psoriatic plaques at baseline. This cutaneous reaction could be probably considered a variant of localized mild breakthrough [4].

After treatment:

• – Rebound: The rate of rebound is approximately 14% and is due mainly to PASI-125 rather than new psoriasis morphologies. The median time of appearance is 36 days [3, 58, 60].
• – Relapse: The rate of relapse is 86% with a median time of appearance of 67 days [58, 60].
• – Lymphoma: Even if trials have demonstrated that there is no increased risk of malignacies in comparison with the general population, there is a case report of a CD8+ lymphoproliferative disorder after treatment with efalizumab [32].

Conclusion

Acknowledgements

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