The study, presented today at the annual meeting of the American College of Rheumatology, ACR Convergence 2024, was led by researchers at the University of Colorado School of Medicine in collaboration with investigators from HSS and other centers within the Accelerating Medicines Partnership® Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP® RA/SLE) Network.¹

“These research findings validate the importance of certain immune cells in the development of RA, particularly in how they drive the change from asymptomatic to symptomatic,” said Laura Donlin, PhD, scientist and co-director of the HSS Precision Medicine Program and co-principal investigator of the National Institutes of Health-supported AMP Rheumatoid Arthritis research consortium. “We hope that one day we can use these insights to stop RA before it even begins.”

Rheumatoid arthritis is a type of inflammatory arthritis that can occur when specific types of immune cells attack the body’s healthy tissues, resulting in pain, swelling and stiffness in joints. It can also result in problems in other areas of the body, such as the heart, lungs, eyes, nerves and skin. Diagnosis typically relies on an evaluation by a rheumatologist for clinical signs and symptoms supported by further evidence from X-rays and blood tests.

For the study, the participating rheumatologists collected tissue and blood samples from patients who either had RA or were considered at risk due to specific antibodies, called ACPA, in their blood and having a first-degree relative with the disease. Researchers at the Broad Institute of MIT and Harvard then used advanced single-cell sequencing techniques to analyze the samples and compared the results to those from healthy individuals.

The analysis found higher numbers of certain immune cells in the patients at risk for RA, including CCR2+ T helper cells, T peripheral helper cells, type 1 T helper cells, and granzyme B-positive memory T helper cells. Advanced sequencing also gave the investigators a better understanding of which genes were activated in these cells, offering insight into how the immune cells in patients with RA differ from those in at-risk individuals and healthy people.

“We knew that the presence of ACPA in blood and having a first-degree relative with rheumatoid arthritis indicate risk, but this new research has allowed us to learn more about the underlying biology driving increased risk,” said HSS rheumatologist Susan M. Goodman, MD, a co-author of the study. “These insights will pave the way toward helping us develop a new tool for determining which patients may benefit from early intervention.”

“There is some evidence that existing RA drugs, such as abatacept or rituximab, may help prevent the disease, but they are relatively expensive and come with side effects,” said co-author S. Louis Bridges, Jr., MD, PhD, physician-in-chief and chief of the Division of Rheumatology at HSS. “Pending validation in larger studies, the new patterns of immune cells identified in this research could represent potential targets for the development of new, more effective therapies.”

HSS Authors: S. Louis Bridges, Jr., MD, PhD, Vivian P. Bykerk, BSc, MD, FRCPC, Susan M. Goodman, MD, Laura Donlin, PhD.

Reference:

¹ Inamo J, Keegan J, Griffith A, Ghosh T, Horisberger A, Howard K, Pulford J, Murzin E, Hancock B, Eisenhaure T, Dominguez S, Gurra M, Gurajala S, Jonsson A, Seifert J, Feser M, Norris J, Cao Y, Apruzzese W, Bridges S, Bykerk V, Goodman S, Donlin L, Firestein G, Bathon J, Hughes L, Tabechian D, Filer A, Pitzalis C, Anolik J, Moreland L, Hacohen N, Guthridge J, James J, Cuda C, Perlman H, Brenner M, Raychaudhuri S, Sparks J, Holers M, Deane K, Lederer J, Rao D, Zhang F. Deciphering Pathogenic Phenotypes by Multi-modal Deep Single-cell Blood Immunophenotyping in Individuals At-risk for Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/deciphering-pathogenic-phenotypes-by-multi-modal-deep-single-cell-blood-immunophenotyping-in-individuals-at-risk-for-rheumatoid-arthritis/. Accessed October 10, 2024.

The studies focus on the tapering of treatment in patients whose disease is well controlled, real-world outcomes for targeted therapies, assessing the effects of biologic treatments on immune cells from patients with RA, and the underlying mechanisms of arthritis triggered by immune checkpoint therapies used to treat cancer.

What follows are some highlights from the meeting:

Effectiveness of Upadacitinib in the Treatment of Rheumatoid Arthritis: Analysis of 6-Month Real-World Data from the United Rheumatology Normalized Integrated Community Evidence (UR-NICETM) Database

Upadacitinib, an oral Janus kinase (JAK) inhibitor, was approved for the treatment of RA in 2019 after clinical trials suggested that it reduced symptoms and had acceptable side effects. But since that time, few real-world data have been reported on how patients respond to upadacitinib outside of clinical trials. This six-month study looked at outcomes for 140 patients receiving upadacitinib alone and 223 receiving upadacitinib plus conventional synthetic disease-modifying antirheumatic drugs (DMARDs). The investigators, led by HSS rheumatologist Allan Gibofsky MD, JD, MACR, FACP, FCLM, found that overall 46% of patients receiving upadacitinib achieved low disease activity and 14% achieved remission, with better results for patients in the combination therapy group than those who got upadacitinib alone. The effectiveness of upadacitinib was not impacted by prior therapy with a tumor necrosis factor inhibitor or tofacitinib. This study supported the use of upadacitinib in clinical practice, including in patients with prior exposure to advanced therapy.

Authors: Allan Gibofsky, MD, JD, MACR, FACP, FCLM (HSS), Mark E. Pearson, MD (West Suburban Center for Arthritis), Andrew Concoff, MD (United Rheumatology), Anna Shmagel, MD, Patrick Zueger, PhD, Yanna Song, MS, Lauren D. Smith, MD (AbbVie Inc.), Grace C. Wright, MD, PhD (Grace C. Wright MD PC, Association of Women in Rheumatology).

Can Patients with Controlled RA Receiving Any Class of Targeted Therapy with Methotrexate (MTX) Sustain Disease Control after Tapering MTX? A Systematic Review and Meta-Analysis 

People with RA frequently wish to taper the use of methotrexate therapy due to its side effects, but there are questions about the best way to do that. Guidelines that recommend tapering methotrexate before tapering biologic DMARDs are not based on direct evidence. In this study, a team of HSS investigators led by rheumatologist Charis F. Meng, MD, and Director of the Inflammatory Arthritis Center Vivian P. Bykerk, MD, FRCPC, conducted a literature search to look at whether patients who are taking the combination of methotrexate and targeted therapy (biologic therapies and JAK-inhibitors) can taper methotrexate and still be in remission from their RA, while continuing their targeted therapies. They identified 10 studies that met their inclusion criteria. These studies included a number of different targeted therapies. Based on their analysis, the team concluded that patients with controlled RA have a high probability of maintaining disease control for at least 18 months after tapering their methotrexate and continuing targeted therapies. They noted that this review may inform patients who are experiencing controlled disease while taking methotrexate in combination with any of a range of targeted therapies and who are struggling with methotrexate-related side effects. However, they concluded longer follow-up studies are needed to confirm the disease will not worsen over time and that patients should be told about this possibility.

Authors: Charis F. Meng, MD, Diviya Rajesh, Deanna Jannat-Khah, DrPH, Omar Bruce, MPH, Bridget Jivanelli, MLIS, Vivian P. Bykerk, BSc, MD, FRCPC (HSS).

Differential Pharmacodynamic Alterations After Treatment with Abatacept or Adalimumab in MTX-Inadequate Responder Patients with Early RA: Whole Blood RNA-Seq Analysis of the Early AMPLE Study

A number of novel agents for RA are now available for treatment, but tools to predict which patients are likely to respond to specific drugs are lacking. To ensure that patients are matched with the best treatment, more research is needed to determine the molecular signatures of these drugs and their mechanisms of action. In this study, part of a Phase 4 trial called Early AMPLE, investigators including HSS Physician-in-Chief and Chair of the Department of Medicine S. Louis Bridges, Jr., MD, PhD, and Director of the Inflammatory Arthritis Center Vivian P. Bykerk, MD, FRCPC, looked at pharmacodynamic changes in patients in response to treatment with either abatacept or adalimumab. The aim was to identify and differentiate the impact of each drug on modulation of immune cells at the molecular level. The investigators performed pharmacodynamic and other analyses for 14,540 protein-coding genes in 664 RNA- Seq samples, with materials collected from 79 patients with RA who were predicted to respond better to abatacept. They found that after treatment, twice as many genes and pathways were significantly altered in the adalimumab arm versus the abatacept arm and that abatacept treatment decreased immune cell cycle gene expression while adalimumab treatment increased expression of these genes. The differential gene expression was seen in genes known to correlate with RA disease activity. The investigators concluded that these findings may explain the greater clinical improvements seen with abatacept versus adalimumab. Because patients in the Early AMPLE study were predicted to respond differentially to abatacept, these findings may be relevant only to this subgroup of patients. These findings warrant further studies to investigate the potential positive correlation between RA-relevant effects and better therapeutic outcomes.

Authors: Chun Wu (Bristol Myers Squibb), Yicong Li (Parexel International), Neelanjana Ray, Michael A. Maldonado, Peter Schafer (Bristol Myers Squibb), S. Louis Bridges, Jr., MD, PhD (HSS), William Rigby (Dartmouth-Hitchcock Medical Center), Vivian P. Bykerk, MD, FRCPC (HSS), Jane Buckner (Benaroya Research Institute at Virginia Mason), Jinqi Liu (Bristol Myers Squibb).

The Probability of Sustaining Rheumatoid Arthritis Remission in Patients Tapering Targeted Therapy Used as Monotherapy: a Systematic Review and Meta-Analysis 

A second study led by HSS rheumatologist Charis F. Meng, MD, and Director of the Inflammatory Arthritis Center Vivian P. Bykerk, MD, FRCPC, also used a literature review to look at the effects of tapering drugs for RA in people whose disease is well controlled. This study focused on patients receiving either biologic DMARDs or JAK inhibitors being used alone. A search resulted in five studies that compared tapering of targeted monotherapy (TNF-i, tocilizumab, abatacept, or baricitinib) with continuing therapy or other tapering regimens. A meta-analysis including data from 800 patients found a trend for lower odds of disease remission with targeted therapies versus comparator treatment regimens, but these data were not conclusive. The investigators noted that the lack of trials designed to compare tapering targeted monotherapy to continuing it led to a significant gap in knowledge in an area of research that is increasingly relevant for patients. Their review suggests that stopping targeted monotherapy is unlikely to maintain disease control, but that more gradual tapering schemes, dose reduction, and early treatment of disease may be associated with more successful tapering. More studies are needed to better inform patients, and it is not recommended to stop targeted monotherapy in RA based on this analysis.

Authors: Charis F. Meng, MD, Diviya Rajesh, Deanna Jannat-Khah, DrPH, Omar Bruce, MPH, Bridget Jivanelli, MLIS, Vivian P. Bykerk, MD, FRCPC (HSS).

Less ACPA Epitope Expansion Is Found in ACPA-Positive Immune Checkpoint Inhibitor Arthritis Patients Compared to ACPA-Positive Rheumatoid Arthritis Patients

Immune checkpoint inhibitors (ICI) have improved the treatment of many advanced cancers. However, they can lead to immune-related adverse events, including treatment-induced arthritis. This form of arthritis is similar to RA. About 9% of people with this condition test positive for the anti-citrullinated peptide antibody (ACPA). In RA, the increase in ACPA occurs over the years prior to onset of clinical disease. In this study, led by HSS rheumatologist Nilasha Ghosh, MD, MS, investigators examined the degree of ACPA epitope expansion in patients receiving ICI to determine whether treatment-induced arthritis is similar to early RA, or more suggestive of the pre-clinical phase of disease. The analysis employed clinical data and serum samples from 12 patients with ICI arthritis (ICI-A) as well as from 39 ACPA-positive RA patients. There were a number of differences between the patients in the two groups, including age and smoking history. The investigators reported that, overall, people with ICI-A had lower ACPA titers and targeted fewer ACPA epitopes than people with early RA, suggesting that ICI-A may represent an accelerated model of RA pathogenesis with ICI triggering an early transition from pre-clinical to clinical disease. They noted that sequential sampling and analysis are warranted to further determine how the pathogenesis of ICI-A relates to that of RA.

Authors: Diviya Rajesh, Nilasha Ghosh, MD, MS (HSS), Jessica Kirschmann (Stanford University), Karmela Kim Chan, MD, Deanna Jannat-Khah, Susan M. Goodman, MD, Vivian P. Bykerk, BSc, MD, FRCPC (HSS), William Robinson, MD, PhD (Stanford University), Anne R. Bass, MD (HSS).

The research focuses on the diagnosis of renal disorders, the risk of venous thromboembolism after total knee replacement (TKR), and the care of pediatric and young adult patients with rheumatologic diseases. There are also studies related to the care of rheumatology patients during the COVID-19 pandemic.

“While there have been significant advances in science over the years, there are areas of unmet needs warranting continued investigation,” said S. Louis Bridges, Jr., MD, PhD, Physician-in-Chief, Chair of the Department of Medicine and Chief of the Division of Rheumatology at HSS. “HSS has a relentless focus on improving patient care through innovation and discovery. By spearheading multi-center studies, clinical trials, and laboratory-based research, we continue to improve the quality of life for patients affected by rheumatic and musculoskeletal conditions.”

What follows are some highlights from the meeting:

Geographical Variations in COVID-19 Perceptions and Patient Management: A National Survey of Rheumatologists

A study led by HSS rheumatologist Bella Mehta, MBBS, MS, looked at the perceptions and behaviors of rheumatologists in the United States regarding the risk of COVID-19 for patients with autoimmune disorders and how those patients were managed with immunosuppressive and anti-inflammatory medications. The 271 respondents were asked whether patients with rheumatic diseases were at higher risk of COVID-19 and whether the pandemic had led them to reduce the use, dosage, or frequency of biologics or steroids. Overall, the survey found geographical variations regarding perceptions of patients’ risk of COVID-19, with responses that were significantly different in the Northeast region of the United States compared with other regions.

Can a Clinical Disease Activity Index Based on Patient-Reported Joint Counts (PT-CDAI) Be Used to Inform Target-Based Care in Telemedicine? An Analysis of 2 Early RA Cohort Studies 

A team that included HSS rheumatologist Vivian P. Bykerk, BSc, MD, FRCPC, looked at data from two cohort studies on patients with early rheumatoid arthritis (RA) that compared patient and physician assessment of tender and swollen joints. This research is important because COVID-19 has forced rheumatologists to shift from in-person clinical visits to telemedicine, which limits their ability to carry out complete joint exams. The study found that patient and physician assessments had good agreement when it came to identifying active versus controlled disease activity. In addition, the researchers reported that predictors of higher discrepancies between patient and physician assessments may help identify patient subsets that could benefit the most from more physician-guided training at joint self-assessments as well as more probing questioning during telehealth visits to confirm active synovitis.

Characterization of Antiphospholipid Antibody-Associated Nephropathy: An International Survey of Renal Pathology Society Members

A survey led by HSS rheumatologist Medha Barbhaiya, MD, MPH, sought to determine whether pathologists worldwide use uniform criteria to distinguish antiphospholipid antibody-associated nephropathy (aPL-N) from other forms of thrombotic microangiopathy. The study was done in parallel with an international effort to develop new classification criteria for antiphospholipid syndrome. The web-based survey included 780 members of an international Renal Pathology Society; 111 renal pathologists responded, representing 33 countries. The participants were asked to determine whether two acute and eight chronic aPL-N features were consistent with acute or chronic aPL-N without and were not provided with serology information. Results from the survey indicated that more than 90% of pathologists worldwide agreed that the renal pathologic features most specific for aPL nephropathy are noninflammatory glomerular or small arterial microthrombi and organized microvascular thrombi with recanalization. In the absence of serologic data, more than 75% of pathologists indicated lack of specificity of chronic glomerular or small arterial changes. These findings indicate the importance of serologic test results in biopsy interpretation and suggest higher specificity for certain acute or chronic features.

The Risk of Venous Thromboembolism After Septic Total Knee Replacement (TKR) Revision Is Double the Risk After Aseptic TKR Revision: An Analysis of Administrative Discharge Data

A team led by HSS rheumatologist  Anne R. Bass, MD, assessed the 90-day risk of postoperative venous thromboembolism (VTE) in people who underwent revision TKR surgery. Although it was already known that infection can increase the risk of thrombosis by triggering coagulation pathways, the impact of infection in this context was not well understood. The study, which included 25,441 of these surgeries performed between 1998 and 2014, used data from the New York Statewide Planning and Research Cooperative System. Overall, 69% of these revisions were for mechanical causes (aseptic), 28% were for infection (septic), and 3% were related to a periprosthetic fracture. The researchers found that the risk of VTE after septic revision surgery was double the risk after aseptic revision surgery, and was 2.6-fold higher after revision surgeries for fracture. These findings point to the importance of taking infection and fracture status into account when planning VTE prophylaxis for patients having revision surgery.

Using a Patient-Engaged Approach to Identify Cross-Cutting Disease Factors Impacting Mental Health in Youth with Rheumatologic Disease

A team including HSS chief of pediatric rheumatology Karen Brandt Onel, MD, examined the mental health experiences of those with juvenile arthritis, juvenile dermatomyositis, or systemic lupus erythematous. It included patients aged 14 to 24 and parents of patients between the ages of 8 and 24. The primary outcome was the presence of any clinical or self-diagnosed mental health problem. The survey included information on cross-cutting disease factors such as disease duration, active disease status, current steroid medication, history of disease flare following remission, and appearance-altering comorbidities (such as psoriasis, stretch marks, alopecia, skin ulceration, and visible scarring). The researchers also examined results by mental health problem (depression, anxiety, and self-harm/suicidal ideation). Overall, they found that certain rheumatologic disease factors, including those that alter appearance, are predictive of mental health problems such as depression or anxiety. The findings will help identify targets for mental health screening in youth with rheumatologic diseases.

New Juvenile Idiopathic Arthritis Quality Measure Set for the Pediatric Rheumatology Care and Outcomes Improvement Network

A team that included HSS pediatric rheumatologist Nancy Pan, MD, reported highlights of new quality measures for the treatment of juvenile idiopathic arthritis. The study also provided information about the performance of these new measures, which were created by the Pediatric Rheumatology Care and Outcomes Improvement Network. The measures take into consideration clinical health importance, scientific validity, and feasibility, as well as best practices. They include both clinical evaluations based in part on the clinical Juvenile Arthritis Disease Activity Score and patient-reported outcomes such as pain, physical function, and overall well-being. An analysis of the new measures found that they are feasible for use on patients with juvenile idiopathic arthritis and can help to maximize quality improvement efforts and optimize the delivery of care.

Vivian P. Bykerk, BSc, MD, FRCPC, rheumatologist at HSS, explained that some ongoing work is demonstrating a benefit with sublingual B-12 for methotrexate intolerance in general and appears to allow for much higher methotrexate dosing.

Read the full article at MDedge.com.
 

Vivian Bykerk, BSc, MD, FRCPC, rheumatologist and director of the Inflammatory Arthritis Center at HSS, explains that randomized, controlled trials and observational studies have found that de-escalating treatment (i.e. reducing a dose) can lead to drug-free remission in some patients but can sometimes see a worse outcome when it isn't successful.

De-escalating treatment does have its own practical challenges. "Worsening in terms of symptoms and impacts may occur between scheduled clinical encounters," she says. "Worsening may not occur for many months or even one to two years," when a patient might not have a follow-up visit.

Dr. Bykerk says that personalized strategies of integrated induction followed by de-escalation will likely be the key to cost-effective improved care.

Read the full article at The-Rheumatologist.org.

"We like the conventional DMARDs, but the problem with them is some people have side effects, as they could have side effects to anything. It's hard to remember always to take the medication. There are some conventional DMARDs you have to take 4, 6 times a day, which is not so easy," said Dr. Bykerk.

However, she explained that the DMARD methotrexate helps reduce the body's rejection of biologics.

"We see in study after study after study, that when you combine methotrexate and a biologic, even if the methotrexate is at a lower dose, those people do better over time," Dr. Bykerk added.

Watch the full video interview at centerforbiosimilars.com.

According to HSS rheumatologist Vivian P. Bykerk, BSc, MD, FRCPC, overdiagnosis does not occur very often in rheumatology.

"In 25 years of treating early [rheumatoid arthritis (RA)] patients, I have observed that they usually present with very obvious RA. I can think of only a few that might have come too early," said Dr. Bykerk.

Dr. Bykerk noted that there could be new opportunities to find new treatment targets by focusing on precision medicine. However, she explained the importance of listening to the patient's symptoms and needs.

She said "if they aren't in pain, they are less likely to agree to medication with a potential or experienced side effect list that is worse than their perceived problem. I have always said, 'Treat the patient, not the test.'"

Read the full article at Medscape.com [subscription required].

According to Dr. Bykerk, all patients with very active rheumatoid arthritis (RA) will have similar shifts in body composition, including reduced muscle mass and increased central obesity associated with metabolic changes, potentially placing them at higher risk for cardiovascular disease (CVD). If a patient has well-controlled disease and lipids are still high, adding a statin may be effective in reducing this risk.

Patients ideally should participate in physical rehabilitation, working to increase their strength, stamina, and exercise capacity. By being more active, they can self-manage and potentially reduce risks for common RA-associated comorbid conditions, including osteoporosis and CVD, she added.

Read the full article at rheumatologyadvisor.com.

Dr. Bykerk explained that muscle stiffness is common for those with RA. If you feel like you can't move the joint or fully straighten it, and this continues for more than six weeks, Dr. Bykerk recommended seeing a doctor.

Additionally, the article noted that nearly everyone with RA experiences fatigue. However, Dr. Bykerk said that once the disease is under control with treatment, the fatigue fades away.

Read the full article at prevention.com

"My overall message is to proceed with caution and to do it strategically," said Dr. Bykerk. In general, she would typically advise against tapering with the exception of steroids.

According to the article, a recent study found that discontinuing tumor necrosis factor (TNF) inhibitor treatment was associated with an increased risk of relapse.

However, Dr. Bykerk noted that "people who have sustained and [have] really good disease control are most likely to be successful".

Additionally, she stressed the importance of physicians monitoring their patients undergoing treatment tapering, and that patients should report any concerns.

"I think that treatment tapering really goes hand-in-hand with early diagnosis, modifying the immune response, and achieving good control really quickly," she concluded.

Read the full article at rheumatology.medicinematters.com

"Often, patients adjust their own medications and dosing intervals, so before making a change like this, the prescriber should be clear on what the patient is taking and how often they're taking it," Dr. Bykerk said.

Read the full article at centerforbiosimilars.com

Dr. Bykerk said that shared decision making between the provider and patient is ideal for managing treatment.

When discussing medications, Dr. Bykerk gauges the patient's beliefs about medication and tailors doses to their individual needs.

"An early investment of time in these discussions cements a fruitful relationship and partnership that is more likely to improve adherence of the agreed upon treatment strategy," said Dr. Bykerk.

Additionally, Dr. Bykerk helps compile the patient's support team which includes nutritionists, physical therapists and social workers as well as their family members.

Read the full article at the-rheumatologist.org