Sjögren Syndrome or Sjögren Disease? The Histological and Immunological Bias Caused by the 2002 Criteria

Abstract

The current 2002 classification criteria do not cover the broad clinical and immunological heterogeneity of primary Sjögren syndrome (SS), since five of the six criteria focus exclusively on glandular involvement and the remaining criterion is the mandatory presence of anti-Ro/La antibodies. The aim of this study was to analyze the clinical features of patients with a well-established diagnosis of primary SS who do not fulfill the 2002 classification criteria. Five hundred seven patients diagnosed with primary SS (1993 criteria) were consecutively included and followed up. Two hundred twenty-one (44%) patients did not fulfill the 2002 criteria. These patients were older at diagnosis (p < 0.001) and had a lower frequency of parotid enlargement (p = 0.002), fever (p = 0.041), arthritis (p = 0.041), vasculitis (p = 0.050), peripheral neuropathy (p = 0.002), cranial nerve involvement (p = 0.015), raised erythrocyte sedimentation rate ( ESR) levels (p < 0.001), anemia (p < 0.001), leukopenia (p = 0.037), hypergammaglobulinemia (p < 0.001), positive rheumatoid factor ( RF; p = 0.002), and cryoglobulinemia (p = 0.049) in comparison with those fulfilling 2002 criteria. However, there were no significant differences in the prevalence of sicca features, diagnostic tests, overall systemic involvement, antinuclear antibodies , complement levels, development of B-cell lymphoma, or survival. Patients with anti-Ro antibodies had the highest frequencies of systemic features, hematological abnormalities, and altered immunological markers. In conclusion, patients fulfilling the 2002 criteria, who have either a specific histological diagnosis (lymphocytic infiltration) or highly specific autoantibodies (Ro/La), might well be considered to have Sjögren "disease." In contrast, etiopathogenic mechanisms other than lymphocytic-mediated epithelial damage could be involved in patients with negative Ro and negative biopsy, in whom the term Sjögren "syndrome" seems more adequate.

Classification criteria for Sjogren’s syndrome: A critical review

“…Patients with anti-Ro/SSA antibodies had the highest frequencies of systemic features, haematological abnormalities, and altered immunological markers. Ramos-Casals M. et al [18] concluded that not particular differences could be detected between the two group of patients as far as sicca features and overall systemic involvement was related. The authors therefore suggested that patients fulfilling the AECG-criteria might be considered affected by Sjögren's disease while those with negative anti-RoSSA/anti-La/SSB and negative biopsy might be defined as affected by Sjögren's syndrome.…”

“…Similarly, Locht H et al [14], in 2005, found that when the AECGcriteria were administered to a cohort of 321 patients with pSS, initially diagnosed according to the Copenhagen criteria [18], only 205/321 patients still satisfied the criteria for pSS. The authors documented a high degree of concordance between non-exocrine clinical features in the group classified according to the AECGcriteria compared to the group classified according to the Copenhagen criteria.…”

“…The key point of the debate was that these criteria could be fulfilled in the absence of either autoantibodies or positive findings on labial salivary gland biopsy. Therefore, the crucial point was whether it was acceptable to apply the definition of "Sjögren's syndrome" not only to the rather restricted group of individuals with a clear systemic autoimmune pathological response, but also to the larger group of patients complaining for sicca symptoms but not showing any autoimmune basis for the exocrinopathy [18]. Furthermore, two out of the six items of the European criteria were devoted to subjective complaints [12].…”

“…In the study by Novljan MP et al [15] those patients fulfilling the AECG-criteria set had a only a higher prevalence of arthritis and leukopenia while in the other studies no specific differences emerged from the comparison of the disease clinical presentation. Recently, Ramos-Casals M et al [18] explored the expression and the evolution of pSS in 507 patients: 221/507 fulfilling only the European criteria and 286 fulfilling both the European and the AECG-criteria. Patients who did not fulfil the AECG-criteria were older at the diagnosis and had a lower frequency of parotid enlargement, fever, arthritis, vasculitis, peripheral neuropathy, cranial nerve involvement, raised erythrocyte sedimentation rate levels, anemia, leukopenia, hypergammaglobulinemia, positive Rheumatoid factor and cryoglobulinemia.…”

Pathogenesis and diagnosis of Sjögren’s syndrome

“…Syndroms als Labormarker der Erkrankung nur noch Antikörper gegen Ro und La zulassen, kann das Sjögren-Syndrom leicht übersehen werden, obwohl sich Patienten ohne Ro-Antikörper hinsichtlich der klinischen Manifestationen, insbesondere der Trockenheit, nicht von den Ro-positiven Patienten unterscheiden[23].Daher werden zusätzliche Biomarker benötigt, um das Sjögren-Syndrom auch bei den Patienten ohne Antikörper gegen Ro zu erkennen. Folgende Marker wurden oder werden hierzu verwendet bzw.…”