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ID PMID Title PublicationDate abstract
28535470 Pharmacophore guided discovery of small-molecule interleukin 15 inhibitors. 2017 Aug 18 Upregulation of interleukin 15 (IL-15) contributes directly i.a. to the development of inflammatory and autoimmune diseases. Selective blockade of IL-15 aimed to treat rheumatoid arthritis, psoriasis and other IL-15-related disorders has been recognized as an efficient therapeutic method. The aim of the study was to identify small molecules which would interact with IL-15 or its receptor IL-15Rα and inhibit the cytokine's activity. Based on the crystal structure of IL-15Rα·IL-15, we created pharmacophore models to screen the ZINC database of chemical compounds for potential IL-15 and IL-15Rα inhibitors. Twenty compounds with the highest predicted binding affinities were subjected to in vitro analysis using human peripheral blood mononuclear cells to validate in silico data. Twelve molecules efficiently reduced IL-15-dependent TNF-α and IL-17 synthesis. Among these, cefazolin - a safe first-generation cephalosporin antibiotic - holds the highest promise for IL-15-directed therapeutic applications.
28304002 Influence of free drug samples on prescribing by physicians: A cross sectional survey. 2017 Mar Free drug samples are distributed among doctors as a promotional tool. We investigated the effects of dispensing samples on prescriptions by the doctors and their opinion about samples through a cross-sectional survey. A questionnaire was distributed among the doctors in the Department of Medicine, Nishtar Hospital Multan. It contained drug choices for two hypothetical scenarios, options and reasons for using free samples and doctors' views about them. Response rate remained 83% (166/198). In scenario 1 (rheumatoid arthritis), 100 % and in scenario 2 (acid peptic disease), 13% of sample users dispensed against their preference while in both cases 78 % prescribed the same brand afterwards. Trainees used samples more frequently in both vignettes (p value 0.24 and 0.001 respectively). Mainly, samples were used as a cost-effective measure and were considered a source of medication for poor, significantly. (p value 0.007). But in this process, physicians ignored their first choice and inadvertently increased the total expenditure.
29267054 Various Types of Arthritis in the United States: Prevalence and Age-Related Trends From 19 2018 Feb OBJECTIVES: To determine the prevalence trends of osteoarthritis (OA), rheumatoid arthritis (RA), and other types of arthritis in the United States from 1999 to 2014. METHODS: We analyzed data on 43 706 community-dwelling adults aged 20 years and older who participated in the 1999-2014 National Health and Nutrition Examination Surveys. We accounted for survey design and sampling weights so that estimates were nationally representative. We assessed temporal trends in age-standardized arthritis prevalence by using joinpoint regression. RESULTS: Age-adjusted prevalence of arthritis was 24.7% (OA = 9.7%; RA = 4.2%; other arthritis = 2.8%; "don't know" type = 8.0%). Prevalence of OA increased from 6.6% to 14.3%, whereas RA prevalence decreased from 5.9% to 3.8%. Increase in OA prevalence was significant in both genders; in non-Hispanic Whites, non-Hispanic Blacks, and Hispanics; and in people with high socioeconomic status. Decrease in RA prevalence was more pronounced in men, non-Hispanic Blacks, and participants with low income or obesity. CONCLUSIONS: Between 1999 and 2014, nearly one quarter of American adults reported arthritis. The prevalence of OA has more than doubled over time, whereas RA prevalence has declined.
28497863 CTLA-4 expressed by FOXP3(+) regulatory T cells prevents inflammatory tissue attack and no 2017 Sep Cytotoxic T-lymphocyte antigen 4 (CTLA-4) -mediated regulation of already tolerized autoreactive T cells is critical for understanding autoimmune responses. Although defects in CTLA-4 contribute to abnormal FOXP3(+) regulatory T (Treg) cell function in rheumatoid arthritis, its role in autoreactive T cells remains elusive. We studied immunity towards the dominant collagen type II (CII) T-cell epitope in collagen-induced arthritis both in the heterologous setting and in the autologous setting where CII is mutated at position E266D in mouse cartilage. CTLA-4 regulated all stages of arthritis, including the chronic phase, and affected the priming of autologous but not heterologous CII-reactive T cells. CTLA-4 expression by both conventional T (Tconv) cells and Treg cells was required but while Tconv cell expression was needed to control the priming of naive autoreactive T cells, CTLA-4 on Treg cells prevented the inflammatory tissue attack. This identifies a cell-type-specific time window when CTLA-4-mediated tolerance is most powerful, which has important implications for clinical therapy with immune modulatory drugs.
28350428 2017 Feb Spondyloarthritis encompasses a group of inflammatory conditions with some shared features, including extra-articular manifestations. Both peripheral and axial joints can be affected. The spondyloarthritides are distinct from rheumatoid arthritis but are as important to recognise and manage early in their presentation to improve health outcomes. The majority of people with these conditions have either psoriatic arthritis or axial spondyloarthritis, which includes ankylosing spondylitis. Ankylosing spondylitis and non-radiographic axial spondyloarthritis primarily affect the spine, in particular the sacroiliac joint. Both conditions manifest in similar ways; the primary classification difference is whether sacroiliitis is detectable on X-ray. Psoriatic arthritis may manifest in a number of different patterns. These include predominant involvement of small joints in the hands and feet, predominant large joint involvement particularly in the knees or combinations of these. Psoriatic arthritis may also involve the axial joints, and inflammation of the entheses and/or finger and toe joints. Skin and nail involvement may not be present at diagnosis and in its absence, a family history of psoriasis is required to meet the diagnostic criteria. Less common subgroups are enteropathic spondyloarthritis, which is associated with inflammatory bowel disease (Crohn’s disease and ulcerative colitis), and reactive arthritis, which can occur in people following gastrointestinal or genitourinary infections. The final subgroup is people who have undifferentiated spondyloarthritis. These people generally have an asymmetrical oligoarticular (fewer than 5 involved joints) arthritis, often involving the knees. They do not meet the diagnostic criteria of the other subgroups at presentation but their disease may evolve to do so at a later stage. This guideline also includes people who are 16 years or older with axial or peripheral symptoms who have previously been diagnosed with juvenile idiopathic arthritis. Healthcare professionals in non-specialist settings do not always recognise the signs and symptoms of spondyloarthritis, particularly spinal symptoms, which may be mistakenly attributed to other causes of low back pain. This can lead to substantial delays in diagnosis and treatment with consequent disease progression and disability. This guideline seeks to raise awareness of the features of spondyloarthritis and provide clear advice on what action to take when people with signs and symptoms first present in healthcare settings. This guideline also provides advice on the interventions available to people with spondyloarthritis. These include pharmacological and non-pharmacological treatments, and surgery. The guidance also provides advice on how care for people with spondyloarthritis should be organised across healthcare settings, and what information and support should be provided.
28084468 Etanercept-Synthesising Mesenchymal Stem Cells Efficiently Ameliorate Collagen-Induced Art 2017 Jan 13 Mesenchymal stem cells (MSCs) have multiple properties including anti-inflammatory and immunomodulatory effects in various disease models and clinical treatments. These beneficial effects, however, are sometimes inconsistent and unpredictable. For wider and proper application, scientists sought to improve MSC functions by engineering. We aimed to invent a novel method to produce synthetic biological drugs from engineered MSCs. We investigated the anti-arthritic effect of engineered MSCs in a collagen-induced arthritis (CIA) model. Biologics such as etanercept are the most successful drugs used in anti-cytokine therapy. Biologics are made of protein components, and thus can be theoretically produced from cells including MSCs. MSCs were transfected with recombinant minicircles encoding etanercept (trade name, Enbrel), which is a tumour necrosis factor α blocker currently used to treat rheumatoid arthritis. We confirmed minicircle expression in MSCs in vitro based on GFP. Etanercept production was verified from the conditioned media. We confirmed that self-reproduced etanercept was biologically active in vitro. Arthritis subsided more efficiently in CIA mice injected with mcTNFR2MSCs than in those injected with conventional MSCs or etanercept only. Although this novel strategy is in a very early conceptual stage, it seems to represent a potential alternative method for the delivery of biologics and engineering MSCs.
28631065 Framework for Advancing the Reporting of Patient Engagement in Rheumatology Research Proje 2017 Jul PURPOSE OF REVIEW: The term "patient engagement in research" refers to patients and their surrogates undertaking roles in the research process beyond those of study participants. This paper proposes a new framework for describing patient engagement in research, based on analysis of 30 publications related to patient engagement. RECENT FINDINGS: Over the past 15 years, patients' perspectives have been instrumental in broadening the scope of rheumatology research and outcome measurement, such as evaluating fatigue in rheumatoid arthritis. Recent reviews, however, highlight low-quality reporting of patient engagement in research. Until we have more detailed information about patient engagement in rheumatology research, our understanding of how patients' perspectives are being integrated into research projects remains limited. When authors follow our guidance on the important components for describing patients' roles and function as "research partners," researchers and other knowledge users will better understand how patients' perspectives were integrated in their research projects.
25381727 A long-term follow-up of Japanese mother and her daughter with Blau syndrome: Effective tr 2017 Jan Blau syndrome (BS) is an autosomal dominant autoinflammatory disease associated with NOD2 gene mutations. It is characterized by arthritis, skin rash, and uveitis. Here, we report contrasting outcomes of a daughter and her mother with BS. Their long-term follow-up revealed the efficacy of anti-tumor necrosis factor inhibitor (TNF) with respect to BS. Joint findings of BS feature tenosynovitis over articular synovitis on ultrasonography. BS might be one of the differential diagnoses of juvenile idiopathic arthritis and rheumatoid arthritis.
28233015 [Endocrinology and interdisciplinary consultation in internal medicine : Illustrated using 2017 Apr Polyglandular autoimmune syndromes encompass several endocrine and nonendocrine autoimmune disorders with variable onset and phenotype. Rheumatoid and gastroenterological symptoms in patients with autoimmune polyglandular syndromes are suggestive of additional rheumatoid gastrointestinal and hepatological autoimmune diseases. Autoimmune gastritis, celiac disease, autoimmune hepatitis, rheumatoid arthritis, Sjögren syndrome, and systemic Lupus erythematodus are of particular clinical relevance. In addition, unspecific rheumatoid and gastrointestinal attendant symptoms of the existing autoimmune endocrinopathy must be considered. Furthermore, certain disorders of polyglandular autoimmune syndromes, e. g., type 1 diabetes are frequently associated with particular gastrointestinal diseases such as small bowel bacterial overgrowth. An optimal patient-centered care of subjects with autoimmune diseases requires a comprehensive differential diagnostic work up and emphasizes the importance of an interdisciplinary cooperation.
28965771 Enhanced expression of NLRP3 inflammasome-related inflammation in peripheral blood mononuc 2017 Nov OBJECTIVE: The aim of this study was to identify the association of NLRP3 inflammasome-induced inflammation with disease activity and damage in Sjögren's syndrome. METHODS: A total of 33 female patients with Sjögren's syndrome and 34 sex- and age-matched, healthy controls were consecutively enrolled. The mRNA expression levels of NLRP3, ASC, caspase-1, interleukin-1β (IL-1β), and IL-18 in peripheral blood mononuclear cells (PBMCs) were measured, as well as serum IL-1β and IL-18 protein expression levels. Protein levels for mature IL-1β (p17) and caspase-1 (p20) were analyzed by western blotting. The EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) and Sjögren's Syndrome Disease Damage Index (SSDDI) were also evaluated. RESULTS: Patients with Sjögren's syndrome group showed higher expression of mRNA IL-1β and IL-1β at the protein level than controls (p<0.001 of both). Enhanced expression of mature IL-1β (p17) and caspase-1 (p20) proteins in Sjögren's syndrome were noted, compared to controls. The mRNA levels of caspase-1 and ASC were significantly increased in patients with Sjögren's syndrome compared to controls (p=0.001 and p=0.002, respectively). Based on the SSDDI scores, patients with damage (SSDDI≥1) had higher IL-1β mRNA expression compared to patients without damage (SSDDI=0) (p=0.034). SSDDI scores were closely related with IL-18 protein levels (r=0.357, p=0.041). The levels of IL-1β mRNA and IL-1β protein were correlated with the mRNA level of NLRP3 (r=0.597, p<0.001 and r=0.502, p=0.003, respectively). IL-1β mRNA expression was responsible for the presence of damage for Sjögren's syndrome (p=0.034). CONCLUSION: This study confirmed that NLRP3 inflammasome-mediated inflammation might be implicated in the pathogenesis of Sjögren's syndrome.
28528128 Comparison of the diagnostic value of four scoring systems in primary sjögren's syndrome 2017 Aug PURPOSE: We attempted to evaluate the diagnostic value of different salivary gland ultrasonography (SGUS) scoring systems for primary sjögren's syndrome (pSS). METHODS: Total 134 patients with pSS and 109 non-SS sicca controls were included in our study. All the cases were evaluated by four scoring systems (such as 0-16 SGUS, 0-3 SGUS, Parotid glands and Submandibular salivary glands scoring system). The receiver operating characteristic (ROC) analysis was performed for the four scoring systems. RESULTS: The mean scores of pSS patients were significantly higher than that of controls by four scoring systems (P<0.01). The AUC (area under the curve) of (0-16) SGUS scoring system (0.916) was higher than Submandibular salivary glands scoring system (0.885) (P=0.016). No significant difference of AUC was observed in (0-3) SGUS scoring system, compared with 0-16, parotid gland and submandibular salivary glands scoring system. The optimal cutoff value of (0-16) SGUS, (0-3) SGUS, Parotid gland, Submandibular salivary glands scoring system was 5, 2, 3, 2, respectively. There was no significant difference in the sensitivity and specificity of the four scoring systems. CONCLUSION: The simplified parotid gland scoring system may be the simplified and feasible method for pSS diagnosis.
28229405 Compact Bone-Derived Multipotent Mesenchymal Stromal Cells (MSCs) for the Treatment of Sjo 2017 Compact bone (cortical or dense bone) is among the organs that contain multipotent mesenchymal stromal cells (MSCs). Unlike bone marrow plugs where MSCs were initially isolated, compact bone has minimal (amount of) hematopoietic cells and thus facilitates the MSCs isolation process. In vitro, MSCs from compact bone show multipotency and differentiation into mesenchymal tissues such as bone, adipose, and cartilage, under certain conditions. MSCs therapy has been promising in preclinical and clinical studies against autoimmune diseases. Not only can MSCs replace the lost tissue through their regenerative properties, but they can also control the autoimmune attacks by immunoregulatory cytokines. This protocol describes the use of compact bone-derived MSCs to preserve salivary function (saliva flow/output) in the NOD (nonobese diabetic) mouse model affected with Sjogren's-like disease.
27260411 TLR2 signals via NF-κB to drive IL-15 production in salivary gland epithelial cells deriv 2017 Aug Toll-like receptors (TLRs) are pattern recognition receptors linking innate and adaptive immune responses, which resulted overexpressed in primary Sjögren's syndrome (pSS). Interleukin-15 (IL-15) is a pro-inflammatory cytokine which was recently demonstrated to be involved in pSS pathogenesis. The study was undertaken to clarify whether TLR2 is involved in the production of IL-15 in human salivary gland epithelial cells (SGEC) from pSS patients. SGEC primary cell cultures were established from pSS minor salivary gland tissues explanted from patients with a sure diagnosis of SS. After neutralization of TLR2 with a blocking monoclonal antibody, IL-15 production was assayed by immunoblotting and flow cytometry, IL-15 in the culture supernatants was measured by ELISA, and mRNA levels were assessed by RT-PCR and real-time PCR. The production of IL-15 by pSS SGEC decreased in culture supernatants and in protein lysates (p < 0.01) when TLR2 signaling was inhibited in pSS SGEC. In addition, a control at the transcriptional level was also detected; in fact, inhibition of nuclear factor (NF)-κB through the transfection of pSS SGEC with the dominant-negative inhibitory κBα proteins (IκBα) vector (IκBαDN) abrogated the stimulatory effect of TLR2 on IL-15 production. These data suggest that TLR2 activation is involved in the induction of IL-15 production by pSS SGEC and promotes inflammation through NF-κB activation. Therefore, therapeutic strategies that target TLR2/IL-15 pathway might be strong candidates for preventing or treating pSS.
29242559 A functional variant in the OAS1 gene is associated with Sjögren's syndrome complicated w 2017 Dec 14 Hepatitis B virus (HBV) has been suspected to contribute to several autoimmune diseases, including Sjögren's syndrome (SS), although the exact mechanism is unknown. The 2'-5' oligoadenylate synthetase (OAS1) is one of the most important components of the immune system and has significant antiviral functions. We studied a polymorphism rs10774671 of OAS1 gene in Han Chinese descent. The minor allele G was significantly associated with a decreased risk for SS, anti-SSA-positive SS, and anti-SSA-positive SS complicated with HBV infection, which have not been seen in anti-SSA-negative SS and HBcAb-negative SS patients. Gene expression analysis showed that the risk-conferring A allele was correlated with lower expression of p46 and increased expression of p42, p48, and p44. A functional study of enzymatic activities revealed that the p42, p44, and p48 isoforms display a reduced capacity to inhibit HBV replication in HepG2 cells compared to the normal p46 isoform. Our data demonstrated that the functional variant, rs10774671, is associated with HBV infection and anti-SSA antibody-positive SS. The SAS variant switches the primary p46 isoform to three alternatives with decreased capacities to inhibit HBV replication. These data indicated that individuals harboring the risk allele might be susceptible to hepatitis B infection and SS development.
29223133 How stress contributes to autoimmunity-lessons from Sjögren's syndrome. 2018 Jan A large body of clinical evidence on the association between stressful life events and autoimmune diseases suggests that stress may play an important role in the pathogenesis of these disorders. In this article, we discuss the effects of stress, not on the immune system but on specific cell populations against which the autoimmune reactivity is directed. Using Sjögren's syndrome as a model autoimmune disease, we review the role of stress in the initiation and perpetuation of autoimmune reactivity. We present data that reveal the effects of stress on salivary gland epithelial cells, suggesting that stress can become immunogenic through its various effects on salivary gland epithelium.
29220070 Recurrent Hypokalemia leading to Flaccid Quadriparesis: A Renal or Connective Tissue Disor 2017 Dec Hypokalemic periodic paralysis (hypoKPP) is a clinical entity characterized by recurrent skeletal muscle paralysis due to a decrease in serum potassium levels; hypoKPP can have either a primary (familial) or a secondary cause. One of the secondary causes of hypoKPP is distal renal tubular acidosis (dRTA). Distal renal tubular acidosis (dRTA) is diagnosed when the urinary pH is greater than 5.3 and in the presence of hyperchloremic metabolic acidosis and hypokalemia, with one of the causes being primary Sjögren's syndrome (pSS). PSS can have both glandular and extra glandular manifestations, with dryness of the eyes and mouth being the most common presenting symptoms. DRTA arising from pSS is very unusual, occurring in fewer than 2% of the cases of Sjogren's syndrome (SS). Here, we report on a case of recurrent flaccid quadriparesis that appears to have been caused by distal RTA, resulting in hypokalemia; upon further investigation and clinical evaluation, the patient was diagnosed with pSS.
28779180 MTHFR gene variants and non-MALT lymphoma development in primary Sjogren's syndrome. 2017 Aug 4 Primary Sjogren's syndrome (pSS) confers increased risk for non-Hodgkin lymphoma (NHL) development. Two common polymorphisms, the c. 677C > T and c. 1298A > C, of the methylene-tetrahydrofolate reductase (MTHFR) gene, an enzyme essential in DNA synthesis and methylation, have been associated with susceptibility to NHL. Herein, we tested the hypothesis that MTHFR variants contribute to pSS-related lymphomagenesis. 356 pSS patients, of whom 75 had MALT and 19 non-MALT NHL and 600 healthy controls were genotyped for the detection of MTHFR polymorphisms. DNA methylation levels were assessed by pyrosequencing of the LINE-1 retroelement promoter in DNA from 55 salivary gland tissues from pSS patients. DNA double-strand breaks were determined in peripheral blood mononuclear cells from 13 pSS patients, using comet assay. Αnalysis according to lymphoma subtype revealed increased frequency of c. 677C > T TT genotype and T allele, as well as reduced prevalence of the c. 1298A > C C allele in the pSS non-MALT group compared to controls and patients without NHL. MTHFR c. 677C > T TT genotype was associated with reduced DNA methylation levels, while MTHFR c. 1298A > C AC genotype with reduced DNA double-strand breaks levels. MTHFR variants may be involved in SS non-MALT NHL development, through contribution to defective DNA methylation and genomic instability.
28743286 CD4 T lymphocyte autophagy is upregulated in the salivary glands of primary Sjögren's syn 2017 Jul 25 BACKGROUND: Primary Sjögren's syndrome (pSS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands and peripheral lymphocyte perturbation. In the current study, we aimed to investigate the possible pathogenic implication of autophagy in T lymphocytes in patients with pSS. METHODS: Thirty consecutive pSS patients were recruited together with 20 patients affected by sicca syndrome and/or chronic sialoadenitis and 30 healthy controls. Disease activity and damage were evaluated according to SS disease activity index, EULAR SS disease activity index, and SS disease damage index. T lymphocytes were analyzed for the expression of autophagy-specific markers by biochemical, molecular, and histological assays in peripheral blood and labial gland biopsies. Serum interleukin (IL)-23 and IL-21 levels were quantified by enzyme-linked immunosorbent assay. RESULTS: Our study provides evidence for the first time that autophagy is upregulated in CD4(+) T lymphocyte salivary glands from pSS patients. Furthermore, a statistically significant correlation was detected between lymphocyte autophagy levels, disease activity, and damage indexes. We also found a positive correlation between autophagy enhancement and the increased salivary gland expression of IL-21 and IL-23, providing a further link between innate and adaptive immune responses in pSS. CONCLUSIONS: These findings suggest that CD4(+) T lymphocyte autophagy could play a key role in pSS pathogenesis. Additionally, our data highlight the potential exploitation of T cell autophagy as a biomarker of disease activity and provide new ground to verify the therapeutic implications of autophagy as an innovative drug target in pSS.
27957617 Neuromyotonia as an unusual neurological complication of primary Sjögren's syndrome: case 2017 Feb Primary Sjögren's syndrome (PSS) is a systemic autoimmune disorder characterized by chronic inflammation of exocrine glands such as the lachrymal and salivary glands, leading to xerophthalmia and xerostomia. Neurological manifestations are sometimes found in patients with PSS. A variety of neurological complications has been reported in patients with PSS, and both the central nervous system (CNS) and peripheral nervous system (PNS) can be involved in PSS. Several forms of neuropathy, including polyneuropathy, cranial neuropathy, and multiple mononeuropathy, are often seen in PSS patients. Herein, we report for the first time typical neuromyotonia (NMT) symptoms appearing in a patient with PSS. Neuromyotonia is a rare disorder caused by the hyperexcitability of peripheral nerves, causing spontaneous and continuous muscle contraction. We provide an overview of the literature relating to neurological involvement in PSS, and the etiology of acquired NMT. We also discuss the existence of contactin-associated protein-like 2 (Caspr2) antibodies in NMT patients.
27782867 Predictive significance of CCL21 and CXCL13 levels in the minor salivary glands of patient 2017 Mar OBJECTIVES: To investigate whether CCL21 and CXCL13 expression levels in the minor salivary gland are associated with the laboratory and clinical manifestations of Sjögren's syndrome (SS). METHODS: Sociodemographic data on 106 SS patients were obtained and the glandular and extraglandular manifestations of the disease were documented. In addition, minor salivary gland biopsies were performed and the patients' laboratory findings were analysed. European League Against Rheumatism SS disease activity index (ESSDAI) values of SS disease activity at the time of biopsy and the SS disease damage index (SSDDI) values were also recorded. An immunohistochemical approach was used to semiquantitatively measure the CCL21 and CXCL13 expression in the minor salivary glands. RESULTS: The minor salivary glands of SS patients stained positively for CCL21 and CXCL13 in 46.2% (49/106) and 70.7% (75/106) of all cases, respectively. Higher-level expression of CCL21 and CXCL13 was associated with increases in ESR, IgG and rheumatoid factor levels, as well as anti-SS-A and -SS-B titers. A higher focus score and ESSDAI value at the time of biopsy were also associated with these chemokines. In patients with extraglandular manifestations of SS, the prevalence of lymphadenopathy increased with increasing CCL21 levels. CONCLUSIONS: The expression levels of CCL21 and CXCL13 within the lymphocytic infiltrates of SS patients were associated with several laboratory features of the disease as well as lymphadenopathy and the extent of clinical disease activity. CCL21 and CXCL13 levels can therefore serve as useful markers to predict the disease activity and prognosis of patients with SS.