- Email: [email protected]
Correlation Between Dry Eye and Rheumatoid Arthritis Activity
Correlation Between Dry Eye and Rheumatoid Arthritis Activity MIHO FUJITA, MD, TSUTOMU IGARASHI, MD, PHD, TOSHIYUKI KURAI, MD, MANABU SAKANE, MD, SHINICHI YOSHINO, MD, PHD, AND HIROSHI TAKAHASHI, MD, PHD
● PURPOSE:
To evaluate the incidence of dry eye in rheumatoid arthritis (RA) patients with or without Sjögren syndrome (SS), and to investigate the correlation between dry eye and RA activity. ● DESIGN: Prospective case-control study. ● METHODS: In 72 RA patients, the severity of dry eye was assessed by the Schirmer test, tear break-up time, rose bengal staining, and fluorescein staining. The RA activity was evaluated by the Lansbury index (LI), which is based on the duration of morning stiffness, erythrocyte sedimentation rate (ESR), grip strength, and joint score. ● RESULTS: Ten percent of patients met the Japanese criteria for SS. No difference in dry eye tests or LI was observed between SS patients and non-SS patients. Even in the non-SS group, 90% of patients were diagnosed with probable dry eye. In SS patients, positive correlations were observed between LI and Schirmer test (P ⴝ .048), ESR and Schirmer test (P ⴝ .035), ESR and rose bengal staining (P ⴝ .001), and grip strength and rose bengal staining (P ⴝ .047). No such correlations were observed in the non-SS patients. ● CONCLUSIONS: Dry eye is common in RA patients, including those without SS. We found that there was a correlation between LI and Schirmer test in RA patients with SS, but no correlation when the entire group was analyzed. Dry eye always should be taken into consideration regardless of the RA activity, because the severity of dry eye is independent of RA activity. (Am J Ophthalmol 2005;140:808 – 813. © 2005 by Elsevier Inc. All rights reserved.)
See accompanying Editorial on page 898. Accepted for publication May 9, 2005. From the Departments of Ophthalmology (M.F., T.I., T.K., H.T.) and Joint Disease and Rheumatism (M.S., S.Y.), Nippon Medical School, Tokyo, Japan. M.F. and T.I. contributed equally to this work. Inquiries to Tsutomu Igarashi, MD, PhD, Department of Ophthalmology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 1138602, Japan; fax: ⫹81-3-5685-0988; e-mail: [email protected]
808
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CONSIDERABLE AMOUNT OF INFORMATION RE-
garding the pathogenic factors involved in dry eye (keratoconjunctivitis sicca [KCS]) has been accumulated. The term “dry eye” is used to describe a variety of conditions with diverse origins that affect the tear film and/or the ocular surface.1 Dry eye can result from teardeficient eyes due to lacrimal gland dysfunction, or from evaporative eyes primarily due to meibomian gland disease.2 The most important disease that leads to teardeficient dry eye is Sjögren syndrome (SS), which is a systemic autoimmune disease of unknown cause that is characterized by progressive lymphocytic and plasma cell infiltration of the salivary and lacrimal glands.3 The infiltrating lymphocytes play a major role in the glandular destruction that causes dry eye.4 By use of restrictive criteria (such as the San Diego or San Francisco criteria), the frequency of SS was found to be 0.5% on the basis of the requirement for characteristic autoantibody profiles and findings of minor salivary gland biopsy.5 SS is categorized into two groups: primary SS, in which the patients do not fulfill criteria for another well-defined associated autoimmune disease; and secondary SS, in which the symptoms of dryness are associated with another well-defined autoimmune disorder, such as systemic lupus erythematosus, scleroderma, or rheumatoid arthritis (RA). It has been reported that RA tends to cause KCS, scleritis, episcleritis, and peripheral corneal ulcers, and SS develops as a complication in 11% to 31% of RA patients.6 – 8 In RA patients with SS, KCS is naturally a frequent complication. In RA patients without SS, however, there have been few reports on the incidence of dry eye. Furthermore, although it is well established that dry eye is frequently associated with RA, the correlation between the severity of dry eye and the activity of RA is unclear. RA involves inflammation of the lining of the joints and/or other internal organs. Because RA is a chronic disease that typically affects various joints and can flare up at different times, the activity of RA should be assessed for proper treatments. One of the methods for the quantification of RA activity is the Lansbury index (LI),9,10 which has long been used clinically and is a good
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0002-9394/05/$30.00 doi:10.1016/j.ajo.2005.05.025
index for assessing the patient’s condition. In this study, we examined the incidence of dry eye in RA patients with or without SS, and we investigated the correlation between the severity of dry eye and the activity of RA (as determined by LI).
TABLE 1. Population Between SS and Dry Eye in RA Patients Patient
DN
DP
DE
Total
SS Non-SS
0 (0%) 6 (8%) 6 (8%)
3 (4%) 29 (40%) 32 (44%)
4 (6%) 30 (42%) 34 (47%)
7 (10%) 65 (90%) 72 (100%)
METHODS THIS STUDY WAS A PROSPECTIVE CASE-CONTROL STUDY.
During October 2003 to November 2003, we examined 72 RA patients (five men and 67 women) at the Department of Joint Disease and Rheumatism, Nippon Medical School. We excluded patients who had any other ocular surface disease besides dry eye. The mean ⫾ SD patient age was 64.0 ⫾ 11.6 years (range 30 to 85 years). RA was diagnosed according to the American Rheumatism Association 1987 revised criteria for the classification of RA.11 Eleven patients were prescribed sodium hyaluronate 0.1% eyedrops by local ophthalmologists. Twenty patients were using commercially available eyedrops. This study followed the tenets of the Declaration of Helsinki, and informed consent was obtained from all patients. The rheumatologists evaluated LI on the basis of duration of morning stiffness, value of erythrocyte sedimentation rate (ESR) at 1 hour, grip strength (mm Hg), and joint score on the same day of the ophthalmic tests. The joint score was determined as the total sum of painful, tender, and swollen joints. SS was diagnosed according to Japanese criteria for SS (Appendix). The Japanese criteria were compared with the European criteria proposed by the American-European consensus group at the 8th International Symposium on Sjögren’s Syndrome.12 According to Fujibayashi’s findings, the 1999 Revised Japanese Criteria for Sjögren Syndrome is more sensitive and accurate than the 2002 AmericanEuropean Revised Classification Criteria. To follow the criteria, we examined SS-specific antibodies such as anti-Ro antibodies (SS-A, titer ⱖ1:30) and anti-La antibodies (SS-B, titer ⱖ1:25). Moreover, antinuclear antibody (titer ⱖ1:160) was also evaluated. Dry eye was diagnosed on the basis of the presence of both compromised tear dynamics and ocular surface abnormalities13,14 according to the reported criteria for dry eye.15 Tear dynamics were assessed by the Schirmer test and tear break-up time (BUT). Throughout the study, we examined the more severely affected eye of each patient, as determined by the Schirmer test. If one of these tests was positive (Schirmer test ⬍5 mm; BUT ⬍5 seconds), the tear dynamics were considered abnormal. Ocular surface abnormalities were identified by positive vital staining with rose bengal or fluorescein. The degree of rose bengal staining in the temporal and nasal conjunctiva and the cornea, which were divided into three parallel sections, was recorded and quantified on a scale of 0 to 3 points. Thus, the maximum score VOL. 140, NO. 5
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DE ⫽ definite dry eye; DN ⫽ non– dry eye; DP ⫽ probable dry eye; RA ⫽ rheumatoid arthritis; SS ⫽ Sjögren syndrome.
that could be obtained from the staining of one eye was 9. Fluorescein staining, which was evaluated only in the cornea, was similarly rated on a scale of 0 to 3. If either type of staining was positive, the ocular surface was considered to be abnormal. Patients in whom both tear dynamics and ocular surface were abnormal were considered to have definite dry eye, whereas patients in whom only one of the tests was positive were considered to have probable dry eye. The profiles of SS and non-SS patients were analyzed by Mann-Whitney U test or the 2 test. The correlation between LI and various values in the dry eye tests were analyzed by Spearman’s rank correlation test. The analysis was performed by StatView (Abacus Concepts Inc, Berkeley, California, USA). P ⬍ .05 was considered statistically significant.
RESULTS WE EXAMINED THE PERCENTAGE OF RA PATIENTS WITH SS,
dry eye, or both (Table 1). According to the Japanese criteria for SS, 10% of RA patients were diagnosed with SS. According to the Japanese criteria for dry eye, 92% of RA patients developed dry eye, including probable dry eye. Even in the non-SS group, 90% of patients were diagnosed with dry eye. The profiles of SS and non-SS patients are listed in Table 2. The difference in the age and sex of the members of these two groups was not statistically significant (P ⬍ .05). Interestingly, there were no significant differences observed between the SS and non-SS patients in any factors examined (with the exception of SS antibodies). All SS patients were positive for SS-A and all non-SS patients were negative for SS-A. The correlations between LI and each dry eye test are listed in Table 3. No significant correlation was observed in the entire patient group or in the non-SS patients. In the SS patients, the LI showed a significant correlation with the Schirmer test (P ⫽ .041) and a weak (but not significant) correlation with BUT (P ⫽ .057) and rose bengal staining (P ⫽ .101). To investigate more detailed correlations between RA activity and dry eye tests, correlations between each LI factor and each dry eye test were then analyzed (Figure). No significant correlations were RA ACTIVITY
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TABLE 2. Profiles of SS and Non-SS Patients With Rheumatoid Arthritis* Characteristic
SS Patients
Non-SS Patients
P Value†
Age, yr Sex, M:F Tear function Break-up time Schirmer Ocular surface condition Rose bengal score Fluorescein score Lansbury index Morning stiffness Grip strength (mm Hg) Joint score Erythrocyte sedimentation rate Systemic conditions SS-A SS-B
64 (5.3) 0:7
64.2 (12.6) 5:60
.48 .36
3.71 (2.14) 5.00 (4.58)
3.78 (2.23) 0.646
.9 .65
1.43 (1.62) 3 (3.51) 42.4 (10.4) 0 (0) 21.3 (3.40) 11.7 (6.07) 9.57 (7.23)
1 (1.80) 1.22 (2.16) 35.3 (18.4) 2.11 (5.71) 16.3 (7.36) 8.25 (6.78) 8.83 (8.35)
.31 .17 .12 .14 .88 .43 .64
7/7 1/7
0/65 0/65
⬍.001‡ .002‡
*Values are expressed as average (SD). † P value ( ‡P ⬍ .05) was calculated by the Mann-Whitney U test or the 2 test.
TABLE 3. Spearman’s Rank Correlation Between Lansbury Index and Ocular Tests Lansbury Index
SS patients Non-SS patients
Correlation
r P r P
BUT
⫺0.74 .057 0.287 .02
FUL
SCH
RB
0.173 .711 ⫺0.242 .052
⫺0.774 .041 ⫺0.005 .968
0.668 .101 0.096 .447
FUL ⫽ fluorescein score; r ⫽ Spearman correlation coefficient; RB ⫽ rose bengal score; SCH ⫽ Schrmer test.
found in the non-SS patients, whereas in the SS patients, the Schirmer test and ESR, rose bengal staining and ESR, and rose bengal staining and grip strength revealed a statistically significant correlation.
patients, 90% of the patients were diagnosed with definite or probable dry eye. Eleven patients were prescribed sodium hyaluronate 0.1% eyedrops by ophthalmologists. Twenty patients were using commercially available eyedrops. A previous study found no statistically significant improvement in rose bengal staining scores in patients who received sodium hyaluronate; conversely, the fluorescein scores of these patients were improved.22 Another study showed that sodium hyaluronate improved scores of both fluorescein and rose bengal staining.23,24 Aragona and associates25 reported that long-term treatment with sodium hyaluronate– containing artificial tears reduced ocular surface damage. Accordingly, our data may have been affected by possible improvements in patients who were using eyedrops. The main purpose of this study was to investigate possible correlations between RA activity and dry eye tests. From clinical observations, we had expected that RA activity may have a positive correlation with the severity of dry eye. However, we found no significant correlation
DISCUSSION BECAUSE ONE OF THE PURPOSES OF THIS STUDY WAS TO
identify dry eye in ordinary RA patients, we examined patients who visited the department of rheumatology for rheumatic treatment and not patients who visited the ophthalmology department with ophthalmic symptoms. The reported incidence of dry eye in the normal population is generally 5% to 17%,16 –18 but its incidence in RA patients is higher (19% to 31%).8,9,19,20 In this study, the incidence of dry eye in RA patients (47%) was similar to the incidence reported by a previous study that used the same method.21 When the probable dry eye was included, the frequency of dry eye was extremely high (91.7%). Moreover, it should be emphasized that even in non-SS 810
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FIGURE. Spearman’s rank correlation in rheumatoid arthritis activity and ocular tests. (Top left) Profiles of Lansbury index (LI) and ocular tests in Sjögren syndrome (SS) patients and (bottom left) the profiles of LI and ocular tests in non-SS patients shown score by score. Spearman correlation coefficients, and brackets in SS patients (top right) and non-SS patients (bottom right) indicate P values (*P < .05). BUT ⴝ tear break-up time; E ⴝ erythrocyte sedimentation rate; FUL ⴝ fluorescein score; G ⴝ grip strength; J ⴝ joint score; M ⴝ the duration of morning stiffness; RB ⴝ rose bengal score; SCH ⴝ Schirmer test.
between these variables when the entire patient group was analyzed. When the patients were divided into two groups, SS and non-SS, some correlations were found in the SS group. There were no significant correlations in the non-SS group. Most of the RA population does not have SS. Our results imply two things. First, the deterioration of the systemic condition of RA does not necessarily lead to the aggravation of dry eye symptoms. Conversely, dry eye cannot be excluded, even in patients with only mild RA. Therefore, dry eye always should be taken into consideration—regardless of the RA activity— because dry eye patients often lack the signs and symptoms of dry eye.26 Second, the cause of dry eye may be different in SS patients and non-SS patients. The cause of dry eye in RA patients might be a result of local pathology affecting the tear fluid, conjunctiva, or cornea because anti-Ro/SSA and anti-La/SSB antibodies have been found not only in the serum27 but also in VOL. 140, NO. 5
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the saliva,28 labial salivary glands,29 and tear fluid in SS patients.30 RA patients often show some indication of the important role of inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and IL-10, in the serum and synovial fluids.31,32 Prada and associates33 reported that TNF-␣ and IL-6 gene expression in keratocytes from patients with rheumatoid corneal ulcerations tended to be upregulated. Several inflammatory cytokines were expressed at increased levels within the conjunctival epithelium of SS patients as compared with non– dry eye controls34 –36; however, there have been no such reports regarding RA patients. In summary, dry eye is common even in RA patients without SS. We found some correlations between LI and dry eye tests in SS patients, but not in non-SS patients. Our findings suggest that the presence and severity of dry eye are independent of RA activity. Because most of the RA population does not have SS, dry eye should always be taken into consideration regardless of the RA activity. RA ACTIVITY
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22. Shimmura S, Ono M, Shinozaki K, et al. Sodium hyaluronate eyedrops in the treatment of dry eyes. Br J Ophthalmol 1995;79:1007–1011. 23. Condon PI, McEwen CG, Wright M, Mackintosh G, Prescott RJ, McDonald C. Double blind, randomised, placebo controlled, crossover, multicentre study to determine the efficacy of a 0.1% (w/v) sodium hyaluronate solution (Fermavisc) in the treatment of dry eye syndrome. Br J Ophthalmol 1999;83:1121–1124. 24. Papa V, Aragona P, Russo S, Di Bella A, Russo P, Milazzo G. Comparison of hypotonic and isotonic solutions containing sodium hyaluronate on the symptomatic treatment of dry eye patients. Ophthalmologica 2001;215:124 –127. 25. Aragona P, Di Stefano G, Ferreri F, Spinella R, Stilo A. Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjögren’s syndrome patients. Br J Ophthalmol 2002;86:879 – 884. 26. Nichols KK, Nichols JJ, Mitchell GL. The lack of association between signs and symptoms in patients with dry eye disease. Cornea 2004;23:762–770. 27. Tan EM. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol 1989;44:93–151. 28. Ben-Chetrit E, Fischel R, Rubinow A. Anti-SSA/Ro and anti-SSB/La antibodies in serum and saliva of patients with Sjögren’s syndrome. Clin Rheumatol 1993;12:471– 474. 29. Tengner P, Halse AK, Haga HJ, Jonsson R, WahrenHerlenius M. Detection of anti-Ro/SSA and anti-La/SSB autoantibody-producing cells in salivary glands from patients with Sjögren’s syndrome. Arthritis Rheum 1998;41:2238 – 2248. 30. Toker E, Yavuz S, Direskeneli H. Anti-Ro/SSA and anti-La/ SSB autoantibodies in the tear fluid of patients with Sjögren’s syndrome. Br J Ophthalmol 2004;88:384 –387. 31. Miossec P. Pro- and antiinflammatory cytokine balance in rheumatoid arthritis. Clin Exp Rheumatol 1995;13(suppl 12):S13–S16. 32. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996;14:397– 440. 33. Prada J, Noelle B, Baatz H, Hartmann C, Pleyer U. Tumour necrosis factor alpha and interleukin 6 gene expression in keratocytes from patients with rheumatoid corneal ulcerations. Br J Ophthalmol 2003;87:548 –550. 34. Jones DT, Monroy D, Ji Z, Pflugfelder SC. Alterations of ocular surface gene expression in Sjögren’s syndrome. Adv Exp Med Biol 1998;438:533–536. 35. Tishler M, Yaron I, Geyer O, Shirazi I, Naftaliev E, Yaron M. Elevated tear interleukin-6 levels in patients with Sjögren syndrome. Ophthalmology 1998;105:2327–2329. 36. Solomon A, Dursun D, Liu Z, Xie Y, Macri A, Pflugfelder SC. Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis Sci 2001;42:2283–2292.
REFERENCES 1. Lemp M. Basic principles and classification of dry eye disorders. New York: Springer, 1992:103–131. 2. Lemp MA. Report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes. CLAO J 1995;21: 221–232. 3. Manthorpe R, Frost-Larsen K, Isager H, Prause JU. Sjögren’s syndrome: a review with emphasis on immunological features. Allergy 1981;36:139 –153. 4. Fox RI, Howell FV, Bone RC, Michelson P. Primary Sjögren syndrome: clinical and immunopathologic features. Semin Arthritis Rheum 1984;14:77–105. 5. Fox RI. Sjögren’s syndrome: evolving therapies. Expert Opin Investig Drugs 2003;12:247–254. 6. Robin J, Dugel R. Immunologic disorders of the cornea and conjunctiva. New York: Churchill Livingstone, 1988:533–537. 7. Lipsky P. Rheumatoid arthritis. New York: McGraw-Hill, 1991:1437–1443. 8. Jabs D. Ocular manifestations of the rheumatic diseases. Philadelphia: JB Lippincott, 1992:1–5. 9. Lansbury J. Quantitation of the activity of rheumatoid arthritis. I. A method for recording its systemic manifestations. Am J Med Sci 1956;231:616 – 621. 10. Lansbury J. Numerical method of evaluating the status of rheumatoid arthritis. Ann Rheum Dis 1958;17:101–107. 11. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31: 315–324. 12. 8th International Symposium on Sjögren’s Syndrome. Available at: http://info.fujita-hu.ac.jp/⬃ktorikai/DiagCriteriaE.htm. Accessed Jul 26, 2005. 13. Tsubota K. New approaches to dry-eye therapy. Int Ophthalmol Clin 1994;34:115–128. 14. Tsubota K, Fujihara T, Kaido M, Mori A, Mimura M, Kato M. Dry eye and Meige’s syndrome. Br J Ophthalmol 1997; 81:439 – 442. 15. Shimazaki JaDERGiJ. Definition and criteria of dry eye. Ganka 1995;37:765–770. 16. Hikichi T, Yoshida A, Fukui Y, et al. Prevalence of dry eye in Japanese eye centers. Graefes Arch Clin Exp Ophthalmol 1995;233:555–558. 17. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol 2003;136:318 –326. 18. Moss SE, Klein R, Klein BE. Incidence of dry eye in an older population. Arch Ophthalmol 2004;122:369 –373. 19. Mody GM, Hill JC, Meyers OL. Keratoconjunctivitis sicca in rheumatoid arthritis. Clin Rheumatol 1988;7:237–241. 20. Ausayakhun S, Louthrenoo W, Aupapong S. Ocular diseases in patients with rheumatic diseases. J Med Assoc Thai 2002;85:855– 862. 21. Mokudai Y, Watanabe M, Fukushima A, et al. Keratoconjunctivitis sicca in patients with rheumatoid arthritis. Nihon Ganka Kiyo 1998;49:582–585.
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APPENDIX. Revised Japanese Diagnostic Criteria for Sjören Syndrome (1999) 1. Histopathology. Definition. Positive for at least one of (A) or (B): A) Focus score ⱖ1 (periductal lymphoid cell infiltration ⱖ50) in a 4 mm2; minor salivary gland biopsy B) Focus score ⱖ1 (periductal lymphoid cell infiltration ⱖ50) in a 4 mm2; lacrimal gland biopsy 2. Oral examination. Definition. Positive for at least one of (A) or (B): A) Abnormal findings in sialography ⱖstage I (diffuse punctate shadows of less than 1 mm) B) Decreased salivary secretion (flow rate ⱕ10 ml/10 minutes according to chewing gum test or ⱕ2 g/2 minutes according to the Saxon test) and decreased salivary function according to salivary scintigraphy 3. Ocular examination. Definition. Positive for at least one of (A) or (B): A) Schirmer test ⱕ5 mm/5 minutes and rose bengal test ⱖ3 according to van Bijsterveld score B) Schirmer test ⱕ5 mm/5 minutes and positive fluorescein staining test 4. Serological examination. Definition. Positive for at least one of (A) or (B): A) Anti-Ro/SS-A antibody B) Anti-La/SS-B antibody Diagnostic criteria: Diagnosis of Sjören syndrome can be made when the patient meets at least two of the four above criteria.
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● PURPOSE:
To evaluate the incidence of dry eye in rheumatoid arthritis (RA) patients with or without Sjögren syndrome (SS), and to investigate the correlation between dry eye and RA activity. ● DESIGN: Prospective case-control study. ● METHODS: In 72 RA patients, the severity of dry eye was assessed by the Schirmer test, tear break-up time, rose bengal staining, and fluorescein staining. The RA activity was evaluated by the Lansbury index (LI), which is based on the duration of morning stiffness, erythrocyte sedimentation rate (ESR), grip strength, and joint score. ● RESULTS: Ten percent of patients met the Japanese criteria for SS. No difference in dry eye tests or LI was observed between SS patients and non-SS patients. Even in the non-SS group, 90% of patients were diagnosed with probable dry eye. In SS patients, positive correlations were observed between LI and Schirmer test (P ⴝ .048), ESR and Schirmer test (P ⴝ .035), ESR and rose bengal staining (P ⴝ .001), and grip strength and rose bengal staining (P ⴝ .047). No such correlations were observed in the non-SS patients. ● CONCLUSIONS: Dry eye is common in RA patients, including those without SS. We found that there was a correlation between LI and Schirmer test in RA patients with SS, but no correlation when the entire group was analyzed. Dry eye always should be taken into consideration regardless of the RA activity, because the severity of dry eye is independent of RA activity. (Am J Ophthalmol 2005;140:808 – 813. © 2005 by Elsevier Inc. All rights reserved.)
See accompanying Editorial on page 898. Accepted for publication May 9, 2005. From the Departments of Ophthalmology (M.F., T.I., T.K., H.T.) and Joint Disease and Rheumatism (M.S., S.Y.), Nippon Medical School, Tokyo, Japan. M.F. and T.I. contributed equally to this work. Inquiries to Tsutomu Igarashi, MD, PhD, Department of Ophthalmology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 1138602, Japan; fax: ⫹81-3-5685-0988; e-mail: [email protected]
808
©
2005 BY
A
CONSIDERABLE AMOUNT OF INFORMATION RE-
garding the pathogenic factors involved in dry eye (keratoconjunctivitis sicca [KCS]) has been accumulated. The term “dry eye” is used to describe a variety of conditions with diverse origins that affect the tear film and/or the ocular surface.1 Dry eye can result from teardeficient eyes due to lacrimal gland dysfunction, or from evaporative eyes primarily due to meibomian gland disease.2 The most important disease that leads to teardeficient dry eye is Sjögren syndrome (SS), which is a systemic autoimmune disease of unknown cause that is characterized by progressive lymphocytic and plasma cell infiltration of the salivary and lacrimal glands.3 The infiltrating lymphocytes play a major role in the glandular destruction that causes dry eye.4 By use of restrictive criteria (such as the San Diego or San Francisco criteria), the frequency of SS was found to be 0.5% on the basis of the requirement for characteristic autoantibody profiles and findings of minor salivary gland biopsy.5 SS is categorized into two groups: primary SS, in which the patients do not fulfill criteria for another well-defined associated autoimmune disease; and secondary SS, in which the symptoms of dryness are associated with another well-defined autoimmune disorder, such as systemic lupus erythematosus, scleroderma, or rheumatoid arthritis (RA). It has been reported that RA tends to cause KCS, scleritis, episcleritis, and peripheral corneal ulcers, and SS develops as a complication in 11% to 31% of RA patients.6 – 8 In RA patients with SS, KCS is naturally a frequent complication. In RA patients without SS, however, there have been few reports on the incidence of dry eye. Furthermore, although it is well established that dry eye is frequently associated with RA, the correlation between the severity of dry eye and the activity of RA is unclear. RA involves inflammation of the lining of the joints and/or other internal organs. Because RA is a chronic disease that typically affects various joints and can flare up at different times, the activity of RA should be assessed for proper treatments. One of the methods for the quantification of RA activity is the Lansbury index (LI),9,10 which has long been used clinically and is a good
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/05/$30.00 doi:10.1016/j.ajo.2005.05.025
index for assessing the patient’s condition. In this study, we examined the incidence of dry eye in RA patients with or without SS, and we investigated the correlation between the severity of dry eye and the activity of RA (as determined by LI).
TABLE 1. Population Between SS and Dry Eye in RA Patients Patient
DN
DP
DE
Total
SS Non-SS
0 (0%) 6 (8%) 6 (8%)
3 (4%) 29 (40%) 32 (44%)
4 (6%) 30 (42%) 34 (47%)
7 (10%) 65 (90%) 72 (100%)
METHODS THIS STUDY WAS A PROSPECTIVE CASE-CONTROL STUDY.
During October 2003 to November 2003, we examined 72 RA patients (five men and 67 women) at the Department of Joint Disease and Rheumatism, Nippon Medical School. We excluded patients who had any other ocular surface disease besides dry eye. The mean ⫾ SD patient age was 64.0 ⫾ 11.6 years (range 30 to 85 years). RA was diagnosed according to the American Rheumatism Association 1987 revised criteria for the classification of RA.11 Eleven patients were prescribed sodium hyaluronate 0.1% eyedrops by local ophthalmologists. Twenty patients were using commercially available eyedrops. This study followed the tenets of the Declaration of Helsinki, and informed consent was obtained from all patients. The rheumatologists evaluated LI on the basis of duration of morning stiffness, value of erythrocyte sedimentation rate (ESR) at 1 hour, grip strength (mm Hg), and joint score on the same day of the ophthalmic tests. The joint score was determined as the total sum of painful, tender, and swollen joints. SS was diagnosed according to Japanese criteria for SS (Appendix). The Japanese criteria were compared with the European criteria proposed by the American-European consensus group at the 8th International Symposium on Sjögren’s Syndrome.12 According to Fujibayashi’s findings, the 1999 Revised Japanese Criteria for Sjögren Syndrome is more sensitive and accurate than the 2002 AmericanEuropean Revised Classification Criteria. To follow the criteria, we examined SS-specific antibodies such as anti-Ro antibodies (SS-A, titer ⱖ1:30) and anti-La antibodies (SS-B, titer ⱖ1:25). Moreover, antinuclear antibody (titer ⱖ1:160) was also evaluated. Dry eye was diagnosed on the basis of the presence of both compromised tear dynamics and ocular surface abnormalities13,14 according to the reported criteria for dry eye.15 Tear dynamics were assessed by the Schirmer test and tear break-up time (BUT). Throughout the study, we examined the more severely affected eye of each patient, as determined by the Schirmer test. If one of these tests was positive (Schirmer test ⬍5 mm; BUT ⬍5 seconds), the tear dynamics were considered abnormal. Ocular surface abnormalities were identified by positive vital staining with rose bengal or fluorescein. The degree of rose bengal staining in the temporal and nasal conjunctiva and the cornea, which were divided into three parallel sections, was recorded and quantified on a scale of 0 to 3 points. Thus, the maximum score VOL. 140, NO. 5
DRY EYE
AND
DE ⫽ definite dry eye; DN ⫽ non– dry eye; DP ⫽ probable dry eye; RA ⫽ rheumatoid arthritis; SS ⫽ Sjögren syndrome.
that could be obtained from the staining of one eye was 9. Fluorescein staining, which was evaluated only in the cornea, was similarly rated on a scale of 0 to 3. If either type of staining was positive, the ocular surface was considered to be abnormal. Patients in whom both tear dynamics and ocular surface were abnormal were considered to have definite dry eye, whereas patients in whom only one of the tests was positive were considered to have probable dry eye. The profiles of SS and non-SS patients were analyzed by Mann-Whitney U test or the 2 test. The correlation between LI and various values in the dry eye tests were analyzed by Spearman’s rank correlation test. The analysis was performed by StatView (Abacus Concepts Inc, Berkeley, California, USA). P ⬍ .05 was considered statistically significant.
RESULTS WE EXAMINED THE PERCENTAGE OF RA PATIENTS WITH SS,
dry eye, or both (Table 1). According to the Japanese criteria for SS, 10% of RA patients were diagnosed with SS. According to the Japanese criteria for dry eye, 92% of RA patients developed dry eye, including probable dry eye. Even in the non-SS group, 90% of patients were diagnosed with dry eye. The profiles of SS and non-SS patients are listed in Table 2. The difference in the age and sex of the members of these two groups was not statistically significant (P ⬍ .05). Interestingly, there were no significant differences observed between the SS and non-SS patients in any factors examined (with the exception of SS antibodies). All SS patients were positive for SS-A and all non-SS patients were negative for SS-A. The correlations between LI and each dry eye test are listed in Table 3. No significant correlation was observed in the entire patient group or in the non-SS patients. In the SS patients, the LI showed a significant correlation with the Schirmer test (P ⫽ .041) and a weak (but not significant) correlation with BUT (P ⫽ .057) and rose bengal staining (P ⫽ .101). To investigate more detailed correlations between RA activity and dry eye tests, correlations between each LI factor and each dry eye test were then analyzed (Figure). No significant correlations were RA ACTIVITY
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TABLE 2. Profiles of SS and Non-SS Patients With Rheumatoid Arthritis* Characteristic
SS Patients
Non-SS Patients
P Value†
Age, yr Sex, M:F Tear function Break-up time Schirmer Ocular surface condition Rose bengal score Fluorescein score Lansbury index Morning stiffness Grip strength (mm Hg) Joint score Erythrocyte sedimentation rate Systemic conditions SS-A SS-B
64 (5.3) 0:7
64.2 (12.6) 5:60
.48 .36
3.71 (2.14) 5.00 (4.58)
3.78 (2.23) 0.646
.9 .65
1.43 (1.62) 3 (3.51) 42.4 (10.4) 0 (0) 21.3 (3.40) 11.7 (6.07) 9.57 (7.23)
1 (1.80) 1.22 (2.16) 35.3 (18.4) 2.11 (5.71) 16.3 (7.36) 8.25 (6.78) 8.83 (8.35)
.31 .17 .12 .14 .88 .43 .64
7/7 1/7
0/65 0/65
⬍.001‡ .002‡
*Values are expressed as average (SD). † P value ( ‡P ⬍ .05) was calculated by the Mann-Whitney U test or the 2 test.
TABLE 3. Spearman’s Rank Correlation Between Lansbury Index and Ocular Tests Lansbury Index
SS patients Non-SS patients
Correlation
r P r P
BUT
⫺0.74 .057 0.287 .02
FUL
SCH
RB
0.173 .711 ⫺0.242 .052
⫺0.774 .041 ⫺0.005 .968
0.668 .101 0.096 .447
FUL ⫽ fluorescein score; r ⫽ Spearman correlation coefficient; RB ⫽ rose bengal score; SCH ⫽ Schrmer test.
found in the non-SS patients, whereas in the SS patients, the Schirmer test and ESR, rose bengal staining and ESR, and rose bengal staining and grip strength revealed a statistically significant correlation.
patients, 90% of the patients were diagnosed with definite or probable dry eye. Eleven patients were prescribed sodium hyaluronate 0.1% eyedrops by ophthalmologists. Twenty patients were using commercially available eyedrops. A previous study found no statistically significant improvement in rose bengal staining scores in patients who received sodium hyaluronate; conversely, the fluorescein scores of these patients were improved.22 Another study showed that sodium hyaluronate improved scores of both fluorescein and rose bengal staining.23,24 Aragona and associates25 reported that long-term treatment with sodium hyaluronate– containing artificial tears reduced ocular surface damage. Accordingly, our data may have been affected by possible improvements in patients who were using eyedrops. The main purpose of this study was to investigate possible correlations between RA activity and dry eye tests. From clinical observations, we had expected that RA activity may have a positive correlation with the severity of dry eye. However, we found no significant correlation
DISCUSSION BECAUSE ONE OF THE PURPOSES OF THIS STUDY WAS TO
identify dry eye in ordinary RA patients, we examined patients who visited the department of rheumatology for rheumatic treatment and not patients who visited the ophthalmology department with ophthalmic symptoms. The reported incidence of dry eye in the normal population is generally 5% to 17%,16 –18 but its incidence in RA patients is higher (19% to 31%).8,9,19,20 In this study, the incidence of dry eye in RA patients (47%) was similar to the incidence reported by a previous study that used the same method.21 When the probable dry eye was included, the frequency of dry eye was extremely high (91.7%). Moreover, it should be emphasized that even in non-SS 810
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FIGURE. Spearman’s rank correlation in rheumatoid arthritis activity and ocular tests. (Top left) Profiles of Lansbury index (LI) and ocular tests in Sjögren syndrome (SS) patients and (bottom left) the profiles of LI and ocular tests in non-SS patients shown score by score. Spearman correlation coefficients, and brackets in SS patients (top right) and non-SS patients (bottom right) indicate P values (*P < .05). BUT ⴝ tear break-up time; E ⴝ erythrocyte sedimentation rate; FUL ⴝ fluorescein score; G ⴝ grip strength; J ⴝ joint score; M ⴝ the duration of morning stiffness; RB ⴝ rose bengal score; SCH ⴝ Schirmer test.
between these variables when the entire patient group was analyzed. When the patients were divided into two groups, SS and non-SS, some correlations were found in the SS group. There were no significant correlations in the non-SS group. Most of the RA population does not have SS. Our results imply two things. First, the deterioration of the systemic condition of RA does not necessarily lead to the aggravation of dry eye symptoms. Conversely, dry eye cannot be excluded, even in patients with only mild RA. Therefore, dry eye always should be taken into consideration—regardless of the RA activity— because dry eye patients often lack the signs and symptoms of dry eye.26 Second, the cause of dry eye may be different in SS patients and non-SS patients. The cause of dry eye in RA patients might be a result of local pathology affecting the tear fluid, conjunctiva, or cornea because anti-Ro/SSA and anti-La/SSB antibodies have been found not only in the serum27 but also in VOL. 140, NO. 5
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the saliva,28 labial salivary glands,29 and tear fluid in SS patients.30 RA patients often show some indication of the important role of inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and IL-10, in the serum and synovial fluids.31,32 Prada and associates33 reported that TNF-␣ and IL-6 gene expression in keratocytes from patients with rheumatoid corneal ulcerations tended to be upregulated. Several inflammatory cytokines were expressed at increased levels within the conjunctival epithelium of SS patients as compared with non– dry eye controls34 –36; however, there have been no such reports regarding RA patients. In summary, dry eye is common even in RA patients without SS. We found some correlations between LI and dry eye tests in SS patients, but not in non-SS patients. Our findings suggest that the presence and severity of dry eye are independent of RA activity. Because most of the RA population does not have SS, dry eye should always be taken into consideration regardless of the RA activity. RA ACTIVITY
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22. Shimmura S, Ono M, Shinozaki K, et al. Sodium hyaluronate eyedrops in the treatment of dry eyes. Br J Ophthalmol 1995;79:1007–1011. 23. Condon PI, McEwen CG, Wright M, Mackintosh G, Prescott RJ, McDonald C. Double blind, randomised, placebo controlled, crossover, multicentre study to determine the efficacy of a 0.1% (w/v) sodium hyaluronate solution (Fermavisc) in the treatment of dry eye syndrome. Br J Ophthalmol 1999;83:1121–1124. 24. Papa V, Aragona P, Russo S, Di Bella A, Russo P, Milazzo G. Comparison of hypotonic and isotonic solutions containing sodium hyaluronate on the symptomatic treatment of dry eye patients. Ophthalmologica 2001;215:124 –127. 25. Aragona P, Di Stefano G, Ferreri F, Spinella R, Stilo A. Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjögren’s syndrome patients. Br J Ophthalmol 2002;86:879 – 884. 26. Nichols KK, Nichols JJ, Mitchell GL. The lack of association between signs and symptoms in patients with dry eye disease. Cornea 2004;23:762–770. 27. Tan EM. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol 1989;44:93–151. 28. Ben-Chetrit E, Fischel R, Rubinow A. Anti-SSA/Ro and anti-SSB/La antibodies in serum and saliva of patients with Sjögren’s syndrome. Clin Rheumatol 1993;12:471– 474. 29. Tengner P, Halse AK, Haga HJ, Jonsson R, WahrenHerlenius M. Detection of anti-Ro/SSA and anti-La/SSB autoantibody-producing cells in salivary glands from patients with Sjögren’s syndrome. Arthritis Rheum 1998;41:2238 – 2248. 30. Toker E, Yavuz S, Direskeneli H. Anti-Ro/SSA and anti-La/ SSB autoantibodies in the tear fluid of patients with Sjögren’s syndrome. Br J Ophthalmol 2004;88:384 –387. 31. Miossec P. Pro- and antiinflammatory cytokine balance in rheumatoid arthritis. Clin Exp Rheumatol 1995;13(suppl 12):S13–S16. 32. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996;14:397– 440. 33. Prada J, Noelle B, Baatz H, Hartmann C, Pleyer U. Tumour necrosis factor alpha and interleukin 6 gene expression in keratocytes from patients with rheumatoid corneal ulcerations. Br J Ophthalmol 2003;87:548 –550. 34. Jones DT, Monroy D, Ji Z, Pflugfelder SC. Alterations of ocular surface gene expression in Sjögren’s syndrome. Adv Exp Med Biol 1998;438:533–536. 35. Tishler M, Yaron I, Geyer O, Shirazi I, Naftaliev E, Yaron M. Elevated tear interleukin-6 levels in patients with Sjögren syndrome. Ophthalmology 1998;105:2327–2329. 36. Solomon A, Dursun D, Liu Z, Xie Y, Macri A, Pflugfelder SC. Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis Sci 2001;42:2283–2292.
REFERENCES 1. Lemp M. Basic principles and classification of dry eye disorders. New York: Springer, 1992:103–131. 2. Lemp MA. Report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes. CLAO J 1995;21: 221–232. 3. Manthorpe R, Frost-Larsen K, Isager H, Prause JU. Sjögren’s syndrome: a review with emphasis on immunological features. Allergy 1981;36:139 –153. 4. Fox RI, Howell FV, Bone RC, Michelson P. Primary Sjögren syndrome: clinical and immunopathologic features. Semin Arthritis Rheum 1984;14:77–105. 5. Fox RI. Sjögren’s syndrome: evolving therapies. Expert Opin Investig Drugs 2003;12:247–254. 6. Robin J, Dugel R. Immunologic disorders of the cornea and conjunctiva. New York: Churchill Livingstone, 1988:533–537. 7. Lipsky P. Rheumatoid arthritis. New York: McGraw-Hill, 1991:1437–1443. 8. Jabs D. Ocular manifestations of the rheumatic diseases. Philadelphia: JB Lippincott, 1992:1–5. 9. Lansbury J. Quantitation of the activity of rheumatoid arthritis. I. A method for recording its systemic manifestations. Am J Med Sci 1956;231:616 – 621. 10. Lansbury J. Numerical method of evaluating the status of rheumatoid arthritis. Ann Rheum Dis 1958;17:101–107. 11. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31: 315–324. 12. 8th International Symposium on Sjögren’s Syndrome. Available at: http://info.fujita-hu.ac.jp/⬃ktorikai/DiagCriteriaE.htm. Accessed Jul 26, 2005. 13. Tsubota K. New approaches to dry-eye therapy. Int Ophthalmol Clin 1994;34:115–128. 14. Tsubota K, Fujihara T, Kaido M, Mori A, Mimura M, Kato M. Dry eye and Meige’s syndrome. Br J Ophthalmol 1997; 81:439 – 442. 15. Shimazaki JaDERGiJ. Definition and criteria of dry eye. Ganka 1995;37:765–770. 16. Hikichi T, Yoshida A, Fukui Y, et al. Prevalence of dry eye in Japanese eye centers. Graefes Arch Clin Exp Ophthalmol 1995;233:555–558. 17. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol 2003;136:318 –326. 18. Moss SE, Klein R, Klein BE. Incidence of dry eye in an older population. Arch Ophthalmol 2004;122:369 –373. 19. Mody GM, Hill JC, Meyers OL. Keratoconjunctivitis sicca in rheumatoid arthritis. Clin Rheumatol 1988;7:237–241. 20. Ausayakhun S, Louthrenoo W, Aupapong S. Ocular diseases in patients with rheumatic diseases. J Med Assoc Thai 2002;85:855– 862. 21. Mokudai Y, Watanabe M, Fukushima A, et al. Keratoconjunctivitis sicca in patients with rheumatoid arthritis. Nihon Ganka Kiyo 1998;49:582–585.
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APPENDIX. Revised Japanese Diagnostic Criteria for Sjören Syndrome (1999) 1. Histopathology. Definition. Positive for at least one of (A) or (B): A) Focus score ⱖ1 (periductal lymphoid cell infiltration ⱖ50) in a 4 mm2; minor salivary gland biopsy B) Focus score ⱖ1 (periductal lymphoid cell infiltration ⱖ50) in a 4 mm2; lacrimal gland biopsy 2. Oral examination. Definition. Positive for at least one of (A) or (B): A) Abnormal findings in sialography ⱖstage I (diffuse punctate shadows of less than 1 mm) B) Decreased salivary secretion (flow rate ⱕ10 ml/10 minutes according to chewing gum test or ⱕ2 g/2 minutes according to the Saxon test) and decreased salivary function according to salivary scintigraphy 3. Ocular examination. Definition. Positive for at least one of (A) or (B): A) Schirmer test ⱕ5 mm/5 minutes and rose bengal test ⱖ3 according to van Bijsterveld score B) Schirmer test ⱕ5 mm/5 minutes and positive fluorescein staining test 4. Serological examination. Definition. Positive for at least one of (A) or (B): A) Anti-Ro/SS-A antibody B) Anti-La/SS-B antibody Diagnostic criteria: Diagnosis of Sjören syndrome can be made when the patient meets at least two of the four above criteria.
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