Lida Radfar

Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome

Sjögrens syndrome is a common autoimmune disease (affecting ∼0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjögrens syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (Pmeta = 7.65 × 10−114), we establish associations with IRF5-TNPO3 (Pmeta = 2.73 × 10−19), STAT4 (Pmeta = 6.80 × 10−15), IL12A (Pmeta = 1.17 × 10−10), FAM167A-BLK (Pmeta = 4.97 × 10−10), DDX6-CXCR5 (Pmeta = 1.10 × 10−8) and TNIP1 (Pmeta = 3.30 × 10−8). We also observed suggestive associations (Pmeta < 5 × 10−5) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjögrens syndrome.

Comparison of the American-European Consensus Group Sjögren's syndrome classification criteria to newly proposed American College of Rheumatology criteria in a large, carefully characterised sicca cohort

Abstract Objective To compare the performance of the American–European Consensus Group (AECG) and the newly proposed American College of Rheumatology (ACR) classification criteria for Sjögrens Syndrome (SS) in a well-characterised sicca cohort, given ongoing efforts to resolve discrepancies and weaknesses in the systems. Methods In a multidisciplinary clinic for the evaluation of sicca, we assessed features of salivary and lacrimal gland dysfunction and autoimmunity as defined by tests of both AECG and ACR criteria in 646 participants. Global gene expression profiles were compared in a subset of 180 participants. Results Application of the AECG and ACR criteria resulted in classification of 279 and 268 participants with SS, respectively. Both criteria were met by 244 participants (81%). In 26 of the 35 AECG+/ACR participants, the minor salivary gland biopsy focal score was ≥1 (74%), while nine had positive anti-Ro/La (26%). There were 24 AECG−/ACR+ who met ACR criteria mainly due to differences in the scoring of corneal staining. All patients with SS, regardless of classification, had similar gene expression profiles, which were distinct from the healthy controls. Conclusions The two sets of classification criteria yield concordant results in the majority of cases and gene expression profiling suggests that patients meeting either set of criteria are more similar to other SS participants than to healthy controls. Thus, there is no clear evidence for increased value of the new ACR criteria over the old AECG criteria from the clinical or biological perspective. It is our contention, supported by this report, that improvements in diagnostic acumen will require a more fundamental understanding of the pathogenic mechanisms than is at present available.

Genome-wide DNA methylation patterns in naive cd4+ t cells from patients with primary sjögren's syndrome

Primary Sjögrens syndrome (SS) is a systemic autoimmune disease with incompletely understood etiology. This study was undertaken to investigate the role of epigenetic dysregulation in the pathogenesis of primary SS.

Structural and functional injury in minipig salivary glands following fractionated exposure to 70 Gy of ionizing radiation: an animal model for human radiation-induced salivary gland injury

This study explored the feasibility of developing an animal model for radiation-induced salivary gland injury with a radiation protocol identical to current clinical practice. Three male Hanford minipigs were subjected to fractionated daily irradiation with a total dose of 70 Gy; structural and functional measures were compared with those of a control group of minipigs. We found that irradiated submandibular and parotid glands were one-third to one-half the gross size of control glands. Whereas no pathologic changes were noted in control glands, irradiated glands consistently demonstrated significant parenchymal loss with extensive acinar atrophy and interstitial fibrosis, enlarged nuclei in remaining acinar cells, and ductal dilatation and proliferation. Stimulated salivary flow was reduced by 81% in irradiated animals compared with preirradiation flow (P <.001); salivary flow in the control group increased by 30% during the same period (P <.001). The observed radiation-induced structural and functional salivary gland changes are comparable in every respect to those observed following irradiation of human salivary glands.

A comparative treatment study of topical tacrolimus and clobetasol in oral lichen planus

BACKGROUND Existing clinical trials have shown that topical corticosteroids are often effective in the management of oral lichen planus (OLP). However, tacrolimus has recently been shown to be an effective treatment of OLP. OBJECTIVE To compare the effectiveness of clobetasol and tacrolimus in the topical management of OLP. STUDY DESIGN In this randomized comparative double-blind study, 30 consecutive patients with oral lesions consistent clinically and histologically with OLP were recruited. The patients were divided into 2 groups to receive clobetasol 0.05% or tacrolimus 0.1% ointment and were treated for 6 weeks. RESULTS The profiles of mean lesion sizes and mean pain measures did not differ between the tacrolimus and clobetasol treatment groups. CONCLUSION We found tacrolimus to be as useful as clobetasol in treatment of OLP. We believe that up-to-date evidence indicates the effectiveness of tacrolimus in treating OLP.

Fungal load and candidiasis in Sjögren’s syndrome

OBJECTIVE We sought to investigate the prevalence of Candida carriage and the relationships between salivary flow rates and oral Candida load in patients with Sjögrens syndrome (SS). METHODS The oral Candida load of patients with SS was evaluated by culturing oral rinse (swish and spit) samples. Culture, Gram stain, and wet-mount test results were reported. RESULTS One hundred three patients (96 women) met European criteria for SS (91 with primary SS and 12 with secondary SS). The mean age (95% confidence interval) was 55 years (range, 51-57 years). Oral rinse cultures were positive in 77% of subjects. The total stimulated salivary flow rate was inversely correlated with oral Candida load (r = -0.47; P </=.0001). The oral rinse samples yielded gram-positive results in 38% of patients with SS, and the Fungi-Fluor assay (wet mount) results were positive in 49%. CONCLUSIONS The prevalence of Candida carriage varies according to the methods used to determine the presence of the organism and is similar to that reported in the literature. A low stimulated salivary flow rate-not a low unstimulated flow rate-was associated with Candida carriage.

X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome.

More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ∼1 in 1,000 live female births) would be increased in patients with female‐predominant diseases (systemic lupus erythematosus [SLE], primary Sjögrens syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls.

Antibody-secreting cell specificity in labial salivary glands reflects the clinical presentation and serology in patients with sjögren's syndrome

The serologic hallmark of primary Sjögrens syndrome (SS) is the presence of IgG antibodies specific for Ro (SSA) and La (SSB). The molecular characteristics of gland‐derived B cells at the site of primary SS inflammation have been described previously; however, parallels between glandular antibody‐secreting cells (ASCs) and serologic antibody specificities have not been evaluated. We used recombinant monoclonal antibody (mAb) technology to study the specificities of salivary gland (SG)–derived ASCs, evaluate their molecular characteristics, and identify IgG antibody specificity.

Interaction between innate immunity and Ro52-induced antibody causes Sjögren's syndrome-like disorder in mice

Objectives Autoantibodies reactive with Ro52 are often found in sera of patients with Sjögrens syndrome (SS). This study was undertaken to investigate the role of Ro52-induced immune responses in pathogenesis of SS. Methods New Zealand Mixed (NZM) 2758 mice were immunised with Ro52 in alum adjuvant. Control mice were immunised either with maltose-binding protein or injected with alum alone. Mice were monitored for anti-Ro52 antibody, sialoadenitis and pilocarpine-induced salivation. Antibody binding to salivary gland (SG) cells was analysed in vivo and in vitro by immunofluorescence. Sera from immunised mice were passively transferred into untreated or alum injected NZM2758 mice. Results By day 30 post-immunisation, Ro52 immunised mice generated immunoprecipitating anti-Ro52 antibodies and they had the maximum drop in saliva production. Both Ro52 immunised and control mice showed evidence of mild sialoadenitis. However, only Ro52 immunised mice had antibody deposition in their SG. Passive transfer of Ro52-immune sera induced SG dysfunction in recipient mice, only if the recipients were primed with alum. In vitro, antibodies from Ro52-immune sera were internalised by a SG cell line and this uptake was inhibited by cytochalasin D treatment. Conclusions Our data show for the first time that antibodies induced by Ro52 are capable of inducing SG dysfunction, and that this phenomenon is dependent on the activation of innate immunity. The mouse model described in this study implies that autoantibody deposition in the SG might be an important step in the induction of xerostomia and pathogenesis of SS.

Previous diagnosis of Sjögren's Syndrome as rheumatoid arthritis or systemic lupus erythematosus

OBJECTIVE The diagnosis of SS is often difficult and many patients are symptomatic for years with other diagnoses before confirmation of SS. Our aim was to determine whether overlapping clinical and serologic features with RA and SLE may in part drive the misdiagnoses. METHODS A total of 1175 sicca patients were evaluated in a multidisciplinary clinic and classified as having SS based on the American-European Consensus Group Criteria. They were interrogated for a past history of suspicion or diagnosis of RA, SLE or SSc. These diseases were confirmed or ruled out by applying the corresponding classification criteria if the patients responded affirmatively. RESULTS Of these, 524 (44.6%) subjects reported previous diagnosis or suspicion of RA, SLE or SSc, which was confirmed in 130 (24.8%) but excluded in 394 (75.2%) subjects. Of those previously diagnosed with another illness, 183 (34.9%) met the criteria for primary SS. RF was present in 70/191 patients with previous diagnosis of RA compared with 445/845 without a prior RA diagnosis (P = 3.38E-05), while 128/146 with a diagnosis of SLE had positive ANA compared with 622/881 without the diagnosis (P = 8.77E-06). Age also influenced former diagnoses: people with suspected RA were older than those without the diagnosis (P = 5.89E-06), while patients with SLE suspicion were younger (P = 0.0003). Interestingly, the previous diagnoses did not significantly delay a final classification of SS. CONCLUSION Among subjects classified as SS, the presence of a positive ANA or RF was associated with a previous, apparently erroneous diagnosis of SLE or RA, respectively.