Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and joint destruction. As with many autoimmune diseases, RA disproportionally affects females. The development of RA is believed to involve complex interactions that include both environmental and genetic factors, and understanding the contributions of these factors continues to evolve. Many people with RA have detectable circulating autoantibodies—immune proteins that react to an individual’s own proteins—in their serum for years before experiencing any symptoms. The presence of these autoantibodies prior to joint inflammation suggests that the autoimmune process is initiated elsewhere in the body. 

Recent studies have pointed to an imbalance of commensal bacteria in mucosal sites as a possible cause of inflammation leading to the initiation of the autoimmune process. In particular, expansion of Prevotella copri in stool was associated with new-onset RA, and additional studies found that people living with RA were more likely to have immune reactivity against P. copri, making this an opportune candidate to further investigate. Given that several previous studies using samples from people with RA reported immune reactivity to a P. copri protein called Pc-p27, this study aimed to further characterize the development and timing of antibody responses to this protein in people at risk for or with RA. 

Researchers examined levels of immunoglobulin (Ig)G, an antibody associated with systemic immune responses, and IgA, an antibody associated with immune responses at mucosal sites, in individuals at risk for developing RA, those with early-onset RA, and those with established RA. Overall, people with RA had higher levels of both IgA and IgG anti-Pc-p27 antibodies than their matched healthy controls. When participants were stratified into early and established RA groups, there were notable differences in antibody level trends. Those in the early RA group had trending increases in IgG anti-Pc-p27 antibody levels, while participants with established RA had a significant elevation in IgA anti-Pc-p27 antibody levels. Furthermore, at-risk participants did not have higher IgA or IgG anti-Pc-p27 levels than their matched controls. In the 23 participants in the at-risk group who developed RA during the study, there was no significant increase in either IgA or IgG anti-Pc-p27 antibody levels between the visits before and after receiving their RA diagnosis.

Additional analysis was done to further interrogate the connection between the two known autoantibodies associated with the development of RA, anti-CCP and RF, and the observed differences in IgA and IgG anti-Pc-p27 antibody levels between the RA groups. All RA participants who were positive for both autoantibodies had significantly higher IgA and IgG anti-Pc-p27 antibody levels compared to matched healthy participants in the control group. In addition, at-risk participants who were anti-CCP positive but RF negative had higher IgG anti-Pc-p27 antibody levels than those in the control group.

Taken together, the findings of this study extend the conclusions of previous studies associating immune activity against P. copri with the development of RA. Additional work is needed to understand how P. copri and other microorganisms may contribute to disease pathogenesis, which may ultimately lead to the development of novel interventions to prevent disease in individuals at risk of developing RA. A thorough understanding of the underlying mechanisms that lead to increased susceptibility to autoimmune diseases in women is a critical step in prevention.

References:

Seifert, JA et al. Association of Antibodies to Prevotella copri in Anti–Cyclic Citrullinated Peptide-Positive Individuals At Risk of Developing Rheumatoid Arthritis and in Patients With Early or Established Rheumatoid Arthritis. Arthritis & Rheumatology. DOI 10.1002/art.42370

NIH Trial Gives People with Lupus Data to Inform Treatment Decisions 

In people with a form of lupus called systemic lupus erythematosus (SLE), the risk for a severe flare-up of disease was low for both individuals who tapered off long-term immunosuppressive therapy and those who remained on it, a clinical trial has found. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, sponsored and funded the trial. The findings were reported today in the journal The Lancet Rheumatology.

SLE is a chronic autoimmune disease in which the immune system attacks healthy tissues and organs.  An estimated 450,000 people in the United States have the disease. Medications that doctors prescribe for people with SLE help suppress or tamp down their overactive immune systems. One of the most prescribed immunosuppressants for SLE, mycophenolate mofetil or MMF, effectively treats moderate and severe forms of the disease but also increases the risk of infections, cancers, severe birth defects, miscarriage, and impaired responses to vaccines when the drug is used long-term. Tapering off MMF once SLE symptoms subside reduces these side effects but could risk exposing the individual to a disease flare with the potential to cause a range of symptoms, including fatigue, rash, arthritis, and internal organ damage. 

Until today's report, little evidence existed to help people with SLE and their physicians understand the likelihood of a flare after tapering off MMF. The new findings will help people with SLE make informed decisions about withdrawing treatment based on their personal circumstances and risk tolerance. 

The NIAID-funded Autoimmunity Centers of Excellence network conducted the trial under the leadership of Judith A. James, M.D., Ph.D., and Eliza F. Chakravarty, M.D. Dr. James is professor and chair of the Arthritis & Clinical Immunology Research Program at the Oklahoma Medical Research Foundation. Dr. Chakravarty was an associate professor in the same program during the study. The National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of NIH, supports the database for the biological samples processed during the trial.

The trial involved 102 people with SLE ages 18 to 70 whose symptoms had subsided after treatment with MMF. Participants had been taking the drug for an average of 6.6 years. Eighty-four percent of participants were female, reflecting the disproportionate prevalence of lupus in women. Seventy-six percent of participants had a history of lupus nephritis—kidney inflammation that can harm kidney function. Forty-one percent of participants were Black, 40% were White, 21% were Hispanic/Latino, 10% were Asian, and 2% were American Indian/Alaska Native.

The study team assigned participants at random to either taper off MMF over a 12-week period or to remain on their baseline MMF dose. Investigators followed the participants for 60 weeks to monitor if and when they experienced a flare severe or persistent enough to require either new immunosuppressive therapy or higher doses of it. 

By week 60, 9 of 51 participants in the MMF withdrawal group and 5 of 49 in the MMF maintenance group had severe or persistent flares requiring new or increased immunosuppressive therapy. The estimated risk of such flares by week 60—a metric that reflected both occurrence and timing—was up to 18% in the withdrawal group and 11% in the maintenance group. The investigators also looked at five different measures of lupus flares and found that treatment withdrawal consistently led to a 6% to 8% increase in the risk for flares. For participants with a history of kidney disease, the increase in risk was higher, at 14%. One benefit of MMF withdrawal, however, was a reduction in infections. Forty-six percent of the withdrawal group had at least one infection compared with 64% of the maintenance group. 

This study is the first clinical trial of therapy withdrawal in people with SLE who no longer experience symptoms on long-term MMF, according to the researchers. Their findings suggest that MMF may be safely withdrawn in many people with stable SLE, they write, but larger studies and longer follow-up are still needed.

Reference: EF Chakravarty, et al. Mycophenolate mofetil withdrawal in systemic lupus erythematosus patients. The Lancet Rheumatology DOI: 10.1016/S2665-9913(23)00320-X (2024).

NIAID scientists and colleagues are one step closer to developing a safe and effective therapy against alphaviruses with the identification of SKT05, a monoclonal antibody (mAb) derived from macaques vaccinated with virus-like particles (VLPs) representing three encephalitic alphaviruses.

Spread by mosquitos, alphaviruses primarily affect people in one of two ways: causing severe neurological impairment such as encephalitis (brain swelling) or crippling muscle pain similar to arthritis. Western, eastern and Venezuelan equine encephalitis viruses (EEV) are examples of the former, while chikungunya and Ross River viruses are examples of the latter.

Building on studies from the past decade, scientists in NIAID’s Vaccine Research Center and colleagues knew that macaques produce dozens of different protective antibodies when experimentally vaccinated against the EEVs. In a new study published in Cell, the research team identified 109 mAbs in macaques immunized with the experimental western, eastern, and Venezuelan EEV VLP vaccine. All antibodies were individually tested for binding and neutralization against the three EEVs, with the best ones also assessed against arthritogenic alphaviruses not included in the vaccine. Collaborators included scientists from NIAID’s Laboratory of Viral Diseases, USAMRIID’s Virology Division, and Columbia University.

Their work identified SKT05 as the most broadly reactive antibody – remarkably, it also provided protection against both types of alphaviruses, those that cause encephalitis and those that cause arthritic-like disease. High-resolution structural studies further revealed that the way SKT05 binds to alphaviruses could make it resistant to surface changes that can occur in viruses – which means the mAb is likely to have lasting effectiveness.

Further studies are planned to investigate potential clinical development of SKT05. They aim to better define how SKT05 interacts with viruses and whether it can confer protective benefits against additional alphaviruses.

References:
M Sutton et al. Vaccine elicitation and structural basis for antibody protection against alphaviruses. Cell DOI: https://doi.org/10.1016/j.cell.2023.05.019 (2023).

EE Coates, et al. Safety and immunogenicity of a trivalent virus-like particle vaccine against western, eastern, and Venezuelan equine encephalitis viruses: a phase 1, open-label, dose-escalation, randomised clinical trial. Lancet Infectious Diseases (2022).

SY Ko, et al. A virus-like particle vaccine prevents equine encephalitis virus infection in nonhuman primates. Science Translational Medicine (2019).