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ID PMID Title PublicationDate abstract
9484711 Stimulation of articular cartilage repair in established arthritis by local administration 1998 Feb A severe consequence of rheumatoid arthritis is depletion of proteoglycans (PGs) from articular cartilage leading to functional impairment of this tissue. We investigated whether local administration of anabolic factors (transforming growth factors-beta1 and -beta2 [TGF-beta1 and -beta2, respectively] and bone morphogenetic protein-2 (BMP-2) into joints could stimulate cartilage repair during arthritis. A unilateral arthritis was induced in mice by intra-articular injection of zymosan. Starting on Day 4 after the induction of arthritis, three injections of TGF-beta1 (200 ng) were given (Days 4, 6, and 8). On Day 11, articular cartilage PG synthesis was measured by 35S-sulfate incorporation, and histologic knee joint sections were prepared, which were used to analyze cartilage PG content by quantification of safranin O staining. Additionally, histologic sections were used to analyze inflammation and chondrophyte-formation. Local administration of TGF-beta1 did not modify inflammation but clearly stimulated PG synthesis and restored PG content of depleted cartilage. TGF-beta2 appeared to be as potent as TGF-beta1 in the stimulation of cartilage repair, and both TGF-beta isoforms also stimulated the formation of chondrophytes in this rodent model. In contrast to TGF-beta, three intra-articular injections with 200 ng BMP-2 did not stimulate the repair process. In summary, this study demonstrates for the first time that local administration of TGF-beta into arthritic joints stimulates the replenishment of PGs in depleted cartilage.
11268408 Susceptibility to autoimmune disease and drug addiction in inbred rats. Are there mechanis 2000 DA and LEW inbred rats are extraordinarily susceptible to a wide range of experimental autoimmune diseases. These diseases include rheumatoid arthritis models such as collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA), multiple sclerosis models such as myelin-basic-protein (MBP)-induced experimental autoimmune encephalomyelitis (MBP-EAE), and autoimmune uveitis models such as retinal S antigen (SAG) and interphotoreceptor-retinoid-binding-protein (IRBP)-induced experimental autoimmune uveitis (SAG-EAU and IRBP-EAU, respectively). DA and LEW rats are also addiction-prone to various drugs of abuse, such as cocaine. Moreover, they exhibit a variety of behavioral and biochemical characteristics that appear to be related to their susceptibility to addiction. By contrast, F344 and BN rats show quite different phenotypes. They are relatively resistant to CIA, AIA, MBP-EAE, SAG-EAU, and IRBP-EAU, and they are relatively resistant to addiction. Interestingly, both DA and LEW rats, in contrast to F344 and BN rats, have abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function. For example, circadian production of corticosteroids is very abnormal in DA and LEW rats; that is, they exhibit minimal circadian variation in corticosterone levels. Since corticosteroids potentially have significant influences on immune function and autoimmune disease susceptibility and may also influence sensitivity to drugs of abuse, we have begun to dissect genetic control of these various phenotypic differences, focusing initially on the regulation of autoimmune disease expression. Using genomewide scanning techniques involving F2 crosses of DA x F344 (CIA and AIA), DA x BN (CIA), and LEW x F344 [IRBP-EAU and streptococcal-cell-wall arthritis (SCWA)], we have identified, to date, 14 genomic regions [quantitative trait loci (QTL)] that regulate disease expression in these crosses. Development and analysis of QTL-congenic rats involving these loci are in progress and should permit us to address the relationships among autoimmune disease susceptibility, drug addiction, and HPA axis and stress response function. These initial data, however, indicate that the genetic control of the autoimmune disease traits is highly complex.
9558085 Critical roles of glycosaminoglycan side chains of cartilage proteoglycan (aggrecan) in an 1998 Apr 15 Systemic immunization of BALB/c mice with proteoglycan (aggrecan) from fetal human cartilage induces progressive polyarthritis, an experimental disease similar to human rheumatoid arthritis. The development of the disease in this genetically susceptible murine strain is based on cross-reactive immune responses between the immunizing fetal human and mouse self-proteoglycans. One of the cross-reactive and arthritogenic T cell epitopes (92GR/QVRVNSA/IY) is localized in the G1 domain of human/murine proteoglycan. Susceptible BALB/c mice, however, develop arthritis only if both the chondroitin sulfate (CS) and keratan sulfate (KS) side chains of the arthritogenic human proteoglycans are removed. The function of these two glycosaminoglycan side chains is opposite. The presence of a KS side chain in adult proteoglycan inhibits the recognition of arthritogenic T cell epitopes, prevents the development of T cell response, and protects animals from autoimmune arthritis. In contrast, the depletion of the CS side chain generates clusters of CS stubs and provokes a strong B cell response. These carbohydrate-specific B cells are the most important proteoglycan APC. Taken together, proteoglycan-induced progressive polyarthritis is dictated by three major components: genetic background of the BALB/c strain, highly specific T cell response to epitope(s) masked by a KS chain in aging tissue, and the presence of proteoglycan (CS stub)-specific B cells required for sufficient Ag presentation.
11503136 Bromocriptine in rheumatic and autoimmune diseases. 2001 Aug BACKGROUND AND OBJECTIVES: Multiple lines of evidence support the concept that the anterior pituitary hormone prolactin has a pathogenic role in rheumatic and autoimmune diseases including, but not limited to, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Reiter's syndrome, psoriatic arthritis, and uveitis. Conversely, the dopaminergic agonist bromocriptine appears to have therapeutic effects through suppression of pituitary prolactin secretion and, perhaps, through actions on peripheral dopamine receptors. This article reviews the experimental and clinical data supporting the therapeutic use of bromocriptine as a nonstandard or adjunctive therapy in rheumatic and autoimmune diseases. METHODS: Data addressing the potential therapeutic role of bromocriptine in rheumatic and autoimmune diseases, as well as frequently associated comorbidities, was accumulated from the author's work, online literature search of the National Library of Medicine, and references from these identified publications. RESULTS: There have been a number of clinical therapeutic trials using 2.5 to 30 mg of bromocriptine per day in a single or divided dose, which have shown efficacy with minimal side effects in the treatment of rheumatic and autoimmune diseases. In RA, bromocriptine administration has induced immunosuppression of several immune parameters and has been associated with improvements in morning stiffness, grip strength, numbers of swollen/painful joints, and the Health Assessment Questionnaire disability index. In two blinded studies, bromocriptine reduced the number of SLE flares and was as effective as hydroxychloroquine in reducing lupus disease activity indices, respectively. In case reports, bromocriptine has been used successfully in the treatment of Reiter's syndrome enthesopathy and psoriatic arthritis. The potential efficacy of bromocriptine in the treatment of uveitis and multiple sclerosis is suggested but remains to be verified. CONCLUSIONS: Double-blind, placebo-controlled studies are limited, but clinical observations and trials support the use of bromocriptine as a nonstandard primary or adjunctive therapy in the treatment of recalcitrant RA, SLE, Reiter's syndrome, and psoriatic arthritis and associated conditions unresponsive to traditional approaches. Additional investigation is needed to verify this conclusion and extend preliminary results. RELEVANCE: In patients with rheumatic and autoimmune diseases, bromocriptine may be a relatively safe and efficacious alternative therapy. Semin Arthritis Rheum 31:21-32.
9010265 Dynamic expression of transforming growth factor-betas (TGF-beta) and their type I and typ 1997 Jan A well characterized animal model that shares many characteristic features with rheumatoid arthritis (RA) is collagen-induced arthritis (CIA) in DA rats. Recent studies have demonstrated that TGF-beta, a multifunctional cytokine, is an important modulator of the immune response in CIA, and possibly also in RA. In this study we have investigated the expression of the precursor forms of TGF-beta1, TGF-beta2, TGF-beta3, as well as TGF-beta type I receptor (TGF-betaRI) and TGF-beta type II receptor (TGF-betaRII) in the synovial tissue of arthritic rats during the course of the disease. By using immunohistochemical techniques, an abundant expression of all three TGF-beta isoforms and their receptors was observed in the arthritic synovia, an expression that increased with time after onset of disease. Antibodies to TGF-beta1, TGF-beta2, TGF-betaRI and TGF-betaRII stained blood vessels intensively, already at the early onset of inflammation, whereas the synovial lining layer and chondrocytes expressed strong immunoreactivity later on in the inflammatory process. The most intense staining with these antibodies was detected in fibroblasts within fibrotic tissue, in particular at the cartilage pannus junction. Interestingly, TGF-beta3 only stained macrophage-like cells and chondrocytes in the synovia. The data suggest that the abundant expression of TGF-beta1, TGF-beta2, TGF-beta3 as well as TGF-betaRI and TGF-betaRII in the synovia, is of pathogenic importance in the development of CIA, although the question of how the different TGF-beta isoforms may enhance or counteract different arthritogenic events remains open.
11005360 Cyclooxygenase-2 inhibitor celecoxib: a possible cause of gastropathy and hypoprothrombine 2000 Sep Gastrointestinal side effects from nonsteroidal anti-inflammatory drugs (NSAIDs) result mainly from inhibition of the enzyme cyclooxygenase (COX)-1; it is responsible for the synthesis of prostaglandin E2, which leads to increased mucosal blood flow, increased bicarbonate secretion, and mucus production, thus protecting the gastrointestinal mucosa. In inflammation, COX-2 is induced, causing synthesis of the prostaglandins in conditions such as osteoarthritis and rheumatoid arthritis. Two NSAIDs (celecoxib and rofecoxib) with very high specificity for COX-2 and virtually no activity against COX-1 at therapeutic doses have been approved for clinical use. In trials of celecoxib and rofecoxib, only 0.02% of patients had clinically significant gastrointestinal bleeding, compared to a 1% to 2% yearly incidence of severe gastrointestinal side effects with NSAIDs. Our patient had arthritis of the hips and chronic atrial fibrillation and was on warfarin therapy for stroke prevention; less than a week after starting celecoxib therapy, gastrointestinal bleeding and hypoprothrombinemia occurred.
9754708 The role of helper T cell subsets in autoimmune diseases. 1998 Jun CD4 helper T cells can be divided into Th1 and Th2 subsets based upon the cytokines they produce. Th1 and Th2 cells have been found to be mutually antagonistic, leading to either Th1- or Th2-dominated responses upon immunization. In recent years, several authors have suggested that in chronic inflammatory autoimmune diseases such as diabetes, multiple sclerosis and rheumatoid arthritis, Th1 cells are pathogenic and Th2 cells are protective. Therefore, a successful deviation from a Th1-dominated to a Th2-dominated response could have clinical benefits for individuals suffering from these diseases. Unfortunately, data accumulated over recent years have not supported this approach, in particular regarding the protective role of Th2 cells. In this review we discuss these data and conclude that, at least using currently available tools, immune deviation from Th1 to Th2-dominated responses is ineffective unless started at very early (subclinical) stages of the disease. In addition, we examine some recent data suggesting that, under some circumstances, Th2 cells can be pathogenic.
9644741 [Significance of antibodies to herpesviridae viruses detectable in rheumatic diseases]. 1998 AIM: To assay antibodies to cytomegalovirus (CMV), herpes simplex virus type 1 and 2 (HSV-1, HSV-2) and Epstein-Barr virus (EBV) in rheumatic patients and to clarify clinical correlations. MATERIALS AND METHODS: A total of 66 patients were examined: 7, 19, 6, 3, 5, 2 and 24 with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), reactive arthritis (ReA), scleroderma systematica (SS), erythema nodosum (EN), hemorrhagic vasculitis (HV), active or chronic viral infection (A/CVI), respectively. Clinical, laboratory tests, tests for specific IgM- and IgG-antibodies to CMV, HSV-1, HSV-2, EBV, x-ray examinations were performed. RESULTS: IgG-antibodies to CMV were detected in 79%, VCA-IgG-antibodies to EBV in 70.3%, EA-IgG-antibodies to EBV in 56.6%, IgG-antibodies to HSV-1 in 42.1% of patients. Active CMV infection was diagnosed in 27.8%, active EBV infection in 56.6%, combination of CMV and EBV infection in 46.9% of cases. High titers of antibodies to CMV and EBV correlated with such symptoms as fever, arthritis, myalgia, carditis, hepatomegalia, migrating erythematous eruption. Acute-phase indices were related to high titers of antibodies to CMV and EBV. Elevated titers of antibodies to CMV and EBV were registered both in untreated patients and in patients treated with corticosteroids, nonsteroid antiinflammatory drugs and aminoquinoline drugs. CONCLUSION: In differential diagnosis of rheumatic diseases it is necessary to consider possibility of CMV and EBV infections. If these are detected, antiviral measures should be taken.
9487234 Rheumatic findings in Gulf War veterans. 1998 Feb 23 BACKGROUND: Rheumatic symptoms were commonly described among soldiers who served in previous wars. OBJECTIVE: To describe the frequency of rheumatology consultations, along with the diagnoses, and abnormal results on serologic testing in Gulf War veterans evaluated for Gulf War syndrome. METHODS: The medical records of the first 250 consecutive Gulf War veterans referred to the comprehensive clinical evaluation program at Wilford Hall Air Force Medical Center and Brooke Army Medical Center, San Antonio, Tex, were reviewed for demographic characteristics and frequency of subspecialty consultations. A retrospective review of rheumatic diagnoses and the frequency of abnormal serologic test results was recorded. RESULTS: Of the 250 Gulf War veterans evaluated in the comprehensive clinical evaluation program, 139 (56%) were referred for rheumatology consultation, which was the most common elective subspecialty referral. Of the patients evaluated, 82 (59%) had soft tissue syndromes, 19 (14%) had rheumatic disease, and 38 (27%) had no rheumatic disease. The most common soft tissue syndromes were patellofemoral syndrome (33 patients [25%]), mechanical low back pain (23 patients [18%]), and fibromyalgia (22 patients [17%]). Of the 19 patients with rheumatic disease, 10 had osteoarthritis, 2 had rheumatoid arthritis, 2 had gout, and 1 each had systemic lupus erythematosus, Behcet disease, parvovirus arthritis, psoriatic arthritis, and hypothyroid arthropathy. Abnormal serologic test results were common among the Gulf War patients regardless of the presence or absence of rheumatic disease. CONCLUSIONS: The rheumatic manifestations in Gulf War veterans are similar to symptoms and diagnoses described in previous wars and are not unique to active duty soldiers. Overall, the results of serologic screening were poor predictors of the presence of rheumatic disease.
9767455 CD4+ T-cell-mediated cytotoxicity against staphylococcal enterotoxin B-pulsed synovial cel 1998 Sep Apoptosis of synovial cells in rheumatoid arthritis (RA) synovium determined in vivo is suggested to counteract the overgrowth of synovium. Immunohistological examination has revealed the infiltration of activated CD4+ T cells, which express Fas ligand (FasL), in RA synovium. The presence of a putative antigen (Ag) of autoimmune disorders in a target organ may induce the activation of specific T cells in the inflammatory region such as RA synovium. We examined the possible role of CD4+ T cells activated by synovial cells in a staphylococcal enterotoxin B (SEB)-dependent manner, inducing synovial cell apoptosis. Synovial cells were cultured with or without interferon-gamma (IFN-gamma) and further incubated with CD4+ T cells in the presence of SEB. After the cocultivation, both the cytotoxicity and FasL expression of CD4+ T cells were investigated. Constitutive Fas expression was detected on both unstimulated and IFN-gamma-stimulated synovial cells. CD4+ T cells did not kill SEB-pulsed unstimulated synovial cells efficiently. In contrast, when CD4+ T cells were incubated with IFN-gamma-stimulated synovial cells with SEB whose human leucocyte antigen (HLA)-DR and -DQ expression was markedly induced, significant cytotoxicity by these cells against synovial cells was detected. The addition of anti-HLA-DR and -DQ monoclonal antibodies (mAbs) or human Fas chimeric protein (hFas-Fc) reduced this cytotoxicity. FasL expression of CD4+ T cells cocultured with IFN-gamma-stimulated synovial cells with SEB was significantly induced. Furthermore, the addition of mAbs against CD54, CD58 and CD106 inhibited both the cytotoxicity and FasL expression of CD4+ T cells induced by IFN-gamma-stimulated synovial cells in the presence of SEB, indicating the importance of costimulatory molecules on synovial cells in activating CD4+ T cells. Our results suggest that CD4+ T cells are activated by synovial cells by an SEB-dependent manner and express FasL, inducing Fas-mediated apoptosis of the latter cells. These phenomena may regulate the overgrowth of synovial cells in RA synovium.
11491496 Circulating levels of Th1/Th2 cytokines in patients with primary Sjögren's syndrome: corr 2001 Jul OBJECTIVE: To analyse the circulating levels of Th1 and Th2 cytokines in patients with primary Sjögren's syndrome (SS), as well as to investigate their association with clinical and immunological manifestations. METHODS: We included 62 consecutive patients (58 women and 4 men) seen in our Unit. All patients fulfilled 4 or more of the European diagnostic criteria for SS. Serum levels of IL-6 (pg/mL), IL-2 (pg/mL), srIL-2 (pM), TNFalpha (pg/mL) and IL-10 (pg/mL) were determined using a solid phase enzyme immunoassav performed on microtiter plate. RESULTS: When compared with the control group, high levels of Th1 (11-2, srIL-2) and Th2 (IL-6, IL-10) cytokines were detected in SS patients, although only IL-6 levels reached statistical significance. On the other hand, analysis of the mean serum concentrations of cytokines showed distinct patterns of elevated cytokines according to the organ involved, and elevated levels of IL-6 (126.5 v 20.6 pg/mL, p < 0.05) and IL-10 (10.6 v 2.2 pg/mL, p < 0.005) were observed in those patients with liver involvement. Analysis of the cytokine levels according to the presence of immunological features showed: higher levels of srIL-2 (95.6 v 54.0 pM, p < 0.05) in patients with anti-Ro/SS-A antibodies; increased levels of srIL-2 (111.4 v 59.4 pM, p < 0.05) in patients with antiLa/SS-B antibodies; higher levels of srIL-2 (90.4 vs 50.8 pM, p < 0.05) and TNFalpha (37.9 v 22.6 pg/mL, p = 0.001) in patients with RF and higher levels of IL-6 (88.0 v 23.1 pg/mL, p < 0.05) in patients with cryoglobulins and in those with hypocomplementemia (130.3 vs 21.0 pg/mL, p < 0.05). CONCLUSION: We found a significant elevation of several circulating cytokines in some clinical and immunological subsets of patients with primary SS. These cytokine patterns may be markers for specific extraglandular involvement in SS and could be of interest in assessing the response to treatment protocols or in monitoring the disease evolution.
11249598 AnergiX.RA Corixa. 2000 Sep Corixa (formerly Anergen), in collaboration with Organon, is developing AnergiX.RA, a complex of solubilized HLA DRB1-0401(a) together with a specific peptide from the human cartilage glycoprotein HCgp39, for the potential treatment of rheumatoid arthritis (RA) [307156]. Phase I/II trials were completed in April 2000 and the final results from the randomized, blinded, placebo-controlled dose-escalation study are expected later this year [363409]. The product utilizes Anergen's AnergiX technology, and combines an MHC-derived protein with an Organon autoantigen peptide, derived from myelin basic protein and involved in the development of RA [212659,363409]. Engagement of T-cell receptors with AnergiX.RA induces apoptosis in autoreactive T-cells [227421]. Researchers at Organon identified the central component in AnergiX.RA; results from preclinical studies identifying this target protein were published in June 1997 in Arthritis & Rheumatism. Researchers demonstrated that HC (human cartilage) gp39 is recognized by T-cells from RA patients and has the potential to block arthritis in the mouse model [248543,354821].
10524697 Toward a multidimensional Health Assessment Questionnaire (MDHAQ): assessment of advanced 1999 Oct OBJECTIVE: To develop components of a multidimensional Health Assessment Questionnaire (MDHAQ) through the addition of new items in the "patient-friendly" HAQ format, including advanced activities of daily living (ADL), designed to overcome "floor effects" of the HAQ and modified HAQ (MHAQ) in which patients may report normal scores although they experience meaningful functional limitations, and psychological items, designed to screen efficiently for psychological distress in routine care. METHODS: The new MDHAQ items, as well as scales for pain, fatigue, helplessness, and global health status on a 2-page questionnaire, were completed by 688 consecutive patients with various rheumatic diseases, including 162 with rheumatoid arthritis (RA), 114 with fibromyalgia, 63 with osteoarthritis, 34 with systemic lupus erythematosus, 20 with vasculitis, 18 with psoriatic arthritis, 16 with scleroderma, and 261 with various other rheumatic diseases, over 2 years at a weekly academic rheumatology clinic. RESULTS: The new MDHAQ items have good test-retest reliability and face validity. MHAQ scores were highest in patients with RA, and scores for other scales were highest in patients with fibromyalgia. On the advanced ADL, 58% of patients reported difficulty with errands, 68% with climbing stairs, 79% with walking two miles, 87% with participating in sports and games, and 94% with running or jogging two miles. On the psychological items, 75% of patients reported difficulty with sleep, 63% with stress, 61% with anxiety, and 57% with depression. Normal MHAQ scores were reported by 23% of patients and normal HAQ scores by 16% of patients who completed these questionnaires, while fewer than 5% had normal scores on the MDHAQ. CONCLUSION: The MDHAQ items overcome in large part the "floor effects" seen on the HAQ and MHAQ, and are useful to screen for problems with sleep, stress, anxiety, and depression in the "patient-friendly" HAQ format. These data support the value of completion of a simple 2-page patient questionnaire by each patient at each visit to a rheumatologist.
9623900 Periodontal status and serum antibody responses to oral microorganisms in Sjögren's syndr 1998 May Sjögren's syndrome is an autoimmune disease characterized by keratoconjunctivitis sicca and xerostomia. Rapid bacterial plaque accumulation occurs in Sjögren's syndrome patients due to decreases in salivary flow rate. The purpose of this study was to evaluate the periodontal status of patients with Sjögren's syndrome and evaluate serum antibody responses to selected oral microorganisms, including major periodontopathogens, compared to healthy controls. Seventeen Sjögren's syndrome patients and 14 healthy subjects were included in the study. Plaque (PL), sulcular bleeding (SBI), periodontal index scores (PI), probing depths (PD), and total number of teeth were recorded. An ELISA was used to determine the serum IgG antibody level to a panel of 13 oral microorganisms. Significantly higher PL, SBI, PD, and PI scores, as well as an increased number of lost teeth were observed in patients with Sjögren's syndrome compared to healthy subjects (P <0.0001). Antibody levels to Streptococcus oralis were significantly lower in Sjögren's syndrome patients than controls (P <0.0002). These patients exhibited significantly elevated antibody levels to Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis compared to controls (P <0.006 to 0.0004). Our findings indicate that Sjögren's syndrome patients have established periodontal disease and serum antibody responses to oral microorganisms previously identified as periodontopathogens in systemically healthy subjects. These results suggest that Sjögren's syndrome may affect bacterial colonization in plaque and contribute to increased periodontal disease in this compromised population.
11678303 Study of hepatitis C virus infection in 213 Hungarian patients with Sjögren's syndrome. 2001 Sep In the current study we investigated 213 randomly selected Hungarian patients diagnosed with primary Sjögren's syndrome (SS). All patients were monitored for hepatitis C virus (HCV) infection and 13 were positive. We compared HCV-negative and -positive patients and made observations on how HCV infection alters the clinical and laboratory features of Sjögren's syndrome. On the basis of these findings, we conclude that HCV infection is more frequent in Hungarian SS patients than in the normal population and that the presence of this virus has a disease-modifying effect on SS.
10441181 Th1 predominance and perforin expression in minor salivary glands from patients with prima 1999 Aug Objectives of this study were to examine the cytokine and perforin mRNA expression in minor salivary glands from patients with primary Sjögren's syndrome (pSS), searching for possible correlation with clinical parameters and to identify the dominant cytokine pattern in the different groups. Oral mucosa biopsy samples from 42 pSS patients were studied. Total RNA was analysed by normalized RT-PCR using oligo-dT as the RT primer and IL-2, IFN-gamma, IL-12, IL-18, IL-4, IL-10, TGF-beta, TNF-alpha and perforin-specific primers for amplification. Results were analysed taking into account: (1) biopsy grade I to IV (Chisholm's classification); (2) diagnosis of either definite pSS (n=30) or probable pSS (n=12), following the European classification criteria (ECC), and (3) length of disease evolution from the beginning of symptoms to the time of biopsy, using an arbitrary cut-off point of 12 months. This studied showed that Th1-related cytokines (IL-2, IFN-gamma, IL-12, IL-18, TNF-alpha) and perforin were present in most samples. IL-4 (Th2) was totally absent but other Th2 and regulatory cytokines (IL-10, TGF-beta) were detected in the majority of samples. No significant differences were found between definite and probable pSS nor between grades II, III, IV and fibrous tissue biopsies. A statistically significant increase of IL-2 (P=0.012) and IFN-gamma (P=0.019) was observed in samples from patients with longer disease evolution, whereas the two Th1-inducer cytokines IL-12 and IL-18 were equally and highly expressed in all samples. In conclusion, a predominant Th1 pattern of cytokines was observed in all pSS samples, irrespective of biopsy classification. In addition, a significant increase of Th1 cytokine expression frequency was associated with longer disease evolution.
11560955 SS-56, a novel cellular target of autoantibody responses in Sjögren syndrome and systemic 2001 Sep Certain autoimmune disorders, including Sjögren syndrome (SS) and systemic lupus erythematosus (SLE), are characterized by autoantibodies against the Ro/SSA and La/SSB cellular antigens. Although the implication of these autoantibodies in disease pathogenesis is still unclear, it is believed that the aberrant responses against autoantigens may extend to other proteins that are not yet well defined. In an attempt to analyze the regulated gene expression in lymphocytes by an HIV-suppressive immunomodulator, we have identified and cloned a novel gene encoding a 56-kDa protein, named SS-56, which is structurally related to the 52-kDa Ro/SSA antigen. The new protein showed primarily perinuclear cytoplasmic localization, and recombinant SS-56 was found to react in ELISA with sera from most patients with SS or SLE. Western blot analysis confirmed the autoantigenic nature of native SS-56 in extracts from HeLa cells. Interestingly, the incidence of antibodies to SS-56 was associated with visceral complications in SLE, and roughly half of the 17 SS or SLE patients with no detectable antibodies to SSA and SSB antigens presented measurable antibodies against recombinant SS-56. Thus, SS-56 represents a new member of the SS family of autoantigens and could become an additional and important diagnostic marker for SS and SLE.
11246683 Corneal melt as the initial presentation of primary Sjögren's syndrome. 2001 Feb Corneal melting is a rare complication of S ogren's syndrome (SS). Previously reported cases of corneal ulceration occurred in patients with established SS, usually secondary to RA. We describe the first case of corneal ulceration with stromal melting as the initial presentation of primary SS. A 79-year-old man without prior sicca symptoms developed a large sterile corneal ulcer that required extensive treatment over several months with ocular lubricants, systemic immunosuppressives, and surgical repair. Evaluation for an underlying connective tissue disease revealed positive antinuclear antibodies (1:640 speckled) and anti-SSA antibody. A lip biopsy established the diagnosis of SS. Ulceration later occurred in the contralateral eye. Two years after the last corneal ulcer and no longer taking prednisone, the patient's ocular disease remained quiescent taking azathioprine 175 mg and hydroxychloroquine 400 mg daily. This case highlights the potential for primary SS to present with serious ocular complications despite lack of a priori sicca symptoms, as well as the importance of immunosuppressive therapy in the treatment of this complication.
10771708 Thyroid disease in primary Sjögren syndrome. Study in a series of 160 patients. 2000 Mar We studied 160 consecutive patients (147 female and 13 male) with primary Sjögren syndrome (SS) to determine the prevalence and clinical significance of thyroid disease in a large series of patients with primary SS from our unit and to compare the prevalence and significance with those in 75 individuals without SS from a primary care center. Serum levels of thyroid hormones (free thyroxine, triiodothyronine, and thyroid-stimulating hormone) and autoantibodies against thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) were measured in all SS patients and in 75 control patients. Fifty-eight (36%) of the 160 patients with primary SS had evidence of thyroid disease. Autoimmune thyroid disease (ATD) was diagnosed in 32 (20%) patients and nonautoimmune thyroid disease (NATD) in 26 (16%). No significant differences were found when these prevalences were compared with those in control patients. On the other hand, comparing those patients with altered hormonal profiles, patients with NATD showed mainly hyperthyroidism (10/17, 59% versus 2/20, 10% in patients with ATD, p = 0.001). Finally, when clinical and immunologic manifestations of SS were analyzed in patients with and without thyroid disease, respectively, we found that patients with thyroid disease had a higher prevalence of female gender (98% versus 88%, p = 0.03), antiparietal cell autoantibodies (33% versus 12%, p = 0.002), TgAb (30% versus 5%, p < 0.001), and TPOAb (40% versus 5%, p < 0.001). In conclusion, thyroid disease occurred in more than one-third of patients with primary SS; the main cause was ATD, which was present in 20% of the patients studied. We note that no significant differences were observed when the prevalence of thyroid disease (either ATD or NATD) was compared with that in a control group of similar age and gender. Our results indicate that middle-aged women (with or without SS) should be screened periodically for thyroid function.
10585759 Autoantibodies to La/SSB in patients with primary Sjögren's syndrome (pSS) are associated 1999 Dec Recent studies have shown that minor salivary glands (MSGs) of patients with primary Sjögren's syndrome (pSS) are sites of anti-La/SSB autoantibody production. The aim of this study was to investigate the expression of La/SSB mRNA in MSGs of patients with pSS. La/SSB mRNA expression was studied by in situ hybridization in six biopsies of pSS patients with anti-La/SSB antibodies, nine pSS patients without anti-La/SSB and 10 patients with non-specific sialadenitis. Oligonucleotide probes corresponding to c-DNA encoding four linear epitopes of La/SSB (bp 423-471, bp 861-909, bp 903-954 and bp 1048-1092) were utilized. cDNA encoding linear epitopes of Ro52 (bp 786-837), Ro60 (bp 654-702) and the housekeeping genes of Sm and GAPDH were used as controls. The results were expressed as percent of positive cells by image analysis. Serum levels of anti-La/SSB autoantibodies were correlated with the presence and the intensity of La/SSB mRNA labeling. All pSS patients with anti-La/SSB antibodies in their serum expressed mRNA transcripts of epitopes 301-318 aa and 349-364 aa (encoded by the cDNA probes bp 903-954 and bp 1048-1092 respectively), predominantly in acinar and mononuclear cells of MSGs. These epitopes are the major targets of anti-La/SSB antibodies. Serum levels of anti-La/SSB antibodies were correlated with the number of positively stained cells in MSGs. Two of the nine pSS patients without anti-La/SSB autoantibodies and 2/10 non-pSS patients expressed the mRNA of the La/SSB molecule. The probes of RO52 and Ro60 epitopes did not react, while mRNA encoding the housekeeping genes of Sm and GAPDH was positive in all samples. In conclusion, pSS patients with anti-La/SSB antibodies showed upregulation of La/SSB mRNA in acinar and mononuclear cells of MSGs. Thus, active synthesis of La/SSB in MSGs of pSS seems to play an important role in the autoimmune response of the affected tissues.