Sjögren’s syndrome: when dry eye is an autoimmune disease

Most cases of dry eye stem from the environment, screens, age or the eyelids. A minority stem from a systemic disease that attacks the lacrimal and salivary glands. The distinction is not academic: it changes the monitoring, the corneal risk, and it leads to a work-up that the ophthalmologist cannot complete alone.

UNDERSTANDING

At what point should dry eye prompt a search for something else?

When it no longer looks like ordinary dry eye. Three features raise the question: established dryness that does not respond to a properly conducted course of artificial tears, objective signs out of proportion to the complaint, and above all accompanying dryness of the mouth. In an American centre specialising in dry eye, 24 out of 220 patients (10.9%) had primary Sjögren’s syndrome, and only 8 of them had already been diagnosed when they arrived.

This proportion can be read both ways. Nine in ten patients in this cohort did not have Sjögren’s, and investigation most often starts with the common causes: meibomian gland dysfunction, prolonged exposure to screens, systemic medication with a drying effect, hormonal factors. But this figure comes from a specialist centre, not the general population, and one patient in four there had an underlying rheumatic disease, nearly half of whom had Sjögren’s.

Sjögren’s syndrome is an autoimmune disease in which lymphocytes infiltrate the exocrine glands, first and foremost the lacrimal and salivary glands, to the point of lastingly reducing their output. It exists in an isolated form, known as primary, and in a form associated with another connective tissue disease — rheumatoid arthritis, lupus, scleroderma — with the phenotype varying according to geographical origin. It affects women in the vast majority of cases — around ten women for every man according to a meta-analysis of 21 studies, in which the mean age of patients was 56 — but the disease can first show itself through any of its facets: each specialist sees one piece of the picture, and no single piece establishes the diagnosis on its own.

MOUTH

Why a dry mouth matters as much as the eye

Because it is what tips the interpretation of the case. Isolated dry eye is commonplace; dry eye combined with a daily feeling of dry mouth for more than three months — one of the entry questions of the classification criteria — justifies, in routine practice, considering an immunological work-up. In the survey of 255 members of a Japanese patients’ association, the presence of dry mouth was associated with a faster diagnosis, with an adjusted odds ratio of 0.55, at the limit of statistical significance, for a diagnosis made after one year or more, whereas having only eye symptoms was associated with this same outcome with an adjusted odds ratio of 2.69.

The useful questions are concrete. Do you need to drink to swallow dry food? Do you wake up at night to drink? Have you developed multiple cavities even though your dental hygiene has not changed? In practice, these three signs are more telling than a general impression of a dry, sticky mouth; the first is one of the entry questions of the classification criteria. A five-item screening questionnaire has been developed from the international SICCA cohort, but its performance remains modest — area under the curve of 0.65 — which rules out using it to settle the question.

It is also important to hear what patients report. An Irish survey, offered to participants in a webinar designed with people who have the disease, shows that the symptom burden extends well beyond dryness: 57% of respondents reported fatigue and 54% joint pain. A patient who describes crushing fatigue alongside their dry eyes is not complaining about something beside the point: they are describing the disease.

TIME TO DIAGNOSIS

How long does it take to reach the diagnosis?

Years, and the figure is documented: in the Japanese survey already cited, the mean time to diagnosis was 3.47 years. The difficulty lies in the very structure of the disease, whose manifestations are spread across several specialties that do not always talk to each other.

The most instructive detail of this survey concerns ophthalmology. Seeing an ophthalmologist first was associated with a delayed diagnosis, with an adjusted odds ratio of 2.63, just as a first consultation in internal medicine was. The patient had indeed gone to see a doctor, and that doctor could be the ophthalmologist. The breaking point is therefore not access to care: it is the moment when the ophthalmologist stops at symptomatic treatment of the ocular surface without asking about the mouth.

Other points of entry sometimes precede the diagnosis by several years. A meta-analysis of 49 studies estimates the prevalence of peripheral neuropathy in primary Sjögren’s syndrome at 15.0%, and notes that, in patients with neuropathy, neurological symptoms precede or reveal the diagnosis in a ratio of two to one. On the lung side, interstitial lung disease affects around 20% of patients according to most studies, and depending on the series 10 to 51% of patients develop it years before the onset of Sjögren’s. These figures explain why patients so often feel they have told their story in pieces to several different people.

EXAMINATION

What the ophthalmologist sees and you do not feel

A gap between what you describe and what the slit lamp shows. This is the most useful finding of the international SICCA cohort, which compared 3,380 participants, 1,532 of whom were classified as having Sjögren’s syndrome. Symptom scores did not differ to a clinically relevant degree between the two groups. By contrast, the ocular surface staining score was 3.47 points higher in patients with the disease, with more corneal abnormalities, a shorter tear film break-up time and a Schirmer test that was more often abnormal.

Three simple measurements structure this examination. The tear film break-up time measures, in seconds, how long the film stays uniform after a blink: it assesses stability, not quantity. The Schirmer test measures aqueous tear production with a paper strip placed for five minutes in the conjunctival fornix; 5 mm or less is considered abnormal. The ocular surface staining score quantifies, after fluorescein and lissamine green, the points where the epithelium is damaged.

This third examination is the most demanding, and taken on its own it remains imperfect. A study of 994 participants measured its performance and reproducibility: at a threshold of 5, its sensitivity was 56% and its specificity 75%; agreement between scores from one examiner to another was very low, and among 20 subjects re-examined after a median interval of 5.5 years, 35% had changed status on the ocular criterion. The authors estimate that this variability could alter the classification of 5 to 10% of patients, around 1 to 3% with the 2016 ACR/EULAR criteria, in which this score counts for only one point. A borderline score read on a given day is therefore not a verdict: it needs to be rechecked, ideally by the same examiner.

In vivo confocal microscopy adds a further level by visualising the sub-basal nerve plexus of the cornea, whose involvement has been studied in 71 patients with Sjögren’s syndrome, 19 of them with small fibre neuropathy. This examination remains the preserve of specialist centres.

CRITERIA

How is the diagnosis actually made?

Through a body of weighted evidence, never through a single test. The classification criteria established jointly by the American College of Rheumatology and EULAR in 2016 rest on five weighted items. Positive anti-SSA/Ro antibodies and the presence of focal lymphocytic sialadenitis on minor salivary gland biopsy, with a focus score of at least 1 per 4 mm², are worth 3 points each. An ocular staining score of at least 5, a Schirmer test of 5 mm or less in five minutes and an unstimulated salivary flow of 0.1 ml per minute or less are worth 1 point each. A total of at least 4 points in a patient with suggestive signs meets the criteria, with a sensitivity of 96% and a specificity of 95% in the validation cohort.

Two practical consequences follow. The first: the ophthalmologist provides at most 2 of the 9 possible points. They therefore cannot make the diagnosis alone, nor can they rule it out alone. Their role is to produce reliable measurements, to record them, and to refer to a rheumatologist or an internist who will gather the rest.

The second: these criteria were built to select patients for clinical trials, not to settle an individual case. A patient who does not reach 4 points is not thereby in the clear: they may be early in the course of the disease, or have a seronegative form. This is a nuance that is often missing from reports, and the one that sends home a patient who should have been seen again, in routine practice within the year.

CORNEA

What is the real risk to the cornea?

It is uncommon but serious, and it has been quantified by hospital series. A series of 919 patients, or 1,838 eyes, seen in an eye care network in India, 69% of them with a secondary form, found severe visual impairment (corrected visual acuity below 20/200) in 10% of eyes, and a vision-threatening corneal complication, ulceration or perforation, in 2.5% of eyes as early as the first consultation. The factors associated with visual impairment were corneal scarring, ulceration, a low Schirmer score, cataract and glaucoma; the risk of corneal complication was higher in the presence of scleritis and of a secondary form.

A second series, of 46 ulcerated or perforated eyes, sharpens the picture. These ulcers were peripheral in 63% of cases, sterile in 38 of the 46 eyes (but infected in the other 8), and they were the first presenting sign of Sjögren’s syndrome in 26% of these patients. Healing took 49 days on average, at the cost of bandage contact lenses, cyanoacrylate glue, amniotic membrane grafts and, in a few cases, a corneal transplant (keratoplasty).

The disease can also affect the eye in other ways (uveitis, scleritis, retinal vasculitis, optic neuritis) and, with the exception of optic neuritis, which is scored under the neurological domain, none of them is taken into account in the ESSDAI activity index used in rheumatology. This is a documented blind spot in follow-up. What I take from it for the consultation: monitoring is not judged on the patient’s comfort, but on the state of the corneal epithelium, which can deteriorate in someone who is not complaining any more than before, since corneal sensitivity, which ought to raise the alarm, is itself reduced in Sjögren’s.

TREATMENTS

What is done beyond artificial tears?

Inflammation is treated, the tears that are produced are retained, and what the glands no longer supply is replaced. Artificial tears remain the foundation, but they relieve without altering the course of the disease, and a recent mechanism-based review points out their limited effect on the stability of the tear film itself. On eyelid hygiene and the choice of substitutes, our dedicated article on dry eye sets out an approach that is no different in Sjögren’s.

Among topical anti-inflammatory agents, ciclosporin eye drops improve mainly the signs on the ocular surface, with a less consistent effect on symptoms. A study comparing the 0.05% and 0.1% concentrations in 60 patients with Sjögren’s syndrome found improvement in both groups, with an advantage for the 0.1% concentration on inflammatory markers and goblet cell density, but markedly poorer tolerability, with 26.7% of patients stopping treatment versus 3.3%. This work is retrospective: it points the way, it does not prove.

Punctal plugs, which block the lacrimal puncta (the tear drainage openings), hold a particular place. The same review concludes that they improve tear retention but that their effectiveness varies from one study to another. This is a procedure whose clinical use outstrips the level of evidence: the Cochrane review of 18 trials (711 participants) judges the improvement in symptoms and signs inconclusive, and reports fairly frequent adverse effects (watering, itching, eyelid tenderness and swelling with discharge, displacement of the plug), and more rarely inflammation of the tear drainage system. In practice, they are offered once the inflammation is under control, in addition to its treatment and not in place of it.

A final word on corneal refractive surgery. Dryness of autoimmune origin is not favourable ground for LASIK or PRK, and post-operative dryness is covered separately in our article on dry eye after LASIK. The decision is made case by case, but a known, active Sjögren’s syndrome most often leads to the procedure being ruled out.

SERUM

Does autologous serum live up to its promise?

The clinical results are encouraging, the overall level of evidence remains modest, and both statements are true at the same time. Autologous serum involves preparing eye drops from the patient’s own blood, diluted and then packaged in frozen vials: it provides growth factors that artificial tears do not contain.

The Cochrane review on the subject included five randomised trials, totalling 92 participants with dry eye of various causes (Sjögren’s, other causes, after LASIK), with a level of certainty judged low to very low. It concludes that there may be a symptomatic benefit over artificial tears in the short term, with no evidence of an effect maintained beyond two weeks, and calls for larger trials. That is not much, for a widely used treatment.

A recent, very small trial is more favourable. A randomised, double-blind trial using each patient as their own control (one eye treated with 50% autologous serum, the other with artificial tears, in 10 patients with a severe form) shows, at three months, an improvement in break-up time, the Schirmer test, visual acuity and the corneal nerves on confocal microscopy. The same work found Gram-negative bacteria in the vials after use, which calls for strict storage rules.

Platelet-rich plasma was compared with autologous serum in a randomised trial of 38 patients with primary Sjögren’s syndrome. Corneal and conjunctival staining scores and break-up time improved in both arms at 4 and 12 weeks, with no difference between them; neither the Schirmer test nor the symptom score changed significantly. This last point deserves to be said to the patient before starting: these eye drops act first on the state of the surface, and the improvement the patient feels does not always follow.

THE DISEASE

Is there a treatment for the disease itself?

No authorised disease-modifying treatment yet, but trials that are moving forward, and one instructive counter-example. Rituximab, long hoped for, was the subject of a randomised placebo-controlled trial in 133 patients with fatigue and dry mouth. The response rate was 39.8% on rituximab versus 36.8% on placebo, with an adjusted odds ratio of 1.13 whose confidence interval included 1: the authors conclude that there was no clinical effectiveness and no cost-effectiveness.

More recent molecules are more promising. Ianalumab, directed against the BAFF receptor, showed in a phase 2b study of 190 patients an efficacy maintained at 52 weeks for the 300 mg dose, with tolerability judged favourable through two years of follow-up. Dazodalibep, which blocks the CD40 ligand, met both of its primary endpoints in a phase 2 placebo-controlled trial. None of this is prescribed routinely, and none of it falls to the ophthalmologist: these treatments are discussed in rheumatology or internal medicine, in patients whose systemic involvement justifies it, with the 2020 European recommendations framing the use of topical and systemic treatments, on levels of evidence that are most often modest.

FOLLOW-UP

What does the diagnosis actually change?

It changes the monitoring, the intensity of local treatment and the general follow-up, not immediately the comfort. This is a frequent disappointment, and it is better to say so in advance: putting a name on the disease does not make the dryness go away.

What the diagnosis brings lies elsewhere. The frequency of ophthalmological monitoring increases, with attention paid to the corneal epithelium rather than to the complaint alone. The threshold for using a topical anti-inflammatory is lowered. Systemic involvement (lung, kidney, nervous system) is actively looked for instead of being waited for. And the patient stops being an isolated attender in several different departments.

If the rheumatologist prescribes hydroxychloroquine, retinal monitoring is added. The recommendations of the American Academy of Ophthalmology (Marmor 2016) provide for a baseline examination within the first year of treatment, then annual screening from the fifth year onwards, earlier in the presence of a risk factor: a dose above 5 mg per kilogram per day, reduced kidney function, tamoxifen use. This screening relies on automated visual field testing and an OCT scan of the macula, not on fundus examination alone, because retinal toxicity is irreversible but detectable before any loss of vision.

Follow-up of severe dry eye requires regular assessment: break-up time, surface staining, and a check for filamentary keratitis or peripheral thinning. You can consult the ophthalmology practice for an ocular surface assessment; confirming the diagnosis and the overall management fall to the rheumatologist or the internist.

Some signs do not wait for the next check-up. In routine practice, unusual eye pain, a drop in vision or a red eye with discomfort in the light require seeing an ophthalmologist the same day or, failing that, an ophthalmic emergency department: they may indicate keratitis or a corneal ulcer, and in a series of 46 ulcerated or perforated eyes, 8 were infected. Likewise, persistent swelling of a salivary gland, in particular a parotid gland, should be reported to the rheumatologist without delay: primary Sjögren’s carries an increased risk of non-Hodgkin lymphoma, with a standardised incidence ratio of 8.78 in a meta-analysis of 15 cohort studies, and parotid swelling is among the most consistent predictors of lymphoma.

A degree of uncertainty remains to be accepted: no available test perfectly identifies the patients concerned, the reproducibility of ocular scores is imperfect and disease-modifying treatments are still under evaluation. Asking the question earlier remains what the literature supports best.

Frequently asked questions

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Scientific sources

• Beydon M, McCoy S, Nguyen Y, et al. Epidemiology of Sjögren syndrome. Nat Rev Rheumatol. 2024;20(3):158-169. PMID 38110617
• Akpek EK, Bunya VY, Saldanha IJ. Sjögren’s Syndrome: More Than Just Dry Eye. Cornea. 2019;38(5):658-661. PMID 30681523
• Komori K, Komori M, Horino T, et al. Factors associated with delayed diagnosis of Sjögren’s syndrome among members of the Japanese Sjögren’s Association for Patients. Clin Exp Rheumatol. 2021;39 Suppl 133(6):146-152. PMID 33822710
• Shiboski CH, Shiboski SC, Seror R, et al. 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren’s Syndrome. Arthritis Rheumatol. 2017;69(1):35-45. PMID 27785888
• Xiong F, Pula D, Akpek EK, et al. Sjögren’s Versus Non-Sjögren’s Ocular Features: Similar Symptoms, But Significantly Worse Signs. Invest Ophthalmol Vis Sci. 2024;65(1):23. PMID 38193760
• Rasmussen A, Stone DU, Kaufman CE, et al. Reproducibility of Ocular Surface Staining in the Assessment of Sjögren Syndrome-Related Keratoconjunctivitis Sicca. ACR Open Rheumatol. 2019;1(5):292-302. PMID 31453437
• Singh S, Das AV, Basu S. Ocular Involvement in Sjögren Syndrome: Risk Factors for Severe Visual Impairment and Vision-Threatening Corneal Complications. Am J Ophthalmol. 2021;225:11-17. PMID 33385368
• Singh S, Chaudhary S, Das AV, Basu S. Presentation, aetiology and outcomes of corneal ulceration in Sjogren’s Syndrome. Eye (Lond). 2023;37(15):3217-3220. PMID 36944710
• Betz J, Galor A. Navigating the Dry Eye Therapeutic Puzzle: A Mechanism-Based Overview of Current Treatments. Pharmaceuticals (Basel). 2025;18(7):994. PMID 40732283
• Jee D, Han SY, Kim HS, Kim EC. Comparison of effects of cyclosporine 0.05% and 0.1% in dry eye with Sjögren’s syndrome. BMC Ophthalmol. 2025;25(1):369. PMID 40597071
• Pan Q, Angelina A, Marrone M, Stark WJ, Akpek EK. Autologous serum eye drops for dry eye. Cochrane Database Syst Rev. 2017;2(2):CD009327. PMID 28245347
• Bachtalia K, Plakitsi A, Voudouri A, et al. The Effect of Autologous Serum Tears 50% on the Ocular Surface of Patients With Severe Dry Eye Disease due to Sjogren Syndrome. Cornea. 2025;44(7):856-865. PMID 39808128
• Kang MJ, Lee JH, Hwang J, Chung SH. Efficacy and safety of platelet-rich plasma and autologous-serum eye drops for dry eye in primary Sjögren’s syndrome: a randomized trial. Sci Rep. 2023;13(1):19279. PMID 37935760
• Bowman SJ, Everett CC, O’Dwyer JL, et al. Randomized Controlled Trial of Rituximab and Cost-Effectiveness Analysis in Treating Fatigue and Oral Dryness in Primary Sjögren’s Syndrome. Arthritis Rheumatol. 2017;69(7):1440-1450. PMID 28296257
• Dörner T, Bowman SJ, Fox R, et al. Safety and Efficacy of Ianalumab in Patients With Sjögren’s Disease: 52-Week Results From a Randomized, Placebo-Controlled, Phase 2b Dose-Ranging Study. Arthritis Rheumatol. 2025;77(5):560-570. PMID 39557617
• St Clair EW, Baer AN, Ng WF, et al. CD40 ligand antagonist dazodalibep in Sjögren’s disease: a randomized, double-blinded, placebo-controlled, phase 2 trial. Nat Med. 2024;30(6):1583-1592. PMID 38839899
• Liampas A, Parperis K, Erotocritou MF, et al. Primary Sjögren syndrome-related peripheral neuropathy: A systematic review and meta-analysis. Eur J Neurol. 2023;30(1):255-265. PMID 36086910
• Luppi F, Sebastiani M, Silva M, et al. Interstitial lung disease in Sjögren’s syndrome: a clinical review. Clin Exp Rheumatol. 2020;38 Suppl 126(4):291-300. PMID 33095142
• Luzu J, Labbé A, Réaux-Le Goazigo A, et al. In vivo confocal microscopic study of corneal innervation in Sjögren’s Syndrome with or without small fiber neuropathy. Ocul Surf. 2022;25:155-162. PMID 35872076
• Yu K, Ying GS, Vivino FB, et al. Preliminary Screening Questionnaire for Sjögren’s Syndrome in the Rheumatology Setting. J Clin Rheumatol. 2022;28(2):e456-e461. PMID 34262002
• Greenan E, Tynan G, Collins D, et al. Beyond dry eye: The greater extent of Sjögren’s systemic disease symptoms, the impact of COVID-19 and perceptions towards telemedicine identified through a patient co-designed study. Health Expect. 2023;26(6):2252-2263. PMID 37470291
• Ramos-Casals M, Brito-Zerón P, Seror R, et al. Characterization of systemic disease in primary Sjögren’s syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal involvements. Rheumatology (Oxford). 2015;54(12):2230-2238. PMID 26231345
• Akpek EK, Klimava A, Thorne JE, et al. Evaluation of patients with dry eye for presence of underlying Sjögren syndrome. Cornea. 2009;28(5):493-497. PMID 19421051
• Qin B, Wang J, Yang Z, et al. Epidemiology of primary Sjögren’s syndrome: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74(11):1983-1989. PMID 24938285
• Ansari N, Salesi M. The association between primary Sjogren’s syndrome and non-Hodgkin’s lymphoma: a systematic review and meta-analysis of cohort studies. Clin Rheumatol. 2024;43(7):2177-2186. PMID 38722505
• Nishishinya MB, Pereda CA, Muñoz-Fernández S, et al. Identification of lymphoma predictors in patients with primary Sjögren’s syndrome: a systematic literature review and meta-analysis. Rheumatol Int. 2015;35(1):17-26. PMID 24899571
• Ervin AM, Law A, Pucker AD. Punctal occlusion for dry eye syndrome. Cochrane Database Syst Rev. 2017;6(6):CD006775. PMID 28649802
• Seror R, Bowman SJ, Brito-Zeron P, et al. EULAR Sjögren’s syndrome disease activity index (ESSDAI): a user guide. RMD Open. 2015;1(1):e000022. PMID 26509054
• Ramos-Casals M, Brito-Zerón P, Bombardieri S, et al. EULAR recommendations for the management of Sjögren’s syndrome with topical and systemic therapies. Ann Rheum Dis. 2020;79(1):3-18. PMID 31672775
• Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology. 2016;123(6):1386-1394. PMID 26992838

This article is intended for information purposes and does not replace a medical consultation. Indications, expected benefits and risks depend on each individual situation. For any question concerning your vision, consult an ophthalmologist.