Can Lupus Be Prevented? Research Reveals Clues to Who’s Most Likely to Transition to Classified Disease

ATLANTA—Is it possible to identify preclinical signs of systemic lupus erythematosus (SLE) very early and intervene to prevent a patient’s transition to active disease? Who is most at risk to develop lupus among blood relatives of people with the disease, and why?

To answer these questions, researchers study different patient subsets to identify the initial events that occur as at-risk individuals transition to active disease, said Judith A. James, MD, PhD, chair of arthritis and clinical immunology at the Oklahoma Medical Research Foundation, Oklahoma City. Dr. James delivered the 2019 Rheumatology Research Foundation Paul Klemperer, MD, Memorial Lecture, The Winding Road to Lupus at the 2019 ACR/ARP Annual Meeting.

From Health to Active SLE
How does a person transition from health to active lupus? A genetically predisposed individual may experience environmental insults, such as infection with the Epstein-Barr virus, to develop benign autoimmunity. Next, they may experience pathogenic autoimmunity with increased activation of T cells and B cells and increased cytokine production, followed by early symptom development and—finally—disease that meets classification criteria.¹

Judith A. James, MD, PhD

Researchers are searching for interventions that may eliminate lupus, said Dr. James. To reach that goal, “we have to better understand these early events and how we can stop the process before it’s too late. This will require better preclinical cohorts, better understanding of early pathogenesis and predictors of transition. We also need to understand mechanisms of non-transition, such as deciphering how the many people who are ANA [anti-nuclear antibody] positive may regulate their autoimmunity so that it doesn’t become clinical disease. Of course, the overall goal is prevention.”

To find clues, Dr. James’ laboratory has developed several patient cohorts, including one composed of 1,000 healthy individuals, with a subset of autoantibody-positive patients, and a collection of sera from the Oklahoma Blood Institute. Altogether, they have screened nearly 8,000 donors for autoantibody production and identified almost 200 individuals with significant titers of lupus-associated autoantibodies, such as anti-Ro, anti-La, anti-dsDNA and anti-Sm. The researchers also identified and studied cohorts of patients with incomplete lupus who did not advance to classified disease and first-degree relatives of people with SLE. Additionally, they conducted studies using the U.S. Department of Defense Serum Repository of more than 50 million serum samples from active-duty military personnel to identify people with SLE whose sera was stored before diagnosis.

We have to better understand these early events [of SLE] & how we can stop the process before it’s too late. —Judith A. James, MD, PhD

For a retrospective study published in 2007, researchers analyzed the sera and medical charts of 130 patients who met ACR classification criteria for SLE, finding that the early clinical features of lupus include arthritis, discoid lesions and lymphopenia, said Dr. James.²

“We found that associated autoantibodies, such as anti-dsDNA, occur before the onset of nephritis, anti-cardiolipins before thrombosis and rheumatoid factor before polyarthritis,” she said.

In a study using the military repository sera, researchers found different ethnic groups and genders progress to SLE differently. “African American men tend to have a very rapid clinical presentation, with many presenting with no prodrome at all—men who are just defined as healthy throughout their medical records, until they present at an intensive care unit with renal failure and major organ involvement,” Dr. James said. “Caucasian women tend to be more likely to sequentially add criteria slowly along the way.”³

The repository sera was used for another study that showed lupus patients with anti-cardiolipin antibodies early in their disease course tend to have more severe, varied outcomes.⁴

Pre-Classification Autoantibodies
Autoantibodies are present in approximately 88% of lupus patients’ blood years before diagnosis. Anti-Ro, anti-La and anti-cardiolipin tend to be present for 3.4 years or more before patients meet SLE classification criteria. Anti-Sm, anti-dsDNA and anti-C1Q, tend to occur within six to nine months of lupus classification.⁵

Interferon (IFN) activity occurs before SLE patients develop classified disease, said Dr. James. In a multi-center, collaborative study published in 2016, she and her fellow researchers analyzed active duty military personnel who had developed lupus, and tested interferon activity and several interferon-associated mediators. Then, they examined when these mediators occurred: either before or concurrent with autoantibody production or after disease onset. Several autoantibodies preceded interferon-alpha activity, which preceded classified SLE.⁶

“In these patients, anti-Ro was still one of the first autoantibodies we saw,” she said. “They developed a number of different autoantibodies before we saw increases in interferon activity. Anti-chromatin occurs early, but anti-dsDNA tends to occur very close to the same time that we see elevations in interferon activity.”

The number of interferon-related soluble mediators, including IP-10, BLyS and IFN-c, increased as patients moved toward lupus classification. When researchers matched SLE patients with healthy controls for age, gender and length of time in the military, so that samples would have been stored for the same length of time, “what we [saw was] not only an increase in interferon-associated molecules as they moved toward the time of diagnosis, but also an increase in the number of different inflammatory markers. But some are still present very early, like IL-6,” Dr. James said.

Soluble mediators may help differentiate who will transition to active lupus. Within 0.84 to 3.4 years before diagnosis, researchers identified soluble mediators, such as interleukin (IL) 4 and IL-5, that drive autoantibody development in preclinical lupus patients, along with interferons and IL-17. In one model, they found ANA, MIG, IFN-a and IP-10 may be predictors of lupus in that approximate three-to-one-year, pre-diagnosis window, while a model that did not incorporate ANA information showed IL-5, IL-6 and TGF-b as possible predictors.

In a review published in 2019, Dr. James’ laboratory collaborated with rheumatology researchers from the University of Colorado to compare elevations of soluble mediators that precede both clinical SLE and rheumatoid arthritis (RA) in patient cohorts from the U.S. military. Within one to two years before patients meet the classification criteria for RA, certain cytokines and chemokines, including IL-6, IFN-c and TNF-b, dramatically increase. In lupus, cytokines and chemokines elevate within the final year before classification, with BLyS ramping up very close to diagnosis, she said.⁷

Risk Influencers
Research teams are using very large patient cohorts, such as the Nurses’ Health Study I and II, and the Black Women’s Health Study, to identify epidemiological factors, including age at menarche, smoking status, obesity and alcohol use, that may influence lupus risk. Nurses’ Health Study data were used to show that moderate drinking is somewhat protective when it comes to lupus risk in women, and depression is associated with elevated SLE risk.^8,9

Relatives of SLE patients often ask Dr. James about their risk of developing lupus or other autoimmune diseases. She and her colleagues studied patients and first-degree relatives of people with SLE and RA in a study published in 2019.¹⁰ They examined serum samples from family members to look for disease-specific autoantibodies and tested samples for antibodies against thyroid disease, celiac disease and type-1 diabetes. The study grouped patients as having alternative autoantibodies if they had at least one autoantibody not associated with their relative’s autoimmune disease and having expanded autoimmunity if they had autoantibodies associated with two or more different diseases.

SLE patients’ relatives were more likely than RA patients’ relatives to have either alternative or expanded autoimmunity. Alternative autoimmunity was primarily systemic in the SLE cohort, while it was organ-specific in families of patients with type-1 diabetes. People in the RA cohort were more likely to have both systemic and organ-specific alternative autoimmunity, and they had mostly anti-TPO antibodies.

In a follow-up study, Dr. James and her collaborators studied blood samples from lupus patients’ relatives to look for factors that may indicate which autoantibody-positive relatives had the highest risk of transitioning to lupus. They identified 45 relatives of lupus patients from lupus genetics studies who had transitioned to having four or more ACR SLE classification criteria during a mean follow-up period of 6.4 years; 73.8% were European American, 14.7% were African American, 2.5% were Hispanic and 9% were from other ethnic backgrounds, including Native Americans. European Americans had the lowest transition rate, 0.81 transitions per 100 follow-up years, while African Americans had 1.45 transitions and Native Americans had 2.27 transitions.¹¹

“Women had a much higher rate of transition to lupus compared with their male family members,” said Dr. James. The study also examined how those who transitioned were related to the original lupus patient. “We thought this would be all sisters, but what we found was that there were transitions in all kinds of family members, including cousins, nieces and a few nephews of lupus patients too.”

Each person who transitioned to lupus had at least a positive ANA test and most also had either a clinical symptom or another autoantibody. Analysis of the transitioned patients’ baseline results on the Connective Tissue Disease Screening Questionnaire showed that individuals with higher scores were more likely to transition to lupus.

When they looked at soluble mediators, “we found altered cytokines … in first-degree blood relatives of lupus patients who transitioned. First-degree relatives who transitioned had higher levels of BLyS even at baseline compared with those who did not transition and with family members who were ANA negative and unaffected,” said Dr. James.

The researchers also found increased levels of TNF receptor 1, MCP-3 and stem cell factor in relatives who transitioned to SLE, but surprisingly low levels of regulatory cytokines, such as IL-10 and TGF-b.

Environmental Exposures
Epstein-Barr virus has interested lupus researchers as one early trigger of autoimmunity. In a 2019 paper, Dr. James and her colleagues recontacted 436 family members of SLE patients who did not have the disease at baseline to see if they had transitioned to classified disease within a 6.3-year follow-up period.¹²

Analyzing blood samples, researchers measured patients’ antibodies against Epstein-Barr viral capsid antigen and early antigen. They found transitioning patients had higher levels of anti-early antigen antibodies and serological evidence of Epstein-Barr virus reactivation. Their recent research also identified environmental factors that may increase family members’ transition risk, including vitamin D deficiency, especially if individuals also have risk alleles for a single-nucleotide polymorphism in the CYP24A1 allele, and sleeping less than seven hours per night.^13,14

Possible Protective Factors
Of women in the U.S., up to 30% will have a positive ANA test at some point, but few develop systemic autoimmune disease, Dr. James said. How are they able to escape the development of autoimmune disease?

Using the Oklahoma Immune Cohort of 789 individuals, she and her colleagues found 57 individuals who were ANA positive and had anti-dsDNA, anti-chromatin, anti-Ro, anti-La, anti-Sm and other lupus-associated autoantibodies. “We also looked at the racial composition of those individuals who were autoantibody-positive,” she said. “African Americans were on the lower end of positivity, with only 4.0% having one of these autoantibody specificities. Native Americans had the highest rate of autoantibodies and European Americans were in the middle. When we looked at multivariable logistic regression, only female sex was a significant, independent predictor.”¹⁵

They compared the immune system profiles of 31 European American, ANA-positive, healthy individuals with those of 31 patients with active SLE not on immunosuppressive therapy and 31 ANA-negative controls matched for age, sex, race and body mass index. They found the ANA-positive, healthy individuals had a unique serum cytokine profile: inflammatory cytokines similar to the lupus patients and levels of suppressive cytokines even lower than in ANA-negative individuals. BLyS levels were elevated in the lupus patients and lower in the healthy controls, but BLyS levels were even lower in the ANA-positive, healthy individuals.

“When we compared IL-1 receptor antagonist panels, one of our most striking findings was that ANA-negative, healthy individuals tended to have lower levels of IL-1RA, and lupus patients had levels in the middle, but ANA-positive, healthy individuals have really elevated levels,” she said. “This makes for an interesting pathway to consider and one that ANA-positive, healthy individuals may use to suppress the transition to full-blown disease.”

Could any autoantibodies protect ANA-positive individuals from transition to lupus? Recent research suggests anti-DFS70 antibodies, or dense-fine speckled autoantibodies that bind to the lens-epithelium-derived growth factor, a stress survival protein, protects the immune system from environmental stressors.¹⁶ In a 2018 study of sera from 1,758 individuals, researchers found anti-DFS70 autoantibodies were highly enriched in healthy people and are typically negatively associated with systemic autoimmune disease development, said Dr. James. ¹⁷

Is Hydroxychloroquine Protective?
Lupus researchers want to identify any potential early interventions that may prevent disease onset in at-risk individuals. When Dr. James’ team first analyzed the military repository cohort, they documented which individuals had ever received hydroxychloroquine or chloroquine before meeting ACR SLE classification criteria compared with those who had not received these anti-malarial drugs.

“If we looked at time to diagnosis, there was actually a time delay to developing lupus in the group who were treated with hydroxychloroquine compared with those who were not. At the time, I was a little concerned people were being put on hydroxychloroquine because they had lupus symptoms, but some were put on chloroquine because of where they were deployed. We went back and looked at accrual of autoantibodies between those two groups,” said Dr. James.

Accrual of autoantibodies was lower, and then plateaued, in individuals who had received hydroxychloroquine compared with those who did not take the drug. Hydroxychloroquine treatment prior to SLE diagnosis was also associated with a longer mean time between first clinical symptom onset and diagnosis.¹⁸

These findings contributed to the development of the first lupus prevention trial, the Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE). This multi-center, randomized, placebo-controlled, double-blind, parallel group, 36-month clinical trial will evaluate the efficacy and safety of hydroxychloroquine intervention to prevent autoantibody accrual and future onset of clinically apparent SLE. SMILE will enroll 120 patients who are ANA positive and have at least one clinical lupus criterion, testing whether a high-risk soluble mediator score, genetic risk score or some combination best predicts who will transition to lupus. SMILE is now recruiting patients.

“We are testing whether we can slow progression to lupus, or if we can decrease the number of autoantibodies. We’re also testing some of these high-risk soluble mediator scores identified in other cohorts to see if we can identify who will or won’t transition, and we’re looking at the total genetic load using data from recent trials,” said Dr. James.

Clinical rheumatologists who receive questions about lupus risk from family members should stress that most relatives will not transition to disease. “If you have family members who are really stressed about whether they will develop lupus, or if they have a positive ANA or some clinical feature, we can share lifestyle choices that may help them, based on data that these may be associated with lupus transition and are good ideas for your health anyway,” such as quitting smoking, getting adequate sleep, ensuring adequate vitamin D levels and maintaining ideal body weight, she concluded.

Susan Bernstein is a freelance journalist based in Atlanta.

References

1. Harley JB, James JA. Epstein-Barr virus infection induces lupus autoimmunity. Bull NYU Hosp Jt Dis. 2006;64(1–2):45–50.
2. Heinlen LD, McClain MT, Merrill J, et al. Clinical criteria for systemic lupus erythematosus precede diagnosis and associated autoantibodies are present before clinical symptoms. Arthritis Rheum. 2007 Jul;56(7):2344–2351.
3. Arbuckle MR, James JA, Dennis GJ, et al. Rapid clinical progression to diagnosis among African-American men with systemic lupus erythematosus. Lupus. 2003;12(2):99–105.
4. McClain MT, Arbuckle MR, Heinlen LD, et al. The prevalence, onset and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematosus. Arthritis Rheum. 2004 Apr;50(4):1226–1232.
5. Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. New Engl J Med. 2003 Oct 16;349:1526–1533.
6. Munroe ME, Lu R, Zhao YD, et al. Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification. Ann Rheum Dis. 2016 Nov;75(11):2014–2021.
7. Slight-Webb S, Bourn RL, Holers VM, et al. Shared and unique immune alterations in pre-clinical autoimmunity. Curr Opin Immunol. 2019 Dec;61:60–68.
8. Barbhaiya M, Lu B, Sparks JA, et al. Influence of alcohol consumption on the risk of systemic lupus erythematosus among women in the Nurses’ Health Study cohorts. Arthritis Care Res (Hoboken). 2017 Mar;69(3):384–392.
9. Roberts AL, Kubzansky LD, Malspeis S, et al. Association of depression with risk of incident systemic lupus erythematosus in women assessed across two decades. JAMA Psychiatry. 2018 Dec 1;75(12):1225–1233.
10. James JA, Chen H, Young KA, et al. Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients. EBioMedicine. 2019 Apr;42:76–85.
11. Munroe ME, Young KA, Kamen DL, et al. Soluble mediators and clinical features discern risk of transitioning to classified disease in relatives of systemic lupus erythematosus patients. Arthritis Rheumatol. 2017 Mar;69(3):630–643.
12. Jog NR, Young KA, Munroe ME, et al. Association of Epstein-Barr virus serological reactivation with transitioning to systemic lupus erythematosus in at-risk individuals. Ann Rheum Dis. 2019 Sep;78(9):1235–1241.
13. Young KA, Munroe ME, Guthridge JM, et al. Combined role of vitamin D status and CYP24A1 in the transition to systemic lupus erythematosus. Ann Rheum Dis. 2017 Jan;76(1):153–158.
14. Young KA, Munroe ME, Harley JB, et al. Less than seven hours of sleep per night is associated with transitioning to systemic lupus erythematosus. Lupus. 2018 Aug;27(9):1524–1531.
15. Slight-Webb S, Lu R, Rittenhouse LL, et al. Autoantibody-positive healthy individuals display unique immune profiles that may regulate autoimmunity. Arthritis Rheumatol. 2016 Oct;68(10):2492–2502.
16. Ochs RL, Mahler M, Basu A, et al. The significance of autoantibodies to DFS70/LEDGFp75 in health and disease: Integrating basic science with clinical understanding. Clin Exp Med. 2016 Aug;16(3):273–293.
17. Carter JB, Carter S, Saschenbrecker S, et al. Recognition and relevance of anti-DFS70 autoantibodies in routine antinuclear autoantibodies testing at a community hospital. Front Med (Lausanne). 2018 Apr 9;5:88.
18. James JA, Kim-Howard XR, Bruner BF, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus. 2007;16(6):401–409.