Ethylmalonic encephalopathy associated with crescentic glomerulonephritis

Ethylmalonic encephalopathy (EE) is a rare autosomal recessive disorder caused by mutations in the ETHE1 gene and characterized by chronic diarrhea, encephalopathy, relapsing petechiae and acrocyanosis. Nephrotic syndrome has been described in an infant with EE but the renal histology findings were not described in previous reports. We report a Palestinian girl with EE who presented with chronic diarrhea, encephalopathy, petechial rash and acrocyanosis. Subsequently, she developed progressive deterioration of renal function caused by rapidly progressive glomerulonephritis resulting in death within few days. This is, to our knowledge, the first reported occurrence of rapidly progressive glomerulonephritis in a child with ethylmalonic encephalopathy. Its presence is a serious complication associated with poor prognosis and may be explained by the diffuse vascular damage     

A multi-institutional comparison of mitoxantrone,etoposide, and cytarabine vs high-dose cytarabine and mitoxantrone therapy for patients with relapsed or refractory acute myeloid leukemia

Relapsed or refractory acute myeloid leukemia (R/R AML) has a poor prognosis and is best treated with salvage chemotherapy as a bridge to allogeneic stem cell transplant (alloSCT). However, the optimal salvage therapy remains unknown. Here we compared two salvage regimens; mitoxantrone, etoposide, and cytarabine (MEC) and mitoxantrone and high-dose Ara-C (Ara-C couplets). We analyzed 155 patients treated at three academic institutions between 1998 and 2017; 87 patients received MEC and 68 received Ara-C couplets. The primary endpoint was overall response (OR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and nonhematologic toxicities, and success in proceeding to alloSCT. Baseline characteristics of the cohorts were well matched, though patients receiving Ara-C couplets had more co-morbidities (48.5% vs 33%; P = .07). OR was achieved in 43.7% of MEC and 54.4% of Ara-C couplets patients (P = .10). Ara-C couplets patients also trended towards a longer OS and PFS, more frequently proceeded to alloSCT (31% vs 54.4%; P = .003), and experienced less febrile neutropenia (94% vs 72%; P < .001) and grade 3/4 gastrointestinal toxicities (17.2% vs 2.94%; P = .005). No significant differences in other toxicities or median duration of hospitalization were noted. This is the first multi-institutional study directly comparing these regimens in a racially diverse population of R/R AML patients. Although these regimens have equivalent efficacy in terms of achieving OR, Ara-C couplets use is associated with significant reductions in toxicities, suggesting it should be used more frequently in these patients.     

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease

We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between January 2014 and March 2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor-specific antibodies (DSAs), and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells. The initial 2 were conditioned with alemtuzumab/total body irradiation (TBI) 3?Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University with TBI 3?Gy. Granulocyte colony-stimulating factor was administered from day +12 in those with HbS < 30%. All 8 patients engrafted with a median time to neutrophil >.5 × 10⁹/L of 22 days (range, 18 to 23). One patient subsequently lost the graft, and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute graft-versus-host disease (GVHD) of at least grade II. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow-up of 16 months (range, 11 to 29), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSAs, and patient declining HSCT may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter, prospective clinical trials.     

Minor salivary gland inflammation in Devic's disease and longitudinally extensive myelitis

Devic's disease is often considered as a variant of multiple sclerosis (MS). However, evidence suggests that Devic's disease may be distinct from MS. Devic's disease can coexist with connective tissue diseases, particularly Sj?gren's disease, but this association is rare with MS. Diagnosis of Sj?gren's disease in patients with neurological symptoms is often difficult. During early stages of Sj?gren's disease, patients may not fulfill all criteria for Sj?gren's disease. A high percentage of patients with Sj?gren's disease have inflammatory infiltrates in minor salivary glands, and this may be a reliable indicator of early or subclinical disease. We show high prevalence (80%) of salivary gland inflammation in Devic's disease and longitudinally extensive transverse myelitis (LETM). We diagnosed 16 patients with Devic's disease, and 2 of these satisfied criteria for Sj?gren's disease as did 2 of 9 patients with LETM. Anti-SSA/B titers were infrequently elevated. Although most did not satisfy criteria for Sj?gren's disease. 9 of 12 Devic's disease patients and 7 of 8 LETM patients had severe salivary gland inflammation. Thus: (1) patients with Devic's disease or with LETM who have positive labial biopsies but do not satisfy criteria for Sj?gren's disease could have subclinical Sj?gren's diseases. Alternatively, (2) as patients with Devic's disease have elevated titers of several autoantibodies, so there may exist a set of antibodies that react with antigens in minor salivary glands and cause inflammation. Minor salivary gland biopsy is more sensitive than anti-SSA/B serology in providing histological evidence for possible Sj?gren's disease with CNS lesions.     

Sweet and simple as syrup: A review and guidance for use of novel antihyperglycemic agents for post-transplant diabetes mellitus and type 2 diabetes mellitus after kidney transplantation

Uncontrolled type 2 diabetes mellitus (T2DM) and post-transplant diabetes mellitus (PTDM) increase morbidity and mortality after kidney transplantation. Conventional strategies for diabetes management in this population include metformin, sulfonylureas, meglitinides and insulin. Limitations with these agents, as well as promising new antihyperglycemic agents, create a need and opportunity to explore additional options for transplant diabetes pharmacotherapy. Novel agents including sodium glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1RA), and dipeptidyl peptidase IV inhibitors (DPP4i) demonstrate great promise for T2DM management in the non-transplant population. Moreover, many of these agents possess renoprotective, cardiovascular, and/or weight loss benefits in addition to improved glucose control while having reduced risk of hypoglycemia compared with certain other conventional agents. This comprehensive review examines available literature evaluating the use of novel antihyperglycemic agents in kidney transplant recipients (KTR) with T2DM or PTDM. Formal grading of recommendations assessment, development, and evaluation (GRADE) system recommendations are provided to guide incorporation of these agents into post-transplant care. Available literature was evaluated to address the clinical questions of which agents provide greatest short- and long-term benefits, timing of novel antihyperglycemic therapy initiation after transplant, monitoring parameters for these antihyperglycemic agents, and concomitant antihyperglycemic agent and immunosuppression regimen management. Current experience with novel antihyperglycemic agents is primarily limited to single-center retrospective studies and case series. With ongoing use and increasing comfort, further and more robust research promises greater understanding of the role of these agents and place in therapy for kidney transplant recipients.     

IRAK4 inhibition: a promising strategy for treating RA joint inflammation and bone erosion

Flares of joint inflammation and resistance to currently available biologic therapeutics in rheumatoid arthritis (RA) patients could reflect activation of innate immune mechanisms. Herein, we show that a TLR7 GU-rich endogenous ligand, miR-Let7b, potentiates synovitis by amplifying RA monocyte and fibroblast (FLS) trafficking. miR-Let7b ligation to TLR7 in macrophages (MΦs) and FLSs expanded the synovial inflammatory response. Moreover, secretion of M1 monokines triggered by miR-Let7b enhanced Th1/Th17 cell differentiation. We showed that IRAK4 inhibitor (i) therapy attenuated RA disease activity by blocking TLR7-induced M1 MΦ or FLS activation, as well as monokine-modulated Th1/Th17 cell polarization. IRAK4i therapy also disrupted RA osteoclastogenesis, which was amplified by miR-Let7b ligation to joint myeloid TLR7. Hence, the effectiveness of IRAK4i was compared with that of a TNF inhibitor (i) or anti-IL-6R treatment in collagen-induced arthritis (CIA) and miR-Let7b-mediated arthritis. We found that TNF or IL-6R blocking therapies mitigated CIA by reducing the infiltration of joint F480⁺iNOS⁺ MΦs, the expression of certain monokines, and Th1 cell differentiation. Unexpectedly, these biologic therapies were unable to alleviate miR-Let7b-induced arthritis. The superior efficacy of IRAK4i over anti-TNF or anti-IL-6R therapy in miR-Let7b-induced arthritis or CIA was due to the ability of IRAK4i therapy to restrain the migration of joint F480⁺iNOS⁺ MΦs, vimentin⁺ fibroblasts, and CD3⁺ T cells, in addition to negating the expression of a wide range of monokines, including IL-12, MIP2, and IRF5 and Th1/Th17 lymphokines. In conclusion, IRAK4i therapy may provide a promising strategy for RA therapy by disconnecting critical links between inflammatory joint cells.