Severe Joint Damage Research Articles

Cartilage oligomeric matrix protein/thrombospondin-5 (COMP/TSP-5) levels do not correlate to functional class in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) can be an incapacitating disorder. The cartilage oligomeric matrix protein/thrombospondin-5 (COMP/TSP-5), a member of extracellular proteins involved in tissue genesis and remodeling, has been considered a potential prognostic marker of RA [1]. Data on the association of functional status of RA with COMP/TSP-5 levels are virtually nonexistent. In the current study, we set up to determine the serum levels of COMP/TSP-5 in RA patients of different functional classes and in healthy controls. The study was cross-sectional. Fifty-eight patients with RA [2] followed in the Outpatient Rheumatology Clinic of Sao Lucas Hospital of PUCRS comprised the target population. The Hochberg classification [3] was used to estimate the functional status of RA patients. The control group included 100 consecutive blood donors. Levels of COMP/TSP-5 were evaluated by immunoenzimatic assay (AnaMar Medical TM, Lund, Sweden). Levels above 12 U/L were considered positive [4]. Comparison of groups was obtained by analysis of variation. A 5% significance level was considered for P values. The medium age was 48±6 years for the control group and of 54±14 years for RA patients (P>0.05). The female gender predominated in patients with RA (P<0.05). After adjustment for sex and age, the average levels of COMP/ TSP-5 were 7.0 U/L (95% CI 6.1–7.9) for the control group and 12.6 U/L (95% CI 11.1–14.1) for RA patients (P<0.01). Among RA patients, 25 showed functional class I (43.1%), 14 functional class II (24.13%), 10 functional class III (17.2%), and 9 functional class IV (15.5%). With the exception of individuals in class III, patients from other functional status presented higher frequency of positive test for COMP/TSP-5 as compared to controls (P<0.001). In each of the functional classes, the average levels of COMP/ TSP-5 were significantly higher than those of the control group (P<0.05). The 28 RA patients with elevated COMP/ TSP-5 were distributed uniformly in all four functional classes (P=0.65). COMP/TSP-5 serum levels may be a predicting factor for joint damage in RA [5]. High COMP/TSP-5 levels were described in patients with early RA [6]. A positive correlation of COMP/TSP-5 levels with cartilage damage (as measured by the Larsen radiographic score) was described in 62 RA patients [7]. RA patients with severe joint damage had higher COMP/TSP-5 and C-reactive protein levels than patients with milder disease [8]. Nevertheless, other authors reported low levels of COMP/ TSP-5 in patients with decreased functional status, probably due to cartilage degradation [9]. A recent report showed that neither baseline serum COMP/TSP-5 levels nor its individual change after 3 months from start of intensive F. D. Andrade :A. L. Bender : I. G. da Silveira :H. Stein : C. A. von Muhlen :H. L. Staub Rheumatology Department, Sao Lucas Hospital, Faculty of Medicine of Pontiphical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil

Interleukin‐10 protects against blood‐induced joint damage

Despite prophylactic treatment, haemophilia patients suffer from spontaneous joint bleeds, which lead to severe joint damage. Also after joint trauma, an intra-articular haemorrhage can add to joint damage over time. This study evaluated interleukin 10 (IL-10) in the search for possible interventions to prevent or limit the damaging effects of joint bleeds. Human articular cartilage tissue explants were cultured in the presence or absence of 50% v/v blood (or its cellular components) for 4 d (the expected blood load in vivo after a joint haemorrhage), followed by a recovery period of 12 d. Pharmacological dosages of IL-10 reached during treatment (1 or 10 ng/ml) were added. Additionally, cartilage and synovial tissue obtained from joints with end-stage haemophilic arthropathy (HA) were cultured in the presence of IL-10 (10 ng/ml). IL-10 protected cartilage from the damaging effects of blood exposure, measured by its effects on proteoglycan turnover. In addition, IL-10 beneficially influenced cartilage from patients with HA and reduced the production of the inflammatory cytokines IL-1beta and tumour necrosis factor-alpha by haemophilic synovial tissue. Taken together, although effects were obtained in vitro, IL-10 protects against blood-induced joint damage and might be further evaluated as candidate in treatment of tissue damaging effects of joint haemorrhages.

An evidence‐informed, integrated framework for rheumatoid arthritis care

Introduction Providing adequate care for persons with rheumatoid arthritis (RA) is an ongoing challenge. Although the current evidence supports the use of disease-modifying antirheumatic drugs (DMARDs) within the first 3 months of symptoms appearing (1–3), delay in DMARD use and other gaps in care have been reported across communities (4–9). The situation has worsened due to the shortage of specialists (10). The process of seeking medical treatment begins with the person’s recognition of the symptoms and the action of visiting a family physician (FP) (Figure 1, levels A and B). The FP then performs the appropriate investigations, and if RA is suspected, the FP refers the person to a rheumatologist (levels B and C) who then conducts further tests, provides a diagnosis, and prescribes DMARDs and other appropriate medications (level D). Next, the person may be referred to the available community resources and/or rehabilitation programs that enable self-management (levels E1–E4), and will be periodically assessed by a rheumatologist (level F). Successful delivery of these interventions is largely dependent on the availability of local programs and the coordination among the rheumatologist, the FP, and other health professionals. In the case of severe joint damage, the person is referred for an orthopedic consultation and surgery may be considered (levels G1–G4). Moving from one level to the next involves a potential wait period, which may be caused by, for example, delays in patients’ and health professionals’ recognition of RA symptoms, delays in referral to rheumatologists, lack of access to specialist care or community resources, or patients’ own choices. Delays may occur at any of the following periods (Figure 1): Wait 1: the time between a person’s development and awareness of the seriousness of the symptoms and the first visit with an FP; Wait 2: the time between the first visit with an FP and the first visit with a rheumatologist; Wait 3: from the first rheumatology visit to the date the patient starts the appropriate therapy; Wait 4: from a patient starting medication to the date when he or she has access to adequate resources that enable self-management; andWait 5: from the decision date for an orthopedic consultation to the date of the patient’s first visit with a surgeon and, subsequently, the date of surgery. The delay between symptom onset and DMARD prescription for individuals with RA is a problem across countries (Waits 1–3), with a median lag time ranging from 6.5 to 19 months (5–9). A few studies have attempted to estimate the length of Wait 1, but the findings are inconsistent. Two studies, a retrospective cohort from the US (11) and a prospective study from Norway (12), estimated a median delay of 4 weeks for the first FP visit. However, more recent research from the UK estimated 12 weeks (13), with 38% of people waiting more than 3 months before seeing an FP (14). The lag time from FP visit to rheumatologist consultation is believed to be a major source of the delay (Wait 2). In a UK study, 44% waited more than 3 months for a specialist referral (14). Recent research from Canada also found a median lag time of 79 days between the FP visit and the first rheumatologist visit (15). In contrast, the Linda C. Li, PT, PhD: University of British Columbia and Arthritis Research Centre of Canada, Vancouver, British Columbia, Canada; Elizabeth M. Badley, DPhil: Arthritis Community Research and Evaluation Unit, Toronto Western Research Institute and University of Toronto, Toronto, Ontario, Canada; Crystal MacKay, PT, MHSc: Arthritis Community Research and Evaluation Unit, Toronto Western Research Institute, Toronto, Ontario, Canada; Dianne Mosher, MD, FRCP(C): Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada; Shahin (Walji) Jamal, MD, FRCP(C): St. Michael’s Hospital and University of Toronto, Toronto, Ontario, Canada; Anamaria Jones, PT, PhD(Candidate): Arthritis Research Centre of Canada, Vancouver, British Columbia, Canada, and Federal University of Sao Paulo, Sao Paulo, Brazil; Claire Bombardier, MD, FRCP(C): University Health Network, University of Toronto, Institute for Work & Health, and Mount Sinai Hospital, Toronto, Ontario, Canada. Dr. Mosher has received honoraria (less than $10,000) from serving on the advisory board for Pfizer, and has received speaking fees (less than $10,000 each) from Schering, Amgen, and Wyeth. Address correspondence to Linda C. Li, PT, PhD, Arthritis Research Centre of Canada, 895 West 10th Avenue, Room 324, Vancouver, British Columbia V5Z 1L7, Canada. E-mail: lli@arthritisresearch.ca. Submitted for publication December 27, 2007; accepted in revised form April 22, 2008. Arthritis & Rheumatism (Arthritis Care & Research) Vol. 59, No. 8, August 15, 2008, pp 1171–1183 DOI 10.1002/art.23931 © 2008, American College of Rheumatology

197 INTERLEUKIN-10 PROTECTS AGAINST BLOOD-INDUCED JOINT DAMAGE

Purpose: Joint bleeds occur frequently in patients suffering from haemophilia or can occur as a consequence of joint trauma or major joint surgery. Even a limited number of bleeds has been demonstrated to lead to severe joint damage in time. Small amounts of IL-1 that are produced by activated monocytes/macrophages as present within blood increase the production of hydrogen peroxide (H2O2) by chondrocytes. The hydrogen peroxide reacts with haemoglobin-derived iron from damaged and phagocytosed red blood cells in the joint cavity, which results in the formation of hydroxyl radicals in the vicinity of chondrocytes. This leads to chondrocyte apoptosis and with that the irreversible inhibition of cartilage matrix synthesis. This primary cartilage-driven joint damage is followed by synovial inflammation adding to joint damage. In search of possible interventions to prevent or limit the cartilage damaging effects of joint bleeds, we evaluated the potential of IL-10. Methods: Healthy human articular cartilage tissue explants were cultured in the presence or absence of 50% v/v blood for 4 days, followed by a recovery period of 12 days. IL-10 was added in 0.1, 1 or 10 ng/ml. Also cartilage and synovium in case of haemophilic arthropathy, obtained at joint replacement surgery, were cultured in the presence of IL-10 (10 ng/ml). The effect on cartilage matrix proteoglycan synthesis, -release, and -content were determined as well as the IL-1β and TNFα production by the synovium. Results: IL-10 was able to prevent dose dependently the decrease in proteoglycan synthesis and the increase in proteoglycan release of cartilage exposed to blood (p<0.05). As a consequence, the decrease in proteoglycan content after blood exposure could be prevented dose dependently (p<0.05). With 10 ng/ml IL-10, which is still a low dose for local therapeutic treatment, at least 50% reduction in adverse effects was observed (p<0.05). The matrix turnover of haemophilic cartilage improved upon addition of IL-10 and also the production of IL-1β and TNFα by haemophilic synovium decreased in the presence of IL-10 (all p<0.05). Conclusions: The present results show that interleukin-10 prevents the direct harmful effects of blood on articular cartilage and has a beneficial effect on the matrix turnover of haemophilic cartilage and pro-inflammatory cytokine production by haemophilic synovium. Therefore, although treatment studies in addition to prevention studies have to be performed; IL-10 might be worthwhile to test in clinical practice for local treatment of joint haemorrhages, to prevent joint damage in time.

Protective Abilities of Interleukin-10 in Blood-Induced Joint Damage.

PURPOSE: Joint bleeds occur frequently in patients suffering from haemophilia or can occur as a consequence of joint trauma. Even a limited number of bleeds has been demonstrated to lead to severe joint damage in time (1,2). With respect to the mechanisms of blood induced joint damage, we have demonstrated that monocytes/macrophages within the mononuclear cell population together with the red blood cells as present in blood are responsible for the irreversible inhibition of cartilage matrix synthesis. Small amounts of IL-1 that are produced by activated monocytes/macrophages increase the production of hydrogen peroxide (H2O2) by chondrocytes. The hydrogen peroxide reacts with haemoglobin-derived iron from damaged and phagocytosed red blood cells, which results in the formation of hydroxyl radicals in the vicinity of chondrocytes. This leads to chondrocyte apoptosis and with that the irreversible inhibition of cartilage matrix synthesis (2). In search of possible interventions to prevent or limit the cartilage damaging effects of joint bleeds, we tested interleukin-10 (IL-10) as an inflammation controlling cytokine on blood-induced cartilage damage.METHODS: Healthy human articular cartilage tissue explants were cultured in the presence or absence of 50% v/v blood for 4 days, followed by a recovery period of 12 days. IL-10 was added in 0.1, 1 or 10 ng/ml. Also cartilage and synovium in case of haemophilic arthropathy, obtained at joint replacement surgery, was cultured in the presence of IL-10 (10 ng/ml). The effect on cartilage matrix proteoglycan synthesis, -release, and -content were determined as well as the IL-1β and TNFα production by the synovium.RESULTS: IL-10 was able to prevent the decrease in proteoglycan synthesis and the increase in proteoglycan release of cartilage exposed to blood dose dependently (p<0.05). As a consequence, the decrease in proteoglycan content after blood exposure could be prevented dose dependently (p<0.05). With 10 ng/ml IL-10, which is still a low dose for local therapeutic treatment, at least 50% reduction in adverse effects was observed (p<0.05). The matrix turnover of haemophilic cartilage improved upon addition of IL-10 and also the production of IL-1β and TNFα by haemophilic synovium decreased in the presence of IL-10 (all p<0.05).CONCLUSIONS: The present results show that interleukin-10 prevents the direct harmful effects of blood on articular cartilage and has a beneficial effect on the matrix turnover of haemophilic cartilage and pro-inflammatory cytokine production by haemophilic synovium. Therefore, although treatment studies in addition to prevention studies have to be performed; IL-10 might be worthwhile to test in clinical practice for local treatment of joint haemorrhages, to prevent joint damage in time.

Decreased induction of IL-1β in fibroblast-like synoviocytes: A possible regulatory mechanism maintaining joint homeostasis

The response of fibroblast-like synoviocytes (FLS) to inflammatory stimuli was compared to their, respectively, derived dermal fibroblasts (DF) to determine whether regulatory controls exist within FLS to insure normal joint homeostasis. We further analyzed whether the loss of the normal regulatory controls present within the FLS could predispose to the development of non-rheumatic joint disease (non-RA). Primary fibroblast cell lines were generated from synovial and skin tissue from ten rheumatoid arthritis (RA) and ten non-RA patients. Cell lines were pulse labeled with [ 35S]-methionine and stimulated with TNFα or IL-1β. Protein synthesis of IL-1β, IL-6 and IL-8 was quantitated following immunoprecipitation. Gene expression was determined by Northern blot analysis. We noted, IL-1β was minimally detected in FLS under nonstimulated conditions. In response to stimulation with IL-1β or TNFα, production of IL-1β was found to be 3.5 and 5-fold lower in FLS, respectively, when compared to DF from the same individual. In contrast, the production of IL-6 and IL-8 in FLS upon stimulation was 3-fold and 1.6-fold higher, respectively, than in DF. Furthermore, induced IL-1β production in FLS, normalized relative to their, respectively, stimulated DF, was 2.5 times higher in non-RA versus RA-derived cells ( p = 0.032), an effect noted even after several passages of growth. Our data suggest that inductive expression of IL-1β in FLS is under specific inhibitory control. Increased production of IL-1β in FLS of susceptible individuals may lead to a higher risk of developing severe joint damage even in the absence of systemic inflammation.

The response of immunoreactive nerve fibres in osteoarthritis to orally administered Zingiber officinale extract

Zingiber officinale, commonly known as ginger is a well known natural remedy that has long been used by people in many parts of the world as food additive and traditional medicine. Knowing the anti-inflammatory action of Z. officinale, it has become the most popular herbal medication for rheumatic diseases. The current work was undertaken to evaluate the effect of this extract on the efferent and afferent components of the peripheral nervous system, since this system had been shown to contribute to the inflammatory process which in turn will cause a severe joint damage in arthritis. Chemical lesioning of these fibres showed a decrease in the inflammatory response in arthritis [2], and oral administration of SP antagonist or dorsal rhizotomy markedly reduces the severity of inflammation in animal models [1]. This improved the cure from arthritis. Therefore, the respond of PGP 9.5-, SP-, CGRP- and NPY- immunoreactivity in experimentally-induced osteoarthritis with supplementation of Z. officinale extract was studied. Changes after the treatment were statistically evaluated by innervations of the synovial membrane. There was significant improvement in PGP 9.5-, SP-, CGRP- and NPY- immunoreactivity in the synovial membrane of treated animals compared with that for controls. Results of this study suggest oral administration of Z. officinale extracts can be a good alternative treatment for osteoarthritis.

Exposure of human cartilage tissue to low concentrations of blood for a short period of time leads to prolonged cartilage damage: An in vitro study

Joint bleeding, or hemarthrosis, leads in time to severe joint damage. This study was carried out to test the in vitro thresholds of exposure time and concentration that lead to irreversible joint damage, to add to the discussion on the usefulness of aspiration of the joint after a hemorrhage. Explants of healthy human articular cartilage tissue were cultured in the presence or absence of 50% (volume/volume) blood for 1, 2, 3, or 4 days or in the presence of 0%, 5%, 10%, 20%, 30%, or 50% (v/v) blood for 4 days, followed by a 12-day period of recovery after withdrawal of blood. The effect of blood exposure on cartilage was determined by measuring the rate of proteoglycan synthesis as well as the release and content of cartilage matrix proteoglycans and the activity of matrix metalloproteinases. Exposure of cartilage to 50% (v/v) blood led to adverse changes that were largely independent of the exposure time. The adverse effects persisted after an initial exposure of up to or exceeding 2 days. Exposure of cartilage to increasing concentrations of blood for 4 days led to concentration-dependent adverse changes. These effects persisted when the concentration equaled or exceeded 10% (v/v) blood. Moreover, after 2 days of exposure to a blood load of 10% (v/v), the adverse effects on cartilage were not reversible. A 2-day exposure of cartilage in vitro to 10% (v/v) blood leads to prolonged impairment of joint cartilage. This suggests that aspiration of blood from the joint within 2 days after hemarthrosis should be considered to prevent blood-induced joint damage in the long term.

Effects of rheumatoid factor isotypes on disease activity and severity in patients with rheumatoid arthritis: a comparative study

The value of rheumatoid factor (RF) isotypes for assessing rheumatoid arthritis (RA) remains debatable. In this study, we have examined the relationships between RF isotypes and disease activity and severity in RA patients. Sixty-two patients with RA, 48 women and 14 men, were studied. RF was measured by nephelometry (RF-N) and IgG-, IgA-, and IgM-RF isotypes were measured using enzyme-linked immunosorbent assay. Serum C-reactive protein and erythrocyte sedimentation rate were also determined. The patients were classified according to disease activity, joint damage, functional status, and presence of pulmonary involvement, rheumatoid nodule, and secondary Sjögren's syndrome. Although the patients with active disease had significantly higher IgA-RF and IgM-RF levels compared to inactive patients, IgA-RF and IgM-RF were not found to be independently associated with disease activity in multivariate analysis. In patients with severe joint damage, IgA-RF and RF-N were significantly higher than those of the other patients. Multiple regression analysis showed that IgA-RF was the unique variable independently associated to severe joint damage. The patients with class III and IV functional index had significantly higher IgM-RF, IgA-RF, and RF-N levels compared to the patients with class I and II functional index; however, RFs were not significantly associated with functional status in multivariate analysis. IgA-RF and IgM-RF were significantly associated with pulmonary involvement and rheumatoid nodule, respectively. No significant associations were found between RF isotypes and secondary Sjögren's syndrome. Our results suggest that the clinical usefulness of IgA and IgM isotypes is better than RF-N. Elevated IgA-RF may be a marker of erosive disease. The usefulness of RF isotypes for monitoring disease activity or functional status appears to be limited.

Acute Neuropathic Joint Disease

Charcot neuroarthropathy, or, as it is also known, neuropathic joint disease (NJD), is a particularly severe form of osteoarthritis. It is recognized by severe joint damage in the context of relatively little pain in the presence of neuropathy and associated with characteristic radiographic changes in well-established disease. Patients with diabetes are at particular risk of NJD; permanent disability through foot deformity or amputation as a consequence of peripheral neuropathy (1) and diabetes is now the leading cause of NJD. The midfoot or ankle joints are most commonly affected in diabetic patients (2). The limited epidemiologic data on NJD suggest that ∼0.1–0.4% of patients with diabetes develop NJD (3), usually 10–15 years after the onset of diabetes, and up to 16% of diabetic patients with peripheral neuropathy have been reported to be affected by NJD (4), which therefore represents a considerable cause of diabetic ankle- and foot-related morbidity. NJD often presents acutely, resulting in misdiagnosis and inappropriate treatment and consequently leading to disastrous damage and possible loss of the affected limb (3). Typically, in the acute phase, NJD presents as a warm, edematous, and erythematous joint (5,6). As a result of sensory neuropathy, there may be little pain or tenderness, and the patient may not even seek medical assistance. During examination, a bounding pedal pulse compared with the other limb is found (7). The radiographic changes of chronic NJD include florid new bone formation, joint space loss, and severe joint destruction and deformity, but these characteristic changes are usually absent in early NJD. In this clinical context, cellulitis, osteomyelitis, or infection may be diagnosed instead and treated accordingly, and the window of opportunity for the initiation of treatment designed to minimize subsequent NJD joint …

Rheumatoid nodulosis. Two cases with destructive polyarthritis after 20 years

The term “rheumatoid nodulosis” was coined by Ginsberg in 1975 to designate a rare and distinctive form of rheumatoid disease. Anecdotal case reports suggest a benign nondestructive course, although prolonged follow-up data are usually unavailable. We describe two cases of typical rheumatoid nodulosis with follow-ups exceeding 25 years. Onset occurred at 14 and 22 years of age, respectively. Both patients presented with palindromic rheumatism, positive tests for rheumatoid factors, negative tests for other biological markers, and normal radiographs. Multiple subcutaneous nodules developed after 4 and 6 years with palindromic flares, respectively. Functional impairments and disfigurement required several surgical procedures to remove nodules. Histology was typical for rheumatoid nodules. Neither patient responded to disease-modifying anti-rheumatic drugs (gold, antimalarials, and d-penicillamine). Treatment consisted of nonsteroidal anti-inflammatory drugs combined with prednisone as needed. After 20 and 22 years of follow-up, respectively, both patients had typical rheumatoid arthritis with deformities and radiological joint destruction. In conclusion, these two cases establish that rheumatoid nodulosis can occur as a presentation of rheumatoid arthritis with a potential for severe joint damage after many years.

Correlation of rheumatoid arthritis severity with the genetic functional variants and circulating levels of macrophage migration inhibitory factor

To study whether genetic variants of macrophage migration inhibitory factor (MIF), the MIF -173G>C and CATT(5-8) alleles, are associated with disease severity and levels of circulating MIF in patients with rheumatoid arthritis (RA). Genotyping was performed in patients with early RA and in healthy controls. Demographic data, disease activity, and outcome measurements were compared between patients with and without the MIF variants. MIF -173G>C and CATT(5-8) polymorphisms were genotyped, and a newly developed enzyme-linked immunosorbent assay for human MIF was used. Allele and genotype distributions of the MIF -173G>C and CATT(5-8) polymorphisms were compared between patients and controls by chi-square test. Multiple regression analysis was performed to assess the independence of the MIF functional genetic variants as risk factors for radiologic joint damage. Genotyping of the -173G>C and CATT(5-8) polymorphisms of MIF in RA patients and healthy individuals (n = 277 each) revealed similar frequencies of genotypes and haplotypes in both groups. No significant differences in demographic or clinical features were observed between RA patients carrying the MIF -173C allele or the MIF CATT7 allele or both and non-carrier RA patients. Radiologic joint damage was significantly higher in patients carrying risk alleles of the MIF -173G>C or the MIF CATT(5-8) functional variants. No synergistic effects between both genetic variants were observed. Multivariate regression analysis revealed that presence of the MIF -173C/C and MIF CATT(7/7) genotypes and having 1 MIF -173C allele were independent prognostic variables. Carriership of the MIF -173C allele (P = 0.002) or MIF CATT7 allele (P = 0.004) was associated with significantly higher circulating MIF levels compared with those in subjects having none of the risk-conferring alleles, and greater circulating MIF levels correlated with more severe radiologic joint damage (r = 0.64, P = 0.001). The MIF polymorphisms are not associated with RA susceptibility but are associated with high levels of radiologic joint damage. High circulating MIF levels were shown to correlate strongly with radiologic joint damage, suggesting that MIF expression is genetically determined and can be used as a novel prognostic tool in RA.

Posterior Cruciate Ligament Revision Reconstruction, Part 1

Background Posterior cruciate ligament reconstructions have not shown uniformly predictable results in restoration of normal posterior tibial translation. The authors are unaware of any study that has assessed the causes of failure of these operations, and they investigated 52 prior unsuccessful posterior cruciate ligament procedures to determine the factors that contributed to failure of the operations. Study Design Case series; Level of evidence, 4. Methods The authors studied 52 prior failed posterior cruciate ligament surgeries that had been done in 41 knees (40 patients). Graft reconstructions had been done in 31 cases, primary repairs in 14, synthetic replacements in 4, and thermoplasties in 3. Medical records, operative notes, radiographs, and magnetic resonance imaging scans were reviewed, and a comprehensive knee examination was conducted. Results A single factor that caused the operations to fail was identified in 23 (44%) of 52 operations, and multiple factors were identified in 29 (56%). The most common probable causes of failure were associated posterolateral ligament deficiency (40%), improper graft tunnel placement (33%), associated varus malalignment (31%), and primary suture repair (25%). Sixteen of 21 (76%) prior posterolateral ligament procedures had failed, as had 9 of 19 (47%) prior anterior cruciate ligament reconstructions. Twenty-nine knees (71%) presented with pain with activities of daily living. Thirty-four knees (83%) had compounding problems of joint arthritis, prior meniscectomy, associated ligament deficiencies, or varus malalignment. Posterior cruciate revision surgery was done in 22 knees (54%). Eleven knees (27%) had severe joint damage that contraindicated revision, and 8 (19%) declined further operations. Conclusions Failure to restore associated ligament instabilities and incorrect tunnel placement were major factors contributing to surgical failure. The results suggest the need for greater emphasis on the initial reconstruction in graft tunnel placement, correction of associated ligament instabilities, and correction of varus osseous malalignment. Failure of concurrent posterolateral ligament reconstructions was frequently encountered, suggesting the need for higher strength augmentation procedures or anatomical graft replacement.

Anti-Sa antibodies and antibodies against cyclic citrullinated peptide are not equivalent as predictors of severe outcomes in patients with recent-onset polyarthritis

The prognostic value of two antibodies targeting citrullinated antigens, anti-Sa and anti-cyclic citrullinated peptide (CCP), present at inclusion, was evaluated prospectively in a cohort of 165 consecutive patients with recent-onset or early polyarthritis (EPA) followed for up to 30 months. Patients were treated according to current Good Clinical Practice standards. Predefined outcomes were severe arthritis and persistent arthritis. At inclusion, a median of 3 months after disease onset, 133 (81%) patients fulfilled at least four American College of Rheumatology criteria for rheumatoid arthritis and 30 (18%) had erosive changes on radiographs of hands and feet. Disease-modifying anti-rheumatic drugs were used in close to 80% of the patients at 30 months. Joint damage increased linearly over time, whereas disease activity declined markedly and remained low at each follow-up. Autoantibodies were identified in 76 (46%) patients: rheumatoid factor (RF) in 68 (41%), anti-CCP in 53 (33%), and anti-Sa in 46 (28%). All three antibodies were correlated, but anti-Sa antibodies best predicted severity at 18 and 30 months. RF and anti-CCP performed less well. For both outcomes, anti-Sa alone performed better than any combination of antibodies. The presence of any autoantibody identified about 50 to 60% of the patients with poor outcomes. In multivariate analysis, anti-Sa (odds ratio (OR) 8.83), the presence of erosions at inclusion (OR 3.47) and increasing age (OR 1.06/year) were significantly associated with severity, whereas RF and anti-CCP were not significant predictors. Persistent arthritis was present in up to 84% of patients; autoantibodies were specific but poorly sensitive predictors of this outcome. We conclude that assays for antibodies against citrullinated antigens differ in their ability to predict poorer outcomes in patients with EPA. In our EPA cohort treated in accordance with current standards, detection of anti-Sa but not of RF or anti-CCP antibodies, in combination with clinical and radiological variables present at the first encounter, allowed the identification of a subgroup of EPA patients suffering more rapid and more severe joint damage over 30 months.

Virulence potential of the staphylococcal adhesin CNA in experimental arthritis is determined by its affinity for collagen.

Staphylococcus aureus is a major cause of bacterial arthritis, which often results in severe joint damage. CNA, a collagen adhesin of S. aureus, was shown to be a virulence factor in several animal models. However, the precise molecular mechanism by which CNA contributes to virulence remains unclear. We examined the role of the collagen-binding function of CNA in a mouse model of septic arthritis by comparing the virulence of isogenic strains of S. aureus expressing (1) wild-type CNA, (2) a truncated form of CNA (CNA35) with a higher affinity for collagen than the wild type, (3) CNA35 containing a single point mutation resulting in loss of collagen binding, (4) CNA lacking the collagen-binding domain, and (5) the collagen-binding domain of ACE (adhesin of collagen from Enterococcus faecalis). The results provide, for the first time, direct evidence that the virulence of CNA depends on its collagen-binding ability. Collagen binding facilitated early colonization of the joints of mice. Furthermore, the virulence potential of the adhesin is determined by the adhesin's affinity for its ligand, as well as its binding kinetics.

The levels of serum-soluble Fas in patients with rheumatoid arthritis and systemic sclerosis.

Different defects in Fas/APO-1 interaction with its ligand or in signaling of apoptosis may contribute to autoimmune disease. The aim of this study was to examine whether elevated serum-soluble Fas (sFas) levels are associated with rheumatoid arthritis (RA) or systemic sclerosis (SSc). sFas level was assayed using a sandwich ELISA in serum from 37 patients with RA, 30 patients with SSc and 20 healthy controls. The RA patients were classified according to disease activity, anatomical joint damage, and the presence of pulmonary involvement. Presence of pulmonary fibrosis, CO diffusion capacity (DLCO) and skin score were determined in patients with SSc. Serum sFas levels were not significantly different between study groups. Serum sFas level in the active RA patients was significantly higher than in the patients with inactive disease (p < 0.05). The untreated active RA patients had significantly higher sFas level than healthy controls (p < 0.05). In RA patients, sFas level was significantly correlated with rheumatoid factor titer (p = 0.01), C-reactive protein (p < 0.05), and erythrocyte sedimentation rate (p < 0.05). The RA patients with severe joint damage had significantly higher sFas level than those with mild joint damage (p < 0.05). The untreated SSc patients had significantly higher sFas levels than the treated SSc patients and healthy controls (p < 0.01). Serum sFas level was not correlated with presence of pulmonary fibrosis, DLCO or skin score. The soluble Fas molecule may provide a useful additional marker for assessment of disease activity and severity in patients with RA.

A role for leptin in immune-mediated inflammatory diseases?

Leptin, the product of the Ob gene, is a polypeptide hormone that plays an important role in the regulation of body weight by inhibiting food intake and stimulating energy expenditure. Moreover, leptin exhibits a variety of other effects including the regulation of endocrine function, reproduction and hematopoiesis. Consistently, leptin-deficient mice are not only obese, but display major hormonal disturbances, including hypercorticosteronemia, diabetes, and infertility. In addition, it has been known for many years that leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice have an altered immune response. More recent studies have shown that T cells and B cells express the long signaling leptin receptor isoform (ObRb) and that leptin exerts direct effects on T lymphocytes, including the stimulation of cell proliferation, the promotion of Th1 responses, and the protection of thymocytes from corticosteroid-induced apoptosis. Consistently, ob/ob mice are protected from inflammation mediated by T cells and B cells in some models such as experimental colitis, experimental autoimmune encephalomyelitis, and concanavalin A-induced hepatitis. Conversely, the administration of recombinant leptin increased the severity of experimental autoimmune encephalomyelitis. Using a model of antigen-induced arthritis, we demonstrated that ob/ob and db/db mice have a milder form of arthritis and that cellular and humoral immune responses to the injected antigen are decreased as compared with wild-type mice. Furthermore, ex vivo stimulated lymph node cells from ob/ob and db/db mice produced less interferon gamma and more IL-10 than cells obtained from control mice. Leptin production is regulated by various proinflammatory cytokines during the acute-phase response, and leptin stimulates the production of both proinflammatory and antiinflammatory cytokines in vitro. ob/ob mice exhibit increased susceptibility to lipopolysaccharide-induced and tumor necrosis factor alpha-induced lethality, suggesting that leptin is also involved in regulating the innate immune response. We recently examined the role of leptin in zymosan-induced arthritis (ZIA), where joint inflammation is dependent on innate immunity. Our results demonstrate that, as opposed to antigen-induced arthritis, ZIA is not impaired in ob/ob and db/db mice. On the contrary, these mice exhibit a delayed resolution of the inflammatory process, with increased circulating levels of IL-6 and serum amyloid A, and a tendency to develop more severe joint damage. Leptin deficiency thus appears to interfere with adequate control of the inflammatory response in ZIA. Although data obtained in different models of inflammatory diseases suggest that leptin plays a role in immune response, the analysis of direct effects of leptin on lymphocytes in vivo is precluded by the important hormonal and metabolic alterations, which are linked to leptin deficiency. To our knowledge, it has never been thoroughly investigated to which extent immune defects in ob/ob or db/db animals are linked to leptin deficiency or, respectively, leptin receptor deficiency per se, as opposed to confounding factors such as hypercorticosteronemia. To examine the importance of direct effects of leptin on lymphopoiesis and immune response, we generated bone marrow chimeras by transplantation of db/db bone marrow cells into lethally irradiated normal recipient mice, which provide a normal environment for the grafted cells. Donor db/db mice display a marked atrophy of the thymus as compared with db/+ controls. In bone marrow chimeras, the size and cellularity of the thymus were not different between mice grafted with db/db or db/+ bone marrow 12 weeks after the graft, suggesting that the thymic atrophy observed in db/db donors is not due to direct effects of leptin on lymphocytes. Moreover, RT-PCR analyses suggest that CD4/CD8 double positive thymocytes do not express ObRb. Further studies are in progress in order to examine which cell types respond to leptin in the thymus and whether impaired leptin signaling in lymphocytes affects immune responses after antigen challenge in db/db bone marrow chimeras.

Group B Streptococcal Sacroiliitis: Case Report and Review

Streptococcus agalactiae, or group B Streptococcus (GBS), is the major cause of neonatal meningitis and sepsis but is an uncommon infection in adults. GBS arthritis is rare, and axial involvement with sacroiliitis is even more uncommon. Microbiological diagnosis frequently relies upon positive blood cultures as synovial fluid cultures are usually negative. Severe joint damage may result due to delay in the initiation of antibiotic treatment.

Intraarticular envenomation by Trimeresurus flavomaculatus mcgregori resulting in joint destruction

Intraarticular envenomation by Trimeresurus flaromaculutus mcgregori resulting in joint destruction. Toxicon 35, 837–842, 1997. - This article reports a case of digital intraarticular envenomation from a T. flaromaculatus mcgregori pit viper resulting in severe joint damage. Bites by these snakes are rare in the U.S.A. since this species is only found in collections and zoos. Intraarticular envenomations from crotalids are rare and may result in joint destruction.

A time-study analysis to evaluate albumin carbamylation in vitro

Carbamylation is a non-enzymatic post-translational modification in which cyanate binds to molecules containing primary amine or thiol groups and forms carbamyl groups. Cyanate is in equilibrium with urea in body fluid and increased carbamylation was first reported in patients with increased urea levels such as patients suffering renal diseases. Next, increased carbamylation related to inflammation has also been described in other conditions such as cardiovascular disease.Recently, a new consequence of carbamylation has been observed: induction of an autoantibody response. We identified anti-carbamylated protein (anti-CarP) antibodies in rheumatoid arthritis (RA) patients and in patients having ‘pre-RA’ symptoms, arthralgia. The presence of anti-CarP antibodies in arthralgia patients is associated with an increased risk of developing RA. The presence of anti-CarP antibodies in RA patients is associated with more severe joint damage in RA patients who do not have anti-citrullinated protein antibodies. It is currently unknown to what extent carbamylation and/or the formation of anti-CarP antibodies contributes to the disease processes of chronic diseases such as renal diseases, cardiovascular diseases and RA. This review summarizes the current knowledge on carbamylation and the formation of anti-CarP antibodies and discusses their possibly important implications.