Joint Destruction In Patients Research Articles

Progression of joint destruction in patients with rheumatoid arthritis

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Class effects of tyrosine kinase inhibitors on osteoclastogenesis in vitro

Background/objectivesBone destruction in rheumatoid arthritis (RA) is mediated by osteoclasts (OCs). Imatinib, a tyrosine kinase inhibitor (TKI), has been shown to exert an inhibitory effect on osteoclastogenesis. The aim of...

Analysis of Joint Destruction in Patients with Rheumatoid Arthritis Treated with Infliximab

Analysis of Joint Destruction in Patients with Rheumatoid Arthritis Treated with Infliximab

Rheumatoid cachexia and cardiovascular disease

Both cachexia and cardiovascular disease are strongly associated with rheumatoid arthritis (RA) and linked to the chronic inflammatory process. Typically, rheumatoid cachexia occurs in individuals with normal or increased BMI (reduced muscle mass and increased fat mass). Classic cachexia (reduced muscle mass and reduced fat mass) is rare in RA but is associated with high inflammatory activity and aggressive joint destruction in patients with a poor cardiovascular prognosis. Conversely, obesity is linked to hypertension and dyslipidemia but, paradoxically, lower RA disease activity and less cardiovascular disease-related mortality. Rheumatoid cachexia might represent the 'worst of both worlds' with respect to cardiovascular outcome, but until diagnostic criteria for this condition are agreed upon, its effect on cardiovascular disease risk remains controversial.

Immunologic rheumatic disorders

We provide the basics for clinicians who might be called on to consider the diagnosis of diseases such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) in their practice. We will emphasize clinical recognition and first-line laboratory testing. Only characteristics of the classic rheumatic inflammatory diseases (ie, RA, seronegative spondyloarthropathy, SLE, antiphospholipid syndrome, Sjögren syndrome, scleroderma, and polymyositis/dermatomyositis) will be covered. In the past decade, treatment for RA and seronegative spondyloarthropathy has substantially improved. Their treatment has been revolutionized by the use of methotrexate and, more recently, TNF inhibitors, T-cell costimulation modulators, and B-cell depletion. The goal of RA treatment today is to induce a complete remission as early as possible in the disease process, with the mantra being "elimination of synovitis equals elimination of joint destruction." The hope is that if the major mediators of Sjögren syndrome, SLE, or scleroderma can be identified and then blocked, as in the example of TNF inhibitors in patients with RA, more specific treatments will become available. Thus RA has become an excellent model of this evolving paradigm. Through the identification of major mediators in its pathogenesis, novel and highly efficacious therapeutic agents have been developed.

Radiographic measurements in the evaluation and classification of elbow joint destruction in patients with rheumatoid arthritis

We developed two new radiographic parameters-the humeral surface height ratio and ulnar surface height ratio-to precisely detect changes in the bony structure of rheumatoid elbows. Of the 59 patients with rheumatoid arthritis, 101 elbows were classified into four types (osteoarthritis, ankylosis, erosive, and resorptive) according to the radiographic appearance. Clinically, osteoarthritis type and ankylosis type were considered to be stable form, and erosive type and resorptive type were unstable form. Patients' clinical data and yearly radiographic changes in the bony structure evaluated by the humeral surface height ratio and ulnar surface height ratio were compared among the four types and between the two forms. There were significant differences between the two forms and among the three types except for the ankylosis type in yearly radiographic changes in the bony structure evaluated by the humeral surface height ratio and ulnar surface height ratio. Stable and unstable forms were distinguished by a cut-off point of 0.65 and 2.58 in yearly radiographic changes in the bony structure evaluated by the humeral surface height ratio and the ulnar surface height ratio, respectively. These parameters might be useful for monitoring the structural changes of the elbow joint in rheumatoid arthritis.

Gait changes precede overt arthritis and strongly correlate with symptoms and histopathological events in pristane-induced arthritis

IntroductionPristane-induced arthritis (PIA) in the rat has been described as an animal model of inflammatory arthritis which exhibits features similar to rheumatoid arthritis in humans, such as a chronic, destructive, and symmetrical involvement of peripheral joints. However, so far little is known about the earliest inflammatory events and their influence on locomotor behaviour during the course of PIA. To investigate this issue a detailed analysis of the pathologic changes occurring during the prodromal and early stages of PIA was performed.MethodsArthritis was induced in DA.rats by injection of 150 μl 2,6,10,4-tetramethyl-pentadecane (pristane) at the base of the tail and changes in locomotor behaviour of the affected paws were monitored using the CatWalk quantitative gait analysis system. The pathologic events occurring in the joints of pristane-injected animals were studied before onset, at onset, and during acute phase of arthritis by histological methods.ResultsGait analysis revealed that changes in locomotion such as reduced paw print areas and stance phase time are already apparent before the onset of clinically discernible arthritis symptoms (erythema, paw swelling) and correlate with PIA scores. In agreement with these findings, inflammatory tenosynovitis could be observed by histology already before the onset of erythema and swelling of the respective paws. In the most heavily affected rats also irregularities in step sequence patterns occurred A kinetic analysis of clinical and histological findings demonstrated that gait changes precede the pathological changes occurring during the acute phase of pristane-induced arthritis.ConclusionsGait analysis allows for pinpointing the initial inflammatory changes in experimental arthritis models such as pristane-induced arthritis. Analysis of early clinically relevant symptoms in arthritis models may facilitate the search for novel therapeutics to interfere with pain, inflammation and joint destruction in patients suffering from inflammatory arthritis.

A critical role of Cyr61 in interleukin‐17–dependent proliferation of fibroblast‐like synoviocytes in rheumatoid arthritis

Fibroblast-like synoviocytes (FLS) are a major component of the hyperplastic synovial pannus that aggressively invades cartilage and bone during the course of rheumatoid arthritis (RA). Cyr61 (CCN1) is a product of a growth factor-inducible immediate early gene and is involved in cell adhesion, proliferation, and differentiation. However, the role that Cyr61 plays in FLS proliferation has remained undetermined. The aim of this study was to identify the role of Cyr61 in regulating the proliferation of FLS derived from patients with RA. Expression of Cyr61 in synovial tissue (ST) and in FLS was determined simultaneously using immunohistochemistry, real-time polymerase chain reaction, and Western blotting. Cyr61 levels in synovial fluid (SF) were determined by enzyme-linked immunosorbent assay. FLS proliferation stimulated by SF, Cyr61, and interleukin-17 (IL-17) was measured by thymidine incorporation. Activation of signal transduction pathways was determined by Western blotting and confocal microscopy. Cyr61 was overexpressed in ST, FLS, and SF samples from RA patients as compared with samples from normal controls. Elevated levels of Cyr61 in RA SF promoted the proliferation of FLS, an effect that was abrogated by a neutralizing monoclonal antibody against human Cyr61. Furthermore, in samples from RA patients, Cyr61 was found to protect FLS from apoptosis and to sustain the expression of Bcl-2 in FLS. Most importantly, the expression of Cyr61 in FLS was regulated by IL-17 mainly via the p38 MAPK and NF-kappaB signaling pathways. Knockdown of expression of the Cyr61 gene inhibited IL-17-stimulated FLS proliferation. Our findings indicate that Cyr61 plays a critical role in IL-17-mediated proliferation of FLS in RA and likely contributes to hyperplasia of synovial lining cells and eventually to joint destruction in patients with RA.

Association of a single‐nucleotide polymorphism in CD40 with the rate of joint destruction in rheumatoid arthritis

The severity of joint destruction in rheumatoid arthritis (RA) is highly variable from patient to patient and is influenced by genetic factors. Genome-wide association studies have enormously boosted the field of the genetics of RA susceptibility, but risk loci for RA severity remain poorly defined. A recent meta-analysis of genome-wide association studies identified 6 genetic regions for susceptibility to autoantibody-positive RA: CD40, KIF5A/PIP4K2C, CDK6, CCL21, PRKCQ, and MMEL1/TNFRSF14. The purpose of this study was to investigate whether these newly described genetic regions are associated with the rate of joint destruction. RA patients enrolled in the Leiden Early Arthritis Clinic were studied (n=563). Yearly radiographs were scored using the Sharp/van der Heijde method (median followup 5 years; maximum followup 9 years). The rate of joint destruction between genotype groups was compared using a linear mixed model, correcting for age, sex, and treatment strategies. A total of 393 anti-citrullinated protein antibody (ACPA)-positive RA patients from the North American Rheumatoid Arthritis Consortium (NARAC) who had radiographic data available were used for the replication study. The TT and CC/CG genotypes of 2 single-nucleotide polymorphisms, rs4810485 (CD40) and rs42041 (CDK6), respectively, were associated with a higher rate of joint destruction in ACPA-positive RA patients (P=0.003 and P=0.012, respectively), with rs4810485 being significant after Bonferroni correction for multiple testing. The association of the CD40 minor allele with the rate of radiographic progression was replicated in the NARAC cohort (P=0.021). A polymorphism in the CD40 locus is associated with the rate of joint destruction in patients with ACPA-positive RA. Our findings provide one of the first non-HLA-related genetic severity factors that has been replicated.

Effect of the oral application of a highly selective MMP-13 inhibitor in three different animal models of rheumatoid arthritis

ObjectiveTo evaluate the decrease of cartilage destruction by a novel orally active and specific matrix metalloproteinase 13 (MMP-13) inhibitor in three different animal models of rheumatoid arthritis (RA).Materials and methodsThe...

A combination of biochemical markers of cartilage and bone turnover, radiographic damage and body mass index to predict the progression of joint destruction in patients with rheumatoid arthritis treated with disease-modifying anti-rheumatic drugs

The aim of this study was to evaluate the predictive value of biological, radiological and clinical parameters for the progression of radiographic joint damage in rheumatoid arthritis (RA) patients treated with conventional disease-modifying anti-rheumatic drugs (DMARDs). We analyzed the 145 patients with active RA for less than 5 years who were participating in the prospective 1-year randomized controlled trial of tocilizumab (SAMURAI trial) as a control arm treated with conventional DMARDs. Progression of joint damage was assessed by sequential radiographs read by two independent blinded X-ray readers and scored for bone erosion and joint space narrowing (JSN) using the van der Heijde-modified Sharp method. Multivariate analysis revealed that increased urinary levels of C-terminal crosslinked telopeptide of type II collagen (U-CTX-II), an increased urinary total pyridinoline/total deoxypyridinoline (U-PYD/DPD) ratio and low body mass index (BMI) at baseline were independently associated with a higher risk for progression of bone erosion. In addition to these three variables, the JSN score at baseline was also significantly associated with an increased risk of progression of the JSN score and total Sharp score. High baseline U-CTX-II levels, U-PYD/DPD ratio and JSN score and a low BMI are independent predictive markers for the radiographically evident joint damage in patients with RA treated with conventional DMARDs.

A combination of biochemical markers of cartilage and bone turnover, radiographic damage and body mass index to predict the progression of joint destruction in patients with rheumatoid arthritis treated with disease-modifying anti-rheumatic drugs

The aim of this study was to evaluate the predictive value of biological, radiological and clinical parameters for the progression of radiographic joint damage in rheumatoid arthritis (RA) patients treated with conventional disease-modifying anti-rheumatic drugs (DMARDs). We analyzed the 145 patients with active RA for less than 5 years who were participating in the prospective 1-year randomized controlled trial of tocilizumab (SAMURAI trial) as a control arm treated with conventional DMARDs. Progression of joint damage was assessed by sequential radiographs read by two independent blinded X-ray readers and scored for bone erosion and joint space narrowing (JSN) using the van der Heijde-modified Sharp method. Multivariate analysis revealed that increased urinary levels of C-terminal crosslinked telopeptide of type II collagen (U-CTX-II), an increased urinary total pyridinoline/total deoxypyridinoline (U-PYD/DPD) ratio and low body mass index (BMI) at baseline were independently associated with a higher risk for progression of bone erosion. In addition to these three variables, the JSN score at baseline was also significantly associated with an increased risk of progression of the JSN score and total Sharp score. High baseline U-CTX-II levels, U-PYD/DPD ratio and JSN score and a low BMI are independent predictive markers for the radiographically evident joint damage in patients with RA treated with conventional DMARDs.

Rx for the Pharmaceutical Industry: Call Your Doctors

Pharmaceutical companies are guilty of moral misconduct. They stretch the definitions of illnesses, such as bipolar disorder, in order to expand markets. (1) They sponsor seeding studies, such as Merck's ADVANTAGE trial (Assessment of Differences between Vioxx and Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness), in order to facilitate the rapid uptake of a new drug at the time of its launch. (2) They promote unapproved uses of drugs, such as Lilly's Viva Zyprexa campaign, in which sales representatives recommended the drug for dementia. (3) These activities all aim to maximize sales. Yet drug companies have translated scientific discoveries into products that have improved and extended the lives of millions of people. For example, statins prolong survival in patients with coronary artery disease, (4) tumor necrosis factor inhibitors retard joint destruction in patients with rheumatoid arthritis, (5) and imatinib induces remission in most patients with chronic myeloid leukemia. (6) Sometimes alone and sometimes in collaboration with investigators from academia or government, the pharmaceutical industry has helped people live longer, better lives. Drug companies are also a source of crucial research funding. The U.S. pharmaceutical industry invested $47.9 billion in research and development in 2007. (7) If the current level of productivity and investment from the private sector is to continue without repeating the pitfalls of the past, we must collaborate with industry to find better ways of ensuring ethical drug development. Multiple changes will be necessary to achieve this end. External reforms so far have come from the government, (8) academia, (9) and journal editors. (10) Internal ethics initiatives have also been introduced at several companies. (11) For example, Roche established an external Science and Ethics Advisory Group. (12) Merck and Abbott have established ethics offices. (13) GlaxoSmithKline, Lilly, Merck, and Abbott maintain confidential helplines that employees may call to report potential violations. (14) The industry deserves credit for taking these steps. Whether they actually have a positive impact or serve simply as window-dressing intended to disarm critics remains to be seen. What else can be done to bridge the gap between the industry's key role in producing important products and the parade of unethical actions that plague it? As a physician and a former vice-president of Pfizer, I believe that a previously unrecognized way of addressing the problem may already exist inside the pharmaceutical industry itself, in the form of the physicians who work there. In order for industry physicians to ensure ethical behavior, it is necessary that they: 1) make decisions about ethical issues; 2) acknowledge they have a moral duty to ensure that their company behaves ethically; 3) possess the knowledge and skills required to perform their jobs; 4) have the responsibility and the incentive to conduct clinical research ethically, rather than just to increase revenue; and 5) work in a culture that recognizes and supports their expertise and their role. Roles and Obligations of Physicians in Industry Approximately eighty-six thousand medical and scientific professionals work in drug companies in the United States. (15) Pharmaceutical physicians are deployed throughout the industry in many positions--as bench researchers, focusing on the discovery of new drugs; as clinical researchers, designing, implementing, and overseeing phase I--IV trials; and as safety experts, focusing on pharmacovigilance, which refers to monitoring the side effects of a drug. Others compile medical information, review promotional materials, create speakers bureaus, and review independent medical grants. Many work with marketers and other colleagues to create product development plans, launch new products, and implement strategies to support approved compounds. Given the diversity of jobs carried out by physicians in industry, it is not surprising that they participate in making many ethically laden decisions, ranging from the selection of disease targets to the proper conduct of trials in the third world to the monitoring and management of potential safety issues. …

Rheumatoid Arthritis and Fibromyalgia: A Frequent Unrelated Association Complicating Disease Management

To assess the value of the 28-joint Disease Activity Score (DAS28) in evaluating disease activity in rheumatoid arthritis (RA) associated with fibromyalgia (FM). In this situation, because of the weight of the subjective measures included in the DAS28 equation, the patient's status may be overestimated, leading to inappropriate treatment. We analyze the relationship between RA and FM and discuss whether the association is random or a marker of poor prognosis. A questionnaire, developed when biologic therapies were introduced, was administered and the results analyzed in a consecutive, female outpatient population including 105 patients with RA, 49 with RA and FM (RAF), and 28 with FM. Psychosocial characteristics, disease presentation, and radiographic joint destruction evaluation were compared in the 3 populations. The presentation of RA was the same in patients with RA and RAF, but the 2 populations differed by socioprofessional characteristics, significantly higher disease activity in patients with RAF, and significantly more severe joint destruction in patients with RA. The RAF group was similar to the FM control population in socioprofessional and some physical characteristics. Regression analysis using the DAS28 measures differed significantly in the weight allowed to 28-joint counts for pain and swelling, but the constant factor was higher in patients with RAF. DAS28 overestimated objective RA severity in patients who also had FM. The association between RA and FM does not appear to be a marker of worse prognosis, but rather a fortuitous association between the 2 diseases and one that may afford these patients some protection against joint destruction.

Inhibition of IL-1β-mediated inflammatory responses by the IκBα super-repressor in human fibroblast-like synoviocytes

The IL-1β-NF-κB axis is a key pathway in the pathogenesis of rheumatoid arthritis (RA) and is central in the production of proinflammatory mediators in the inflamed synovium. Therefore, we examined whether fibroblast-like synoviocytes (FLS) could be spared from IL-1β-induced toxicity by an overexpressing IκB super-repressor. Infection of FLS with Ad-IκBα (S32A, S36A), an adenovirus-containing mutant IκBα, inhibited IL-1β-induced nuclear translocation and DNA binding of NF-κB. In addition, Ad-IκBα (S32A, S36A) prevented IL-1β-induced inflammatory responses; namely, the production of chemokines, such as ENA-78 and RANTES, and activation of MMP-1 and MMP-3. Finally, increased cellular proliferation of FLS after IL-1β treatment was significantly reduced by Ad-IκBα (S32A, S36A). However, Ad-IκBβ (S19A, S23A), the IκBβ mutant, was not effective in preventing IL-1β toxicity. These results suggest that inhibition of IκBα degradation is a potential target for the prevention of joint destruction in patients with RA.

Adverse effects of low-dose glucocorticoids and DMARD therapy in patients with RA—a complex relationship?

Although low-dose glucocorticoids, in conjunction with DMARDs, are known to halt or severely retard the erosive destruction of joints in patients with early rheumatoid arthritis (RA), the potential adverse effects of low-dose glucocorticoids and the benefit:risk ratio of treatment are a concern for many clinicians. Malysheva and colleagues undertook a retrospective, open-label review of the incidence and severity of adverse effects associated with DMARD treatment with or without glucocorticoids in patients with RA. Their results suggest that low-dose glucocorticoids actually help to postpone the occurrence of adverse effects caused by most standard DMARDs, which, if translated into a delay before biologic agents were required, would provide a substantial cost saving. Unfortunately, an increased incidence of adverse reactions was noted for glucocorticoid-treated patients compared with those patients on monotherapy; however, the undesirable effects were mostly mild in nature. This study sheds new light on the relative risks and benefits of low-dose glucocorticoid therapy in RA and adds further weight to the arguments for its appropriate use in early disease.

Guggulsterone blocks IL-1β-mediated inflammatory responses by suppressing NF-κB activation in fibroblast-like synoviocytes

Guggulsterone is a plant sterol that is used to treat hyperlipidemia, arthritis, and obesity. Although its anti-inflammatory and anti-hyperlipidemic effects have been well documented, the effect of guggulsterone on fibroblast-like synoviocytes (FLS) has not yet been reported. Therefore, in this study, the effect of guggulsterone on interleukin (IL)-1β-induced inflammatory responses in the FLS of rheumatic patients was investigated. Treatment of FLS with IL-1β induced production of chemokines such as RANTES and ENA-78. In addition, Western blot analysis and gelatin zymography revealed that IL-1β activated matrix metalloproteinase (MMP)-1 and -3 in FLS. However, pre-incubation with guggulsterone completely inhibited the ability of IL-1β to induce the production of chemokines and to activate MMPs. Although the NF-κB binding activity and nuclear p50 and p65 subunit levels, as well as IκBα degradation in the cytoplasm was greater in cells stimulated with IL-1β than in unstimulated cells, treatment with guggulsterone abolished all of these increases. Collectively, these results suggest that guggulsterone would be useful as an inhibitor of joint destruction in patients with rheumatoid arthritis.

Antibodies to citrullinated peptides are not associated with the rate of joint destruction in patients with a well-established diagnosis of rheumatoid arthritis

Antibodies to citrullinated peptides are highly specific for rheumatoid arthritis (RA) and represent a significant risk factor for undifferentiated polyarthritis. This prognostic ability may be related to the very diagnostic performance of these autoantibodies, since RA is a more erosive disease than other forms of arthritis. The present study evaluated an association of antibodies to citrullinated peptides and the rate of joint destruction in patients with a well-established diagnosis of RA. Seventy-one patients with RA were evaluated in 1994 and again in 2002 (functional class, joint count, Health Assessment Questionnaire score, hands X-ray). Autoantibodies (rheumatoid factor (RF), anti-perinuclear factor, anti-cyclic citrullinated peptide (CCP) antibodies) and Sharp's index were analyzed blindly. Delta Sharp was calculated as the difference in Sharp's index obtained in 1994 and 2002. During the follow-up the Health Assessment Questionnaire score increased from 0.91 +/- 0.74 to 1.39 +/- 0.72 (P < 0.001). Similarly, the number of swollen joints increased from 4.6 +/- 5.71 to 6.4 +/- 4.1 (P = 0.002). The frequency of autoantibodies and anti-CCP titer remained stable; however, serum RF concentration increased from 202.8 +/- 357.6 to 416.6 +/- 636.5 IU/mL (P = 0.003). Sharp's index increased from 56.7 +/- 62.1 to 92.4 +/- 80.9 (P < 0.001). No correlation was observed between Delta Sharp and the presence of RF, anti-perinuclear factor, and anti-CCP antibodies at baseline. Antibodies to citrullinated epitopes are specific and early markers for the diagnosis of RA but do not seem to be associated with the rate of joint destruction in patients with a well-established diagnosis of RA.

Pedography and radiographic imaging for the detection of foot deformities in rheumatoid arthritis

Background Patients with Rheumatoid Arthritis often suffer from pain and deformities in the feet. Previous studies demonstrated that pedography is a useful tool in clinical practice for detecting structural changes. Therefore, the aim of the present study was to compare Rheumatoid Arthritis patients’ clinical, radiographic and pedographic status in order to investigate the relationship between mechanical damage and plantar pressure distribution under the forefoot. Methods Sixteen right feet of sixteen patients with Rheumatoid Arthritis and 21 right feet of healthy controls were included. Weight-bearing radiographs of the forefoot were obtained for all rheumatoid feet. The grade of erosion in the forefoot was assessed with the established Larsen score. Foot loading parameters were analyzed with pedography. Findings The present study revealed no correlation between walking pain and the level of joint destruction in patients with Rheumatoid Arthritis. However, the study revealed a strong correlation between joint erosion in the lateral metatarsophalangeal joints and local pressure values under the lateral forefoot ( r = 0.85) and a negative correlation between joint erosion in the proximal interphalangeal joint and local pressure values under the lateral toes ( r = −0.64). Interpretation In patients with Rheumatoid Arthritis, the intensity of walking pain does not characterize the degree of joint destruction under the forefoot. Pedography appears useful for an early diagnosis of pathologic changes in the forefoot. However, even though pedographic measurements might be able to provide indications for destructive changes, they cannot provide information about the exact grade of joint erosion.

Associations between the PTPN22 1858C→T polymorphism and radiographic joint destruction in patients with rheumatoid arthritis: results from a 10-year longitudinal study

Objective:To investigate whether the PTPN22 1858T risk variant is associated with the rate of radiographic progression in rheumatoid arthritis (RA).Methods:A longitudinally followed cohort of 238 Norwegian patients with RA (the...