Sandra Lora Cremers MD, FACS: Auto immune disease work up for Dry Eye disease symptoms

The Complete Autoimmune Disease Blood Work Guide

From Dry Eye & Dry Mouth to Chronic Eye Pain: Every Test You Need

Sandra Lora Cremers, MD, FACS
Board-Certified Ophthalmologist

Introduction

Please follow up with your primary care provider if you have significant symptoms symptoms of Dry Eye disease that are not improving with standard treatment. All the suggestions below are dependent on what your primary care provider finds on a general examination.

Many insurances will not cover these blood tests below unless your primary care provider orders them.

If you suffer from dry eyes, dry mouth, joint pain, and/or severe meibomian gland atrophy (MGA), an autoimmune condition may be the underlying cause. The average time from disease onset to diagnosis of Sjögren’s syndrome alone is 4.7 years[1] — nearly half a decade of unnecessary suffering.

A comprehensive blood work evaluation is the key to early detection and treatment. We have seen numerous patients present with their first sign of an autoimmune disease as a dry eye type of symptom: burning, itching the most patient that have dry eye symptoms (like burning, dryness, grittiness, itching, reflex tearing, redness, blurry vision, discharge) though the MAJORITY of patient do not have an autoimmune disease. Still, the first symptom an autoimmune disease may be a sign of ocular surface inflammation/disease and we want to be sure we do not miss an autoimmune disease

If you suffer from dry eyes, dry mouth, joint pain, or severe meibomian gland atrophy (MGA), an autoimmune condition may be the underlying cause. The average time from disease onset to diagnosis of Sjögren’s syndrome alone is 4.7 years[1] — nearly half a decade of unnecessary suffering. A comprehensive blood work evaluation is the key to early detection and treatment.

This guide organizes the most important blood tests from most likely to be positive to least likely, so you and your doctor can prioritize efficiently. At the end, you’ll find a specialized workup for chronic eye pain.

Of note, I’ve seen some of these blood tests become positive with a gluten-free, sugar-free, dairy free diet. While that could be due to a false positive there have been other papers and books to indicate that the level of inflammation in the body decreases with certain types of anti-inflammatory diets. If one of the blood test comes back positive I generally recommend patients to go on this anti-inflammatory diet and recheck the bloodwork before worrying about the positive blood test.

1. Core Autoimmune Screening Panel— Start Here

These are the most commonly positive markers in patients presenting with dry eye, dry mouth, and arthritis, listed in approximate order of diagnostic yield.

ANA (Antinuclear Antibody) — The broadest autoimmune screening test. Positive in approximately 80% of Sjögren’s patients and nearly all lupus patients[5]. It is a sensitive but non-specific marker, so a positive result warrants further testing.

ESR (Erythrocyte Sedimentation Rate) and CRP (C-Reactive Protein) — General inflammation markers. Elevated in active autoimmune disease including Sjögren’s, rheumatoid arthritis, lupus, vasculitis, and giant cell arteritis[6]. These are non-specific but help confirm active inflammation.

RF (Rheumatoid Factor) — Positive in 60–70% of rheumatoid arthritis patients and approximately 50% of Sjögren’s patients[7]. While included in the Sjö test, it is important as a standalone marker for arthritis evaluation.

Anti-CCP (Anti-Cyclic Citrullinated Peptide) — More specific than RF for rheumatoid arthritis (specificity >95%)[8]. Should always be ordered alongside RF when arthritis is part of the clinical picture.

SSA (Ro) and SSB (La) Antibodies — The classic Sjögren’s antibodies. SSA is positive in 33–74% and SSB in 23–52% of Sjögren’s patients[9]. Also elevated in lupus. Note: 26–67% of confirmed Sjögren’s patients are SSA-negative, which is why the Sjö test’s novel biomarkers are so valuable[10].

CBC with Differential — Screens for anemia (common in chronic autoimmune disease), leukopenia (low white count seen in lupus and Sjögren’s), and thrombocytopenia[11].

Comprehensive Metabolic Panel (CMP) — Evaluates kidney and liver function. Autoimmune diseases including lupus and vasculitis can cause renal involvement. Also serves as a baseline before starting immunosuppressive therapy.

HLA-B27 — Strongly associated with ankylosing spondylitis, reactive arthritis, and anterior uveitis[12]. Essential when patients present with both joint pain and eye inflammation.

Complement Levels (C3, C4) — Low complement indicates active immune complex–mediated disease. Reduced in active lupus, cryoglobulinemia, and some forms of vasculitis[13].

2. Expanded Autoimmune Markers

If core tests are inconclusive or clinical suspicion remains high, the following tests help identify specific autoimmune conditions:

Anti-dsDNA and Anti-Smith Antibodies — Highly specific for systemic lupus erythematosus (SLE)[14]. Anti-dsDNA levels can correlate with disease activity.

ANCA (c-ANCA and p-ANCA) — Critical for diagnosing granulomatosis with polyangiitis (formerly Wegener’s) and microscopic polyangiitis, which can cause severe scleritis, orbital inflammation, and corneal melting[15].

Immunoglobulin Levels (IgG, IgA, IgM) — Elevated IgG4 specifically can indicate IgG4-related disease, a now-recognized cause of chronic orbital pain and lacrimal gland swelling[16]. Hypergammaglobulinemia is common in Sjögren’s.

ACE (Angiotensin Converting Enzyme) and Lysozyme — Screening markers for sarcoidosis, which causes uveitis, lacrimal gland inflammation, and dry eye[17].

Anti-Phospholipid Antibodies (Lupus Anticoagulant, Anti-Cardiolipin, Anti-Beta-2 Glycoprotein) — Antiphospholipid syndrome can cause retinal vascular occlusion and is associated with lupus[18].

Celiac Panel (Anti-tTG IgA) — Celiac disease frequently co-occurs with Hashimoto’s thyroiditis and Sjögren’s syndrome and is often overlooked. It causes malabsorption-related neuropathy that can worsen dry eye[19].

3. Complete Thyroid Panel

Thyroid autoimmune disease is one of the most common co-occurring conditions with Sjögren’s syndrome. Graves’ disease specifically causes thyroid eye disease with severe dry eye and orbital pain. A complete thyroid evaluation includes:

TSH, Free T4, Free T3 — The foundational thyroid function tests. Many providers only order TSH and Free T4, but Free T3 is the more metabolically active hormone and can reveal subclinical dysfunction[20].

Reverse T3 — Helps identify T4-to-T3 conversion problems, especially in the setting of chronic inflammation or stress.

TPO Antibodies (Anti-Thyroid Peroxidase) — The most important thyroid autoimmune marker. Elevated in Hashimoto’s thyroiditis, the most common autoimmune thyroid disease[21].

Thyroglobulin Antibodies (Anti-Tg) — Some patients are TPO-negative but Anti-Tg positive, so both antibodies should always be tested together[22].

TSI (Thyroid Stimulating Immunoglobulin) and TRAb (TSH Receptor Antibodies) — Key markers for Graves’ disease. TSI is the primary driver of thyroid eye disease, which causes deep orbital aching, proptosis, and severe dry eye[23].

4. Vitamins, Nutrients & Metabolic Tests

Nutritional deficiencies are both a consequence and an aggravating factor in autoimmune disease. These tests are essential for a complete picture:

Vitamin D — Deficiency is strongly linked to increased autoimmune activity and chronic pain syndromes[24].

Vitamin B12, B1 (Thiamine), and B6 — Deficiencies cause neuropathy, including corneal nerve dysfunction that presents as chronic burning eye pain. B12 deficiency is especially common alongside autoimmune thyroid disease[25].

Methylmalonic Acid and Homocysteine — Detect functional B12 deficiency even when serum B12 levels appear normal.

Folate — Often deficient alongside B12 and in celiac disease.

Iron and Ferritin — Low iron impairs thyroid hormone production and is common in chronic autoimmune disease.

Selenium — Essential for T4-to-T3 conversion and thyroid gland protection. Deficiency worsens Hashimoto’s[26].

HbA1c and Fasting Glucose — Diabetes causes corneal neuropathy, presenting as chronic burning eye pain, and is associated with autoimmune thyroid disease.

Uric Acid — Gout can rarely cause scleritis and keratitis.

Cortisol (AM level) or DHEA-S — Adrenal and thyroid function are closely linked; chronic stress and adrenal dysfunction can suppress thyroid conversion and worsen autoimmune flares.

5. The Sjö Test

The Sjö® test (Bausch + Lomb) is the single most valuable screening panel for early Sjögren’s syndrome. It tests for 7 biomarkers total: 4 traditional markers and 3 novel early biomarkers[2]:

Traditional Markers: Anti-SS-A/Ro, Anti-SS-B/La, ANA (Antinuclear Antibody), RF (Rheumatoid Factor)

Novel Early Biomarkers: Anti-SP-1 (Salivary Gland Protein-1), Anti-CA-6 (Carbonic Anhydrase VI), Anti-PSP (Parotid Secretory Protein)

Each novel biomarker is tested across three immunoglobulin isotypes (IgG, IgA, IgM), totaling 9 individual early biomarker items[3]. In an analysis of 6,300 dry eye patients, 72.6% of positive cases were positive only for the novel early biomarkers, meaning traditional tests alone would have missed them entirely[4]. This makes the Sjö test the single highest-yield first step.

6. Specialized Workup for Chronic Eye Pain

Chronic eye pain is not always “just dry eye.” It can be neuropathic (damaged corneal nerves), inflammatory (scleritis, uveitis), autoimmune, infectious, endocrine, or vascular. Beyond all the tests listed above, the following are specifically indicated for chronic eye pain:

Infectious Causes to Rule Out

RPR/VDRL and FTA-ABS — Syphilis can cause uveitis, scleritis, and optic neuritis[27].

Lyme Disease Panel (ELISA + Western Blot) — Lyme causes keratitis, uveitis, cranial nerve palsies, and orbital pain[28].

QuantiFERON-TB Gold or T-SPOT — Tuberculosis can cause chronic granulomatous uveitis and scleritis[29].

HSV and VZV Titers — Herpes-related keratitis, uveitis, and post-herpetic neuralgia are among the most common causes of chronic unilateral eye pain.

Toxoplasma IgG/IgM — Toxoplasmosis causes recurrent posterior uveitis with pain.

Bartonella Titers — Cat scratch disease can cause neuroretinitis and orbital pain.

HIV Test — Immunocompromised patients are at higher risk for multiple ocular infections.

Vascular: Giant Cell Arteritis (Patients Over 50)

ESR, CRP, and Platelet Count — A markedly elevated ESR (often >50 mm/hr) combined with elevated CRP and thrombocytosis is the classic triad for GCA[30]. This is an emergency because GCA can cause permanent blindness. Temporal artery biopsy remains the gold standard for confirmation.

Less Common but Important

Serum Protein Electrophoresis (SPEP) — Screens for multiple myeloma and lymphoproliferative disorders that can involve the orbit[31].

Paraneoplastic Antibodies (Anti-CV2, Anti-Hu) — Rare but can cause chronic neuropathic eye pain.

Additional Non-Blood Tests to Consider

Salivary Gland Biopsy — The gold standard for confirming Sjögren’s when blood markers are negative but clinical suspicion remains high[32].

Thyroid Ultrasound — Evaluates for nodules, inflammation, and structural changes even when blood work appears normal.

Temporal Artery Biopsy — Required when GCA is suspected, especially in patients over 50 with new-onset headache and eye pain.

Conclusion

Early detection changes outcomes. If you are experiencing dry eyes, dry mouth, arthritis, severe meibomian gland atrophy, or chronic eye pain, do not accept “it’s just dry eye” as a final answer. A comprehensive autoimmune workup — starting with the Sjö test and building outward based on your clinical picture — can identify the root cause and open the door to targeted treatment.

Bring this guide to your next appointment. Your doctor can prioritize which tests to run based on your specific symptoms. The most commonly missed tests are Free T3, Reverse T3, both thyroid antibodies together (TPO and Anti-Tg), TSI for Graves’ disease, and the celiac panel.

References

[1] Beckman KA, et al. “The Potential Role for Early Biomarker Testing as Part of a Modern, Multidisciplinary Approach to Sjögren’s Syndrome Diagnosis.” Advances in Therapy. 2017;34(4):799–812.

[2] Shen L, Suresh L. “Autoantibodies, detection methods and panels for diagnosis of Sjögren’s syndrome.” Clinical Immunology. 2017;182:24–29.

[3] Nguyen CQ, et al. “The Diagnostic Performance of Early Sjögren’s Syndrome Autoantibodies in Juvenile Sjögren’s Syndrome.” Front Immunol. 2021;12:668174.

[4] Beckman KA, et al. “Sjö, an Advanced Diagnostic Panel for Detection of Sjögren’s Syndrome Autoantibodies.” ACR Meeting Abstracts. 2014.

[5] Fayyaz A, et al. “Haematological manifestations of lupus.” Lupus Science & Medicine. 2015;2(1):e000078.

[6] Weyand CM, Goronzy JJ. “Medium- and large-vessel vasculitis.” N Engl J Med. 2003;349(2):160–169.

[7] Nishimura K, et al. “Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis.” Ann Intern Med. 2007;146(11):797–808.

[8] Avouac J, et al. “Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis.” Arthritis Res Ther. 2006;8(5):R149.

[9] Shiboski CH, et al. “2016 ACR-EULAR Classification Criteria for Primary Sjögren’s Syndrome.” Arthritis Rheumatol. 2017;69(1):35–45.

[10] Baer AN, et al. “The SSB-positive/SSA-negative antibody profile is not associated with key phenotypic features of Sjögren’s syndrome.” Ann Rheum Dis. 2015;74(8):1557–1561.

[11] Ramos-Casals M, et al. “Primary Sjögren Syndrome.” BMJ. 2012;344:e3821.

[12] Khan MA. “HLA-B27 and its subtypes in world populations.” Curr Opin Rheumatol. 1995;7(4):263–269.

[13] Petri M, et al. “Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus.” Arthritis Rheum. 2012;64(8):2677–2686.

[14] Kavanaugh A, et al. “Guidelines for clinical use of the antinuclear antibody test.” Arthritis Rheum. 2003;47(4):434–444.

[15] Jennette JC, Falk RJ. “Small-vessel vasculitis.” N Engl J Med. 1997;337(21):1512–1523.

[16] Stone JH, et al. “IgG4-related disease.” N Engl J Med. 2012;366(6):539–551.

[17] Iannuzzi MC, et al. “Sarcoidosis.” N Engl J Med. 2007;357(21):2153–2165.

[18] Miyakis S, et al. “International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome.” J Thromb Haemost. 2006;4(2):295–306.

[19] Caio G, et al. “Celiac disease: a comprehensive current review.” BMC Med. 2019;17(1):142.

[20] Jonklaas J, et al. “Guidelines for the treatment of hypothyroidism.” Thyroid. 2014;24(12):1670–1751.

[21] Caturegli P, et al. “Hashimoto thyroiditis: clinical and diagnostic criteria.” Autoimmun Rev. 2014;13(4–5):391–397.

[22] McLachlan SM, Rapoport B. “Thyroid peroxidase as an autoantigen.” Thyroid. 2007;17(10):939–948.

[23] Smith TJ, Hegedus L. “Graves’ disease.” N Engl J Med. 2016;375(16):1552–1565.

[24] Holick MF. “Vitamin D deficiency.” N Engl J Med. 2007;357(3):266–281.

[25] Stabler SP. “Vitamin B12 deficiency.” N Engl J Med. 2013;368(2):149–160.

[26] Rayman MP. “Selenium and human health.” Lancet. 2012;379(9822):1256–1268.

[27] Moradi A, et al. “Ocular syphilis: a review.” Surv Ophthalmol. 2015;60(5):483–492.

[28] Mikkilä HO, et al. “The expanding clinical spectrum of ocular Lyme borreliosis.” Ophthalmology. 2000;107(3):581–587.

[29] Gupta V, et al. “Tubercular uveitis: an update.” Expert Rev Ophthalmol. 2012;7(4):341–349.

[30] Salvarani C, et al. “Giant cell arteritis.” Lancet. 2008;372(9634):234–245.

[31] Kottler UB, et al. “Orbit involvement in multiple myeloma.” Br J Ophthalmol. 2003;87(2):218–222.

[32] Daniels TE, et al. “Salivary gland biopsy in Sjögren’s syndrome.” Oral Surg Oral Med Oral Pathol. 2011;111(2):169–176.

Disclaimer: This blog post is for educational purposes only and does not constitute medical advice. The workup should be tailored to each patient’s individual symptoms and clinical presentation. Always consult with your physician before ordering or interpreting laboratory tests.

Sandra Lora Cremers, MD, FACS | Page The Complete Autoimmune Disease Blood Work Guide