Apoptosis and estrogen deficiency in primary Sjögren syndrome

PURPOSE OF REVIEW: Primary Sj?gren syndrome is an autoimmune disorder characterized by lymphocytic infiltrates and destruction of the salivary and lacrimal glands, and systemic production of autoantibodies to the ribonucleoprotein particles SS-A/Ro and SS-B/La. The purpose of this review is to discuss recent advances in the pathogenesis of primary Sj?gren syndrome. RECENT FINDINGS: Although several candidate autoantigens including alpha-fodrin have been reported in Sj?gren syndrome, the pathogenic roles of the autoantigens in initiation and progression of SS are still unclear. It is possible that individual T cells activated by an appropriate self antigen can proliferate and form a restricted clone. Recent evidence suggests that the apoptotic pathway plays a central role in tolerizing T cells to tissue-specific self antigen, and may drive the autoimmune phenomenon. Cleavage of certain autoantigens during apoptosis may reveal immunocryptic epitopes that could potentially induce autoimmune response. The studies reviewed imply that Fas-mediated cytotoxicity and caspase-mediated alpha-fodrin proteolysis are involved in the progression of tissue destruction in Sj?gren syndrome. Fas ligand (FasL), and its receptor Fas are essential in the homeostasis of the peripheral immune system. It can be considered that a defect in activation-induced cell death of effector T cells may result in the development of autoimmune exocrinopathy in Sj?gren syndrome. SUMMARY: Although the mechanisms by which estrogen deficiency influences autoimmune lesions remain unclear, it is possible that antiestrogenic actions might be a potent factor in the formation of pathogenic autoantigens.     

Gastrointestinal and liver lesions in primary childhood Sjögren syndrome

Clinical Rheumatology - Sjögren syndrome (SS) is characterized by lymphocytic infiltration of exocrine glands, mainly the lacrimal and salivary glands, leading to keratoconjunctivitis sicca...     

Small fibre neuropathy in primary Sjögren syndrome

Purpose

About forty percent of the patients with primary Sjögren's syndrome (pSS) experience chronic neuropathic pain with normal electrodiagnostic studies. Two previous studies suggest that chronic neuropathic pain in pSS is due to small fiber neuropathy (SFN). Quantification of epidermal nerve fiber density after skin biopsy has been validated to diagnose small fiber neuropathy.

Methods

Skin biopsy was performed in 14 consecutive pSS patients (satisfying the american-european classification criteria) with chronic neuropathic pain and normal electrodiagnostic studies suggesting SFN.

Résults

Fourteen female pSS patients exhibited chronic neuropathic pain [burning sensation (n = 14), prickling (n = 4), dysesthesia (n = 8)] with paroxystic exacerbations (n = 10) and allodynia (n = 13), for a mean period of 18.4 ± 12.4 months. Neuropathic pain involved mostly hands and feet (n = 13), with a distal (n = 9) and leg (n = 4) predominant distribution. Neurological examination disclosed normal deep tendon responses and absence of motor weakness (n = 14). Small fiber neuropathy was confirmed by skin biopsy in 13 cases. Epidermal nerve fiber density was decreased in distal [(n = 12), mean 3.5 ± 1.7 fibers/mm (N > 6.9)] and proximal site of biopsy [(n = 9), mean 7.04 ± 2.63 fibers/mm (N > 9.3)].

Conclusion

Small fiber neuropathy is commonly responsible of chronic neuropathic pain in pSS. Prevalence, physiopathology and neurological evolution of such neuropathies still remain unknown.     

Interstitial lung disease in primary Sjögren syndrome

BACKGROUND: Primary Sj?gren syndrome (pSS) has been associated with various histologic patterns of interstitial lung disease (ILD). METHODS: We retrospectively identified 18 patients with pSS and suspected ILD who underwent lung biopsies (14 surgical biopsies and 9 bronchoscopic biopsies) at our institution during a 13-year period from 1992 through 2004. Histopathologic findings were analyzed and correlated with radiologic features and outcome. RESULTS: Median age was 62 years (range, 34 to 78 years), and 15 patients (83%) were women. Most patients presented with dyspnea and cough. Chest radiographs demonstrated bilateral infiltrates, and high-resolution CT revealed abnormalities of various types including ground-glass, consolidation, reticular, and nodular opacities. The major histopathologic patterns included nonspecific interstitial pneumonia (NSIP) [five patients], organizing pneumonia (OP) [four patients], usual interstitial pneumonia (UIP) [three patients], lymphocytic interstitial pneumonia (three patients), primary pulmonary lymphoma (two patients), and diffuse interstitial amyloidosis (one patient). In four patients (three with OP and one with amyloidosis), the diagnosis was established on transbronchial biopsy results. Treatment commonly included prednisone with or without another immunosuppressive agent. During the follow-up period (median, 38 months), most patients improved or remained stable except three patients with UIP, one patient with NSIP, and one patient with amyloidosis. Seven patients (39%) died, including three deaths from acute exacerbation of interstitial pneumonia. CONCLUSIONS: A variety of histologic patterns can be seen in patients with pSS-associated ILD. Those with UIP tended to have progression of lung disease. Death from acute exacerbation of interstitial pneumonia may occur in patients with pSS-associated ILD.     

Clinically significant and biopsy-documented renal involvement in primary Sjögren syndrome

Clinically significant renal involvement in patients with primary Sj?gren syndrome (pSS) has been described previously only in isolated case reports. The prevalence and significance of the 2 described syndromes, interstitial nephritis (IN) and glomerulonephritis (GMN), are not well known. In a cohort of 471 patients with pSS who were followed for a mean of 10 years, 20 patients (4.2%) developed overt renal disease. Eighteen patients underwent a percutaneous renal biopsy; 2 patients declined. Ten patients had IN, 8 patients had GMN, and 2 patients presented with both entities. Glomerular histology disclosed changes compatible with membranoproliferative GMN in 5 patients and mesangial proliferative GMN in 4 patients. Patients with IN had a younger disease onset compared with patients with GMN (mean, 36.8 compared with 46.0 yr, p 5 0.063). Patients with GMN had longer disease duration compared with patients with IN (mean, 2.2 compared with 8.0 yr, p 5 0.001). The majority of patients with GMN (80%) had mixed monoclonal cryoglobulinemia IgMk (type II) and lower complement C4 levels. Two patients (both with GMN) developed chronic renal failure requiring hemodialysis. Overall, clinically significant renal involvement is infrequent in pSS. IN occurs early in the disease process, while GMN is a late sequela and may have a less favorable prognosis.     

Prognosis and outcome of non-Hodgkin lymphoma in primary Sjögren syndrome

Sj?gren syndrome (SS) has been associated with the development of non-Hodgkin lymphoma (NHL). From a cohort of 584 SS patients followed in our department from 1980 to 2010, we retrospectively analyzed 53 consecutive NHL cases. Considerations included histologic type, clinical manifestation and NHL staging, treatment, response rate and overall survival (OS), event-free survival (EFS), and standardized mortality ratio (SMR).Mucosa-associated lymphoid tissue (MALT) lymphomas constituted the majority (59%) of NHL subtypes, followed by nodal marginal zone lymphomas (NMZLs) (15%) and diffuse large B-cell lymphomas (DLBCLs) (15%). Six lymphoma patients died during the median follow-up of 40.8 months. The corresponding age/sex-adjusted SMR of SS with and without NHLs versus the general population was 3.25 (95% confidence interval [CI] 1.32-6.76) and 1.08 (95% CI, 0.79-1.45), respectively. A "watch and wait" policy was adopted for 9 patients with asymptomatic localized salivary MALT lymphomas. Eight patients with limited-stage MALT lymphomas and extraglandular manifestations were treated with rituximab. Ten MALT lymphoma patients with disseminated disease received chemotherapy with or without rituximab. The 3-year OS and EFS in patients with MALT lymphomas was 97% and 78%, respectively. Rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) was the chosen therapeutic intervention for patients with DLBCLs. A successful outcome was recorded for this group, with 100% OS and EFS at 3 years. Patients with NMZLs had a less favorable outcome, with a 3-year OS of 80% and EFS of 53%. Our results describe the course and prognosis of SS-associated NHL and highlight the need for a risk-stratified treatment approach.     

Polymyalgia rheumatica in primary Sjögren’s syndrome

The aim of the study was to describe the clinical and laboratory aspects of primary Sjögren’s syndrome (pSS) associated with polymyalgia rheumatica (PMR). The retrospective study compares the clinical and laboratory aspects of patients with pSS associated with PMR on a relatively large cohort of patients (n=16) and pSS patients without PMR (n=531). The prevalence of PMR among pSS patients was 3%, while in the average population, the prevalence of PMR is only 0.75%. PMR developed 8.7 years after the diagnosis of pSS in the older female pSS population (over 50 years of age), and in those with only glandular features. Interestingly the pSS/PMR patients had hypo gammaglobuline levels, while in the pSS patient group hypergammaglobulinaemia presented. Furthermore, positive ANA serology was more frequent among pSS/PMR patients. Since the clinical management of pSS/PMR is different from pSS, a better understanding of this clinical entity is essential.     

Parotid gland non-Hodgkin lymphoma in primary Sjögren syndrome

The risk of malignant non-Hodgkin lymphoma is increased in primary Sjögren syndrome. In the literature, most studies evaluating this risk were conducted in tertiary reference university hospital. So, selection bias in series exists, in particular selection of the most severe cases in tertiary reference university care centers. Some studies had also a selection bias because patients were hospitalized (data were obtained from hospital discharge registries) and therefore the more severe cases were considered. Between October 1999 and November 2009, 109 adult patients were admitted to our department of internal medicine (non-university hospital, secondary level of the healthcare system, hospitalized patients and outpatient) with diagnosis of primary Sjögren syndrome. Two cases of parotid gland lymphoma occurred during the period of follow-up. No other lymphoma was detected. In this study, clinically identifiable parotid gland non-Hodgkin lymphoma occurs in 1.8% of patients with primary Sjögren syndrome. Because most non-Hodgkin lymphoma initially involves the neck organs, meticulous imaging studies mainly focused on the cervical regions are recommended in the follow-up of patients with primary Sjögren syndrome. Patients whose main complaint is persistent parotid gland swelling may have a parotid biopsy in order to diagnose non-Hodgkin lymphoma.     

Targeting primary Sjögren’s syndrome

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease that is estimated to affect 35 million people worldwide. Hallmarks of the disease are a loss of salivary and lacrimal gland function as well as lymphocytic infiltration, elevated proinflammatory cytokines, and circulating autoantibodies. Patients often experience significant fatigue and a decrease in their quality of life. Approximately 30–50% of pSS patients develop extra-glandular manifestations including malignant lymphoma. Although therapeutic approaches for pSS target both dryness and systemic manifestations, effective treatments are limited. However, new therapies targeting specific immune pathways associated with pSS are being developed. This review describes current and future targeted therapies against pSS.     

Update in Sjögren syndrome

Sj?gren syndrome (SS), the second most common autoimmune rheumatic disease, refers to keratoconjunctivitis sicca and xerostomia resulting from immune lymphocytes that infiltrate the lacrimal and salivary glands. However, differential diagnosis remains confusing due to the high prevalence of vague symptoms of dryness, fatigue, and myalgias in the general population. The problems of diagnosis are further compounded by the finding of "positive" antinuclear antibodies in a high percent of the general population. Unless minor salivary gland biopsies are read by experienced observers, nonspecific changes of sialadenitis are frequently confused with the focal lymphocytic infiltrates that are characteristic of SS. The distinction between fibromyalgia patients with low titer antinuclear antibodies and primary SS remains difficult. Even in patients fulfilling strict criteria for SS, the genomic search for critical genes has proven difficult due to the multigenic pattern of inheritance and strong role of currently undefined environmental factors. No single environmental factor has been detected in the majority of SS patients. SS-like syndrome has been detected in certain patients with HTLV-1 and hepatitis C infection, providing clues to pathogenesis. Even in SS patients with marked sicca symptoms, minor salivary gland biopsy shows that almost 50% of glandular cells are still detected on biopsy. These results imply the importance of immune factors such as cytokines and autoantibodies in decreasing neuro-secretory circuits and induction of glandular dysfunction. Of potential importance, an antibody against muscarinic M3 receptor that can decrease secretory function when injected into rodents is frequently found in the sera of SS patients. Newly developed topical and oral therapies can ease the oral and ocular dryness. Orally administered agonists of the muscarinic M3 receptor (pilocarpine and cevimeline) have recently been approved by the US Food and Drug Administration to increase salivary secretion. Topical ocular use of low-dose corticosteroids or cyclosporin may decrease conjunctival surface inflammation. In a Phase II double-blind study, orally administered interferon alpha (150 U) led to improved saliva flow and symptoms. In pregnant patients with evidence of fetal distress, oral dexamethasone is preferred because this agent crosses the placenta effectively. In animal models, antagonists of tumor necrosis factor and inhibitors of de novo pyrimidine synthesis appear promising.     

Apoptosis and Sjögren syndrome

OBJECTIVE: To examine the role of apoptosis in the pathogenesis of Sj?gren syndrome (SS), a chronic autoimmune disease characterized by the infiltration of mononuclear cells in the salivary and lacrimal glands, leading to the destruction of the parenchymal tissue. METHODS: A detailed search via MEDLINE (PubMed) and Biosis, covering the period from January 1994 to July 2002, was accomplished, combining the key terms SS and apoptosis. A qualitative review of the articles was undertaken and the obtained information was summarized. RESULTS: Apoptosis of the acinar and ductal epithelial cells of the salivary and lacrimal glands has been proposed as a possible mechanism responsible for the impairment of secretory function. Apoptotic cell death may be induced by either cytotoxic T cells through the release of proteases, such as perforin and granzyme B, or the interaction of Fas ligand (FasL/CD95L), expressed by T lymphocytes, with Fas (Apo-1/CD95) on epithelial cells. The increased rate of apoptosis of epithelial cells in SS may result from either the imbalance between the down-regulated apoptosis-inhibitor Bcl-2 and the up-regulated apoptosis-inducer Bax, or the autocrine and/or paracrine Fas/FasL interaction. Lymphocytes infiltrating the salivary glands are blocked in their ability to commit to apoptosis, despite the expression of the apoptosis-inducer Fas. The expression of Bcl-2 in these cells may explain their resistance to apoptosis, resulting in a prolonged production of proinflammatory cytokines and autoantibodies, as well as in their longer survival that may result in the late development of lymphoma in some SS patients. Studies of the SS-like sialoadenitis of nonobese diabetic (NOD) mice with severe combined immunodeficiency (NOD.scid) suggest that the primary defect responsible for the initiation of SS resides in the epithelial cells that undergo apoptosis mediated by the autocrine Fas/FasL interaction. This first not-immune-mediated phase of target cell destruction is followed by a lymphocyte-dependent autoimmune aggression, which leads to extensive tissue damage and subsequent loss of secretory function. Apoptosis of the salivary epithelial cells has been shown in other animal models of SS and in cell lines in vitro. Apoptosis may also play a role in the pathogenesis of some extraglandular manifestations of SS, such as interstitial nephritis and peripheral CD4(+) lymphocytopenia. CONCLUSIONS: The possible role of apoptosis in SS is suggested from the literature review. A better understanding of the mechanisms responsible for the epithelial cell apoptosis may allow the discovery of new therapeutic strategies. By inhibiting programmed cell death, the glandular damage and the subsequent impairment of the secretory function should be reduced.     

Exposure-lag-response associations between extreme environmental conditions and primary Sjögren’s syndrome

Clinical Rheumatology - Patients with primary Sjögren’s syndrome (pSS) reportedly believe that their symptoms worsen on extreme weather days due to variations in environmental...     

Persistent serological activity in primary Sjögren’s syndrome

Clinical Rheumatology - To assess the presence of persistent serological activity and its association with clinical outcomes in primary Sjögren’s syndrome. Clinical charts of 275...     

Neurological manifestations in Sjögren syndrome

PURPOSE: To describe clinical and physiopathological aspects of neurological involvement in neurological Sj?gren syndrome (SS) and to overview biological markers and therapeutical aspects. CURRENT KNOWLEDGE AND KEY POINTS: Neurological complications during SS may occur between 8.5 and 70%. Peripheral nervous system (PNS) involvement is well none but data concerning central nervous system (CNS) symptoms have been rarely described. In the present study we detail more precisely the heterogeneity of the neurological manifestation in SS. Recently new biological of SS such as alpha-fodrin antibodies have been described but there interest remain controversial. Furthermore, therapeutical data are scarce and there is to date no consensual guidelines for the therapeutical approach. PERSPECTIVE: Recent data concerning neurological involvement in SS confirm the heterogeneity of clinical presentations that may mimic stroke or multiple sclerosis. They underline the need for new biological markers. Furthermore, multicentric, randomized trials should be assessed in order to give us some therapeutical guidelines.     

Nephrocalcinosis and hypokalemia in a patient with primary Sjögren’s syndrome

Clinically significant renal involvement is uncommon in primary Sjögren’s syndrome, amid which tubulointerstitial disorders, distal renal tubular acidosis (dRTA) particularly, account for the majority. Conversely, Sjögren’s syndrome comprises at least half the patients presenting with renal tubular acidosis. While underlying dRTA itself is an important cause of nephrocalcinosis and urolithiasis, nephrocalcinosis is rarely a presenting feature of primary Sjögren’s syndrome. I report a 41-year-old female contracting nephrocalcinosis and hypokalemia as complications of primary Sjögren’s syndrome with dRTA, hereby to emphasize the importance of alkali therapy.     

Early onset primary Sjögren syndrome,clinical and laboratory characteristics

Clinical Rheumatology - Primary Sjögren syndrome (pSS) is usually encountered between the fourth and sixth decades. It is known that the age of onset in autoimmune diseases may affect the...