International Journal of Rheumatic Diseases 2014; 17: 578–579
CORRESPONDENCE
€ gren’s syndrome in monozygotic twins Primary Sjo Dear Editor, Sj€ ogren’s syndrome (SS) is a chronic autoimmune disease, characterized by a progressive lymphocytic and plasma cell infiltration of the salivary and lachrymal glands, and accompanied by the production of autoantibodies leading to xerostomia and keratoconjunctivitis sicca.1 Although population and family studies have suggested the involvement of a number of genetic factors, definitive genetic associations with the development of the disease or its outcome have not been found.2 Disease concordance rates (CRs: defined as the proportion of affected pairs concordant for the disease) in monozygotic twins are powerful tools for estimating the contribution of genetic and environmental factors to the susceptibility to a multifactorial disease. Although CRs for monozygotic twins in other autoimmune diseases range between 25% and 50%, such data are not available for SS.3 Several families involving two or more cases of SS have been reported, but monozygotic twins with primary SS are infrequent, and only a few case reports have been published in the literature. In the present report, we describe a case of monozygotic twins presenting with different phenotypes, clinical symptoms and serologic data, including the presence of antiRo/SSA and anti-La/SSB autoantibodies. A 20-year-old man (twin A) presented to our department with fatigue, dry eyes and a dry mouth. Upon physical examination, no facial rash or oral ulcers were observed. Laboratory tests indicated elevated rheumatoid factor levels (80.1 IU/mL; normal value, 0–14 IU/ mL), and tests for antinuclear antibodies (ANA) showed a positive titer (1 : 640) with a speckled pattern. Tests for the anti-Ro/SSA antibody (by enzyme-linked immunosorbent assay [ELISA]) yielded positive results, but tests for other autoantibodies to specific antigens yielded negative results. The 5-min Schirmer’s test showed 10 mm (left eye) and 7 mm (right eye) wetting of a filter paper; salivary gland scintigraphy revealed deficient drainage from both the parotid and submandibular glands. Based on his history, clinical presentation and the above-mentioned findings, a confirmatory diagnosis of primary SS was made.
The monozygotic twin brother (twin B) also presented to our department, because of the possibility of a combined rheumatic disease, such as SS. Twin B did not have a dry mouth, dry eyes or any systemic symptoms. The results of his physical examination were unremarkable. Laboratory tests for ANA and anti-Ro/ SSA yielded negative results, but tests for anti-La/SSB (by ELISA) antibody yielded positive results. In this individual, salivary gland scintigraphy revealed mildly deficient drainage from both parotid glands; however, an excisional biopsy of the minor salivary glands was not performed. Although a definitive diagnosis of SS was not possible, he was invited for regular follow-up examinations because his examination results suggested the possibility of future SS. Various studies have demonstrated that genetic predisposition is a major factor in disease susceptibility and several familial aggregations have been reported for SS.4,5 The powerful impact of genetic predisposition on susceptibility is usually based on disease CRs in monozygotic twins; however, cases of monozygotic twins with primary SS are rarely observed and only a few case reports have been published in the literature. The best identified genetic factors for primary SS are the major histocompatibility complex class II genes, mainly HLADR and HLA-DQ.2 Recently, Bolstad et al. described monozygotic twin sisters with primary SS, who were human leukocyte antigen (HLA) genotyped. The HLA type of both twins was the B*08-DRB1*03-DQB1*02 haplotype, but the healthy sister lacked this haplotype.6 Other cases of monozygotic twins with primary SS have also demonstrated very similar phenotypes, clinical symptoms and serologic data between the siblings.7–9 In the present case, twin A complained of clinical symptoms (dry eyes and mouth), but twin B did not have classic sicca symptoms and his laboratory findings were also different, including the ANA, anti-Ro, anti-La and rheumatoid factor results. Thus, the immune dysregulation appears to be orchestrated by genetic factors, including certain HLA phenotypes and polymorphisms in genes encoding cytokines or factors implicated in cytokine signaling, but it may be altered by environ-
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
mental factors. However, large SS twin studies are lacking, and thus reliable twin CRs cannot be obtained. As mentioned, genetic predisposition is an important factor in SS susceptibility, but the degree of genetic contribution to primary SS is unknown. This case report is limited by the absence of HLA haplotypes for the identical twin with primary SS. Nevertheless, this case supports the role of genetics and also emphasizes that other epigenetic factors and/or the environment play a critical role, thus resulting in different clinical presentations and serologic markers in monozygotic twin SS patients. We suggest that a vigorous study using, for example, inheritance by descent or linkage analysis, is essential to determine the genetic basis of SS. We encourage an international effort to develop a database on a larger number of twin sets, or representative families wherein more than one member is affected, to define the genetic basis of SS.
DISCLOSURE No conflict of interest. Won-Seok LEE and Wan-Hee YOO
Division of Rheumatology, Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine of Chonbuk National University Hospital-Chonbuk National University, Deokjin-gu, Jeonju, South Korea
International Journal of Rheumatic Diseases 2014; 17: 578–579
Correspondence: Wan-Hee Yoo, M.D., Ph.D. email: [email protected]
REFERENCES 1 Vardar R, Vardar E, Bor S (2010) Is the prevalence of intestinal metaplasia at the squamocolumnar junction different in patients with progressive systemic sclerosis? Turk J Gastroenterol 21, 251–6. 2 Ice JA, Li H, Adrianto I et al. (2012) Genentic of Sj€ ogren’s syndrome in the genome-wide association era. J Autoimmun 39, 57–63. 3 Selmi C, Mayo MJ, Bach N et al. (2004) Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 127, 485–92. 4 Mason AM, Golding PL (1971) Multiple immunological abnormalities in a family. J Clin Pathol 24, 732–5. 5 Sabio JM, Milla E, Jimenez-Alonso J (2001) A multicase family with primary Sj€ ogren’s syndrome. J Rheumatol 28, 1932–4. 6 Bolstad AI, Haga HJ, Wassmuth R, Jonsson R (2000) Monozygotic twins with primary Sj€ ogren’s syndrome. J Rheumatol 27, 2264–6. 7 Besana C, Salmaggi C, Pellegrino C et al. (1991) Chronic bilateral dacryo-adenitis in identical twins: a possible incomplete form of Sj€ ogren syndrome. Eur J Pediatr 150, 652–5. 8 Ostuni PA, Ianniello A, Sfriso P et al. (1996) Juvenile onset of primary Sj€ ogren’s syndrome: report of 10 cases. Clin Exp Rheumatol 14, 689–93. 9 Scofield RH, Kurien BT, Reichlin M (1997) Immunologically restricted and inhibitory anti-Ro/SSA in monozygotic twins. Lupus 6, 395–8.
579
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
CORRESPONDENCE
€ gren’s syndrome in monozygotic twins Primary Sjo Dear Editor, Sj€ ogren’s syndrome (SS) is a chronic autoimmune disease, characterized by a progressive lymphocytic and plasma cell infiltration of the salivary and lachrymal glands, and accompanied by the production of autoantibodies leading to xerostomia and keratoconjunctivitis sicca.1 Although population and family studies have suggested the involvement of a number of genetic factors, definitive genetic associations with the development of the disease or its outcome have not been found.2 Disease concordance rates (CRs: defined as the proportion of affected pairs concordant for the disease) in monozygotic twins are powerful tools for estimating the contribution of genetic and environmental factors to the susceptibility to a multifactorial disease. Although CRs for monozygotic twins in other autoimmune diseases range between 25% and 50%, such data are not available for SS.3 Several families involving two or more cases of SS have been reported, but monozygotic twins with primary SS are infrequent, and only a few case reports have been published in the literature. In the present report, we describe a case of monozygotic twins presenting with different phenotypes, clinical symptoms and serologic data, including the presence of antiRo/SSA and anti-La/SSB autoantibodies. A 20-year-old man (twin A) presented to our department with fatigue, dry eyes and a dry mouth. Upon physical examination, no facial rash or oral ulcers were observed. Laboratory tests indicated elevated rheumatoid factor levels (80.1 IU/mL; normal value, 0–14 IU/ mL), and tests for antinuclear antibodies (ANA) showed a positive titer (1 : 640) with a speckled pattern. Tests for the anti-Ro/SSA antibody (by enzyme-linked immunosorbent assay [ELISA]) yielded positive results, but tests for other autoantibodies to specific antigens yielded negative results. The 5-min Schirmer’s test showed 10 mm (left eye) and 7 mm (right eye) wetting of a filter paper; salivary gland scintigraphy revealed deficient drainage from both the parotid and submandibular glands. Based on his history, clinical presentation and the above-mentioned findings, a confirmatory diagnosis of primary SS was made.
The monozygotic twin brother (twin B) also presented to our department, because of the possibility of a combined rheumatic disease, such as SS. Twin B did not have a dry mouth, dry eyes or any systemic symptoms. The results of his physical examination were unremarkable. Laboratory tests for ANA and anti-Ro/ SSA yielded negative results, but tests for anti-La/SSB (by ELISA) antibody yielded positive results. In this individual, salivary gland scintigraphy revealed mildly deficient drainage from both parotid glands; however, an excisional biopsy of the minor salivary glands was not performed. Although a definitive diagnosis of SS was not possible, he was invited for regular follow-up examinations because his examination results suggested the possibility of future SS. Various studies have demonstrated that genetic predisposition is a major factor in disease susceptibility and several familial aggregations have been reported for SS.4,5 The powerful impact of genetic predisposition on susceptibility is usually based on disease CRs in monozygotic twins; however, cases of monozygotic twins with primary SS are rarely observed and only a few case reports have been published in the literature. The best identified genetic factors for primary SS are the major histocompatibility complex class II genes, mainly HLADR and HLA-DQ.2 Recently, Bolstad et al. described monozygotic twin sisters with primary SS, who were human leukocyte antigen (HLA) genotyped. The HLA type of both twins was the B*08-DRB1*03-DQB1*02 haplotype, but the healthy sister lacked this haplotype.6 Other cases of monozygotic twins with primary SS have also demonstrated very similar phenotypes, clinical symptoms and serologic data between the siblings.7–9 In the present case, twin A complained of clinical symptoms (dry eyes and mouth), but twin B did not have classic sicca symptoms and his laboratory findings were also different, including the ANA, anti-Ro, anti-La and rheumatoid factor results. Thus, the immune dysregulation appears to be orchestrated by genetic factors, including certain HLA phenotypes and polymorphisms in genes encoding cytokines or factors implicated in cytokine signaling, but it may be altered by environ-
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
mental factors. However, large SS twin studies are lacking, and thus reliable twin CRs cannot be obtained. As mentioned, genetic predisposition is an important factor in SS susceptibility, but the degree of genetic contribution to primary SS is unknown. This case report is limited by the absence of HLA haplotypes for the identical twin with primary SS. Nevertheless, this case supports the role of genetics and also emphasizes that other epigenetic factors and/or the environment play a critical role, thus resulting in different clinical presentations and serologic markers in monozygotic twin SS patients. We suggest that a vigorous study using, for example, inheritance by descent or linkage analysis, is essential to determine the genetic basis of SS. We encourage an international effort to develop a database on a larger number of twin sets, or representative families wherein more than one member is affected, to define the genetic basis of SS.
DISCLOSURE No conflict of interest. Won-Seok LEE and Wan-Hee YOO
Division of Rheumatology, Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine of Chonbuk National University Hospital-Chonbuk National University, Deokjin-gu, Jeonju, South Korea
International Journal of Rheumatic Diseases 2014; 17: 578–579
Correspondence: Wan-Hee Yoo, M.D., Ph.D. email: [email protected]
REFERENCES 1 Vardar R, Vardar E, Bor S (2010) Is the prevalence of intestinal metaplasia at the squamocolumnar junction different in patients with progressive systemic sclerosis? Turk J Gastroenterol 21, 251–6. 2 Ice JA, Li H, Adrianto I et al. (2012) Genentic of Sj€ ogren’s syndrome in the genome-wide association era. J Autoimmun 39, 57–63. 3 Selmi C, Mayo MJ, Bach N et al. (2004) Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 127, 485–92. 4 Mason AM, Golding PL (1971) Multiple immunological abnormalities in a family. J Clin Pathol 24, 732–5. 5 Sabio JM, Milla E, Jimenez-Alonso J (2001) A multicase family with primary Sj€ ogren’s syndrome. J Rheumatol 28, 1932–4. 6 Bolstad AI, Haga HJ, Wassmuth R, Jonsson R (2000) Monozygotic twins with primary Sj€ ogren’s syndrome. J Rheumatol 27, 2264–6. 7 Besana C, Salmaggi C, Pellegrino C et al. (1991) Chronic bilateral dacryo-adenitis in identical twins: a possible incomplete form of Sj€ ogren syndrome. Eur J Pediatr 150, 652–5. 8 Ostuni PA, Ianniello A, Sfriso P et al. (1996) Juvenile onset of primary Sj€ ogren’s syndrome: report of 10 cases. Clin Exp Rheumatol 14, 689–93. 9 Scofield RH, Kurien BT, Reichlin M (1997) Immunologically restricted and inhibitory anti-Ro/SSA in monozygotic twins. Lupus 6, 395–8.
579
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
