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ID PMID Title PublicationDate abstract
16142869 Pregnancy outcome in patients with primary Sjögren's syndrome. a case-control study. 2005 Sep OBJECTIVE: To study the outcome of pregnancy in patients with primary Sjögren's syndrome (pSS). METHODS: A questionnaire covering demographic data and the outcome of pregnancies was answered by 58 patients with pSS and 157 controls. For 36 patients and 93 controls, we analyzed detailed data about pregnancy, birth, and status of the newborn from the Medical Birth Registry of Norway (MFR) for birth order one, 2, and 3. Thirty-two of 36 patients registered in MFR were diagnosed with pSS after the last birth. RESULTS: Pregnancy outcomes were not different in patients compared to controls. Two patients (3.4%) reported giving birth to a child with congenital heart block. CONCLUSION: PSS had no impact on pregnancy outcome before disease onset. The most important condition associated with pSS in anti-SSA positive mothers was congenital heart block in the offspring.
15893711 Clinical and pathological characteristics of Mikulicz's disease (IgG4-related plasmacytic 2005 Apr Mikulicz's disease (MD) has been considered part of primary Sjogren's syndrome (SS) since Morgan's report in 1953. MD represents a unique condition involving enlargement of the lacrimal and salivary glands, as is also seen in SS; however, MD is characterized by few autoimmune reaction and its good responsiveness to glucocorticoid. Recent reports have shown that the frequency of apoptosis in glands of MD patients is lower when compared with SS. This phenomenon reflects the histologically reversible gland secretion in MD. Elevated IgG4 concentrations in the serum and prominent infiltration by plasmacytes expressing IgG4 in the lacrimal and salivary glands have also been confirmed in MD. Plasma cells expressing IgG4 are also detected in lymph nodes and bone marrow. MD may be a systemic disease, rather than a lacrimal and salivary gland disease. We here propose the new entity "IgG4-related plasmacytic exocrinopathy" and expect future development with regard to its relationship with autoimmune pancreatitis, which similarly presents elevated serum IgG4 levels.
16792727 Dynamic magnetic resonance sialography as a new diagnostic technique for patients with Sjà 2006 Jul OBJECTIVE: To evaluate the clinical utility of dynamic magnetic resonance (MR) sialographic images as a diagnostic tool for patients with Sjögren's syndrome. METHODS: The morphological findings and various kinds of functional parameters in volunteers on dynamic MR sialographic images were compared with those in five patients with definite Sjögren's syndrome. RESULTS: On the MR sialographs of all five patients with Sjögren's syndrome, the so-called 'apple-tree appearance' was seen. The difference in two functional parameters using the dynamic MR sialographic data was elucidated between the two groups. The maximum area of the detectable ducts in the group of patients was significantly smaller (P < 0.001) than that in the group of volunteers. The ratio of change in the detectable ducts in the group of patients was significantly lower (P = 0.011) than that in the group of volunteers. CONCLUSIONS: Our study suggests that dynamic MR sialographic data in addition to MR sialographic images might be useful for the diagnosis of Sjögren's syndrome.
16421015 Unique ultrastructure of exorbital lacrimal glands in male NOD and BALB/c mice. 2006 Jan Lacrimal glands of male NOD and BALB/c mice have very small, pleomorphic acinar lumens. Acini contain isolated zones of highly complex cell surface interdigitations at the basal surface, sometimes occurring between acinar and myoepithelial cells. In NOD mice, cytological abnormalities, including mitochondrial deterioration, pleomorphic and heterogeneous cytoplasmic vacuoles, and lipid accumulation are evident within acinar cells at 1 month. Accumulation of lipid is further increased as the animal ages, accompanied by lymphocytic infiltration and destruction of acini. These results demonstrate alterations from normal cytology as early as 1 month in NOD mice, well before detection of clinical signs of Sjögren syndrome.
16138452 [Non-neoplastic enlargement of salivary glands: clinico-histologic analysis]. 2005 May We carried out a retrospective study on non-neoplastic enlargement of the salivary glands at the Oral Histopathology Diagnostic Center of the Autonomous Metropolitan University at Xochimilco (UAM-Xochimilco) in Mexico during a period of 24 years (1979-2003). From 5,625 biopsies received and analyzed, a total of 461 (8.2%) were non-neoplastic enlargement of the salivary glands; for each case, we registered demographic data as well as clinic characteristics. These lesions were characterized as a heterogeneous group of pathologic entities among which we included local, obstructive, infectious, and immunopathologic lesions. The most frequent lesion was the extravasation cyst in 341 (74%) cases, followed by chronic sialoadenitis and Sjögren's syndrome with 54 (11.7%) and 41 (8.8%) cases, respectively, and at a lesser percentage mucous retention cyst, sialosis, benign lymphoepithelial lesions and those related with sialolytes. Females were affected more frequently; mean age was second to third life decades. These lesions were most frequently localized on inferior labial mucosa.
16084956 Multilocular thymic cyst associated with follicular hyperplasia: clinicopathologic study o 2005 Jul We report here 4 cases of multilocular thymic cysts (MTCs) with reactive lymphoid follicular hyperplasia. They were admitted to our hospital to examine anterior mediastinal masses demonstrated on chest computed tomographic scans. Three patients presented high-grade intermittent fever, and 2 patients were associated with Sjogren syndrome with elevated serum antinuclear antibody levels. All patients were subjected to extended thymectomy. Interestingly, their fever disappeared immediately after surgery. Histologically, the lesions were characterized by several cystic spaces separated by various thick walls with dense lymphoid tissue containing large reactive germinal centers. The inner cyst walls were lined by flattened cuboidal epithelia in some portions. Columnar epithelia with focal cilia were partially observed in 2 cases. These pathological findings led to a diagnosis of MTCs that were thought to result from cystic transformation of medullary duct derivatives by acquired inflammatory processes. The pathological findings, together with clinical courses of our cases, suggest that inflammation accompanied by autoimmune diseases may play, in part, an important role in the development of MTCs.
16838655 [Interferon alpha (IFNalpha) treatment for Sjögren's syndrome]. 2006 Jul IFNalpha is important for the defense against viral infection. By using a sensitive radioimmunoassay, we previously established the existence of endogenous IFNalpha in human. Serum IFNalpha, i.e., endogenous IFNalpha gradually increases with age, reaching the highest peak at young adults and then gradually declining with aging. We also found that serum IFNalpha levels were significantly low in the patients with Sjögren's syndrome. Subsequent treatment with a small dose 450 IU/day of orally administered IFNalpha significantly improved saliva secretion and the pathology of salivary glands of the patients as well. Since natural killer (NK) cell activity has been reported to be significantly decreased in the patients likely because of the decrease of IFNalpha, we may assume that correction of endogenous levels of IFNalpha by administering small amounts of IFNalpha will improve the vicious cycle in the pathology of the patients with Sjögren's syndrome.
15934079 Rapid responses to anakinra in patients with refractory adult-onset Still's disease. 2005 Jun OBJECTIVE: To assess the efficacy of anakinra treatment in patients with adult-onset Still's disease (AOSD) that is refractory to corticosteroids, methotrexate (MTX), and etanercept. METHODS: Four patients with AOSD were treated with prednisone and MTX and 2 patients were also treated with etanercept for worsening symptoms and indicators of systemic inflammation. White blood cells (WBCs), C-reactive protein (CRP) levels and/or erythrocyte sedimentation rate, and ferritin levels were measured and, in 1 patient, serum creatinine levels were determined. Treatment with anakinra at 100 mg/day was initiated. RESULTS: The index patient's disease was refractory to treatment with prednisone (30 mg/day) and MTX, with spiking fevers, rash, synovitis, a serum ferritin level of 8,400 ng/ml (normal 20,000/mm(3) with prominent neutrophilia, the CRP level rose to >200 mg/liter, and the ferritin level rose to >3,000 ng/ml. Upon restarting anakinra, the patient became afebrile, the WBC count fell to 8,000/mm(3), the CRP level fell to <3 mg/liter, and the ferritin level fell to <300 ng/ml. Three additional patients with refractory AOSD who experienced rapid reductions in fever, symptoms, and markers of inflammation when treated with anakinra are reported. CONCLUSION: Refractory AOSD appears to be IL-1-mediated since anakinra decreases hematologic, biochemical, and cytokine markers and also produces rapid reductions in systemic and local inflammation. Reported efficacy of tumor necrosis factor-blocking therapies in AOSD may be due to a reduction in IL-1.
16573263 Primary cutaneous nodular amyloidosis in a patient with Sjögren's syndrome. 2006 Mar A 71-year-old woman with a history of Sjögren's syndrome presented for evaluation of a waxy nodule present on the scalp for 6 months. Histopathologic examination revealed deposition of homogenous eosinophilic material throughout the reticular dermis consistent with amyloidosis. Primary cutaneous nodular amyloidosis is a rare phenomenon characterized by the deposition of immunoglobin light chains by a clonal plasma cell population. Patients need to be monitored for progression to systemic amyloidosis or plasma cell dyscrasias.
15889604 [Transient lower limbs paralysis--a rare presenting symptom of Sjögren's syndrome]. 2005 Apr Sjögren's syndrome is commonly presented with eye and mouth dryness caused by an autoimmune destruction of lacrimal and salivary glands. Kidney involvement is not common but may appear in patients with long standing disease. We present a patient with Sjögren's syndrome whose first manifestation of the disease was related to type 1 renal tubular acidosis (RTA) causing severe hypokalemia with lower limb paralysis. The uneven distribution of limb weakness necessitated the exclusion of cord compression.
16394643 [Analysis of clinical questionnaire of Tokyo Metropolitan Government for Sjogren's syndrom 2005 Dec Sjögren's syndrome is not one of the forty-five diseases included in the incurable disease treatment research project funded by the government. However, it is approved as a designated incurable disease for government funded treatment in Tokyo. The criteria of approval are based on diagnostic criteria revised in 1999. Complications and other factors are taken into consideration in the recognition standard established independently in Tokyo. In this study we examined the recognition standard of approval and their significance by analyzing the clinical questionnaires of patients with Sjögren's syndrome in Tokyo through 2003. The major objective of the recognition standard (2003) appears to have been the approval of subjects with severe Sjögren's syndrome with such conditions as advanced glandular involvement xerosis affecting their daily lives and visceral complications. However, examinations using biopsy, salivary gland scintigraphy, and contrast sialography can only be performed at an institution with appropriate facilities. For an approval process that is impartial and accomplished with ease, we believe that combinations of simple multiple tests should be considered as auxiliary items which could be substituted for the aforementioned examinations. In addition, future investigation is necessary to examine the high cost incurred in requiring findings within six months for an approval application, performing of annual invasive tests, and the validity of the process for determining the approved or unapproved status using the present clinical questionnaire profiles.
16855134 Stress in autoimmune disease models. 2006 Jun The release of endogenous glucocorticoids is critical in regulating the severity of disease activity in patients with inflammatory conditions such as rheumatoid arthritis (RA). Blocking cortisol production results in a flare-up in disease activity in RA patients, and surgical removal of the adrenals in patients with Cushing's disease has been reported to exacerbate autoimmune disease. In adjuvant-induced arthritis (AA; a rat model of RA), there is an activation of the hypothalamo-pituitary-adrenal (HPA) axis associated with the development of inflammation. In addition, there are profound changes in peptides within the paraventricular nucleus, which are responsible for regulating the HPA axis. These changes have profound implications on the ability of AA rats to respond to acute stress. Understanding the regulation of the HPA axis in health and disease holds out the promise of targeted therapy to alleviate inflammatory conditions. This article will consider the impact of stress on an individual and his or her susceptibility to inflammation. We wish to question the idea that stress is "all bad." As we shall see, exposure to a single acute stressor can alter the phenotype of the rat to change it from being susceptible to resistant in autoimmune disease models. This alteration in susceptibility takes days to manifest itself, but can last for weeks, suggesting beneficial effects of exposure to an acute stressor.
15905514 Intrinsic tolerance in autologous collagen-induced arthritis is generated by CD152-depende 2005 Jun 1 Collagen-induced arthritis is a mouse model of rheumatoid arthritis (RA) and is commonly induced after immunization with type II collagen (CII) of a non-mouse origin. T cell recognition of heterologous CII epitopes has been shown to be critical in development of arthritis, as mice with cartilage-restricted transgenic expression of the heterologous T cell epitope (MMC mice) are partially tolerized to CII. However, the mechanism responsible for tolerance and arthritis resistance in these mice is unclear. The present study investigated the regulatory mechanisms in naturally occurring self-tolerance in MMC mice. We found that expression of heterologous rat CII sequence in the cartilage of mice positively selects autoreactive CD4(+) T cells with suppressive capacity. Although CD4(+)CD25(+) cells did not play a prominent role in this suppression, CD152-expressing T cells played a crucial role in this tolerance. MMC CD4(+) T cells were able to suppress proliferation of wild-type cells in vitro where this suppression required cell-to-cell contact. The suppressive capability of MMC cells was also demonstrated in vivo, as transfer of such cells into wild-type arthritis susceptible mice delayed arthritis onset. This study also determined that both tolerance and disease resistance were CD152-dependent as demonstrated by Ab treatment experiments. These findings could have relevance for RA because the transgenic mice used express the same CII epitope in cartilage as humans and because autoreactive T cells, specific for this epitope, are present in transgenic mice as well as in patients with RA.
16240334 Anti-RANKL therapy for inflammatory bone disorders: Mechanisms and potential clinical appl 2006 Feb 1 Focal bone loss around inflamed joints in patients with autoimmune disease, such as rheumatoid arthritis, remains a serious clinical problem. The recent elucidation of the RANK/RANK-ligand/OPG pathway and its role as the final effector of osteoclastogenesis and bone resorption has brought a tremendous understanding of the pathophysiology of inflammatory bone loss, and has heightened expectation of a novel intervention. Here, we review the etiology of inflammatory bone loss, the RANK/RANK-ligand/OPG pathway, and the clinical development of anti-RANK-ligand therapy.
17194641 Relationship between angiogenesis and inflammation in experimental arthritis. 2006 Sep Background. Angiogenesis is involved in rheumatoid arthritis (RA) leading to leucocyte recruitment and inflammation in the synovium. Furthermore, synovial inflammation itself further potentiates endothelial proliferation and angiogenesis. In this study, we aimed at evaluating the reciprocical relationship between synovial inflammation and angiogenesis in a RA model, namely collagen-induced arthritis (CIA). Methods. CIA was induced by immunization of DBA/1 mice with collagen type II in adjuvant. Endothelial cells were detected using a GSL-1 lectin-specific immunohistochemical staining on knee joint sections. Angiogenesis, clinical scores and histological signs of arthritis were evaluated from the induction of CIA until the end of the experiment. Angiogenesis was quantified by counting both the isolated endothelial cells and vessels stained on each section. To evaluate the effect of increased angiogenesis on CIA, VEGF gene transfer was performed using an adeno-associated virus encoding VEGF (AAV-VEGF), by intra-muscular or intra-articular injection in mice with CIA. Results. We showed an increase in synovial angiogenesis from day 6 to day 55 after CIA induction, and, moreover, joint vascularization and clinical scores of arthritis were correlated (p < 0.0001, r = 0.61). Vascularization and histological scores were also correlated (p = 0.0006, r = 0.51). Systemic VEGF overexpression in mice with CIA was followed by an aggravation of arthritis as compared to AAV-lacZ control group (p < 0.0001). In contrast, there was no difference in clinical scores between control mice and mice injected within the knee with AAV-VEGF, even if joint vascularization was higher in this group than in all other groups (p = 0,05 versus non-injected group). Intra-articular AAV-VEGF injections induced more severe signs of histological inflammation and bone destruction than AAV-Lac Z or no injection. Conclusion. Angiogenesis and joint inflammation evolve in parallel during collagen-induced arthritis. Furthermore, this work shows that exogenous VEGF can aggravate CIA. It is direct evidence that the increase in joint vascularization leads to an exacerbation of arthritis. Taken together, these results emphasize the role of angiogenesis in inflammatory arthritis. It also suggests an early involvement of angiogenesis in joint inflammation.
15818667 Effects of treatment with small interfering RNA on joint inflammation in mice with collage 2005 Apr OBJECTIVE: RNA interference is a process in which genes can be silenced sequence-specifically. In mammals, RNA interference can be invoked by introduction of small (19-21-nucleotide) double-stranded RNA molecules known as small interfering RNA (siRNA) into cells. Thereby, siRNA offers promise as a novel therapeutic modality. However, siRNA is a relatively large, highly charged molecule and does not readily enter cells. This study was undertaken to investigate the use of electroporation for in vivo transfection of siRNA into joint tissue in arthritic mice to achieve local RNA interference. METHODS: Proof of principle that siRNA is able to inhibit gene expression in vivo in the mouse joint was studied by local injection and electroporation of siRNA designed to silence reporter genes. In mice with collagen-induced arthritis (CIA), the disease-modulating activity of siRNA designed to silence tumor necrosis factor alpha (TNFalpha) was investigated. RESULTS: Luciferase activity could be reduced by >90% with luciferase-specific siRNA as compared with the activity measured after electroporation without siRNA or with irrelevant siRNA. The effect was observed only locally. In mice with CIA, electroporation of siRNA designed to inhibit TNFalpha strongly inhibited joint inflammation, whereas electroporation of irrelevant siRNA or injection of siRNA against TNFalpha without electroporation failed to produce therapeutic effects. CONCLUSION: Local electroporation of siRNA in joint tissue can inhibit CIA in mice. These results offer promise for the use of siRNA as a new strategy for therapeutic intervention in rheumatoid arthritis and may serve as a tool to study arthritis disease pathways through loss-of-function phenotypes.
16507120 Attenuation of murine antigen-induced arthritis by treatment with a decoy oligodeoxynucleo 2006 The transcription factor STAT-1 (signal transducer and activator of transcription-1) plays a pivotal role in the expression of inflammatory gene products involved in the pathogenesis of arthritis such as various cytokines and the CD40/CD40 ligand (CD40/CD40L) receptor-ligand dyad. The therapeutic efficacy of a synthetic decoy oligodeoxynucleotide (ODN) binding and neutralizing STAT-1 was tested in murine antigen-induced arthritis (AIA) as a model for human rheumatoid arthritis (RA). The STAT-1 decoy ODN was injected intra-articularly in methylated bovine serum albumin (mBSA)-immunized mice 4 h before arthritis induction. Arthritis was evaluated by joint swelling measurement and histological evaluation and compared to treatment with mutant control ODN. Serum levels of pro-inflammatory cytokines, mBSA-specific antibodies and auto-antibodies against matrix constituents were assessed by enzyme-linked immunosorbent assay (ELISA). The transcription factor neutralizing efficacy of the STAT-1 decoy ODN was verified in vitro in cultured synoviocytes and macrophages. Single administration of STAT-1 decoy ODN dose-dependently suppressed joint swelling and histological signs of acute and chronic arthritis. Delayed-type hypersensitivity (DTH) reaction, serum levels of interleukin-6 (IL-6) and anti-proteoglycan IgG titres were significantly reduced in STAT-1 decoy ODN-treated mice, whereas mBSA, collagen type I and type II specific immunoglobulins were not significantly affected. Intra-articular administration of an anti-CD40L (anti-CD154) antibody was similarly effective. Electrophoretic mobility shift analysis (EMSA) of nuclear extracts from synoviocytes incubated with the STAT-1 decoy ODN in vitro revealed an inhibitory effect on STAT-1. Furthermore, the STAT-1 decoy ODN inhibited the expression of CD40 mRNA in stimulated macrophages. The beneficial effects of the STAT-1 decoy ODN in experimental arthritis presumably mediated in part by affecting CD40 signalling in macrophages may provide the basis for a novel treatment of human RA.
15641090 Suppression of the onset and progression of collagen-induced arthritis by chebulagic acid 2005 Jan OBJECTIVE: Chebulagic acid (CHE) from the immature seeds of Terminalia chebula was identified from a natural product library as a potent suppressor of T cell activity. This study examined the effectiveness of CHE against the onset and progression of collagen-induced arthritis (CIA) in mice. METHODS: Arthritis was induced in DBA/1J mice by subcutaneous immunization with bovine type II collagen on days 0 and 21. CHE was administered intraperitoneally for 3 weeks, either as prophylaxis (10 or 20 mg/kg) before disease onset or as therapy (20 mg/kg) after disease onset. Clinical scores, serum antibody levels, and cytokines were measured, and flow cytometric analysis and real-time reverse transcription-polymerase chain reaction were performed to evaluate the knee joints of mice with CIA. RESULTS: In both the prophylactic and therapeutic CHE dosing models, all clinical scores, serum levels of total and anticollagen IgG, and levels of interleukin-10 (IL-10) and IL-6 were reduced, while serum levels of transforming growth factor beta (TGFbeta) were markedly elevated. The number of granulocytes was reduced, but the proportion of CD4+,CD25+ T cells was greater in the knee joints of CHE-treated CIA mice. Expression of Foxp3 and TGFbeta messenger RNA was also augmented significantly in the knee joints of CHE-treated CIA mice in the therapeutic dosing model. CONCLUSION: CHE significantly suppressed the onset and progression of CIA in mice. Immune suppression via the induction of TGFbeta and CD4+,CD25+ T cells may represent a new strategy in the development of therapies for managing rheumatoid arthritis and other inflammatory diseases.
15680277 Prevention of progressive joint destruction in adjuvant induced arthritis in rats by a nov 2005 Jan 31 Matrix metalloproteinase (MMP) has been implicated in joint destruction of chronic arthritis diseases, such as rheumatoid arthritis. FR217840 (2R)-1-([5-(4-fluorophenyl)-2-thienyl]sulfonyl)-N-hydroxy-4-(methylsulfonyl)-2-piperazinecarboxamide is a potent, orally active synthetic MMP inhibitor that inhibits human collagenases (MMP-1, MMP-8 and MMP-13), gelatinases (MMP-2 and MMP-9) and membrane type MMP (MT-MMP) (MT1-MMP/MMP-14). FR217840 also inhibits rat collagenase and gelatinase. We studied the effect of FR217840 on a rat adjuvant induced arthritis model. Although oral administration (days 1-21) of FR217840 (3.2, 10, 32 mg/kg) to adjuvant injected Lewis rats did not affect inflammation, as indicated by both hind paw swelling and histological inflammatory infiltration, FR217840 suppressed both bone destruction and serum pyridinoline content in a dose-dependent manner. Also, FR217840 (32 mg/kg) reduced tartrate-resistant acid phosphatase (TRAP) cell number in the ankle joints of rats with arthritis. These results indicate that FR217840 successfully suppressed joint destruction and suggest that FR217840 may have potential as a novel anti-rheumatic drug.
17181930 The effects of TNF alpha inhibition on plasma fibrinolytic balance in patients with chroni 2006 Sep OBJECTIVE: Recent studies support an inflammatory basis for atherosclerosis. Patients with chronic inflammatory rheumatical disorders are at increased risk for cardiovascular events, and this can be partially attributed to the inhibition of fibrinolytic system. TNF a inhibitors such as infliximab are shown to retard the progression of inflammatory arthritides. In this study, we investigated the effects of infliximab on plasma fibrinolytic parameters. METHODS: Thirteen patients (7 female, 6 male; mean age: 44 +/- 11 years) with a clinical indication for infliximab (rheumatoid arthritis (RA) (n = 8), ankylosing spondylitis (AS) (n = 5)) were selected. Plasma plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (t-PA) antigens (Ag) and high sensitive C-reactive protein (hs-CRP) levels were measured during low salt intake at baseline. All patients received infliximab (Remicaide, i.v. infusion, 3 mg/kg). Plasma PAI-1 Ag, t-PA Ag and hs-CRP were measured during low salt intake at the end of 2 weeks. All samples were collected at 9 AM. Antigen levels were determined using a 2-site enzyme-linked immunosorbent assay. RESULTS: Patients experienced significant improvement in disease related activity scores after infliximab treatment. DAS score (for rheumatoid arthritis) and BASDAI index (for ankylosing spondylitis) decreased significantly after treatment (p = 0.01 and p = 0.04 respectively). Infliximab significantly reduced the marker of inflammation (hs-CRP) (8.3 +/- 3.9 vs. 4 +/- 4.1 mg/L, p < 0.01). Plasma PAI-1 antigen (64.7 +/- 26.9 vs. 40 +/- 31.1 ng/ml, p = 0.03) and PAI-1/t-PA ratio (10.8 +/- 5.9 vs. 6.6 +/- 3.8, p = 0.02) were significantly lower after the treatment. In contrast, plasma t-PA levels were unchanged (9.4 +/- 4.4 vs. 9.0 +/- 4.3 ng/ml, p = 0.73). CONCLUSION: This study provides evidence that TNF alpha inhibition with infliximab decreases PAI-1 Ag level and PAI-1/t-PA ratio, and hence activates fibrinolytic system in patients with chronic inflammatory disorders.