Dry Eye Research in 2001: 31 Notable Human Studies

The 2001 picture

What the research shows

In 2001, a large hormone-therapy cohort, refractive-surgery studies, and work on ocular-surface inflammation broadened the picture of dry eye. Treatment results were mixed: some approaches improved selected measures, but many studies were short, small, or uncontrolled.

Treatments and tear conservation

Controlled trials tested artificial tears, autologous serum, and supplements. Smaller clinical studies examined punctal plugs and the ocular surface effects of topical products.

1. Cyclosporine reduced a marker of conjunctival inflammation

   In a masked substudy of a six-month randomized trial, researchers analyzed conjunctival cells from 158 patients with moderate to severe keratoconjunctivitis sicca. Both cyclosporine concentrations reduced HLA-DR expression more than the vehicle, supporting an anti-inflammatory effect on the ocular surface. These biomarker results came from an existing clinical trial and do not, by themselves, establish how much patients' symptoms improved.

2. A small controlled serum-drop trial found no clear advantage

   Twelve people with severe dry eye received their own serum in one randomly assigned eye and preservative-free saline in the other for two months. Symptoms and some surface measures improved in both eyes, but the between-eye differences were not statistically significant; tear production and breakup time did not improve. The sample was too small to settle whether serum drops help this population.

3. Serum drops showed promise in difficult ocular surface disease

   A clinical pilot treated 11 eyes with keratoconjunctivitis sicca and 15 eyes with persistent epithelial defects using autologous serum drops. Six of the dry-eye eyes improved on both subjective and fluorescein measures, while nine epithelial defects healed. Because there was no randomized clinical comparison, the improvements cannot be assigned confidently to serum alone.

4. Two hyaluronate tear formulations performed similarly

   A multicenter, double-masked crossover trial randomized 158 people with dry eye to hypotonic or isotonic sodium hyaluronate drops. Both formulations improved symptoms and clinical signs to a similar degree, and neither produced reported adverse events. Since both groups received active lubricants, the trial does not measure their benefit against no treatment.

5. Punctal plugs relieved symptoms but were often lost

   Investigators reviewed 50 patients who received lower punctal silicone plugs after lubricants failed to control their dry eye. At six months, 43 reported no symptoms, but the estimated plug retention rate was only 63%. The retrospective study had no untreated comparison, and some patients also received additional care.

6. Canalicular plugs helped selected patients with trachomatous dry eye

   In a controlled study of 44 patients with severe trachomatous dry eye, 22 received silicone canalicular plugs while 22 continued medical treatment. After six months, 18 plug recipients reported improvement, and staining, tear tests, and conjunctival cell measures improved relative to the comparison group. Treatment was not described as randomized, and the findings apply to a selected scarring-related form of dry eye.

7. An antioxidant trial improved tear stability, not convincing symptom relief

   Forty people with marginal dry eye received an oral antioxidant supplement, placebo, and no treatment in a randomized crossover sequence. Tear stability and conjunctival cell measures improved after the active supplement, while symptom reports also showed a placebo response and tear volume did not change. Each phase lasted only one month, so the trial cannot establish lasting clinical benefit.

8. Preserved drops were associated with more conjunctival changes

   Researchers compared conjunctival cell samples from 134 people with dry eye who were untreated or using preserved or preservative-free topical products. The preserved-treatment group had fewer goblet cells and higher inflammatory marker expression than the preservative-free group. Because treatment choice was not randomized, differences between the patient groups could partly explain the findings.

9. Several viscous tear formulations showed no clear short-term advantage

   A randomized, double-masked study tested three viscoelastic tear formulations and saline in 28 patients with keratoconjunctivitis sicca, using each treatment for about a week. Symptoms and tear tests did not clearly favor any formulation over saline, though people with more severe disease appeared more likely to respond to viscous drops. The small sample and brief treatment periods limit conclusions about sustained relief.

Symptoms after surgery, contact lens wear, and other exposures

Several independent patient groups were followed after LASIK, and other studies examined symptoms during contact lens wear or after radioiodine treatment.

10. A prospective LASIK cohort found lasting sensory changes

    Researchers measured symptoms, staining, tear production, tear clearance, and surface sensitivity in 48 patients before and up to 16 months after LASIK. Corneal and conjunctival sensitivity remained below baseline at 12 and 16 months, while irritation scores were also higher at those visits; some other signs recovered sooner. Without an unoperated comparison group, the study cannot fully separate surgical effects from other changes over time.

11. Dry-eye symptoms increased after LASIK in a second cohort

    A retrospective series assessed 124 eyes of 64 patients before LASIK and at several visits through one year. Dryness complaints rose after surgery, while tear function and breakup time declined early and then returned toward baseline; corneal sensitivity recovered by six months. The uncontrolled design and use of eyes as well as patients limit estimates of an individual's risk.

12. Tear secretion recovered more slowly than early sensitivity changes

    In a prospective series of 24 people undergoing LASIK, investigators repeatedly measured tear secretion and corneal sensitivity through nine months. Both measures fell after surgery, and tear secretion returned to its preoperative level only at the nine-month assessment. The cohort was small and lacked a nonsurgical control group.

13. A survey compared dryness after PRK and LASIK

    A questionnaire sent at least six months after refractive surgery drew responses from 231 PRK and 550 LASIK patients. Dryness was reported by 43% and 48%, respectively, while pain and eyelid-sticking symptoms suggestive of recurrent erosion were more common after PRK. Fewer than half of the 1,731 people contacted responded, and the survey lacked comparable preoperative symptom measurements.

14. Contact lens wear increased reported dryness in presbyopes

    A clinical trial followed 150 presbyopic adults for six months of soft contact lens wear, recording tear tests and symptoms before and during lens use. The proportion reporting dryness rose from 28% before lens wear to 68% while wearing lenses, even though measured ocular surface changes were generally modest. Without a group that did not wear lenses, the study cannot isolate every effect of lens wear.

15. Radioiodine treatment was followed by ocular dryness

    A prospective cohort tracked 79 patients after high-dose radioiodine therapy using dryness questionnaires and gland-function tests. In the first year, 25.3% reported eye dryness and 17.7% had measured lacrimal dysfunction; keratoconjunctivitis sicca persisted in 7.6% more than three years later. There was no untreated comparison group, and the findings concern patients receiving this particular therapy.

16. Ocular discomfort often grew worse later in the day

    At six North American optometry practices, 1,054 patients completed symptom questionnaires before clinicians made their own dry-eye assessments. Discomfort was common in both contact lens wearers and nonwearers, and many symptoms intensified by evening. This clinic sample and its nonstandardized diagnoses do not provide a population prevalence estimate.

Tear tests and ocular surface biology

These studies examined inflammatory signals, mucins, tear proteins, and the reliability of clinical tests. Most were small and exploratory, so their findings are more useful for understanding disease than for choosing a stand-alone diagnostic test.

17. Dry-eye tears showed a shift toward active inflammatory signals

    Researchers compared tear and conjunctival interleukin-1 forms in healthy eyes and eyes with meibomian gland disease or Sjögren-related tear deficiency. The dry-eye groups had more active inflammatory forms and higher tear MMP-9 activity, with some measures related to corneal staining. These associations support an inflammatory pathway but do not show that the measured molecules caused the surface damage.

18. A tear assay found less MUC5AC in dry eye

    Investigators developed an immunoassay for the tear mucin MUC5AC and applied it to 31 patients with dry eye and 19 healthy volunteers. Average tear MUC5AC was lower in the dry-eye group, suggesting altered goblet-cell secretion or tear composition. Concentrations varied widely, and this small comparison did not establish a diagnostic cutoff.

19. A modified fluorescein strip produced more repeatable breakup times

    In a contralateral-eye comparison, 100 patients received a standard fluorescein strip in one eye and a modified Dry Eye Test strip in the other; 75 met the analysis criteria. Three repeated breakup-time readings fell within three seconds for 96% with the modified strip versus 71% with the standard strip, and patients reported less discomfort. Since different eyes received the two methods, eye-level differences could contribute to the comparison.

20. Many people with dryness symptoms had another explanation

    A clinic assessed 1,200 people reporting dry-eye symptoms using tear, staining, and conjunctival cell tests. Only 57.1% met the investigators' dry-eye diagnosis; the rest had other forms of discomfort or conjunctivitis, underscoring the value of examining more than symptoms alone. This was a selected symptomatic clinic group, and its diagnostic profiles were not tested against an independent reference standard.

21. A modified tear function index was less variable

    Researchers compared fluorescein delivery methods for the tear function index in 42 people with Sjögren's syndrome and 126 without it. A prepared strip gave broadly similar index results to the standard method with less between-eye variability. The study assessed a specialized procedure and did not show how it performs as a stand-alone dry-eye diagnosis in routine care.

22. Room humidity changed tear-ferning patterns

    Tears from five healthy volunteers were dried under controlled combinations of temperature and humidity for microscopic ferning analysis. Higher humidity worsened the pattern grading even though the tears came from people with normal tear function. The small laboratory study shows a measurement problem, not the test's accuracy in patients with dry eye.

23. Contact lens discomfort had measurable conjunctival correlates

    Impression cytology compared 27 contact lens wearers with dry eye, 11 wearers without dry eye, and 20 controls. The dry-eye lens group expressed more conjunctival HLA-DR and CD23 than the symptom-free lens group, while lens wear itself was associated with fewer goblet cells than in controls. This cross-sectional comparison cannot determine whether inflammation preceded or followed the symptoms.

24. Tear-protein patterns separated groups in a small sample

    A chromatography study compared tears from 56 eyes across diabetic dry-eye, nondiabetic dry-eye, and healthy groups. Protein patterns differed, and a statistical model classified most samples into their original groups. The same small dataset appears to have been used to build and assess the model, so its diagnostic performance needs independent validation.

25. Graft-versus-host dry eye showed a distinct gland pattern

    Lacrimal gland tissue from five patients with chronic graft-versus-host disease and dry eye was compared with tissue from five patients with Sjögren's syndrome. The graft-versus-host samples showed prominent fibrosis and more activated stromal fibroblasts, particularly in severe cases. Tissue from only ten patients cannot establish how common or predictive this pattern is.

26. Muscarinic-receptor antibodies were explored as a Sjögren marker

    Investigators tested blood from patients with Sjögren-related dry eye and comparison groups for antibodies against the M3 muscarinic receptor, then examined biological activity in laboratory assays. Patient antibodies bound the target and activated a related signaling measure, unlike the tested controls. This exploratory work did not establish a clinically validated diagnostic test or prove that the antibodies caused dry eye.

Population patterns and associated conditions

Large observational datasets revealed who received treatment or reported symptoms, while smaller comparisons examined possible links with systemic disease and pterygium.

27. Hormone therapy was associated with more dry-eye reports

    In the Women's Health Study, 25,665 postmenopausal women reported hormone use over time and dry-eye diagnoses or severe symptoms at follow-up. Compared with no hormone therapy, the adjusted odds of the combined dry-eye outcome were 1.69 for estrogen alone and 1.29 for estrogen with a progestin. The outcome relied on participants' reports, and this observational study cannot show that the hormones caused dry eye.

28. Insurance claims measured treated dry eye, not all dry eye

    A managed-care database covering roughly ten million members identified dry-eye diagnoses and punctal-occlusion procedures in 1997 and 1998. Treated prevalence was 0.48% and 0.39%, respectively, with higher recorded rates in women and older adults. Claims omit people who did not seek or receive coded care, so these figures should not be read as the disease's true prevalence.

29. Community records documented new Sjögren diagnoses

    Researchers reviewed Olmsted County medical records from 1976 through 1992 and identified 53 new physician-diagnosed cases of primary Sjögren's syndrome. The age- and sex-adjusted incidence was 3.9 per 100,000 people each year, but about one in five cases lacked documented objective eye, mouth, or laboratory abnormalities. Case finding through routine records may miss people with milder or undiagnosed sicca disease.

30. Ocular sicca was more common in lupus than rheumatoid arthritis

    A matched comparison assessed 81 people with lupus, 81 with rheumatoid arthritis, and 81 healthy controls using symptom questions and tear tests. Ocular sicca symptoms occurred in 43% of the lupus group versus 21% of the rheumatoid arthritis group; reduced Schirmer readings were also more frequent in lupus. The cross-sectional data cannot establish when dryness began or whether lupus itself caused it.

31. Pterygium was linked with less stable tears in paired eyes

    Investigators compared tear tests between the affected and unaffected eyes of people with a pterygium in only one eye. Tear breakup time was shorter in the eye with pterygium, while differences in tear production measures were less certain. Because this was a paired-eye observational comparison, it cannot show whether tear instability preceded the growth or resulted from it.