{"doi":"10.1111/bjd.16063","title":"Dynamics of plasma cytokines in a patient with deficiency of interleukin-36 receptor antagonist successfully treated with anakinra","abstract":null,"journal":"British Journal of Dermatology","year":2018,"id":654788,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1708953,"name":"D. Morgado-Carrasco","orcid":null,"position":1,"is_corresponding":false},{"id":1708954,"name":"X. Fustà-Novell","orcid":"0000-0001-6631-6030","position":2,"is_corresponding":false},{"id":1708955,"name":"A. Mensa-Vilaró","orcid":null,"position":3,"is_corresponding":false},{"id":1708956,"name":"J.I. Arostegui","orcid":null,"position":4,"is_corresponding":false},{"id":1708957,"name":"M. Alsina-Gibert","orcid":null,"position":5,"is_corresponding":false},{"id":1708958,"name":"J.M. Mascaró Jr","orcid":null,"position":6,"is_corresponding":false},{"id":620920,"name":"Sebastián Podlipnik","orcid":"0000-0003-4150-0522","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Dynamics of plasma cytokines in a patient with deficiency of interleukin-36 receptor antagonist successfully treated with anakinra","abstract":"Dear Editor, Generalized pustular psoriasis (GPP) is an autoinflammatory disease characterized by abrupt‐onset episodes of erythematous skin plaques with countless pustules, fever, marked neutrophilia and increased acute‐phase reactants.1 Loss‐of‐function mutations in the IL36RN gene, encoding interleukin (IL)‐36 receptor antagonist (IL‐36Ra), have been described in a significant proportion of patients with GPP.2 3 Previous studies have shown in vitro and ex vivo enhanced production of proinflammatory cytokines (IL‐1, IL‐6 and IL‐8) and successful outcomes with anti‐IL‐1 drugs in patients carrying IL36RN mutations.1 2 However, little is known about the correlation of plasma cytokines, inflammatory markers and clinical follow‐up, before and after treatment with anti‐IL‐1 drugs. An otherwise healthy 54‐year‐old man had been monitored at our department since his initial presentation of GPP 7 years earlier. He was first treated with acitretin, topical corticosteroids and ciclosporin (5 mg kg−1 per day). In the last 2 years, he had presented multiple GPP flares requiring hospital admissions. Combined treatment with intravenous infliximab (5 mg kg−1) and subcutaneous methotrexate (5 mg per week) was started, but after the third infliximab dose, a severe Pneumocystis jirovecii pneumonia was diagnosed (described elsewhere)4 that required immediate infliximab withdrawal. Intravenous trimethoprim–sulfamethoxazole and corticosteroids were initiated, resulting in a favourable outcome. The corticosteroids were slowly tapered, but at the 15‐mg‐daily dose the patient relapsed with extremely painful pustules, fever and increased acute‐phase reactants. On the basis of previous reports describing IL36RN mutations in patients with GPP, a complete IL36RN gene analysis was performed using Sanger sequencing. This revealed the heterozygous missense variant p.Ser113Leu, which was previously described as a pathogenic mutation.3 Treatment with the anti‐IL‐1 drug anakinra (100 mg daily subcutaneously) was started, resulting in rapid improvement of his symptoms. Plasma levels of 20 cytokines were measured before and after starting anakinra using a custom bead‐based multiplex Luminex immunoassay (ProcartaPlex Mix&Match Human 20‐plex; eBioscience, Hatfield, U.K.). During active disease, increased levels of IL‐6, IL‐8, IL‐17A, IL‐1Ra and interferon γ‐induced protein 10 (IP‐10) were detected (Fig. 1). Treatment with anakinra was associated with a rapid decrease to normal values of plasma levels of IL‐6, IL‐8, IP‐10 and IL‐17A, as well as neutrophil and platelet counts and C‐reactive protein plasma level. Levels of cytokines in the patient post‐treatment were matched with those of healthy controls. The horizontal dotted line of each graph represents the value of cytokines of healthy controls (****P < 0·0001). Treatment with anakinra was associated with a rapid decrease to normal plasma levels of interleukin (IL)‐6, IL‐8, interferon‐γ‐induced protein 10 (IP‐10) and IL‐17A. The complete set of cytokines includes IL‐1α, IL‐1β, IL‐1Ra, IL‐2, IL‐4, IL‐5, IL‐6, IL‐8, IL‐9, IL‐10, IL‐12p70, IL‐13, IL‐17A, IL‐18, tumour necrosis factor (TNF)‐α, interferon (IFN)‐α, IFN‐β, IFN‐γ, IP‐10 and granulocyte–macrophage colony‐stimulating factor. Cytokines that yielded values of zero or below the lower limit of quantification (LLOQ) in analysed serum samples are not displayed in the figure. After 14 months of treatment with anakinra, during which the patient remained asymptomatic, the drug was first tapered and subsequently stopped. However, 5 months later the patient presented a new inflammatory flare requiring admission. Anakinra was then reinitiated, resulting in a rapid improvement of the lesions and normalization of laboratory parameters. IL‐36 is a member of the IL‐1 family widely expressed by keratinocytes. After binding to its membrane‐bound receptor, IL‐36 activates the nuclear factor‐κB and mitogen‐activated protein kinase pathways, resulting in proinflammatory signalling. Loss‐of‐function IL36RN mutations provoke a reduction of the inhibitory activity of IL‐36Ra, resulting in an increase in proinflammatory signalling and the development of severe flares of GPP.2 Furthermore, following exposure to IL‐36 agonist stimulation, a positive regulatory feedback loop between IL‐1 and IL‐36 has been described, increasing levels of IL‐1A, IL‐6, IL‐8 and tumour necrosis factor.1 Thus, IL‐1 blockade has been shown to be beneficial in these patients, as in ours. The most common parameter to evaluate systemic inflammation is the plasma level of C‐reactive protein, which is synthesized mainly in the liver under the transcriptional control of IL‐6.5 In this study, we also measured multiple circulating cytokines before and after starting anakinra. The results revealed that plasma levels of IL‐8, IL‐6, IL‐17A and IP‐10 were those showing marked changes with anakinra treatment. The changes of IL‐8 level accord with previous reports describing enhanced IL‐8 levels in patients with deficiency of interleukin‐36 receptor antagonist (DITRA) and IL‐8 reduction with IL‐1 blockade in a model of tissue inflammation.6 Finally, the involvement of IP‐10 in active psoriatic plaques has been well known since 1998.7 However, to our knowledge, no data are available concerning the involvement of IP‐10 in DITRA. Moreover, it has been documented that migration of neutrophils to psoriatic lesions can be mediated by IL‐17, and its levels are increased in lesional skin.8 Previous reports have shown the efficacy of IL‐17 blockade in patients with GPP, but further studies are needed in patients with DITRA. As limitations of our study, the cytokine levels were not analysed during the time when anakinra was interrupted, and IL‐36 and IL‐36Ra molecules were not included in this set because they were not commercially available at the time when we designed the custom panel. We believe that the present study will give a starting point to future researchers in finding different interleukin signatures and profiles that might relate to the disease evolution and treatment outcomes. Additional data are available on request from the corresponding author or at www.researchgate.net/profile/Sebastian_Podlipnik. The authors would like to thank Paul Hetherington for his help with the English editing of the manuscript. Funding sources: This work has been partially funded by the CERCA Programme/Generalitat de Catalunya (to J.I.A.), grant SAF2015‐68472‐C2‐1‐R from the Spanish Ministry of Economy and Competitiveness and Fondo Europeo de Desarrollo Regional (FEDER) (to J.I.A.) and grant AC15/00027 from the Instituto de Salud Carlos III/Transnational Research Projects on Rare Diseases (to J.I.A.). Conflicts of interest: none declared.","is_dataset_classified":null,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"29030861","pmcid":null,"openalex_id":"https://openalex.org/W2761748352","authors":[],"funders":[{"funder_name":"CERCA Programme/Generalitat de Catalunya","grant_id":"SAF2015-68472-C2-1-R","title":null},{"funder_name":"Spanish Ministry of Economy and Competitiveness and Fondo Europeo de Desarrollo Regional","grant_id":"AC15/00027","title":null}],"total_grants":2,"fwci":0.7974,"citation_percentile":0.6931409,"influential_citations":0,"citation_trend":[{"year":2017,"count":1},{"year":2018,"count":1},{"year":2019,"count":5},{"year":2020,"count":1},{"year":2021,"count":1},{"year":2022,"count":1}],"oa_status":"closed","license":"https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model","oa_locations":[{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1111%2Fbjd.16063","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1111/bjd.16063","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/full-xml/10.1111/bjd.16063","host_type":"publisher"},{"url":"https://academic.oup.com/bjd/article-pdf/178/4/e258/47587730/bjde258.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1111/bjd.16063","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/29030861","host_type":"repository"}],"fields_of_study":["Psoriasis: Treatment and Pathogenesis","Immunodeficiency and Autoimmune Disorders","Dermatology and Skin Diseases"],"mesh_terms":["Dermatologic Agents","Humans","Interleukins","Male","Middle Aged","Psoriasis","Cytokines","Interleukin 1 Receptor Antagonist Protein"],"keywords":["Anakinra","Generalized pustular psoriasis","Neutrophilia","Interleukin 1 receptor antagonist","Medicine","Receptor antagonist","Interleukin","Immunology","Interleukin-1 receptor","Antagonist","Inflammation","Proinflammatory cytokine","Cytokine","Psoriasis","Disease","Receptor","Internal medicine"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-11T08:24:13.640841Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}