Few ANA-positive, at-risk individuals progress to lupus beyond 1 year

By Jeff Evans

Progression to systemic lupus erythematosus (SLE) among individuals with antinuclear antibody (ANA) positivity appears mostly limited to the first year after presentation to primary care and referral to rheumatology for suspected autoimmune connective tissue disease (CTD), according to findings from a 3-year study of 148 people with ANA-positivity that was presented at the EULAR 2021 Virtual Congress.

But many individuals who did not develop SLE or another autoimmune CTD nevertheless had some baseline blood markers that were different from ANA-negative controls. That finding suggests that ANA positivity alone is insufficient to develop SLE among those at risk, or that some other mechanism may be keeping the illness in check, according to presenter and first author Sabih-Ul Hassan, MD, a clinical research fellow at the University of Leeds (England).

The team hopes to identify characteristics of patients who ultimately progress to SLE or other autoimmune CTDs. That information could help physicians to counsel patients on their risks, as well as guide patient follow-up. The group is now looking at developing a risk model that could incorporate patient demographics, symptoms, and biomarker data to guide clinicians. They are also continuing to investigate the immunology of these patients in hopes of understanding what mechanisms may be preventing the majority of ANA-positive individuals from going on to develop SLE or other autoimmune CTDs.

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Dr. Edward Vital
“It’s like the immune system remains on the edge of causing disease for years and years, but something keeps it there,” Edward Vital, MBChB, PhD, a lead investigator in the study and associate professor of medicine at the university, said in an interview.

The work extends a previous study in Annals of the Rheumatic Diseases in which 118 ANA-positive individuals were followed for a year to see how many developed SLE or another autoimmune CTD such as primary Sjögren’s syndrome (pSS), systemic sclerosis, or an idiopathic inflammatory myopathy. Family history combined with baseline interferon A and B scores could be used to distinguish those who progressed to SLE or pSS versus nonprogressors and healthy controls, despite having similar baseline clinical characteristics and ultrasound findings.

In the previous study, 19 (16%) individuals developed SLE (12%) or pSS (4%) by 1 year. The current work expands the number of participants, extends follow-up to 3 years, and looks at subjects in greater detail.

Over 3 years, the rate of progression increased to 20% of an expanded cohort of 148 patients, including 15% who developed SLE and 5% pSS. A total of 80% were nonprogressors, and 47% were absolute nonprogressors, meaning that they never developed any symptoms. That finding suggests that some individuals with ANA remain in a holding pattern, with altered immune systems but no signs of illness.

“The key differences to highlight in terms of demographics are a strong family history of autoimmune rheumatic disease in year 1 progressors [13 of 21; 62%] and those with undifferentiated CTD who were taking immunosuppressants [4 of 7; 57%],” Dr. Hassan said. There was also a lower percentage of women who were absolute nonprogressors (84%) vs. those in other outcome categories (range of 91%-100%).

In 2020, the team published an experimental immunology paper in Nature Communications that found these at-risk, nonprogressing, ANA-positive patients had dysregulated production of interferons. They also determined that plasmacytoid dendritic cells (pDC) are not a source of type 1 interferon in people with preclinical autoimmunity and SLE. The source of interferon production is rather nonhematopoietic cells in non-inflamed tissue in the skin.

The pDC cells are “completely exhausted, and that extends to all ANA-positive people, even the ones who don’t get lupus,” Dr. Vital said.

ANA positivity is quite common, affecting about 5% of adults, and the evidence suggests that these people have lost pDC cells. “They’re walking around with this very disturbed immune system. Obviously, it doesn’t appear to do them too much harm. Is there something keeping it in check and stopping it? That would be a very useful thing to understand to cure or prevent” progression, he said.

In the 3-year outcomes study, researchers used flow cytometry to measure baseline blood biomarkers among the 148 ANA-positive individuals, grouping them into progressors and nonprogressors over the ensuing follow-up period and comparing them with ANA-negative healthy controls. The progressors showed immunological differences from healthy controls, as would be expected, but nonprogressors also differed from healthy controls in interferon score A, percentage of CD4 T cells, percentage of naïve B cells, and percentage of memory B cells.

“One of the things that surprised us a bit is that people who never came anywhere near lupus [absolute nonprogressors] had quite a few abnormalities in their immune system as well. It wasn’t just ANA,” Dr. Vital said.

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The group that wasn’t categorized as progressors but nevertheless developed some symptoms also proved intriguing to the researchers. “They didn’t exactly have lupus, but they weren’t quite well. They’re an interesting group that we haven’t really accounted for before,” Dr. Vital said.

In particular, interferon score B was associated with SLE and progression at 1 year, but not in late progressors, and CD8 T cells were reduced to a similar extent in progressors and nonprogressors vs. healthy controls except that significantly lower levels were seen among absolute nonprogressors vs. healthy controls, Dr. Hassan said.

Patients’ immunophenotype at baseline was related to clinical progression when compared with healthy controls, except for late progressors. “In essence, other than late progressors, where there was no difference from healthy controls, all other groups showed a high B cell and CD4 T cell population, and a low monocyte and CD8 T cell population,” Dr. Hassan said.

“Despite this complexity, immune profiling may allow prediction of disease and preclinical intervention,” he said.

One of the things that surprised us a bit is that people who never came anywhere near lupus [absolute nonprogressors] had quite a few abnormalities in their immune system as well. It wasn’t just ANA.

In response to a question about how long clinicians should follow ANA-positive patients who are referred for possible autoimmune CTD, Dr. Hassan said at least 1 year of follow-up should be done, but perhaps even longer since some still progress beyond 1 year.

The researchers have not yet examined whether environmental triggers such as infections or UVB radiation exposure may lead to progression, he said.

The study’s patient population also may not necessarily reflect all ANA-positive patients who come to a primary care office since there is likely to be some selection bias toward patients who are likely to progress, he said.

Dr. Vital disclosed receiving a grant from AstraZeneca for related research. Dr. Hassan has no relevant financial disclosures.