Prolonged response after TPO-RA discontinuation in primary ITP: results of a prospective multicenter study.

Sustained response off treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in immune thrombocytopenia (ITP). This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response (CR) on TPO-RAs. The primary end point was the proportion of patients achieving SROT (platelet count >30 × 109/L and no bleeding) at week 24 (W24) with no other ITP-specific medications. Secondary end points included the proportion of sustained CR off-treatment (SCROT, platelet count >100 × 109/L and no bleeding) and SROT at W52, bleeding events, and pattern of response to a new course of TPO-RAs. We included 48 patients with a median age of 58.5 years; 30 of 48 had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27 of 48 achieved SROT, 15 of 48 achieved SCROT at W24; 25 of 48 achieved SROT, and 14 of 48 achieved SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients rechallenged with TPO-RA, 11 of 12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA sequencing revealed enrichment of a tumor necrosis factor α signaling via NF-κB signature in CD8+ T cells of patients with no sustained response after TPO-RA discontinuation, which was further confirmed by a significant overexpression of CD69 on CD8+ T cells at baseline in these patients as compared with those achieving SCROT/SROT. Our results strongly support a strategy based on progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. This trial was registered at www.clinicaltrials.gov as #NCT03119974.

Molecular Signatures of Kidney Antibody-Secreting Cells in Lupus Patients With Active Nephritis Upon Immunosuppressive Therapy.

OBJECTIVE: This study was undertaken to characterize kidney and urine antibody-secreting cells (ASCs) from patients with active lupus nephritis, before and after induction therapy. METHODS: We included patients with biopsy-proven active lupus nephritis and performed anti-CD138 staining of kidney biopsy samples to visualize ASCs. We performed single-cell gene expression profiling on sorted ASCs from fresh biopsy samples using multiplex reverse transcriptase-polymerase chain reaction. We used a gene set that allowed for the study of ASC maturation from plasmablasts to long-lived plasma cells. We quantified urine ASCs from untreated patients with lupus nephritis at diagnosis and after 6 months of prospective follow-up during induction therapy. RESULTS: The number of kidney CD138+ ASCs in 46 untreated patients with lupus nephritis was correlated with a low estimated glomerular filtration rate and with tubulointerstitial damage. Most kidney ASCs from 3 untreated patients had a plasmablast molecular signature; in contrast, in 4 patients with refractory lupus nephritis, the kidney ASCs were mainly long-lived plasma cells, representing an ASC transcriptional profile similar to that in the bone marrow of 2 healthy donors. Some urine ASCs with a plasmablast signature were detected in patients with untreated active lupus nephritis. The presence of urine ASCs at 6 months was associated with treatment failure. CONCLUSION: Our results suggest potential for ASC-directed therapy in refractory lupus nephritis.

Obesity and Preoperative Anaemia as Independent Risk Factors for Sternal Wound Infection After Coronary Artery Bypass Graft Surgery with Pedicled (Non-Skeletonized) Internal Mammary Arteries: The Role of Thoracic Wall Ischemia?

PURPOSE: Obesity remains statistically associated with coronary artery disease, for which coronary artery bypass graft surgery (CABG) remains the standard of care. However, obesity is also associated with sternal wound infection (SWI) which is a severe complication of CABG despite advances in surgery and in infection prevention and control. Strategies to reduce the incidence of SWI are still being investigated, and we therefore conducted a retrospective study to revisit factors other than obesity associated with SWI after CABG. PATIENTS AND METHODS: Data were extracted from the medical records of 182 patients who underwent elective on-pump CABG using one or both pedicled internal mammary artery grafts in Reims University Hospital between May 2015 and May 2016. All preoperative or perioperative variables with a p value<0.10 in univariate analysis were entered into a stepwise logistic regression model. RESULTS: Among the 182 patients (145 male (79.6%), median age 68.0 [45.0-87.0] years), 138 (75.8%) underwent CABG using bilateral internal mammary artery grafts. Median BMI was 27.7 [18.7-50.5] kg/m2, and there were 51 (28.0%) and 79 (43.4%) patients with obesity and overweight, respectively. Twenty-three out of the 182 patients (12.6%) developed SWI. In-hospital mortality was not statistically different between patients with and without SWI but the median length of stay was (6.0 [2.0-38.0] versus 5.0[3.0-21.0] days in the intensive care unit, p=0.03, and 26.0 [9.0-134.0] versus 9.0 [7.0-51.0] days in hospital, p<0.0001). Obesity and preoperative anaemia were independently associated with SWI, as was the number of red blood cell (RBC) units transfused (OR 14.61 [2.64-80.75], OR 4.64 [1.61-13.34] and OR 1.27 [1.02-1.58], respectively). CONCLUSION: The independent association of SWI with the number of RBC units transfused and the existence of preoperative anaemia and obesity suggests a mechanism of thoracic wall ischemia in SWI after CABG, thus leaving insufficient perfusion of the thoracic wall in patients with obesity. Medical strategies are warranted to try to prevent this costly complication.

BAFF and CD4+ T cells are major survival factors for long-lived splenic plasma cells in a B-cell-depletion context.

Previous data have suggested that B-cell-depletion therapy may induce the settlement of autoreactive long-lived plasma cells (LLPCs) in the spleen of patients with autoimmune cytopenia. To investigate this process, we used the AID-CreERT2-EYFP mouse model to follow plasma cells (PCs) engaged in an immune response. Multiplex polymerase chain reaction at the single-cell level revealed that only a small fraction of splenic PCs had a long-lived signature, whereas PCs present after anti-CD20 antibody treatment appeared more mature, similar to bone marrow PCs. This observation suggested that, in addition to a process of selection, a maturation induced on B-cell depletion drove PCs toward a long-lived program. We showed that B-cell activating factor (BAFF) and CD4+ T cells play a major role in the PC survival niche, because combining anti-CD20 with anti-BAFF or anti-CD4 antibody greatly reduce the number of splenic PCs. Similar results were obtained in the lupus-prone NZB/W model. These different contributions of soluble and cellular components of the PC niche in the spleen demonstrate that the LLPC expression profile is not cell intrinsic but largely depends on signals provided by the splenic microenvironment, implying that interfering with these components at the time of B-cell depletion might improve the response rate in autoimmune cytopenia.

Rapidly evolving conjunctivitis due to Pasteurella multocida, occurring after direct inoculation with animal droplets in an immuno-compromised host.

BACKGROUND: The rare descriptions, in the literature, of ocular infections due to Pasteurella multocida include: endophtalmitis, keratitis and corneal ulcers, Parinaud's oculoglandular syndrome, and conjunctivitis. Here, we report a rare case of rapidly evolving conjunctivitis due to Pasteurella multocida, occurring after direct inoculation with animal droplets in an immuno-compromised host. CASE PRESENTATION: A 69-year-old, Caucasian male was referred to our department with purulent conjunctivitis, occurring five days after chemotherapy for an angioimmunoblastic-T-cell-lymphoma, and thirty-three hours after being struck in his right eye by his sneezing Dachshund dog. Physical examination revealed purulent conjunctivitis of the right eye associated with inflammatory edema of both lids. Direct bacteriological examination of conjunctival secretions showed gram-negative bacilli and regular, grey non-hemolytic colonies appearing the next day on blood agar. The oxidase test was positive for these colonies. An antibiotherapy associating intravenous amoxicillin and amoxicillin/clavulanate was administered. The outcome was favorable in the next three days allowing discharge of the patient with amoxicillin (2 g tid per os). CONCLUSION: This case report may be of interest for infectious diseases, ophthalmology or oncology specialists, especially nowadays with chemotherapy being administered in day care centres, where unusual home pathogens can be encountered in health related infections. In this case, previous animal contact and conjunctival samples showing Enterobacteriaceae like colonies with positive oxidase test were two important clues which could help clinicians to make the diagnosis of Pasteurella conjunctivitis in every day practice.