Letter to the Editor
Arthritis during dupilumab therapy
Artritis secundaria a dupilumab
Elena García-Zamora
, Enrique Gómez de la Fuente, José Luis López-Estebaranz
Corresponding author
Servicio de Dermatología, Hospital Universitario Fundación Alcorcón, Alcorcón (Madrid), Spain
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Its mechanism of action is based on blocking interleukin (IL) 4 and IL-13 signalling. In general, it is a very well tolerated drug. The most common adverse effects include injection site reactions (8%–19%), conjunctivitis (3%–19%) and herpetic infections (2%–5%). The first cases of inflammatory arthritis due to dupilumab in patients with AD were published in 2019.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">We report a new case of dupilumab-associated seronegative inflammatory arthritis in a 28-year-old woman with severe AD since childhood. The patient had been treated with topical and oral corticosteroids, ciclosporin A and methotrexate, with partial control of the disease. Treatment with dupilumab was started in November 2020, according to the SmPC. After 4 weeks of treatment (initial dose of 600 mg and 300 mg 2 weeks later), the patient went to the emergency department for pain and stiffness in the axial skeleton and peripheral joints. Rheumatological evaluation confirmed stiffness for more than 30 min and pain with inflammatory features in shoulders, hips, left knee and ankles. Laboratory tests showed only increased erythrocyte sedimentation rate: ESR 27 mm/h (<20 mm/h). Rheumatic tests were negative (parvovirus B19, Epstein–Barr, <span class="elsevierStyleItalic">Chlamydia trachomatis</span>, rubella, CMV, <span class="elsevierStyleItalic">Borrelia</span>, rheumatoid factor, HLA B27, ANA, anti-Jo-1, anti-dsDNA, anti-Ro, anti-La, anti-RNP, anti-Sm and anti-cyclic citrullinated peptide antibodies). The patient was diagnosed with dupilumab-induced inflammatory seronegative arthritis with axial and peripheral involvement. Symptoms slowly resolved within 3 weeks after discontinuation of dupilumab and initiation of prednisone.</p><p id="par0015" class="elsevierStylePara elsevierViewall">New adverse reactions have been identified in recent years in relation to dupilumab which had not been described in phase III clinical trials, such as arthritis, enthesitis, psoriasis and uveitis. To date, more than 45 cases have been published in the literature of patients with inflammatory arthritis or enthesitis after dupilumab initiation.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–5</span></a> Although the aetiology remains unknown, some studies postulate that inhibition of the IL-4/IL-13 pathway by dupilumab may increase the IL-17 mediated response and thus lead to an arthritis pattern similar to psoriatic arthritis. The enthesis would act as a key tissue in the switch from Th2 to Th17 response, which would occur in patients treated with dupilumab.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Joint symptoms secondary to dupilumab usually manifest within the first 12–16 weeks after drug treatment initiation, although there are reports of later onset (more than a year after treatment initiation). Currently, there are no treatment guidelines for this adverse reaction, although in most cases a first approach is to discontinue dupilumab administration. In addition, the resolution and relief of joint symptoms often requires the use of non-steroidal anti-inflammatory drugs (celecoxib is the most commonly used).</p><p id="par0025" class="elsevierStylePara elsevierViewall">It remains to be seen whether this manifestation of arthritis/enthesitis mediated by Th2 pathway inhibition becomes a serious or common adverse reaction over time, as published cases are slowly emerging. What this adverse reaction does highlight is the plasticity of Th responses in humans. Moreover, similar effects have recently begun to be seen with drugs that block IL-13 alone, such as tralokinumab.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> A therapeutic alternative in these cases could be the use of JAK inhibitors, which, acting as pan-cytokines, simultaneously affect the Th1, Th2 and Th17 pathways (either directly or indirectly) and would not produce any Th17-mediated adverse reactions.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0030" class="elsevierStylePara elsevierViewall">This paper has not received any funding.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interest</span><p id="par0035" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest in the publication of this manuscript.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Development of inflammatory arthritis and enthesitis in patients on dupilumab: a case series" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Z.N. Willsmore" 1 => "R.T. Woolf" 2 => "C. Hughes" 3 => "B. Menon" 4 => "B. Kirkham" 5 => "C.H. Smith" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Br J Dermatol" "fecha" => "2019" "volumen" => "181" "paginaInicial" => "1068" "paginaFinal" => "1070" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Portuguese Group of Atopic Dermatitis. Dupilumab for atopic dermatitis: a real-world Portuguese multicenter retrospective study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. Torres" 1 => "M.J. Paiva-Lopes" 2 => "M. Gonçalo" 3 => "C. Claro" 4 => "M. Oliveira" 5 => "J. Gomes" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/09546634.2022.2035309" "Revista" => array:6 [ "tituloSerie" => "J Dermatolog Treat" "fecha" => "2022" "volumen" => "33" "paginaInicial" => "2554" "paginaFinal" => "2559" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/35083945" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Unexpected connections of the IL-23/IL-17 and IL-4/IL-13 cytokine axes in inflammatory arthritis and enthesitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "C. Bridgewood" 1 => "D. Newton" 2 => "N. Bragazzi" 3 => "M. Wittmann" 4 => "D. 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Watad" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/rheumatology/keaa568" "Revista" => array:6 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2021" "volumen" => "60" "paginaInicial" => "2461" "paginaFinal" => "2466" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33253386" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tralokinumab for moderate-to-severe atopic dermatitis patients: first daily practice results" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A.R. Schlösser" 1 => "M. Shareef" 2 => "J. Olydam" 3 => "T.E.C. Nijsten" 4 => "D.J. 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