Vasculitis Associated with Increased Pregnancy Complications

Vasculitis and pregnancy do not mix well, and multiple types of vasculitis have their highest prevalence among individuals of child-bearing age. A retrospective analysis of nationwide administrative claims data found that compared to a reference population, about 12% of pregnancies with vasculitis were complicated by preeclampsia. Vasculitis was also associated with increased risk of preterm delivery, spontaneous abortion, and other comorbidities. Maternal risk of complications varied by vessel size and parity.

“We know so little about the risk of vasculitis to parent and fetus because, for so many years, vasculitis therapies were essentially prohibitive of pregnancy because they caused birth defects,” said Audra Horomanski, MD, RhMSUS, Clinical Assistant Professor of Immunology & Rheumatology at Stanford University and Director of the Stanford Vasculitis Clinic. “We always assumed there was an increased risk of hypertensive disorders in pregnancy and preterm delivery extrapolating from other rheumatic diseases, but we had very little hard data.”

Dr. Horomanski opened Plenary III with a discussion of the latest data on vasculitis and pregnancy. The session is available on demand for registered ACR Convergence 2023 participants through Oct. 31, 2024, on the meeting website.

“This is the largest population of vasculitis and pregnancy reported to date,” Dr. Horomanski said. “This information is valuable for the counseling of vasculitis patients considering pregnancy and in caring for these patients.”

Beta-catenin plays key role in synovial lining fibroblast differentiation

One of the key features of rheumatoid arthritis (RA) is a marked decrease of fibroblasts in the synovial lining. New approaches to 3-D synovial tissue culture showed that beta-catenin is a key factor in the differentiation of synovial lining fibroblasts.

“We wanted to identify the molecular signals that maintain a healthy synovial lining compartment as an important next step to better understand regulators of synovial fibroblast identity,” said Sonia Presti, BS, Technical Research Assistant at Brigham & Women’s Hospital and Harvard Medical School. “Understanding this pathway could provide novel therapeutic approaches to restore healthy synovial lining in patients with RA.”

Researchers used confocal microscopy, histology, and single-cell RNA sequencing to explore fibroblast differentiation in patient-derived synovial organoids. Gene editing techniques identified candidate transcription factors driving fibroblast differentiation. Beta-catenin emerged as a necessary upregulator of synovial lining marker genes in the models, suggesting a novel mechanism in fibroblast differentiation.

“What regulates beta-catenin activity endogenously?” asked Dr. Presti. “We want to know more in a biologically relevant context what regulates beta-catenin.”

Urinary PR3 suggests potential urinary biomarker, therapeutic targets in refractory LN 

Renal involvement is common in lupus, but more than 50% of lupus nephritis (LN) patients do not respond well to current treatments. Urinary PR3, a product of kidney neutrophil degranulation, could be a biomarker for kidney inflammation in proliferative LN, the most aggressive type of the disease. New data show an abundance of degranulating myeloid cells in LN, which may mediate kidney damage. These findings could offer novel therapeutic targets.

“We have, for the first time, a correlation between the presence of degranulating myeloid cells in lupus nephritis kidneys in proliferative disease,” said Alessandra Ida Celia, MD, Postdoctoral Research fellow at Johns Hopkins University School of Medicine. “These findings could shed light on the most aggressive phenotype of lupus nephritis. In addition, we have identified a potential urinary biomarker, PR3, and are talking about potential therapeutic targets.”

Working with the Accelerating Medicines Partnership, researchers previously showed an association between urinary PR3 and histological activity in proliferative LN. They then identified PR3-positive cells in kidney biopsy samples from patients with proliferative LN and membranous LN. PR3-positive cells were more abundant in proliferative LN, particularly in the glomeruli, Dr. Celia noted.

Glomerular PR3-positive cell density strongly corelated with histological activity, particularly in proliferative LN.

“Lupus nephritis patients who have persistent PR3 in the urine despite six or 12 months of treatment are more likely to develop permanent loss of kidney function in the following three years,” Dr. Celia said. “Persistence of PR3 is linked to kidney damage, nominating PR3 as a potential therapeutic target.”

Premature mortality in gout independent of serum urate

A new analysis of adults in the U.S. National Health and Nutrition Examination Survey (NHANES) and a matched cohort in the UK Biobank found that gout is associated with 20% increased all-cause mortality. Hazard ratios for excess mortality associated with gout changed minimally when adjusted for serum urate and were larger for key subgroups by sex (HR=1.32 for female versus male) and self-reported race/ethnicity (HR=1.90 for self-reported Black versus white).

“Mortality has been improving in other rheumatic diseases, including rheumatoid arthritis and lupus, but not in gout before and after adjustment for serum urate,” said Natalie McCormick, PhD, MSc, Instructor in Medicine in Rheumatology, Allergy, and Immunology at Massachusetts General Hospital and Harvard Medical School. “There is increased risk above and beyond the traditional risk factors in cardiovascular disease that gout patients have. These data point to a more specific pathway in gout.”

Dr. McCormick noted that their findings point to inflammation that is not well managed under current gout care with anti-inflammatory approaches, such as interleukin-1 (IL-1) inhibition or colchicine, an anti-inflammatory long used to treat acute gout flares.

“Among gout patients, colchicine use is associated with a decreased risk of cardiovascular events as well as all-cause mortality,” Dr. McCormick said. “Low-dose daily colchicine has now been approved by the U.S. Food and Drug Administration (FDA) for cardiovascular disease risk mitigation.”

Romosozumab superior to denosumab to improve spine BMD

A single-center study has found romosozumab improves lumbar spine bone mineral density (BMD) more than denosumab in adults on long-term corticosteroid therapy at moderate/high risk of osteoporotic fracture. A total of 70 patients were randomized to romosozumab or denosumab for 12 months followed by an additional 12 months of denosumab. The primary outcome was change in lumbar spine BMD at 12 months. Secondary endpoints included BMD changes at lumbar spine and non-dominant hip at 24 months. The trial was investigator initiated and locally funded.

“Both drugs showed a significant increase in BMD at 12 months, but romosozumab was clearly superior, an increase of 7.31% versus 2.76% and 9.67% versus 2.96% at 24 months,” said Chi Chiu Mok, MD, FRCP, Chief of Rheumatology, Tuen Mun Hospital, Hong Kong. “Romosozumab is very attractive for first-line therapy, especially in patients with a history of fracture and poor BMD.”

Differences in BMD at month 12 were significant after adjustment for baseline BMD, age, sex, osteoporosis risk factors, and the cumulative glucocorticoid doses in the preceding 12 months, Dr. Mok added.

“Romosozumab may offer a new treatment approach for patients at high risk of fracture,” he concluded.

Increasing dose, duration, recency increase glucocorticoid risk of MACE in RA

Most patients with rheumatoid arthritis (RA) at some point use glucocorticoids to manage their symptoms. A retrospective analysis of claims data from the Veterans Administration found that the dose, duration, and recency of glucocorticoid exposure all affect the risk of major adverse cardiovascular events (MACE) in patients with RA. Earlier studies had concluded that increasing current glucocorticoid exposure increased MACE risk but did not sufficiently examine the impact of prior glucocorticoid dose or duration.

“We are, as a field, moving away from the idea that only ongoing, prolonged steroid exposure affects your risk of MACE,” said Beth Wallace, MD, Associate Investigator at the Center for Clinical Management Research and Assistant Professor of Rheumatology at the University of Michigan. “Glucocorticoid use is associated with a dose- and duration-dependent increase in the risk of MACE even at doses as small as 5 mg. and durations as short as 15 days.”

Existing ACR guidelines already recommend against glucocorticoid use if at all possible, Dr. Wallace added.