Adenoviral transfer of the viral IL-10 gene periarticularly to mouse paws suppresses development of collagen-induced arthritis in both injected and uninjected paws.
(9/2657)
Gene therapy is a promising new approach in the treatment of rheumatoid arthritis. Gene delivery to diseased joints offers the prospect of achieving high, local concentrations of a therapeutic gene product in a sustained manner, while minimizing exposure of nontarget organs. We report that a single administration of a modified adenovirus encoding the Epstein-Barr-derived homologue of IL-10 can suppress the development of disease for extended periods of time when injected locally within the periarticular tissue surrounding the ankle joints of mice with collagen type II-induced arthritis. Furthermore, we show that injection of an adenoviral vector carrying the IL-10 gene into a single paw can suppress development of arthritis in other, noninjected paws of the same individual. The systemic protection resulting from local gene therapy occurred in the absence of detectable levels of viral IL-10 in the serum. Circulating Ab levels to heterologous collagen were unaffected; however, treatment with viral IL-10 significantly suppressed the development of Abs to autologous mouse type II collagen. Thus, the treatment of a single joint by local delivery of the vIL-10 gene may protect multiple joints of the same individual while avoiding deleterious side effects often associated with systemic therapy. (+info)
Prevention of nonsteroidal anti-inflammatory drug-induced gastropathy: clinical and economic implications of a single-tablet formulation of diclofenac/misoprostol.
(10/2657)
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage arthritis. While controlling symptoms and improving quality of life, NSAID use is associated with gastroduodenal injury and a 2%-4% annual risk for symptomatic gastroduodenal ulceration, hemorrhage, and perforation. This requires clinicians to balance the efficacy of NSAIDs against the potential risk of serious gastrointestinal events. Identification and stratification of risk can help guide the optimal approach for arthritis management of individual patients or large populations such as managed care organizations. NSAID-induced gastroenteropathy carries considerable economic consequences; 46% of arthritis costs are related to managing serious adverse events. It is reasonable to assume that these costs may not be incurred if high-risk patients are recognized and optimally managed. Newer therapies with proven safety margins present an attractive option, especially for patients at higher risk. The single-tablet formulations of diclofenac and misoprostol (Arthrotec) offer an alternative in managing NSAID patients because of their inherent safety profile. Studies with diclofenac/misoprostol indicate its effectiveness in treating signs and symptoms of arthritis and in reducing the incidence of NSAID-induced gastroenteropathy. As such, this agent may provide improved medical and economic outcomes. This review discusses the clinical aspects of NSAID-induced gastroenteropathy, including available preventive therapies. Approaches to assessing patients' risk for developing complications, and the relationship of medical risk and economic outcomes, are also examined. Although not all patients require preventive therapy, patients with heightened risk may benefit clinically and economically from gastroprotective NSAIDs. Additional research or modeling may provide further insight into the economic implications of managing and preventing NSAID-induced gastroenteropathy. (+info)
Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies.
(11/2657)
We addressed the impact of deleting TNF AU-rich elements (ARE) from the mouse genome on the regulation of TNF biosynthesis and the physiology of the host. Absence of the ARE affected mechanisms responsible for TNF mRNA destabilization and translational repression in hemopoietic and stromal cells. In stimulated conditions, TNF ARE were required both for the alleviation and reinforcement of message destabilization and translational silencing. Moreover, the mutant mRNA was no longer responsive to translational modulation by the p38 and JNK kinases, demonstrating that TNF ARE are targets for these signals. Development of two specific pathologies in mutant mice, i.e., chronic inflammatory arthritis and Crohn's-like inflammatory bowel disease, suggests that defective function of ARE may be etiopathogenic for the development of analogous human pathologies. (+info)
Total knee arthroplasty in bony ankylosis in gross flexion.
(12/2657)
Between June 1993 and December 1994, we performed total knee arthroplasty (TKA) on 27 knees in 24 patients with spontaneous bony ankylosis in severe flexion. The mean age at operation was 43.5 years (30 to 60). No patient had preoperative pain. Three were unable to walk and 21 could manage less than five blocks. The mean duration of the ankylosis was 18.7 years (13 to 25) and its mean position was 105 degree flexion (75 to 135). The preoperative Hospital for Special Surgery Knee Score of 60 points was improved to 87 at the final follow-up three to five years later. All knees were free from pain. The mean range of active flexion in 24 knees was 97 degrees (78 to 115) and the mean arc of movement 91 degrees (78 to 98). The mean fixed flexion deformity was 6 degrees (0 to 25) and the extension lag 8 degrees (0 to 25). Angular deformity was corrected to between 0 degrees and 10 degrees of valgus. Four patients were able to walk one block and 20 five to seven blocks. Thirteen knees (48%) showed some necrosis at the skin edge; one knee required arthrodesis and another resection arthroplasty. One had a recurrence of tuberculous infection requiring arthrodesis. One patient had a rupture of the quadriceps tendon. To date no prosthesis has required revision for loosening. Radiolucency of 1 mm or less about the tibial prosthesis was observed at follow-up in four of the 24 knees. Our results have shown that one-stage TKA and skeletal traction after operation can achieve correction of severe flexion deformity of the knee with marked improvement in the function and quality of life. (+info)
Quantifying the exact role of HLA-DRB1 alleles in susceptibility to inflammatory polyarthritis: results from a large, population-based study.
(13/2657)
OBJECTIVE: To accurately determine the contributions of HLA-DRB1 alleles in explaining susceptibility to inflammatory polyarthritis in a large, true population-based cohort of new-onset cases. METHODS: A cohort of 680 consecutive patients with inflammatory polyarthritis, of whom 404 satisfied the American College of Rheumatology (ACR) criteria for rheumatoid arthritis (RA), was recruited from the population-based Norfolk Arthritis Register. All cases were compared with 286 local population controls. A standardized clinical assessment was performed on all patients. HLA-DRB1 phenotypes, including DR4 subtypes, were determined using a semiautomated, reverse dot-blot method. Results were expressed as odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: There was only a modest association (OR 1.8, 95% CI 1.4-2.4) between inflammatory polyarthritis and the presence of any shared epitope (SE) allele; the strongest individual risk was with DRB1*0404 (OR 3.5, 95% CI 1.8-6.8). Comparison of the genotypes demonstrated that the effect of being SE homozygous (OR 2.1, 95% CI 1.5-3.0) was only moderately greater than the effect of being SE heterozygous (OR 1.3, 95% CI 1.1-1.6). The exception to this was genotypic combinations that included HLA-DRB1*0404, which exhibited ORs ranging up to 18.0. There were no differences between either the phenotype or genotype data when the patients were stratified by RA status (defined by the ACR criteria). In contrast, the associations were substantially stronger in patients who were positive for rheumatoid factor. CONCLUSION: Previous studies had not been able to clarify whether the influence of HLA-DRB1 on RA was related to disease susceptibility or to disease severity and progression. These data on a unique population-based incident cohort suggest only weak effects on susceptibility, with the exception of the clearly distinct influence of HLA-DRB1*0404. (+info)
Spinal blockade of opioid receptors prevents the analgesia produced by TENS in arthritic rats.
(14/2657)
Transcutaneous electrical nerve stimulation (TENS) is commonly used for relief of pain. The literature on the clinical application of TENS is extensive. However, surprisingly few reports have addressed the neurophysiological basis for the actions of TENS. The gate control theory of pain is typically used to explain the actions of high-frequency TENS, whereas, low-frequency TENS is typically explained by release of endogenous opioids. The current study investigated the role of mu, delta, and kappa opioid receptors in antihyperalgesia produced by low- and high-frequency TENS by using an animal model of inflammation. Antagonists to mu (naloxone), delta (naltrinodole), or kappa (nor-binaltorphimine) opioid receptors were delivered to the spinal cord by microdialysis. Joint inflammation was induced by injection of kaolin and carrageenan into the knee-joint cavity. Withdrawal latency to heat was assessed before inflammation, during inflammation, after drug (or artificial cerebral spinal fluid as a control) administration, and after drug (or artificial cerebral spinal fluid) administration + TENS. Either high- (100 Hz) or low- frequency (4 Hz) TENS produced approximately 100% inhibition of hyperalgesia. Low doses of naloxone, selective for mu opioid receptors, blocked the antihyperalgesia produced by low-frequency TENS. High doses of naloxone, which also block delta and kappa opioid receptors, prevented the antihyperalgesia produced by high-frequency TENS. Spinal blockade of delta opioid receptors dose-dependently prevented the antihyperalgesia produced by high-frequency TENS. In contrast, blockade of kappa opioid receptors had no effect on the antihyperalgesia produced by either low- or high-frequency TENS. Thus, low-frequency TENS produces antihyperalgesia through mu opioid receptors and high-frequency TENS produces antihyperalgesia through delta opioid receptors in the spinal cord. (+info)
The role of joint innervation in the pathogenesis of arthritis.
(15/2657)
Recently, an expanding body of knowledge has documented the nature and functions of receptors in joint tissues and their potential importance in preserving the smooth normal functioning of the motor-skeletal system and in amplifying the inflammatory response to joint injuries and diseases. This review summarizes the current knowledge of the anatomical and physiological substrates of these mechanisms. The distribution, morphologic and functional characteristics of joint receptors have been well described. In the past decade there has been a new appreciation of the major role played by sensory neurons in promoting regional inflammatory responses, and many of the specific neuronal mechanisms and molecules that mediate these reflexes have been identified. This knowledge promises to significantly improve the selectivity and effectiveness of pharmacologic approaches to pain, trauma and regional inflammatory disorders. Other investigations have revealed important contributions of joint receptors to motor function. These refer not to proprioception or the sense of limb position in space, but rather to a more sophisticated tailoring of muscle activity to increase joint stability and to protect joint structures from damaging loads. Whether a loss of these reflexes may play a role in the pathogenesis of osteoarthritis remains controversial. However, there is a growing consensus that a loss of these reflexes may contribute to the morbidity associated with disruption of the anterior cruciate ligament. Synovial joints are sites of major interactions between the musculoskeletal and the nervous systems. Understanding the mechanisms that activate and control these interactions will certainly offer the opportunity to develop new, more effective treatments for patients with joint disorders. (+info)
Diagnostic classification of shoulder disorders: interobserver agreement and determinants of disagreement.
(16/2657)
OBJECTIVES: To assess the interobserver agreement on the diagnostic classification of shoulder disorders, based on history taking and physical examination, and to identify the determinants of diagnostic disagreement. METHODS: Consecutive eligible patients with shoulder pain were recruited in various health care settings in the Netherlands. After history taking, two physiotherapists independently performed a physical examination and subsequently the shoulder complaints were classified into one of six diagnostic categories: capsular syndrome (for example, capsulitis, arthritis), acute bursitis, acromioclavicular syndrome, subacromial syndrome (for example, tendinitis, chronic bursitis), rest group (for example, unclear clinical picture, extrinsic causes) and mixed clinical picture. To quantify the interobserver agreement Cohen's kappa was calculated. Multivariate logistic regression analysis was applied to determine which clinical characteristics were determinants of diagnostic disagreement. RESULTS: The study population consisted of 201 patients with varying severity and duration of complaints. The kappa for the classification of shoulder disorders was 0.45 (95% confidence intervals (CI) 0.37, 0.54). Diagnostic disagreement was associated with bilateral involvement (odds ratio (OR) 1.9; 95% CI 1.0, 3.7), chronic complaints (OR 2.0; 95% CI 1.1, 3.7), and severe pain (OR 2.7; 95% CI 1.3, 5.3). CONCLUSIONS: Only moderate agreement was found on the classification of shoulder disorders, which implies that differentiation between the various categories of shoulder disorders is complicated. Especially patients with high pain severity, chronic complaints and bilateral involvement represent a diagnostic challenge for clinicians. As diagnostic classification is a guide for treatment decisions, unsatisfactory reproducibility might affect treatment outcome. To improve the reproducibility, more insight into the reproducibility of clinical findings and the value of additional diagnostic procedures is needed. (+info)