A low-frequency IL4R locus variant in Japanese patients with intravenous immunoglobulin therapy-unresponsive Kawasaki disease

Background: Kawasaki disease (KD) is a systemic vasculitis which may be associated with coronary artery aneurysms. A notable risk factor for the development of coronary artery aneurysms is resistance to intravenous immunoglobulin (IVIG) therapy, which comprises standard treatment for the acute phase of KD. The cause of IVIG resistance in KD is largely unknown; however, the contribution of genetic factors, especially variants in immune-related genes, has been suspected. Methods: To explore genetic variants related to IVIG-unresponsiveness, we designated KD patients who did not respond to both first and second courses of IVIG therapy as IVIG-unresponsive patients. Using genomic DNA from 30 IVIG-unresponsive KD patients, we performed pooled genome sequencing targeting 39 immune-related cytokine receptor genes. Results: The single nucleotide variant (SNV), rs563535954 (located in the IL4R locus), was concentrated in IVIG-unresponsive KD patients. Individual genotyping showed that the minor allele of rs563535954 was present in 4/33 patients with IVIG-unresponsive KD, compared with 20/1063 individuals in the Japanese genome variation database (odds ratio = 7.19, 95% confidence interval 2.43-21.47). Furthermore, the minor allele of rs563535954 was absent in 42 KD patients who responded to IVIG treatment (P = 0.0337), indicating that a low-frequency variant, rs563535954, is associated with IVIG-unresponsiveness in KD patients. Although rs563535954 is located in the 3'-untranslated region of IL4R, there was no alternation in IL4R expression associated with the mior allele of rs563535954. However, IVIG-unresponsive patients that exhibited the minor allele of rs563535954 tended to be classified into the low-risk group (based on previously reported risk scores) for prediction of IVIG-resistance. Therefore, IVIG-unresponsiveness associated with the minor allele of rs563535954 might differ from IVIG-unresponsiveness associated with previous risk factors used to evaluate IVIG-unresponsiveness in KD. Conclusion: These findings suggest that the SNV rs563535954 could serve as a predictive indicator of IVIG-unresponsiveness, thereby improving the sensitivity of risk scoring systems, and may aid in prevention of coronary artery lesions in KD patients.ArticlePEDIATRIC RHEUMATOLOGY.17:34(2019)journal articl

JOA Back Pain Evaluation Questionnaire: initial report

AbstractBackgroundThere is no widely accepted objective evaluation for lumbar spine disorders. New outcome measures should be patient-oriented and should measure symptoms and self-reported functional status in multiple dimensions. The aim of this study was to identify items to be included in the disease-specific quality of life (QOL) questionnaire for the assessments of patients with lumbar spine disorders.MethodsThe draft of the QOL questionnaire that consisted of a total of 60 items, including 24 items derived from the Japanese version of the Roland Morris Disability Questionnaire (RDQ) and 36 items derived from the Japanese version of Short Form 36 (SF-36), were administered to patients and controls. After obtaining written informed consent, the following data were collected from the patient group (n = 328) and the control group (n = 213): (1) background characteristics, including age, diagnosis, Japanese Orthopaedic Association (JOA) score, and finger to floor distance; (2) responses to the questionnaire; (3) the identification rate by discrimination analysis to select the candidates for adoption and by adopting explanatory variables. The items to be excluded were determined by examining the explanatory variables, which were selected after the discrimination analysis, by setting the candidate to-be-excluded items as an objective variable.ResultsBased on the distribution of the responses, two items, RDQ-15 and RDQ-19, were excluded. From the results of the correlation coefficient calculation for each question in the patient group, 33 items were excluded and 27 candidate items were adopted. Based on the adoption explanatory variable used in the discrimination analysis, 25 of the 27 candidate items for adoption were accepted.ConclusionsThis study identified the 25 specific questionnaire items that should be included in the questionnaire to evaluate QOL of patients with various lumbar spine disorders

Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ): Part 2. Endorsement of the alternative item

AbstractBackgroundA new self-administered questionnaire as an outcome measure for patients with cervical myelopathy was drawn up in Part 1 (Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire, JOACMEQ). Because a question with regard to driving a car (C-41) was not suitable for this patient group, the authors composed an alternative question related to neck motion (C-41-2). The purposes of the present study were to perform a secondary survey on patients with cervical myelopathy and to statistically analyze the responses to validate the JOACMEQ, and also to determine if it was possible to convert item C-41 to the alternative question.MethodsA member of the Subcommittee on Low Back Pain and Cervical Myelopathy Evaluation from each hospital administered the questionnaire to more than 50 patients with cervical myelopathy in each hospital. The questionnaire consisted of 25 questions, 24 of which were extracted in the primary survey. The authors statistically examined whether it was possible to convert question C-41 to C-41-2.ResultsThree hundred and sixty-eight patients with cervical myelopathy were enrolled in the present study. No questions elicited no answer or “I am not sure” in more than 5% of patients except question C-41. There were no questions that the patients answered with difficulty. There was no tendency that was concentrated on one option as an answer to questions. There was a high correlation between questions C-41 and C-41-2. Spearman’s correlation coefficient and κ value showed that there was high coincidence between the two questions C-41 and C-41-2. It is possible to convert the question C-41 to the alternative question C41-2.ConclusionThe questionnaire has sufficient reliability for clinical use. It is possible that the JOACMEQ will prevail and become a global standard to evaluate outcomes in patients with cervical myelopathy

Japanese Orthopaedic Association Back Pain Evaluation Questionnaire. Part 3. Validity study and establishment of the measurement scale: Subcommittee on Low Back Pain and Cervical Myelopathy Evaluation of the Clinical Outcome Committee of the Japanese Orthopaedic Association, Japan

AbstractBackgroundThe Japanese Orthopaedic Association decided to revise the JOA score for low back pain and to develop a new outcome measure. In February 2002, the first survey was performed with a preliminary questionnaire consisting of 60 evaluation items. Based on findings of that survey, 25 items were selected for a draft of the JOA Back Pain Evaluation Questionnaire (JOABPEQ). The second survey was performed to confirm the reliability of the draft questionnaire. This article further evaluates the validity of this questionnaire and establishes a measurement scale.MethodsThe subjects of this study consisted of 355 patients with low back disorders of any type (201 men, 154 women; mean age 50.7 years). Each patient was asked to fill in a self-administered questionnaire. Superficial validity was checked in terms of the completion rate for filling out the entire questionnaire. Factor analysis was then performed to evaluate the validity of the questionnaire and establish a measurement scale.ResultsAs a result of the factor analysis, 25 items were categorized into five factors. The factors were named based on the commonality of the items: social function, mental health, lumbar function, walking ability, and low back pain. To establish a measurement scale for each factor, we determined the coefficient for each item so the difference between the maximum factor scores and minimum factor scores was approximately 100. We adjusted the formula so the maximum for each factor score was 100 and the minimum was 0.ConclusionsWe confirmed the validity of the JOA Back Pain Evaluation Questionnaire and est ablished a measurement scale

Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ): part 4. Establishment of equations for severity scores: Subcommittee on low back pain and cervical myelopathy, evaluation of the clinical outcome committee of the Japanese Orthopaedic Association

AbstractBackgroundThe project to develop a new Japanese Orthopaedic Association (JOA) score rating system for low back disorders, the JOA Back Pain Evaluation Questionnaire (JOABPEQ), is currently in progress. Part 1 of the study selected 25 “candidate” items for use on the JOABPEQ. The purpose of this current Part 2 of the study was to verify the reliability of the questionnaire.MethodsA total of 161 patients with low-back disorders of any type participated in the study. Each patient was interviewed twice at an interval of 2 weeks using the same questionnaire. The reliability of the questionnaire was evaluated by determining the extension of the kappa and weighted kappa coefficients.ResultsBoth kappa and weighted kappa were more than 0.50 for all but one item, which was 0.48. The lower 95% confidence interval exceeded 0.4 in all but two items, which was 0.39. This implied that the test-retest reliability of JOABPEQ was acceptable as a measure of outcome.ConclusionsThe tentative questionnaire of the JOABPEQ with 25 items was confirmed to be reliable enough to describe the quality of life of patients who suffer low back disorders

Identification of a high incidence region for retroviral vector integration near exon 1 of the LMO2 locus

Therapeutic retroviral vector integration near the oncogene LMO2 is thought to be a cause of leukemia in X-SCID gene therapy trials. However, no published studies have evaluated the frequency of vector integrations near exon 1 of the LMO2 locus. We identified a high incidence region (HIR) of vector integration using PCR techniques in the upstream region close to the LMO2 transcription start site in the TPA-Mat T cell line. The integration frequency of the HIR was one per 4.46 × 10(4 )cells. This HIR was also found in Jurkat T cells but was absent from HeLa cells. Furthermore, using human cord blood-derived CD34(+ )cells we identified a HIR in a similar region as the TPA-Mat T cell line. One of the X-linked severe combined immunodeficiency (X-SCID) patients that developed leukemia after gene therapy had a vector integration site in this HIR. Therefore, the descriptions of the location and the integration frequency of the HIR presented here may help us to better understand vector-induced leukemogenesis