Juvenile interleukin-36 receptor antagonist deficiency (DITRA) with c.80T&gt;C (p.Leu27Pro) mutation successfully treated with etanercept and acitretin

Cuperus, Edwin; Koevoets, Rosanne; Smagt, Jasper J. van der; Toonstra, Johan; Graaf, Marlies de; Frenkel, Joost; Pasmans, Suzanne G.M.A.

doi:10.1016/j.jdcr.2017.08.019

Cited by 24 publications

(26 citation statements)

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“…The reason for the heterogeneous response to biologicals is unclear, although a correlation between the severity of the disease and the degree of the functional impairment of the mutated IL36RN could be shown [34]. Besides this proposed phenotype-genotype association with severe clinical manifestation in patients with nonsense mutation further factors seem to play a role as reported by several authors who showed that similar treatments in patients with identical mutations resulted in different outcome [5, 10, 28, 31, 32]. Our review did not show an association of treatment response with genetic mutation either, be it because of the small number of the cohort or because there is no direct one (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Scoping review of biological treatment of deficiency of interleukin-36 receptor antagonist (DITRA) in children and adolescents

et al. 2019

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Background Deficiency of interleukin-36 receptor antagonist (DITRA) is a life threatening monogenic autoinflammatory disease caused by loss of function mutations in the IL36RN gene. Affected patients develop recurrent episodes of generalized pustular psoriasis (GPP) with systemic inflammation and fever. We here review and analyze the literature on pediatric DITRA patients who have been treated by biologicals targeting inflammatory cytokines. Method A database research was performed to identify all relevant articles on pediatric DITRA patients treated with biologicals. According to defined response criteria therapeutic efficacy was analyzed. Results Our literature research revealed 12 pediatric patients with DITRA who have received treatment with biologicals and we add a further not yet reported patient. Out of these 13 patients 10 were homozygous including 6 with the p.Leu27Pro, 3 with the p.Arg10 Argfs* and 1 with the p.Thr123Met mutation. 3 patients were compound heterozygous. In total 28 flares were treated with biological agents- targeting IL-1, IL-17, IL-12/23 and TNF-α. Complete response was achieved in 16 flares (57%), a partial reponse was seen in 2 flares (7%), and no response was observed in 10 flares (36%). Response rates were heterogeneous among the different agents. While complete/partial/no response with inhibition of TNF-alpha could be achieved in 7 (58%)/1 (8%)/4 (33%), the inhibition of IL-17 and of IL-12/23 led in each 4 flares to a 100% complete response. IL-1 inhibition led to complete/partial response in each 1 (13%) and was not effective in 6 (76%) flares. Of note, the novel patient was successfully treated with weekly dosed adalimumab. Conclusions DITRA is a rare disease that has to be considered in GPP with systemic inflammation and fever. It can be effectively treated with specific biological inhibition of TNF-alpha, IL-12/23 and IL- 17, while anti-IL-1 treatment seems less effective. Weekly dosed adalimumab appears to be a treatment option for pediatric patients. Further reports and studies of biological treated pediatric DITRA patients are warranted for evaluation of optimal treatment.

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Section: Discussionmentioning

confidence: 99%

Scoping review of biological treatment of deficiency of interleukin-36 receptor antagonist (DITRA) in children and adolescents

et al. 2019

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“…In five of eight patients in whom anti-IL-1 drugs failed, the final therapeutic regimens were etanercept and acitretin [ 19 ], adalimumab and methotrexate [ 20 ], secukinumab [ 21 ], ustekinumab [ 22 ], and infliximab [ 23 ].…”

Section: Resultsmentioning

confidence: 99%

“… + − ? + − Homozygous for 175-kb deletion on chromosome 2q13 a [ 19 ] #12 NA NA 30 1.5 M − − + + M ? + − ?…”

Section: Methodsmentioning

confidence: 99%

Scoping Review on Use of Drugs Targeting Interleukin 1 Pathway in DIRA and DITRA

Gómez-García

Sanz-Cabanillas

Viguera-Guerra

et al. 2018

Dermatol Ther (Heidelb)

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IntroductionDeficiencies in interleukin (IL)-1 receptor (IL-R) antagonist (DIRA) and IL-36R antagonist (DITRA) are rare genetic autoinflammatory diseases related to alterations in antagonists of the IL-1 pathway. IL-1 antagonists may represent therapeutic alternatives. Here, we aim to provide a scoping review of knowledge on use of IL-1-targeting drugs in DIRA and DITRA.MethodsAn a priori protocol was published, and the study was conducted using the methodology described in the Joanna Briggs Institute Reviewer’s Manual and the recently published PRISMA Extension for Scoping Review statement. A three-step search using MEDLINE and EMBASE databases until March 2018 with additional hand searching was performed. Data charting was performed. The search, article selection, and data extraction were carried out by two researchers independently.ResultsTwenty-four studies on use of anti-IL-1 drugs were included [15 studies including patients with diagnosis of DIRA (n = 19) and 9 studies including patients with diagnosis of DITRA (n = 9)]. Most studies followed a multicenter observational design. Among all patients who received treatment with anti-IL-1 drugs, nine and four mutations in IL1RN and IL36RN were found, respectively. Patients with DIRA were treated with anakinra (n = 17), canakinumab (n = 2), or rinolacept (n = 6). All patients with DITRA were treated with anakinra, and only one case was also treated with canakinumab. Time-to-response frequencies were evaluated as immediate, short, and medium–long term for DIRA (17/17, 15/17, and 9/10, respectively) and DITRA (7/9, 3/9, and 2/9, respectively). Most DITRA patients in whom anti-IL-1 treatment failed experienced good response to anti-tumor necrosis factor alpha or anti-IL-12/23 drugs. The safety profiles of treatments were similar in both diseases.ConclusionsEvidence on use of anti-IL-1 drugs in DIRA and DITRA is scarce and based on observational studies. Larger studies with better methodological quality are needed to increase confidence in use of these drugs in patients with DIRA and DITRA.Electronic supplementary materialThe online version of this article (10.1007/s13555-018-0269-7) contains supplementary material, which is available to authorized users.

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“…Table 1 Next generation sequencing outcome of (likely) pathogenic mutations in nine prospective (1)(2)(3)(4)(5)(6)(7)(8)(9) and eight retrospective (10-17) patients with neonatal erythroderma.…”

Section: Clinical Lettermentioning

confidence: 99%

“…In contrast, in patients without a collodion membrane, other diagnoses are more likely (OR 6, chi-squared: 0.03). In the patient with DITRA, the diagnosis resulted in a significant therapeutic change later on [6]. Since results are limited to a Dutch population, genetic differences are possible in other populations [7,8].…”

mentioning

confidence: 99%

Diagnostic next generation sequencing in neonatal erythroderma

Cuperus

Sigurdsson

Akker

et al. 2020

J Deutsche Derma Gesell

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Juvenile interleukin-36 receptor antagonist deficiency (DITRA) with c.80T>C (p.Leu27Pro) mutation successfully treated with etanercept and acitretin

Cited by 24 publications

References 10 publications

Scoping review of biological treatment of deficiency of interleukin-36 receptor antagonist (DITRA) in children and adolescents

Scoping review of biological treatment of deficiency of interleukin-36 receptor antagonist (DITRA) in children and adolescents

Scoping Review on Use of Drugs Targeting Interleukin 1 Pathway in DIRA and DITRA

Diagnostic next generation sequencing in neonatal erythroderma

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