2013 April-June; 2(2): 67–71. ISSN: 2282-4103
Published online 2013 October 23.

Skin manifestations associated with anti TNF-α therapy

Emanuele Cozzani, Maddalena Larosa, and Aurora Parodi

DISSAL - Section of Dermatology, University of Genoa, Italy, IRCCS, Azienda Ospedaliera San Martino

Address for correspondence: Emanuele Cozzani, MD, PhD, DISSAL - Section of Dermatology, University of Genoa, Via Pastore 1, 16132 Genoa, Italy, Tel. +390103538426; Fax + 390103538401, E-mail: emanuele.cozzani@unige.it

Summary

The efficacy of anti-TNFα agents in the treatment of patients with moderate-to-severe psoriasis is well recognized in several clinical trials as well as in daily clinical practice. However, in a proportion of patients these agents can induce skin adverse events that are usually well tolerated. Secondary reactions induced by these agents are variable with regard to symptoms and severity and may be divided into two main groups: 1) skin reactions that could be defined as paradoxical, essentially being psoriasis exacerbations; 2) skin adverse reactions which can be of various kinds. There are some skin reactions which are secondary to the immunosuppressive drug effect, including sarcoidosis, induced lupus-like skin manifestations, skin lupus, Hodgkin-type lymphoproliferative skin disorders, skin mycobacterial infections. Besides the above, there are also the classical drug reactions: eczema reactions, erythema multiforme major, Stevens-Johnson syndrome, skin vasculites, lichen planopilaris induction, morphea and skin reactions at the site of injection including erythema, edema, burning which are generally mild. The authors will present and discuss this data.

Keywords: TNF-α inhibitors, skin adverse events, psoriasis, lupus-like syndrome

 

Skin manifestations that may occur during treatment with anti TNF-α drugs are classified as definite, probable, possible or fortuitous according to their likelihood of direct relationship with the drug. Figure 1 shows the main associations classified as definite and probable.

Figure 1Figure 1
Skin manifestations associated with anti TNF-α therapy: definite and probable associations.

Among the reactions that are definitely drug-related there are infusion-associated skin reactions: from a semiotic point of view, these reactions are characterized by the appearance of erythema, urticaria, eczema and urticarial-like skin rash. In most cases, these reactions are of mild to moderate intensity, with rare severe cases that usually do not require treatment discontinuation.

Infusion-associated reactions can be either acute or chronic. In literature, cases of acute reactions – occurring during infusion or within 24 hours – during therapy with infliximab (1) have been reported to account for 3–6% of all cases, and are mostly of mild to moderate intensity. Of these, only less than 1% are considered to be severe reactions. The mechanism is not immune complex-mediated, and reactions usually resolve by reducing infusion rate and administering pre-medication with anti-histamines and/or corticosteroids; these measures have allowed to reduce the number of infusion-associated reactions in the last few years (2). Chronic reactions associated with infliximab infusion usually appear from 24 hours to 14 days after infusion. They occur in 1–2.8% of cases and generally involve face swelling and urticaria; these are type III immune complex-mediated reactions, as demonstrated by the presence of high levels of infliximab antibodies.

Injection-related skin reactions usually appear during the first month of therapy, with a tendency to reduce afterwards. They are characterized by mild to moderate erythema in the site of injection, accompanied by a burning sensation. They are reported in 10–20% of patients treated with etanercept, in 6–12% of cases for adalimumab and in 2.4% with golimumab (3).

Among probable associations are psoriasis, psoriasiform lesions, lupus and lupus-like syndrome, morphea, skin infections, vasculites, granuloma annulare, vitiligo, alopecia and bullous diseases.

As regards psoriasis, about 200 cases have been described in literature, with an estimated prevalence ranging between 0.6% and 5.3%; the disease appears from a few days to some years after the beginning of treatment (mean, 10–17.1 months), regardless of age and sex. Usually, it occurs in patients who have shown an initial good response to the biological therapy (4). As reported in a meta-analysis published in 2008, in 120 patients treated with anti TNF-α drugs who developed psoriasis, 74 were patients with de novo disease without a prior personal or family history of psoriasis (5). The results of a study published in 2008 and conducted in 9826 patients treated with an anti TNF-α drug showed that 25 patients developed a psoriasis during therapy; of these, 50% were receiving adalimumab, while the remaining patients were treated with infliximab or etanercept. Infliximab and adalimumab appear to be responsible for the development of psoriasis de novo, while etanercept may induce an exacerbation of an existing disease. In 2880 patients of the control group – who received other drugs –none developed psoriasis (6).

A French study also showed that in most cases the type of psoriasis observed was the pustular form, and that in half of these cases patients were treated with infliximab (7).

Another study has described the development of both pustular and plaque psoriasis in 54% of cases during therapy with infliximab, in 34% with adalimumab and in 7% with etanercept (4).

Basically, two theories have been suggested to explain this event that may be considered as a paradox: anti TNF-α drugs may cause a cytokine unbalance resulting in local induction of type 1 interferon-α, which in turn is responsible for the development of psoriasis. Another theory is based on the increased number of peripheral T cells which express CXCR3 receptor, that promotes autoreactive T cell infiltration into the skin. From a clinical viewpoint, the most frequently reported forms of psoriasis include: pustular (palmoplantar) psoriasis in 56% of cases, plaque psoriasis in 50% of cases, guttate psoriasis in 12% of cases, as well as inverse psoriasis, nail psoriasis and scalp psoriasis; 15% of patients also shows more than one type of psoriasis (8). The association between anti TNF-α drugs and psoriasis seems to be supported by two events: the first is the improvement of psoriasis following drug discontinuation, and the second is the relapse of psoriasis – in some cases – after re-introduction of the drug (9).

It has been reported that most cases of psoriasis and psoriasiform reactions can be controlled with a treatment (often a topical treatment or phototherapy), and rarely require treatment discontinuation or modification; persistence of the lesions was observed only in 5% of cases (8, 10).

Anti TNF-α drugs appear to significantly induce the development of antinuclear antibodies and partly of anti-dsDNA antibodies in treated patients (Table 1).

Table 1Table 1
Skin manifestations associated with anti TNF-α therapy: lupus and lupus-like syndromes.

However, it should be noted that the literature describes only a few cases of systemic lupus systemicus, either of the subacute or discoid type, that developed during treatment with anti TNF-α drugs; in a work that included 11000 patients on treatment, 0.18% (25 cases overall) of patients receiving infliximab or etanercept developed a type of lupus. Twelve out of 25 had a (systemic lupus erythematous, with the disease appearing from one month to some years after the beginning of therapy) (11, 12). In this cases, the pathogenesis is not completely clear; on the one hand, anti TNF-α drugs may induce apoptosis, immunosuppression or humoral autoimmunity, on the other hand they could cause type 1 interferon-α dysregulation, development of ANA and therefore a lupus-like syndrome (13, 14). In most cases, therapy discontinuation is followed by complete remission of the disease (12).

The literature describes anecdotal cases of morphea or localized sclerodermia that have developed during therapy with biological drugs: in these cases, TNF-α inhibition may have acted on the cascade of TGF-β1 and other pro-fibrotic cytokines, while suppressing Th1 lymphocytes and activating Th2 lymphocytes, that are responsible for tissue damage and amplification of fibrosis (1518).

Studies available in literature have shown that the incidence of skin infections in patients receiving anti TNF-α therapy has increased by 2–4 times compared to controls: skin infections during infliximab therapy were reported in 11.6% of cases, while those reported with adalimumab accounted for 6.6% (19, 20).

In a retrospective study, 28 out of 709 observed patients reported skin infections: in approximately half of cases, these infections were of bacterial etiology, 30.5% of viral origin and 6.5% were fungal infections. The clinical severity of these infections was modest and easy to treat (19).

Among the clinical manifestations regarded as probably associated with anti TNF-α therapy there are vasculites. Leukocytoclastic vasculitis (LCV), the necrotizing form, Schönlein Henoch purpura and urticarial vasculitis are the most commonly reported forms. There have been reports of 35 cases of LCV in 116.000 patients treated with etanercept and 344.000 receiving infliximab, of which 17 cases were histologically confirmed. The close chronological association and the resolution of vasculitis (in 22 of 35 affected patients) following therapy discontinuation support the correlation between vasculitis and anti TNF-α drugs (21).

Cutaneous granulomatous reactions are also regarded as probably associated with anti TNF-α therapy. They may develop as atypical granuloma annulare or the disseminated form. Atypical granuloma annulare has been associated with the use of infliximab, etanercept and adalimumab; it is characterized, in its classical form, by ring-like macules, papules with raised edges – with a typical central clearing – usually asymptomatic and with a rapid development. The trigger role of anti TNF-α drugs seems to be supported by the close chronological association between the therapy and the development of lesions, as well as by the resolution of the condition following treatment discontinuation (22).

Regarding disseminated granuloma annulare, 9 cases have been reported in literature, all of which were treated with topical corticosteroids; only two cases required discontinuation of the systemic therapy (23).

Only a few cases of vitiligo during anti TNF-α therapy, usually infliximab therapy, have been reported in literature (12).

With regard to alopecia areata, there are only a few cases reported in literature, i.e. 15 patients who developed total or universal alopecia areata associated with anti TNF-α therapy from 1–2 days to 24 months after starting the treatment; despite therapy discontinuation, alopecia had a clinical progression in 50% of cases. The observation of several cases associated with different anti TNF-α drugs is suggestive of a probable relationship (12). For this condition too, the suggested pathogenesis is much like those described up to now: anti TNF-α drugs might induce a dysregulation of cytokines such as interferon-α, and the activation of autoreactive T-cell clones that are able to induce the disease in genetically predisposed subjects (12).

Finally, among probable associations there are auto-immune bullous diseases. Very few cases have been reported, including a 72-year-old woman with a diagnosis of rheumatoid arthritis who was treated with etanercept, infliximab and eventually with adalimumab, and who developed a bullous pemphigoid of mucous membranes; another case concerned a 62-year-old patient treated with infliximab who developed, after the 7th infusion, a pemphigus foliaceous confirmed by the target antigen test (24).

Figure 2 shows the skin reactions that are classified as possible and fortuitous.

Figure 2Figure 2
Skin manifestations associated with anti TNF-α therapy: possible and fortuitous associations.

From a clinical viewpoint, the observed eczema presentations are mainly of the nummular or dyshydrosic form, but may also present as atopic dermatitis (19). Other possible associations include lichen planus and lichenoid reactions. The number of cases is limited: 15 cases of lichen planus or lichenoid reactions, mainly associated with infliximab, but also with etanercept and adalimumab. These skin reactions usually develop during the first two months of therapy (19).

There have also been reports of a certain number of cases of erythema multiforme, Stevens-Johnson syndrome and TEN induced by anti TNF-α drugs. These reactions seem to be more frequently associated with infliximab (4–22%), while a certain relationship has been observed between adalimumab and localization of these affections in the oral cavity (25, 26).

About sarcoidosis there have been reports of 28 cases in literature, of which 16 during etanercept therapy, 8 with infliximab and 4 with adalimumab. The time to onset of this condition may vary, ranging from none to 60 months, and in the majority of cases a complete or partial resolution can be achieved (27). The pathogenesis is unknown, it may be secondary to an infection caused by Mycobacterium tubercolosis and Corynebacterium acnes which would be activated by the anti TNF-α drug, or the granulomatous reaction could be part of an auto-immune response resulting from cytokine changes secondary to TNF-α suppression (28).

An increased incidence of lymphoma in patients treated with anti TNF-α drugs has been reported in literature, although there have been no studies that provided real evidence of such association (2).

The development of actinic keratosis, Bowen’s disease, spinocellular carcinoma, basal cell carcinoma and acanthoma in patients receiving anti TNF-α drugs (etanercept, infliximab) has been reported in literature, but their incidence was comparable to that observed in the normal control population (29, 30).

Regarding melanoma, there have been reports of anecdotal cases of development or relapse of the disease in subjects receiving anti TNF-α drugs, which suggested a possible relationship; for the time being, these cases have been included in the class of fortuitous associations. There have been reports of two cases of locoregional relapse occurring 90 days after anti TNF-α therapy (etanercept, adalimumab), after 6 and 9 years from the diagnosis of melanoma, respectively (31). A case of melanoma (Breslow’s depth, 0.51 mm) occurring 25 weeks after the start of adalimumab therapy has been reported in a patient with a past history of PUVA therapy (32).

In conclusion, literature provides a wide range of skin manifestations related to the use of anti TNF-α drugs, although only some of them (infusion-related reactions and reactions at the site of injection) are definitely related to the therapy. Many of these reactions are validated by the literature because of the chronological association with the treatment and by the observation that the disease resolves following drug discontinuation. In the majority of cases, such manifestations are of mild or moderate intensity and resolve either spontaneously or with a short topical or systemic treatment; only rare cases require therapy discontinuation.

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