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OBJECTIVE: Although Chlamydia trachomatis-induced arthritis is among the most common rheumatic diseases having an identified infectious trigger, the pathogenesis of this arthritis is not well defined. We sought to investigate the host-microbe interactions that contribute to the severity of arthritis initiated by chlamydial infection. METHODS: We established an experimental rat model of C. trachomatis-induced arthritis that recapitulates many pathologic features of the clinical disease. The severity of the arthritis was defined using an established histopathologic scoring system. Host clearance of the pathogen and local cytokine production were examined by enzyme-linked immunosorbent assays. RESULTS: Lewis rats were susceptible to C. trachomatis-induced arthritis, whereas BN rats were relatively resistant to this disease. Significant differences in the histopathologic severity of arthritis were originally observed on day 21, and this prompted an examination of the acute phase of the arthritis. As early as day 5 after the onset of the arthritis, pathologic changes in Lewis rats were more severe than those in BN rats. An evaluation of the role of complement using cobra venom factor treatment excluded complement as being the key to differential sensitivity, because decomplementation did not eliminate the differences in arthritis severity between Lewis and BN rats. Host clearance, in contrast, was significantly different between the rat strains, with BN rats showing more prompt and effective clearance of the pathogen from both synovial tissues and spleen compared with Lewis rats. Local cytokine profiles demonstrated that host resistance was characterized by enhanced synovial expression of tumor necrosis factor alpha, interferon-gamma (IFNgamma), and interleukin-4. CONCLUSION: These studies demonstrated that cytokines thought to be proinflammatory in nature can play an important role in host defense in infection-triggered arthritis and serve to highlight the dynamic cytokine relationships that constitute effective host-pathogen interactions.
OBJECTIVE: Collagen-induced arthritis (CIA) is a model of inflammatory arthritis with many similarities to rheumatoid arthritis (RA). We previously mapped in F(2) offspring of CIA-susceptible DA and CIA-resistant F344 rats, 5 quantitative trait loci (QTLs) for which F344 alleles were associated with reduced CIA severity. In the present study, we sought to characterize the independent arthritis-modulating effects of these 5 QTLs. METHODS: CIA-regulatory regions were transferred from the F344 genome to the DA background or vice versa by repeated backcrossing. The arthritis-modulating effects of the transferred alleles were determined by comparing the severity of experimentally induced arthritis in congenic rats with that in DA rats. RESULTS: Congenic lines with either the F344 major histocompatibility complex (MHC) on the DA background or the DA MHC on the F344 background were resistant to CIA, confirming both MHC and non-MHC contributions to the genetic regulation of CIA. F344 alleles at the Cia3 and Cia5 regions of chromosomes 4 and 10 reduced CIA severity relative to that observed in DA rats. F344 Cia4 and Cia6 regions of chromosomes 7 and 8 failed to significantly alter CIA severity. Arthritis-modifying effects of Cia4 and Cia6 were, however, detected in pristane-induced and/or Freund's incomplete adjuvant oil-induced arthritis. The arthritis-modifying effects of the non-MHC CIA-regulatory loci differed in males and females. CONCLUSION: These congenic lines confirmed the existence and location of genes that regulate the severity of experimental arthritis in rats. Mechanisms responsible for the sex-specificity of individual arthritis-regulatory loci may explain some of the sex differences observed in RA and other autoimmune diseases in humans.
OBJECTIVE: The role of innate immunity in Chlamydia-induced arthritis has not been defined. The purpose of this study was to examine the role of neutrophils in experimental arthritis in mice with targeted elimination of the small GTPases Rac1 and Rac2, as well as the role of Toll-like receptors (TLRs) in this model. METHODS: Arthritis was induced by intraarticular inoculation of synoviocyte-packaged Chlamydia trachomatis. The degree of arthritis was assessed according to joint swelling and pathology scores. The persistence of Chlamydia in joints was assessed by immunoassay. The expression of TLR-2 and TLR-4 in neutrophils was detected by semiquantitative reverse transcription-polymerase chain reaction. RESULTS: In the acute phase, wild-type mice developed more severe arthritis than did Rac-deficient mice, with abundant infiltration of neutrophils into the joint. In the chronic phase, the Rac-deficient mice developed more severe arthritis and demonstrated defective clearance of the pathogen from the joint. In vitro stimulation of neutrophils with Chlamydia up-regulated the expression of TLR-4, but not TLR-2, in wild-type mice. However, neutrophils from Rac-deficient mice did not show this up-regulation of TLR-4. Sustained TLR-4 expression in neutrophils was found to be dependent on the expression of Rac. Mice genetically deficient in TLR-4 demonstrated more severe arthritis than did the controls. Thus, Rac expression plays a profound role in infection-triggered arthritis and demonstrates a bimodal influence on the disease process, exacerbating acute joint inflammation but controlling chronic arthritis. Rac deficiency was associated with diminished TLR-4 expression, impaired host clearance of the pathogen, and more severe chronic arthritis. CONCLUSION: In infection-triggered arthritis, innate immunity plays a critical role. Effective host clearance of an arthritogenic pathogen depends on intact expression of Rac and appropriate expression of TLR-4 by neutrophils.
The term 'reactive arthritis' was first used in 1969 to describe the development of sterile inflammatory arthritis as a sequel to remote infection, often in the gastrointestinal or urogenital tract. The demonstration of antigenic material (e.g. Salmonella and Yersinia lipopolysaccharide), DNA and RNA, and, in occasional cases, evidence of metabolically active Chlamydia spp. in the joints has blurred the boundary between reactive and post-infectious forms of arthritis. No validated and generally agreed diagnostic criteria exist, but the diagnosis of reactive arthritis is mainly clinical based on acute oligoarticular arthritis of larger joints that develops within 2-4 weeks of the preceding infection. In about 25% of patients, the infection can be asymptomatic. Diagnosis of the triggering infection is very helpful for the diagnosis of reactive arthritis. This is mainly achieved by isolating the triggering infection (stools, urogenital tract) by cultures (stool cultures for enteric microbes) or ligase reaction (Chlamydia trachomatis). However, after the onset of arthritis, this is less likely to be possible. Therefore, the diagnosis must rely on various serological tests to demonstrate evidence of previous infection, but, these serological tests are unfortunately not standardized. Treatment with antibiotics to cure Chlamydia infection is important, but the use of either short or prolonged courses of antibiotics in established arthritis has not been found to be effective for the cure of arthritis. The long-term outcome of reactive arthritis is usually good; however, about 25-50% of patients, depending on the triggering infections and possible new infections, subsequently develop acute arthritis. About 25% of patients proceed to chronic spondyloarthritis of varying activity.
In an effort to implicate immune responses to specific Borrelia burgdorferi proteins that may have a role in chronic Lyme arthritis, we studied the natural history of the antibody response to B. burgdorferi in serial serum samples from 25 patients monitored throughout the course of Lyme disease. In these patients, the immunoglobulin G (IgM) and IgG antibody responses to 10 recombinant B. burgdorferi proteins, determined during early infection, early arthritis, and maximal arthritis, were correlated with the severity and duration of maximal arthritis. The earliest responses were usually to outer surface protein C (OspC), P35, P37, and P41; reactivity with OspE, OspF, P39, and P93 often developed weeks later; and months to years later, 64% of patients had responses to OspA and OspB. During early infection and early arthritis, the levels of IgG antibody to P35 correlated inversely with the subsequent severity or duration of maximal arthritis. In contrast, during periods of maximal arthritis, the levels of IgG antibody to OspA and OspB, especially to a C-terminal epitope of OspA, correlated directly with the severity and duration of arthritis. Thus, the higher the IgG antibody response to P35 earlier in the infection, the milder and briefer the subsequent arthritis, whereas during maximal arthritis, the higher the IgG response to OspA and OspB, the more severe and prolonged the arthritis.
Arthritis is costly (86 billion dollars annually), highly prevalent (affecting 43 million U.S. adults), the leading cause of disability, and associated with substantial disparities in pain, activity limitations, and compromised quality of life. State-based estimates of arthritis prevalence and impact help define the burden of arthritis and provide state arthritis programs with data for program planning. This report summarizes results from the 2003 Behavioral Risk Factor Surveillance System (BRFSS) survey on state-specific prevalence of self-reported doctor-diagnosed arthritis and arthritis-attributable activity limitation in 50 states, the District of Columbia (DC), and three territories. The findings indicated that the prevalence of adults with self-reported doctor-diagnosed arthritis ranged from 17.9% to 37.2% (state median: 27.0%) and with arthritis-attributable activity limitation ranged from 6.3% to 16.7% (state median: 9.9%); the proportion of adults with arthritis-attributable activity limitation among those with self-reported doctor-diagnosed arthritis ranged from 30.1% to 49.8% (state median: 37.4%). These high rates of arthritis prevalence and activity limitation are projected to increase with the aging of the population, requiring increased intervention measures to reduce this impact.
Oral gold (auranofin) has been used in 31 patients, 20 with active rheumatoid arthritis and 11 with active psoriatic arthritis. In rheumatoid arthritis the oral gold treatment was compared to parenteral gold treatment in a patient blind trial for two years. The psoriatic arthritis cases were incorporated in an open trial. Auranofin 6 mg once daily reduced significantly the activity in rheumatoid arthritis and in psoriatic arthritis. The beneficial effect obtained with auranofin at a dose of 6 mg/day during the first year of treatment could not be maintained by 3 mg/day in the second year. Auranofin compared to parenteral gold had a distinct advantage of better systemic tolerability, although parenteral gold was found to be more potent. There was no greater risk for toxic skin reaction to oral gold in psoriatic arthritis than in rheumatoid arthritis. The overall conclusion of this longterm study is that oral gold (auranofin) 6 mg once daily, although slightly less effective than parenteral gold, can be considered to be the first choice of gold treatment for rheumatoid arthritis and psoriatic arthritis, because the compliance, which is a reflection of a combination of tolerance and efficacy, for oral gold therapy was, in our hands, undoubtedly superior to parenteral gold.
We present a novel animal model for rheumatoid arthritis induced with a well defined synthetic adjuvant oil, pristane. Two weeks after a single intradermal injection of 150 microliters of pristane, the rats developed severe and chronic arthritis. The inflammation was restricted to the joints and involved pannus formation, major histocompatibility complex (MHC) class II expression, and T lymphocyte infiltration. The initial development as well as the chronic stage of pristane-induced arthritis was ameliorated by treatment with antibodies to the alpha beta-T-cell receptor showing that the disease is T cell dependent. Increased levels of interleukin in serum was seen after pristane injection but not during the chronic stage of arthritis. Joint erosions were accompanied by elevated serum levels of cartilage oligomeric matrix protein. Comparison of MHC congenic LEW strains showed that the severity and chronicity of arthritis varied among the different MHC haplotypes. Rats with RT1f haplotype showed a significantly higher susceptibility to pristane-induced arthritis. A strong influence of non-MHC genes was also suggested by the variability of arthritis susceptibility among different strains with the same MHC haplotype; the most susceptible background was the DA and the least susceptible was the E3. Arthritis induced with a well defined nonimmunogenic adjuvant, with a disease course that closely resembles that of rheumatoid arthritis, makes a suitable animal model for future studies of the pathology and genetics of rheumatoid arthritis.
OBJECTIVE: To assess relations between self-reported arthritis-related disruptions in sleep, physical activity, and social functioning and use of medical care, complementary therapies, and self-care for arthritis in older adults. DESIGN: A survey of self-reported arthritis-related disruptions in sleep and daily life as risk factors for use of 15 medical, complementary, and self-care modalities for relief of arthritis symptoms. SETTING: General community from 38 urban and 12 rural areas in the contiguous United States. PARTICIPANTS: Nine hundred thirty-seven older persons reporting arthritis; of the 1925 in the 1993 to 1994 follow-up of the National Survey of Self-care and Aging, a population-based, stratified, random sample of noninstitutionalized Medicare beneficiaries aged 65 years and older. MAIN OUTCOME MEASURES: Use of 15 medical, self-care, and complementary modalities for relief of arthritis symptoms. RESULTS: Most respondents reported use of at least 1 medical, complementary, or self-care strategy for arthritis. Arthritis was reported to disrupt sleep and leisure in 32.8% and 33.4% of respondents, respectively. Individuals with sleep disruption were more likely than those without sleep disturbance to use medical, complementary, and self-care strategies (adjusted odds ratio [95% confidence interval], 2.31 [1.59-3.37] for seeing a physician; and 2.23 [1.60-3.10] for using physical modalities). Reported disruption in sleep from arthritis was associated with use of more medical, complementary, and self-care strategies than was any other disruption. CONCLUSIONS: Self-reported arthritis-related disruption in sleep is associated with use of a wide range of medical, complementary, and self-care strategies. Physicians, other health care providers, and researchers should not overlook the importance of this common and often-neglected symptom.
OBJECTIVE: To compare the conclusions of studies addressing the outcome of early-arthritis cohorts. METHODS: The methodologies of previous reports on early-arthritis cohorts were examined, and their results and conclusions were compared. RESULTS: Thirty-four reports on 23 cohorts of early arthritis were found. The methodology was poor in most studies, with numerous inclusion and exclusion biases, frequently short follow-up periods, and a lack of precision about the rationale for diagnosis. However, similar conclusions were reached on several points: a large number of cases of early arthritis remained undifferentiated and/or resolved spontaneously, about 80% of cases initially classified as undifferentiated or rheumatoid arthritis retained this diagnosis during follow-up, and the incidence of psoriatic arthritis in most studies was similar (2% to 4%). Conversely, there were striking discrepancies among studies concerning the frequency of crystal arthropathies (0% to 18%), spondyloarthropathy (1% to 33%) and rheumatoid arthritis (15% to 47%). CONCLUSIONS: There appears to be a lack of agreement among researchers about the nosology and/or taxonomy of many cases of mild arthritis, despite the existence of classification criteria. RELEVANCE: Recognition of cultural bias in the diagnosis of early arthritis could be a prerequisite for the optimization of new sets of criteria for the diagnosis of early rheumatoid arthritis and spondyloarthropathy.
OBJECTIVE: To investigate the arthritis inhibiting effect of endostatin, known to have potent antiangiogenic activity, systemically given to animal models of rheumatoid arthritis (RA). METHODS: Four kinds of monoclonal anti-type II collagen antibody followed by lipopolysaccharide (LPS) three days later were given to 6 week old, female Balb/c mice to induce arthritis. Three groups of mice received 0.2 mg/kg/day, 2 mg/kg/day, and 10 mg/kg/day of endostatin, respectively, whereas a control group received phosphate buffered saline (PBS). Endostatin or PBS was given for 13 days, starting before the development of arthritis. Arthritis was evaluated by arthritis scores and hind paw thicknesses. Mice were killed for histological examination on the 22nd day after the administration of monoclonal anti-type II collagen antibody. RESULTS: Arthritis developed within three days after LPS administration in both the control and endostatin treatment groups. No difference in the development rate of arthritis was noted between the control and endostatin treatment groups. Arthritis scores remained significantly lower in the endostatin 10 mg/kg/day group than in the control group. Hind paw thicknesses also remained significantly smaller in the endostatin 10 mg/kg/day group than in the control group. Histopathological examination showed that synovial thickening and subchondral bone erosion improved more in the endostatin treatment groups than in the control group. CONCLUSION: The systemic administration of endostatin had an arthritis inhibiting effect in RA animal models. Endostatin inhibited, in particular, pannus formation and bone destruction.
OBJECTIVES: To assess the presence of anti-cyclic citrullinated peptide antibodies in a cohort of patients with juvenile idiopathic arthritis. METHODS: Anti-cyclic citrullinated peptide antibodies was tested for with an enzyme linked immunoabsorbent assay (ELISA) in serum samples of patients from the Hospital de Clínicas de Porto Alegre, all less than 18 years old and with previous diagnosis for at least 6 months. IgMRF (rheumatoid factor) and antinuclear antibodies in Hep-2 cells were also assayed. RESULTS: Serum samples were analyzed from 45 patients. The presence of high levels of anti-cyclic citrullinated peptide antibodies was found in the serum of just one child (2%), who presented sero-positive polyarthritis. CONCLUSIONS: Anti-cyclic citrullinated peptide antibodies can be detected in children with juvenile idiopathic arthritis, but much less frequently than in adults with rheumatoid arthritis. It still remains to be determined whether anti-cyclic citrullinated peptide antibodies can identify a subset of juvenile idiopathic arthritis patients with the potential to progress to adult rheumatoid arthritis.
OBJECTIVE: . The Behavioral Risk Factor Surveillance System (BRFSS) telephone interview study provides estimates indicating that approximately one-third of US adults meet the Centers for Disease Control and Prevention (CDC) case definition for arthritis. However, this population includes very diverse groups with major differences in health status, risk factors and disability. METHODS: BRFSS data for 2001 were compared for 4 roughly equal size groups of respondents reporting joint symptoms or a physician's diagnosis of arthritis: those with transient joint symptoms (TJS), chronic joint symptoms (CJS), a physician diagnosis of arthritis (PDA), and those with both PDA and CJS. RESULTS: By far the greatest burden of arthritis related disability is concentrated among individuals reporting both CJS and PDA. After controlling for age, sex, race, ethnicity, and education, this group had over 7 times the likelihood of fair to poor health status compared to the general adult population without arthritis. About one-third of those with undiagnosed CJS reported activity limitations, one-quarter were without health insurance at some point during the previous year, and this group had over 3 times the likelihood of reporting fair to poor health compared to the general population. Obesity was an even more prevalent arthritis risk factor than physical inactivity. CONCLUSION: The results support the validity of the CDC case definition of arthritis, which excludes TJS. However, a previous PDA in the absence of current symptoms was in itself a poor predictor of activity limitations due to arthritis. Findings will be useful in evaluating subsequent revisions of the CDC arthritis case definition and monitoring the burden of arthritis.
OBJECTIVE: To evaluate a community-based educational intervention designed to improve the diagnosis and treatment of arthritis in primary care. METHODS: The educational intervention, entitled "Getting a Grip on Arthritis", consisted of a 2-day workshop and followup reinforcement activities for healthcare providers (providers) and was supported by a toolkit of written materials for providers and clients. The content of the intervention was designed around 10 arthritis best practices derived from published arthritis guidelines. Five community health centers (CHC) participated as intervention sites and 2 as control sites. Intervention impact was determined through a mailed survey to clients with arthritis. Primary outcome analysis compared responses to questions about arthritis best practices between intervention and control sites at baseline and followup. RESULTS: The workshop was attended by 21 multidisciplinary providers from intervention CHC. At baseline, 423 of 624 eligible and consenting clients completed the survey and 376 of 593 completed the followup survey. At followup clients in the intervention group reported significantly higher referrals to The Arthritis Society therapy program, and were more often provided information on type of arthritis, medications and their side effects, disease management strategies, and arthritis community resources. CONCLUSION: This demonstration project is one of the first to show changes in the management of arthritis in a primary care setting. This project has recently received funding from Health Canada's Primary Health Care Transition Fund for implementation across Canada and is expected to provide a template for use in other chronic diseases.
OBJECTIVE: To develop Canadian projections for the prevalence and numbers of people with arthritis and arthritis disability, overall and in major age groups. METHODS: Age and sex specific data from the 1991 General Social Survey and the 1994 National Population Health Survey on the prevalence of arthritis and arthritis disability were applied to population projections for Canada for every 5 years between 1991 and 2031. RESULTS: Between 1991 and 2031 we project that the prevalence of arthritis diagnosed by a health professional as a longterm condition in Canada will increase from 10.7 to 15.7%, an increase of 46.7%, and the number of people with arthritis will increase from 2.9 to 6.5 million, an increase of 124%. Comparable changes in prevalence and numbers of people with self-reported arthritis are 17.1% (4.7 million) to 23.6% (9.7 million). Most of the increase will be in the population aged 45+, and not until after 2020 will the comparative increase in the 65+ age group be greater than that for the 45-64 age group. Disability attributed to arthritis in the population aged 15+ is projected to increase from a prevalence of 2.3% (595,000) in 1991 to 3.3% (1.13 million) in 2031. CONCLUSION: There are large projected increases in both the prevalence and numbers of people with arthritis and arthritis related disability that, at least in the next 20 years, will be split between the older half of the working population and those aged 65 and older.
Early arthritis is challenging because the clinical picture often does not allow a distinction between rheumatoid arthritis (RA), self-limiting disease, and other forms of inflammatory arthritis. In Germany the first early synovitis clinic and several inception cohorts of patients with early RA were initiated and evaluated during the 1980s and 1990s to learn more about diagnostic classification, psycho-social problems and socio-economical status including sick-leave, work loss, and indirect costs of patients with early arthritis and early RA. Unclassified arthritis was described as the most frequent diagnosis and the term "undifferentiated arthritis" was chosen to underline the heterogeneity of theses arthritides and the preliminary state of this classification as a working diagnosis. A large National Databank of the German Regional Collaborative Arthritis Centres has been established over the last 10 years. In total, there are some 170,000 cases in the database. Moreover, a prospective multicentre inception cohort of early RA of less than 1 year's disease duration has been started recently to evaluate parameters of potential relevance for the pathogenesis of RA and eventually for the prediction of erosive disease. Studies are in progress to test the diagnostic performance of specific antibodies and antibody patterns for RA. Another topic of research addresses the identification of bacterial DNA in synovial fluid and synovial tissues to improve the differentiation of patients with reactive arthritis from those with early RA and to narrow the working diagnosis of undifferentiated arthritis.