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ID PMID Title PublicationDate abstract
19099567 Monocytes are essential for inhibition of synovial T-cell glucocorticoid-mediated apoptosi 2008 INTRODUCTION: Rheumatoid arthritis (RA) is characterized by synovial inflammation with local accumulation of mononuclear cells such as macrophages and lymphocytes. We previously demonstrated that intra-articular glucocorticoids decrease the synovial tissue (ST) T-cell population and therefore aimed to investigate whether this is mediated through modulation of apoptosis. METHODS: Apoptosis and cell phenotype were evaluated by immunohistochemistry and dual-immunofluorescence in synovial biopsy sections from 12 RA patients before and after a mean of 11 days of an intra-articular triamcinolone knee injection. In vitro, RA synovial fluid (SF)-derived T cells were evaluated for Annexin V expression by multicolor flow cytometry after 24-hour exposure to dexamethasone, methylprednisolone, or triamcinolone. We also tested induction of apoptosis by dexamethasone on psoriatic arthritis SF-derived T cells using the same method. RESULTS: Intra-articular glucocorticoids reduced ST T cells but not macrophage number. ST apoptosis levels were unchanged following treatment, virtually absent from lymphoid aggregates, and minimal in CD3+ cells both before and after treatment. RA SF T cells were resistant to glucocorticoid-induced apoptosis when cultured in the presence of monocytes but were rendered sensitive to all three tested compounds upon SF isolation. Furthermore, transwell coculture of monocytes and T cells demonstrated that soluble factor(s) and not cellular contact are essential for T-cell resistance to glucocorticoid-mediated apoptosis. This feature is RA-specific as far as dexamethasone-induced apoptosis in nonisolated SF T cells obtained from psoriatic arthritis patients is concerned. CONCLUSIONS: We demonstrate that monocytes rescue synovial T cells from glucocorticoid-induced apoptosis, a feature that is specific for RA. To overcome this, we propose the use of monocyte-targeted therapies rather than T-cell apoptosis-inducing therapies.
16641043 Conversion towards an atherogenic lipid profile in rheumatoid arthritis patients during lo 2006 Mar OBJECTIVES: To analyse the effects of infliximab infusions on serum levels of lipids in patients with rheumatoid arthritis (RA) treated for 2 years. METHODS: Fifty-two patients (41 females and 11 males) with RA undergoing infliximab treatment (3 mg/kg) were consecutively recruited into the study. The mean (+/-SD) age of the patients was 54.6+/-12.5 years and mean disease duration was 14.1+/-8.6 years. Blood was sampled before infusion at baseline, and at 3, 6, 12, 18 and 24 months. Forty-one of the patients were also treated with methotrexate, 13 with other disease-modifying anti-rheumatic drugs (DMARDs) and 28 with prednisolone (<10 mg daily). For comparison, lipid levels were followed for 2 years in 70 consecutively included patients with early RA during treatment with conventional DMARDs. RESULTS: There was an initial increase in plasma levels of cholesterol, high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol, and LDL/HDL and total/HDL cholesterol ratios. However, after 3 months HDL-cholesterol decreased significantly, followed after 6 months by cholesterol and LDL-cholesterol. The LDL/HDL and total/HDL-cholesterol ratios remained significantly raised. HDL-cholesterol increased and the ratios improved in patients with early RA receiving conventional treatment. The changes over time differed significantly between the patient groups. CONCLUSION: During infliximab infusion a pro-atherogenic lipid profile developed despite reduced inflammatory activity. The long-term decrease in HDL-cholesterol was unexpected considering the known effects of tumour necrosis factor-alpha (TNFalpha).
18425249 Periodontal condition in patients with rheumatoid arthritis. 2008 Jan The purpose of this clinical study was to investigate if periodontal disease and rheumatoid arthritis (RA) are associated. The study included 39 RA patients (test group) and 22 age- and gender-matched healthy individuals (control group). Questionnaires on general and oral health were applied and a complete periodontal exam, including visible plaque, marginal bleeding, attachment loss (AL) and number of teeth present, was also performed by a single calibrated examiner. Diabetes mellitus patients and smokers were excluded. RA patients had fewer teeth, higher prevalence of sites presenting dental plaque and a higher frequency of sites with advanced attachment loss. Although the prevalence of dental plaque was higher in the test group (Chi-square test, p = 0.0006), the percentage of sites showing gingival bleeding was not different (Fishers exact test, p > 0.05). Based on our results, we suggest that there is an association between periodontal disease and RA.
17850590 In active chronic rheumatoid arthritis, dipeptidyl peptidase IV density is increased on mo 2007 Oct The effect of low-dose methotrexate (MTX) treatment on the CD26 density on circulating monocytes and CD4(+) T lymphocytes or levels of soluble CD26 (sCD26) has not yet been described in rheumatoid arthritis (RA). While CD26 in T lymphocytes is involved in the activation and proliferation of T lymphocytes, little is known of the role of CD26 in monocytes as it has only recently been localized to monocytes. We analysed the CD26 density by flow cytometry and levels of sCD26 in plasma before initiation of MTX treatment and 12 weeks later. This was done on 34 RA patients fulfilling the 1987 American College of Rheumatology (ACR) criteria followed for 16 weeks after starting MTX treatment. CD26 density on monocytes was increased in RA patients compared with healthy controls before MTX treatment (P < 0.01). After 12 weeks of MTX treatment, the CD26 density on monocytes decreased significantly in the ACR-50% group (P = 0.03), but not in the ACR-20% and the non-responder group (P = 0.15 and 0.87). The increased CD26 density on CD4(+) T lymphocytes (P < 0.01) was unaffected by the reduction in disease activity in relation to MTX treatment. The percentage of monocytes and CD4(+) T lymphocytes among peripheral blood circulating mononuclear cells did not change during MTX treatment. No effect of MTX treatment was observed on the plasma levels of sCD26. Active chronic RA is characterized by enhanced CD26 density on circulating monocytes and CD4(+) T lymphocytes. MTX treatment decreased CD26 density on monocytes in the ACR-50% responder group and was associated with decreased disease activity. The enhanced CD26 density on CD4(+) T lymphocytes was uninfluenced by MTX treatment.
19032823 Relationship of angiogenic factors to disease activity and radiographic damage in rheumato 2008 Sep OBJECTIVE: To determine the association between angiogenic factor mRNA expression and disease activity and radiographic damage in patients with rheumatoid arthritis (RA). METHODS: We enrolled 42 RA patients and assessed their disease activity (DAS28) and Larsen scores. We used a semi-quantitative reverse transcriptase-polymerase chain reaction to measure levels of angiogenin, endoglin, survivin and angiomotin mRNA in peripheral blood mononuclear cells (PBMCs) from 42 patients and in fibroblasts-like synoviocytes (FLS) from 14 RA patients. Then, we compared the angiogenic factor mRNA expression levels and parameters for disease activity and radiographic damage between RA patients and 42 healthy controls. We also compared the mRNA levels from FLS between 14 RA patients and 12 osteoarthritis (OA) patients. RESULTS: PBMCs from RA patients showed increased expression of survivin and angiomotin mRNA compared to controls, while rheumatoid FLS showed increased expression for all genes tested compared to OA FLS. Angiogenin, endoglin, and angiomotin mRNA levels of PBMCs did not show any significant correlation with DAS28, but the survivin mRNA level in PBMCs showed a significant positive correlation with DAS28 (p=0.003) and Larsen scores (p=0.012). Survivin was the only angiogenic factor that showed a significant association with the Larsen score. CONCLUSION: The systemic and local production of angiogenic factors are increased in patients with RA and, of the genes tested in this study, survivin gene expression correlated well with disease activity and radiographic damage in patients with RA.
16096328 Antibodies against cyclic citrullinated peptide (CCP) in psoriatic patients with or withou 2006 Mar OBJECTIVE: To compare the prevalence of anti-CCP antibodies in psoriatic patients with and without joint inflammation, patients with early RA, and controls. METHODS: Anti-CCP antibodies (cut off level 5 U/ml) were measured in 160 patients with psoriatic arthritis (PsA), 146 patients with psoriasis but no arthritic disease, 101 patients with early RA, and 102 healthy controls by ELISA. RESULTS: 11 (7%) patients with PsA, 75 (74%) patients with early RA, 2 (2%) healthy controls (2%), and 1 (0.7%) patient with psoriasis without arthritis had anti-CCP antibodies above the cut off level. The presence of anti-CCP antibodies was not related to radiological changes and/or deformity and functional impairment in PsA. 8/11 patients with PsA and anti-CCP antibodies had a polyarthritic disease, and all fulfilled the ACR criteria for RA at 4 year follow up. Five of these 8 patients also had manifestations such as dactylitis, DIP involvement, radiological changes associated with PsA, and/or enthesitis. In multiple logistic regression analysis with polyarthritis as the dependent variable, anti-CCP antibodies and rheumatoid factor significantly distinguished RA from PsA. CONCLUSIONS: Anti-CCP antibodies were more prevalent in patients with PsA than in patients with psoriasis without arthritis, but less prevalent than in patients with early RA. Patients with PsA positive for anti-CCP antibodies more often had polyarthritic disease, but the presence of anti-CCP antibodies did not relate to radiological changes and/or deformity and functional impairment.
19277223 Anti-cyclic citrullinated peptide, rheumatoid factor, and ocular symptoms typical of rheum 2008 PURPOSE: To correlate the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) with ocular symptoms typical of rheumatoid arthritis (RA). METHODS: The records of 451 patients who had been examined by an ophthalmologist and tested for anti-CCP antibodies over a 3-year period at the Mayo Clinic were reviewed. Records of 255 patients with titers of anti-CCP and RF were analyzed for ocular surface and inflammatory disease associated with ocular RA. RESULTS: Of the 33 anti-CCP+/RF+ patients, all were diagnosed with RA; ocular surface disease was present in 11 (33%) and inflammatory disease in 7 (21%). Of the 17 anti-CCP-/RF+ patients, 4 were diagnosed with an unspecified inflammatory arthritis and 1 with rheumatoid arthritis; a separate 5 (29%) had ocular surface disease. Out of 5 anti-CCP+/RF- patients, 3 were diagnosed with RA but none had ocular symptoms. Out of 200 anti-CCP-/RF- patients, 32 (16%) had ocular surface disease and 2 (1%) had ocular inflammation. Of the 74 patients diagnosed with any form of inflammatory arthritis, anti-CCP+/RF+ patients had more and worse inflammatory ocular RA disease compared to the other groups. CONCLUSIONS: Patients who were both anti-CCP and RF positive tended to have more and worse ocular disease. In patients diagnosed with an inflammatory arthritis, the presence of anti-CCP antibodies and RF provides useful information to ophthalmologists for identifying patients most at risk for inflammatory ocular disease.
17765838 Joint-preserving surgery in rheumatoid forefoot: preliminary study with more-than-two-year 2007 Sep The authors propose a joint-preserving surgery for rheumatoid forefoot deformities as an alternative to the "classic" surgical approach to the rheumatoid forefoot. The main principle is joint preservation by shortening osteotomies of all the metatarsals performed at the primary location of the rheumatoid forefoot lesions, namely the metatarsophalangeal (MTP) joints and metatarsal heads. A scarf osteotomy is normally performed on the first ray. A Weil osteotomy is performed on the lesser metatarsals. Excellent correction of the hallux valgus deformity in the rheumatoid forefoot can be achieved with a scarf osteotomy in 92% of cases without the need for MTP joint arthrodesis. Similarly, 86% of the lateral metatarsal heads can be preserved using Weil osteotomies.
19213340 [Clinical observation on treatment of active rheumatoid arthritis with Chinese herbal medi 2008 Nov OBJECTIVE: To study the efficacy and safety of Chinese drugs for expelling evil-wind, removing dampness, promoting blood circulation and invigorating yin in treating active rheumatoid arthritis (RA). METHODS: Sixty-seven patients with active RA were randomized into 3 groups, the Group A, B and C. They were made coequal in terms of age, sex and condition of disease and treated respectively with basic treatment (non-steroid anti-inflammation drug combined with immune inhibitor) only, basic treatment + small dose prednisone, and basic treatment + Chinese herbal medicine, all for 8 weeks. The efficacy and adverse effects of treatment were analyzed by scoring. RESULTS: The total effective rate was 20.0% (4/20) in Group A, 810% (17/21) in Group B and 85.7% (18/21) in Group C, the latter two were superior to the former one (P <0.01). Before treatment, comparison of disease activity score (DAS) among the three groups showed no significant difference (P > 0.05). After treatment, improvements of Ritchie arthritis index (RAI), number of swollen joint, erythrocyte sedimentation rate (ESR), general health (GH), and DAS were shown in Group B and C (P <0.05), while in Group A, improvement was only shown in GH (P <0.05). The difference of DAS between pre- and post-treatment was 0.25 +/- 0.77 in Group A, 0.87 +/- 0.60 in Group B and 0.92 +/- 0.59 in Group C, showing statistical significance between Group A vs B and A vs C (P = 0.0000). The total accumulative score of adverse reaction was 3.76 +/- 2.72 in Group C, 9.10 +/- 6.01 in Group A and 14.38 +/- 9.36 in Group B, also showing statistical significance among groups (P < 0.05). CONCLUSION: The combination of Chinese and Western medicine for active RA is effective and safe.
16885604 Interleukin-1 receptor antagonist gene polymorphism in patients with rheumatoid arthritis 2006 Jun BACKGROUND & OBJECTIVES: Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring anti-inflammatory molecule that blocks action of IL-1. Polymorphism in IL-1Ra gene intron 2 results in differences in production of IL-1Ra. These polymorphisms are reportedly associated with autoimmune disease susceptibility in different studies. However, such data are lacking from India. We undertook this study to examine the IL-1Ra polymorphism as a susceptibility marker in patients with rheumatoid arthritis (RA). METHODS: DNA samples from 107 patients with RA and 111 healthy controls were used to study genotypes of the IL-1RA gene by PCR. Allelic frequencies and carriage rates were calculated and compared in both the groups. RESULTS: Among the 107 patients with RA, 93 were females and 75 per cent were seropositive for rheumatoid factor. The frequencies of IL-1RA alleles in controls were as follows: Allele 1 (IL- 1RN*1) was 83.33 per cent, IL-1RA allele 2 (IL-1RN*2) was 16.21 per cent and allele 3 (0.46%). In RA patients the allele frequencies were 84.11 per cent for IL-1RN*1, 14.95 per cent for IL- 1RN*2, 0.47 per cent each for IL-1RN*3 and IL-1RN*4. There was no difference in frequency of different alleles between the two groups. However, homozygosity for allele 2 was more frequent in controls (9.91%) as compared to patients (4.67%). INTERPRETATION & CONCLUSION: Our findings indicated that IL-1RA polymorphism was not a susceptibility marker in RA nor did it show any association with seropositivity, Sjögren's syndrome or subcutaneous nodules. Further studies with large sample need to be done to confirm these findings.
16284099 The association between periodontal disease and joint destruction in rheumatoid arthritis 2006 Jul OBJECTIVE: To evaluate a possible association between wrist and periodontal destruction in rheumatoid arthritis, and between periodontal destruction, dry mouth, and labial salivary gland biopsy and the contribution of genetic factors (the shared epitope (SE) and IL1B (+3954) or TNFA (-238 or -308) gene polymorphisms). METHODS: 147 patients with rheumatoid arthritis were enrolled. Periodontal damage was defined according to the Hugoson and Jordan criteria on panoramic dental x rays. Typing for the SE and cytokine polymorphisms was undertaken by enzyme linked oligosorbent assay. Odds ratios (OR), relative risk (RR), and chi2 values were calculated to quantify associations. RESULTS: An association was observed between wrist and periodontal bone destruction (chi2=11.82; p<0.001): 63 patients had both wrist and periodontal destruction, 31 had wrist destruction alone, 20 had periodontal destruction alone, and 33 had no destruction at either site. An association was seen between a positive labial salivary gland biopsy and periodontal bone destruction (RR=2.73 (95% CI, 1.35 to 5.51), p<0.01, n=41) or wrist bone destruction (RR=4.52 (1.96 to 10.45), p<0.001, n=41). The SE was associated with wrist bone destruction (OR=2.5 (1.16 to 5.42), p<0.05) and periodontal bone destruction (OR=2.2 (1.04 to 4.84), p<0.05). No association was found between the selected cytokine polymorphisms and bone destruction. CONCLUSIONS: A strong association was found between wrist and periodontal bone destruction. The destruction risk was further increased in patients with sicca syndrome. The SE appears to be a severity genetic marker for both wrist and periodontal bone destruction.
17502358 Cigarette smoking significantly increases basal metabolic rate in patients with rheumatoid 2008 Jan OBJECTIVE: Basal metabolic rate (BMR) is the most important indicator of human metabolism and its abnormalities have been linked to undesirable health outcomes. Cigarette smoking associates with increased BMR in healthy individuals; it is also related with worse disease outcomes in patients with rheumatoid arthritis(RA), in whom BMR is high due to hypercatabolism caused by systemic inflammation. We aimed to investigate whether smokers with RA demonstrated higher BMR levels than their non-smoking counterparts. METHODS: A total of 53 patients with RA (36 female, 17 male, 20 current smokers) were assessed for: BMR(indirect calorimetry), anthropometrical data, fat-free mass (bioelectrical impedance), physical function (health assessment questionnaire; HAQ) and disease activity(disease activity score DAS28 and C reactive protein). RESULTS: RA smokers and non-smokers were not significantly different for age, height, weight, body mass index and fat-free mass. Compared to non-smokers,smokers with RA demonstrated significantly higher BMR (mean (SD) 1513.9 (263.3) vs 1718.1 (209.2) kcal/day; p,0.001) and worse HAQ (1.0 (0.8) vs 1.7 (0.8); p=0.01). The BMR difference was significantly predicted by the interaction smoking/gender (p=0.04). BMR was incrementally higher in light, moderate and heavy smokers (p=0.018), and correlated with the daily number of cigarettes smoked (r=0.68, p=0.04). CONCLUSION: Current cigarette smoking further increases BMR in patients with RA and has a negative impact on patients self-reported functional status. Education regarding smoking cessation is needed for the RA population.
17195212 Evaluation of protease-activated receptor 2 in murine models of arthritis. 2007 Jan OBJECTIVE: Protease-activated receptor 2 (PAR-2) activation has been linked to pro- and antiinflammatory cellular responses. We undertook this study to explore the importance of PAR-2 activation in 4 murine models of arthritis and to analyze the expression of PAR-2 in human arthritic synovium. METHODS: Zymosan-induced arthritis (ZIA), K/BxN serum-induced arthritis, and Freund's complete adjuvant (CFA)-induced arthritis were generated in naive PAR-2(-/-) mice and PAR-2(+/+) littermates. Antigen-induced arthritis (AIA) was generated in immunized mice using methylated bovine serum albumin (mBSA). The severity of arthritis was assessed by clinical scoring, technetium uptake measurement, and histologic analysis. Immune responses to mBSA were also evaluated from AIA. The expression of PAR-2 in synovial tissues from rheumatoid arthritis (RA) and osteoarthritis (OA) patients was compared. RESULTS: In AIA, arthritis was significantly decreased in PAR-2-deficient mice and was associated with decreased levels of anti-mBSA IgG antibodies and lymph node cell proliferation. No difference in arthritis severity was seen in mice with ZIA, K/BxN serum-induced arthritis, and CFA-induced arthritis. Synovial biopsy specimens from RA patients demonstrated significantly increased expression of PAR-2 compared with those from OA patients. CONCLUSION: PAR-2 deficiency was found to modulate articular inflammation in murine models of arthritis that require prior immunization and was associated with reduced levels of anti-mBSA IgG and lymph node cell proliferation in AIA. Expression of PAR-2 in RA synovium was significantly higher than that in OA synovium, and this suggests that PAR-2 is implicated in the pathogenesis of immune-mediated forms of arthritis.
17028857 Radiological and functional assessment of pulmonary involvement in the rheumatoid arthriti 2007 Mar The aim was to evaluate the findings of high resolution computed tomography (HRCT) and pulmonary function tests (PFT) in the rheumatoid arthritis (RA) patients with and without pulmonary symptoms and to determine their role in prediction of respiratory system involvement. Among 54 consecutive RA patients, 22 (41%) were symptomatic and 32 (59%) were asymptomatic after detailed respiratory examination. Abnormal findings in PFTs were present in 10 (45%) symptomatic and 15 (47%) asymptomatic patients. PFT results were similar in both groups. A total of 18 (82%) symptomatic and 16 (50%) asymptomatic patients had abnormalities in HRCT scans. About 16 (80%) of 20 patients with normal HRCT scans had no pulmonary symptoms at all and we noted a significant correlation (P < 0.05). HRCT was more useful mean than PFTs in evaluation of pulmonary involvement in the RA patients; however, no correlation was present between various respiratory symptoms and abnormal findings both in PFTs and HRCT scans.
16510530 Gene therapy as a therapeutic approach for the treatment of rheumatoid arthritis: innovati 2006 Jun In recent years, significant progress has been made in the treatment of rheumatoid arthritis (RA). In addition to conventional therapy, novel biologicals targeting tumour necrosis factor-alpha have successfully entered the clinic. However, the majority of the patients still has some actively inflamed joints and some patients suffer from side-effects associated with the high systemic dosages needed to achieve therapeutic levels in the joints. In addition, due to of the short half-life of these proteins there is a need for continuous, multiple injections of the recombinant protein. An alternative approach might be the use of gene transfer to deliver therapeutic genes locally at the site of inflammation. Several viral and non-viral vectors are being used in animal models of RA. The first gene therapy trials for RA have already entered the clinic. New vectors inducing long-term and regulated gene expression in specific tissue are under development, resulting in more efficient gene transfer, for example by using distinct serotypes of viral vectors such as adeno-associated virus. This review gives an overview of some promising vectors used in RA research. Furthermore, several therapeutic genes are discussed that could be used for gene therapy in RA patients.
18078616 Simvastatin inhibits cytokine production and nuclear factor-kB activation in interleukin 1 2007 Sep OBJECTIVES: Recent studies demonstrated in vivo the effectiveness of statins in reducing the inflammatory response in rheumatic diseases, and still more recently, simvastatin has been reported to inhibit in vitro IL-6 and IL-8 production by unstimulated fibroblast-like-synoviocytes (FLS) from rheumatoid arthritis (RA) patients. However, no data are available on the effect of statins on the production of these cytokines induced by IL-1, which plays a crucial role in joint inflammation in the course of active RA in vivo. METHODS: In 12 RA patients, synovial tissue specimens were taken to obtain cultures of FLS. Cultures were incubated with IL-1 +/- simvastatin (5-50 micromol/l), and IL-6 and IL-8 production was evaluated (ELISA), also following the addition of mevalonate and its isoprenoid derivatives. Moreover, nuclear factor-kB (NF-kB) activation (immunocytochemistry and Western Blot analysis) were also evaluated. RESULTS: Culture incubation with IL-1 produced a dramatic increase (up to 40-fold) in cytokine production with respect to unstimulated cells. Simvastatin significantly inhibited (about 20%) IL-6 and IL-8 production from IL-1-stimulated FLS. This effect was completely reverted by the concomitant incubation with mevalonate or geranylgeraniol (but not farnesol or squalene). Moreover, simvastatin produced a clear-cut inhibition of IL-1-induced NF-kB activation. CONCLUSION: Simvastatin significantly inhibits the production of IL-6 and IL-8 also in IL-1-stimulated FLS, even though to a lesser extent than in unstimulated cells, via a HMG-CoA-reductase block with an interference in prenylation process and NF-kB activation. Our results further support the rationale for the use of statins in the treatment of rheumatoid synovitis.
18568145 Prolonged treatment with interferon alpha and peginterferon induces rheumatoid arthritis s 2008 Jun The antiviral treatment of chronic C hepatitis has improved significantly over the past decade with the introduction of interferons (IFNs), and more recently, pegylated IFNs. Up to two-thirds of all patients treated with pegylated IFN combined with ribavirin can now achieve viral eradication if treated according to current guidelines. Despite this success rate, hematological, immunological, rheumatological and dermatological side effects have been reported in chronic hepatitis C patients treated with IFN-alpha. The subjects of this report are two young females with chronic hepatitis C, who developed rheumatoid syndrome and/or erythema nodosum during antiviral treatment with IFN-alpha or pegylated IFN combined with ribavirin.
18953944 [The plasmic translocation and release of high mobility group box chromosomal protein 1 in 2008 May OBJECTIVE: To investigate the release and intracellular localization of high mobility group box chromosomal protein 1 (HMGB1) in the peripheral blood monocytes of rheumatoid arthritis (RA) patients and the inhibitive effect of thalidomide. METHODS: 19 RA patients and 20 healthy controls were included in the study. Monocytes were separated from peripheral blood with Ficoll density gradient centrifugation. Monocytes were treated with 100 ng/ml tumor necrosis factor alpha (TNFalpha) or 100 ng/ml TNFalpha plus 40 microg/ml thalidomide and grown in an incubator at 37 degrees C with 5% CO2 for 24 hours. The culture supernatants of the monocytes were collected. HMGB1 level in the culture medium was detected with Western blot. In addition, the intracellular localization of HMGB1 in the monocytes was investigated with immunocytochemical analysis. RESULTS: Without stimulation, the release of HMGB1 protein was significantly increased in the culture supernatants of peripheral blood monocytes from RA patients as compared with that from healthy controls (P < 0.05). TNFalpha (100 ng/ml) did not further increase the release of HMGB1 in the monocytes from the patients with RA. Thalidomide (40 microg/ml) could inhibit the release of HMGB1 in the monocytes from RA patients stimulated with TNFalpha (P < 0.05). In the monocytes from RA patients, HMGB1 was mainly localized in the nucleus. Treatment with TNFalpha (100 ng/ml) for 24 hours resulted in a cytoplasmic translocation of HMGB1, which was inhibited significantly by thalidomide. CONCLUSION: TNFalpha induces the release and cytoplasmic translocation of HMGB1 in the peripheral blood monocytes of RA patients and thalidomide inhibits the release and translocation of HMGB1.
18375536 Overnight variations in cortisol, interleukin 6, tumour necrosis factor alpha and other cy 2009 Jan OBJECTIVE: To investigate overnight variations in absolute values and patterns of cytokines including interleukin 6 (IL6) and tumour necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA), and to relate any changes to those occurring in blood cortisol. METHODS: A total of 16 people (8 female) with active RA and who had received no recent glucocorticoids were admitted overnight. Blood samples were obtained at 13 time points between 21.00 and 10.00. RESULTS: The geometric mean IL6 concentration rose significantly from 35 pg/ml at 22:00 to 64 pg/ml at 07:15 (repeated measures analysis of variance (ANOVA), p<0.001). The geometric mean cortisol concentration rose significantly overnight from 57 ng/ml at 01:00 to 229 ng/ml at 07:15 (repeated measures ANOVA, p<0.001). Neither TNFalpha nor the other cytokines measured changed significantly. Using cubic regression modelling IL6 began to rise before cortisol (range 0.01 to 4.83 h) in eight participants and after cortisol (range 1.11 to 5.14 h) in three participants. In a random coefficient model including data from all participants, the estimated mean IL6 value began to rise 3.05 h before the estimated mean cortisol value, with the IL6 peak occurring 0.70 h before the cortisol peak. CONCLUSION: The mean IL6 and cortisol concentrations showed a significant overnight variation. Neither TNFalpha nor the other cytokines measured changed significantly. In a random coefficient model IL6 began to rise approximately 3 h, and reached a peak about 40 min, before cortisol. These studies confirm that there are abnormalities in plasma cortisol and IL6 concentrations and dynamics. The data also link the overnight rise in IL6 to the circadian variation in symptoms.
16951351 Crystallographic structure of a rheumatoid arthritis MHC susceptibility allele, HLA-DR1 (D 2006 Sep 15 The expression of HLA-DR1 (DRB1*0101) is associated with an enhanced risk for developing rheumatoid arthritis (RA). To study its function, we have solved the three-dimensional structure of HLA-DR1 complexed with a candidate RA autoantigen, the human type II collagen peptide CII (259-273). Based on these structural data, the CII peptide is anchored by Phe263 at the P1 position and Glu266 at P4. Surprisingly, the Lys at the P2 position appears to play a dual role by participating in peptide binding via interactions with DRB1-His81 and Asn82, and TCR interaction, based on functional assays. The CII peptide is also anchored by the P4 Glu266 residue through an ionic interaction with DRB1-Arg71 and Glu28. Participation of DRB1-Arg71 is significant because it is part of the shared epitope expressed by DR alleles associated with RA susceptibility. Potential anchor residues at P6 and P9 of the CII peptide are both Gly, and the lack of side chains at these positions appears to result in both a narrower binding groove with the peptide protruding out of the groove at this end of the DR1 molecule. From the TCR perspective, the P2-Lys264, P5-Arg267, and P8-Lys270 residues are all oriented away from the binding groove and collectively represent a positive charged interface for CII-specific TCR binding. Comparison of the DR1-CII structure to a DR1-hemagglutinin peptide structure revealed that the binding of these two peptides generates significantly different interfaces for the interaction with their respective Ag-specific TCRs.