ReviewParadoxical immune-mediated inflammation in inflammatory bowel disease patients receiving anti-TNF-α agents
Introduction
Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine that plays a key role in inducing inflammatory response to injuries. Its role in triggering inflammation has been clearly established in immune-mediated diseases, including rheumatoid arthritis, spondylarthritis, inflammatory bowel diseases (IBD) and psoriasis, although some TNF-α-Amediated pathways remain unknown [1]. The pharmacological blockade of TNF-α with selective monoclonal antibodies has revolutionized the management of patients with immune-mediated inflammatory disorders (IMID) [2].
There is substantial evidence supporting the overall good safety profile of the anti TNF-α agents, particularly the lack of any significant increase in risk of serious infections or cancer [3]. However, there are some concerns regarding an increased risk of non-serious infections and lymphoproliferative disorders. Moreover, the number of reports of autoimmune or IMID induced by anti-TNF-α agents themselves is increasing [4], [5]. Some of these disorders correspond to paradoxical inflammation or to autoimmune diseases.
Paradoxical inflammation is defined by the development of inflammatory manifestations in patients who develop IMID after the initiation of anti-TNF agents, normally used to treat such disorders. Paradoxical inflammatory events have been described in patients with diverse IMID treated with anti-TNF agents. IBD patients treated with anti-TNF agents can paradoxically experience the onset of other IMID, particularly skin inflammatory lesions resembling psoriasis. These anti-TNF-induced paradoxical inflammatory lesions observed in IMID suggest that anti-TNF agents promote inflammation in non-inflamed tissues in some patients.
The timing of onset of this paradoxical phenomenon after starting anti-TNF-α therapy, the disappearance after medication withdrawal, the and re-challenge phenomenon have been suggested as criteria to assess whether such conditions are due to anti-TNF-α-induced IMID [6]. In some cases, these inflammatory diseases may be pre-existing in a latent state in a patient prior to starting anti TNF-α therapy and in others may depend upon the method of the administration of a biological agent.
Diverse systemic autoimmune diseases may appear in patients receiving anti-TNF agents, including lupus and vasculitis. Of note, while immunological alterations are frequently observed in patients receiving anti-TNF monoclonal antibodies, only a small fraction of patients develop clinical manifestations. Clinicians need to be aware that cutaneous or articular manifestations may be part of such autoimmune diseases and not always related to paradoxical inflammation.
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Incidence and characteristics
The anti-TNF-α agents have been associated with the onset of both eczematiform and psoriasiform skin eruptions [7]. Eczema-like lesions are characterized by the association of xerosis and pruriginous ill-limited plaques with erythematous or squamous vesicules, while psoriasiform eruptions are characterized by scaly erythematous plaques, pustulosis and eventually nail involvement [6]. Psoriasiform lesions in particular in patients receiving anti-TNF-α agents (Fig. 1) are considered to be
Paradoxical joint inflammation
Reports of de novo joint manifestations in IBD patients receiving anti-TNF-α agents have emerged but appear to be less frequent than paradoxical skin lesions.
In one case series that included 1300 patients receiving adalimumab or infliximab for IBD, 21 patients developed disabling polyarthralgia (10 while receiving infliximab, 11 while receiving adalimumab) (Van Moerkercke, unpublished results). This case series is the first to describe these paradoxical joint manifestations. Among these 21
De Novo IBD in patients receiving anti-TNF
Development of de novo IBD or exacerbation of previously diagnosed IBD in patients receiving anti-TNF-α may also be related to paradoxical inflammation. Cases corresponding to Crohn's or Crohn's like diseases have been reported. Case series have been described in patients with ankylosing spondyloarthritis. Toussirot et al. [23] reported 16 cases and reviewed 23 cases in the literature. Most patients had received etanercept. However, IBD is a well-known extra-articular manifestation in
Ocular manifestations
Inflammatory ocular disease (IOD), mainly uveitis and scleritis, may also be induced by anti-TNF monoclonal antibodies [4]. A recent review identified 152 cases in the literature [28]. Most of the cases concerned patients with ankylosing spondyloarthritis (72%) treated with etanercept (84%). The outcome of IOD was favorable even when anti-TNF was continued.
Neurological manifestations
Cases of demyelinating central nervous system disorders after initiation of anti-TNF therapies have been reported, mainly optic neuritis
Autoimmune diseases
Immunological alterations, with positivity of anti-nuclear antibodies (ANA), are frequently observed in patients receiving anti-TNF-α monoclonal antibodies. In various clinical studies, the percentages of patients found to have ANA and double-stranded DNA antibodies (anti-dsDNA) after infliximab treatment were 46 to 57% and 23 to 34%, respectively [32]. In rare cases, these elevated ANA values are paired with clinical symptoms that are consistent with the “lupuslike” syndrome, such as
Conclusions
Current evidence suggests that paradoxical inflammation is a possibility during treatment with anti-TNF-α agents and that it can be considered a drug class effect, seen across all treatment indications. Although there is a lack of precise data regarding the incidence of paradoxical inflammatory events during treatment with these agents, available data suggest that skin lesions are not rare, with an incidence likely to be around 10%. Joint manifestations, which are less frequent, may also be
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