Juvenile interleukin-36 receptor antagonist deficiency (DITRA) with c.80T>C (p.Leu27Pro) mutation successfully treated with etanercept and acitretin.
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ABSTRACT:
SUBMITTER: Cuperus E
PROVIDER: S-EPMC5993535 | biostudies-literature | 2018 Mar
REPOSITORIES: biostudies-literature
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Juvenile interleukin-36 receptor antagonist deficiency (DITRA) with c.80T>C (p.Leu27Pro) mutation successfully treated with etanercept and acitretin.
Cuperus Edwin E Koevoets Rosanne R van der Smagt Jasper J JJ Toonstra Johan J de Graaf Marlies M Frenkel Joost J Pasmans Suzanne G M A SGMA
JAAD case reports 20180202 2
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Project description:BackgroundDeficiency 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.MethodA 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.ResultsOur 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.ConclusionsDITRA 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.
| S-EPMC6615208 | biostudies-literature
Project description: Not available
| S-EPMC8235915 | biostudies-literature
Project description:BackgroundMutations in ITCH, which encodes an E3 ubiquitin-protein ligase, can result in systemic autoimmunity and immunodeficiency. The clinical phenotype and mechanism of disease have not been fully characterized, resulting in a paucity of therapeutic options for this potentially fatal disease.ObjectiveWe aimed to (1) expand the understanding about the phenotype of human ITCH deficiency (2) further characterize the associated immune dysregulation, and (3) report the first successful hematopoietic cell transplant (HCT) in a patient with ITCH deficiency.MethodsDisease profiling was performed in a patient with multisystem immune dysregulation. Whole exome sequencing with trio analysis and functional validation of candidate disease variants were performed, including mRNA and protein expression. Analyses to further delineate the immunophenotype included quantitative evaluation of lymphoid and myeloid subsets with flow cytometry and mass cytometry.ResultsA patient with multisystem immune dysregulation presenting with growth failure, very-early-onset inflammatory bowel disease, arthritis, uveitis, psoriasis, and type 1 diabetes mellitus underwent whole exome sequencing, which identified novel compound heterozygous mutations in ITCH. Reduced expression of ITCH mRNA and absent ITCH protein were found. Abnormalities in both lymphoid and myeloid lineages were identified. The patient underwent HCT. He demonstrated excellent immune reconstitution and resolution of many manifestations of his systemic disease.ConclusionsHere we report ITCH deficiency with unique clinical features of colonic very-early-onset inflammatory bowel disease, arthritis, and uveitis in the setting of immune dysregulation and further characterize the underlying immune dysregulation. We demonstrate that HCT can be an effective, and potentially curative, therapy for ITCH deficiency.
| S-EPMC9053103 | biostudies-literature
Project description:BackgroundEtanercept, a soluble tumor necrosis factor receptor, and acitretin have been shown to be effective in treating psoriasis. Acitretin is widely used in Korea. However, the combination of etanercept plus acitretin has not been evaluated among Korean patients with psoriasis. The objective of this study was to investigate the efficacy and safety of combination therapy with etanercept and acitretin in patients with moderate to severe plaque psoriasis.MethodsSixty patients with psoriasis were randomized to receive etanercept 50 mg twice weekly (BIW) for 12 weeks followed by etanercept 25 mg BIW for 12 weeks (ETN-ETN); etanercept 25 mg BIW plus acitretin 10 mg twice daily (BID) for 24 weeks (ETN-ACT); or acitretin 10 mg BID for 24 weeks (ACT). The primary efficacy measurement was the proportion of patients achieving 75 % improvement in Psoriasis Area and Severity Index (PASI 75) at week 24. Secondary end points included 50 % improvement in PASI (PASI 50) at week 24 and clear/almost-clear by Physician Global Assessment (PGA) at each visit through week 24.ResultsThe proportions of patients achieving PASI 75, PASI 50, and PGA clear/almost-clear at week 24 in the ETN-ETN (52.4, 71.4, and 52.4 %, respectively) and ETN-ACT groups (57.9, 84.2, and 52.6 %, respectively) were higher than in the ACT group (22.2, 44.4, and 16.7 %, respectively). The incidence of adverse events was similar across all arms. This was an open-label study with a small number of patients.ConclusionIn Korean patients with moderate to severe plaque psoriasis, etanercept alone or in combination with acitretin was more effective than acitretin. All treatments were well tolerated throughout the study.Trial registrationThis study was registered on July 7, 2009 at ClinicalTrials.gov, NCT00936065 .
| S-EPMC4960797 | biostudies-literature
Project description:Loss-of-function mutations in the interleukin (IL)-36 gene IL36RN are associated with psoriasis. The importance of neutrophil extracellular traps (NETs), web-like structures composed of neutrophil DNA, in the pathogenesis of psoriasis has been unclear. Here, we aimed to clarify the role of NET signaling in the deficiency of IL36 receptor antagonist (DITRA). We evaluated the severity of psoriasis-like lesions induced by imiquimod cream treatment in Il36rn-/- mice. The mRNA levels of psoriasis-related cytokines were measured via real-time reverse transcription polymerase chain reaction, and the effects of Cl-amidine, a peptidyl arginine deiminase 4 (PAD4) inhibitor, on psoriasis-like lesions were evaluated. PAD4 is a histone-modifying enzyme that is involved in NET formation. Psoriasis area and severity index scores, epidermal thickness, and infiltrated neutrophil counts were significantly increased in Il36rn-/- mice; NET formation was confirmed pathologically. Several cytokines and chemokines were upregulated in the skin lesions of Il36rn-/- mice and Cl-amidine treatment improved these psoriasis-like lesions. These results suggest that NET formation plays an important role in the pathology of psoriasis-like lesions in these mice and might represent a promising therapeutic target for DITRA.
| S-EPMC7678853 | biostudies-literature
Project description:BackgroundAutoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone.MethodsWe studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN.ResultsWe identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly.ConclusionsWe propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)
| S-EPMC2876877 | biostudies-literature
Project description:BackgroundJuvenile ossifying fibromas (JOF) are benign osteofibrous tumors very rarely located in paranasal sinus. The diagnostic and therapeutic tools applied in sinonasal inflammatory pathologies and other tumors fail to address a specific management in this rare pathology. Currently, the only available treatment is surgery. Endoscopic sinus surgery (ESS) allows a complete but minimally invasive approach compared to the open technique, especially for the minor demolition on growing bone structures.Case descriptionWe describe a case of a 13-year-old boy presenting in the Emergency Department for a head trauma. The computerized tomography (CT) revealed an ethmoid-maxillary bony mass suspected to be a juvenile ossifying fibroma. The patient underwent ESS. Histological examination confirmed a juvenil psammomatoid ossifyng fibroma (JPOF). A revision surgery with the same technique was required after 7 months due to relapse of the tumor. He did not develop postoperative complications. The 3-years follow-up did not show any signs of relapse.ConclusionsParanasal JOF is a challenge for the ear-nose-throat (ENT) surgeon. The principles of local disease control for relapse reduction are different from inflammatory diseases and other paranasal tumors. Severe organ damage and recurrences are possible if caution is not observed. Specific guidelines about management are required on the basis of the shared experiences in the few cases reported in literature.
| S-EPMC10130680 | biostudies-literature
Project description: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.
| S-EPMC6261121 | biostudies-literature
Project description:Biologic agents have been designed with the help of immunological studies to target particular areas of the immune system which are thought to play a role in the pathogenesis of disease. Etanercept is a soluble anti-tumor necrosis factor alpha (TNF-alpha) agent licensed for the treatment of active poly-articular juvenile idiopathic arthritis (JIA) in children aged 4 to 17 years who have failed to respond to methotrexate alone, or who have been intolerant of methotrexate. The safety and efficacy of etanercept in this patient group has been established by one randomized controlled trial and several longitudinal studies. This, together with the fact that until recently etanercept was the only anti-TNF licensed in JIA, has made it the most common first choice biologic for many clinicians. However, there are still many unanswered questions about etanercept, including its efficacy and safety in different subtypes of JIA, in children under 4 years of age and in those with uveitis. There are still concerns about the long term safety of TNF antagonists in the pediatric age group and unanswered questions about increased risks of malignancy and infection. Although adult studies are useful to improve understanding of these risks, they are not a substitute for good quality pediatric research and follow-up studies. Adult trials often include greater numbers of patients. However, they evaluate a different population and drug behavior may vary in children due to differences in metabolism, growth and impact on a developing immune system. In addition, rheumatoid arthritis is a different disease than JIA. Clinicians need to carefully weigh up the risk benefit ratio of anti-TNF use in children with JIA and push for robust clinical trials to address the questions that remain unanswered. This article summarizes the evidence available for use of etanercept in children with JIA and highlights aspects of treatment in need of further research.
| S-EPMC2726066 | biostudies-literature
Project description:BackgroundGeneralized pustular psoriasis (GPP) is a systemic inflammatory disease with poor outcomes, and several studies have suggested that the mutation of the interleukin 36 receptor antagonist gene (IL36RN) is related to GPP, where the polymorphism c.115+6T>C is reported to be the most common mutation of IL36RN. This study was performed to clarify and comprehensively evaluate the relationship between IL36RN gene polymorphism and the susceptibility of GPP subtypes.MethodsTo conduct a thorough literature review, studies were obtained using databases such as Pubmed, EMBASE, Cochrane, China National Knowledge Infrastructure, and the Wanfang database. Only studies published up to December 2019 were included. The quality of the research studies was estimated using the Newcastle-Ottawa scale. The total odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were pooled and analysed using STATA 14. The publication bias was evaluated through the Egger test, performed using the aforementioned software. Five common gene models were built and analysed to assess the association between the polymorphism c.115+6T>C and subtypes of GPP.ResultsA total of 10 studies were selected, including 683 cases of GPP patients. Meta-analyses showed that there was a significant statistical correlation of IL36RN mutation between GPP with or without psoriasis vulgaris (OR = 3.82, 95%CI 2.63-5.56) and between adult GPP and paediatric GPP (OR = 0.42, 95%CI 0.23-0.77). No obvious discrepancy between European patients (OR = 4.03, 95%CI 2.23-7.26) and Asian patients was found. The gene models showed clear associations between the polymorphism c.115+6T>C and GPP through the dominant model (CC+ TC vs TT, OR 2.74, 95%CI 2.06-3.64), recessive model (CC vs CT + TT, OR 4.33, 95%CI 2.84-6.60), homozygote model (CC vs TT, OR 4.37, 95%CI 2.88-6.62), heterozygote model (CT vs TT, OR 2.26, 95%CI 1.32-3.85) and allelic model (C vs T, OR 3.35, 95%CI 2.63-4.27).ConclusionThe IL36RN mutation is strongly related to GPP without psoriasis vulgaris and the early onset of GPP. Furthermore, the single-nucleotide polymorphism c.115+6T>C of the IL36RN gene plays a significant role in GPP vulnerability, especially in homozygous mutation. GPP could be a different inflammatory disease, independent of psoriasis.
| S-EPMC7647532 | biostudies-literature