Sicca Manifestations Research Articles

Whole phenotype of patients with systemic sclerosis and sicca manifestations: Comparison with sicca manifestations from other causes

Introduction & objectivesThis study aimed to characterize the whole phenotype of Systemic sclerosis (SSc) patients with sicca symptoms, using major salivary glands Ultrasound (SGUS) parameters, minor salivary glands biopsies (mSGB) and clinical findings, and to compare these characteristics with those from patients with Sjogren's Disease (SjD), and patients with sicca manifestations from other causes. MethodsSixty SSc patients fulfilling the 2013 ACR/EULAR classification criteria and with subjective self-declared sicca symptoms were consecutively recruited and had SGUS and mSGB. Fifteen SSc patients without subjective sicca symptoms and 65 patients with sicca symptoms from other causes (including 37 SjD with no SSc). ResultsSSc patients with subjective sicca symptoms had frequent objective clinical (up to 83 %), histological (44 % of Focus score≥1/ mm2) and US anomalies (63 % of OMERACT ≥2). 53 % patients without subjective clinical complaint also had abnormal objective tests, suggesting the existence of a sub clinical involvement of salivary glands in SSc. SjD-SSc patients had more severe glandular involvement as compared to patients with isolated SjD and isolated Sicca-SSc patients (70%, 48,6 % and 38% of patients with OMERACT ≥2 respectively) suggesting additive impact of both diseases on glandular physiology and structure. ConclusionSjD-SSc overlap have more severe sicca features as compared to isolated sicca-SSc and isolated SjD, suggesting a specific impact of SSc on salivary gland physiology. Further translational studies are needed to identify the underlying pathways that could serve as therapeutic targets.

Clinical and laboratory findings of primary Sjögren's syndrome patients without sicca symptoms.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterised by oral and eye dryness. A minority of patients can present without dryness but studies on their clinico-laboratory manifestations are scarce. Our purpose was to describe the clinical phenotype of pSS patients lacking sicca symptoms. From a total of 1738 consecutive pSS patients fulfilling the 2016 ACR-EULAR criteria, those who presented without sicca symptoms were identified (non-dryness group). Their medical data was collected and compared with 2 control groups: a) the remaining unmatched sicca pSS patients with both oral and eye dryness (unmatched dryness group) and b) matched sicca pSS patients according to age, sex, and disease duration, in 1:2 ratio (matched dryness group). Thirty-eight (2.19%) patients lacked sicca manifestations presenting mainly with arthralgias (47%), parotid enlargement (24%), Raynaud's phenomenon (11%) and persistent lymphadenopathy (11%) that led them to be evaluated for pSS. Non-dryness pSS patients were younger than the unmatched sicca controls, displaying a higher frequency of anti-Ro/SSA antibodies (100% vs. 79.7%, p<0.001), ANA positivity (100% vs. 90.4%, p<0.001), neutropenia (20.8% vs. 7.5%, p=0.04) and thrombocytopenia (13.8% vs. 4.2%, p=0.04). They also had lower frequency of positive ocular tests compared to both unmatched and matched dryness patients. No differences were found between non-dryness pSS patients and both control groups regarding focus score or any other extraglandular manifestation. pSS patients without sicca complaints constitute a distinct phenotype involving younger patients, sharing common immunopathologic mechanisms with typical sicca patients.

Scleroderma-specific autoantibodies: Should they be included in the diagnostic work-up for Sjögren's syndrome?

ObjectivesSicca complaints are a frequent reason for rheumatologic consultation. Testing for specific antibodies against Ro/SSA and La/SSB antigens and minor salivary gland (MSG) biopsy are among the main tools implemented in the diagnostic work-up. Anticentromere antibodies and sicca manifestations are frequently detected in Sjögren's syndrome (SS) and systemic sclerosis (SSc), respectively. Herein, we aimed to determine the frequency and clinical associations of a wide spectrum of scleroderma (SSc)-specific autoantibodies in consecutive patients referred for evaluation of possible SS. MethodsDemographic, clinico-pathological, and laboratory data were recorded in 216 consecutive patients with sicca complaints. All study participants were tested for SSc-specific autoantibodies (against CENP, PM/Scl, Scl-70, Ku, NOR90, RP11, RP155, fibrillarin, PDGFR, and Th/To) using a commercially available immunoblot kit. According to band intensity, the identified autoantibodies were further classified in those with strong and medium titers. ResultsSSc-specific autoantibodies were detected in 41.7% (90/216) patients evaluated (19% at strong, 22.7% at medium titers) without significant differences between anti-Ro/SSA positive and negative groups. At strong titers was significantly higher in patients with MSG biopsies fulfilling SS histopathological criteria (30% vs 12.5%, p = 0.009). This association remained significant after adjustment for antibodies against Ro/SSA and La/SSB autoantigens [OR 95% (CI): 4.1 (1.5–10.6)]. ConclusionSSc-specific autoantibodies are frequently detected among patients presenting with sicca complaints and at strong but not medium titers are independently associated with MSG biopsy positivity. Taken together, these data imply a useful role of SSc antibody testing in the diagnostic work-up and possibly in the classification criteria for SS.

Clinical Phenotype and Mechanisms of Leukopenia/Neutropenia in Patients with Primary Sjögren's Syndrome.

Sjögren’s syndrome (SS) is a chronic, systemic autoimmune disease which afflicts mainly the exocrine salivary and lachrymal glands, leading to mouth and eye dryness. However, any organ can be affected during the disease course, resulting in a variety of clinical manifestations. Sjögren’s syndrome clinical manifestations can be classified into glandular (sicca manifestations or parotid swelling), extra-glandular, either nonspecific (arthralgias, arthritis, Raynaud’s phenomenon, fatigue) or peri-epithelial (primary biliary cirrhosis, interstitial nephritis, bronchiolitis), and extra-epithelial (palpable glomerulonephritis, peripheral neuropathy, purpura). In addition, SS patients display high risk for B cell lymphomas due to chronic antigenic stimulation. Although disease pathogenesis remains unclear, genetic, environmental, and immunologic factors are implicated. In the context of systemic autoimmune manifestations, SS patients may also present with hematologic abnormalities including anaemia, leukopenia (mainly neutropenia or lymphopenia), and thrombocytopenia. Although leukopenia has been reported as a laboratory finding in many case series or cohorts of SS patients and in very few studies it has been proposed as an independent risk factor for lymphoma, the clinical phenotype of SS patients with leukopenia/neutropenia and the implicated pathogenetic mechanisms have not been elucidated. In the current study, we intend to analyse the clinical phenotype of leukopenic/neutropenic SS patients and explore the possible pathogenetic mechanisms by detecting anti-neutrophil antibodies and investigate the role of apoptotic pathways, especially the contribution of TRAIL pathway and the cFLIP molecule.

EP28 A case of ANCA vasculitis presenting with Sjögren’s serology

EP28 A case of ANCA vasculitis presenting with Sjögren’s serology

JAK Inhibitors and Oxidative Stress Control.

Primary Sjögren's syndrome (SjS) is a complex autoimmune epithelitis, with few treatment options, but the use of Janus kinase (JAK) inhibitors is promising because suppression of the JAK/signal transducer and activator of transcription (STAT) pathway improves sicca manifestations. Playing a primary and pathogenic role in disease development, the oxidative stress response is upregulated in activated salivary gland epithelial cells (SGECs) from patients with SjS. Therefore, the aim of this study was to investigate whether JAK inhibitors would suppress SGEC activation in response to an oxidative stress. For this purpose, the human salivary gland (HSG) cell line was used, and cells were treated with the reactive oxygen species (ROS) inducer hydrogen peroxide (H2O2) or with interferons (IFN Type I and Type II), used as positive controls, to mimic activated SGECs as observed in SjS patients. Afterward, the levels of the intracellular adhesion molecule-1 (ICAM-1) and the regulatory programmed-death ligand-1 (PD-L1) were measured by real-time PCR and flow cytometry, and the STAT1/3 phosphorylation status was assessed by Western blotting. Using the HSG cell line, our results showed that both ICAM-1 and PD-L1 are induced by ROS through pSTAT3, and that this activation pathway is reversed by the use of JAK inhibitors, AG490 and ruxolitinib, as well as by N-acetylcysteine, which is a direct inhibitor of ROS. These findings open new perspectives regarding the pathogenesis and therapeutic possibilities for SjS.

Frequency and distribution of various rheumatic disorders associated with checkpoint inhibitor therapy.

Immune checkpoint inhibitors have advanced the treatment paradigm of various cancers, achieving remarkable survival benefits. However, a myriad of immune-related adverse events (irAE) has been recognized in almost every organ system, presumably because of persistent immune system activation. Rheumatic symptoms such as arthralgia or myalgia are very common. More specific irAE are increasingly being reported. The most frequent ones are inflammatory arthritis, polymyalgia-like syndromes, myositis and sicca manifestations. These rheumatic irAE can develop in ∼5–10% of patients treated with immune checkpoint inhibitors, although true incidence rates cannot be estimated given the lack of prospective cohort studies, and likely underreporting of rheumatic irAE in oncology trials. In this review, we will provide a summary of the epidemiologic data reported for these rheumatic irAE, until more robust prospective longitudinal studies become available to further define the true incidence rate of rheumatic irAE in patients receiving these novel cancer therapies.

Magnetic resonance sialography of the parotid glands in chronic hepatitis C virus patients with and without vasculitis.

Hepatitis C virus (HCV) is sialotropic. The pathogenesis of sicca manifestations in patients with chronic HCV infection is not fully understood. We aimed to detect changes in magnetic resonance sialography (MRS) of HCV patients with and without vasculitis. We studied 32 HCV patients (19 female, mean age 48.8±10.3years) and 20 age- and gender-matched healthy controls. Half of the patients had vasculitis. Demographic, clinical and serological data were prospectively evaluated. In patients with vasculitis, the disease activity was assessed by the Birmingham Vasculitis Activity Score (BVAS). MRS was performed on all patients and controls. Abnormal MRS was found in 25% of patients, (6/16 and 2/16 in patients with and without vasculitis, respectively). Among patients with vasculitis, those with abnormal MRS had longer disease duration, higher leukocytic and lymphocytic counts and more frequent cryoglobulinemia (P<0.01, P<0.001, P<0.001 and P<0.008, respectively), while BVAS scores were not significantly different. Among HCV patients with vasculitis, longer disease duration and cryoglobulinemia were associated with abnormal findings on MRS. To confirm our results, we propose larger-scale, multicentre studies with longer evaluation periods.

Primary Sjögren′s syndrome without ocular involvement: A rare case report

Sjogren's Syndrome (SS) is a chronic systemic autoimmune disorder, characterized by the lymphocytic infiltration of lacrimal and salivary glands, giving rise to dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). Primary Sjogren's Syndrome commonly presents only with sicca manifestations; whereas, secondary Sjogren's syndrome occurs in connection with other autoimmune rheumatic diseases. Primary Sjogren's syndrome without ocular manifestation is rarely reported in the literature. Here we report a case of a 45-year-old female, who presented to us with complaints of dryness of mouth and dysphagia, without any ocular and systemic manifestations. On further evaluation she was diagnosed as a case of Primary Sjogren's syndrome. With this case report, we intend to emphasize the importance of an early diagnosis of this disorder, along with a brief review of various diagnostic criteria.

Topical and systemic medications for the treatment of primary Sjögren's syndrome

The treatment of primary Sjögren's syndrome (SS) is based principally on the management of sicca features and systemic manifestations. Sicca manifestations are treated symptomatically through administration of topical therapies, such as saliva substitutes and artificial tears; in patients with residual salivary gland function, stimulation of salivary flow with a sialogogue is the therapy of choice. The management of extraglandular features must be tailored to the specific organ or organs involved; however, limited data have been obtained from controlled trials in SS to guide the treatment of systemic symptoms using therapies including antimalarials, glucocorticoids, immunosuppressive drugs and biologic agents. Nevertheless, randomised controlled trials of biologic agents that target molecules and receptors involved in the aetiopathogenesis of primary SS have initiated a new era in the therapeutic management of the disease, although the potential risks and benefits of these agents must be carefully considered. In this Review, we analyse the evidence regarding the efficacy of the therapeutic agents currently available to treat the manifestations of SS. On the basis of this evidence, we provide guidance on the use of these agents in different clinical scenarios.

Keratoconjunctivitis Sicca Manifestations in Ocular Graft Versus Host Disease: Pathogenesis, Presentation, Prevention, and Treatment

Graft versus host disease (GVHD) that develops from allogeneic hematological stem cell transplantations (HSCT) is a major cause of morbidity and mortality. Allogeneic HSCT were developed as a curat...

Anticentromere antibody positive Sjögren's Syndrome: a retrospective descriptive analysis

IntroductionA subgroup of patients with primary Sjögren's Syndrome (SS) and positive anticentromere antibodies (ACA) were recognized as having features intermediate between SS and systemic sclerosis (SSc). Our goal was to describe this group clinically and serologically and define its tendency to evolve to full blown SSc.MethodsAmong 535 patients with primary SS we identified 20 ACA positive (ACA+/SS). We compared them to 61 randomly selected ACA negative SS patients (ACA-/SS), 31 ACA positive SSc patients with sicca manifestations [SSc/(+) sicca] and 20 ACA positive SSc patients without sicca manifestations [SSc/(-) sicca].ResultsPrevalence of ACA among SS patients was 3.7%. Cases and controls did not differ in sex ratio and age at disease onset. ACA+/SS patients had a lower prevalence of dry eyes, hypergammaglobulinaemia, anti-Ro and anti-La antibodies and a higher prevalence of Raynaud's phenomenon and dysphagia compared to ACA-/SS patients. They also had lower prevalence of telangiectasias, puffy fingers, sclerodactyly, Raynaud's phenomenon, digital ulcers and gastroesophageal reflux in comparison to both of the SSc subgroups and a lower prevalence of dyspnoea and lung fibrosis compared to the SSc/(+) sicca subgroup. Two patients originally having ACA+/SS evolved to full blown SSc. Four deaths occurred, all among SSc patients. Kaplan Meier analysis showed a significant difference between cases and controls in time from disease onset to development of gastroesophageal reflux, telangiectasias, digital ulcers, arthritis, puffy fingers, xerostomia, hypergammaglobulinaemia and dysphagia.ConclusionsACA+/SS has a clinical phenotype intermediate between ACA-/SS and SSc and shows little tendency to evolve to SSc.

Sjogren's syndrome in a patient with ulcerative colitis and primary sclerosing cholangitis: Case report and review of the literature

Inflammatory bowel disease has been reported to co-exist with other autoimmune diseases. Sjogren's syndrome is an autoimmune disorder characterized by xerostomy and/or xerophthalmy. Sjogren's syndrome occurring in IBD has been very rarely reported. A 45-year old woman diagnosed ten years ago with ulcerative pancolitis and primary sclerosing cholangitis was referred to our outpatient IBD clinic because of xerostomy but not for xerophthalmy for the previous three months. The patient had been under azathioprine maintenance treatment (2 mg/kg) and achieved long-term disease remission for the past 4 years. Patient clinical examination and laboratory tests were unremarkable. Salivary gland biopsy and complete ophthalmologic investigation were performed and the patient was diagnosed with Sjogren's syndrome. Understanding sicca manifestations in IBD is difficult since the pathogenesis of this intestinal disorder is not yet clear. Of these complex autoimmune phenomena which occur along with IBD it is quite difficult to categorize concomitant Sjogren's syndrome as primary or secondary and literature is conflicting. The possibility of Sjogren's syndrome should always be considered and properly investigated in patients diagnosed with inflammatory bowel disease who develop a constellation of constitutional sicca symptoms.

New approaches in Sjögren’s syndrome therapy

At present, there is no treatment capable of modifying the evolution of Sjögren’s syndrome (SS) and the therapeutic approach is based mainly on symptomatic replacement or stimulation of glandular secretions, while extraglandular involvement requires an organ-specific therapy. New therapeutic approaches for sicca manifestations include oral muscarinic agonists (e.g., pilocarpine and cevimeline) for dry mouth, as well as topical agents (e.g., cyclosporine A and diquafosol) for dry eye. Turning to biological agents, recent studies have demonstrated the lack of efficacy of anti-tumor necrosis factor (TNF) agents in primary SS. By contrast, a promising treatment is rituximab (anti-CD20). Advances in our knowledge of etiopathogenic mechanisms will allow the development of future treatments for SS, including localized gene transfer and agents antagonizing B cell-activating factor from the TNF family and CD22-positive cells.

Functional and biologic evaluation of immunoregulatory cytokines in the immunopathologic lesion of Sjogren's syndrome

Autoimmune diseases are commonly considered to involve a Th1/Th2 imbalance in favor of Th1. Studies in mice suggest that the Th1 cytokines overexpression may be implicated in the pathogenesis of autoimmunity. Recent results, though, in humans challenge this notion. Conflicting data have been published on the cytokine profile in patients with Sjogren's syndrome (S.s.). These data were mainly obtained using PCR based techniques and in-situ hybridization. Some of them indicate that a Th1 response is prevalent. To clarify this issue, small salivary glands (SGL) from patients with S.s. with different grades of infiltration as well as patients without S.s. but with sicca manifestations, were cultured in RPMI plus 40 IU/ml of recombinant IL2. IL4, IL13 and IFNgamma production in the culture supernatants (SN) was evaluated with a sensitive ELISA and, in parallel, mRNA levels for the same cytokines were evaluated with a quantative RT-PCR. Within a period of a week, lymphocytes were evident in the cultures in numbers depending on the infiltration of the gland. The phenotype of these lymphocytes, as determined by flow cytometry, was similar to that published previously from SGL immunochemistry, suggesting that these cells derive from the salivary gland. SN were collected on various time intervals and mRNA was extracted from the lymphocytes on day 12 of the culture. Interestingly, IL13 mRNA was detected in almost all (17/19) of the samples, and both IFNgamma and IL4 on the majority (16/19 and 14/19, respectively). The cytokine production in the culture SN was examined in a set of 8 biopsies. IL 4 couldn't be detected ( 0.6 it was undetectable. These results show that in Sjogren's syndrome the distinction between Th1 and Th2 doesn't apply as both play a role to its pathogenesis. Moreover it seems that Th2 response prevails at the early stages whereas Th1 gradually augments as the disease progresses.

Cholinergic-drug induced sicca syndrome in Parkinson’s disease:: a case report and a review of the literature

A 67-year-old woman developed severe sicca manifestations after initial treatment of Parkinson’s disease with an anti-cholinergic drug, which prompted us to look for the presence of Sjögren’s syndrome. The results of sialography, labial salivary gland biopsy, Rose–Bengal test as well as the presence of antinuclear antibody were consistent with the diagnosis of Sjögren’s syndrome. The sicca symptoms diminished by cessation of the anti-cholinergic drug, and the parkinsonian features were controlled by levodopa. We suggest that Sjögren’s syndrome should be considered, if patients with Parkinson’s disease complain severe xerostomia.

New developments in Sjögrenʼs syndrome

The growing number of conditions associated with sicca manifestations and focal sialadenitis has shed further light on the heterogeneity of Sjögren's syndrome. Viral and retroviral infections, lymphoproliferative disorders, as well as various autoimmune syndromes, target the lacrimal and salivary glands and incite a local immune response. This awareness has not only intensified the search for a viral or retroviral cause of Sjögren's syndrome, but it has also provided a daunting challenge to investigators who are striving to improve diagnostic testing and classification. A better understanding of Sjögren's syndrome is needed to develop innovative and more effective therapies.

Histologic lesion in labial salivary glands of patients with systemic lupus erythematosus

In an attempt to evaluate the presence or incidence of Sjo¨gren's syndrome in patients with systemic lupus erythematosus (SLE), 72 randomly selected patients with SLE, regardless of sicca manifestations, underwent labial salivary gland biopsy. Thirty-seven patients (51%) had normal labial salivary gland tissue. Seventeen patients (24%) had a mild perivascular infiltration of 15 to 20 lymphocytes per focus. In the remaining 18 patients (25%) heavy infiltration of more than 50 lymphocytes per focus was observed. From the latter group five specimens showed perivascular distribution of the infiltrates. About 40% of patients with any infiltration had keratoconjunctivitis sicca. Patients with severe lymphocytic infiltration in minor salivary gland tissue rarely had kidney involvement and often had lymphadenopathy and circulating rheumatoid factor, cryoglobulins, and antibodies to SS-A (Ro) and SS-B (La) antigens. Vasculitis was not found more frequently in any group of patients. Our results suggest that perivascular lymphocytic infiltrates in the labial salivary glands of patients with SLE may be the initial histologic lesion of Sjo¨gren's syndrome.