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Anti-TNF and skin inflammation in IBD: a new paradox in gastroenterology?
  1. Jan Hendrik Niess1,
  2. Silvio Danese2
  1. 1Division of Gastroenterology, University Clinics of Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland
  2. 2Department of Gastroenterology, Humanitas Clinical and Research Centre, Milan, Italy
  1. Correspondence to Dr Jan Hendrik Niess, Division of Gastroenterology, University Clinics of Visceral Surgery and Medicine, Inselspital Bern, Bern CH-3014, Switzerland; jan.niess{at}insel.ch

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Introduction

Tumour necrosis factor-α (TNF-α) is a proinflammatory cytokine with a key role in inducing the inflammatory response to injuries. While its role in triggering inflammation has been clearly established, some TNF-α-mediated pathways remain unknown.1 Pharmacological blockade of TNF-α with selective monoclonal antibodies has revolutionised the management of patients with immune-mediated inflammatory disorders (IMIDs).2 However, inflammatory bowel disease (IBD) patients treated with anti-TNF agents can paradoxically experience other IMIDs, including inflammatory skin lesions, joint lesions and sarcoidosis.3 ,4 In most patients, symptoms included morning stiffness and pain in the hands and wrists, without signs of arthritis with synovitis and an association with high titres of antinuclear antibodies (ANAs; >1:280) has been reported.5

Paradoxical skin lesions

The anti-TNF-α agents have been associated with the onset of eczematiform and psoriasiform skin eruptions.6 The association of xerosis and pruriginous ill-limited plaques with erythematous or squamous vesicles characterises the eczema-like lesions developing with such treatment, while the psoriasiform eruptions are characterised by scaly erythematous plaques and pustolosis with eventual nail involvement (figure 1). Psoriasiform lesions in patients receiving anti-TNF-α agents can be considered paradoxical, as these agents are used to treat psoriasis.7

Figure 1

A 32-year-old Crohn's disease patient developed psoriasis after nine infusions of scheduled infliximab treatment at the dose of 5 mg/kg.

A 2008 systematic review identified all cases of TNF-α-antagonist-induced psoriasis within the literature, revealing more than 110 reports of patients developing new-onset psoriasis while receiving such treatment, or experiencing paradoxical worsening of existing psoriasis.5 Almost 50% of these patients were receiving treatment for rheumatoid arthritis, 22% for a seronegative spondylarthritis and 16% were receiving treatment for IBD. Mechanism of paradoxical inflammation induced by TNF antagonists.

Mechanism of paradoxical inflammation induced by TNF antagonists

There are currently three TNF antagonists available for IBD, infliximab, adalimumab and certolizumab pegol. TNF antagonists bind to TNF-α, a cytokine with proinflammatory effects in the mucosa. Soluble TNF-α is cleaved from membrane TNF-α (mTNF-α) and binds to the TNF-receptors TNF-RI and TNF-RII, inducing secretion of proinflammatory cytokines and inducing apoptosis by activating caspase 8. In addition, reverse signalling of mTNF-α induces apoptosis of lymphocytes and macrophages by activating the intrinsic mitochondrial apoptosis pathway.8 It has been suggested that infliximab and adalimumab activate the reverse mTNF-α signalling pathway by binding to mTNF-α, thus inducing the apoptosis of macrophages and lymphocytes that is key for the therapeutic effects of TNF antagonists in IBD (figure 2).

Figure 2

(A) The tumour necrosis factor (TNF) antagonist infliximab binds with the Fab fragment to the membrane TNF-α (mTNF-α). Reverse signalling is initiated leading to apoptosis. (B) Infliximab binds with the Fc region to the Fc-gamma receptor I (FcγRI; CD64) and to the Fc-gamma receptor III/II (FcγRIII/II; CD16/32) expressed by monocytes and macrophages. Activation of macrophages by Fc-gamma receptor induces secretion of interleukin (IL)-23, which drives the production of IL-17 and IL-22 by T lymphocytes required for the development of psoriasiform skin lesions. Ustekinumab binds to the p40 subunit of IL-12 and IL-23 and neutralises both IL-12 and IL-23.

Exposure to cell fragments due to TNF antagonist treatment may lead to increased levels of ANAs. However, Tillack et al9 failed to observe any significant differences in ANA levels between patients who develop psoriasis-like skin lesions and patients without such skin lesions. This raises the question of how then do TNF antagonists induce this paradoxical inflammation? First, Tillack et al9 demonstrate that only patients carrying the rare IL23R variant rs11209026 (p.Arg381Gln) develop psoriasis-like skin lesion with TNF antagonist treatment. Second, the TNF-induced skin lesions are characterised by infiltrating interferon (IFN)-γ-expressing Th1 lymphocytes and by increased numbers of interleukin (IL)-17A/IL-22-expressing Th17 cells.9 It is important to note that in addition to binding with their Fab (antigen-binding region) fragment to TNF, infliximab and adalimumab also bind with their Fc (crystillazable fragment) region to the Fc receptors CD64 (Fc-gamma receptor I (FcγRI)) and CD16/32 (Fc-gamma receptor III/II (FcγRIII/II)) expressed by monocytes and macrophages.10 The activation of the Fc receptors may lead to the paradoxical secretion of proinflammatory cytokines, such as IL-12 and IL-23 (figure 2). However, this is unlikely to completely explain the development of paradoxical skin lesions; no improvement in such skin lesions was observed in one patient switched to certolizumab pegol.9 Third, anti-TNF-induced skin lesions are characterised by the presence of type I IFN,9 beneficial effects of which have been shown in a colitis model.11

Studies in experimental autoimmune enzephalomyelitis (EAE) and patients with multiple sclerosis have shed some lights on these paradoxical effects of type I IFN. The type I IFN IFN-β is able to suppress Th1-mediated EAE, but has been shown to exacerbate Th17-mediated EAE.12 Hence, the presence of type I IFN in psoriasis-like skin lesions induced by TNF antagonists could augment IL-17/IL-22 responses leading to psoriasis-like skin lesions, although this remains speculative.

Management of psoriasiform lesions

In the study by Tillack et al9 62% of patients improved with topical therapies, a proportion similar to that observed previously.13 The switch from infliximab to adalimumab did not lead to significant improvements in anti-TNF antagonist-induced skin lesions. In patients who failed to improve with topical therapies, Tillack et al9 stopped TNF antagonist treatment and introduced ustekinumab (an antibody directed against the p40 subunit of IL-12 and IL-23). IL-12 is of importance for differentiation of naïve cells into Th1 cells. TGF-β and IL-6 drive the differentiation of naïve cells into Th17 cells (that also produce IL-22). IL-23 interacts with differentiated Th17 cells (by binding the then expressed IL-23 receptor) to stabilise and expand Th17 cells. The IL-12–Th1 axis is critical for the development of Crohn's disease.14 The importance of Th17 expansion for the pathology of Crohn's disease is under debate. Blocking of IL-17 with human anti-IL-17 antibodies failed to induce remission in Crohn's disease patients.15 In contrast to Crohn's disease, blocking of IL-17 with human anti-IL-17 antibodies can induce clearance of psoriasis.16 By binding the p40 subunit, ustekinumab blocks both IL-12 and IL-23. Ustekinumab improves flares in patients with severe Crohn's disease resistant to treatment with TNF antagonists17 and is used to treat patients with psoriasis. In the study by Tillack et al9 the psoriasiform skin lesions improved in all patients treated in two independent centres without significant flares of their Crohn's disease. Ustekinumab is approved for the treatment of psoriasis. For Crohn's disease phase II studies with ustekinumab have been reported17 and patients are currently recruited for phase III studies. The switch to ustekinumab may be an option in Crohn's disease patients with psoriasiform skin lesions not responding to topical therapies who require ongoing therapy for Crohn's disease.

References

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Footnotes

  • Contributors JHN and SD reviewed the literature, wrote and edited the manuscript.

  • Funding JHN is supported by the Deutsche Forschungsgemeinschaft (DFG; grant Ni575/7-1).

  • Competing interests JHN does not have any competing interests. SD has served as a speaker, a consultant and an advisory board member for Schering-Plough, Abbott Laboratories, Merck & Co, UCB Pharma, Ferring, Cellerix, Millenium Takeda, Nycomed, Pharmacosmos, Actelion, Alphawasserman, Genentech, Grunenthal, Pfizer, Astra Zeneca, Novo Nordisk, Cosmo Pharmaceuticals, Vifor, and Johnson and Johnson.

  • Provenance and peer review Commissioned; externally peer reviewed.

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