Explaining arthropathy development through IL-4 and IL-13 blockade

Evidence has been found of a previously unknown protective role of IL-4/IL-13 in entheseal induction of the IL-23/IL-17 axis. This might explain clinical observations of emerging musculoskeletal entheseal pathology following dupilumab therapy.

IL-4 and IL-13 are key cytokines that are involved in typical Th2 diseases such as atopic dermatitis, asthma, and allergy. Thus, according to Dr Charlie Bridgewood (University of Leeds, UK), blocking IL-4 and IL-13 can be an interesting option for treating Th2 disease. “Something very interesting is that dupilumab therapy has been associated early on with paradoxical disease,” Dr Bridgewood said. Numerous patients show not only new onset of psoriasis but also psoriatic arthritis (PsA) and enthesitis. A possible explanation of this phenomenon is the polarisation of one T-cell pathway that might come at the expense of another. If one pathway is blocked T cells might enter opportunistic pathways (see Figure). “Maybe that is why we get Th17 disease. However, there are 2 sides to this coin: if we give patients ustekinumab, they sometimes develop eczema – a type 2 phenotype,” Dr Bridgewood explained.

Figure: T-cell effector functions [1]
IFNγ, interferon gamma; IL, interleukin; ILC, innate lymphoid cell; TGFβ, transforming growth factor beta; Tc2, cytotoxic T cell type 2; Th2, T helper 2; TNF, tumour necrosis factor.

 

IL-4/IL-13 blockade: a more than 12-fold risk for enthesitis

To better understand paradox reactions following dupilumab therapy, Dr Bridgewood and his team analysed 37,849 patients on dupilumab for incidence of psoriatic and other inflammatory diseases in VigiBase, a World Health Organization’s global Individual Case Safety Report (ICSR). The researchers formed disease groups according to autoimmune or autoinflammatory nature. Following dupilumab therapy, the rates of seronegative arthritis (OR 9.61), enthesitis (OR 12.6), psoriasis (OR 1.48), and nail psoriasis (OR 4.71) were all elevated. In addition, the frequency of certain Th1 diseases, such as acne and vitiligo, also increased after dupilumab intake. “Interestingly, Crohn´s disease was less frequent with dupilumab therapy, so the take-home message is that classical autoimmunity with autoantibody involvement is less common, whereas Th1-driven and Th17-driven disease are more common,” Dr Bridgewood concluded.

In vitro studies revealed that myeloid cells in the human enthesis are the main source of local IL-23 production [2]. Both IL-4 and IL-13 block IL-23 from these cells. “If you remove IL-4 and IL-13, you can increase IL-23,” Dr Bridgewood said. These novel findings point towards a previously unknown role for IL-4 and IL-13 as having a protective function in entheseal induction of IL-23/IL-17 axis cytokines and their associated disease such as psoriasis and PsA. This is the molecular explanation for why anti-IL-4/IL-13 therapy may induce musculoskeletal entheseal pathology as has been demonstrated in this analysis of a large database.

 

1. 
   
   1. Bridgewood C, et al. Interleukin (IL)-4/IL-13 blockade is associated with psoriatic disease: evidence from the clinic and in vitro. FC25, Psoriasis from Gene to Clinic 2021, 9–11 December.
   
   
   2. Bridgewood C, et al. Rheumatol (Oxford) 2021;60:2461–2466.

 

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Posted on 3 February, 20223 February, 2022