Rheumatic Disease During Pregnancy Significantly Increases Perinatal CV Risk

Autoimmune rheumatic disease (ARD), antiphospholipid syndrome (APS), and pregnancy all increase the risk of maternal cardiovascular events (CVEs) during the perinatal period. A retrospective study of 19,240 pregnant women who delivered singleton liveborn infants in California between 2005 and 2020 found that any ARD increased the risk of CVE 4.1-fold. Pregnant women with both systemic lupus erythematosus (SLE) and APS were at 18.1-fold risk for CVE compared to similar women with neither ARD nor APS.

Cardiovascular conditions occur in 1–4% of pregnancies and represent the most common cause of maternal deaths in the United States, said Rashmi Dhital, MD, Postdoctoral Fellow in Rheumatology, Allergy & Immunology at the University of California, San Diego (UCSD) School of Medicine.

Dr. Dhital opened the Plenary I on Sunday with a discussion of ARD and increased risk for CVE during pregnancy and the first six weeks postpartum. The session is available on demand for registered ACR Convergence 2023 participants through Oct. 31, 2024, on the meeting website.

A retrospective analysis of the California Study of Outcomes in Mothers and Infants, housed at UCSD, found the relative risk of CVEs ranged from 1.7 for spondylarthritis to 18.1 for SLE with APS. Rheumatoid arthritis, the most common ARD, carried a 2.9-fold risk for CVE. Between 25% and 30% of CVEs occurred during the first six weeks after delivery.

“Given that a quarter of CVEs occur early in the postpartum period, close follow-up is essential even after delivery,” Dr. Dhital said.

TRAF5 may be biomarker and target for PAH in SLE

Individuals with SLE and pulmonary arterial hypertension (PAH) often show rapid disease progression and poor prognosis. The pathogenesis of PAH in SLE appears to be a combination of inflammation and genetic alterations leading to dysfunction of pulmonary artery endothelial cells (PAEC), cellular proliferation, and pulmonary vascular remodeling.  

“PAH is one of the most important complications that seriously threatens the prognosis of patients with SLE,” said Xiaoyue Deng, PhD, Postdoctoral Fellow of Rheumatology and Clinical Immunology at Peking Union Medical College Hospital, China. “We are trying to reverse pulmonary vascular remodeling through a better understanding of the genetic background of PAH in SLE.”

Whole-exome sequencing on 150 SLE-PAH patients, genomewide association studies, transcriptional studies, and other approaches identified tumor necrosis factor receptor-associated factor 5 (TRAF5) as a susceptible gene in SLE-PAH. Researchers have developed a novel animal model that mimics human SLE-PAH.

TRAF5 deficiency activates transforming growth factor-beta signaling with increased PAEC apoptosis, while overexpression of TRAF5 attenuated PAH symptoms.

“The lack of TRAF5 triggers the pathogenesis of PAH in SLE through inducing dysfunction in PAEC,” Dr. Deng said. “TRAF5 could be a potential marker for the diagnosis and therapy of SLE-PAH.”

First sexually dimorphic gene expression of synovial macrophages in RA confirmed

Rheumatoid arthritis (RA) and other autoimmune diseases are more common in females than in males, but the mechanism for this female bias has been elusive. New work in single-cell RNAseq (scRNAseq) suggests a pathogenic role for specific synovial macrophage subtypes. A novel mouse model of RA identified myeloid synovial subsets with a sexually dimorphic gene expression pattern that maps to human RA.

“Women have increased incidence of autoimmune disease,” said Richard Bell, PhD, Postdoctoral Fellow at the Hospital for Special Surgery. “There’s a difference of 3:1 for multiple sclerosis, RA, and myositis, and 8:1 for SLE, Sjogren’s, scleroderma and systemic sclerosis, and Hashimoto’s.”

Researchers analyzed myeloid scRNAseq data from the Accelerating Medicines Partnership-RA consortium with about 76,000 cells from human synovial biopsies. Differential gene expression and gene set enrichment analysis identified two macrophage subsets, CXCL10+ and SPP1+, enriched with inflammatory and interferon (IFN) gene signatures showing clear female bias. Similar sex-based bias of the same subsets was seen in a mouse model of RA.

Dr. Bell said mechanistic studies are exploring potential roles for sex-dependent factors such as hormone signaling and X-inactivation and interactions with IFN signaling pathways.

“I fully expect to find new therapeutics in the next 10 years as we learn more about this,” he added.

PEXIVAS reduced-dose glucocorticoid regimen increases risk of death, ESKD, progression in severe GPA, MPA

A retrospective analysis of patients with severe granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) treated at 19 hospitals in France found that reducing glucocorticoid dosing increased the risk of death and end-stage kidney disease (ESKD).

“There is an association between steroids and potentially fatal adverse events, including severe infections,” said Sophie Nagle, MD, Service de Médecine Interne, Hôpital Bichat, Assistance Publique Hôpitaux de Paris, Université Paris Cité, France. “In this context, the clinician’s objective is to minimize cumulative doses of steroids as much as possible.”

The Plasma Exchange in Vasculitis (PEXIVAS) trial, published in 2020, concluded that a reduced-dose glucocorticoid regimen is not inferior to standard glucocorticoid dosing for death or ESKD, Dr. Nagle noted. A subgroup analysis of PEXIVAS showing a numerical trend toward increased risk of death or ESKD in patients taking RTX prompted this retrospective study of real-world treatment results.

The analysis included 234 patients, 40% with MPA and 60% with GPA, treated with either PEXIVAS reduced glucocorticoid regimen or standard glucocorticoid dosing between January 2018 and April 2022. Of the group, 126 patients received reduced glucocorticoid dosing and 108 received standard glucocorticoid dosing. The primary endpoint included the occurrence of death, ESKD, or progression before remission requiring treatment modification or relapse, whichever occurred first. Patients with reduced glucocorticoid dosing were more likely to meet the primary endpoint (HR=1.72) versus the standard regimen. Patients with creatine levels above 300 μmol/L were more likely to meet the primary endpoint (HR=2.14). Those on RTX as induction therapy were also more likely to meet the primary outcome (HR=1.61) and more likely to die or develop ESKD (HR=2.42) versus standard GC dosing.

New consensus recommendations call for mandatory MSUS training during residency in Canada

Canada’s first-ever consensus recommendations on musculoskeletal ultrasound (MSUS) training calls for mandatory training on hand, wrist, foot, knee, and ankle imaging as part of residency training. If adopted, the recommendations could form the basis for a standardized MSUS residency curriculum.

“These are recommendations for the minimum training requirements and are not meant to be limiting,” said Maria Powell, MD, Fellow-in-Training at the University of Calgary Cumming School of Medicine, Calgary, Canada. “Centers that have the resources, time, and expertise to teach more can do that. This is a starting point.”

Dr. Powell led a three-stage consensus design to establish priorities, define competencies, and final review with a group of rheumatology MSUS experts and non-MSUS experts. The working group prioritized competency based on clinical utility and learnability of specific MSUS approaches and affected joints.

Mandatory competencies included focused inflammatory arthritis exams for specific joints of the hands, wrists and feet, as well as limited knee and ankle exams for joint effusion. Optimal anatomic competencies include additional joints in the hand, wrist, and feet, and additional views of the ankle and knee.

Optional pathology competencies include select inflammatory pathologies and non-inflammatory pathologies. MSUS-guided aspiration and injection are also optional competencies.

“We started with a very comprehensive list of competencies and, through a robust consensus design, were able to refine this list to what is predicted to be the most clinically useful and learnable for rheumatology residents,” Dr. Powell said. “We hope to pilot these competencies nationally and develop professional activities to align with competency-based medical education.”