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ID PMID Title PublicationDate abstract
21640041 The psychological defensive profile of primary Sjögren's syndrome patients and its relati 2011 May OBJECTIVES: We aimed to assess the defensive profile of primary Sjögren's syndrome (SS) patients and to investigate the independent associations of psychological distress and personality variables with health-related quality of life (HRQOL). METHODS: In 40 primary SS patients we assessed psychological distress (SCL-90-R), ego defense mechanisms (Defense Style Questionnaire), hostility features (HDHQ) and HRQOL (WHOQOL-BREF). Fifty-six patients with Systemic Lupus Erythematosous (SLE) and 80 healthy participants matched for age and sex served as controls. RESULTS: Primary SS patients presented higher rates of general psychological distress compared to SLE and healthy participants. Symptoms of somatisation were more prominent in SS than SLE or healthy controls. SS patients presented less use of humour defense and more help-rejecting complains and delusional guilt hostility, compared to controls. Primary SS patients' HRQOL was more impaired than healthy participants and comparable to SLE. Psychological distress was a constant independent correlate of SS patients' HRQOL, while less use of humour (p<0.001) and higher rates of delusional guilt (p=0.032) were also significantly associated with Physical HRQOL independently of psychological distress; more use of schizoid fantasy was also independently associated with impaired Environment HRQOL (p=0.005). CONCLUSIONS: Primary SS patients exhibit several specific psychological difficulties in adaptation to life stressors, and clinicians and consultation-liaison psychiatrists, apart from the early assessment and treatment of psychological distress and somatisation symptoms, should consider the patients' underlying defensive profile and coping capacities, since such personality traits, although usually underestimated, are also independently associated with the disease outcome.
21508113 In vivo confocal microscopy of conjunctival roundish bright objects: young, older, and Sjà 2011 Jul 1 PURPOSE: To investigate by laser scanning confocal microscopy (LSCM) the density of presumed epithelial, presumed goblet, and presumed inflammatory cells in the tarsal conjunctiva of healthy young and older subjects and in patients with Sjögren's syndrome (SS). To evaluate the interobserver variability and to compare the measured densities with known age-related and SS-related changes. METHODS: The authors studied 24 eyes of 12 healthy young subjects (8 women, 4 men; average age, 26 years; age range, 21-30 years), 24 eyes of 12 healthy older subjects (10 women, 2 men; average age, 68 years; age range, 67-74 years), and 24 eyes of 12 patients with SS (10 women, 2 men; average age, 62 years; age range, 49-72 years). The inferior tarsal conjunctiva of each patient was examined in vivo by LSCM. The density of the three cell types was independently analyzed by two masked investigators. RESULTS: The density of presumed epithelial, presumed goblet, and presumed inflammatory cells was significantly higher in SS patients than in both control groups (P < 0.001; Mann-Whitney U test). The densities for presumed goblet cells calculated by the two investigators were significantly different from one another (P < 0.01, Mann-Whitney U test) and were not correlated. CONCLUSIONS: LSCM is a promising tool that should profoundly change the study of the ocular surface, but it requires accurate standardization before it is used in clinical practice.
21885875 Malignancies associated with tumour necrosis factor inhibitors in registries and prospecti 2011 Nov OBJECTIVES: This project was undertaken to assess the risk of malignancy in patients with rheumatoid arthritis treated with tumour necrosis factor inhibitors (TNFi) in clinical practice, as recorded in prospective, observational studies. METHODS: The authors undertook comprehensive searches of MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and American College of Rheumatology, European League against Rheumatism and British Society for Rheumatology conference abstracts according to a prespecified protocol. RESULTS: The searches identified 2039 full-text papers and 1979 conference abstracts, of which 21 full texts and eight abstracts met the inclusion criteria. The pooled estimate for the risk of all-site malignancy from seven studies was 0.95 (95% CI 0.85 to 1.05). Two studies reported there was no evidence that longer exposure to TNFi agents increased the risk of malignancy. In patients with previous malignancies there was a higher risk of a new/recurring malignancy. This risk was not increased further by exposure to TNFi, although CI were wide. Results from four studies showed that patients treated with TNFi have a significantly increased risk of developing a non-melanoma skin cancer (1.45, 95% CI 1.15 to 1.76). In addition, patients are at an increased risk of developing melanoma, as the pooled estimate from two studies was 1.79 (95% CI 0.92 to 2.67). The pooled estimate for the risk of lymphoma was 1.11 (95% CI 0.70 to 1.51). CONCLUSIONS: This systematic review and meta-analysis shows that TNFi treatments do not increase the risk of malignancy, particularly lymphoma. However, they do appear to increase the risk of skin cancer, including melanoma.
22153664 Significance of complement components C1q and C4 bound to circulating immune complexes in 2011 Nov OBJECTIVES: Immune complexes (ICs) from sera of juvenile idiopathic arthritis (JIA) patients show increased complement opsonisation; however, a definitive role for involvement of the classical or alternative pathway is not entirely clear. To delineate the role of these pathways, we measured activated complement products bound to circulating IC (CICs) in the sera of JIA patients. METHODS: Sera from 100 JIA patients and 22 healthy children were collected. C1q, C4, C3, C3d, and membrane attack complex (MAC) bound to CICs were measured by enzyme-linked immunosorbent assay. Data was compared to IgM rheumatoid factor (RF), IgG anti-cyclic citrullinated peptide (CCP) antibodies, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) levels. RESULTS: Mean levels of C1q, C4, and MAC bound to CICs were significantly elevated in JIA patients compared to healthy children. C1q correlated significantly with C4 and MAC bound to CICs and C4 and MAC also demonstrated significant correlation. No significant differences were noted in complement components bound to CICs when evaluating IgM RF, anti-CCP antibody, and CRP positivity. A significant correlation was noted between MAC bound to CICs and ESR. C1q and MAC bound to CICs mean levels were significantly higher in patients with an elevated ESR compared to those with a normal ESR level. CONCLUSIONS: JIA patients have elevated levels of complement components bound to CICs, particularly from the classical pathway. Moreover, classical pathway components were associated with ESR, a marker of disease activity. MAC bound to CICs also correlated significantly with ESR, further supporting the notion of complement-mediated tissue injury that is triggered by IC-mediated classical pathway activation.
22168390 Inhibition of acid-sensing ion channels by amiloride protects rat articular chondrocytes f 2012 Jul A significant decrease in tissue pH or acidosis is a common feature of numerous diseases, including RA (rheumatoid arthritis). Cartilage homoeostasis is profoundly affected by local acidosis in the joints. The diuretic, amiloride, is neuroprotective in models of cerebral ischaemia, a property attributable to the inhibition of ASICs (acid-sensing ion channels) by the drug. However, little is known about the effect of amiloride on apoptosis induced by extracellular acid in articular chondrocytes. We have found that amiloride could restrain the acid-induced apoptosis of rat articular chondrocytes in vitro. Primary rat articular chondrocytes were isolated, cultured and induced to apoptose by exposure to extracellular solution (pH 6.0), while simultaneously treated with 50-200 μM amiloride. Apoptotic rate, mitochondrial function, levels of apoptosis-related gene Bcl-2 family mRNA and activity of caspase 3/9 in chondrocytes were examined. Amiloride inhibited chondrocyte apoptosis in a dose-dependent manner. Furthermore, amiloride partly restored the levels of mitochondrial membrane potential by regulation of Bcl-2 family gene mRNA expression, and activity of caspase 3/9 in chondrocytes induced by extracellular acid. Our results indicated that amiloride protected against acid-induced apoptosis in rat articular chondrocytes by increasing anti-apoptotic ability and down-regulation of pro-apoptotic factors, thus protecting mitochondrial function.
23071417 Oral calcitonin. 2012 Calcitonin is a hormone secreted by the C-cells of the thyroid gland in response to elevations of the plasma calcium level. It reduces bone resorption by inhibiting mature active osteoclasts and increases renal calcium excretion. It is used in the management of postmenopausal osteoporosis, Paget's disease of bone, and malignancy-associated hypercalcemia. Synthetic and recombinant calcitonin preparations are available; both have similar pharmacokinetic and pharmacodynamic profiles. As calcitonin is a peptide, the traditional method of administration has been parenteral or intranasal. This hinders its clinical use: adherence with therapy is notoriously low, and withdrawal from clinical trials has been problematic. An oral formulation would be more attractive, practical, and convenient to patients. In addition to its effect on active osteoclasts and renal tubules, calcitonin has an analgesic action, possibly mediated through β-endorphins and the central modulation of pain perception. It also exerts a protective action on cartilage and may be useful in the management of osteoarthritis and possibly rheumatoid arthritis. Oral formulations of calcitonin have been developed using different techniques. The most studied involves drug-delivery carriers such as Eligen(®) 8-(N-2hydroxy-5-chloro-benzoyl)-amino-caprylic acid (5-CNAC) (Emisphere Technologies, Cedar Knolls, NJ). Several factors affect the bioavailability and efficacy of orally administered calcitonin, including amount of water used to take the tablet, time of day the tablet is taken, and proximity to intake of a meal. Preliminary results looked promising. Unfortunately, in two Phase III studies, oral calcitonin (0.8 mg with 200 mg 5-CNAC, once a day for postmenopausal osteoporosis and twice a day for osteoarthritis) failed to meet key end points, and in December 2011, Novartis Pharma AG announced that it would not pursue further clinical development of oral calcitonin for postmenopausal osteoporosis or osteoarthritis. A unique feature of calcitonin is that it is able to uncouple bone turnover, reducing bone resorption without affecting bone formation and therefore increasing bone mass and improving bone quality. This effect, however, may be dose-dependent, with higher doses inhibiting both resorption and formation. Because so many factors affect the pharmacokinetics and pharmacodynamics of calcitonin, especially orally administered calcitonin, much work remains to be done to explore the full pharmacologic spectrum and potential of calcitonin and determine the optimum dose and timing of administration, as well as water and food intake.
22915936 High molecular weight hyaluronan for treatment of chronic shoulder pain associated with gl 2011 BACKGROUND: There is insufficient evidence to determine whether intra-articular injections may be effective for treatment of glenohumeral osteoarthritis. Euflexxa(®) (high molecular weight hyaluronate), a bioengineered high molecular weight hyaluronan, has been shown to be a safe and effective treatment for patients with knee osteoarthritis. There is also support for the use of hyaluronate injection for the treatment of chronic shoulder pain associated with osteoarthritis or rotator cuff damage. This small-scale exploratory study was conducted to evaluate the safety and efficacy of high molecular weight hyaluronate for the treatment of chronic shoulder pain associated with osteoarthritis. METHODS: Subjects with glenohumeral osteoarthritis and chronic pain (n = 27) received one injection per week for 3 weeks of high molecular weight hyaluronate and were assessed for changes in pain (100 mm visual analog scale [VAS]), range of motion, and the subject's and physician's global assessment over 26 weeks. Subjects were also assessed for pain, stiffness, and physical functioning using the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Finally, responses were evaluated using modified Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT)-Osteoarthritis Research Society International (OARSI) Proposition D criteria. Safety was assessed by recording adverse events. RESULTS: High molecular weight hyaluronate significantly improved pain (VAS, WOMAC), range of motion, stiffness, and physical functioning scores; 77.8% of subjects were rated as having an OMERACT-OARSI Proposition D high response. There were no serious adverse events, and none were considered to be related to treatment. CONCLUSION: Treatment with high molecular weight hyaluronate improves pain, stiffness, and range of motion, and may have an acceptable safety and tolerability profile. A randomized, double-blind, placebo-controlled clinical trial may be warranted to investigate further the efficacy and safety of intra-articular high molecular weight hyaluronate for treatment of chronic shoulder pain in patients with glenohumeral osteoarthritis.
22004920 Age-related loss of CpG methylation in the tumour necrosis factor promoter. 2011 Dec BACKGROUND: Dysregulated production of TNF has been implicated in the pathogenesis and severity of inflammatory rheumatic diseases, many of which show age-related increased incidence. Ageing is also associated with changes in the immune system including higher systemic levels of pro-inflammatory cytokines. Methylation of DNA is an important regulator of gene expression and changes with age. OBJECTIVE: In this study we investigated whether the DNA methylation status of the TNF promoter changed with age in peripheral blood leucocytes and macrophages. METHODS AND RESULTS: Using pyrosequencing assays we detected age-related demethylation of CpG motifs (-304, -245 and -239) in the TNF promoter in human peripheral blood cells from 312 healthy controls (0.8% per decade, confidence interval (CI)=0.44-1.13%, p=1×10(-5)) and primary monocyte-derived macrophages (MDM) from a separate population of 78 healthy controls (1.4% per decade, CI=0.79-2.13%, p=7×10(-5)). Methylation a TNF promoter fragment (-345-+154) resulted in 78% reduction of reporter gene activity compared with the unmethylated promoter construct. CONCLUSIONS: These data suggest a potential role of accrued changes in DNA methylation in the development of age-related inflammatory diseases, such as rheumatoid arthritis and polymyalgia rheumatica, in which TNF is a pivotal mediator.
22336076 Onset of lupus like syndrome in patients with spondyloarthritis treated with anti-TNF-α. 2012 Feb 15 BACKGROUND: The anti-TNFα therapy has been since its approval by the FDA, along with nonsteroidal antiinflammatory drugs (NSAIDs), one of the most important therapies for control of spondyloarthritis (SpA). The onset of Lupus Like Syndrome (LLS) has been described in patients with rheumatoid arthritis (RA) treated with anti-TNFα therapy but there is little literature on the occurrence of this entity in patients with SpA. METHODS: We studied 57 patients with SpA who received more than 1 year of anti-TNFα therapy (infliximab, adalimumab or etanercept). Patients were analyzed for the development of LLS, in addition to measuring ANA levels ≥ 1:160 and Anti-dsDNA (measured by IIF). RESULTS: In total, 7.01% of patients treated with anti-TNFα had titers of ANA ≥ 1:160, whereas 3.5% of patients had serum levels of dsDNA. However, only one patient (1.75%; n = 1) experienced clinical symptoms of LLS; this was a female patient with a history of psoriatic arthritis. CONCLUSIONS: The presence of LLS secondary to anti-TNFα therapy in patients with SpA is observed less frequently compared with patients with RA. LLS was only detected in a patient with a history of psoriasis since youth, who developed psoriatic arthritis after 27 years of age and had received anti-TNFα therapy for > 2 years. This may be because LLS is an entity clearly associated with innate immunity, with little central role of B and T cells.
22334272 Successful use of interleukin 6 antagonist tocilizumab in a patient with refractory cutane 2012 Mar Tocilizumab (Actemra; Genentech, Inc) is the first biologic therapy targeting the cytokine interleukin 6 (IL-6). It is a humanized monoclonal immunoglobulin G1 antibody against the α-chain of the IL-6 receptor that prevents the binding of IL-6 to membrane-bound and -soluble IL-6 receptor. It was approved by the US Food and Drug Administration in January 2010 for rheumatoid arthritis refractory to other approved therapies and in April 2011 for systemic juvenile idiopathic arthritis. It has been used as an off-label treatment in many autoimmune diseases, where IL-6 plays a major role in pathogenesis. We report a case of refractory systemic lupus erythematosus in a 22-year-old woman with recurrent high-grade fever, polyarthritis, diffuse rash with urticarial vasculitis, and tumid lupus who did not respond to topical corticosteroids, photoprotection, antimalarials, methotrexate, anakinra, mycophenolate mofetil, etanercept, and intravenous immunoglobulin therapy. Symptoms recurred after corticosteroid tapers below 10 mg. She was noted to have an elevated IL-6 level, and tocilizumab was started. She responded favorably with remission of fever, arthritis, and skin manifestations and was able to taper corticosteroid therapy successfully.
22137887 Autoantibodies in primary Sjögren's syndrome patients induce internalization of muscarini 2012 Feb OBJECTIVES: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized by lymphocyte infiltration into the salivary and lachrymal glands, leading to dry mouth and eyes. The presence of functional autoantibodies against muscarinic type 3 receptor (M3R) has been reported in pSS patients. However, the pathological role of anti-M3R autoantibodies in pSS salivary dysfunction remains controversial. METHODS: Purified IgGs were obtained from normal (control) and primary SS patients' sera (pSS IgG). Internalization of M3R and clathrin was analyzed by biochemical assay and immunofluorescence confocal microscopy using human submandibular gland (hSMG) cells. Cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)) was measured by microspectrofluorimetry. RESULTS: Incubation of hSMG cells with pSS IgG (1mg/ml) significantly decreased M3R expression levels at the membrane. Carbachol-induced [Ca(2+)](i) transients (CICTs) in these cells were also inhibited by pSS IgG. In contrast to pSS IgG, control IgG had no effect on both the M3R expression level and CICTs. We found that binding of pSS IgG to M3R induces phosphorylation of the receptor, and that the pSS IgG-induced M3R internalization is prevented by the lysosomal inhibitor, chloroquine. In addition, pSS IgG decreased membrane clathrin expression, which was inhibited by atropine. Our immunofluorescence study further confirmed that pSS IgG induces a co-localization of M3R with clathrin and subsequent internalization of M3R. CONCLUSION: pSS IgG induces internalization of M3R partly through a clathrin-mediated pathway. The results suggest M3R internalization as a potential mechanism to explain the exocrinopathy seen in pSS patients.
21571549 Moyamoya disease presenting as thalamic hemorrhage in a patient with neuromyelitis optica 2012 Oct A 52-year-old woman was admitted to the hospital with right thalamic hemorrhage. A carotid angiogram revealed occlusion of the terminal portions of the bilateral internal carotid arteries with basal moyamoya vessels, which was diagnosed as moyamoya disease (MMD). At 31 years of age, she was diagnosed with multiple sclerosis because of optic neuritis and myelitis. Paraplegia appeared 14 days after admission. T2-weighted thoracic magnetic resonance imaging revealed a high intensity lesion extending from T4 to T6. Her left upper limb was partially paralytic and her lower limbs exhibited paraplegia and dysesthesia. Anti-aquaporin 4 and anti-Sjögren's syndrome-A and -B antibodies were positive. The pathogenesis of neuromyelitis optica may be associated with such immunologic factors, but there are no reports of simultaneous presentations of neuromyelitis optica and MMD. Autoimmunity may be associated with the etiology of MMD.
22709497 Monoclonal gammopathies presenting as inflammatory arthritis: uncommon but important--a ca 2012 Jun OBJECTIVE: To review the clinical profile of patients with plasma cell dyscrasias presenting with inflammatory arthritis. MATERIAL AND METHODS: Retrospective analysis was performed on clinical, laboratory and imaging data of patients who presented with inflammatory arthritis between May 2009 and April 2010 and were subsequently diagnosed as having plasma cell dyscrasias. Six out of 630 patients presenting with inflammatory arthritis were identified. The demographic, clinical and laboratory characteristics of these patients were analyzed. The diagnosis of monoclonal gammopathy was based on protein electrophoresis, immunoelectrophoresis and bone marrow biopsy. The outcomes of the treatments were analyzed. RESULTS: Four patients had monoclonal gammopathy of unknown significance and two patients had multiple myeloma. Mean age of the patients was 65 years (range 59-74). Three patients presented with oligoarticular arthritis, two with symmetrical polyarticular joint pains and one with fleeting periarticular pains. Wrist and shoulder were the most commonly involved joints. Three patients had carpal tunnel syndrome. Five patients were seronegative for both rheumatoid factor and anti-cyclic citrullinated peptide antibodies. Mean erythrocyte sedimentation rate (ESR) was high in all patients (range: 82-120 mm/h with a mean of 99.6 mm/h). Arthritis improved with chemotherapy in patients with multiple myeloma. CONCLUSION: Occurrence of inflammatory arthritis with plasma dyscrasias is more than a chance association. Plasma cell dyscrasias should be ruled out in any elderly patient presenting with atypical arthritis with disproportionately high ESR, high creatinine and hyperglobulinemia.
21953132 Decreased collagen-induced arthritis severity and adaptive immunity in MKK-6-deficient mic 2012 Mar OBJECTIVE: The MAPK kinases MKK-3 and MKK-6 regulate p38 MAPK activation in inflammatory diseases such as rheumatoid arthritis (RA). Previous studies demonstrated that MKK-3 or MKK-6 deficiency inhibits K/BxN serum-induced arthritis. However, the role of these kinases in adaptive immunity-dependent models of chronic arthritis is not known. The goal of this study was to evaluate MKK-3 and MKK-6 deficiency in the collagen-induced arthritis (CIA) model. METHODS: Wild-type (WT), MKK-3(-/-) , and MKK-6(-/-) mice were immunized with bovine type II collagen. Disease activity was evaluated by semiquantitative scoring, histologic assessment, and micro-computed tomography. Serum anticollagen antibody levels were quantified by enzyme-linked immunosorbent assay. In vitro T cell cytokine response was measured by flow cytometry and multiplex analysis. Expression of joint cytokines and matrix metalloproteinases (MMPs) was determined by quantitative polymerase chain reaction. RESULTS: MKK-6 deficiency markedly reduced arthritis severity compared with that in WT mice, while the absence of MKK-3 had an intermediate effect. Joint damage was minimal in arthritic MKK-6(-/-) mice and intermediate in MKK-3(-/-) mice compared with WT mice. MKK-6(-/-) mice had modestly lower levels of pathogenic anticollagen antibodies than did WT or MKK-3(-/-) mice. In vitro T cell assays showed reduced proliferation and interleukin-17 (IL-17) production by lymph node cells from MKK-6(-/-) mice in response to type II collagen. Gene expression of synovial IL-6, MMP-3, and MMP-13 was significantly inhibited in MKK-6-deficient mice. CONCLUSION: Reduced disease severity in MKK-6(-/-) mice correlated with decreased anticollagen antibody responses, indicating that MKK-6 is a crucial regulator of inflammatory joint destruction in CIA. MKK-6 is a potential therapeutic target in complex diseases involving adaptive immune responses, such as RA.
24116282 Anti-Arthritic and Analgesic Effect of NDI10218, a Standardized Extract of Terminalia cheb 2012 Jan The fruit of Terminalia chebula Retzius has been used as a panacea in India and Southeast Asia but its biological activities have not been fully elucidated. Here we report anti-arthritic and analgesic effect of NDI10218, a standardized ethanol extract of Terminalia chebula, on collagen-induced arthritis and acetic acid-induced writhing model, respectively. Arthritis was induced in DBA/1J mice by immunizing bovine type II collagen and mice were treated with NDI10218 daily for 5 weeks after the onset of the disease. NDI10218 reduced the arthritis index and blocked the synovial hyperplasia in a dose-dependent manner. The serum levels of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β were significantly reduced in mice treated with NDI10218. Production of the inflammatory IL-17, but not immunosuppressive IL-10, was also inhibited in splenocytes isolated from NDI10218-treated arthritis mice. Administration of NDI10218 markedly decreased the number of T cell subpopulations in the regional lymph nodes of the arthritis mice. Finally, NDI10218 reduced the number of abdominal contractions in acetic acid-induced writhing model, suggesting an analgesic effect of this extract. Taken together, these results suggest that NDI10218 can be a new therapeutic candidate for the treatment of rheuma-toid arthritis.
22549726 Multiple juvenile idiopathic arthritis subtypes demonstrate proinflammatory IgG glycosylat 2012 Sep OBJECTIVE: Rheumatoid arthritis is associated with an excess of agalactosylated (G0) IgG that is considered relatively proinflammatory. Assessment of this association in juvenile idiopathic arthritis (JIA) is complicated by age-dependent IgG glycan variation. The aim of this study was to conduct the first large-scale survey of IgG glycans in healthy children and patients with JIA, with a focus on early childhood, the time of peak JIA incidence. METHODS: IgG glycans from healthy children and disease-modifying antirheumatic drug-naive patients with JIA were characterized using high-performance liquid chromatography. Agalactosylated glycans were quantitated with reference to monogalactosylated (G1) species. Associations were sought between the G0:G1 ratio and disease characteristics. RESULTS: Among healthy children ages 9 months to 16 years (n = 165), the G0:G1 ratio was highly age dependent, with the ratio peaking to 1.19 in children younger than age 3 years and declining to a nadir of 0.83 after age 10 years (Spearman's ρ = 0.60, P < 0.0001). In patients with JIA (n = 141), the G0:G1 ratio was elevated compared with that in control subjects (1.32 versus 1.02; P < 0.0001). The G0:G1 ratio corrected for age was abnormally high in all JIA subtypes (enthesitis-related arthritis was not assessed), most strikingly in systemic JIA. Glycosylation aberrancy was comparable in patients with and those without antinuclear antibodies and in both early- and late-onset disease and exhibited at most a weak correlation with markers of inflammation. CONCLUSION: IgG glycosylation is skewed toward proinflammatory G0 variants in healthy children, in particular during the first few years of life. This deviation is exaggerated in patients with JIA. The role for IgG glycan variation in immune function in children, including the predilection of JIA for early childhood, remains to be defined.
21498479 Heterotopic ossification of the temporomandibular joint in juvenile idiopathic arthritis. 2011 Jul OBJECTIVE: To describe the clinical, laboratory, pathologic, and radiographic imaging characteristics of a series of children with juvenile idiopathic arthritis (JIA) and radiographic imaging evidence of heterotopic ossification of their temporomandibular joint (TMJ). METHODS: Children were identified through search of an administrative database of imaging results at Seattle Children's Hospital. Retrospective chart review was performed to collect data on each patient's clinical and laboratory characteristics, systemic therapies, timing and number of TMJ intraarticular corticosteroid injections (IAS), TMJ symptoms, and TMJ findings on physician examination. TMJ imaging studies for which heterotopic ossifications were reported were reviewed. Pathology specimens were reviewed for the 2 children who underwent synovial biopsy of their TMJ. RESULTS: Twelve children were identified. The average duration between onset of JIA and detection of heterotopic ossification of TMJ on an imaging study was 36 months (range 19-94). Half the children had abnormal mouth-opening for age when the calcifications were first detected. In each case, the heterotopic ossification was first detected by computed tomography scan, and in 11 of the cases they were associated with synovial pannus formation as documented on an imaging study. Two children underwent synovial biopsy, which revealed reactive parosteal osteochondromatosis in one case and findings consistent with an intraarticular rheumatoid nodule in the other. CONCLUSION: Heterotopic ossifications of the TMJ may be seen in children with JIA and are associated with particularly severe TMJ arthritis, joint destruction, and pannus formation. Pathology from these joints suggests that the heterotopic ossification may result from multiple pathological processes.
22076633 Identification of two new arthritis severity loci that regulate levels of autoantibodies, 2012 May OBJECTIVE: Cia3 is a locus on rat chromosome 4 that regulates severity and joint damage in collagen- and pristane-induced arthritis (CIA and PIA). This study was undertaken to refine the Cia3 gene-containing interval toward gene identification and obtain insights into its mode of action. METHODS: Five DA.F344(Cia3) subcongenic rat strains were generated and studied using the PIA and CIA models. Levels of antibodies against type II collagen (both allo- and autoantibodies) were measured. Joints and synovial tissue were collected 32 days after the induction of PIA (chronic stage) for histologic and quantitative polymerase chain reaction analysis of interleukin-1β (IL-1β) and matrix metalloproteinase (MMP) levels. RESULTS: Three subcongenic strains sharing the centromeric Cia3d interval were protected and 2 subcongenic strains sharing the telomeric Cia3g interval, which did not overlap with Cia3d, were also protected, developing significantly less severe CIA and PIA. Normal joint architecture was preserved in DA.F344(Cia3) and DA.F344(Cia3d) congenic rats with PIA, while DA rats had pronounced synovial hyperplasia, angiogenesis, inflammatory infiltration, and bone or cartilage erosions. The DA.F344(Cia3d) and DA.F344(Cia3g) strains had significantly lower synovial levels of IL-1β (5-fold and nearly 2-fold, respectively [the latter not reaching statistical significance]), MMP-1 (expressed predominantly in DA rats), MMP-3 (79-fold and 8-fold, respectively), and MMP-14 (21-fold and 1.4-fold, respectively) and reduced levels of pathogenic autoantibodies against type II collagen, compared with DA rats. CONCLUSION: We have identified 2 new arthritis severity and articular damage loci within Cia3. These loci regulate pathogenic processes in 2 different models of rheumatoid arthritis, and the identification of these genes has the potential to generate new targets for therapies aimed at reducing disease severity and articular damage, and may additionally have prognostic value.
22290145 Toxoplasma gondii infection inhibits Th17-mediated spontaneous development of arthritis in 2012 Apr Interleukin 1 receptor antagonist (IL-1Ra)-deficient BALB/c mice develop spontaneous arthritis resembling human rheumatoid arthritis. We herein report that infection with Toxoplasma gondii, an intracellular protozoan, is capable of ameliorating the spontaneous development of arthritis in IL-1Ra-deficient mice. The onset of arthritis development was delayed and the severity score of arthritis was significantly suppressed in T. gondii-infected mice. Expression of IL-12p40 mRNA from CD11c(+) cells of mesenteric lymph nodes (mLN) and spleen markedly increased at 1 week after peroral infection. While CD11c(+) cells also produced IL-10, IL-1β, and IL-6, CD4(+) T cells from T. gondii-infected mice expressed significantly high levels of T-bet and gamma interferon (IFN-γ) mRNA in both mLN and spleen. Levels of GATA-3/IL-4 mRNA or RORγt/IL-17 mRNA decreased in the infected mice, indicating Th1 cell polarization and the reduction of Th2 and Th17 cell polarization. The severity of arthritis was related to Th1 cell polarization accompanied by Th17 cell reduction, demonstrating the protective role of the T. gondii-derived Th1 response against Th17 cell-mediated arthritis in IL-1Ra-deficient mice.
21984130 Definitive differences in laboratory and radiological characteristics between two subtypes 2012 Aug We performed this study to investigate the differences in radiological and laboratory findings between systemic juvenile idiopathic arthritis (s-JIA) and polyarthritis (p-JIA). Twenty-two patients with s-JIA and 18 with p-JIA were enrolled. Their laboratory findings and radiographs were examined retrospectively. Plain radiographs were obtained before the induction of biological agents. All radiographs were examined for the presence of soft tissue swelling, juxta-articular osteopenia, joint space narrowing, subchondral bone cyst, erosion, epiphyseal irregularity, and growth abnormalities. Carpal length and bone mineral density of the lumbar spine, an indicator of generalized osteoporosis, were also investigated in all the patients enrolled. Laboratory examinations involved white blood cell counts, platelets, C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibody, and matrix metalloproteinase (MMP)-3. Comparisons of the laboratory findings between s-JIA and p-JIA indicated that the titers of anti-CCP antibody and RF were significantly increased in p-JIA sera (P < 0.05). There was no difference in BMD between the two groups of patients. Carpal length was significantly shorter in p-JIA patients than in s-JIA patients (P < 0.05). The most frequent radiological abnormality in s-JIA was juxta-articular osteopenia (93.8%), in comparison to a frequency of 50.0% in p-JIA. Joint space narrowing was shown in 9.8% of the s-JIA patients compared to 35.7% of the p-JIA patients. Subchondral bone cyst and erosion were more frequent in p-JIA than s-JIA. In conclusion, there were differences in radiographic characteristics and laboratory data between s-JIA and p-JIA in this study. In the radiological evaluation, bone-related abnormality was prominent in s-JIA and joint-related abnormality was striking in p-JIA, and these results indicated that the pathogenic bases of arthritis appear to differ between these two subtypes of JIA.