Intensive diet and exercise can reduce knee pain in knee OA community treatment settings
It has long been recognized that intensive diet and exercise can reduce knee pain and other symptoms associated with knee osteoarthritis (OA) in overweight and obese patients in strictly supervised academic settings. A pragmatic randomized trial showed similar results in multiple community-based settings.
“Diet and exercise was 20 percent more likely to attain a clinically important 2-point improvement in pain compared to an attention control group,” said Stephen Messier, PhD, Professor of Health and Exercise Science, Wake Forest University. “The 8 kg weight loss, combined with a 9 cm reduction in waist circumference, is evidence that weight loss achieved in community settings can have important health benefits.”
Dr. Messier opened Plenary III on Monday, November 14, with the results of WE-CAN, an 18-month trial of intensive diet and exercise in rural and urban community settings across North Carolina. The session is available for on-demand viewing for registered ACR Convergence participants through October 31, 2023, on the virtual meeting website.
A total of 823 patients aged 50 and older with knee OA and a body mass index (BMI) of 27 or more were randomized to either an attention control group (409) that participated in five one-hour, face-to-face coaching sessions with information packets or phone sessions in alternate months, or an intensive program of two 15-minute walking sessions plus 20 minutes of weight training three times weekly and a diet of 1,100 calories daily for women and 1,200 daily for men. The diet goal was 10 percent or more weight loss over 18 months.
The primary outcome was the between-group difference in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee pain. Secondary outcomes included WOMAC function, seven-minute walk distance, 36-Item Short Form Health Survey (SF36) quality-of-life answers, and change in waist circumference.
Diet-plus-exercise patients lost a mean of 10.9 kg (10.8 percent) of body weight versus 2.7 kg (2.7 percent) for the attention group. Diet and exercise also resulted in significantly less WOMAC pain at both six and 18 months, including a 32 percent reduction at 18 months versus a 24 percent reduction for the control group (p=0.02). The mean waist circumference declined 9 cm for the diet-plus-exercise group versus a reduction of 4 cm for the control group (p<0.001).
“This study provides a blueprint for the implementation of a successful treatment for a pervasive public health problem in clinical and community settings,” Dr. Messier said. “This community-based trial resulted in improvements in weight and knee pain similar to earlier academic center-based programs.”
Sarilumab effective in treating refractory PMR
Polymyalgia rheumatica (PMR) is one of the most common inflammatory diseases of older individuals. It can usually be treated with glucocorticoids (GC), but relapses are common, which can subject patients to long, repeating regimens of high-dose GC treatment.
“We need a steroid-sparing treatment for PMR,” said Robert Spiera, MD, Director of the Scleroderma, Vasculitis, and Myositis Center, Hospital for Special Surgery, and Professor of Clinical Medicine, Weill Cornell Medicine. “The phase 9 SAPHYR trial showed that sarilumab, an interleukin 6 (IL-6) receptor inhibitor, has greater and clinically relevant improvements in disease remission, risk of PMR flare, and quality of life and function compared to conventional GC treatment in this difficult-to-treat population.”
Sarilumab is currently approved by the U.S. Food and Drug Administration for rheumatoid arthritis (RA). The agent targets the IL-6 receptor and inhibits IL-6 signaling.
SAPHYR randomized 59 patients to sarilumab 200 mg administered subcutaneously every two weeks with a 14-day GC taper and 58 patients to the conventional 52-week GC taper. All patients were on 7.5 mg or more GC and had a flare within 12 weeks of their initial screening. The trial was powered for 280 patients but was halted early due to COVID-19.
The primary endpoint was disease remission by week 12 and sustained through week 52, C-reactive protein normalization, and adherence to per protocol GC taper from weeks 12–52.
“This was a typical group of patients for PMR, early 70s, two-thirds female, and 80 percent white,” Dr. Spiera said. “Sustained remission was significantly higher in the sarilumab arm, 28.4 percent versus 10.3 percent (p=0.0193). All of the components of sustained remission, patient-reported outcomes, and most physician-reported outcomes favored sarilumab with no surprises in safety. The protocol set a very high bar for sustained remission and in clinical terms, these are very significant results.”
CATCR-T cell approach promises precision immunotherapy
Chimeric antigen receptor (CAR)-T cell therapies have revolutionized cancer therapy and can be curative for some tumors. CD19-targeted CAR-T cells promise similar results for autoimmune diseases, but at the cost of depleting all B cells and increasing the risk of infection, impaired vaccine response, reduced anti-tumor immunity, and other toxicities.
“All current immunotherapies are indiscriminate,” explained Maximilian F. Konig, MD, Assistant Professor of Rheumatology, Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine. “They lack the precision we need for our patients. Using antiphospholipid syndrome (APS) as a model, we are developing a precision, autoantigen-specific T-cell therapy that selectively eliminates autoreactive B cells and transforms the treatment for our patients with rheumatic diseases.”
Chimeric autoantigen-T cell receptor (CATCR)-T cells are engineered receptors that contain an autoantigen to produce antigen-specific T cells. These CATCRs reprogram T cells to selectively kill autoreactive B cells while ignoring normal B cells.
Preclinical data suggest that CATCR-T cells are both selective and potent against APS, a B cell-driven autoimmune disease. Concentrations as low as 0.625:1 can eliminate more than 50 percent of autoreactive beta-2 glycoprotein I (B2GPI) B cells and 100 percent of B2GPI target B cells at 5:1 with no effect on other B cells.
“Beyond APS, these autoantigen-specific immunotherapies promise a future of treating autoimmune diseases without increasing the risk of infection,” Dr. Konig said.
GWAS reveals pathogenic CHIP pathways in gout
Recent genome-wide association studies (GWAS) in gout have identified more than 200 loci that control serum urate levels, largely through renal and gut excreting of urate. These loci also confer risk of gout that is proportional to their effect on urate, but few confer gout risk without hyperuricemia.
“We needed GWAS to identify genes and pathways associated with inflammation in gout,” said Tony R. Merriman, PhD, Professor of Immunology and Rheumatology, University of Alabama Birmingham. “We combined data from 13 separate cohorts to explore 120,282 people with gout and 2,502,548 without gout and found a total of 378 loci, including 148 new loci, associated with 5,300 genes, for gout.”
Researchers identified 1,486 candidate causal genes for pathway analysis. In addition to familiar urate metabolism pathways, the most important pathways included epigenetic regulation, type 2 diabetes/insulin signaling, organic ion transport, and defective pyroptosis.
Top contributors included genes for amino acid metabolism, epigenomic modification, and most importantly, clonal hematopoiesis of indeterminate potential (CHIP).
“We know there is an inherited propensity for CHIP and that CHIP associates with gout,” Dr. Merriman said. “Some of the top prioritized genes include fatty acid regulators that are important in immune response, interferon regulatory factors, and interleukin receptors that are antagonized by anakinra and tocilizumab. These results implicate CHIP and other new processes with dozens of new genes in gout inflammation, emphasize epigenomic programming in gout, and implicate urate production by the prostate in gout.”
STOP-JIA three-year outcomes favor early combination therapy
Three-year results from the STOP-JIA study in juvenile idiopathic arthritis (JIA) suggest benefits from combining conventional disease-modifying antirheumatic drug (DMARD) and biologic treatment early in disease compared to conventional step therapy or using biologics alone. Patients in the early combination (EC) therapy group were more likely to achieve clinically inactive disease (CID) and spend significantly longer time in CID versus other strategies.
“We know our polyarticular JIA patients are at high risk for poor outcomes,” said Yukiko Kimura, MD, Chief of Rheumatology and Professor of Pediatrics, Hackensack Meridian School of Medicine, and Co-Chair, Childhood Arthritis and Rheumatology Research Alliance (CARRA) Research and Registry Oversight Committee. “We know that initial therapy may affect outcomes, but we have very little evidence to suggest the best time to start biologic therapy.”
STOP-JIA compared the three most common biologic starting strategies. Step up (SU) treatment begins with DMARD monotherapy with a biologic added as needed after three months. Biologic first (BF) uses a biologic as initial monotherapy.
Initial 12-month data showed no statistically significant difference between the three strategies, though EC showed numerical superiority. Two-year results showed clear separation in CID, 45.8 percent for EC, 30 percent for BF, and 26.8 percent for SU, with a significant advantage for EC versus SU of 15.7 percent (p=0.04).
Three-year results showed 67.1 percent CID for EC, 49.1 percent for BF, and 47.3 percent for SU. EC had a significant advantage over SU, 19.8 percent (p=0.007). EC patients also spent more time in inactive disease, 52.4 percent versus 40 percent for SU (p=0.004).
“Even knowing these results, 40–60 percent of our patients still fail CID,” Dr. Kimura said. “We need more and more effective treatments for JIA.”
Single-cell states can identify disease phenotypes in early RA
New data comparing synovial immune infiltrates and circulating immune cells using single-cell sequencing suggest that specific single-cell synovial signatures in early, treatment-naïve RA are associated with longer-term treatment outcomes. Single-cell signatures can predict treatment response, use of biologics, and the progression of structural damage over the course of RA.
“Synovial biopsies have showed us that RA is a heterogenous disease with multiple inflammatory infiltrates associated with increased disease severity and radiographic progression and signal treatment response,” said Felice Rivellese, MD, PhD, Clinical Senior Lecturer, Centre of Experimental Medicine and Rheumatology, Queen Mary University of London, United Kingdom. “But when we look at peripheral blood, we aren’t sure how to fit immune cell subsets to the synovium and clinical outcomes.”
Single-cell analysis of matched synovial and peripheral blood suggest that T peripheral helper cells (Tph) may be useful circulating markers and predictors of disease activity.
There are 18 known synovium immune cell signatures associated with RA, Dr. Rivellese said. The top five genes represented in those signatures form three clusters: a lympho-myeloid pathotype of immune cell signatures, a fibroid-pauci-immune fibroblast signature, and a mixed signature.
Comparing synovial single-cell signatures to peripheral blood immune cell signatures, only circulating Tph correlate with clinical outcomes. Patients who reached remission at six months in response to conventional synthetic DMARDs had significantly higher pre-treatment Tph. Patients who progressed to biologics had significantly higher baseline B cells, plasmablasts, C1QA+ monocytes, and GZMK+ CD8 T cells. Radiographic progression at one year was associated with baseline plasmablasts and NUPR1+ monocytes.
“We need to scale down the huge amounts of data to the most significant signatures in peripheral blood for clinical monitoring,” Dr. Rivellese noted. “We see the potential for biomarker-driven therapeutic approaches.
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