Clinical manifestations correlated to the prevalence of autoantibodies in a large (n=321) cohort of patients with primary Sjögren's syndrome: A comparison of patients initially diagnosed according to the Copenhagen classification criteria with the American–European consensus criteria

doi:10.1016/j.autrev.2004.12.002

Autoimmunity Reviews

Volume 4, Issue 5, June 2005, Pages 276-281

https://doi.org/10.1016/j.autrev.2004.12.002 Get rights and content

Abstract

In this study we imposed the recently described American–European consensus criteria for primary Sjögren's syndrome (pSS) on a large cohort of patients originally classified according to the Copenhagen set of criteria. Of the 321 patients fulfilling the Copenhagen criteria, 205 conformed to the Consensus criteria. When comparing clinical manifestations and laboratory findings between the two groups defined by different standards we found only small variations. Thus, the consequence of using the Consensus criteria in daily clinical practice will lead to the exclusion of a considerable proportion of patients with classical features of pSS. The main reason for this discrepancy is probably the absolute requirement of a positive test for anti-Ro/La or a characteristic lymphocytic infiltration in the labial gland biopsy. The sensitivity and specificity of testing for autoantibodies to Ro-52, Ro-60, and La were calculated for each set of criteria. Antibodies to La but not to Ro-52 or Ro-60 were strongly correlated to internal organ (kidney, lung, liver) dysfunction in pSS (OR 6; 95% CI 3–12), p<0.0001. Although presence of ANA was slightly more prevalent among patients with internal organ involvement it did not reach statistical significance. The fine speckled ANA pattern was most often found followed by the homogeneous and centromere pattern. Individual ANA patterns did not correlate with any particular organ manifestation.

Section snippets

Introduction; primary Sjögrens syndrome

Primary Sjögrens syndrome (pSS) is a chronic autoimmune condition, which primarily starts to affect women (female/male ratio 9:1) in their fourth, fifth, or sixth decade of life although it can involve people from all age groups. The main histology feature is a focal lymphocytic infiltration of the exocrine salivary and lachrymal glands leading to irritated eyes (keratoconjunctivitis sicca) and dry mouth (stomatitis sicca). A significant proportion of patients with pSS develop non-exocrine

The diagnosis of pSS according to individual classification criteria

Since 1984 patients with pSS have consecutively been registered at the Sjögren's Syndrome Research Centre (SSRC) at the University Hospital in Malmö, Sweden. Clinical and laboratory data have been collected according to a standardised research protocol and stored in a database. With the appearance of a new set of classification criteria for SS from the American–European (EU/US) Consensus Group [12] we evaluated whether these criteria would have any impact on the distribution of disease

Specificity and sensitivity of anti-Ro-52, anti-Ro-60, and anti-La in pSS

All pSS-sera were tested for presence of anti-Ro-52, anti-Ro-60, and anti-La in order to establish the sensitivity according to each set of classification criteria. Specificity was determined by control groups comprising normal donors (n=76), SLE patients (n=108), and patients with rheumatoid arthritis (RA; n=95). When the Copenhagen criteria was used, the sensitivity for anti-Ro-52, anti-Ro-60, and anti-La were 38%, 26%, and 20%, respectively. The Consensus criteria performed, not surprisingly

Correlation of anti-Ro and anti-La antibodies with internal organ affection in pSS

The cohort of pSS patients fulfilling the Consensus criteria (n=205) was divided into those with (n=108) or without (n=97) at least one internal organ affected, defined as above.

Impaired kidney function was found in 78 (38%) patients, pulmonary involvement in 38 (19%), liver in 21 (10%), and pancreas involvement in 5 (2%) patients. Abnormal liver or pancreas enzyme levels are not necessarily markers of permanent injury or damage to the particular organ, but it might indicate a certain level of

Distribution of ANA patterns among patients with pSS

From the cohort of 205 patients with pSS classified according to the EU/US criteria sera, 170 individuals were tested by indirect immunofluorescence for ANA on HEp-2 slides (ImmunoConcepts, USA), initial dilution of 1:160. Both nuclear and cytoplasmic patterns were recorded. 101 (59%) sera were positive and 69 (41%) were negative for ANA. The nuclear fine-speckled pattern prevailed and was found in 62 sera (62% of the positives), followed by the homogeneous pattern in 16 (16%), and centromere

Conclusions

In this study we have tried to illustrate that the introduction of a new set of classification criteria might have a significant impact on the clinical practice of diagnosing patients with pSS especially when patients are recruited for research or treatment purposes. By applying the recent EU/US set of criteria on a large cohort of patients classified according to the Copenhagen criteria, more than a third of patients did not qualify for the diagnosis of pSS although it was apparent that the

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Cited by (46)

Association of anti-Ro52, anti-Ro60 and anti-La antibodies with diagnostic, clinical and laboratory features in a referral hospital in Jerez, Spain
2016, Reumatologia Clinica
Several antibodies have proven to be useful in autoimmune diseases, as markers for diagnosis, prognosis or clinical manifestations. Our objective was to evaluate the diagnosis and manifestations associated for antibodies anti-Ro52, anti-Ro60 and anti-La at a referral hospital in Spain.
We retrospectively analyzed the antigenic specificities of the consecutive samples submitted to the Immunology Unit for antinuclear antibody screening between 2002 and 2012. We included patients with more than one positive sample for some of the autoantibodies anti-Ro52, anti-Ro60 or anti-La. We also reviewed diagnosis, clinical and laboratory features. As dependent variable we evaluated possible combinations of anti-Ro52, anti-Ro60 and anti-La.
322 patients, 91% females, were studied (age 44.3 ± 15.51 years). The most frequent diagnosis was Sjögren's syndrome (40.06%) and systemic lupus erythematosus (SLE) (36.6%). The most prevalent pattern by indirect immunofluorescence was the fine speckled (69.9%). Anti-Ro52+/anti-Ro60+/anti-La+ combination was positively associated with fine speckled pattern (p: 0.001) and negatively with homogeneous (p: 0.016) and cytoplasmic pattern (p: 0.002). Isolated anti-Ro52+ was negatively associated with fine speckled pattern (p < 0.001) and positively with the cytoplasmic one (p < 0.001). The main positive associations with clinical symptoms were xerostomia and xerophthalmia with anti-Ro52+/anti-Ro60+/anti-La+ (p < 0.001), oral ulcers with anti-Ro52+/anti-Ro60+/anti-La− (p: 0.002) and alopecia with anti-Ro52−/anti-Ro60+/anti-La− (p: 0.003). Negative associations were xerophthalmia and photosensitivity with anti-Ro52+/anti-Ro60−/anti-La− (p: 0.003). Laboratory positive associations were hypergammaglobulinemia with anti-Ro52+/anti-Ro60+/anti-La+ (p: 0.003), and hypocomplementemia with anti-Ro52−/anti-Ro60+/anti-La− (p: 0.003). Leucopenia was negatively associated with anti-Ro52+/anti-Ro60−/anti-La− (p: 0.003).
Our study found significant relationships between clinical and laboratory manifestations with different patterns of antibodies to anti-Ro52, anti-Ro60 and anti-La. The combination of antibodies might be clinically useful due to prognostic and therapeutic implications.
Varios anticuerpos han demostrado ser útiles en enfermedades autoinmunes, como marcadores de diagnóstico, pronóstico o manifestaciones clínicas. Nuestro objetivo fue evaluar el diagnóstico y las manifestaciones asociadas a anticuerpos anti-Ro52, anti-Ro60 y anti-La en un hospital de referencia en España.
Se analizaron retrospectivamente las especificidades antigénicas de todas las muestras consecutivas solicitadas a la Unidad de Inmunología para la detección de anticuerpos antinucleares entre 2002 y 2012. Se incluyeron pacientes con más de una muestra positiva para algunos de los autoanticuerpos anti-Ro52, anti-Ro60 o anti-La, y se revisaron sus características diagnósticas, clínicas y de laboratorio. Como variable dependiente se evaluaron las combinaciones de anti-Ro52, anti-Ro60 y anti-La.
322 pacientes, 91% mujeres, fueron estudiados (edad 44.3 ± 15.51 años). El diagnóstico más frecuente fue el síndrome de Sjögren (40.06%), y el lupus eritematoso sistémico (LES) (36.6%). El patrón por inmunofluorescencia indirecta más prevalente fue el moteado fino (69.9%). La combinación Anti-Ro52+/anti-Ro60+/anti-La+ se asoció positivamente con el patrón moteado fino (p: 0.001) y negativamente con el homogéneo (p: 0.016) y el citoplasmático (p: 0.002). Anti-Ro52+ aislado se asoció negativamente con el patrón moteado fino (p < 0.001) y positivamente con el citoplasmático (p < 0.001). La principal asociación con síntomas clínicos fue de xerostomía y xeroftalmia con anti-Ro52+/anti-Ro60+/anti-La+ (p < 0.001), úlceras orales con anti-Ro52+/anti-Ro60+/anti-La− (p: 0.002) y alopecia con anti-Ro52−/anti-Ro60+/anti-La−. Asociaciones negativas fueron xeroftalmia y fotosensibilidad con anti-Ro52+/anti-Ro60−/anti-La− (p: 0.003). Asociaciones positivas de laboratorio fueron hipergammaglobulinemia con anti-Ro52+/anti-Ro60+/anti-La+ (p: 0.003) e hipocomplementemia con anti-Ro52−/anti-Ro60+/anti-La− (p: 0.003). Leucopenia se asoció negativamente con anti-Ro52+/anti-Ro60−/anti-La− (p: 0.003).
Nuestro estudio encontró una relación significativa entre las manifestaciones clínicas y de laboratorio con diferentes patrones de anticuerpos anti-Ro52, anti-Ro60 y anti-La. La combinación de anticuerpos podría ser clínicamente útil, debido a implicaciones pronósticas y terapéuticas.
The use of auto-antibody testing in the evaluation of interstitial lung disease (ILD) – A practical approach for the pulmonologist
2016, Respiratory Medicine
Citation Excerpt :
Although La/SSB has been shown to shuttle between the nucleus and cytoplasm, the protein is predominantly found in the nucleus of HEp-2 cells. Autoantibodies directed against La produce a speckled nuclear staining pattern and are correlated to internal organ dysfunction (e.g. lung) [84]. Both SSA and SSB antibodies primarily identify patients with Sjögrens Syndrome and Systemic Lupus Erythematodes (SLE).
Interstitial lung diseases (ILD), also defined as diffuse parenchymal lung diseases (DPLD) include a heterogeneous group of pulmonary disorders. They may be caused by an underlying connective tissue disease (CTD), Rheumatoid Arthritis (RA) or ANCA-associated Vasculitis (AAV). Pulmonary manifestations of these conditions may also precede systemic onset and therefore, pulmonologists may be confronted with diagnosing a systemic rheumatic disease. For the discrimination of CTD-related ILD and idiopathic interstitial pneumonia (IIP), serological testing is recommended.
After careful reviewing the available literature, we suggest a serologic diagnostic algorithm for pulmonologists dealing with ILD-patients. This algorithm depicts the consensus for antibody testing that was reached amongst authors. Obviously this consensus approach requires further validation in everyday practice and leaves room for local adaption of the diagnostic strategy depending on the availability of diagnostic capacity and cost. It is our hope, however, that the rational and stepwise approach of serological testing for ILD will ultimately save unnecessary expenses associated with general laboratory screening. Finally a broader consensus on the strategy for laboratory testing in ILD in general might also improve the detection level of these relatively rare diseases and this will ultimately improve management and care of patients suffering from these complex disorders.
Autoantibodies in Sjögren's syndrome: Clinical presentation and regulatory mechanisms
2012, Presse Medicale
Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease mostly affecting the exocrine glands. A large number of autoantibodies have been detected in the serum of patients with pSS. Among them, anti-Ro/SSA and anti-La/SSB autoantibodies are the most common; they serve as disease markers and are involved in the pathogenesis of neonatal lupus syndrome (NLS). Other autoantibodies are associated with significant clinical phenotypes, such as cryoglobulins with development of non-Hodgkin's lymphoma, anti-centromere antibodies with Raynaud's phenomenon and anti-mitochondrial antibodies with liver pathology. As a result, pSS patients can be schematically categorized in subgroups according to their serological profile. Although the clinical utility of these autoantibodies is appreciated, little is known about the mechanisms related to their production and the regulation of the autoimmune response. In the present review, the clinical subsets of patients with pSS related to different autoantibodies as well as the regulating mechanisms of their production with special emphasis on idiotypic/anti-idiotypic network are discussed.
Subgroups of Sjögren syndrome patients according to serological profiles
2012, Journal of Autoimmunity
Citation Excerpt :
Likewise, highly antigenic peptides of the La molecule include the sequences spanning aminoacids 147–154, 291–302, 301–318 and 349–364, with the latter showing a specificity and sensitivity above 90% [20]. Anti-Ro/SSA and anti-La/SSB antibodies can be found in 33–74% and 23–52% of pSS patients respectively, depending on the method used for their identification [5,21–25]. As a rule, anti-Ro/SSA antibodies are detected either solely or concomitantly with anti-La/SSB, whereas anti-La/SSB antibodies only seldom exist in isolation [6] Despite the fact that RNA precipitation is the gold standard for the detection of anti-Ro/SSA and anti-La/SSB autoantibodies, other techniques, such as counter-immunoelectrophoresis, immunodiffusion and enzyme linked immunosorbent assay (ELISA) are more commonly used in the everyday clinical practice [26].
Sjögren Syndrome (SS) is a systemic, autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands. Different clinical associations have been described for each of the diverse autoantibodies found in SS patients. Antibodies directed against the Ro/La ribonucleoprotein complexes have been correlated with younger age, more severe dysfunction of the exocrine glands and a higher prevalence of extraglandular manifestations. Anti-nuclear antibodies and rheumatoid factors have been associated to extraglandular manifestations and an active immunological profile, while cryoglobulins are markers of more severe disease and correlate to lymphoma development and death. Antibodies to cyclic citrullinated peptides are scarce in SS and have been linked in some cases to the development of non-erosive arthritis. Furthermore, the presence of anti-mitochondrial antibodies and anti-smooth muscle antibodies in the sera of primary SS patients is considered indicative of primary biliary cirrhosis and autoimmune hepatitis, respectively. In addition, anti-centromere antibodies have been associated with a clinical phenotype intermediate between primary SS and systemic sclerosis, while antibodies against carbonic anhydrase have been related to renal tubular acidosis. Finally, an association of anti-muscarinic antibodies with cytopenias and a higher disease activity has also been described in primary SS. In conclusion, although not all of the above mentioned antibodies are useful for predicting distinct patient subgroups in SS, knowledge of the clinical associations of the different autoantibody specificities encountered in SS can advance our understanding of the disease and improve patient management.
Classification criteria for Sjogren's syndrome: A critical review
2012, Journal of Autoimmunity
Citation Excerpt :
Nowadays, the AECG-criteria [11] are the most commonly used tool for classification of patients with pSS and sSS both in clinical trials and in epidemiological studies; moreover, given their high sensitivity and specificity they have been largely employed in clinical practice for the diagnosis of the disease. Although, so widely adopted by the scientific community, nonetheless, it is a common believe, that some aspects of these criteria still deserve to be properly addressed [1,12–18]. In this paper we will critically analyse the strengths and limitations of the current AECG classification criteria and we will explore whether they might be improved in the next future.
Over the years, several different criteria sets have been proposed for the classification of Sjögren’s syndrome (SS), but none of them has been widely adopted by the scientific community until the publication of the 1993 Preliminary European Classification criteria. These Classification criteria have been largely employed both in clinical practice and in observational and interventional studies for many years. In 2002 the Preliminary European Criteria were re-examined by a joint American and European Committee. The result of this revision were the American and European Consensus Group classification criteria (AECG-criteria) which introduced more clearly defined rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria. These AECG-criteria set is now considered to be valid to ensure a specific diagnosis of SS by the vast majority of the expert in the field. To date, the AECG-criteria have been cited more than 1.304 in literature and have been used to estimate the point prevalence of the disease in several studies conducted in Greece, UK, Turkey and Norway. However, when employed in epidemiologic studies or in daily practice, the AECG-criteria have demonstrated a higher specificity (75%), but a lesser sensitivity (65.7%) in comparison to the previous Preliminary European criteria, indicating an average prevalence of pSS at ∼ 0.2% in the adult population, which is far lower than previously reported. In this paper we will critically analyse the “pro and cons” of the current AECG-criteria and of the potential usefulness of some potential revisions.
Increased Risk of Glaucoma in Patients with Sjögren’s Syndrome: A Nationwide Population-Based Cohort Study
2024, Ophthalmic Epidemiology

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Clinical manifestations correlated to the prevalence of autoantibodies in a large (n=321) cohort of patients with primary Sjögren's syndrome: A comparison of patients initially diagnosed according to the Copenhagen classification criteria with the American–European consensus criteria

Abstract

Section snippets

Introduction; primary Sjögrens syndrome

The diagnosis of pSS according to individual classification criteria

Specificity and sensitivity of anti-Ro-52, anti-Ro-60, and anti-La in pSS

Correlation of anti-Ro and anti-La antibodies with internal organ affection in pSS

Distribution of ANA patterns among patients with pSS

Conclusions

Adv. Immunol.

Arch. Oral Biol.

J. Autoimmun.

Semin. Arthritis Rheum.

Quantitative assessment of clinical disease status in primary Sjogren's syndrome. A cross-sectional study using a new classification model

Scand. J. Rheumatol.

Mortality and causes of death in primary Sjogren's syndrome: a prospective cohort study

Arthritis Rheum.

Ro small cytoplasmic ribonucleoproteins are a subclass of La ribonucleoproteins: further characterization of the Ro and La small ribonucleoproteins from uninfected mammalian cells

Mol. Cell. Biol.

Xenopus Ro ribonucleoproteins: members of an evolutionarily conserved class of cytoplasmic ribonucleoproteins

Proc. Natl. Acad. Sci. U. S. A.

The La antigen shuttles between the nucleus and the cytoplasm in CV-1 cells

Mol. Cell. Biochem.

Purification of antigenically intact Ro ribonucleoproteins: biochemical and immunological evidence that the 52-kD protein is not a Ro protein

Clin. Exp. Immunol.

Autoantibodies in human anti-Ro sera specifically recognize deproteinized hY5 Ro RNA

Clin. Exp. Immunol.

Intracellular localization and nucleocytoplasmic transport of Ro RNP components

Eur. J. Cell Biol.