Risk factors and comorbidity in primary Sjögren’s syndrome

Primary Sjögren’s syndrome is an autoimmune disease, in which the immune system targets the exocrine glands. The disease is characterized by inflammation and dysfunction of the salivary and lacrimal glands, leading to dry eyes and mouth.

The etiopathogenesis of autoimmune diseases is not entirely known. Genetic factors, primarily relating to the immune system, are central in the development of disease. In Sjögren’s syndrome, such genetic variations are associated with the production of autoantibodies to the Ro/SSA and La/SSB autoantigens and a more aggressive course of the disease. However, environmental factors are also involved in the development of autoimmunity. Viruses, smoking, alcohol and radiation include some of the more frequently proposed risk factors, although a causal relationship remains to be been proven.

To expand the current understanding of environmental risk factors, the relationship between exposure to infections and smoking and the development of Sjögren’s syndrome were investigated in Study I and Study II, respectively. A clear association between infections and subsequent development of Sjögren’s syndrome was observed, as a history of infections was significantly more prevalent in individuals with Sjögren’s syndrome compared to controls from the general population. Notably, this association was even more prominent in patients who developed Ro/SSA and La/SSB autoantibodies. Exposure to smoking could however not be linked to an increased risk of the disease, despite the wellknown association with development of other rheumatic diseases. Rather, we observed that individuals who developed Sjögren's syndrome were more prone to stop smoking during the decades preceding diagnosis. This finding may indicate that the appearance of very early symptoms of the disease leads to the discontinuation of smoking.

Sjögren’s syndrome is a systemic disease, and may cause adverse events in various organ systems. The risk of cardiovascular and hematological disease in patients with Sjögren’s syndrome was analyzed using the Swedish national health-care registers in Study III and Study IV, respectively. Compared to the general population, individuals with Sjögren’s syndrome had a significantly increased risk of myocardial infarction, cerebral infarction, and venous thromboembolism. Moreover, the results indicate that Ro/SSA and La/SSB autoantibodies demark the subgroup of patients with the highest risk of cardiovascular comorbidity. Similarly, an increased risk of multiple myeloma was observed in patients with Sjögren’s syndrome, which was confined to individuals with Ro/SSA and La/SSB autoantibodies.

Long-term outcomes for individuals with congenital heart block, which may develop in fetuses whose mothers carry Ro/SSA autoantibodies, were analyzed in Study V. The results indicate that these individuals have an increased risk of cardiovascular complications, and also illnesses related to infections and chronic inflammation, suggesting that a systematic follow-up would benefit these patients.

In conclusion, the findings indicate that infections contribute to the development of Sjögren’s syndrome. Furthermore, the presence or absence of Ro/SSA and La/SSB autoantibodies discriminate between two distinct patient subgroups, and is a useful parameter for predicting the risk of comorbidity. Lastly, the findings reveal the risk of longterm complications in patients with congenital heart block

List of scientific papers

I. Infections increase the risk of developing Sjögren's syndrome. Johannes Mofors, Elizabeth V. Arkema, Albin Björk, Linnea Westermark, Marika Kvarnström, Helena Forsblad-d’Elia, Sara Magnusson Bucher, Per Eriksson, Thomas Mandl, Gunnel Nordmark, Marie Wahren-Herlenius. J Intern Med. 2019 Jun;285(6):670-680.
https://doi.org/10.1111/joim.12888

II. Cigarette smoking patterns preceding primary Sjögren’s syndrome. Johannes Mofors*, Albin Björk*, Elina Richardsdotter Andersson, Marika Kvarnström, Helena Forsblad-d’Elia, Sara Magnusson Bucher, Leonid Padyukov, Ingrid Kockum, Jan Hillert, Per Eriksson, Thomas Mandl, Gunnel Nordmark, Lars Alfredsson, Marie Wahren-Herlenius. RMD Open. 2020 Sep;6(3):e001402.
https://doi.org/10.1136/rmdopen-2020-001402

III. Concomitant Ro/SSA and La/SSB antibodies are biomarkers for the risk of venous thromboembolism and cerebral infarction in primary Sjögren's syndrome. Johannes Mofors, Marie Holmqvist, Linnea Westermark, Albin Björk, Marika Kvarnström, Helena Forsblad-d’Elia, Sara Magnusson Bucher, Per Eriksson, Elke Theander, Thomas Mandl, Marie Wahren-Herlenius, Gunnel Nordmark. J Intern Med. 2019 Oct;286(4):458-468.
https://doi.org/10.1111/joim.12941

IV. Increased risk of multiple myeloma in primary Sjögren's syndrome is limited to individuals with Ro/SSA and La/SSB autoantibodies. Johannes Mofors, Albin Björk, Karin E. Smedby, Marika Kvarnström, Helena Forsblad-d’Elia, Sara Magnusson Bucher, Per Eriksson, Thomas Mandl, Eva Baecklund, Gunnel Nordmark, Marie Wahren-Herlenius. Ann Rheum Dis. 2020 Feb;79(2):307-308.
https://doi.org/10.1136/annrheumdis-2019-216287

V. Comorbidity and long-term outcome in patients with congenital heart block and their siblings exposed to Ro/SSA autoantibodies in utero. Johannes Mofors, Håkan Eliasson, Aurélie Ambrosi, Stina Salomonsson, Amanda Skog Andreasson, Michael Fored, Anders Ekbom, Gunnar Bergman, Sven-Erik Sonesson, Marie Wahren-Herlenius. Ann Rheum Dis. 2019 May;78(5):696-703.
https://doi.org/10.1136/annrheumdis-2018-214406