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Do Male Patients with Primary Sjögren's Syndrome Have a Higher Frequency of Autoantibodies? To the Editor: The higher prevalence of autoantibodies found by Díaz-López, et al1 in their male patients with primary Sjögren's syndrome (SS), compared with that found in a large series of female patients with a similar mean age, is somewhat surprising and contrasts with previous reports. We would like to analyze various methodological aspects of their article. First, the main conclusion of the study is in opposition to a generally accepted idea in autoimmunity, namely, that a higher degree of autoimmune activity (both clinical and serological) is found in women compared with men. Various reports demonstrated this higher rate of autoimmune abnormality in females, including a higher frequency of autoantibodies among healthy females2, higher levels of serum immunoglobulins3, and stronger humoral and cell-mediated immune responses4 in women. These differences are especially marked in patients with autoimmune diseases characterized by B cell hyperreactivity, such as systemic lupus erythematosus or primary SS. Second, the authors have not included previous reports that specifically analyzed gender differences in large series of patients with primary SS5-8, all of which found results in opposition to the present study. We have recently analyzed a large series of patients with primary SS using the same classification criteria and including patients from the same geographical area, and found a significantly lower prevalence of antinuclear antibodies (ANA), rheumatoid factor (RF), and anti-Ro/SSA antibodies in 27 male patients compared with 363 females with primary SS6. Other recent studies have found a lower prevalence of clinical, histopathologic, and sialographic abnormalities in male SS patients7,8. All previous studies5-12 have described a lower autoimmune expression (whether clinical, histological, sialographic, or immunological) in male patients with primary SS, in contrast to the study by Diaz-Lopez, et al1. Third, the atypical epidemiologic and clinical characteristics of the 549 patients presented by Diaz-Lopez, et al1 deserve specific consideration. The mean age of female patients in the Diaz-Lopez series (64 years) is notably higher than that reported in the recently published large series6,13,14, in which the mean age was at least 10 years lower. In addition, it is surprising that the authors state that "all our females are postmenopausal." Were none of their 521 female patients pre or peri-menopausal? The clinical characteristics of the patients are also unusual. In the description of the systemic involvement of patients, the authors include several nonspecific, nonautoimmune manifestations highly prevalent in the general population, which are not usually considered as part of the extraglandular involvement typical of primary SS, such as carpal tunnel syndrome, osteoarthritis, or fibromyalgia. In contrast, the prevalence of the main typical and specific extraglandular features of primary SS (cutaneous vasculitis, neurological, pulmonary, renal, muscular...) is not detailed. Although systemic SS involvement seems to be included under the term "other clinical visceropathy," the frequency stated (only 5% of patients) is unexpectedly low, and contrasts greatly with that found in other large series6,15, in which these extraglandular features are usually observed in 20–30% of patients. Fourth, the immunological profile of the 521 females presented by Diaz-Lopez, et al1 should also be carefully analyzed. The extremely low prevalence of autoantibodies in their female SS patients (60% ANA, 28% RF, 18% anti-Ro, and 9% anti-La) is not reflected in previous studies (Table 1). It is difficult to explain these extremely low prevalences, other than possible methodological differences. These low prevalences in women mean that the comparison with men assumes statistical significance. Specifically, it is striking that less than 20% of 521 female SS patients are Ro/La positive, since previous studies report a prevalence for anti-Ro/SSA ranging between 41% and 63% (only 18% in the study), and for anti-La/SSB between 20% and 27% (9% in the study).
In summary, it seems that the profile of the female patients reported by Diaz-Lopez, et al is atypical, both epidemiologically (higher mean age), clinically (high presence of noninflammatory disorders and extremely lower presence of classical extraglandular SS features), and immunologically (only 18% of females being Ro/La positive). This profile is very different from that usually described in patients with primary SS. The higher prevalence of autoantibodies in male SS patients found by Diaz-Lopez, et al1 is in contrast to our clinical experience and that of other groups working in the field of primary SS. MANUEL RAMOS-CASALS, MD; RICARD CERVERA, MD; JOSEP FONT, MD, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Spain. REFERENCES 1. Díaz-López C, Geli C, Corominas H, et al. Are there clinical or serological differences between male and female patients with primary Sjogren's syndrome? J Rheumatol 2004;31:1352-5. 2. Fritzler MJ, Pauls JD, Kinsella TD, Bowen TJ. Antinuclear, anticytoplasmic, and anti-Sjogren's syndrome antigen A (SS-A/Ro) antibodies in female blood donors. Clin Immunol Immunopathol 1985;36:120-8. 3. Butterworth M, McClellan B, Allansmith M. Influence of sex in immunoglobulin levels. Nature 1967;214:1224-5. 4. Eidinger D, Garrett TJ. Studies of the regulatory effects of the sex hormones on antibody formation and stem cell differentiation. J Exp Med 1972;136:1098-116. 5. Cervera R, Font J, Ramos-Casals M, et al. Primary Sjogren's syndrome in men: clinical and immunological characteristics. Lupus 2000;9:61-4. 6. Garcia-Carrasco M, Ramos-Casals M, Rosas J, et al. Primary Sjogren syndrome: clinical and immunologic disease patterns in a cohort of 400 patients. Medicine (Baltimore) 2002;81:270-80. 7. Brennan MT, Sankar V, Leakan RA, et al. Risk factors for positive minor salivary gland biopsy findings in Sjogren's syndrome and dry mouth patients. Arthritis Rheum 2002;47:189-95. 8. Salto T, Sato J, Kondo K, Horikawa M, Ohmori K, Fukuda H. Low prevalence of clinicopathologic and sialographic changes in salivary glands of men with Sjogren's syndrome. J Oral Pathol Med 1999;28:312-6. 9. Molina R, Provost TT, Arnett FC, et al. Primary Sjogren's syndrome in men. Clinical, serologic, and immunogenetic features. Am J Med 1986;80:23-31. 10. Anaya JM, Liu GT, D'Souza E, Ogawa N, Luan X, Talal N. Primary Sjogren's syndrome in men. Ann Rheum Dis 1995; 54:748-51. 11. Drosos AA, Tsiakou EK, Tsifetaki N, Politi EN, Siamopoulou-Mavridou A. Subgroups of primary Sjogren's syndrome. Sjogren's syndrome in male and paediatric Greek patients. Ann Rheum Dis 1997;56:333-5. 12. Brennan MT, Fox PC. Sex differences in primary Sjogren's syndrome. J Rheumatol 1999;26:2373-6. 13. Theander E, Manthorpe R, Jacobsson LT. Mortality and causes of death in primary Sjogren's syndrome: a prospective cohort study. Arthritis Rheum 2004;50:1262-9. 14. Ioannidis JP, Vassiliou VA, Moutsopoulos HM. Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjogren's syndrome. Arthritis Rheum 2002;46:741-7. 15. Skopouli FN, Dafni U, Ioannidis JP, Moutsopoulos HM. Clinical evolution, and morbidity and mortality of primary Sjogren's syndrome. Semin Arthritis Rheum 2000;29:296-304.
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