Mortality in Sjögren’s patients
A 2015 study by Soledad Retamozo et al. showed that the presence of cryoglobulinemic vasculitis (CV) at diagnosis is associated with increased mortality risk.
Of 515 consecutive pSS patients with a mean follow-up of 110 months, 65 (12%) had cryoglobulins detected, and 21 of those (32%) fulfilled CV criteria. The patients with cryoglobulins had higher cumulative mean disease activity, 45 (9%) developed B-cell lymphoma, and 33 (6%) died (Arthritis Rheumatol. 2015;67[suppl 10]. Abstract 628).
Additionally, both CV-positive and CV-negative patients had higher risk of B-cell lymphoma, but the risk was greatest in the CV-positive group (hazard ratios, 7.47 and 2.56, respectively), and the CV-positive patients had a higher risk of death (HR, 11.68).
“This actually has changed practice in our Sjögren’s clinic because we didn’t used to do cryos on everybody unless they had leukocytoclastic vasculitis, because they also have a higher risk of death,” Dr. James said.
Systemic activity also predicts pSS mortality, according to findings published in 2016 by Pilar Brito-Zerón et al. Of 1,045 patients who were part of the Spanish Group of Autoimmune Disease-SS Study Group and who were followed for a mean of 117 months, mortality was 11%. Survival was 96% at 5 years, 90% at 10 years, 81% at 20 years, and 60% at 30 years (Ann Rheum Dis. 2016;75:348-55).
Baseline factors associated with increased mortality on multivariate analysis included male gender, cryoglobulins, and low complement levels; the strongest model for death included high activity in at least one ESSDAI domain, baseline ESSDAI of at least 14, more than one laboratory predictive marker such as lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4, and/or cryoglobulins.
Predicting progression to pSS
Progress has also been made with respect to predicting progression to pSS among patients who present with some related symptoms but don’t meet Sjögren’s criteria, Dr. James noted.
A 2017 study by Caroline Shiboski et al. looked at 771 patients from the Sjögren’s International Collaborative Clinical Alliance (SICCA) registry who had previously had objective measures of salivary hypofunction, dry eyes, focal lymphocytic sialadenitis or anti-Ro/anti-La. When these patients were recalled 2-3 years after their baseline evaluation, 28 (9%) of 308 patients who did not meet pSS criteria at baseline had then progressed to pSS (Arthritis Care Res. 2017;70[2]:284-94).
Those with baseline hypergammaglobulinemia were four times more likely to progress, and those with baseline low complement levels were six times more likely to progress.
Many patients will present with symptoms, but won’t ever develop Sjögren’s, but the subset of patients with these baseline characteristics may be at greater risk, she said.
Autoantibodies and pathogenesis
Up to 90% of pSS patients will have one or more of anti-Ro, anti-La, or rheumatoid factor, and many will have a positive antinuclear antibody (ANA) level of at least 1:320, Dr. James said, adding that anti-Ro and anti-La are linked with earlier disease onset, increased disease severity, longer disease duration, and extraglandular involvement.
Ro52, a target of Sjögren’s autoantibodies, may also confer more severe disease, and autoantibodies to muscarinic acetylcholine receptors appear to contribute to pathogenesis in Sjögren’s patients “above and beyond what we see with lymphocytic infiltrates and other things that are happening in the salivary gland,” she said.
Other exciting progress with respect to disease pathogenesis includes an increased focus on genetics and genetic predisposition beyond human leukocyte antigen associations.
Mutations in genes that overlap with Sjögren’s and lupus or Sjögren’s and RA, such as IRF5, Blk, and STAT4 appear to contribute to Sjögren’s syndrome development.
“And then there’s also some new genetics looking at Sjögren’s-specific genes, and these may help us as we think about new targetable pathways in this disorder,” she said.
Genomics and gene-environment interactions, such as interactions with viral infections or “other things that lead to molecular mimicry that get the disease process started,” are also getting increased attention; gene-expression profiling has shown overlap between Sjögren’s and lupus (shared genetics, autoantibodies, and similarly strong interferon signatures, for example), which isn’t surprising.
“But we’re also seeing NF-kB [NF-kappa B] activation, antigen presentation, and migration pathways that are being found in Sjögren’s that aren’t necessarily the ones that we see in lupus,” she added.