IT IS NOT UNUSUAL for dry eye patients to have disease that extends beyond the ocular surface. An astute dry eye practitioner can not only assist in the diagnosis of systemic diseases such as rheumatoid arthritis, lupus, and Sjögren’s syndrome, but also warn patients with these conditions about any associated comorbidities. 

Primary Sjögren’s syndrome (pSS) is known to be associated with an increased risk of lymphoma, but its relationship with this and other pathologies is significant and extremely complex (Nocturne et al, 2021). The pathophysiology of pSS involves chronic antigenic stimulation of B cells, leading to autoimmune hyperactivity and lymphocyte infiltration and inflammation (Nocturne et al, 2021). The effects of this take place not only in exocrine glands like the lacrimal and salivary glands, but also in other systems, including the kidneys and lungs and the central nervous, gastrointestinal, and vascular systems (Zhong et al, 2022; Ramos-Casals et al, 2012). 

Notably, systemic manifestations of pSS are estimated to occur in 30% to 40% of patients (Pego-Reigosa et al, 2021), and a leading cause of death in pSS patients is organ-damaging vasculitis and cardiovascular disease (Ramos-Casals et al, 2012). Additionally, pSS may also be linked to increased risk of other cancers, particularly hematological and solid tumor cancers (i.e., thyroid, lung, kidney, liver, prostate, and others) (Pego-Reigosa et al, 2021; Zhong et al, 2022).

It is hypothesized that this chronic B cell overactivation may lead to B-cell malignancy and proliferation, and, in some cases, eventually to non-Hodgkin’s lymphoma (Nocturne et al, 2021). The risk of B-cell lymphoma is 2.7% to 9.8% (plus a 2.2% increase per year of age) in pSS patients and over four times higher than in the general population (Alunno et al, 2018).

While only a minority of pSS patients will develop lymphoma, there are some predictive factors. These include physical manifestations such as enlarged salivary or parotid glands, lymphadenopathy, skin purpura and Raynaud’s phenomenon, and laboratory findings including elevated anti-Ro/SSA and anti-La/SSB antibodies, rheumatoid factor, low complement C4 factor, and monoclonal proteins (Nocturne et al, 2021). The probability of lymphoma development is very low if the patient doesn’t have many of these factors but can be up to 100% if all the factors are present.

This evidence supports the need to aggressively screen dry eye patients for systemic autoimmune conditions like Sjögren’s syndrome. This should be done not only to find more effective treatment options that address the root causes of their dry eye, but also to diagnose and treat systemic concerns sooner and to alert the patient to future potential risks of other comorbidities.

Patients should be questioned about systemic symptoms and a basic lab workup can be ordered to help determine whether autoimmune disease is present. This panel should include testing for SSA, SSB, and antinuclear (ANA) antibodies, rheumatoid factors, and markers of very early pSS disease, such as salivary and parotid gland protein antibodies and carbonic anhydrase VI (Beckman et al, 2015).

Eyecare practitioners can often be the first to diagnose a patient’s autoimmune disease once their dry eye is fully investigated. When positive symptoms or testing results arise, prompt referral to (and ongoing comanagement with) rheumatology for further workup is a critical responsibility of the optometrist treating dry eye patients who have systemic disease.

References

1. Nocturne G, Pontarini E, Bombardieri M, et al. Lymphomas complicating primary Sjögren's syndrome: from autoimmunity to lymphoma. Rheumatology (Oxford). 2021 Aug 2;60:3513-3521.

2. Zhong H, Liu S, Wang Y, et al. Primary Sjögren's syndrome is associated with increased risk of malignancies besides lymphoma: A systematic review and meta-analysis. Autoimmun Rev. 2022 May;21:103084. 

3. Ramos-Casals M, Brito-Zerón P, Sisó-Almirall A, et al. Topical and systemic medications for the treatment of primary Sjögren's syndrome. Nat Rev Rheumatol. 2012 May 1;8:399-411. 

4. Pego-Reigosa JM, Restrepo Vélez J, Baldini C, et al. Comorbidities (excluding lymphoma) in Sjögren's syndrome. Rheumatology (Oxford). 2021 May 14;60:2075-2084.

5. Alunno A, Leone MC, Giacomelli R, et al. Lymphoma and Lymphomagenesis in Primary Sjögren's Syndrome. Front Med (Lausanne). 2018 Apr 13;5:102.

6. Seror R, Bowman SJ, Brito-Zeron P, et al. EULAR Sjögren's syndrome disease activity index (ESSDAI): a user guide. RMD Open. 2015 Feb 20;1:e000022. 

7. Beckman KA, Luchs J, Milner MS. Making the diagnosis of Sjögren's syndrome in patients with dry eye. Clin Ophthalmol. 2015 Dec 24;10:43-53.