A case of Sjögren's syndrome presenting as trigeminal nerve palsy

We herein report the case of a female with Sjogren's syndrome (SS) complicated with trigeminal nerve palsy. Although her sicca symptoms had been unnoticed, head magnetic resonance imaging (MRI) for detecting brain abnormalities revealed parotid gland changes associated with SS. SS should be considerd as a possible cause of trigeminal nerve disturbances. In addition, parotid gland changes related to SS should be aware in examination of cranial nerve disturbances with MRI.     

B-cell hyperactivity in primary Sjögren's syndrome

Primary Sjögren's syndrome (pSS) is characterized by mononuclear inflammatory infiltrates and IgG plasma cells in salivary and lacrimal glands which lead to irreversible destruction of the glandular tissue and is accompanied by sensation of dryness of mouth and eyes. B cells play a central role in the immunopathogenesis and exhibit signs of hyperactivity. Hyperactivity of B cells is the consequence of the coordinated and integrated action of stimulation of the B-cell receptor, CD40 and toll-like receptors in the presence of appropriate cytokines. As discussed, overexpression of type I IFN and BAFF on one hand and IL-6 and IL-21 on the other hand are critically involved in the enhanced plasma cell formation in pSS patients. Hyperactivity of B cells results in secretion of autoantibodies and production of various cytokines. These insights in the role of B cells in the pathogenetic process of pSS offer ample targets for successful therapeutical intervention in pSS.     

Outcome measures for primary Sjögren's syndrome

Lymphocytic infiltration of different exocrine and non-exocrine epithelia is the pathological hallmark of primary Sj?gren's syndrome, whereas involvement of salivary and lachrymal glands with the clinical counterpart of dry eye and dry mouth are the predominant features of the disease, together with fatigue and musculoskeletal pain. In addition, systemic manifestations, like arthritis, skin vasculitis, peripheral neuropathy, glomerulonephritis, may also be present in a consistent number of patients. As result, clinical features in SS can be divided into two facets: the benign subjective but disabling manifestations such as dryness, pain and fatigue, and the systemic manifestations. In the past decades, a core set of domains, which included sicca symptoms, objective measurements of tear and saliva production, fatigue, quality of life, disease activity and damage was indicated as essential for outcome assessment in this disorder. Afterwards, great efforts have been made to develop valid tools for the assessment of different domains. Specific questionnaires such as the Profile of Fatigue and Discomfort (PROFAD) and Sicca Symptoms Inventory (SSI) have been proposed as dedicated tools for the evaluation of patients symptoms, whereas different composite indexes have been suggested for the assessment of disease activity and damage. Some of these preliminary studies served as bases of an international project supported by EULAR, aimed at developing two consensus disease activity indexes: the EULAR Sj?gren's Syndrome Patients Reported Index (ESSPRI), and the EULAR Sj?gren's Syndrome Disease Activity Index (ESSDAI), a systemic activity index to assess systemic manifestations. A detailed and critical review of all these indexes is provided in this article. Both EULAR indexes showed, in recent studies, to be feasible, valid, and reliable instruments. After their final validation, which is currently in process, they could be used as consensus outcome criteria in therapeutic trials and in clinical practice.     

Immunopathogenesis of Sjögren's syndrome

Sjögren's syndrome (SS) is an autoimmune disease characterized by the sicca symptoms of dry eyes and dry mouth. Glandular dysfunction is thought to arise from destruction associated with lymphocytic infiltration. The degree of glandular destruction, however, does not correlate with the severity of sicca symptoms, suggesting that other mechanisms are involved, including abnormalities in parasympathetic neurotransmission. Autoantibodies against the muscarinic acetylcholine receptor have been implicated in this process, but multiple other autoantibodies have been found. Cytokines elaborated in the inflammatory lesions also appear to be involved and dysregulation of apoptosis are also involved in the pathogenesis of SS. A new two-stage model of SS has been proposed. First, there is a lymphocyte-independent phase during which inappropriate apoptosis results in the generation of apoptotic autoantigens which then attract lymphocytes. Subsequently, in the second lymphocyte-dependent phase, an immune attack causes further cell death and salivary dysfunction. Although the disease generally takes a rather stable and benign course, patients with SS have a significant risk of developing B cell lymphoma.     

Immunohistopathology of Sjögren's syndrome

Sj?gren's syndrome (SS) is characterized by keratoconjunctivitis sicca and xerostomia, which occur in an autoimmune lacrimal and salivary gland disease characterized by lymphocyte infiltrates of exocrine glands and/or Sj?gren's syndrome autoantibody production. It has been reported that aquaporin-5 distribution is abnormal in SS, perhaps as a result of paracrine effect of TNF-alpha. Also the neurogenic regulation of the salivary gland is impaired in SS. Apart from functional changes, the syndrome is also characterized by structural abnormalities of the secretory acinar apparatus. The acinar basement membrane is abnormal as it lacks laminin alpha1 chain, which may impair its capability to induce the progenitor cells to differentiate to acinar cells. CRISP-3 and TMPRSS-2 can be used as androgen markers and LIV-1 and Cyr61 as estrogen markers to study the sexual dimorphism of the salivary glands. Patients with SS seem to have low concentrations of dehydroepiandrosterone, which may predispose women and the exocrine glands to this syndrome.     

Sjögren's syndrome

Sjogren's syndrome (SS) describes xeropthalmia and xerostomia due to lymphocytic infiltrates of lacrimal and salivary glands. SS may occur alone (primary SS) or in association with several other autoimmune diseases (secondary SS). The clinical features involve a wide variety of organs, including skin, eyes, oral cavity and salivary glands, and systems, including nervous, musculoskeletal, genitourinary and vascular. Sicca symptoms can be found in a number of other disorders including rheumatoid arthritis, systemic lupus erythematosus, scleroderma, primary biliary cirrhosis, and other rheumatic disorders.     

Pathogenesis of Sjögren's syndrome

The pathogenesis of Sj?gren's syndrome is poorly understood. Genetic and environmental factors appear to contribute to the development of this syndrome. Viral infection is one of the most likely environmental factors. The primary lesion of Sj?gren's syndrome is in the exocrine glands. A majority of the infiltrating cells in the lesion are CD(4+) CD45RO(+) memory T cells. Although antigen-presentation to T cells seems to occur in the exocrine tissues, these T cells are not fully activated. On the other hand, B cells comprise approximately 20% of the infiltrating cells, and several features of this syndrome are attributed to stimulated B cells. The presence of autoantibodies, such as anti-SS-A/Ro and SS-B/La antibodies, is one of the characteristic features and is associated with severe disorders. Some antibodies appear to play a direct pathogenic role, for example, in cases of congenital heart block and sicca symptoms. Chronic inflammation with possible T cell-dependent antigen stimulation appears to induce neoplastic transformation of lymphocytes.     

Neurophysiological assessment of peripheral neuropathy in primary Sjögren's syndrome

Peripheral nervous system complications are rare in patients with primary Sjögren's syndrome. We investigated a group of six women aged 43–64 years who complained of pain and sensory symptoms. Conventional neurophysiological tests reflecting large nerve fiber function revealed normal motor conduction in all patients, whereas sensory nerve action potentials were absent in two. On the other hand, quantitative thermometry and autonomic nerve function tests indicating small nerve fiber function were more sensitive in the assessment of nerve dysfunction; these showed abnormalities in all cases. Vibrametry showed dysfunctions in four patients. The latter methods possess great sensitivity in discovering sensory disturbances. Neurophysiological assessment of the sensory and autonomic nervous system demonstrating sensory neuropathy contributes to early diagnosis of primary Sjögren's syndrome.Abbreviations HRV heart rate variation - PNS peripheral nervous system - pSS primary Sjögren's syndrome - SSEP short-latency somatosensory evoked potentials - SSR sympathetic skin response - SuCV sudomotor nerve conduction velocity     

Clinical significance of autoantibodies recognizing Sjögren's syndrome A (SSA), SSB, calpastatin and alpha-fodrin in primary Sjögren's syndrome

The aim of our study was (i) to compare the clinical and biological characteristics of 148 (137 women, 11 men) primary Sjögren's syndrome (pSS) patients at diagnosis as a function of their sex and (ii) to assess the prognostic value of anti‐calpastatin and anti‐alpha‐fodrin autoantibodies. In addition, the presence of anti‐nuclear antibodies (ANA), anti‐52‐ and 60‐kDa Sjögren's syndrome A (SSA), anti‐Sjögren's syndrome B (SSB), anti‐cyclic citrullinated peptide (CCP) antibodies and rheumatoid factors (RF) of IgA, IgG and IgM isotypes was sought in sera collected at pSS onset. Raynaud's syndrome, significantly more frequent in women, was the only systemic manifestation of pSS whose frequency differed significantly as a function of the patient's sex (P = 0·02). ANA (P = 0·001) and anti‐60‐kDa SSA autoantibodies (P = 0·03) were significantly more common in women, while men never synthesized detectable levels of anti‐SSB, anti‐calpastatin or IgG anti‐alpha‐fodrin autoantibodies. In addition, anti‐CCP autoantibodies were found in low percentages of pSS patients (4% F/18% M). The absence of autoantibodies does not exclude the diagnosis of pSS in men that will be based mainly on the anatomopathological findings of a minor salivary gland biopsy. Positivity of anti‐60‐kDa SSA, anti‐SSB, anti‐calpastatin, IgA and IgG anti‐alpha‐fodrin antibodies is not associated with pSS clinical and biological severity.     

Outcome measures for primary Sjögren's syndrome: A comprehensive review

Lymphocytic infiltration of different exocrine and non-exocrine epithelia is the pathological hallmark of primary Sjögren's syndrome, whereas involvement of salivary and lachrymal glands with the clinical counterpart of dry eye and dry mouth are the predominant features of the disease, together with fatigue and musculoskeletal pain. In addition, systemic manifestations, like arthritis, skin vasculitis, peripheral neuropathy, glomerulonephritis, may also be present in a consistent number of patients. As result, clinical features in SS can be divided into two facets: the benign subjective but disabling manifestations such as dryness, pain and fatigue, and the systemic manifestations. In the past decades, great efforts have been made to develop valid tools for the assessment of these both facets. Disease specific questionnaires such as Profile of Fatigue and Discomfort (PROFAD) and Sicca Symptom Inventory (SSI) have been proposed for evaluation of patients' symptoms, whereas different composite indexes have been suggested for the assessment of systemic disease activity. After that, an international project supported by EULAR, emerged to develop consensus disease activity indexes: the EULAR Sjögren's Syndrome Patients Reported Index (ESSPRI), and the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), a systemic activity index to assess systemic manifestations. Both EULAR indexes have been developed in an international collaboration to be consensual. Both indices have now been validated in a large independent international cohort. They both have been shown to be feasible, valid and reliable instruments. Also, we have found that these two scores did not correlate, suggesting that these two indexes assess two different disease components that poorly overlap, but were complementary. The sensitivity to change of both scores has been assessed, they are both able to detect change, however, ESSDAI score, like other systemic score, is more sensitive to change than ESSPRI and other patient scores. Current work is ongoing to define disease activity levels and clinically important changes for defining significant clinical improvement with the systemic score ESSDAI, and ESSPRI. We hope that this increased knowledge on the way to assess patients with primary SS, along with the emergence of new targeted therapy, will put a great input in the improvement of conduction of clinical trials in pSS.     

Classification criteria of Sjögren's syndrome

Sjögren's syndrome (SS) is a chronic, systemic autoimmune disease that affects typically the exocrine glands causing mucosal dryness. Dry eyes and mouth are considered by far the most common and early symptoms of the disease but systemic complications may also occur. In 1993, the preliminary European criteria were proposed and widely accepted, consisting of both subjective and objective criteria. Almost ten years later, these classification criteria were revised by introducing more stringent rules and precise diagnostic procedures leading to the currently used American-European Consensus Group (AECG) criteria. The AECG criteria have been largely employed to conduct epidemiologic and clinical studies of patients with SS and proved to be more specific compared to the preliminary European criteria. The recent American College of Rheumatology/Sjögren's International Collaborative Clinical Alliance (ACR/SICCA) criteria that are based exclusively on objective tests, the stringency of the AECG criteria and the potential therapeutic use of biologic agents in SS clearly set the need for new classification criteria. Whether the new diagnostic approach will further encompass subclinical and early forms of the disease remains to be addressed by the scientific community.     

A short review of the pathogenesis of Sjögren's syndrome

Sj?gren's syndrome can present in a heterogeneous manner with symptoms varying from systemic features such as unexplained fever, weight loss and neurological manifestations to the more typical symptoms of dry mucus membranes. There is discussion of the wide differential diagnosis, followed by a brief overview of the diagnosis, extraglandular manifestations and pathogenesis of primary Sj?gren's syndrome.     

Autoantigen-specific memory B cells in primary Sjögren's syndrome

Sjögren’s syndrome (SS) is a systemic rheumatic autoimmune disease affecting the exocrine glandular function and is characterized by the presence of autoantibodies against the ribonucleoprotein particles, SS‐A/Ro and SS‐B/La, and mononuclear cell infiltration of exocrine tissues. Our aim is to characterize memory B cell pattern and function in relation to the progression of the disease, by analysing samples from a well‐defined cohort of patients with primary SS. We have measured the number of Ro/La‐specific plasma cells in peripheral blood mononuclear cells (PBMC) from 23 patients and 20 healthy controls by direct enzyme‐linked immunospot (ELISPOT) assay. Furthermore, we quantified the Ro‐ and La‐specific memory B cells in these individuals by a 6‐day in vitro polyclonal stimulation of PBMC followed by an antigen‐specific ELISPOT assay for the detection of memory B cells. In addition to this, ELISA profiling of autoantibodies was carried out using patients’ plasma and supernatant, collected post‐mitogen stimulation of PBMC. The average Ro60‐, Ro52‐ and La48‐specific plasma cells in PB was 9, 17 and 13 cells in 10⁵ PBMC, respectively. After in vitro stimulation, these numbers increased to 43, 50 and 26 for Ro60, Ro52 and La48, correspondingly. However, the fraction of memory B cells activated into antibody‐secreting cells was lower than the overall IgG B cell population. We conclude that these lower Ro/La‐specific memory B cell levels may indicate that a greater portion of the Ro‐ and La‐specific B cells are in an activated stage. This is in tune with previous reports.     

Primary biliary cirrhosis complicated by transverse myelitis in a patient without Sjögren's syndrome

Transverse myelitis is an acute inflammatory process, affecting one or more segments of the spinal cord. Its association with primary biliary cirrhosis has been documented in only four cases--all along with Sj?gren's syndrome. Herein, we report for the first time, a patient who developed recurrent acute transverse myelitis in association with primary biliary cirrhosis without any clinical or histological indication of Sj?gren's syndrome. A 42-year-old woman with primary biliary cirrhosis developed acute onset quadriparesis and urinary retention. Diagnostic evaluation excluded the presence of Sj?gren's syndrome, other autoimmune syndromes, infections and multiple sclerosis. Magnetic resonance imaging of the spinal cord disclosed signal intensity abnormalities from C1 to T2 after gadolinium enhancement. As diagnosis of acute transverse myelitis was prominent, the patient was treated with intravenous methylprednisolone. The patient had a fair outcome despite an early recurrence of the symptoms after treatment withdrawal.     

Variant form of STAT4 is associated with primary Sjögren's syndrome

Single nucleotide polymorphisms in the STAT4 gene have recently been shown to be associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Primary Sj?gren's syndrome (pSS) is a related autoimmune disease thought to have a pathogenesis similar to these diseases. To test the hypothesis that the variant haplotype of STAT4 seen in RA and SLE is also associated with pSS, we genotyped rs7574865, the most strongly disease-associated SNP in the variant STAT4 haplotype, in 124 Caucasian pSS subjects and compared them to 1143 Caucasian controls. The disease-associated T allele was more common in chromosomes of the pSS patients (29.6%) than in controls (22.3%), leading to a P-value for association of 0.01. These results implicate polymorphisms in the STAT4 gene in the pathogenesis of pSS.     

Phenotypic diversity of peripheral blood plasma cells in primary Sjögren's syndrome

Production of autoantibodies is one of the main features of primary Sjögren’s syndrome (pSS). Long‐lived plasma cells (PC) can produce autoantibodies for prolonged period of times without being affected by immunosuppressive therapies. As of today, little is known about the long‐lived PC subset and their contribution to autoimmunity. We have characterized the phenotypic and migratory properties of peripheral blood PC isolated from pSS patients (grouped by focus score, FS) and compared them to PC from rheumatoid arthritis (RA) patients and normal non‐autoimmune subjects. We observed two populations of PC in all study groups, CD19+ PC and CD19? PC. Interestingly, the CD19? PC subset was most prominent in autoimmune patients (pSS and RA) compared to normal controls. Further investigation of the PC phenotype revealed that a high percentage of both CD19+ and CD19? PC isolated from pSS and RA patients did not express the CD27 marker, which is normally highly expressed on all types of PC. Differences in the expression of markers such as IgM, IgG, CD95 and CXCR3 in the group with high FS compared to FS = 1, underscore the heterogeneity of pSS patient group and demonstrate that phenotypic pattern of circulating PC associates with the severity of inflammation in the salivary glands of these patients. Our migration experiments show that addition of CXCL12 to PC in vitro, do not alter the migration potential of PC in any group tested. However, we observed an overall higher spontaneous migration of PC from pSS compared to both RA and normal controls.     

Non-Hodgkin's lymphoma & primary biliary cirrhosis with Sjögren's syndrome

Sj?gren's syndrome (SS) is an autoimmune disease characterized by a lymphocytic infiltration of the salivary and lacrimal glands leading to a progressive destruction of these glands due to the production of autoantibodies. This disorder is either isolated (primary SS) or associated with other systemic diseases (secondary SS). The occurrence of B-cell non-Hodgkin's lymphoma (NHL) represents the major complication in the evolution of SS patients. The risk of developing NHL, which is equivalent for both primary and secondary SS, was estimated to be 44 times greater than that observed in a comparable normal population. NHLs in SS patients occur preferentially in the salivary glands and in other mucosa-associated lymphoid tissues (MALT). However, it can also occur in the lymph nodes or bone marrow. We documented a case of low-grade B-cell lymphoma of MALT in the right eyelid and primary biliary cirrhosis (PBC) of a patient with SS. To the best of our knowledge, this is the first case reported in Korea.     

Differentiation of follicular helper T cells by salivary gland epithelial cells in primary Sjögren's syndrome

Follicular helper T cells (Tfh), which play a pivotal role in B cell activation and differentiation in lymphoid structures, secrete IL-21 whose augmented secretion is a hallmark of several autoimmune diseases. To decipher the cellular and molecular interactions occurring in salivary glands of patients suffering from primary Sjögren's syndrome (pSS), we investigated whether salivary gland epithelial cells (SGECs) were capable to induce Tfh differentiation. Co-cultures of naïve CD4⁺ T cells and SGECs from both patients with pSS and controls were performed. Here, we report that IL-6 and ICOSL expression by SGECs contributes to naïve CD4⁺ T differentiation into Tfh cells, as evidenced by their acquisition of a specific phenotype, characterized by Bcl-6, ICOS and CXCR5 expression and IL-21 secretion, but also but by their main functional feature: the capacity to enhance B lymphocytes survival. We demonstrated an increase of serum IL-21 with systemic activity. Finally, we analyzed the potential occurrence of a genetic association between IL-21 or IL-21R gene polymorphisms and pSS or elevated IL-21 secretion. This study, which demonstrates a direct induction of Tfh differentiation by SGECs, emphasizes a yet unknown pathogenic role of SGECs and suggests that Tfh and IL-21 might be relevant biomarkers and/or therapeutic targets in primary Sjögren's syndrome.     

Sjögren's syndrome: A forty-year scientific journey

My long scientific journey studying as a disease model Sjogren's syndrome (SS) gave me the opportunity to uncover the mysteries of systemic autoimmune diseases. After an extensive training, under the supervision of the major autoimmune disease investigators, I was able to convey and expand the acquired knowledge through inspiring my students and collaborators. Our research enriches the understanding of the wide clinical spectrum of the syndrome and the clinical, laboratory and molecular events predicting or being responsible for lymphomagenesis. Our molecular and cellular studies indicated that the target of autoimmunity in SS, the activated glandular epithelial cells, play significant role in the initiation and perpetuation of the autoimmune process. Furthermore, discovery of the epitopes on autoantigens where the autoimmune humoral reactivity is directed against, provided us tools to develop specific and sensitive diagnostic assays, to unmask similarities of the epitope sequence with infectious agents and gave us the potential to use them as therapeutic modalities.