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Antibodies Against a-Fodrin Are Associated with Dry Eyes and Mouth in the General Population To the Editor: Establishing the diagnosis of Sjögren's syndrome (SS) is difficult, since there are other common causes of reduced tear and saliva production. Further, complaints of dry eyes and mouth are common in the population, may be associated with depression, and barely correlate with objective test results1,2. Autoantibodies against Ro/SSA and La/SSB are used as markers of SS3. A large study has, however, failed to show an association of these autoantibodies with dry eyes and mouth in the general population2. Antibodies against a-fodrin were first described in a mouse model of SS4. There is some dispute on the prevalence of these antibodies in patients with SS, ranging from approximately 20% to 98% in various studies, the average being between 50% and 80%5. We studied whether antibodies against a-fodrin were associated with objective signs of dry eyes and mouth in the general population. Participants of our study approved by the local ethical committee were recruited on a summer festival of Hannover Medical School, visited mostly by personnel and students. We advertised our study with the slogan "400 ml of beer for 4 ml of blood," since participants were rewarded with beer (or alternatively banana juice). After giving informed and written consent, participants had to answer a questionnaire on subjective signs of dry eyes and mouth6. Schirmer's (normal > 5 mm/5 min on both eyes) and Saxon's test (normal at least 3 g/2 min)7 were performed to measure tear and saliva production. Blood was drawn for measurement of antibodies against a-fodrin, Ro, and La (Aesku.Diagnostics, Wendelsheim, Germany). Fisher's exact test was used to calculate associations of presence of autoantibodies with reduction of tear and saliva production. In total, 168 participants (107 women, 61 men) were recruited. Average age was 38 (range 18 to 76) years. Objective reduction of tear production alone was present in 29%, of saliva production alone in 2%, and of both tear and saliva production in 2% of participants. Subjective symptoms of both dry eyes and dry mouth were present in 14% of participants. IgA antibodies against a-fodrin were observed in 5%, IgG antibodies against a-fodrin in 3%, IgA and/or IgG antibodies against a-fodrin in 7%, IgG antibodies against Ro in 1/168 and against La in none of the participants. Both pathologic Schirmer's as well as Saxon's test but not complaints of dry eyes and mouth correlated with age (Figure 1). IgA antibodies against a-fodrin were present in 2% of the participants with neither dry eyes nor dry mouth, but in 3 of 4 participants with both dry eyes and dry mouth (Figure 2) (p = 0.0002 for comparison with normal participants without dry eyes or dry mouth). IgG antibodies against a-fodrin were present in 2% of the participants with neither dry eyes nor dry mouth, but in 2 out of 4 participants with both dry eyes and dry mouth (p = 0.005). The one participant with antibodies against Ro had dry eyes only and did not complain of sicca symptoms. There was no correlation of antibodies against a-fodrin or Ro with subjective complaints of dry eyes or dry mouth or a combination of both. However, complaints of dry eyes and of dry mouth were associated with each other (p = 0.0045; data not shown).
Antibodies against a-fodrin are the first laboratory markers that are associated with both dry eyes and mouth in the general population. However, since in our study salivary gland biopsies could not be taken, none of the 3 participants with a combination of dry eyes and mouth and antibodies against a-fodrin would have fulfilled American/European consensus criteria for classification of SS3. As described in other studies2, subjective complaints of dry eyes and mouth correlated neither with objective test results nor with any of the autoantibodies studied. They probably are symptoms of fibromyalgia and depression rather than of SS8. Differences in reliance on these subjective parameters in classification of SS, that to our point of view will decrease the specificity of diagnostics, may also explain different results of prevalence of antibodies against a-fodrin in SS obtained in various studies. For diagnostics of SS, simple questions are not sufficient, but objective tests for sicca syndrome should always be performed. The crucial issue will be to define whether patients with sicca syndrome and a-fodrin antibodies but without antibodies against Ro and La suffer from SS. If this turns out to be the case, prevalence of SS would be higher than anticipated at present and a-fodrin antibodies would have to be determined in diagnostics of SS in addition to Ro and La antibodies. TORSTEN WITTE, MD; JANINE BIERWIRTH, MD; REINHOLD E. SCHMIDT, MD, Department of Clinical Immunology, Hannover Medical School, Hannover, Germany; TORSTEN MATTHIAS, MD, Aesku.Diagnostics, Wendelsheim, Germany. Supported by a BMBF Kompetenznetz Rheuma grant C2.12 and a Sicca-Forschungsförderung grant to Dr. Witte. REFERENCES 1. Schein OD, Hochberg MC, Munoz B, et al. Dry eye and dry mouth in the elderly: a population-based assessment. Arch Intern Med 1999;159:1359-63. 2. Hay EM, Thomas E, Pal B, Hajeer A, Chambers H, Silman AJ. Weak association between subjective symptoms or and objective testing for dry eyes and dry mouth: results from a population based study. Ann Rheum Dis 1998;57:20-4. 3. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61:554-8. 4. Haneji N, Nakamura T, Takio K, et al. Identification of a-fodrin as a candidate autoantigen in primary Sjogren's syndrome. Science 1997;276:604-7. 5. Witte T. Antifodrin antibodies in Sjogren's syndrome: a review. Ann NY Acad Sci 2005;1051:235-9. 6. Vitali C, Bombardieri S, Moutsopoulos HM, et al. Assessment of the European classification criteria for Sjogren's syndrome in a series of clinically defined cases: results of a prospective multicentre study. The European Study Group on Diagnostic Criteria for Sjogren's Syndrome. Ann Rheum Dis 1996;55:116-21. 7. Kohler PF, Winter ME. A quantitative test for xerostomia. The Saxon test, an oral equivalent of the Schirmer test. Arthritis Rheum 1985;28:1128-32. 8. Rhodus NL, Fricton J, Carlson P, Messner R. Oral symptoms associated with fibromyalgia syndrome. J Rheumatol 2003;30:1841-5. |
