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]

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.
- 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.
- Bridgewood C, et al. Rheumatol (Oxford) 2021;60:2461–2466.
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Table of Contents: PFGC 2021
Featured articles
Letter from the Editor
Guselkumab shows highest drug survival among systemic treatments
Genes in Psoriasis and Psoriatic Arthritis
HLA-C*06:02-positive patients on ustekinumab show higher drug survival in a real-world scenario
Protective factors identified against anti-drug antibody formation to adalimumab in psoriasis
Comorbidity in Psoriasis
Psoriasis associated with a higher cancer risk
Comorbidity and clinical features of psoriasis vary according to HLA-C*06:02 status
Psoriasis patients with cardiovascular comorbidity characterised by high systemic inflammation
Psoriasis Therapy: New Findings
Inhibition of heat shock protein: A novel way to treat psoriasis?
Guselkumab shows highest drug survival among systemic treatments
Tapering biologics: No alarming signs of increased anti-drug antibodies
Intermediate monocytes are possible predictors of response to secukinumab
Gut microbiota of psoriasis patients: less diverse and reduced functionality
COVID-19: What's New
DLQI scores underestimated during lockdowns?
TNF blockers likely beneficial for psoriatic patients with COVID-19
Patients on immunomodulators need 2 COVID-19 vaccinations before seroconversion
Paradoxical Reactions to Biologics
The Yin and Yang of opposing vectors: an explanation for side effects of biologics
Explaining arthropathy development through IL-4 and IL-13 blockade
Best of the Posters
Potential biomarker discovered for treatment response to ustekinumab
TNF inhibitor for immune-mediated inflammatory disease doubles the risk of paradoxical psoriasis
Secukinumab also tolerable in paediatric psoriasis patients
High treatment success with ixekizumab in patients with psoriasis and diabetes
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