Autoantibody profiles associated with morbidity and mortality in scleroderma renal crisis.

OBJECTIVE: The aim of this study was to investigate association of autoantibodies with scleroderma renal crisis (SRC) among Japanese patients. METHODS: The clinical characteristics and mortality of 330 patients with sytemic screlosis (SSc) at Kyoto University Hospital were retrospectively analysed, focusing on possible association with anti-topoisomerase I (anti-topo I), anti-centromere (ACA), anti-RNA polymerase III (RNAPIII) and/or anti-U1-RNP. Logistic regression analyses were performed to reveal any association of these autoantibodies with the development and mortality of SRC. RESULTS: SRC was observed in 24 out of 330 SSc patients, including patients with anti-topo I (n = 12/24, 50%), anti-RNAPIII (n = 7/24, 29%), anti-U1-RNP (n = 5/24, 21%) and ACA (n = 3/24, 13%). Anti-U1-RNP [odds ratio (95% CI), 3.63 (1.11, 10.2)], anti-topo I [3.22 (1.37, 7.57)] and anti-RNAPIII (3.29 [1.16, 8.70]) were associated with the development of SRC. Furthermore, anti-topo I [6.00 (1.11, 41.1)] was associated with 1-year mortality of SRC. The 1-year survival rate after the onset of SRC among all patients and among those positive for anti-topo I was 54% and 33%, respectively. In contrast, the survival rate in patients negative for anti-topo I was 75%, of which the survival rate of patients positive for anti-RNAPIII and ACA was 83% and 100%, respectively. CONCLUSION: Specific SSc-related autoantibodies were associated with the morbidity and mortality of SRC.

Characteristics of rheumatoid arthritis with immunodeficiency-associated lymphoproliferative disorders to regress spontaneously by the withdrawal of methotrexate and their clinical course: A retrospective, multicenter, case-control study.

OBJECTIVE: To investigate clinical characteristics and time course of lymphoproliferative disorders (LPDs) in rheumatoid arthritis (RA) patients after methotrexate (MTX) discontinuation, in those who achieved spontaneous regression (SR). METHODS: We retrospectively reviewed clinical data from RA patients with LPDs obtained from eight institutions between 2000 and 2017 and compared clinical and pathological findings between SR and non-SR groups. RESULTS: Among 232 RA patients with LPDs, 216 were treated with MTX at the onset of LPD and 144 (66.7%) achieved SR after MTX discontinuation. Higher MTX doses, high titers of anti-CCP antibodies (>13.5 U/mL), and lower LDH and soluble IL-2 receptor levels were associated with SR. Lymphocyte count was decreased at LPD onset and increased at 2 weeks after MTX discontinuation in the SR group. Epstein-Barr virus-positive mucocutaneous ulcer, reactive lymphoid hyperplasia and unclassifiable B-cell lymphoma, were more frequent in the SR than in the non-SR group. In multivariable analysis, diffuse large B-cell lymphomas was an independent predictive factor for non-SR. In the patients with SR, 73.9% achieved partial or complete regression as early as 2 weeks after MTX discontinuation. CONCLUSION: SR and non-SR in RA patients with LPDs after MTX discontinuation were associated with certain clinical characteristics.

Treatment of rheumatoid arthritis after regression of lymphoproliferative disorders in patients treated with methotrexate: a retrospective, multi-center descriptive study.

OBJECTIVES: To identify the optimal treatment for rheumatoid arthritis (RA) after the regression of lymphoproliferative disorders (LPDs). METHODS: The subjects were 232 patients with RA who developed LPD between 2000 and 2017 at seven hospitals participating in the LPD-WG study. Kaplan-Meier and Cox proportional regression analyses were performed to determine the factors associated with the rate of LPD relapse and the retention of biological disease-modifying antirheumatic drugs (bDMARDs). RESULTS: Treatment for RA was resumed in 138 patients after spontaneous regression of LPD after the discontinuation of methotrexate and in 52 patients after chemotherapy for LPD (persistent-LPD). LPD relapses occurred in 23 patients. Not DMARDs use but Hodgkin's lymphoma was identified as a risk factor for LPD relapse. In 88 RA patients treated with bDMARDs [tocilizumab, 39 patients; abatacept 20 patients; tumor necrosis factor inhibitor, 29 patients], the one-year retention rate was 67.8%. The risk factors for discontinuation of bDMARDs were persistent-LPD, non-diffuse large B-cell lymphomas (non-DLBCL), and a high clinical disease activity index (CDAI). Tocilizumab showed the highest retention rate among bDMARDs, particularly in DLBCL. CONCLUSION: Although any bDMARD could be used in patients after LPD regression, effectiveness and risk for relapse should be carefully assessed for each LPD subtype.

Overall survival and post-spontaneous regression relapse-free survival of patients with lymphoproliferative disorders associated with rheumatoid arthritis: a multi-center retrospective cohort study.

OBJECTIVES: To clarify factors affecting 5-year survival rates and relapse rates after spontaneous regression (SR) of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA). METHODS: This retrospective longitudinal study comprised 232 patients with RA diagnosed with LPDs between January 2000 and March 2017 at eight hospitals in Japan. The Kaplan-Meier method was used to analyze survival and the Cox proportional hazard model was applied to identify predictive factors. RESULTS: Among all patients, 1-, 2- and 5-year overall survival rates were 89.5%, 86.1%, and 78.2%, respectively. Multivariable analysis revealed four 5-year survival risk factors assessed at diagnosis: age above 70 years (p = .002), deep lymphadenopathy and/or more than one extranodal lesion (p = .008), Eastern Cooperative Oncology Group/Zubrod performance status of 2-4 (p = .004), and classic Hodgkin lymphoma (CHL) histology (p = .047). Among 143 patients who achieved SR, 2- and 5-year relapse rates were 14.2% and 24.9%, respectively. CHL histology (p = .003) and serum soluble interleukin-2 receptor levels exceeding 2000 IU/L (p = .014) were associated with post-SR relapse-free survival. Blood lymphocyte counts were significantly lower at relapse than at 3-6 months prior (p < .001). CONCLUSION: Assessment of the above risk factors and routine inspection of blood lymphocyte counts could aid in the care management of LPDs in RA.

Clinicopathological characteristics of lymphoproliferative disorders in 232 patients with rheumatoid arthritis in Japan: A retrospective, multicenter, descriptive study.

OBJECTIVE: To describe the clinicopathological characteristics of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA). METHODS: In this multicenter case series, we retrospectively reviewed the medical records of RA patients who were newly diagnosed as having LPDs with or without biopsy confirmation between 2000 and 2017 in eight hospitals in Japan. RESULTS: We included 232 patients with LPDs. The median age was 67 years (interquartile range [IQR], 60-73 years), and 77.1% were female. At the time of LPD diagnosis, 94.8% and 62.6% of the patients were methotrexate users and in remission or had low RA disease activity, respectively; lymphadenopathy and extranodal involvement were present in 77.1% and 51.9%, respectively. Major extranodal sites were the lungs and oral/oropharyngeal mucosa. The most common LPD pathological subtype was diffuse large B-cell lymphoma (40.5%), followed by classic Hodgkin lymphoma (10.8%), Epstein-Barr virus-positive mucocutaneous ulcer (7.7%), and reactive lymphoid hyperplasia (6.2%). The clinical and laboratory characteristics varied across the pathological subtypes. CONCLUSION: LPD occurred mainly in methotrexate users, while RA disease activity did not seem to be associated with LPD development. Although the clinical manifestations vary among pathological subtypes, manifestations of LPD in patients with RA can include lymphadenopathy, extranodal mass, and mucocutaneous ulcer.

Carbamylated albumin is one of the target antigens of anti-carbamylated protein antibodies.

Objectives: Anti-carbamylated protein (anti-CarP) antibodies are detected in RA patients. Fetal calf serum is used as an antigen source in anti-CarP ELISA, and the precise target antigens have not been found. We aimed to identify the target antigens of anti-CarP antibodies. Methods: Western blotting of anti-CarP antibodies was conducted. Anti-carbamylated human albumin (CarALB) antibody was detected by in-house ELISA for 493 RA patients and 144 healthy controls (HCs). An inhibition ELISA of anti-CarP antibodies by CarALB and citrullinated albumin (citALB) was performed using eight RA patients' sera. Serum CarALB was detected by liquid chromatography-tandem mass spectroscopy (LC/MS/MS), and the serum MPO concentration was measured by ELISA. Results: We focused on carbamylated albumin because it corresponded to the size of the thickest band detected by western blotting of anti-CarP antibodies. Anti-CarALB antibody was detected in 31.4% of RA patients, and the correlation of the titres between anti-CarALB and anti-CarP was much closer than that between anti-citALB and anti-CCP antibodies (ρ = 0.59 and ρ = 0.16, respectively). The inhibition ELISA showed that anti-CarP antibodies were inhibited by CarALB, but not by citALB. CarALB was detected in sera from RA patients by LC/MS/MS. The serum MPO concentration was correlated with disease activity and was higher in RA patients with anti-CarALB antibody than in those without. Conclusion: We found that carbamylated albumin is a novel target antigen of anti-CarP antibodies, and it is the first reported target antigen that has not been reported as the target of ACPA.

Incidence of adverse drug events and medication errors in Japan: the JADE study.

BACKGROUND: The epidemiology of adverse drug events (ADEs) and medication errors has received little evaluation outside the U.S. and Europe, and extrapolating from these data might not be valid, especially regarding selecting and prioritizing solutions. OBJECTIVE: To assess the incidence and preventability of ADEs and medication errors in Japan. DESIGN: The Japan Adverse Drug Events (JADE) study was a prospective cohort study. PATIENTS: A cohort of 3,459 adults admitted to a stratified random sample of seven medical and eight surgical wards and three intensive care units in three tertiary care hospitals over 6 months. MAIN MEASURES: We measured ADE and medication error rates from daily reviews of charts, laboratories, incident reports, and prescription queries by on-site reviewers; presence of a signal was considered an incident. Two independent physicians reviewed incidents to determine whether they were ADEs or medication errors and to assess severity and preventability. KEY RESULTS: We identified 1,010 ADEs and 514 medication errors (incidence: 17.0 and 8.7 per 1,000 patient-days, respectively) during the study period. Among ADEs, 1.6%, 4.9% and 33% were fatal, life-threatening and serious, respectively. Among ADEs, 14% were preventable. The rate per admission was 29 per 100 admissions, higher than in U.S. studies because associated with of the long length of hospital stay in Japan (mean, 17 days). CONCLUSIONS: The epidemiology and nature of ADEs and medication errors in Japan were similar to other countries, although more frequent per admission. Solutions that worked in these countries might thus improve medication safety in Japan, as could shortening hospital length of stay.

Epidemiology of potentially inappropriate medication use in elderly patients in Japanese acute care hospitals.

PURPOSE: The elderly receive many medications which may have adverse effects. Little evidence is available about the epidemiology of potentially inappropriate medications being prescribed to the elderly in Japan as defined by the Beers criteria, or whether or not these medications result in harm when used in this population. METHODS: We conducted a prospective cohort study of patients aged ≥65 years who were admitted to three acute care hospitals in Japan. Trained research nurses followed up patients from randomly selected wards and collected data about their medications and all potential adverse drug events (ADEs). Two independent reviewers evaluated all the data. The use of potentially inappropriate medications and their effects on patients were identified using the updated Beers criteria. RESULTS: A total of 2155 elderly patients were eligible; 56.1% received at least one drug listed in the Beers criteria (BL drug). The rates of BL drug prescriptions were 103.8 per 100 admissions and 53.6 [DOSAGE ERROR CORRECTED] per 1000 patient-days, and the incidence rate of ADEs related to BL drugs was 1.7 per 100 BL drug prescriptions. Among patients aged ≥65 years, relatively younger patients (p = 0.0002) and those with less complications (p = 0.04) were likely to be prescribed BL drugs. CONCLUSIONS: Although BL drugs were frequently prescribed to elderly Japanese inpatients, the incidence of related ADEs appeared infrequent. These data suggest that re-evaluation of the appropriateness of the Beers criteria is needed before they are used in Japan and other nations to assess quality or for decision support.

A case of systemic lupus erythematosus complicated by subclinical Cushing's syndrome: case report.

An 18-year-old female was diagnosed with subclinical Cushing's syndrome (CS) due to a left adrenal adenoma. When she was 20 years old, she developed lupus nephritis. She was treated with high-dose prednisolone (PSL) and soon developed the symptoms of CS. When she was 25 years old, we evaluated her serum glucocorticoid level while she continued to take oral PSL. The result suggested her CS was affected by both the oral PSL and the endogenous cortisol secreted by the adrenocortical adenoma, which was therefore resected. Seven months after the operation, the patient's body weight was decreasing, and her SLE remained in clinical remission. CS complicated by SLE is rare, and the decision to surgically remove an adrenal tumor in such a case is even more rare.

Effects of BLS training on factors associated with attitude toward CPR in college students.

AIM: In order to elucidate the factors for willingness to perform CPR, we evaluated the responses of college students to questionnaires before and after basic life support (BLS) training. METHODS: Before and after participating in a small group BLS course, 259 students completed questionnaires. A logistic regression model was used to elucidate independent factors for their willingness to attempt resuscitation. RESULTS: Factors associated with willingness to perform BLS for strangers were "anxiety for a bad outcome" (odds ratio (OR) 0.08) and "having knowledge of automated external defibrillator (AED)" (OR 4.5) before training. The proportion of students showing willingness to perform BLS increased from 13% to 77% after the training even when the collapsed person is a stranger. After training, "anxiety for being sued because of a bad outcome" (OR 0.3), and "anxiety for infection" (OR 3.8) were significant factors. Those who preferred to perform BLS without ventilation increased from 40% to 79% (p<0.0001). CONCLUSION: The proportion of students showing willingness to perform BLS increased after the training. Significant association between "anxiety for infection" and willingness to perform BLS might indicate that those who wish to perform BLS developed their awareness of risk of infection more than the counterparts. For future guidelines for resuscitation and the instruction consensus, the reluctance of bystanders to perform CPR due to the hesitation about mouth-to-mouth ventilation should be reconsidered with other recent reports indicating the advantage of compression-only CPR.

Reliability of evaluation for communication competency in pharmaceutical objective structured clinical examination (OSCE).

In the objective structured clinical examination (OSCE), which for pharmaceutical students training, adequate methods should be used for evaluating a student's skill and aptitude for good communication in a medical interview. However, the reliability of the evaluation methods used in the pharmaceutical OSCE has not been investigated sufficiently. In this study, we reviewed the evaluation scores and video recordings obtained in a pharmaceutical OSCE trial, and examined the reasons for disagreement in the scores between two raters. We had two experienced raters in medical communication re-evaluate the students using the vide images, and compared their scores with those on the examination day. The ratio of disagreement was 14.5% (87/600 items in 30 students), and the reason for disagreement could not be identified for 63 items that evaluated communication skills such as 'actively listen' and 'empathy'. A comparison of the scores on examination day and those on re-evaluation revealed a possible reason for the disagreement; the use of a checklist, i.e. binary scores, with criteria that differed between the raters. We suggest that the items used for a detailed performance evaluation be selected carefully and that rating scales be used in order to perform an adequate evaluation, especially regarding communication skill and aptitude.

Public perception of and willingness to perform bystander CPR in Japan.

AIM: Immediate bystander cardiopulmonary resuscitation (CPR) is the most essential factor for life saving in out-of-hospital cardiac arrest patients. We investigated the characteristics associated with willingness to attempt CPR among the Japanese general population. METHODS: We randomly selected 2400 persons from all over Japan and conducted a questionnaire survey regarding their knowledge, experiences of and attitudes toward CPR. We performed descriptive statistics followed by multivariable logistic regression analyses. RESULTS: A total of 1132 persons (47%) completed the questionnaire. Only 13% of the subjects were willing to attempt bystander CPR for their families and friends, and 7% were willing to attempt bystander CPR for strangers. Willingness to attempt CPR was independently associated with office workers or skilled workers [odds ratio (OR) 1.8; 95% confidence interval (CI): 1.1-2.7], having trained in CPR [OR: 3.1; 95% CI: 2.1-4.6], actual experience with CPR [OR: 3.8; 95% CI: 1.7-8.3], and having friends with heart diseases [OR: 1.8; 95% CI: 1.05-3.0]. Having trained in CPR was independently associated with younger age [OR: 1.6; 95% CI: 1.2-2.1], office workers or skilled workers [OR: 1.5; 95% CI: 1.1-2.0], having driver's license [OR: 1.7; 95% CI: 1.2-2.4] and awareness of AED placement in a public space [OR: 2.1; 95% CI: 1.4-3.1]. CONCLUSION: Experience of CPR training closely associated with willingness to attempt CPR, and awareness of AED in a public space are significant factors in CPR training. AED placement might call attention to CPR training and develops willingness to attempt CPR.

Development of ichthyosiform skin compensates for defective permeability barrier function in mice lacking transglutaminase 1.

Transglutaminase 1 (TGase 1) is one of the genes implicated in autosomal recessive congenital ichthyosis. Skin from TGase 1(-/-) mice, which die as neonates, lacks the normal insoluble cornified envelope and has impaired barrier function. Characterization of in situ dye permeability and transepidermal water loss revealed defects in the development of the skin permeability barrier in TGase 1(-/-) mice. In the stratum corneum of the skin, tongue, and forestomach, intercellular lipid lamellae were disorganized, and the corneocyte lipid envelope and cornified envelope were lacking. Neonatal TGase 1(-/-) mouse skin was taut and erythrodermic, but transplanted TGase 1(-/-) mouse skin resembled that seen in severe ichthyosis, with epidermal hyperplasia and marked hyperkeratosis. Abnormalities in those barrier structures remained, but transepidermal water loss was improved to control levels in the ichthyosiform skin. From these results, we conclude that TGase 1 is essential to the assembly and organization of the barrier structures in stratified squamous epithelia. We suggest that the ichthyosiform skin phenotype in TGase 1 deficiency develops the massive hyperkeratosis as a physical compensation for the defective cutaneous permeability barrier required for survival in a terrestrial environment.

Anti-carbamylated Protein Antibodies Are Detectable in Various Connective Tissue Diseases.

OBJECTIVE: Anti-carbamylated protein (anti-CarP) antibodies are possible diagnostic biomarkers of anticitrullinated protein antibody (ACPA)-negative rheumatoid arthritis (RA). We aimed to elucidate the prevalence of anti-CarP antibodies in non-RA connective tissue diseases (CTD) because CTD are important in the differential diagnosis of ACPA-negative RA. METHODS: The sera from 266 patients with RA and 616 patients with CTD and 80 healthy controls were examined using an in-house anti-CarP ELISA. RESULTS: The prevalence and the level of anti-CarP antibodies in several CTD were comparable to those in ACPA-negative RA. CONCLUSION: Anti-CarP antibodies are not useful for differentiating ACPA-negative RA from CTD.

Anti-centromere antibody exhibits specific distribution levels among anti-nuclear antibodies and may characterize a distinct subset in rheumatoid arthritis.

Anti-centromere antibody (ACA) is one of the classical anti-nuclear antibody (ANA) staining patterns. However, characteristics of ACA in comparison with the other ANA patterns and clinical features of ACA-positive subjects have not been elucidated. Here, we examined all ANA patterns by indirect immunofluorescence for 859 rheumatoid arthritis (RA) patients. Together with the ANA data of 9,575 healthy volunteers, we compared distributions of the ANA levels. ACA was the only ANA that demonstrated a definite bimodal distribution of levels. ACA showed significantly higher levels than the other ANA staining patterns in both RA and healthy population (p < 0.0001). ACA-positivity was associated with old age and was observed more in females. We further recruited another cohort of 3,353 RA patients and confirmed the findings. ACA was also associated with Raynaud's phenomenon (p = 6.8 × 10-11) in RA. As a conclusion, ACA displays a specific ANA staining pattern with a bimodal distribution, and ACA-positive RA may constitute a distinct subset with specific clinical features.