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ID PMID Title PublicationDate abstract
24798574 G protein-coupled receptors in rheumatology. 2014 Jul G protein-coupled receptors (GPCRs) are transmembrane receptor proteins that allow the transfer of signals across the cell membrane. In addition to their physiological role, GPCRs are involved in many pathophysiological processes including pathways relevant in rheumatoid arthritis (RA), osteoarthritis (OA) and psoriatic arthritis. Two-thirds of all currently available drugs target GPCRs directly or indirectly. However, the detailed mechanism of GPCR signalling is still unclear. Selective modification of GPCR-dependent signalling cascades to inhibit disease progression in rheumatic diseases is now being investigated. One approach is to use antibodies against ligands activating GPCRs. However, several GPCRs are known to be activated by only one ligand. In this case, targeting the receptor itself is a promising approach. So far, more information is available on GPCR action in RA as compared with OA, and even less information is available for other rheumatic diseases. Additional research on the role of GPCRs involved in the pathophysiology of rheumatic diseases is required to develop specific therapeutic approaches.
24789004 Restarting biologics and management of patients with flares of inflammatory rheumatic diso 2014 May Our aim was to review the evidence concerning optimal timing for restarting biologics in patients with active tuberculosis (TB), and the management of relapsing rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and psoriasis during treatment for TB. Few or no indications are available for 2 important challenges for clinicians: the timing for restarting biologics in patients with TB reactivation and the management of the underlying disorder. In the absence of clear evidence, guidelines and experts suggest restarting anti-tumor necrosis factor-α (TNF-α) agents after completion of an active TB therapy course, but no indications are available on the appropriate management of patients with flares of underlying rheumatic disease or psoriasis. Among anti-TNF-α agents, etanercept is associated with the lowest risk of TB reactivation, and non-anti-TNF-α biologics and several nonbiologic drugs are associated with low/no risk of TB reactivation. Therefore, for patients with relapsing RA, PsA, AS, or psoriasis during TB treatment we propose a therapeutic schedule modulated by disease activity and individual single drug-related TB risk.
24378277 Autoimmune liver disorders and small-vessel vasculitis: four case reports and review of th 2013 Jan Autoimmune liver diseases (AILD) are a group of immunologically induced hepatic disorders that can lead to liver cirrhosis and end-stage liver disease. Extra-hepatic involvement and association with rheumatic diseases (such as Sjögren's syndrome, systemic sclerosis and rheumatoid arthritis) are well known, whereas the coexistence of AILD with small-vessel vasculitis in the same patients have been only occasionally reported. In the present paper we report four such cases and an extensive review of the literature. Clinical features of autoimmune-liver diseases associated with small-vessel vasculitis are discussed, as well as possible common pathogenic pathways including HLA genomics, costimulatory molecules and autoantibodies. In conclusion, knowledge about this association can help physicians in recognising and treating an aggressive disease which could otherwise result in severe and multiple organ damage, compromising the overall prognosis and the indication to liver transplantation.
25789373 The role of peripheral nerve fibers and their neurotransmitters in cartilage and bone phys 2014 The peripheral nervous system is critically involved in bone metabolism, osteogenesis, and bone remodeling. Nerve fibers of sympathetic and sensory origin innervate synovial tissue and subchondral bone of diathrodial joints. They modulate vascularization and matrix differentiation during endochondral ossification in embryonic limb development, indicating a distinct role in skeletal growth and limb regeneration processes. In pathophysiological situations, the innervation pattern of sympathetic and sensory nerve fibers is altered in adult joint tissues and bone. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters. Osteoblasts, osteoclasts, mesenchymal stem cells, synovial fibroblasts, and different types of chondrocytes produce distinct subtypes of adrenoceptors, receptors for vasointestinal peptide, for substance P and calcitonin gene-related peptide. Many of these cells even synthesize neuropeptides such as substance P and calcitonin gene-related peptide and are positive for tyrosine-hydroxylase, the rate-limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters modulate osteo-chondrogenic differentiation of mesenchymal progenitor cells during endochondral ossification in limb development. In adults, sensory and sympathetic neurotransmitters are critical for bone regeneration after fracture and are involved in the pathology of inflammatory diseases as rheumatoid arthritis which manifests mainly in joints. Possibly, they might also play a role in pathogenesis of degenerative joint disorders, such as osteoarthritis. All together, accumulating data imply that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for proper limb formation during embryonic skeletal growth. In adults, they modulate bone regeneration, bone remodeling, and articular cartilage homeostasis in addition to their classic neurological actions.
23473929 Evidence supporting a role for dormant bacteria in the pathogenesis of spondylarthritis. 2013 Mar Spondylarthritis is still viewed as a reaction to infectious agents, as opposed to an infection by persistent bacteria, for several reasons: (a) an infection is considered proven only when the organism can be cultured; (b) no studies have identified dormant bacteria in the tissues targeted by spondylarthritis; (c) the bacterial persistence hypothesis has no therapeutic implications at the time being, since antibiotics are effective neither on dormant bacteria nor on the manifestations of spondylarthritis; and (d) the high prevalence of borderline disorders combining features of spondylarthritis and of psoriatic arthritis, or even rheumatoid arthritis (RA), would indicate a role for dormant bacteria in these last two diseases. However, recent data on dormant bacteria have rekindled interest in the bacterial persistence hypothesis. Dormant bacteria cannot be cultured, because they express only a small group of genes, known as the regulon, which includes genes for transcription factors that block the expression of the usual bacterial genes. Certain forms of cell stress, such as molecule misfolding, promote the entry of bacteria into a state of dormancy, which induces the low-level release by the host cells of cytokines such as TNF. Whether HLA-B27 misfolding facilitates the persistence of dormant bacteria within spondylarthritis tissue targets remains to be determined. If it does, then treatments that reactivate dormant bacteria might make these organisms susceptible to appropriate antibiotics and might therefore serve as useful adjuncts to nonsteroidal anti-inflammatory drugs and TNFα antagonists. TNFα antagonists rarely reactivate dormant bacteria, with the exception of Mycobacterium tuberculosis, which, together with metastatic cells, is the most extensively studied latency model to date.
23293906 Anti-inflammatory role and immunomodulation of mesenchymal stem cells in systemic joint di 2013 Mar INTRODUCTION: Mesenchymal stem cells (MSCs) are multipotent stromal cells characterized by their ability to differentiate into adipocytes, chondrocytes, osteocytes and a number of other lineages. Investigation into their use has increased in recent years as characterization of their immunomodulatory properties has developed, and their role in the pathophysiology of joint disease has been suggested. AREAS COVERED: MSCs demonstrate immunosuppressive functionality by suppressing T- and B-cell responses following activation by cytokines such as IL-6 and IL-1α. They also can be induced to exert pro-inflammatory effects in the presence of acute inflammatory environment due to the actions of TNF-α and IFN-γ. In inflammatory joint diseases such as rheumatoid arthritis, MSCs in bone marrow migrate to joints by a TNF-α-dependent mechanism and may be in part responsible for the disease process. MSCs have also been demonstrated in increased numbers in periarticular tissues in osteoarthritis, which may reflect an attempt at joint regeneration. EXPERT OPINION: Clinical applications for MSCs have shown promise in a number of inflammatory and autoimmune disorders. Future work is likely to further reveal the immunosuppressive characteristics of MSCs, their role in the pathophysiology of joint diseases and provide the basis for new avenues for treatment.
25608693 The value of glucocorticoid co-therapy in different rheumatic diseases--positive and adver 2014 Nov 13 Glucocorticoids play a pivotal role in the management of many inflammatory rheumatic diseases. The therapeutic effects range from pain relief in arthritides, to disease-modifying effects in early rheumatoid arthritis, and to strong immunosuppressive actions in vasculitides and systemic lupus erythematosus. There are multiple indications that adverse effects are more frequent with the longer use of glucocorticoids and use of higher dosages, but high-quality data on the occurrence of adverse effects are scarce especially for dosages above 10 mg prednisone daily. The underlying rheumatic disease, disease activity, risk factors and individual responsiveness of the patient should guide treatment decisions. Monitoring for adverse effects should also be tailored to the patient. Continuously balancing the benefits and risks of glucocorticoid therapy is recommended. There is an ongoing quest for new drugs with glucocorticoid actions without the potential to cause harmful effects, such as selective glucocorticoid receptor agonists, but the application of a new compound in clinical practice will probably not occur within the next few years. In the meantime, basic research on glucocorticoid effects and detailed reports on therapeutic efficacy and occurrence of adverse effects will be valuable in weighing benefits and risks in clinical practice.
24574025 Relationship between levels of neuropeptide Substance P in periodontal disease and chronic 2014 May The aim of the current review was to investigate the relationship between levels of neuropeptide Substance P in periodontal disease and chronic pain. Substance P is a neuropeptide that is directly related with pain. In periodontal disease, it is expressed during the inflammatory process, and is one of the factors responsible for bone resorption. Studies have shown that Substance P levels are highest in the gingival crevicular fluid from sites with active periodontal disease and bone loss. The persistence of these substances could be sufficient to stimulate neurogenic inflammation in susceptible tissues, and cause pain. The scientific literature shows that Substance P expressed during periodontal disease can be a risk factor for patients with systemic inflammatory pathologies, such as chronic arthritis or rheumatoid arthritis. Additional research is needed to confirm the participation of this substance in the origin of some types of chronic pain.
23923383 Albumin as a drug delivery and diagnostic tool and its market approved products. 2013 Jul Albumin is one of the most extensively studied endogenous proteins which are used in the fabrication of drug delivery and diagnostic technologies during last 10 years. This review provides a summary of products involving the use of albumin as a drug delivery tool for getting better the pharmacokinetics of a drug by developing the targetted drug delivery systems and diagnosing the pathologies. Using albumin, following market approved products have been developed: Levemir and Victoza (antidiabetic product), Abraxane (antimetastatic breast cancer product), and Nanocoll and Albures (for lymphoscintigraphy and diagnosis of cancer and rheumatoid arthritis).
23546688 Therapeutic potential of SIGIRR in systemic lupus erythematosus. 2013 Aug Single immunoglobulin IL-1-related receptor (SIGIRR), which is also known as Toll/interleukin-1 receptor 8, is a member of the interleukin-1 receptor (IL-1R) family. Different from other typical IL-1R superfamily members, SIGIRR seems to exert negatively modulates in immune responses. Several previous studies demonstrated that SIGIRR influences chronic inflammatory or autoimmune diseases, such as intestinal inflammation, rheumatoid arthritis and psoriatic arthritis. Recent work has explored the role of SIGIRR in systemic lupus erythematosus (SLE), for example, the role of SIGIRR protects the mice from hydrocarbon oil-induced lupus has been reported. These results indicate that SIGIRR may represent a novel target for the treatment of SLE. In this review, we will discuss the SIGIRR and the therapeutic potential of modulating the pathway in SLE.
25603589 Early treatment of psoriatic arthritis improves prognosis. 2014 Dec Psoriatic arthritis (PsA) is a chronic, autoimmune disease, affecting up to 1% of the adult population and up to 40% of those with psoriasis. There is no universally accepted definition or diagnostic criteria for the disease although the CASPAR classification of PsA is now the most widely used. PsA has a peak age of onset between 35 and 55 years with an equal gender distribution. Around 20% of patients develop PsA before psoriasis, often many years before skin or nail changes. Enthesitis, pain and tenderness at the insertion of any tendon onto the bone, is characteristic and screening for enthesitis should include palpation of the lateral epicondyle of the humerus, the medial condyle of the femur and the achilles tendon insertion. Diagnosis of PsA relies on a detailed history, particularly as many of the manifestations may be mild or transient, and therefore not reported by the patient. There may be a previous, current, or family history of psoriasis. There are no diagnostic blood tests for PsA. The presence of rheumatoid factor or anti-CCP antibodies does not preclude a diagnosis of PsA, but should prompt careful scrutiny of the diagnosis. X-rays of the hands and feet should be performed at baseline for all those with suspected inflammatory arthritis. Features of back pain that suggest an inflammatory cause, rather than a mechanical problem, include the presence of early morning stiffness and pain that is relieved by exercise and exacerbated by rest. Any patient with suspected inflammatory arthritis and a six-week history of painful, swollen joints should be referred for specialist assessment. Patients with PsA have a higher self-rated disease severity than those with psoriasis only and a 60% higher risk of premature mortality than the general population, their life expectancy is estimated to be approximately three years shorter. Aggressive treatment of early stage progressive PsA can substantially improve the long-term prognosis.
25130893 Pathogenesis of juvenile idiopathic arthritis associated uveitis: the known and unknown. 2014 Sep Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and the most prevalent systemic disorder in children with uveitis. The current prevailing opinion is that JIA is a multifactorial, genetically predisposed autoimmune disorder that can be influenced by environmental factors and infections; the specific pathogenesis of JIA-associated uveitis is not understood, however, nor has the relationship between the eye and joint inflammation been established. Nevertheless, subtypes of JIA that are associated with uveitis, oligoarthritis, polyarticular rheumatoid factor negative, and psoriatic arthritis appear to have common pathogenicity. We summarize our current knowledge regarding the pathogenesis of JIA-associated uveitis and discuss the possible role of immune responses and cytokine involvement, genetic associations, and the influence of external triggers in this disease-an association that is supported by data obtained from arthritis research and experimental uveitis models.
25293642 Histopathological environment besides the focus score in Sjögren's syndrome. 2014 Nov AIM: To compare the prevalence of diverse histopathologic features among patients with Sjögren's syndrome (SS) and controls, and to evaluate their relationship with age, a focus score (FS) ≥ 1 and some clinical and serological SS features. METHODS: A blinded pathologist examined 63 SS and 11 control minor salivary gland biopsies. Focal lymphocytic sialadenitis (FLS) was defined as a focus score (FS) ≥ 1. We also evaluated lymphoepithelial lesions, germinal centers (GCs), epithelial metaplasia, dilatation and hyperplasia in the main secretory duct, perivascular cell infiltrate, adipose infiltration, acinar atrophy, interstitial fibrosis and lymphocytes/plasma cells remote from the FLS. We registered demographics, anti-Ro/La status and clinical features. We used Kendall's tau coefficients and logistic regression analysis. RESULTS: Sjögren's syndrome patients had a higher frequency of FS ≥ 1 (92% vs. 27%), acinar atrophy (78% vs. 18%), lymphocytes and plasma cells external to the FSL (92% vs. 64%) and stromal fibrosis (68% vs. 36%). A FS ≥ 1 correlated with the presence of GCs and acinar atrophy; whereas age correlated with duct dilation, duct epithelial hyperplasia, adipose infiltration and fibrosis. SS patients with hepatic involvement exhibited more frequent duct dilatation. After adjusting by age, anti-Ro/SSA (odds ratio [OR] 30.8, 95% CI 2.2-423.5, P = 0.01), a FS ≥ 1 (OR 54.3, 95% CI 4.8-612, P = 0.001) and fibrosis (OR 15.2, 95% CI 1.2-186.2, P = 0.03) were associated with SS. CONCLUSION: Other histologic findings coexist with FLS, but only GC formation and acinar atrophy correlated with a FS ≥ 1. Age is mostly correlated with the remaining histological features. However, the clinical relevance of these findings is unknown.
23983119 Epidemiology of primary Sjögren's syndrome in a French multiracial/multiethnic area. 2014 Mar OBJECTIVE: To describe the epidemiology of primary Sjögren's syndrome (SS) in a multiracial/multiethnic population. METHODS: A cross-sectional study with 5 case-retrieval sources identified adults with primary SS living in the Greater Paris area (population 1,172,482 adults) in 2007. Diagnoses were verified by the American-European Consensus Group (AECG) criteria and study-specific enlarged criteria based on the presence of ≥3 of 4 AECG items among subjective oral or ocular dryness, anti-SSA/SSB positivity, and positive minor salivary gland biopsy results. Prevalence estimates were standardized to those for the world population and a 5-source capture-recapture analysis (CRA) was used. Racial/ethnic differences in primary SS features were evaluated. RESULTS: In all, 133 subjects met the AECG criteria and 203 met the enlarged criteria. The 2007 prevalence of primary SS was 1.02 cases per 10,000 adults (95% confidence interval [95% CI] 0.85-1.22) for the AECG criteria and 1.52 cases per 10,000 adults (95% CI 1.30-1.76) for the enlarged criteria. The CRA indicated completeness of case findings of ∼90%. Compared to subjects with European backgrounds, those with non-European backgrounds had 2.1-2.3 times higher primary SS prevalence and were younger (P < 0.0001) and were more likely to have polyclonal hypergammaglobulinemia (P < 0.0001) and anti-SSA/SSB antibodies (P = 0.0005 and P < 0.0001 for the AECG and enlarged criteria, respectively). CONCLUSION: The figure of 1.02–1.52 cases per 10,000 adults we found and estimates from the few other population-based census surveys support that the prevalence of diagnosed primary SS is between 1 and 9 cases per 10,000 (0.01-0.09%) [corrected] in the general population. Non-European race/ethnicity may be associated with increased primary SS risk and a distinct disease profile.
23190440 Headache in primary Sjøgren's syndrome: a population-based retrospective cohort study. 2013 Mar BACKGROUND: We investigated whether the prevalence of primary headaches was higher in patients with primary Sjøgren's syndrome (PSS) than in healthy individuals. METHODS: This retrospective cohort study included 71 patients with PSS (patients) based on the American European Consensus Classification criteria, and 71 age- and gender-matched healthy subjects (controls). Headaches were classified according to the International Classification of Headache Disorders. We measured depression with the Beck Depression Inventory, and fatigue with the Fatigue Severity Scale. RESULTS: Fifty-one patients and 42 controls had headaches in the previous 12 months (71.8% vs. 59.2%, P = 0.10). Thirty-eight patients and 28 controls had tension type headaches (TTHs) (53.5% vs. 39.4%, P = 0.12). Eight patients (11.3%) and one control had chronic TTHs (P = 0.05). Migraines and migraines with aura were equally prevalent in patients (26.8% and 11.3%, respectively) and controls (28.2% and 15.5%, respectively; P = 0.61). CONCLUSIONS: In general, patients did not have more migraines or headaches than controls. However, patients had more chronic TTHs than controls. Chronic TTHs were not associated with PSS-related autoantibodies, fatigue, depression, abnormalities on magnetic resonance imaging or abnormalities in the cerebrospinal fluid. Patients with PSS did, however, have higher depression and fatigue scores than controls.
25297554 A retrospective, multicenter study evaluating the prognostic value of minor salivary gland 2015 Mar OBJECTIVE: The objective of this report is to investigate the prognostic value of minor salivary glands (MSG) assessment, routinely performed with hematoxilin-eosin (H&E) staining, for the diagnosis of primary Sjögren's syndrome (pSS). METHODS: We retrospectively evaluated clinical, serological and histological features of 794 pSS patients. H&E-stained sections were assessed using the Chisholm and Mason grading system and/or the focus score (FS). RESULTS: FS allowed the identification of a number of differences in the disease spectrum, and its prognostic role was further confirmed by quantifying the association between FS value and clinical/serological variables with binary logistic regression. Moreover, hypocomplementemia and FS resulted the only variables associated with lymphoma at univariate analysis, and FS appeared to be associated with lymphoma independently on complement fraction concentrations. Conversely, when patients were divided according to the Chisholm and Mason grading system, we failed to observe any significant difference between subgroups. CONCLUSION: In addition to its diagnostic role, our data seem to support that the routine assessment of MSG-FS with H&E staining is useful to predict at the time of diagnosis the adverse outcomes, such as lymphoma and extraglandular manifestations, that complicate the pSS course. On this basis, it should be recommended that an MSG biopsy be performed even in those patients displaying clinical and serological criteria, allowing the diagnosis of pSS independent of histological status.
25496408 In vivo confocal scanning laser microscopy in patients with primary Sjögren's syndrome: A 2015 Jul AIMS: (i) To analyze the in vivo corneal structure and sub-basal plexus nerves in patients with primary Sjögren's syndrome (pSS) and no-SS dry eye by confocal scanning laser microscopy (CSLM) and (ii) to correlate CSLM findings with tear function tests and with patients' subjective dryness. METHODS: Seventeen patients with pSS, 16 no-SS dry eye, and 20 healthy volunteers were included. CSLM parameters taken into consideration included: basal epithelial integrity, corneal thickness, epithelial cellular density, keratocyte activation, and sub-basal plexus morphology. Statistical analysis was carried out using SPSS-13 (Chicago IL, USA). RESULTS: CSLM pachymetric data and the superficial epithelium cell density were significantly lower in pSS versus no-SS dry eye (p < 0.0001); keratocyte activation and sub-basal nerve abnormalities were also more frequent in pSS patients (p < 0.0001). CSLM findings well correlated with both the ocular test results and the patients' perception of ocular dryness at the baseline and over the follow-up. CONCLUSION: CSLM might be a useful novel tool in the assessment of the involvement of the lachrymal functional unit in pSS.
25352896 Update knowledge of dry mouth- A guideline for dentists. 2014 Sep BACKGROUND: Dry mouth is usually caused by a reduced salivary flow or by changes in the biochemical composition of saliva. OBJECTIVE: The aim of this paper is a review of the update literature of dry mouth. METHODS: We search in pubmed in the past 10 years using the words «dry mouth», «causes», «symptoms», «treatment» and «dentistry». A large number of papers have been identified. Papers not relevant to the issue were removed reducing the entries to 56 only. RESULTS: There are no clearly established protocols for the treatment of dry mouth in the literature. Most of identified papers were systematic reviews, non-systematic reviews, and observational studies. The most studied patients were Sjögren's syndrome and the irradiated patients. Treatments are focused on the etiology, prevention, symptomatic, local salivary stimulation and systemic treatments. CONCLUSION: It can be concluded that there is no clear evidence for the causes and treatment of dry mouth, therefore the majority of the general dental practitioners refer most of the cases to appropriate specialist. Treatment must be individualized, salivary substitutes and mechanical stimulation techniques can be applied.
23986014 Minor salivary gland biopsy in Sjögren's syndrome: a review and introduction of a new too 2014 Jan 1 OBJECTIVES: To review the existing techniques for minor salivary gland biopsy (MSGB) in the lip and to suggest a new approach to ease the procedure and reduce post-operative complications. STUDY DESIGN: A comprehensive literature review and a descriptive study of a new surgical technique. RESULTS: Diverse incisions have been suggested for MSGB with different designs (ellipse, circular, linear), different directions (parallel, oblique, vertical) and a wide range of lengths (from 1 mm up to 3 cm), but no comparative studies supporting the advantages of a particular type of incision over the others could be retrieved. A variety of features of the existing techniques for MSGB are linked to undesired events and surgical complications which could be minimized by modifying certain aspects of these procedures. The technique described, together with the use of the S forceps, represents a significant improvement over the already described chalazion forceps because it allows for a better access and positioning of the lower lip, improves the ergonomic conditions of the assistant, and facilitates the identification of lip areas with more superficial gland lobules. CONCLUSION: The suggested approach for lip MSGB includes a specifically designed instrument whose performance during lip biopsy may contribute to minimize post-operative complications.
23629427 [Anti-M3 muscarinic acetylcholine receptor antibodies and Sjögren's syndrome]. 2013 Sjögren's syndrome (SS) is an autoimmune disease that affects exocrine glands including salivary and lacrimal glands. It is characterized by lymphocytic infiltration into exocrine glands, leading to dry mouth and eyes. A number of auto-antibodies are detected in patients with SS. However, no SS-specific pathologic auto-antibodies have yet been found in this condition. M3 muscarinic acetylcholine receptor (M3R) plays a crucial role in the secretion of saliva. It is reported that some patients with SS carried inhibitory auto-antibodies against M3R. To clarify the epitopes and function of anti-M3R antibodies in SS, we examined antibodies to the extracellular domains (N terminal region, the first, second, and third extracellular loop) of M3R by ELISA using synthesized peptide antigens encoding these domains in 42 SS and 42 healthy controls (HC). Titers and positivity of anti-M3R antibodies to every extracellular domain of M3R were significantly higher in SS than in HC. Our results indicated the presence of several B cell epitopes on M3R in SS. Moreover, we analyzed the functions of anti-M3R antibodies by Ca(2+)-influx assays using a human salivary gland (HSG) cell line. The functional analysis indicated that the influence of such anti-M3R antibodies on Ca(2+)-influx in HSG cells might differ based on the epitopes to which they bind. Interestingly, both IgG from anti-M3R antibodies to the second extracellular loop positive SS and anti-M3R monoclonal antibodies against the second extracellular loop of M3R, which we generated, suppressed Ca(2+)-influx in the HSG cells induced by cevimeline stimulation. These observations suggested that auto-antibodies against the second extracellular loop of M3R could be involved in salivary dysfunction in patients with SS. These results indicated the presence of several B cell epitopes on M3R in SS and the influence of anti-M3R antibodies on salivary secretion might differ based on these epitopes. Thus, anti-M3R antibodies could be not only potential pathologic auto-antibodies, but also new diagnostic makers and therapeutic targets for SS.