Development of type 1 diabetes in a patient treated with anti‐interleukin‐6 receptor antibody for rheumatoid arthritis

Interleukin‐6 is a pleiotropic cytokine that plays a pathogenic role in type 1 diabetes. Therefore, anti‐interleukin‐6 receptor antibody, tocilizumab, used for the treatment of rheumatoid arthritis, is considered a candidate for immune intervention in type 1 diabetes. Here, we report the case of a 73‐year‐old woman (HLA‐DR9‐DQ3 homozygote) with well‐controlled rheumatoid arthritis who developed type 1 diabetes while receiving tocilizumab treatment. At 57 years‐of‐age, the patient was diagnosed with rheumatoid arthritis, for which she underwent tocilizumab therapy that enabled complete suppression of her joint inflammation. A total of 17 months after starting tocilizumab therapy, she noticed polydipsia, polyuria, general fatigue and weight reduction (−2 kg/month), and was diagnosed with type 1 diabetes with diabetic ketoacidosis based on an arterial pH of 7.26, serum ketone body of 7,437 μmol/L, blood glucose level of 925 mg/dL, glycated hemoglobin of 13.2% and the presence of anti‐islet autoantibodies. This case report shows valuable insight regarding the effect of anti‐interleukin‐6 receptor antibody therapy on type 1 diabetes prevention.     

Osteonecrosis of the Femoral Head: an Updated Review of ARCO on Pathogenesis,Staging and Treatment

Non-traumatic osteonecrosis of the femoral head (ONFH) usually affects adults younger than 50 years and frequently leads to femoral head collapse and subsequent arthritis of the hip. It is becoming more prevalent along with increasing use of corticosteroids for the adjuvant therapy of leukemia and other myelogenous diseases as well as management of organ transplantation. This review updated knowledge on the pathogenesis, classification criteria, staging system, and treatment of ONFH.     

Muir-Torre syndrome caused by exonic deletion of <Emphasis Type="Italic">MLH1</Emphasis> due to homologous recombination

Background

Muir-Torre syndrome (MTS) is characterized by sebaceous neoplasms with internal malignancies and regarded as a variant of hereditary nonpolyposis colorectal cancer (HNPCC). Pathogenic variations of MTS have been identified in the MSH2, MLH1, and MSH6 genes, with the majority of variations located in MSH2.

Objectives

To present an MTS patient who was the only individual with skin malignancies within a cancer-prone pedigree and to showthe usefulness ofRNA-based genetic analysis in the investigation of MTS.

Materials & methods

A 77-year-old man who had operated X-ray equipment at his workplace in his twenties was clinically diagnosed with MTS and investigated by RNA-based analysis, multiplex ligation-dependent probe amplification, and genomic DNA sequencing.

Results

The patient had suffered from sebaceous tumours, squamous cell carcinomas of the skin, and colon cancer. The patient’s family history was remarkable for visceral malignant diseases. Genetic analysis revealed homologous recombination between two Alu elements within intron 4 and 5 of the MLH1 gene. The rearrangement caused a 1,222-bp deletion, including the entire exon 5. Deletion of exon 5 has previously been reported only in two patients with HNPCC, and not in patients with MTS.

Conclusions

For the genetic analysis of MTS, the possibility of rare copy number variations of MLH1, as well as MSH2 variations, should be considered. RNA-based screening using puromycin is recommended in order to identify such variations. It remains unclear why only the proband among the pedigree had skin malignancies, however, the skin carcinogenesis might have been related to occupational radiation exposure.

     

Effects of right atrial pacing preference in prevention of paroxysmal atrial fibrillation: Atrial Pacing Preference study (APP study).

BACKGROUND: Several preliminary studies have indicated that atrial pacing can prevent atrial tachyarrhythmias. The suggested mechanisms by which pacing may be effective include suppression of premature atrial beats. METHODS AND RESULTS: The Atrial Pacing Preference (APP; Guidant, St Paul, MN, USA) algorithm allows the pacemaker to maintain a pacing rate slightly higher than the sinus rate. The preventive effects of APP on paroxysmal atrial fibrillation (AF) were studied in 51 patients (70+/-11 years). Nine patients did not complete the protocol. The pacemaker was programmed in random order to APP off and APP on at 3 different settings (ie, 8, 16 and 32 cycles) for 4 weeks each, using a cross-over design. Percentage atrial pacing was lower in APP off than at the other settings. Premature beat counts were greater in APP off than at the other settings. There was a significant difference in mode switch episode counts between APP off and the most effective setting (3,818+/-15,356 vs 596+/-1,719; p<0.01). CONCLUSIONS: The APP algorithm is a promising method for preventing atrial tachyarrhythmia in patients with an implanted pacemaker and AF. Optimizing the setting of the APP algorithm is an important issue in the prevention of AF.     

Metabolic changes induced by TGF-β1 via reduced expression of phosphatidylserine decarboxylase during myofibroblast transition

Metabolic alteration is increasingly recognized as an important pathogenic process that underlies fibrosis across many organ types, and metabolically targeted therapies could become important strategies for reducing fibrosis. In present study, target enzymes that are involved in changes in phospholipid metabolism during fibroblast-to-myofibroblast transition induced by transforming growth factor beta 1 (TGF-β1) were examined. Different amounts of phospholipids were found in the 2 groups. In response to TGF-β1 stimulation, 17 lipids decreased and 17 increased. The latter included the phospholipids phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylethanolamine (PE). Furthermore, among the rate-limiting enzymes that regulate these phospholipids, phosphatidylserine decarboxylase (PISD), which controls conversion of PS to PE and is localized in mitochondria, decreased in response to TGF-β1. Knockdown of PISD alone without TGF-β1 stimulation increased expression of α-smooth muscle actin mRNA and production of total collagen. Taken together, these results indicate that PISD is involved in the mechanism of fibrogenesis by regulating phospholipid metabolism.     

Limited value of the international staging system for predicting long-term outcome of transplant-ineligible,newly diagnosed,symptomatic multiple myeloma in the era of novel agents

We retrospectively investigated clinical outcomes and prognostic factors of 131 patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) who received melphalan and prednisolone (MP) as first-line therapy from 2006 to 2013. Eighty-one patients received salvage therapies incorporating bortezomib, lenalidomide, and/or thalidomide. The overall response rate to MP was 54.2 %, including 9.2 % of better than very good partial response. With a median follow-up period of 30.2 months, median overall survival (OS) and median time to next treatment (TNT) were 54.4 and 19.0 months, respectively. Univariate analysis revealed that performance status and serum calcium level significantly associated with both OS and TNT, and multivariate analysis revealed that the higher serum calcium level had a significantly unfavorable impact on OS and TNT. Importantly, staging informed by the international staging system (ISS) was not predictive for OS or TNT in the analyzed cohort. Our study revealed that, in the context of first-line MP therapy for NDMM, the salvage therapy incorporating novel agents produced a survival period of >30 months after the initiation of second-line therapy, suggesting that the predictive value of ISS for OS and TNT may be limited in the era of novel agents.