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ID PMID Title PublicationDate abstract
18538829 Antibody clustering helps refine lupus prognosis. 2009 Aug OBJECTIVE: Our aim was to investigate a possible association between patterns of anti-dsDNA antibody isotypes (IgG, IgM, and IgA), rheumatoid factor (RF) isotypes (IgG, IgM, IgA), and IgG anti-C reactive protein (CRP) and systemic lupus erythematosus (SLE) disease activity (SLEDAI). METHODS: Our study group included 98 patients, 86 women and 12 men, with a mean SLEDAI score of 7.9 +/- 4.1. We divided the patients into 4 groups by the serum anti-dsDNA antibody isotype intensity level. RESULTS: We found that patients in group 1 (IgG > IgM, 42 patients) had a statistically significantly higher SLEDAI score than group 2 (IgG < IgM, 13 patients) (10.57 +/- 4.62 versus 5.6 +/- 4, P = 0.0012), group 3 (IgG = IgM, 8 patients) (10.57 +/- 4.62 versus 6.2 +/- 1.98, P = 0.04), and group 4 (none, 35 patients) (10.57 +/- 4.62 versus 6 +/- 1.5, P = 0.0001). SLE patients with IgG RF or IgM RF isotype present had a significantly higher SLEDAI score compared with those without IgG RF or IgM RF (10.57 +/- 4.8 versus 7.6 +/- 4.1, P = 0.03, 10.6 +/- 5 versus 7.6 +/- 3.9, P = 0.046). The presence of IgA RF isotype was not associated with a higher SLEDAI score. IgG anti-CRP did not correlate differentially with SLEDAI scores. CONCLUSIONS: A combination of high-titer IgG anti-dsDNA with a positive RF of IgM isotype may serve as a marker for more active SLE.
16785116 Long term effects of intra-articular botulinum toxin A for refractory joint pain. 2006 Apr The purpose of this case series review is to describe our 12 month clinical experience with intra-articular injections of Botulinum toxin Type A (BoNT/A) for refractory joint pain. Eleven patients with chronic arthritis who had failed treatment with oral and/or intra-articular medications and were not surgical candidates were referred to us for management of moderate to severe refractory joint pain in 15 joints. The use of BoNT/A to treat joint pain is a non-FDA approved "off label" treatment with potential side effects. After a detailed explanation of the joint injection procedure, signed informed consent was obtained for the procedure. Fifteen joints were injected with BoNT/A (Allergan, Inc): six lower extremity joints (3 knees, 3 ankles) with 25-50 units and nine shoulders with 50-100 units. Patients were followed for one year or longer. Maximum relief of pain was measured by comparing baseline pain on a numeric rating scale (0-10) to pain at the time of maximum relief (paired t-test). Maximum improvement in function was assessed using paired t-tests for improvement in active flexion and abduction for the shoulder joint, and by the time to perform sit to stand ten times (the timed stands test, TST) for the lower extremity joints. RESULTS: Two patients were female and nine were male, aged 42-82 years. Five had osteoarthritis (OA), five had rheumatoid arthritis (RA) and one had psoriatic arthritis. All patients were on analgesic and/or anti-inflammatory medications and all joints had previous intra-articular steroid or viscosupplement injections with inadequate or unsatisfactory benefit. A clinically and statistically significant improvement was noted after IA-BoNT/A injections. The mean maximum decrease in lower extremity joint pain was 55% (p =0.02) and the 36% (p =0.044) improvement in the Timed Stands Test was noted at four to ten weeks after injection. There was a 71% mean maximum reduction in shoulder pain severity from 8.2 +/- 1.1 to 2.4 +/- 1.9 (p <0.001). Active range of motion increased 67% in flexion (from 67.8 +/- 27.6 to 113.3 +/- 46.6 degrees, p =0.001) and 42% in abduction (from 50 +/- 18.5 degrees to 71.1 +/- 23.1 degrees p =0.01). No immediate or delayed adverse effects related to BoNT/A were noted after the injection. Duration of pain relief was variable and ranged from 3 to 12 months. Five joints were re-injected with IA-Bont/A and had a similar decrease in joint pain that lasted 3 to 12 months. CONCLUSIONS: This is the first report of the long term effects of intra-articular BoNT/A injections to treat chronic joint pain and the efficacy of repeated injections. Although this study was small, and uncontrolled the results suggest that IA-BoNT/A injections are an effective and safe treatment for chronic joint pain disorders.
18668605 Subgroup analyses to determine cardiovascular risk associated with nonsteroidal antiinflam 2008 Aug 15 OBJECTIVE: To explore the extent to which clinical characteristics influence the association between cyclooxygenase 2 inhibitors (coxibs) and/or nonselective nonsteroidal antiinflammatory drugs (NSAIDs) and increased cardiovascular disease (CVD) risk in specific patient subgroups. There is substantial concern regarding the potential cardiovascular adverse effects of selective coxibs and nonselective NSAIDs, but many patients with arthritis experience important clinical benefits from these agents. METHODS: The study population consisted of Medicare beneficiaries also eligible for a drug benefits program for older adults during the years 1999-2004. We calculated the relative risk (RR) for CVD events (myocardial infarction [MI], stroke, congestive heart failure, and cardiovascular death) among users of coxibs or nonselective NSAIDs in the prior 6 months compared with nonusers. We assessed biologic interaction between these medication exposures and important patient characteristics. RESULTS: In the primary cohort, we identified 76,082 new users of coxibs, 53,014 new users of nonselective NSAIDs, and 46,558 nonusers. Compared with nonusers, the adjusted RR of CVD events for new users of each agent increased for rofecoxib (RR 1.22, 95% confidence interval [95% CI] 1.14, 1.30) and decreased for naproxen (RR 0.79, 95% CI 0.67, 0.93). Several patient characteristics were found to increase the risk of CVD events among users of some agents in both the primary and secondary cohorts, including age >/=80 years, hypertension, prior MI, prior CVD, rheumatoid arthritis, chronic renal disease, and chronic obstructive pulmonary disease. Rofecoxib and ibuprofen appeared to confer an increased risk in multiple patient subgroups. CONCLUSION: Many nonselective NSAIDs and coxibs are not associated with an increased risk of CVD events. However, several patient characteristics identify important subgroups that may be at an increased risk when using specific agents.
18831934 Antibodies to carbonic anhydrase in patients with connective tissue diseases: relationship 2008 Jul The aim of this study is to evaluate the presence of antibodies to carbonic anhydrase I and/or II (ACAI and ACAII) in patients affected by connective tissue diseases (CTD) and to investigate their association with lung involvement evaluated by High resolution CT scan (HRCT). Ninety-six patients affected by CTD were studied, i.e. 33 rheumatoid arthritis (RA), 8 psoriatic arthritis (PA), 8 ankylosing spondilitis (AS), 23 Systemic Lupus Erythematosus (SLE), 10 Sjogren Syndrome (SS), and 14 Systemic Sclerosis (SSc). ACA were detected by ELISA. The lung involvement was evaluated by means of a previously described HRCT score. According to a receiver operator characteristic curve, patients were divided into those with HRCT score > or = 10 and those with HRCT score < 10, where HRCT score > or = 10 was predictive of interstitial lung disease. ACAI and/or ACAII were detected in 30/96 patients (31.2%) (P < 0.0001 in comparison with controls). In particular, the prevalence of ACAI and/or ACAII was significantly higher in patients with RA (P = 0.002), PA (P < 0.0001), SLE (P = 0.0003) and SSc (P < 0.0001). A positive correlation was found between HRCT scores and CRP or ACAI levels (P = < 0.0001 and P = 0.004, respectively). Thirty-nine of 96 patients (40.6%) showed a HRCT score > or = 10 and both their CRP and ACAI levels were significantly higher when compared with patients showing a HRCT score less than 10 (P < 0.0006 and P = 0.0009, respectively). Moreover, C3 and C4 complement fractions inversely correlated with HRCT scores (P = 0.0004 and P < 0.0001, respectively) and lower values of C3 and C4 complement fractions were found in patients with HRCT score > or = 10 than in those with HRCT score less than 10 (P = 0.014 and P = 0.007, respectively). Due to the lower levels of complement fractions detected in patients with HRCT score > or = 10, a possible immune-complex-mediated pathogenic mechanism of lung involvement could be suggested.
18336875 Medication adherence of patients with selected rheumatic conditions: a systematic review o 2009 Apr OBJECTIVE: Nonadherence with medication treatment has been found to occur in large proportions of patients with a broad range of chronic conditions. Our aim was to perform a systematic review of the literature examining adherence with treatments for inflammatory rheumatic conditions to assess the magnitude of the problem in this patient population. METHODS: A MEDLINE search of English language literature was performed to identify studies published between January 1, 1985 and November 30, 2007 that evaluated adherence with chronic medications needed in the treatment of rheumatic conditions. RESULTS: A total of 20 articles met the criteria for evaluation, the majority of which focused on the treatment of rheumatoid arthritis. Most of the studies examined the use of nonsteroidal anti-inflammatory medications and disease-modifying antirheumatic drugs. Adherence was assessed based on self-report, pill counts, pharmacy dispensings, openings of pill containers using electronic devices, laboratory assays, and physician assessment. Adherence varied greatly based on the adherence measure used, arthritic condition evaluated, and medication under study. Overall, the highest rates of adherence were based on self-reports for a wide variety of medications and conditions (range of persons reporting adherence was 30 to 99%), while the lowest adherence rates were for allopurinol based on pharmacy dispensings (18-26%). CONCLUSIONS: Adherence has not been widely examined for most chronic inflammatory rheumatic conditions and the few studies that exist used different definitions and populations, thus limiting any conclusions. However, the current literature does suggest that nonadherence is a substantial problem.
17081465 [Establishment of arthroscopic trans-septal approach and its clinical application]. 2006 Aug 15 OBJECTIVE: To investigate the method and result of arthroscopic trans-septal approach (ATS). METHODS: Ten fresh cadaveric knees were prepared for anatomical study about the posterior septum, and 65 posterior compartment arthroscopy of the knees were performed to view the structure of the posterior septum. The initial diagnosis included: rheumatoid arthritis, pigmented villonodular synovitis, osteoarthritis, loose body or foreign body in the posterior compartment, posterior cruciate ligament (PCL) injury or avulsion fracture, posterior horn tear of meniscus, undiagnosed swollen knee with pain and effusion, osteochondritis dissecans, pyogenic arthritis, gout. From January 2002 to June 2005, 22 cases of ATS were applied. Anterolateral portal was initially created, followed by posterolateral portal under the viewing of arthroscopy which was located at the anterolateral portal. Anteromedial and posteromedial portals were also created using the same technique. Arthroscopy was then transferred to the posteromedial portal, and blade was introduced from the anteromedial portal to gradually remove the synovium covering PCL. Arthroscopy was relocated to the anteromedial portal, Wissinger rod was introduced from the posteromedial portal and pointed to the posterior septum adjacent to the posterior edge of the midportion of PCL. The Wissinger rod was pushed carefully to pierce through the posterior septum under the sight of arthroscopy which was located at the posterolateral portal. ATS was finally created. RESULTS: The posterior septum was in the middle of posterior compartment of the knee, which was film screen-like at the sagittal plane and sandwich-like at the transverse plane. The synovium covered the posterior septum at arthroscopic inspection. Twenty-two cases of ATS were successfully created, amounting to 34% (22/65) of all cases at the same period which had received the arthroscopy of posterior compartments of the knees. Synovectomy of the posterior compartments of the knees was performed in 7 cases, loose body removal was in 6 cases, PCL reconstruction was in 4 cases, reduction and fixation of PCL avulsion fracture was in 2 cases. Chondroplasty, inflammatory synovectomy, and meniscectomy were performed accordingly in 6 osteoarthritis cases. No vascular or nervous injury was encountered. At an average of 20 months follow-up (range, 4 to 45 months), 9 cases still had mild knee pain or swelling, 2 cases had severe pain and were recommended for total knee replacement, the other 11 cases had no recurrence of knee pain or swelling. CONCLUSIONS: ATS has no blind area under arthroscopic vision and facilitate trans-septal operation. It is a safe and effective method to treat the diseases of the posterior compartment of the knee. The direction of inside to outside to create ATS is comparatively reliable, and PCL could be identified as an interior landmark during the passage of Wissinger rod through posterior septum to create ATS.
17786950 Ajulemic acid, a nonpsychoactive cannabinoid acid, suppresses osteoclastogenesis in mononu 2008 Mar Oral administration of ajulemic acid (AjA), a cannabinoid acid devoid of psychoactivity, prevents joint tissue injury in rats with adjuvant induced arthritis. Because activation of osteoclasts is central to the pathogenesis of bone erosion in patients with rheumatoid arthritis (RA), we investigated the influence of AjA on osteoclast differentiation and survival. Osteoclast cultures were established by stimulation of RAW264.7 cells and primary mouse bone marrow cultures with receptor activator of NF-kappaB ligand (RANKL). Simultaneous addition of AjA (15 and 30 microM) and RANKL to both culture systems significantly suppressed development of multinucleated osteoclasts (osteoclastogenesis) in a dose dependent manner, as determined by quantification of multinuclear, tartrate-resistant acid phosphatase (TRAP)-positive cells. AjA impaired growth of RAW264.7 monocytes and prevented further osteoclast formation in cultures in which osteoclastogenesis had already begun. Reduction by AjA of both monocyte growth and osteoclast formation was associated with apoptosis, assayed by annexin V and propidium iodide staining, and caspase activity. The anti-osteoclastogenic effects of AjA did not require the continuous presence of AjA in the cell cultures. Based on these findings, we propose that AjA or other nonpsychoactive synthetic analogs of Cannabis constituents may be useful therapy for diseases such as RA and osteoporosis in which bone resorption is a central feature.
17530713 Serum matrix metalloproteinase 3 is an independent predictor of structural damage progress 2007 Jun OBJECTIVE: In prospective studies, only baseline radiographic damage has been identified as an independent predictor of radiographic progression in ankylosing spondylitis (AS). Several biomarkers have been identified as independent predictors of radiographic progression in rheumatoid arthritis, however, and these may be of use in AS. This study was undertaken to analyze serologic biomarkers as predictors of radiographic progression in AS. METHODS: We measured a panel of biomarkers reflecting cartilage turnover and osteoclasis. These biomarkers were cartilage oligomeric matrix protein, human cartilage gp-39 (YKL-40), type II collagen epitopes detected by the C2C and C1,2C degradation assays and the CPII synthesis assay, aggrecan 846 epitope, osteoprotegerin, and matrix metalloproteinase 3 (MMP-3). The analysis was performed in a cohort of AS patients from the Netherlands, Belgium, and France enrolled in a longitudinal study, the Outcome Assessments in Ankylosing Spondylitis International Study. We examined 2-year radiographic progression data scored using the modified Stoke AS Spine Score (mSASSS). RESULTS: Complete data were available on 97 patients. Only the biomarkers YKL-40 and MMP-3 showed weak to moderate univariate correlation with 2-year progression. After adjustment for sex, age, disease duration, C-reactive protein level, and baseline mSASSS, only MMP-3 was significantly associated with 2-year progression (beta = 0.29, P = 0.004). Logistic regression analysis revealed MMP-3 (cutoff 68 ng/ml; odds ratio 9.4 [95% confidence interval 1.6-56]) and baseline mSASSS (cutoff 10 mSASSS units; odds ratio 18.6 [95% confidence interval 2.5-138]) as the only independent predictors of 2-year progression (cutoff 3 mSASSS units; model R(2) = 50%). MMP-3 was primarily contributory in patients who already had substantial baseline damage (>10 mSASSS units). CONCLUSION: These results indicate that MMP-3 is a significant independent predictor of radiographic progression in patients with AS, particularly in those with preexisting radiographic damage.
18793417 Association of elevated transcript levels of interferon-inducible chemokines with disease 2008 INTRODUCTION: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with a heterogeneous course and varying degrees of severity and organ damage; thus, there is increasing interest in identifying biomarkers for SLE. In this study we correlated the combined expression level of multiple interferon-inducible chemokines with disease activity, degree of organ damage and clinical features in SLE, and we investigated their roles as biomarkers. METHODS: Peripheral blood cells obtained from 67 patients with SLE patients, 20 patients with rheumatoid arthritis (RA) and 23 healthy donors were subjected to real-time PCR in order to measure the transcriptional levels of seven interferon-inducible chemokines (RANTES, MCP-1, CCL19, MIG, IP-10, CXCL11, and IL-8). The data were used to calculate a chemokine score for each participant, after which comparisons were performed between various groups of SLE patients and control individuals. RESULTS: Chemokine scores were significantly elevated in SLE patients versus RA patients and healthy donors (P = 0.012 and P = 0.002, respectively). Chemokine scores were correlated positively with SLE Disease Activity Index 2000 scores (P = 0.005) and negatively with C3 levels (P < 0.001). Compared with patients without lupus nephritis and those with inactive lupus nephritis, chemokine scores were elevated in patients with active lupus nephritis, especially when their daily prednisone dosage was under 30 mg (P = 0.002 and P = 0.014, respectively). Elevated chemokine scores were also associated with the presence of cumulative organ damage (Systemic Lupus International Collaborating Clinics/American Society of Rheumatology Damage Index >or= 1; P = 0.010) and the occurrence of anti-Sm or anti-RNP autoantibodies (both P = 0.021). CONCLUSIONS: The combined transcription level of interferon-inducible chemokines in peripheral blood leucocytes is closely associated with disease activity, degree of organ damage, and specific autoantibody patterns in SLE. The chemokine score may serve as a new biomarker for active and severe disease in SLE.
18470544 Performance of two commercial blood IFN-gamma release assays for the detection of Mycobact 2008 Oct The reactivation of latent tuberculosis (TB) is a major complication of tumor necrosis factor (TNF)-alpha inhibitors. Screening for TB infection is recommended before anti-TNF therapy is initiated; however, the use of tuberculin skin testing (TST) is controversial, due to the high rate of false-negative results in patients receiving immunosuppressive treatment. To compare the performance of two commercial interferon (IFN)-gamma release assays (IGRA), T-SPOT.TB (TS-TB) and QuantiFERON-TB Gold "In-tube" (QFT-GIT), with TST for the detection of TB infection in patients due to start anti-TNF therapy, 69 human immunodeficiency virus (HIV)-negative Italian patients (mean age: 45.2 +/- 12.6 years; male=39) were enrolled between September 2005 to August 2006. Patients affected by rheumatoid arthritis (n = 18), psoriatic arthritis (n = 26), ulcerous rectocolitis (n = 6), and Crohn's disease (n = 19) were tested simultaneously with TST, TS-TB, and QFT-GIT. Overall, 26% of patients were positive by TST, 30.4% by TS-TB, and 31.8% by QFT-GIT. Agreement with TST was similar (kappa = 0.21, p = 0.0002 and kappa = 0.26, p < 0.001, respectively). In 11 TST-negative cases, IFN-gamma release assays were positive. In addition, in seven Mantoux-positive cases with no TB risk factors, TST result agreement was achieved with at least one blood test. Indeterminate results were detected in 5.8% and 2.8% of cases, respectively, with TS-TB and with QFT-GIT (p = not significant [ns]). In conclusion, our results suggest that IGRAs may be helpful for screening purposes in patient candidates for anti-TNF therapy to confirm positive TST results and in selected cases when false-negative results are suspected. The utility of blood tests in patients with low or no TB risk remains to be assessed.
18438857 A novel tumor necrosis factor alpha-responsive CCAAT/enhancer binding protein site regulat 2008 May OBJECTIVE: Inflammatory processes in rheumatoid arthritis are primarily regulated by the cytokines tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta). Previous studies in our laboratory have shown that IL-1beta represses expression of the cartilage characteristic genes, cartilage-derived retinoic acid-sensitive protein (cd-rap) and type II collagen (COL2A1); this mechanism of repression involves activation of a CCAAT/enhancer binding protein (c/EBP) site within promoter regions. The aim of this study was to investigate novel TNFalpha-mediated mechanisms that regulate the expression of cd-rap. METHODS: Rat chondrosarcoma cells were transiently transfected with complementary DNA constructs encoding cd-rap, in the presence of TNFalpha. The expression of c/EBPbeta, SOX9, and p300 in rat chondrosarcoma cells and primary human articular chondrocytes after treatment with TNFalpha was examined by reverse transcription-polymerase chain reaction and Western blotting. The effect of TNFalpha on endogenous binding of c/EBPbeta or SOX9 to the cd-rap promoter was examined by chromatin immunoprecipitation assays. RESULTS: We identified a new c/EBP binding site in the cd-rap promoter (from position -1059 bp to position -1046 bp). Binding of c/EBP to this site was regulated by TNFalpha but not IL-1beta, resulting in down-regulation of cd-rap expression. This effect was reversed by mutational inactivation of the c/EBP motif. In addition, the activation potential of SOX9 and CREB binding protein/p300 on the cd-rap promoter was enhanced after mutation of the new c/EBP binding site, indicating that blockage of this site would increase transcription. CONCLUSION: TNFalpha regulates the expression and/or DNA-binding potential of key positive-acting and negative-acting transcription factors that control the expression of the cartilage matrix gene, cd-rap.
18084859 Etoricoxib: new drug. Avoid using cox-2 inhibitors for pain. 2007 Dec (1) Paracetamol is the first-choice analgesic for joint pain. Nonsteroidal antiinflammatory drugs (NSAIDs), especially ibuprofen, are second-line options. Cox-2 inhibitors are no more effective than traditional NSAIDs and have no tangible advantages in terms of gastrointestinal tolerability. In contrast, they expose patients to an increased risk of cardiovascular adverse effects. (2) Etoricoxib is marketed in some European countries to relieve symptoms of osteoarthritis, rheumatoid arthritis, and gout attacks. (3) Many clinical trials have tested etoricoxib in these indications, as well as in ankylosing spondylitis, low back pain, and various types of acute pain. Etoricoxib was no more effective than other NSAIDs such as ibuprofen, naproxen or diclofenac in these situations. (4) Comparative trials showed a higher overall mortality rate with etoricoxib than with naproxen. A combined analysis of long-term comparative trials including 5441 patients, mainly versus naproxen, showed that etoricoxib does not reduce the risk of perforation, ulcer or severe gastrointestinal haemorrhage. Similarly, it does not reduce the risk of mild gastrointestinal events in at-risk patients: those with a history of gastrointestinal disorders, aspirin use, etc. (5) Three trials including a total of 34 701 patients (MEDAL programme) compared cardiovascular thrombotic events associated with etoricoxib and diclofenac. Overall, the cardiovascular risks appear to be similar but the thrombotic risk may be slightly higher with diclofenac than with other conventional NSAIDs. (6) Etoricoxib provoked arterial hypertension, oedema and heart failure during clinical trials. Serious skin reactions were reported both during clinical trials and after marketing, but their precise incidence is not known. Etoricoxib is partly metabolised by the cytochrome P450 isoenzyme CYP 3A4 and increases the bioavailability of ethinylestradiol. (7) When a NSAID is considered, drugs with which we have the most experience should be chosen, such as ibuprofen, and used at the lowest acceptable dose regimen (daily dose and length of treatment). Etoricoxib should be avoided.
17072319 ADAM10 is a principal 'sheddase' of the low-affinity immunoglobulin E receptor CD23. 2006 Dec CD23, the low-affinity immunoglobulin E receptor, is an important modulator of the allergic response and of diseases such as rheumatoid arthritis. The proteolytic release of CD23 from cells is considered a key event in the allergic response. Here we used loss-of-function and gain-of-function experiments with cells lacking or overexpressing candidate CD23-releasing enzymes (ADAM8, ADAM9, ADAM10, ADAM12, ADAM15, ADAM17, ADAM19 and ADAM33), ADAM-knockout mice and a selective inhibitor to identify ADAM10 as the main CD23-releasing enzyme in vivo. Our findings provide a likely target for the treatment of allergic reactions and set the stage for further studies of the involvement of ADAM10 in CD23-dependent pathologies.
17064404 Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spond 2006 The PD-1 (programmed death 1) molecule is a negative regulator of T cells. PDCD1 (programmed cell death 1) has been reported to have a genetic association in systemic lupus erythematosus and rheumatoid arthritis in Caucasians. However, there are no reports on the association between this gene and ankylosing spondylitis (AS). The present study investigated the association of the PD-1 polymorphisms and the haplotypes with AS in a Korean population sample. In a case-control association study, two single-nucleotide polymorphisms, PD-1.5 C/T and PD-1.9 T/C, were genotyped in 95 AS patients and 130 healthy controls. The T allele of the PD-1.9 polymorphism was more frequent in the Korean male population with AS than in the Korean male controls (21.0% versus 6.9%, odds ratio 1.89, 95% confidence interval 1.483 to 2.408). The frequency of the CT haplotype (PD-1.5 C/T and PD-1.9 T/C) was higher in the AS patients (19%) than the controls (5.4%) (odds ratio 1.83, 95% confidence interval 1.559 to 2.521). The PD-1 polymorphism was demonstrated in Korean AS patients. The results suggest a genetic association between the PD-1 polymorphism and susceptibility to AS.
16447232 Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistanc 2006 Feb OBJECTIVE: To explore the onset and molecular mechanism of resistance to the antimalarial disease-modifying antirheumatic drug (DMARD) chloroquine (CQ) in human CEM T cells. METHODS: Human CEM cells were used as an in vitro model system to study the development of CQ resistance by growing cells in stepwise increasing concentrations of CQ. RESULTS: Over a period of 6 months, CEM cell lines developed 4-5-fold resistance to CQ. CQ resistance was associated with the specific overexpression of multidrug resistance-associated protein 1 (MRP-1), an ATP-driven drug efflux pump. This was illustrated by 1) overexpression of MRP-1 by Western blotting and 2) the complete reversal of CQ resistance by the MRP-1 transport inhibitors MK571 and probenecid. Importantly, CQ-resistant CEM cells retained full sensitivity to other DMARDs, including methotrexate, leflunomide, cyclosporin A, and sulfasalazine, but exhibited a high level of cross-resistance (>1,000-fold) to the glucocorticoid dexamethasone. The mechanistic basis for the latter was associated with aberrant signaling via the cAMP-protein kinase A pathway, since the cAMP-inducing agent forskolin reversed dexamethasone resistance. Finally, CQ-resistant CEM cells displayed a markedly reduced capacity to release proinflammatory cytokines (tumor necrosis factor alpha) and chemokines (interleukin-8). CONCLUSION: Induction of overexpression of the multidrug resistance efflux transporter MRP-1 can emerge after long-term exposure to CQ and results in CQ resistance and collateral resistance to dexamethasone. These findings warrant further detailed investigations into the possible role of MRP-1 and other members of the superfamily of drug efflux pumps in diminishing the efficacy of DMARDs in rheumatoid arthritis treatment.
17530674 Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to inc 2007 Jun 15 OBJECTIVE: To evaluate the causes of new cases of active tuberculosis (ATB) in patients treated with tumor necrosis factor (TNF) antagonists included in the national registry BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) after the dissemination of recommendations to prevent reactivation of latent tuberculosis infection (LTBI). METHODS: Incidence rate of ATB per 100,000 patient-years and 95% confidence intervals (95% CIs) were calculated in patients entering BIOBADASER after March 2002 and were stratified by compliance with recommendations (complete or incomplete). ATB rates in BIOBADASER were compared with the background rate and the rate in the rheumatoid arthritis cohort EMECAR (Estudio de la Morbilidad y Expresión Clínica de la Artritis Reumatoide) not treated with TNF antagonists. In addition, rates of ATB among patients treated with adalimumab, etanercept, and infliximab were estimated and compared only for treatments started after September 2003, when all 3 drugs became fully available. RESULTS: Following March 2002, a total of 5,198 patients treated with a TNF antagonist were registered in BIOBADASER. Fifteen ATB cases were noted (rate 172 per 100,000 patient-years, 95% CI 103-285). Recommendations were fully followed in 2,655 treatments. The probability of developing ATB was 7 times higher when recommendations were not followed (incidence rate ratio 7.09, 95% CI 1.60-64.69). Two-step tuberculosis skin test for LTBI was the major failure in complying with recommendations. CONCLUSION: New cases of ATB still occur in patients treated with all available TNF antagonists due to lack of compliance with recommendations to prevent reactivation of LTBI. Continuous evaluation of recommendations is required to improve clinical practice.
17195234 Natural killer T cells in families of patients with systemic lupus erythematosus: their po 2007 Jan OBJECTIVE: To determine whether there is a link between the frequency of natural killer T (NKT) cells and high levels of IgG in patients with systemic lupus erythematosus (SLE) and their relatives. METHODS: Blood samples were obtained from patients with SLE, their first-degree relatives, patients with rheumatoid arthritis (RA), and healthy control subjects. The frequency of NKT cells (defined as CD56+ T cells) was expressed as a percentage of total blood lymphocytes. Plasma levels of total IgG and IgM, and IgG antibodies to double-stranded DNA (dsDNA) were determined. RESULTS: The frequency of NKT cells was lower in patients with SLE than in control subjects. No such decrease was observed in the relatives of patients with SLE or in patients with RA. High levels of IgG were observed in both patients with SLE and their relatives, while low levels of IgM were observed in these same groups. In relatives of patients with SLE, an inverse correlation between the frequency of NKT cells and IgG levels was observed. Moreover, raised levels of IgG in patients with SLE and their relatives and high levels of IgG anti-dsDNA in patients were associated with low frequencies of NKT cells. CONCLUSION: These results suggest that NKT cells have an important role in the regulation of IgG production, although NKT cells with invariant T cell receptors may not necessarily be involved. NKT cells in the setting of SLE could lack the cytokine stimulus from NK or other cells that is needed to exert control on IgG production. Enhancement of NKT cell activity may provide a novel basis for therapy in SLE.
16545585 Osteoarthritis of the first carpometacarpal joint: a study of radiology and clinical epide 2006 May BACKGROUND: The radiological and epidemiological data from the Copenhagen Osteoarthritis Study (COS) were analysed in order to assess the prevalence of osteoarthritis (OA) of the first carpometacarpal joint (CMCJ). Another aim of the study was to analyse relationships between radiologic CMCJ OA and self-reported pain. The third aim was to analyse if additional information could be obtained applying a new method of correlating individual radiological features to self-reported pain, compared to Kellgren and Lawrence's (K-L's) radiologic OA classification. METHODS: Between 1992 and 1994 standardised radiographs of both hands were recorded in 3,355 participants of the COS cohort. Subjects with known rheumatoid arthritis, other inflammatory arthritis or earlier fractures of the hand were excluded. OA of the CMCJ was assessed according to K-L's radiologic classification by two senior radiologists at our institution. The radiologists further evaluated individual radiologic features of CMCJ OA as recommended by K-L according to the text attached to each picture in their radiologic atlas of OA. To estimate inter- and intraobserver reproducibility a subset of 100 radiographs was reread. RESULTS: Our analyses demonstrated that the K-L method was not able to classify all X-rays. In 608 (18.1%) cases, combinations of joint space width (JSW) measurements, the graduation of osteofytes, sclerosis and cysts fell outside the classification. The radiological evaluation of individual features of OA demonstrated an acceptable reproducibility, intrapersonal (kappa=0.79) as well as interpersonal (kappa=0.65). The prevalence of each radiological feature increased after the fifth decade, progressively more so among women (P<0.001), with the highest prevalence (36.0%) of grades 3 and 4 JSW reduction among women>80 years. A significant correlation was found between signs of radiologic degeneration and self-reported pain (P<0.001); however, different combinations of OA features had different relations to symptoms. Logistic regression analyses revealed sclerosis to have an independent influence on pain in the thumb compared with the presence of osteofytes, cysts and diminished JSW. Body mass index (BMI) was positively related to radiological changes. In logistic regression analyses BMI did not demonstrate an independent positive relation to OA. CONCLUSION: Radiological degenerative changes in the CMCJ by age especially among women are quite common. However, it is demonstrated that global radiologic classifications of OA of the CMCJ have serious limitations in epidemiological studies. Not all cases fit into classification based on the K-L-atlas. Among the radiological features, subchondral sclerosis is significantly related to self-reported pain. Specific radiologic data should be incorporated in epidemiological studies on hand OA.
18684981 Identification of IL-18 and Th17 cells in salivary glands of patients with Sjögren's synd 2008 Aug 15 IL-18 is a proinflammatory cytokine and plays an important pathogenic role in inflammatory and autoimmune disorders. IL-17 is also a proinflammatory cytokine and IL-17-secreting Th17 cells are involved in autoimmunity. However, the pathological roles of IL-18 and Th17 cells in Sjögren's syndrome (SS) remain to be elucidated. This study showed that the expression of IL-18 was detected in acinar cells, intraducts, and CD68(+) macrophages in salivary glands of SS patients, but not in those of healthy subjects or patients with chronic graft-vs-host disease, by immunohistochemistry, and immunoblot analysis revealed that 24-kDa precursor form of IL-18 (proIL-18) and 18-kDa mature IL-18 were detected in SS salivary glands. The majority of the infiltrating cells in the salivary glands of SS patients were CD4(+) T cells, and CD8(+) T cells were infiltrated to a lesser extent. The predominant expression of IL-17 was found in infiltrating CD4(+) T cells, whereas a small number of infiltrating CD8(+) T cells expressed IL-17. Human salivary gland HSY and acinar AZA3 cells constitutively expressed proIL-18 and caspase-1, and a calcium ionophore A23187 induced the secretion of IL-18 from the cells. HSY and AZA3 cells expressed IL-18R and IL-17R on the cell surface, and IL-18 amplified the secretion of IL-6 and IL-8 that were induced by low amounts of IL-17. Primary salivary gland cells from normal subjects partially confirmed these findings. These results suggest that IL-18 and Th17 cells detected in the salivary glands in SS patients are associated with the pathogenesis of SS in the salivary glands.
17665393 Low salivary dehydroepiandrosterone and androgen-regulated cysteine-rich secretory protein 2007 Aug OBJECTIVE: Sjögren's syndrome (SS), an autoimmune disease of exocrine glands, typically starts at the time of adrenopause. We undertook this study to test the hypothesis that SS is characterized by an insufficient androgen effect at the target tissue level. METHODS: We searched for androgen response elements (AREs) in the cysteine-rich secretory protein 3 (crisp-3) gene. Dehydroepiandrosterone (DHEA) responsiveness was experimentally studied using quantitative reverse transcriptase-polymerase chain reaction and immunofluorescence staining of human submandibular gland-derived acinar cells and labial salivary gland explants with or without DHEA. Finally, glandular and salivary CRISP-3 in healthy controls and SS patients was analyzed using immunohistochemistry, in situ hybridization, and enzyme-linked immunosorbent assay. Serum DHEA sulfate (DHEAS) and salivary DHEA levels were measured using a radioimmunometric method. RESULTS: Literature analysis and a search for AREs in gene banks suggested androgen dependency of human CRISP-3, and this was verified by studies of human submandibular gland acinar cells cultured with or without DHEA, in which DHEA increased CRISP-3 messenger RNA (mRNA) levels (P = 0.018). This finding was confirmed by the results of DHEA stimulation of labial salivary gland explants. Glandular CRISP-3 mRNA and protein labeling was weak and diffuse, coupled with low secretion in saliva (mean +/- SEM 21.1 +/- 2.7 mug CRISP-3/15 minutes in SS patients versus 97.6 +/- 12.0 mug CRISP-3/15 minutes in healthy controls; P < 0.0001). Compared with healthy controls, SS patients had low serum levels of DHEAS (P = 0.008) and also low salivary levels of DHEA (mean +/- SEM 224 +/- 33 pmoles versus 419 +/- 98 pmoles; P = 0.005). CONCLUSION: CRISP-3 pathology was seen in acini remote from lymphocyte foci and is apparently not secondary to local inflammation, but may represent some systemic effect in SS. Indeed, androgen deprivation in the salivary glands of SS patients is evidenced both by low salivary levels of DHEA and by low levels of DHEA-regulated CRISP-3. This may explain some of the characteristic features of SS.