Polyautoimmunity in Sjögren Syndrome




Polyautoimmunity is defined as the presence of more than one well-defined autoimmune disease (AD) in a single patient. Polyautoimmunity is a frequent condition in Sjögren syndrome (SS) and follows a grouping pattern. The most frequent ADs observed in SS are autoimmune thyroid disease, rheumatoid arthritis, and systemic lupus erythematosus. Main factors associated with polyautoimmunity in SS are tobacco smoking and some genetic variants. The study of polyautoimmunity provides important clues for elucidating the common mechanisms of autoimmne diseases (ie, the autoimmune tautology).


Key points








  • Polyautoimmunity corresponds to the presence of more than one well-defined autoimmune disease in a single patient.



  • Sjögren syndrome has been described in association with a large variety of both organ-specific and systemic autoimmune diseases.



  • The most frequent polyautoimmunity in Sjögren syndrome is autoimmune thyroid disease.



  • Main factors associated with polyautoimmunity are tobacco smoking and some genetic variants.



  • The study of polyautoimmunity provides important clues for elucidating the common mechanisms of autoimmune diseases (ie, the autoimmune tautology).






Introduction


Autoimmune diseases (ADs) are chronic conditions initiated by the loss of immunologic tolerance to self-antigens due to the interaction of hereditary (ie, genetics and epigenetics) and environmental factors over time. Sjögren syndrome (SS) is an AD characterized by a progressive lymphocytic and plasma cell infiltration of the salivary and lachrymal glands. It is accompanied by the production of autoantibodies leading to xerostomia and keratoconjunctivitis sicca (sicca symptoms). The spectrum of the disease extends from an organ-specific autoimmune disorder (autoimmune exocrinopathy) to a systemic process involving the musculoskeletal, pulmonary, gastrointestinal, hematologic, vascular, dermatologic, renal, and nervous systems ( Fig. 1 ). Because the target tissue involved in the autoimmune histopathologic lesions of SS is the epithelium, the term “autoimmune epithelitis” is currently used to describe the disorder.




Fig. 1


Clinical spectrum of SS. AT, atherosclerosis; CHB, congenital heart block; CNS, central nervous system; CV, cardiovascular; CVD, cardiovascular disease; GI, gastrointestinal; GMN, glomerulonephritis; G-T, genital tract; L-T, laryngotracheal; MALT, mucosal-associated lymphoid tissue; Ph-O, pharyngo-esophageal; PNS, peripheral nervous system.


The diagnosis of SS is based on the combination of symptoms and the presence of the autoimmune characteristics: activation of T cells (ie, positive salivary gland biopsy) or B cells (ie, presence of autoantibodies). However, not all the individuals presenting sicca symptoms have SS. The main differential diagnosis of this disorder includes the use of medications with anticholinergic effects and endocrine diseases (eg, hypothyroidism, diabetes, and hypoandrogenism). No single test of oral or ocular involvement is sufficiently sensitive and specific to form a standard diagnosis of SS. Only the simultaneous positivity of various tests with the presence of subjective symptoms and serologic abnormalities (eg, anti-Ro and anti-La antibodies) and the presence of a score that is more than a “focus score” on the minor salivary gland biopsy (ie, at least 50 cells present in 4 mm 2 of gland surface unit) allow sufficient accuracy to diagnose this condition. The classification criteria for SS are those of the American-European Consensus Group (AECG), which require either salivary gland abnormality showing foci of lymphocytic infiltration or positive serology in the form of anti-Ro or anti-La antibodies. Recently, new classification criteria have been proposed and compared with the AECG criteria.


There is compelling evidence showing that ADs share several physiopathologic mechanisms that are reflected in the clinical similarities they exhibit and in the multiple combination of ADs observed in a single patient and in their families (ie, the autoimmune tautology) ( Fig. 2 ). Polyautoimmunity and the multiple autoimmune syndrome (MAS) are terms used to describe the presence of more than one AD in the same patient. Polyautoimmunity refers to ADs co-occurring within patients, while MAS is a term used when a patient develops 3 or more ADs.




Fig. 2


Fourth-stage model for the pathophysiology of ADs (eg, SS). Each stage shows the known phenomena that, when it has accumulated, will be the causative scenario for the onset of ADs. First, heritable factors have an impact over the life of the individuals. They converge and interact to increase or decrease the risk an individual would have of developing the disease. Second, the autoimmune ecology corresponds to the effect of environmental factors, which, acting stochastically, will also influence the risk and course of disease. Once the autoimmune tolerance is lost by the interaction of heritable and environmental factors, a preclinical stage characterized by B- and T-cell dysregulation arises. This third phase may take years before the phenotype becomes clinically evident. The clinical stage has a broad spectrum of subphenotypes that can influence outcomes, treatment, and mortality. Note that familial autoimmunity corresponds to the presence of different ADs in a nuclear family. AOD, age at onset of disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HCV, hepatitis C virus; MHC, major histocompatibility complex; RF, rheumatoid factor; TCR, T-cell receptor.


Historical Perspective


Since the first description by Henrik Sjögren in 1933, it has been well known that most of the patients with this syndrome present with polyautoimmunity. In fact, of the 19 patients he originally described, 13 (68.4%) also had rheumatoid arthritis (RA).


In the classical description of 62 patients with SS by Bloch and colleagues in 1965, most of them had an additional AD, including RA, systemic sclerosis (SSc), or polymyositis. Moreover, Bloch and Bunim were the first to suggest a shared immunopathologic mechanism for SS, systemic lupus erythematosus (SLE), SSc, and autoimmune thyroid disease (AITD) as well as a possible familial aggregation of these diseases in patients with SS. In 1979, Moutsopoulos and colleagues clarified the distinction between primary and secondary SS and recommended that the disease be termed primary when it occurs alone and secondary when it is associated with another AD. Since then, the term secondary SS has been used to describe the coexistence of SS with mainly RA or SLE. However, and as is shown herein, SS may coexist with all the systemic ADs and with most of the organ-specific ADs. In this case, the authors have proposed the term polyautoimmunity, which groups all the taxonomy terms referring to coexistence of well-defined ADs in a single individual because some of the terms previously used are confusing and exclude various associations. This view has been also adopted by an expert consensus, which stated that regardless of any concurrent organ-specific or multiorgan AD, SS should be diagnosed for all who fulfill the criteria they proposed without distinguishing between primary or secondary.


Polyautoimmunity or Overlap Syndrome?


Polyautoimmunity was used by Sheenan and Stanton-King for the first time while describing a patient with idiopathic thrombocytopenic purpura (ITP), pernicious anemia (PA), AITD, SSc, pancreatic exocrine insufficiency, and celiac disease before dying of vasculitic complications. The case they depicted corresponds to a typical MAS, which is already included in the term polyautoimmunity.


Polyautoimmunity has been referred to as overlap syndrome; some of these are frequent enough to have been given names like rhupus and sclerodermatomyositis. The main difference between polyautoimmunity and the overlapping syndromes lies in the fact that the former is the presence of 2 or more well-defined autoimmune conditions fulfilling validated classification criteria, whereas the latter is the partial presence of signs and symptoms of diverse ADs. Most of the cases of overlapping syndromes have been described in cross-sectional studies. As has been shown, there is a lag in the time interval between the first and the second AD. For example, in the mixed connective tissue disease (MCTD), the classical overlap syndrome, some patients will develop SLE, SSc, or RA during the course of the disease, and some will present with a longstanding MCTD. Long-term studies have shown that MCTD remains an overlap syndrome in about 60% of the patients. The remaining 40% progress to SSc, SLE, or RA, highlighting the fact that ADs are a spectrum ranging from the incomplete forms or “forme frustre” and lenient and slow evolution syndromes to the rapidly progressive and fatal forms (see Fig. 1 ). The imbalance between permissive and protective factors (ie, hereditary and environmental) interacting over time may explain this spectrum and the fact that “there are no diseases but rather patients.”




Introduction


Autoimmune diseases (ADs) are chronic conditions initiated by the loss of immunologic tolerance to self-antigens due to the interaction of hereditary (ie, genetics and epigenetics) and environmental factors over time. Sjögren syndrome (SS) is an AD characterized by a progressive lymphocytic and plasma cell infiltration of the salivary and lachrymal glands. It is accompanied by the production of autoantibodies leading to xerostomia and keratoconjunctivitis sicca (sicca symptoms). The spectrum of the disease extends from an organ-specific autoimmune disorder (autoimmune exocrinopathy) to a systemic process involving the musculoskeletal, pulmonary, gastrointestinal, hematologic, vascular, dermatologic, renal, and nervous systems ( Fig. 1 ). Because the target tissue involved in the autoimmune histopathologic lesions of SS is the epithelium, the term “autoimmune epithelitis” is currently used to describe the disorder.




Fig. 1


Clinical spectrum of SS. AT, atherosclerosis; CHB, congenital heart block; CNS, central nervous system; CV, cardiovascular; CVD, cardiovascular disease; GI, gastrointestinal; GMN, glomerulonephritis; G-T, genital tract; L-T, laryngotracheal; MALT, mucosal-associated lymphoid tissue; Ph-O, pharyngo-esophageal; PNS, peripheral nervous system.


The diagnosis of SS is based on the combination of symptoms and the presence of the autoimmune characteristics: activation of T cells (ie, positive salivary gland biopsy) or B cells (ie, presence of autoantibodies). However, not all the individuals presenting sicca symptoms have SS. The main differential diagnosis of this disorder includes the use of medications with anticholinergic effects and endocrine diseases (eg, hypothyroidism, diabetes, and hypoandrogenism). No single test of oral or ocular involvement is sufficiently sensitive and specific to form a standard diagnosis of SS. Only the simultaneous positivity of various tests with the presence of subjective symptoms and serologic abnormalities (eg, anti-Ro and anti-La antibodies) and the presence of a score that is more than a “focus score” on the minor salivary gland biopsy (ie, at least 50 cells present in 4 mm 2 of gland surface unit) allow sufficient accuracy to diagnose this condition. The classification criteria for SS are those of the American-European Consensus Group (AECG), which require either salivary gland abnormality showing foci of lymphocytic infiltration or positive serology in the form of anti-Ro or anti-La antibodies. Recently, new classification criteria have been proposed and compared with the AECG criteria.


There is compelling evidence showing that ADs share several physiopathologic mechanisms that are reflected in the clinical similarities they exhibit and in the multiple combination of ADs observed in a single patient and in their families (ie, the autoimmune tautology) ( Fig. 2 ). Polyautoimmunity and the multiple autoimmune syndrome (MAS) are terms used to describe the presence of more than one AD in the same patient. Polyautoimmunity refers to ADs co-occurring within patients, while MAS is a term used when a patient develops 3 or more ADs.




Fig. 2


Fourth-stage model for the pathophysiology of ADs (eg, SS). Each stage shows the known phenomena that, when it has accumulated, will be the causative scenario for the onset of ADs. First, heritable factors have an impact over the life of the individuals. They converge and interact to increase or decrease the risk an individual would have of developing the disease. Second, the autoimmune ecology corresponds to the effect of environmental factors, which, acting stochastically, will also influence the risk and course of disease. Once the autoimmune tolerance is lost by the interaction of heritable and environmental factors, a preclinical stage characterized by B- and T-cell dysregulation arises. This third phase may take years before the phenotype becomes clinically evident. The clinical stage has a broad spectrum of subphenotypes that can influence outcomes, treatment, and mortality. Note that familial autoimmunity corresponds to the presence of different ADs in a nuclear family. AOD, age at onset of disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HCV, hepatitis C virus; MHC, major histocompatibility complex; RF, rheumatoid factor; TCR, T-cell receptor.


Historical Perspective


Since the first description by Henrik Sjögren in 1933, it has been well known that most of the patients with this syndrome present with polyautoimmunity. In fact, of the 19 patients he originally described, 13 (68.4%) also had rheumatoid arthritis (RA).


In the classical description of 62 patients with SS by Bloch and colleagues in 1965, most of them had an additional AD, including RA, systemic sclerosis (SSc), or polymyositis. Moreover, Bloch and Bunim were the first to suggest a shared immunopathologic mechanism for SS, systemic lupus erythematosus (SLE), SSc, and autoimmune thyroid disease (AITD) as well as a possible familial aggregation of these diseases in patients with SS. In 1979, Moutsopoulos and colleagues clarified the distinction between primary and secondary SS and recommended that the disease be termed primary when it occurs alone and secondary when it is associated with another AD. Since then, the term secondary SS has been used to describe the coexistence of SS with mainly RA or SLE. However, and as is shown herein, SS may coexist with all the systemic ADs and with most of the organ-specific ADs. In this case, the authors have proposed the term polyautoimmunity, which groups all the taxonomy terms referring to coexistence of well-defined ADs in a single individual because some of the terms previously used are confusing and exclude various associations. This view has been also adopted by an expert consensus, which stated that regardless of any concurrent organ-specific or multiorgan AD, SS should be diagnosed for all who fulfill the criteria they proposed without distinguishing between primary or secondary.


Polyautoimmunity or Overlap Syndrome?


Polyautoimmunity was used by Sheenan and Stanton-King for the first time while describing a patient with idiopathic thrombocytopenic purpura (ITP), pernicious anemia (PA), AITD, SSc, pancreatic exocrine insufficiency, and celiac disease before dying of vasculitic complications. The case they depicted corresponds to a typical MAS, which is already included in the term polyautoimmunity.


Polyautoimmunity has been referred to as overlap syndrome; some of these are frequent enough to have been given names like rhupus and sclerodermatomyositis. The main difference between polyautoimmunity and the overlapping syndromes lies in the fact that the former is the presence of 2 or more well-defined autoimmune conditions fulfilling validated classification criteria, whereas the latter is the partial presence of signs and symptoms of diverse ADs. Most of the cases of overlapping syndromes have been described in cross-sectional studies. As has been shown, there is a lag in the time interval between the first and the second AD. For example, in the mixed connective tissue disease (MCTD), the classical overlap syndrome, some patients will develop SLE, SSc, or RA during the course of the disease, and some will present with a longstanding MCTD. Long-term studies have shown that MCTD remains an overlap syndrome in about 60% of the patients. The remaining 40% progress to SSc, SLE, or RA, highlighting the fact that ADs are a spectrum ranging from the incomplete forms or “forme frustre” and lenient and slow evolution syndromes to the rapidly progressive and fatal forms (see Fig. 1 ). The imbalance between permissive and protective factors (ie, hereditary and environmental) interacting over time may explain this spectrum and the fact that “there are no diseases but rather patients.”




Polyautoimmunity in Sjögren syndrome


SS has been described in association with a large variety of ADs including AITD, RA, SLE, SSc, autoimmune hepatitis (AIH), and primary biliary cirrhosis (PBC), and the like ( Table 1 ). Lockshin and colleagues reported a prevalence of polyautoimmunity in 52% of their patients with SS (defined by ophthalmologist-prescribed artificial tears or punctal plugs, salivary gland hypertrophy, and/or cryoglobulinemia). Patients with polyautoimmunity differed from those with “pure” SS regarding race (ie, “non-white”).



Table 1

Sjögren syndrome and polyautoimmunity

























































Variable Phenotype
SS SS
+AITD b +RA +SLE +SSc
Prevalence 0.1%–4.8% 15%–30% 4%–31% 9%–19% 14%
Autoimmune profile Anti-Ro/SSA (33%–74%)
Anti-La/SSB (23%–52%)
RF (36%–74%)
ACPA (3%–10%)
ANA (59%–85%) a
Anti-TPO
Anti-Tg
ANA
ACPA (71.4%)
Anti-Ro/SSA and anti-La/SSB (12%)
Higher RF, anti-Ro/SSA, and anti-La/SSB
Anti-La/SSB as serologic marker
ACA (37%)
Anti-SCL70 (13%)
Anti-Ro/SSA (39%)
Anti-La/SSB (22%)
Anti-RNA Pol (2%)
Physiopathology Focal lymphocytic sialadenitis (minor salivary glands), with a focus score ≥1
SS may be associated with organ damage due to several mechanisms
Infiltrate consists of primarily CD4 + T lymphocytes
The thyroid epithelial cells express HLA class II molecules and adhesion molecules
Differences in genetic and immunologic pathways Sharing many immunogenetic features Lymphocytic infiltration of salivary glands leading to oral dryness is one of the main features in SS as well as salivary gland fibrosis
Subphenotype characteristics SS has a wide clinical spectrum that extends from benign local exocrinopathy to systemic disorder that affects several organs Milder disease and normal C4 levels Articular involvement and RA activity are independent of SS Milder SLE-related features and a predominance of SS-related features Limited SSc predominantly associated
Prognosis Lymphoma (5%–10%) Progress to B-cell MALT lymphoma is probable
Lymphoma (0.5%)
Doubled standardized incidence ratio for NHL Lower risk of developing glomerulonephritis SS may be protective against SSc-associated pulmonary fibrosis
Treatment approach Immunosuppressant agents (eg, CsA, AZA, MTX, MMF, and LEF are all used empirically in SS with extraglandular manifestations) No immunosuppressant agents required Corticosteroids and immunosuppressants (eg, methotrexate)
Rituximab may be considered in refractory cases
HCQS, corticosteroids, and in more severe cases immunosuppressants have been effectively used, including Rituximab In refractory or severe cases, immunosuppressants, such as AZA, MMF, or CYC, have to be considered
High-dose IVIg can be an effective option

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Sep 28, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Polyautoimmunity in Sjögren Syndrome
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