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Juvenile myasthenia gravis in Norway: HLA-DRB1*04:04 is positively associated with prepubertal onset.

ABSTRACT: Juvenile myasthenia gravis (MG) is a rare autoantibody mediated autoimmune disorder targeting the neuromuscular endplate. The clinical hallmark is muscle weakness and fatigability. Disease aetiology is complex, including both genetic and environmental factors. The involvement of genes in the human leukocyte antigen (HLA) is well established in adult MG. However, HLA associations in European juvenile MG have not been studied. This case-control study aimed to investigate and characterize genetic risk factors in prepubertal and postpubertal onset juvenile MG.A population based Norwegian cohort of 43 juvenile MG patients (17 with prepubertal onset, 26 with postpubertal onset) and 368 controls were included. Next generation sequencing of five HLA loci (HLA-A, -B, -C, -DRB1 and -DQB1) was performed, and a positive association was seen with HLA-B*08 (OR (95% CI) = 3.27 (2.00-5.36), Pc = 0.00003) and HLA-DRB1*04:04 (OR (95% CI) = 2.65 (1.57-4.24), Pc = 0.03). Stratified in postpubertal and prepubertal onset, HLA-DRB1*04:04 was only positively associated with the latter (P = 0.01). The HLA-B*08 allele (12.9% in the controls), previously described associated with early onset adult MG, was most frequently observed in postpubertal onset MG (40.4%, P = 0.0002) but also increased among prepubertal onset MG (23.5%, P = 0.05).This study provides novel information about HLA susceptibility alleles in Norwegian juvenile MG where HLA-DRB1*04:04 was associated with prepubertal onset.

SUBMITTER: Popperud TH

PROVIDER: S-EPMC5643110 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Juvenile myasthenia gravis in Norway: HLA-DRB1*04:04 is positively associated with prepubertal onset.

Popperud T H TH Viken M K MK Kerty E E Lie B A BA

PloS one 20171016 10

<h4>Background</h4>Juvenile myasthenia gravis (MG) is a rare autoantibody mediated autoimmune disorder targeting the neuromuscular endplate. The clinical hallmark is muscle weakness and fatigability. Disease aetiology is complex, including both genetic and environmental factors. The involvement of genes in the human leukocyte antigen (HLA) is well established in adult MG. However, HLA associations in European juvenile MG have not been studied. This case-control study aimed to investigate and cha ...[more]

PMID: 29036181

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Project description:Juvenile Myasthenia Gravis (JMG) is a rare disorder, defined as myasthenia gravis in children younger than 18 years of age. While clinical phenotypes are similar to adults, there are a number of caveats that influence management: broader differential diagnoses; higher rates of spontaneous remission; and the need to initiate appropriate treatment early, to avoid the long-term physical and psychosocial morbidity. Current practice is taken from treatment guidelines for adult MG or individual experience, with considerable variability seen across centers. We discuss our approach to treating JMG, in a large specialist JMG service, and review currently available evidence and highlight potential areas for future research. First-line treatment of generalized JMG is symptomatic management with pyridostigmine, but early use of immunosuppression, where good control is not achieved is important. Oral prednisolone is used as first-line immunosuppression with appropriate prevention and monitoring of side effects. Second-line therapies including azathioprine and mycophenolate may be considered where there is: no response to steroids, inability to wean to a reasonable minimum effective dose or if side-effects are intolerable. Management of ocular JMG is similar, but requires close involvement of ophthalmology in young children to prevent amblyopia. Muscle-specific tyrosine kinase (MuSK)-JMG show a poorer response to pyridostigmine and anecdotal evidence suggests that rituximab should be considered as second-line immunosuppression. Thymectomy is indicated in any patient with a thymoma, and consideration should be given in acetylcholine receptor (AChR) positive JMG allowing time for spontaneous remission. The benefit is less clear in ocular JMG and is not advised in MuSK-JMG. Children experiencing a myasthenic crisis require urgent hospital admission with access to the intensive care unit. PLEX is preferred over IVIG due to rapid onset of action, but this needs to be balanced with feasibility in very young children. Key questions remain in the management of JMG: when to initiate both first- and second-line treatments, choosing between steroid-sparing agents, and determining the optimal dose and treatment duration. We feel that given the rarity of this disease, the establishment of national registries and collaboration across groups will be needed to address these issues and facilitate future drug trials in JMG.

Project description:ObjectiveSystemic sclerosis (SSc) is a rare disease that is particularly uncommon in children. Specific HLA alleles have been associated with SSc in adults. This study was undertaken to investigate HLA class II alleles in juvenile-onset SSc.MethodsDRB1, DQA1, and DQB1 alleles were determined by DNA-based HLA typing. Analyses were conducted comparing Caucasian patients with juvenile-onset SSc (n = 76) to healthy Caucasian controls (n = 581).ResultsInitial analyses focused on HLA class II associations previously reported in adult Caucasian patients with SSc. The frequency of DRB1*11 was not significantly increased in juvenile-onset SSc (22.4% of patients with juvenile-onset SSc versus 17.6% of controls; odds ratio [OR] 1.35, P = 0.34), nor were the specific DRB1*11:01 or *11:04 alleles. DQA1*05, a risk factor previously identified in adult men with SSc, was increased in patients with juvenile-onset SSc versus controls (57.9% versus 44.1%; OR 1.76, P = 0.027), as was DRB1*03 (34.2% versus 22.5%; OR 1.79, P = 0.031). Secondary analyses of all DRB1 allele groups revealed an association with DRB1*10 (10.5% of patients with juvenile-onset SSc versus 1.5% of controls; OR 7.48, P = 0.0002). As this is a new observation, correction was made for multiple comparisons of 13 different DRB1 allele groups; results nevertheless remained significant (P = 0.003). Also, a lower frequency of DRB1*01 was observed in patients with juvenile-onset SSc who were younger at disease onset (OR 0.06, P = 0.01) and in those with antibodies to topoisomerase (OR 0.14, P = 0.024).ConclusionAssociations of HLA alleles with juvenile-onset SSc differed from associations with SSc in women, but were similar to associations with SSc in men. Additionally, a novel association with DRB1*10 was observed in children. The greatest proportion of genetic risk of SSc is contributed by the HLA complex, and the current study reveals the importance of the association of HLA class II genes in juvenile-onset SSc.

Project description:ImportanceUse of biologic agents in generalized myasthenia gravis is generally limited to therapy-refractory cases; benefit in new-onset disease is unknown.ObjectiveTo assess rituximab in refractory and new-onset generalized myasthenia gravis and rituximab vs conventional immunotherapy in new-onset disease.Design, setting, and participantsA retrospective cohort study with prospectively collected data was conducted on a county-based community sample at Karolinska University Hospital, Stockholm, Sweden. Participants included 72 patients with myasthenia gravis, excluding those displaying muscle-specific tyrosine kinase antibodies, initiating rituximab treatment from January 1, 2010, to December 31, 2018, and patients with new-onset disease initiating conventional immunotherapy from January 1, 2003, to December 31, 2012, with 12 months or more of observation time. The present study was conducted from March 1, 2019, to January 31, 2020.ExposuresTreatment with low-dose rituximab (most often 500 mg every 6 months) or conventional immunosuppressants.Main outcomes and measuresTime to remission (main outcome) as well as use of rescue therapies or additional immunotherapies and time in remission (secondary outcomes).ResultsOf the 72 patients included, 31 patients (43%) were women; mean (SD) age at treatment start was 60 (18) years. Twenty-four patients had received rituximab within 12 months of disease onset and 48 received rituximab at a later time, 34 of whom had therapy-refractory disease. A total of 26 patients (3 [12%] women; mean [SD] age, 68 [11] years at treatment start) received conventional immunosuppressant therapy. Median time to remission was shorter for new-onset vs refractory disease (7 vs 16 months: hazard ratio [HR], 2.53; 95% CI, 1.26-5.07; P = .009 after adjustment for age, sex, and disease severity) and for rituximab vs conventional immunosuppressant therapies (7 vs 11 months: HR, 2.97; 95% CI, 1.43-6.18; P = .004 after adjustment). In addition, fewer rescue therapy episodes during the first 24 months were required (mean [SD], 0.38 [1.10] vs 1.31 [1.59] times; mean difference, -1.26; 95% CI, -1.97 to -0.56; P < .001 after adjustment), and a larger proportion of patients had minimal or no need of additional immunotherapies (70% vs 35%; OR, 5.47; 95% CI, 1.40-21.43; P = .02 after adjustment). Rates of treatment discontinuation due to adverse events were lower with rituximab compared with conventional therapies (3% vs 46%; P < .001 after adjustment).Conclusions and relevanceClinical outcomes with rituximab appeared to be more favorable in new-onset generalized myasthenia gravis, and rituximab also appeared to perform better than conventional immunosuppressant therapy. These findings suggest a relatively greater benefit of rituximab earlier in the disease course. A placebo-controlled randomized trial to corroborate these findings is warranted.

Dataset Information

Juvenile myasthenia gravis in Norway: HLA-DRB1*04:04 is positively associated with prepubertal onset.

Publications

Juvenile myasthenia gravis in Norway: HLA-DRB1*04:04 is positively associated with prepubertal onset.

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