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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
12195630 Enthesitis of proximal insertion of the deltoid in the course of seronegative spondyloarth 2002 OBJECTIVE: To study the frequence of deltoideal proximal insertion enthesitis (DPIE) in patients affected with spondyloarthritis (SpA) and to evaluate its clinical, sonographic and radiological characteristics. METHODS: A retrospective study of clinical, sonographic and radiological examinations of the shoulders of 100 symptomatic consecutive outpatients with SpA, compared to 4 groups of control patients: 100 with Rheumatoid Arthritis, 100 with Osteoarthritis, 100 with Painful Shoulder, and 50 with shoulders undamaged by local pathological processes. RESULTS: The frequence of DPIE in the course of SpA was 9%. DPIE appears most frequently in Psoriatic Arthritis (PsA) (17%, 7/41). DPIE does not appear to be related to the sex or the age of the patient. The clinical signs and symptoms are similar to those of an impingement syndrome. Sonography reveals thickening and hypoechogenicity of the enthesis, associated or not to the subchondral osseous rearrangement and enthesophytosis. Radiology only reveals the enthesophytosis in the later stages. CONCLUSIONS: DPIE can determine shoulder pain in the course of SpA, and in particular in PsA. The clinical manifestations of DPIE are very similar to those of an impingement syndrome; sonography can differentiate the two conditions.
12794792 Informed consent in a clinical trial of a novel treatment for rheumatoid arthritis. 2003 Jun 15 OBJECTIVE: To evaluate the informed consent process for a clinical trial of intravenous doxycycline for rheumatoid arthritis. METHODS: Participants completed a self-administered questionnaire about the consent process at baseline and 16 weeks following enrollment in a clinical trial. RESULTS: Respondents (n = 30) affirmed voluntary participation in the parent trial. Participants acknowledged hope and altruism as reasons for entering the trial more than expectation of personal benefit or outside influences. Many respondents did not understand randomization (14/30), placebos (15/30), or risks of study medications; 11/30 respondents believed that the study drug was completely safe. CONCLUSION: Respondents generally understood the experimental nature of the trial and confirmed their participation was voluntary. However, gaps existed in participants understanding of trial design, raising the question of whether they were adequately informed about the research study prior to enrollment. Further education of potential participants in clinical trials may be required to achieve valid informed consent.
15633634 Weather conditions can influence rheumatic diseases. 2004 In daily clinical practice, many patients attribute joint pain to weather conditions. There is little information published on this subject and most of it is contradictory. The objective of this study was to evaluate the effect of climatic conditions in rheumatic patients. The present work was carried out with patients attending the Instituto Poal de Reumatologia of Barcelona and the data were analyzed by Bioibérica Farma (Spain). It was a prospective, double-blind study including 92 patients with rheumatic disorders (80 with osteoarthritis, 12 with rheumatoid arthritis) compared to a control group of 42 subjects. The evaluation of pain (Huskisson VAS) and functional capacity (Health Assessment Questionnaire, HAQ) were determined daily during one month. The climatic variables studied were temperature, humidity and barometric pressure. The results obtained have been subject to binary regression analysis. Our data demonstrate that osteoarthritic patients experience increased joint pain in response to a decrease in pressure, indicating that low atmospheric pressure conditions exacerbate joint pain in these patients. Our work also suggests that some meteorological variables affect the occurrence of pain in rheumatoid arthritis, since we have found that low temperature increases the risk of joint pain. Therefore, these data suggest that in the future it may be possible to modulate pharmacological and non-pharmacological treatments for some osteoarthritic patients depending on the predictable weather conditions in order to avoid, as much as possible, the disease-associated joint pain and functional incapacity, thus improving patients' quality of life.
15552748 [Review of the protective effects of tumor necrosis factor inhibitors in rheumatoid arthri 2004 Sep Rheumatoid arthritis (RA) is a chronic in-flammatory disease with progressive joint damage, generally considered irreversible. A more aggressive therapeutic approach is promoted. Progression of joint damage, gradual functional disability and rate of mortality are lowered by disease modifying antirheumatic drugs (DMARD). Among these, we discuss the relative role of TNF inhibitors and their efficacy on preventing radiographic progression of joint damage. We also touch on the notion of a therapeutic window of opportunity early in the course of RA, as early initiation of aggressive treatment seems to provide a sustained benefit on radiographic progression.
12404036 [Sonographic findings for synovial fluid]. 2002 Jul OBJECTIVE: The aim of this pictorial essay was to evaluate the sonographic features of synovial fluid in patients with arthritis. METHODS: Sixty-nine patients with active synovitis (rheumatoid arthritis, psoriatic arthritis, osteoarthritis, septic arthritis, crystal arthropathies, post-traumatic arthritis) were studied. Sonographic evaluation was performed with a AU-5 Harmonic, Esaote Biomedica (Genoa, Italy) equipped with a 10-14 MHz broadband linear transducer and a Diasus Dynamic Imaging Ltd.(Livingston, Scotland UK) equipped with a 8-16 MHz broadband linear transducer. RESULTS: Six main different sonographic patterns were detected: 1) Anechoic: increased amount of homogeneous anechoic synovial fluid (exudative synovitis). 2) Cloudy: echogenic structures (proteinaceous material). 3) Mixed: anechoic synovial fluid and proteinaceous material. 4) "Snow-storm" aspect: multiple mildly and heterogeneous echoic spots (9 out of 10 patients with acute gouty synovitis). 5) Dotted: multiple sparkling hyperechoic dots without posterior acoustic shadow (10 out of 12 patient with chondrocalcinosis). 6) Granular: irregular turbid aspect of the synovial fluid. It was present in 3 patient with septic arthritis. CONCLUSIONS: The results of this study indicate that high resolution ultrasonography is able to detect different features of synovial fluid. Further studies are needed to assess both sensitivity and specificity of ultrasonography in "in vivo" synovial fluid examination.
12704443 Biomolecular cytokine therapy. 2003 As for the chronicity of inflammatory-immune diseases, the medication of them needs to be longterm and thus, quite safe with respect to side effects due to drug actions. Therapy of these diseases includes steroid and non steroid anti-inflammatories given in monotherapy or in combination with cytotoxic antimetabolites. Longterm administration of these active substances cumulate in side effects, not to speak of the probability of developing unresponsiveness to the drug in use. In principle, the earlier the intervention, the better the outcome of medication in therapy. In harmony with this principle, biopharmacology focuses on specific targets in early (acute) phase of inflammatory-immune diseases. One of these targets is the proinflammatory cascade of cytokines (IL1beta, IL6, IL8, IL12, TNFalpha). Among them, the overproduction of tumor necrosis factor (TNFalpha) is suggested to orchestrate and escalate the disease phenotype. Hence, targeting of TNFa may restrict or stop the propagation of pathological reactions. TNFalpha in its excess can be captured at transcription, translation, secretion levels as well as in the extracellular soluble form. This latter approach is supported by clinical records emphasizing the use of recombinant antibodies and soluble receptors in trapping extra amounts of TNFalpha. This review serves as an illustration for the efficacy and safety of infliximab (antibody) and etanercept (soluble receptor) in the example of rheumatoid arthritis (RA).
15743467 Microcirculation abnormalities in patients with fibromyalgia - measured by capillary micro 2005 This unblinded preliminary case-control study was done to demonstrate functional and structural changes in the microcirculation of patients with primary fibromyalgia (FM). We studied 10 women (54.0 +/- 3.7 years of age) with FM diagnosed in accordance with the classification criteria of the American College of Rheumatology, and controls in three groups (n = 10 in each group) - age-matched women who were healthy or who had rheumatoid arthritis or systemic scleroderma (SSc). All 40 subjects were tested within a 5-week period by the same investigators, using two noninvasive methods, laser fluxmetry and capillary microscopy. The FM patients were compared with the healthy controls (negative controls) and with rheumatoid arthritis patients and SSc patients (positive controls). FM patients had fewer capillaries in the nail fold (P < 0.001) and significantly more capillary dilatations (P < 0.05) and irregular formations (P < 0.01) than the healthy controls. Interestingly, the peripheral blood flow in FM patients was much less (P < 0.001) than in healthy controls but did not differ from that of SSc patients (P = 0.73). The data suggest that functional disturbances of microcirculation are present in FM patients and that morphological abnormalities may also influence their microcirculation.
12074690 Clinical pharmacokinetics of leflunomide. 2002 Leflunomide is the first disease-modifying antirheumatic drug to be approved for rheumatoid arthritis in the past 10 years. Orally administered leflunomide is almost completely converted into its active metabolite A77 1726 (hereafter referred to as M1). M1 displays linear pharmacokinetics at the dosages of leflunomide used in clinical practice. It has a long elimination half-life (approximately 2 weeks), reaching a steady state after approximately 20 weeks. M1 is highly bound to plasma proteins. The pharmacokinetics of M1 are not affected by food intake, and dosage requirements are not influenced by age or gender. Approximately 90% of a single dose of leflunomide is eliminated, 43% in urine, primarily as leflunomide glucuronides and an oxalinic acid derivative of M1, and 48% in faeces, primarily as M1. Elimination can be dramatically increased by using charcoal or cholestyramine. In vitro studies have shown no major influence of leflunomide on the metabolism of analgesics, nonsteroidal anti-inflammatory drugs and methotrexate, drugs usually used in the treatment of rheumatoid arthritis. In clinical studies with a limited number of patients using these drugs concomitantly, no safety problems appeared. Nonspecific inducers of cytochrome P450 (CYP) and some drugs metabolised by CYP2C9 affect the metabolism of M1, and caution should be used in patients cotreated with them. Additional in vitro and in vivo pharmacokinetic studies are needed to better understand the nonenzymatic and enzymatic metabolism of leflunomide. Additional clinical trials should be performed in order to find new indications for leflunomide in other autoimmune diseases, and new combination therapeutic strategies in rheumatoid arthritis. This review is a summary of current knowledge of the pharmacokinetics of leflunomide, focusing primarily on humans and in particular on patients with rheumatoid arthritis.
15026562 Lichenoid drug eruption probably associated with rofecoxib. 2004 May OBJECTIVE: To report a case of lichenoid drug eruption (LDE) probably induced by rofecoxib. CASE SUMMARY: A 73-year-old woman was prescribed rofecoxib 25 mg/day for rheumatoid arthritis in addition to other medications on which the patient had been stabilized. Six months after initiation of rofecoxib, linear plaques over the infra-orbital and bitemporal areas of both eyes were observed. Several itchy violaceous papules also developed on her right wrist and dorsum of the left foot. She also had a hyperpigmented macule on her right buccal mucosa. As the skin rash was localized and the patient was initially unwilling to undergo skin biopsy, rofecoxib was continued and a topical steroid was started. One month later, the patient was seen in the dermatology clinic, and the improvement of her skin reaction was significant. A skin biopsy performed during this visit was consistent with LDE. On the next day, her rheumatologist decided to discontinue the offending drug, rofecoxib. Two months later, all skin lesions had completely resolved. No rechallenge with rofecoxib was attempted. DISCUSSION: LDE is a rare skin reaction that can be associated with several drugs. Rofecoxib, a cyclooxygenase-2 inhibitor, has never before been reported to cause LDE. An objective causality assessment indicates that rofecoxib was the probable cause of the skin reaction. CONCLUSIONS: As of this writing, to our knowledge, this is the first case report in the English literature in which rofecoxib had led to the development of LDE.
14692306 [Effectiveness of infliximab in patients with inflammatory arthritis refractory to convent 2003 Oct BACKGROUND: Tumor necrosis factor antagonists are useful in the treatment of several chronic inflammatory immune mediated diseases. AIM: To assess the effects of infliximab in 21 patients with inflammatory arthropaties, refractary to conventional treatment. PATIENTS AND METHODS: Eleven patients with rheumatoid arthritis, seven with psoriatic arthritis and three with spondyloarthritis were treated. The mean duration of the diseases was 10 years. Infliximab was administered intravenously in a dose of 3 mg/kg body weight. A median of 6 doses in 8 months was administered. Effectiveness was assessed in 19 patients that received three or more doses. RESULTS: Infliximab was effective in 16 patients (10 with rheumatoid arthritis, four with psoriasis and two with spondyloarthritis) and ineffective in three. In responsive patients, a reduction in the number of inflammed joints and morning stiffness and an improvement in functional capacity was observed. Fifteen of the 16 patients perceived an improvement in their health status. This answer was concordant with concomitant medical evaluation in 15. Patients that maintained the treatment felt very well, well or regular, whereas five of six patients that discontinued the treatment felt ill. Thirteen patients had adverse effects. Treatment was discontinued in two patients due to drug induced lupus, allergy in 2, hypertension in one, high costs in three and lack of response in three. CONCLUSIONS: Infliximab reduced arthritic activity in 16 of 19 patients with severe treatment refractary arthritis.
14688072 Identification and characterization of a novel spliced variant that encodes human soluble 2004 Jan Tumor necrosis factor (TNF)-alpha is a pleiotropic cytokine involved in a broad spectrum of inflammatory and immune responses including proliferation, differentiation and cell death induction in several cell types. The biological effects of TNF-alpha are mediated via the cell-surface TNF receptors TNFR1 and TNFR2. Soluble forms of these two receptors, which contain the extracellular ectodomains, are proteolytically cleaved from the membrane. High levels of soluble (s) TNFR2 in serum have been documented in multiple inflammatory pathologies. We describe here a new differential spliced isoform of human TNFR2 missing exons 7 and 8, DS-TNFR2(Delta7,8). This novel isoform lacks the transmembrane and cytoplasmic domains. Expression studies with DS-TNFR2(Delta7,8) cDNA transiently transfected COS cells showed that it encodes a sTNFR2 receptor of approximately 42 kDa. Soluble DS-TNFR2(Delta7,8) blocked TNF-alpha-induced apoptosis, which suggests that it regulates TNF-alpha function by antagonizing its biological activity. An ELISA was developed that quantifies sTNFR2 generated by alternative splicing. Our data show that sTNFR2 generated by alternative splicing can be found in sera of healthy individuals, at increased levels in patients with sepsis and at high concentrations in rheumatoid arthritis patients.
12371064 Tumour necrosis factor blocking agents: a new therapeutic modality for inflammatory disord 2002 Development of anti-tumour necrosis factor-alpha (anti-TNF alpha) treatment offers the potential to alter radically the course of inflammatory diseases such as rheumatoid arthritis and Crohn's disease using modalities directed against a specific inflammatory mediator. Controlled randomised trials in these diseases demonstrate clinical benefit associated with significant improvement in patients with severe active joint and intestinal disease, often when conventional therapies are unsuccessful. To date, anti-TNF alpha therapy has been well tolerated and shows a favourable safety profile. This review considers the nature of this therapy and current evidence of its clinical benefit and adverse effects.
12428226 Regulation of fibronectin and metalloproteinase expression by Wnt signaling in rheumatoid 2002 Nov OBJECTIVE: The enhanced release of extracellular matrix proteins by fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients is suggestive of joint remodeling. Because Wnt proteins play a critical role in joint development, we investigated whether up-regulated Wnt signaling plays a role in the enhanced synthesis of extracellular matrix proteins. The purpose of the present experiments was to determine the role of Wnt-1-like molecules in the expression of matrix proteins by RA FLS and to ascertain the effects of Wnt antagonists on RA FLS function and survival. METHODS: Transfection with a reporter plasmid (TOPflash) was performed to assess whether Wnt signaling is active in RA FLS. Wnt signaling was up-regulated in normal FLS by transfection with a Wnt-1 expression plasmid and was down-regulated in RA FLS by transfection with dominant-negative lymphoid enhancer factor 1 (LEF-1)/T cell factor 4 (TCF-4) and secreted Frizzled receptor protein 1 (sFRP-1) expression plasmids. Recombinant sFRP-1 and anti-Wnt-1 antibody were also administered to RA FLS to block Wnt signaling. RESULTS: RA FLS had constitutive activation of the canonical Wnt signaling pathway. Transfection of normal FLS with a Wnt-1 expression vector enhanced not only fibronectin, but also pro-matrix metalloproteinase 3 (proMMP-3) expression. In a complementary manner, interference with Wnt signaling using anti-Wnt-1 antibody, the Wnt antagonist sFRP-1, or dominant-negative vectors that inhibited the transcription factors TCF-4/LEF-1 blocked the expression of fibronectin by RA FLS and reduced cell survival. Anti-Wnt-1 antibody and sFRP-1 also blocked the expression of proMMP-3. CONCLUSION: Our results indicate that the canonical Wnt pathway regulates fibronectin and metalloproteinase expression in RA FLS.
15457443 Dense genome-wide linkage analysis of rheumatoid arthritis, including covariates. 2004 Sep OBJECTIVE: Rheumatoid arthritis (RA) is a heterogeneous disease that exhibits a complex genetic component. Previous RA genome scans confirmed the involvement of the HLA region and generated data on suggestive signals at non-HLA regions, albeit with few overlaps in findings between studies. The present study was undertaken to detect potential RA gene regions and to estimate the number of true RA gene regions, taking into account the heterogeneity of RA, through performance of a dense genome scan. METHODS: In a study of 88 French Caucasian families (105 RA sibpairs), 1,088 microsatellite markers were genotyped (3.3-cM genome scan), and a multipoint model-free linkage analysis was performed. The statistical assessment of the results relied on 10,000 computer simulations. A covariate-based multipoint model-free linkage analysis was performed on the locations of regions with suggestive evidence for linkage. RESULTS: Involvement of the HLA region was strongly confirmed (P = 6 x 10(-5)), and 19 non-HLA regions showed suggestive evidence for linkage (P < 0.05); 9 of these overlapped with regions suggested in other published RA genome scans. A routine 12-cM genome scan with the same families would have detected only 7 of the 19 regions, including only 4 of the 9 overlapping regions. From the 10,000 computer simulations, we estimated that 8 +/- 4 regions (mean +/- SD) were true-positives. RA covariate-based analysis provided additional linkage evidence for 3 regions, with age at disease onset, erosions, and HLA-DRB1 shared epitope as covariates. CONCLUSION: The results of this study provide evidence of 19 non-HLA RA gene regions, with an estimate of 8 +/- 4 as true-positives, and provide additional evidence for 3 regions from covariate-based analysis.
15335295 Considerations with the use of biological therapy in the treatment of rheumatoid arthritis 2004 Sep The treatment of rheumatoid arthritis (RA) has changed dramatically over the past 15 years with the realisation that earlier, aggressive therapy limits progression. There is evidence that biological response modifiers (BRMs), which target specific cytokines such as TNF-alpha and IL-1, are more effective than traditional disease-modifying antirheumatic drugs (DMARDs), especially in combination with methotrexate. Four therapies are approved for use in RA; three target TNF-alpha (etanercept [Enbrel, Amgen Inc.], infliximab [Remicade, Centocor Inc.], and adalimumab [Humira, Abbott]), and one targets IL-1 (anakinra [Kineret, Amgen Inc.]). It is clear from both the clinical trials and postmarketing reports that all four agents have a different safety profile compared with traditional DMARDs. There are several areas of concern with the use of the BRMs, which include serious and opportunistic infections, malignancy/lymphoma, congestive heart failure, demyelination, injection/infusion reactions, development of autoantibodies and lupus-like disease. It is important to be fully aware of the safety profile and differences between BRMs in order to use them appropriately.
12669475 Technology evaluation: ISIS-104838, OraSense. 2003 Feb OraSense Ltd (a joint venture between Isis Pharmaceuticals Inc and Elan Corp) is developing ISIS-104838, an antisense oligonucleotide specific for TNF alpha mRNA, as an inhibitor of TNF alpha synthesis. The compound is being developed for the potential treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease and psoriasis. This antisense oligonucleotide is currently undergoing phase II clinical trials for RA and Crohn's disease.
15496955 DNA microarray allows molecular profiling of rheumatoid arthritis and identification of pa 2004 Dec This study was undertaken to evaluate the possibility to obtain a molecular signature of rheumatoid arthritis (RA) comparatively osteoarthritis (OA), and to lay the bases to develop new diagnostic tools and identify new targets. Microarray technology was used for such an analysis. The gene expression profiles of synovial tissues from patients with confirmed RA, and patients with OA were established and compared. A set of 63 genes was selected, based, more specifically, on their overexpression or underexpression in RA samples compared to OA. Results for six of these genes have been verified by quantitative PCR using both samples identical to those used in the microarray experiments and entirely separate samples. Expression profile of the 48 known genes allowed the correct classification of additional RA and OA patients. Furthermore, the distinct expression of three of the selected genes was also studied by quantitative RT-PCR in cultured synovial cells. Detailed analysis of the expression profile of the selected genes provided evidence for dysregulated biological pathways, pointed out to chromosomal location and revealed novel genes potentially involved in RA. It is proposed that such an approach allows valuable diagnosis/prognostics tools in RA to be established and potential targets for combating the disease to be identified.
14530646 MR evaluation of radiation synovectomy of the knee by means of intra-articular injection o 2003 Jul OBJECTIVE: To determine whether MRI is able to demonstrate the effect of radiation synovectomy after the intra-articular injection of holmium-166-chitosan complex for the treatment of rheumatoid arthritis of the knee. MATERIALS AND METHODS: Fourteen patients aged 36-59 years were treated with 10-20 mCi of holmium-166-chitosan complex. A criterion for inclusion in this study was the absence of observable improvement after 3- or more months of treatment of the knee with disease-modifying anti-rheumatic drugs. MR images were acquired both prior to and 4-months after treatment. Clinical evaluation included the use of visual analog scales to assess pain, and the circumference of the knee and its range of motion were also determined. MR evaluation included measurement of the volume of synovial enhancement and wall thickness, the amount of joint effusion, and quantifiable scoring of bone erosion, bone edema and lymph nodes. RESULTS: Visual analog scale readings decreased significantly after radiation synovectomy (p < 0.05). MRI showed that joint effusion decreased significantly (p < 0.05), and that the volume of synovial enhancement tended to decrease, but to an insignificant extent (p = 0.107). CONCLUSION: The decreased joint effusion noted at 4-month follow-up resulted from radiation synovectomy of the rheumatoid knee by means of intra-articular injection of holmium-166-chitosan complex.
15198192 A case of legionellosis during treatment with a TNFalpha antagonist. 2004 We report a patient with Legionella pneumophila pneumonia after infliximab therapy for rheumatoid arthritis. Arguments are discussed for an emerging incidence of infections with intracellular microorganisms, granulomatous and non-granulomatous, in patients having received anti-TNFalpha therapy. These discussions consist of clinical and epidemiological data, experimental data in animals, theoretical evidence, and we provide a possible pathogenetic mechanism.
11817611 Association of familial and sporadic rheumatoid arthritis with a single corticotropin-rele 2002 Jan OBJECTIVE: Rheumatoid arthritis (RA) is a common disabling autoimmune disease with a complex genetic component. We have previously described linkage of a region of chromosome 8q12.3 with RA and association of the microsatellite marker CRHRA1 with RA in 295 affected sibling-pair families. In the current study we aimed to physically link the RA-associated marker with the corticotropin-releasing hormone (CRH) candidate gene, and to examine the genomic region for additional short tandem repeat (STR) genetic markers in order to clarify the association with RA. METHODS: We examined the association of 2 STR markers with disease in the original 295 multicase families and in a cohort of 131 simplex families to refine our understanding of this genetic region in disease susceptibility in sporadic and familial RA. Genomic library screening and sequencing were used to generate physical sequences in the CRH genomic region. Bioinformatic analysis of the sequence flanking the CRH structural gene was used to screen for additional STRs and other genetic features. Genotyping was carried out using a standard fluorescence approach. Estimations of haplotype frequencies were performed to assess linkage disequilibrium. The transmission disequilibrium test was performed using TRANSMIT. RESULTS: Physical cloning and sequencing analyses identified the genomic region linking the CRHRA1 marker and the CRH structural locus. Moreover, we identified a further STR, CRHRA2, which was in strong linkage disequilibrium with CRHRA1 (P = 4.0 x 10(-14)). A haplotype, CRHRA1*10;CRHRA2*14, was preferentially carried by unaffected parents at a frequency of 8.6% compared with the expected frequency of 3.1%. This haplotype was overtransmitted in the multiply affected families (P = 0.0077) and, similarly, in the simplex families (P = 0.024). Combined analysis of both family cohorts confirmed significant evidence for linkage (P = 4.9 x 10(-4)) and association (P = 5.5 x 10(-3)) for this haplotype with RA. CONCLUSION: In demonstrating significant linkage disequilibrium between these 2 markers, we have refined the disease-associated region to a single haplotype and confirmed the significance of this region in our understanding of the genetics of RA.