Younger age at Sjögren’s diagnosis tied to higher lung disease risk
'Dysregulated' immune state seen in patients diagnosed before age 45
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Among people with Sjögren’s disease, those diagnosed before age 45 may face an increased risk of unusually high antibody levels in the blood and chronic lung disease, according to a study of more than 5,000 patients in China.
Researchers linked these features to a distinct pattern of immune cells that suggests a more active and dysregulated immune response in early-diagnosed patients compared with those diagnosed later in life.
“These results highlight age-specific immune mechanisms and suggest the need for personalized monitoring and individualized immune regulation strategies in clinical management,” the researchers wrote.
The study, “Age-related clinical heterogeneity and peripheral T cell profile alterations in primary Sjögren’s disease: A retrospective study of 5778 patients,” was published in Rheumatology & Autoimmunity.
Investigating age at diagnosis vs. disease manifestations
Sjögren’s is caused by the abnormal production of self-reactive antibodies that mistakenly attack the body’s own tissues, primarily moisture-producing glands such as the salivary and tear glands. Beyond hallmark Sjögren’s symptoms of persistent dry mouth and dry eyes, the disease can also affect other organs and tissues, including the joints, skin, and lungs.
Research suggests that Sjögren’s is driven by an overactive immune system. In particular, self-reactive B-cells — the immune cells that produce antibodies — become abnormally activated with the help of T-cells, immune cells that help coordinate immune responses.
While previous studies have suggested that disease features may vary depending on age, the relationship between age, immune abnormalities, and disease manifestations has remained unclear.
Because symptoms often develop gradually and diagnosis can be delayed by several years, “age at diagnosis holds greater clinical relevance” than estimated age at symptom onset, the researchers wrote.
To investigate whether people diagnosed at different ages show distinct disease and immune profiles, a team of researchers retrospectively analyzed data from 5,778 people diagnosed with Sjögren’s at a single Chinese hospital between January 2018 and December 2022.
More than 90% of participants were women, and the median age at diagnosis was 55. They were divided into two groups based on age at diagnosis: early-diagnosed if they were diagnosed before age 45 (1,690 participants) and late-diagnosed if their diagnosis occurred at age 45 or older (4,088 participants).
ILD risk doubles for patients diagnosed before age 45
Compared with the late-diagnosed group, the early-diagnosed group was significantly less likely to have dry mouth (58.5% vs. 66.5%) and dry eyes (54.4% vs. 62.3%). Those diagnosed before age 45 also had significantly lower rates of several other disease manifestations, including interstitial lung disease (ILD), a fairly common complication of Sjögren’s that causes inflammation and scarring in the lungs. About 2% of early-diagnosed patients had ILD, while nearly 6% of the late-diagnosed group had the condition.
One notable exception was abnormalities affecting the blood, which were significantly more common among early-diagnosed participants, affecting 30.4% of this group and 27.3% of the late-diagnosed group.
Despite having fewer symptoms and disease manifestations overall, early-diagnosed participants showed stronger signs of immune system activation. They were significantly more likely to have high blood levels of antibodies, or hypergammaglobulinemia, seen in 56.4% of this group compared with 42.8% of the late-diagnosed group. Those diagnosed before age 45 were also more likely to have self-reactive antibodies commonly associated with Sjögren’s, including anti-Ro antibodies (88.9% vs. 69.5%), anti-La antibodies (49.2% vs. 29.3%), and rheumatoid factor (68.17% vs. 44.43%).
Statistical analyses adjusted for potential influencing factors showed that diagnosis before age 45 was independently associated with a higher risk of hypergammaglobulinemia (by nearly fourfold) and ILD (by about twofold). In contrast, early diagnosis was significantly linked to a 22% lower risk of blood-related abnormalities.
Because ILD was more common overall among late-diagnosed participants, the researchers noted that the condition may develop through different mechanisms in the two groups. In late-diagnosed individuals, ILD may be driven largely by aging and the cumulative effects of long-standing disease, whereas in early-diagnosed patients, it may be more closely tied to heightened immune activity.
Age at diagnosis can help guide Sjögren’s care
To better understand, the researchers analyzed immune cells in a subgroup of participants from both groups. Compared with late-diagnosed patients, early-diagnosed patients had significantly fewer helper T-cells, a subset that regulates the activity of other immune cells, and more cytotoxic T-cells, which can directly kill infected or abnormal cells. Among helper T-cells, those diagnosed before age 45 also had significantly more regulatory T-cells, which help keep immune responses in check.
The researchers said the combination of altered T-cell populations and elevated antibody levels points to a distinct and dysregulated immune state in younger patients. In particular, the increase in regulatory T-cells likely represents the body’s attempt to counter excessive immune activation.
However, if these cells do not function properly, they may be unable to effectively suppress autoimmune responses, allowing inflammation to persist and potentially contributing to both hypergammaglobulinemia and ILD seen in younger participants.
These findings point to early diagnosis as an independent driver of a distinct Sjögren’s subtype characterized by increased risk of hypergammaglobulinemia and ILD.
Age at diagnosis may serve “as a practical tool” for “an age‐guided management approach: for early-diagnosed patients, vigilance should focus on assessment of [body-wide] immune activity and ILD screening, whereas late-diagnosed patients may benefit from enhanced screening for cumulative [body-wide] involvement,” the researchers wrote. This approach “can optimize early detection, prevent irreversible organ damage, and support personalized management strategies in [Sjögren’s].”
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