Full article :http://arthritis-research.com/content/7/3/R666
Dermatological conditions during TNF-α-blocking therapy in patients with rheumatoid arthritis: a prospective studyDermatological conditions during TNF-α-blocking therapy in patients with rheumatoid arthritis: a prospective study© 2005 Flendrie et al.; licensee BioMed Central Ltd.
Marcel Flendrie1 email, Wynand HPM Vissers2 email, Marjonne CW Creemers1 email, Elke MGJ de Jong2 email, Peter CM van de Kerkhof2 and Piet LCM van Riel1
1 Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
Discussion:
he present study is the first large prospective study focusing on dermatological conditions in RA patients on TNF-α-blocking therapy. Of the patients studied, 25% needed a dermatological consultation, compared with 13% in a RA control group, naive to TNF-α-blocking therapy. The number of dermatological events per patient-year was significantly higher during treatment than after treatment with TNF-α-blocking therapy. Dermatological events led to withdrawal of TNF-α-blocking therapy in 19 patients of 72 patients (26%). The events recorded most frequently were skin infections, eczema, and drug-related eruptions. Some other interesting events were recorded, such as psoriasis, drug-induced systemic lupus erythematosus, dermatomyositis, and a lymphomatoid-papulosis like eruption.
RA is known to be associated with dermatological conditions such as vasculitis, nodulosis, palmar erythema, and bullous pemphigoid, among others [22,23]. At present, information on the incidence and prevalence of dermatological conditions in RA mainly originates from cross-sectional or retrospective studies [24-26]. Few prospective studies have been conducted focusing on specific conditions affecting the skin [27,28].
In establishing a relation between the use of a drug and the occurrence of dermatological conditions, various factors must be considered. Information on clinical and histological patterns, time and dose relation, dechallenge and rechallenge, and analogy with previously reported cases can provide support in assessing the plausibility of such a relation [29]. The underlying disease and concomitant medication also need careful consideration, as they can provide alternative explanations.
In this study the largest group of dermatological events consisted of skin infections, mostly fungal infections and folliculitis. The use of TNF-α-blocking therapy has raised concerns regarding an increased susceptibility to infections, as TNF-α plays an important role in host-defence mechanisms [30]. An increased incidence of tuberculosis has been described [31], as well as a growing number of serious infections with fungal, mycobacterial, and intracellular bacterial pathogens [32-34]. Infections of the skin have not been the subject of report in clinical trials and observational studies with TNF-α-blocking therapy. Cases of severe necrotizing fasciitis have been described [35,36].
Skin infections have been reported frequently in the normal population and especially in RA patients [24-26]. Host-defence impairments resulting from the underlying disease might play a role in an increased susceptibility to skin infections in RA patients, as well as the use of corticosteroids and DMARDs such as methotrexate [28,37], which were recorded frequently in the present study (see Table 2). They could provide an alternative explanation for the occurrence of skin infections. However, most infections occurred during active treatment with TNF-α-blocking therapy, a finding that could suggest at least a relative contribution to an increased vulnerability to skin infections in the study population. In one patient, a bacterial superinfection of eczema occurred twice immediately after restart of adalimumab, showing a clear time relation.
For the description of the recorded drug-related eruptions, a clinico-morphological classification was chosen [21]. Four eruptions with a time relation and clinically or histological distinct drug-induced patterns also showed an eczematous appearance, both clinically and histologically. This is an unusual presentation for a drug-induced eruption and warrants further investigation.
Two drug-related eruptions occurred during infusion with infliximab or adalimumab, whereas all the others occurred after infusion. This will most likely not reflect the true ratio between acute and delayed reactions involving the skin, since acute reactions with skin involvement occur in 4% of the infusions and are usually treated by the rheumatologist without dermatological consultation [38].
Eczema was reported frequently in this study, even with various dermatitis conditions, such as xerosis cutis, stasis eczema, and seborrheic eczema, classified as separate entities. Previous studies have reported RA, in which Th1 (T helper cell type 1) immune responses dominate, to be negatively associated with Th2-cell-mediated atopic disorders, such as eczema [39-41], although a similar incidence of eczema in RA and non-RA patients has also been reported [42]. TNF-α-blocking therapy down-regulates Th1 immune responses [43], which might induce a shift of the Th1/Th2 balance towards Th2-dominated immune responses and which might promote an increased susceptibility to atopic disorders, such as eczema.
Although the time between the initiation of TNF-α-blocking therapy and the onset of dermatological conditions varied, a probable relation was seen in various events. These included, besides drug-related eruptions, events of cutaneous vasculitis, drug-induced systemic lupus erythematosus, dermatomyositis, and a lymphomatoid papulosis-like eruption.
An association between the use of TNF-α-blocking therapy and the induction of systemic lupus erythematosus and discoid lupus erythematosus is strongly suggested by the number of cases that have been published [10,11,13,44-46]. One case of discoid lupus erythematosus has been described on both etanercept and infliximab in the same RA patient [47].
