Presymptomatic autoantibodies in Sjögren’s syndrome: what significance do they hold for the clinic?

Abstract

In a number of autoimmune diseases, for example, rheumatoid arthritis and systemic lupus erythematosus, it is known that autoantibodies are present before the clinical onset. Recently we have shown that autoantibodies can be found many years before symptom onset in primary Sjögren’s syndrome. This implies that screening for autoantibodies may be used to identify individuals at risk of developing systemic autoimmune disease. Possibly, autoantibody screening may also contribute to detection of incipient malignancy. This concept stems from a novel finding, on scleroderma patients, suggesting that an anti-tumor immune response elicited by a mutated self-antigen will cross-react with the unmodified version of the self-antigen, and thus come to trigger the formation of autoantibodies.

Keywords::

• anti-La/SSB
• anti-Ro52/SSA
• anti-Ro60/SSA
• autoimmune disease
• presymptomatic autoantibody
• Sjögren’s syndrome
• tumor antigen

Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease primarily characterized by diminished function of exocrine glands, mainly the salivary and lachrymal glands. However, several other organs and tissues may also be affected, leading to a broad spectrum of both exocrine and non-exocrine manifestations. The clinical picture with dryness of mouth and eyes, often accompanied by fatigue and musculoskeletal pain, may therefore as well include a variety of other manifestations, for example synovitis, vasculitis, peripheral neuropathy and glomerulonephritis [1].

SS is a relatively common autoimmune disease, and its prevalence has been reported to vary between 0.1% and approximately 1% of the general population [2]. The disease mainly affects women (female : male ratio 9:1), and the onset occurs most frequently between 40 and 60 years of age, but may occur in all ages. In general, the clinical course of SS is protracted and benign, but with decreased health-related quality of life [3]. However, SS patients have an increased risk of lymphoproliferative disease, and the incidence of non-Hodgkin’s lymphoma has been found to be increased almost 16 times [4]. SS is assumed to be a multifactorial disorder, and genetic predisposition, hormonal and environmental factors are thought to be implicated [1].

Periepithelial lymphocytic infiltration in affected exocrine and non-exocrine tissues, and B-cell hyperactivity resulting in the production of autoantibodies against various autoantigens, are characteristics of the disease [5]. Accordingly, in the internationally widely accepted American-European Consensus Criteria for the classification of SS, which were published and implemented 2002, signs of autoimmunity in the form of autoimmune sialadenitis in labial salivary gland biopsy and/or the presence of autoantibodies in serum against the Ro/SSA and/or La/SSB antigens are required for diagnosis [6].

Several autoantibodies have been described in association with SS, but those most frequently found are antibodies directed against nuclear components of the cell and rheumatoid factor (RF) [5]. The most characteristic autoantibodies in SS are directed against the intracellular antigens Ro52/SSA, Ro60/SSA and La/SSB, which are parts of ribonucleoprotein–RNA complexes. In SS, like in many other autoimmune diseases, the autoantibodies may predict specific clinical manifestations and disease severity. It has, for example, been found that the presence of anti-Ro/SSA and anti-La/SSB antibodies in patients with SS is associated with more severe dysfunction of the exocrine glands (such as recurrent or permanent parotid gland enlargement, decreased salivary flow and more intense symptoms from the eyes) and a higher prevalence of extraglandular manifestations (such as cutaneous vasculitis, Raynaud’s phenomenon, arthralgia, arthritis, renal and pulmonary involvement and peripheral neuropathy) [7]. Furthermore, in pregnant women, the presence of anti-Ro/SSA antibodies represents a significant risk factor for neonatal lupus and/or congenital heart block (CHB) in the offspring [8].

For many autoimmune diseases, the presence of autoantibodies has been shown to precede the overt disease by months or years [9]. For example, Nielen et al. [10] found that about half of 79 patients with rheumatoid arthritis (RA) were positive for anti-cyclic citrullinated peptide antibodies and/or IgM-RF a median of 4.5 years before the onset of RA symptoms. Also other studies have found that anti-cyclic citrullinated peptide antibodies and RF precede the onset or the diagnosis of RA with several years [11,12]. In a study of systemic lupus erythematosus (SLE) by Arbuckle et al. [13] including 130 patients, at least one of the autoantibodies tested was present a mean of 3.3 years before the diagnosis in 88% of the patients, and the antibodies which first appeared were antinuclear antibodies (ANAs), antiphospholipid antibodies and antibodies against Ro/SSA and La/SSB antigens. Recently, a SLE study from northern Sweden also showed that autoantibodies against nuclear antigens can be detected in individuals developing SLE several years before the clinical onset and diagnosis [14].

For SS, some early reports have indicated that the autoimmune process may precede the clinical appearance of the disease. Already in 1982, Isenberg et al. reported that among 15 patients with arthralgia who were screened positive for anti-La/SSB autoantibodies, 11 had developed SS up to 2 years later [15]. Interestingly, the authors concluded that ‘A positive test result for SS-B autoantibodies may antedate the development of clinical symptoms of Sicca syndrome by months or even years’. It is known that isolated CHB is associated with maternal antibodies to SS-A and/or SS-B and that mothers of children with CHB can have these antibodies despite being apparently healthy [16]. However, Julkunen and Eronen [17] found that 58% of the mothers of children with CHB had developed an autoimmune disease 10 years after the index delivery and that the most common diagnosis was SS. Anyhow, no systematic investigation of presymptomatic autoantibodies in SS had been performed until we recently showed that 29 of 44 (66%) SS patients produce autoantibodies (primarily ANA, followed by RF, anti-Ro60/SSA, anti-Ro52/SSA and anti-La/SSB) many years before clinical onset of the disease [18]. Autoantibodies could be detected as early as 18 years before symptom onset and with a median time 4–6 years before symptom onset. Nonetheless, the median time is an underestimate since all seropositive cases had autoantibodies in their earliest available serum sample. The odds ratio for developing SS was high for both anti-Ro60/SSA and anti-La/SSB. Also anti-Ro52/SSA was a risk factor for developing SS, but an odds ratio could not be calculated since none of the controls were reactive for this type of autoantibody.

We already know that the presence of anti-Ro/SSA and anti-La/SSB antibodies in patients with diagnosed SS is associated with more severe disease. In further studies, we hope to shed light on if additional information may be obtained by the presence of presymptomatic autoantibodies regarding the possibility to predict specific clinical manifestations, disease severity, rate of progression, prognosis and, in particular, lymphoma development. Then, it will be of interest to determine whether an early appearance of autoantibodies is indicative of any of these parameters.

In the new proposed classification criteria for SS from the American College of Rheumatology [19], the combination of positive RF and ANA titer ≥1:320 is an alternative to positive anti-Ro/SSA and/or anti-La/SSB with respect to serological tests. Thus, it would also be of interest to further examine our presymptomatic data to determine whether this combination of autoantibodies precedes the presence of anti-Ro/SSA and/or anti-La/SSB autoantibodies.

The fact that the presence of autoantibodies precedes overt disease implies possibility to predict onset of SS. Consequently, screening for the presence of autoantibodies may identify individuals at risk of developing SS many years before disease onset. Especially in families with a history of autoimmune disease, detection of autoantibodies may be used to identify high-risk individuals. Even if we today only have limited possibilities to treat SS, with as yet no data supporting a benefit from biological therapy in established SS, in the future the identification of individuals at risk of developing SS hopefully may lead to prevention of the disease or limitation of its clinical impact.

Autoimmune diseases and autoantibodies are thought to be initiated by exposure to foreign antigens that cross-react with endogenous molecules. However, in a recent and most intriguing article on the autoimmune disease systemic sclerosis (scleroderma) [20], the authors suggest that the ‘foreign’ antigen triggering the autoimmune response in scleroderma patients is actually a tumor antigen encoded by somatically mutated genes in incipient cancers. Autoantibody cross-reactivity also leads to immune response to the wild-type autoantigen, and hence the autoantibodies do not discriminate between the mutant and wild-type forms of the antigen. Further, they speculate that in the majority of the patients, the immune response had eradicated the cancer by the time scleroderma developed. Consequently, immunoediting could play a major role in limiting the incidence of human cancer [21]. It is tempting to hypothesize that similar mechanisms are operating in SS. The presence of presymptomatic autoantibodies against the RNA-modifying proteins Ro/SSA and La/SSB may then be caused by an immune response to mutant versions of these antigens in tumors at early stages. It has also been proposed that anti-Ro/SSA autoantibodies may promote complement- or effector-mediated cancer cell lysis and supply proinflammatory signals to dendritic cells through the promotion of FCγR-mediated phagocytosis [22]. Thus, acquired immunity could play a role in controlling naturally occurring tumors, and escape from this control may lead to emergence of cancer [20]. Consequently, screening for the presence of autoantibodies may not only identify individuals at risk of developing SS, but may also contribute to detection of incipient malignancy.

In conclusion, like many other autoimmune diseases, it has now been shown that identification of SS in its preclinical stage is feasible by autoantibody profiling. Gradually, as our understanding of the immunopathogenesis of SS increases, this possibility becomes ever more important. The emergence of new immunosuppressive agents and biologic therapies hopefully implies that autoantibody profiling in the future may contribute to early intervention which may delay or prevent the development of the disease or its more serious sequelae. If screening for the presence of autoantibodies also could contribute toward identifying individuals at risk of developing cancer, autoantibody screening would be of great significance for the clinic.

Acknowledgements

The author has been supported by grants from Malmö University Hospital Foundations, Malmö University Hospital Cancer Foundation and the Foundations of Kock, Österlund and Gustaf V.

Financial & competing interests disclosure

The author has no relevant affiliations with or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending and royalties.

No writing assistance was utilized in the production of this manuscript.