Arthritis Research & Therapy - Latest Articles

An in vivo investigation of the initiation and progression of subchondral cysts in a rodent model of secondary osteoarthritis

David McErlain — 2012-02-03T00:00:00Z

IntroductionSubchondral bone cysts (SBC) have been identified in patients with knee Osteoarthritis (OA) as a cause of greater pain, loss of cartilage and increased chance of joint replacement surgery. Few studies monitor SBC longitudinally, and clinical research using three-dimensional imaging techniques, such as magnetic resonance imaging (MRI), is limited to retrospective analyses as SBC are identified within an OA patient cohort. The purpose of this study was to use dual-modality, preclinical imaging to monitor the initiation and progression of SBC occurring within an established rodent model of knee OA. Methods: Eight rodents underwent anterior cruciate ligament transection and partial medial meniscectomy (ACLX) of the right knee. In vivo 9.4 T MRI and micro-computed tomography (micro-CT) scans were performed consecutively prior to ACLX and 4, 8, and 12 weeks post-ACLX. Resultant images were co-registered using anatomical landmarks, which allowed for precise tracking of SBC size and composition throughout the study. The diameter of the SBC was measured, and the volumetric bone mineral density (vBMD) was calculated within the bone adjacent to SBC. At 12 weeks, the ACLX and contralateral knees were processed for histological analysis, immuno-histochemistry, and OARSI pathological scoring. Results: At 4 weeks post-ACLX, 75 % of the rodent knees had at least 1 cyst that formed in the medial tibial plateau; by 12 weeks all ACLX knees contained SBC. Imaging data revealed the SBC originate in the presence of a subchondral bone plate breach, with evolving composition over time. The diameter of the SBC increased significantly over time (p = 0.0033) and the vBMD significantly decreased at 8 weeks post-ACLX (p = 0.033). Histological analysis demonstrated positive staining for bone resorption and formation surrounding the SBC, which were consistently located beneath the joint surface with the greatest cartilage damage. Trabecular bone adjacent the SBC lacked viable osteocytes and - combined with bone marrow changes - indicated osteonecrosis. Conclusions: This study provides insight into the mechanisms leading to SBC formation in knee OA. The expansion of these lesions is due to stress-induced bone resorption from the incurred mechanical instability. Therefore we suggest these lesions can be more accurately described as a form of OA-induced osteonecrosis, rather than 'subchondral cysts'.

Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies

Chih Long Liu — 2012-02-02T00:00:00Z

IntroductionAutoreactivity to histones is a pervasive feature of several human autoimmune disorders including systemic lupus erythematosus (SLE). Specific post-translational modifications (PTMs) of histones within neutrophil extracellular traps (NETs) may potentially drive the process by which tolerance to these chromatin-associated proteins is broken. We hypothesized that NETs and their unique histone PTMs might be capable of inducing autoantibodies that target histones. Methods: We developed a novel and efficient method for the in vitro production, visualization, and broad profiling of histone-PTMs of human and murine NETs. We also immunized Balb/c mice with murine NETs and profiled their sera on autoantigen and histone peptide microarrays for evidence of autoantibody production to their immunogen. Results: We confirmed specificity toward acetyl-modified histone H2B as well as to other histone PTMs in sera from patients with SLE known to have autoreactivity against histones. We observed enrichment for distinctive histone marks of transcriptionally silent DNA during NETosis triggered by diverse stimuli. However, NETs derived from human and murine sources did not harbor many of the PTMs toward which autoreactivity was observed in patients with SLE or in MRL/lpr mice. Further, while murine NETs were weak autoantigens in vivo, there was only partial overlap in the IgG and IgM autoantibody profiles induced by vaccination of mice with NETs and those seen in patients with SLE. Conclusions: Isolated in vivo exposure to NETs is insufficient to break tolerance and may involve additional factors that have yet to be identified.

Therapy of lupus nephritis: lessons learned from clinical research and daily care to patients

Frédéric Houssiau — 2012-01-31T00:00:00Z

Despite numerous randomized clinical trials over the last three decades for identifying the optimal treatment option for lupus nephritis, renal involvement still significantly impacts the survival and quality of life of patients with lupus and the search for the ideal immunosuppressive regimen is far from complete. The purpose of this review is to summarize the major recent achievements in the field. More specifically, the following topics will be discussed: intravenous cyclophosphamide versus mycophenolate mofetil (MMF) for induction; azathioprine versus MMF for maintenance; targeted therapies. The review will address clues for optimal global care, such as the need for complete initial evaluation, the importance of patient education, the unmasking of non-compliance to therapy, the reason for an early treatment switch in non-responding patients, the need for prolonged immunosuppression, optimal renal protection, and prevention of cardiovascular disease and other comorbidities.

A profile of immune response to herpesvirus is associated with radiographic damage in rheumatoid arthritis

John Davis — 2012-01-31T00:00:00Z

IntroductionProgression of joint damage despite appropriate therapy remains a significant problem for patients with rheumatoid arthritis (RA). This study was undertaken to identify profiles of immune response that correlate with radiographic joint damage as a first step toward the discovery of new pathogenic mechanisms of joint destruction in RA. Methods: The study included 58 patients with RA and 15 healthy controls. The profiles of cytokine release from peripheral blood mononuclear cells (PBMC) in response to stimulation for 48 hours with one of six stimuli, or in media alone, were measured. Immune response profiles identified for each stimulus were correlated with radiographic joint damage as defined by the Sharp-van der Heijde score (SHS), before and after multivariable adjustment. For profiles correlated with the SHS, the distributions of individual cytokines were evaluated in patients according to the severity of joint damage and compared to healthy controls. Results: The immune response profile for cytomegalovirus (CMV) / Epstein-Barr virus (EBV) stimulation was correlated with both the SHS total and erosion scores (r = 0.31, p = 0.018 and r = 0.33, p = 0.011, respectively). After adjusting for age, sex, disease duration, autoantibody status, CMV/EBV serological status, current disease activity, disability, and treatments, the correlation of the CMV/EBV immune response and the SHS erosion score became stronger (r = 0.43, p < 0.003). The CMV/EBV immune response correlated with CMV IgG (r = 0.44, p < 0.001), but not with EBV IgG. The most important cytokines for the CMV/EBV immune response profile were IFN-gamma, IL-2, IL-4, IL-5, IL-13 and IL-17A, all of which are associated with T-cell immunity. Both the summary immune response score and the individual responses of IFN-gamma and IL-13 to CMV/EBV stimulation were associated with greater joint damage. Conclusions: A profile of immune response to purified CMV/EBV lysates is associated with radiographic joint damage. The correlation of this immune response to CMV serology implies possible involvement of latent CMV infection. Therefore, the findings suggest that the immune response to latent CMV infection could play a fundamental role in the progression of inflammation and structural joint damage in patients with RA.

Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis?

Yves Henrotin — 2012-01-30T00:00:00Z

Glucosamine in its acetylated form is a natural constituent of some glycosaminoglycans (for example, hyaluronic acid and keratan sulfate) in the proteoglycans found in articular cartilage, intervertebral disc and synovial fluid. Glucosamine can be extracted and stabilized by chemical modification and used as a drug or a nutraceutical. It has been approved for the treatment of osteoarthritis (OA) in Europe to promote cartilage and joint health and is sold over the counter as a dietary supplement in the United States. Various formulations of glucosamine have been tested, including glucosamine sulfate and glucosamine hydrochloride. In vitro and in vivo studies have uncovered glucosamine's mechanisms of action on articular tissues (cartilage, synovial membrane and subchondral bone) and justified its efficacy by demonstrating structure-modifying and anti-inflammatory effects at high concentrations. However, results from clinical trials have raised many concerns. Pharmacokinetic studies have shown that glucosamine is easily absorbed, but the current treatment doses (for example, 1,500 mg/day) barely reach the required therapeutic concentration in plasma and tissue. The symptomatic effect size of glucosamine varies greatly depending on the formulation used and the quality of clinical trials. Importantly, the effect size reduces when evidence is accumulated chronologically and evidence for the structure-modifying effects of glucosamine are sparse. Hence, glucosamine was at first recommended by EULAR and OARSI for the management of knee pain and structure improvement in OA patients, but not in the most recent NICE guidelines. Consequently, the published recommendations for the management of OA require revision. Glucosamine is generally safe and although there are concerns about potential allergic and salt-related side effects of some formulations, no major adverse events have been reported so far. This paper examines all the in vitro and in vivo evidence for the mechanism of action of glucosamine as well as reviews the results of clinical trials. The pharmacokinetics, side effects and differences observed with different formulations of glucosamine and combination therapies are also considered. Finally, the importance of study design and criteria of evaluation are highlighted as new compounds represent new interesting options for the management of OA.

Extracellular nicotinamide phosphoribosyltransferase (NAMPT/visfatin) inhibits insulin-like growth factor-1 signaling and proteoglycan synthesis in human articular chondrocytes

Raghunatha Yammani — 2012-01-30T00:00:00Z

IntroductionObesity is one of the major risk factors for the development of osteoarthritis (OA). Although the mechanical factors appear to be critical, recent studies have suggested a role for adipokines in cartilage degradation. Chondrocytes from osteoarthritic cartilage respond poorly to Insulin-like growth factor-1 (IGF-1) and the molecular mechanism(s) involved is not clearly understood. The purpose of this study was to determine the role of nicotinamide phosphoribosyltransferase (eNAMPT/visfatin), a newly described adipokine, in regulating IGF-1 function in chondrocytes. Methods: Human articular chondrocytes isolated from normal ankle cartilage were pretreated with (0.1-5.0 ug/ml) eNAMPT overnight followed by stimulation with IGF-1(50 ng/ml) for 24 hours and proteoglycan (PG) synthesis was measured by [35S] sulfate incorporation. Chondrocytes were pretreated with eNAMPT overnight followed by IGF-1 for 10 minutes, and the cell lysates were immunoblotted for various signaling proteins that are activated by IGF-1 by using phospho-specific antibodies. In addition, chondrocytes were pretreated with MEK inhibitor (U0126) prior to stimulation with eNAMPT and IGF-1. Results: Pre-treatment of chondrocytes with eNAMPT inhibited IGF-1-stimulated PG synthesis in a dose-dependent manner. Treatment of chondrocytes with eNAMPT inhibited IGF-1-induced phosphorylation of signaling molecules, including IRS-1 and AKT. Interestingly, pretreatment of chondrocytes with eNAMPT did not inhibit IGF-1-mediated phosphorylation of the IGF-1 receptor; however, it stimulated a sustained phosphorylation of the extracellular signal-regulated kinase (ERK)/ mitogen activated protein kinase (MAPK) signaling pathway. Inhibition of the ERK/MAPK signaling pathway restored IGF-1-mediated IRS-1 and AKT phosphorylation. Conclusions: Our study demonstrates that eNAMPT/visfatin inhibits IGF-1 function in articular chondrocytes by activating the ERK/MAPK pathway independent of the IGF-1 receptor. Since eNAMPT levels are elevated in the synovial fluid of OA patients, the signaling pathway activated by eNAMPT could contribute to IGF-1 resistance in OA.

Predictors of survival in a cohort of patients with polymyositis and dermatomyositis: effect of corticosteroids, methotrexate, and azathioprine

Elena Schiopu — 2012-01-27T00:00:00Z

IntroductionThe idiopathic inflammatory myopathies are rare diseases for which data regarding the natural history, response to therapies, and factors affecting mortality are needed. We performed this study to examine the effects of treatment and clinical features on survival in polymyositis and dermatomyositis patients. Methods: 160 consecutive patients (77 polymyositis, 83 dermatomyositis) seen at the University of Michigan (1997-2003) were included. Medical records were abstracted for clinical, laboratory, and therapeutic data, including initial steroid regimen and immunosuppressive use. State vital records were utilized for mortality and cause of death data. Survival was modeled by left-truncated Kaplan-Meier estimation and Cox regression. Results: 5- and 10-year survival estimates were 77% (95% CI 66, 85), and 62% (95% CI 48, 73), respectively; rates were similar for polymyositis and dermatomyositis. Survival between sexes was similar through 5-years, and thereafter significantly lower for males (10-year survival: 18% male, 73% female; p=0.002 for 5-10 year interval). The sex disparity was restricted to the polymyositis group. Increasing age at diagnosis and non-white race were associated with lower survival. Intravenous versus oral corticosteroid use was associated with a higher risk of death among whites (hazard ratio 10.6, 95% CI 2.1, 52.8). Early survival was similar comparing patients treated with methotrexate versus azathioprine, but survival at 10 years was higher for the methotrexate-treated group (76% vs. 52%, p=0.046 for 5-10 year interval). Conclusions: Patients treated initially with intravenous corticosteroids had higher mortality, likely related to disease severity. Both methotrexate and azathioprine showed similar early survival benefit as first line immunosuppressives; survival was higher between 5-10 years in the methotrexate-treated group but could not be confirmed in multivariable modeling for the full follow-up period. Other important predictors of long-term survival included younger age, female sex, and the Caucasian race.

A randomised controlled trial of a self-management education program for osteoarthritis of the knee delivered by health professionals.

Sophie Coleman — 2012-01-27T00:00:00Z

IntroductionOur aim was to determine whether a disease specific self-management program for primary care people with osteoarthritis (OA) of the knee (the OAK program), implemented by health professionals, would achieve and maintain clinically meaningful improvements in health related outcomes compared with a control group. Methods: Medical practitioners referred 146 primary care participants with OA of the knee. Volunteers with coexistent inflammatory joint disease or serious co-morbidities were excluded. Randomisation was to either control or OAK groups. The OAK group completed a 6 week self-management program. The control group had a 6 month waiting period before receiving the OAK program. Assessments occurred at baseline, 8 weeks and 6 months. Primary outcomes were Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain and function, SF-36. Secondary outcomes were visual analog scale (VAS) pain, timed up and go (TUG), knee range of motion, quadriceps and hamstring strength- isometric contraction. Response to treatment (responders) and minimal clinically important improvements (MCII) were determined. Results: In the OAK group VAS pain improved from baseline to week 8, mean (SE) 5.21 (0.30) to 3.65 (0.29) P=<0.001. During this time period improvements in the OAK group compared with the control group and responses to treatment were demonstrated in the following outcomes: WOMAC pain, physical function and total dimensions; SF-36, physical function, role physical, body pain, vitality and social functioning domains. Additionally from baseline to week 8, the proportion of MCII was greater among the OAK than the control group for all outcomes. For the period between baseline and month 6, WOMAC pain, physical function and total dimensions significantly improved in the OAK group compared to the control group, as did SF-36, physical function, role physical, body pain, vitality and social functioning domains, and hamstring strength in both legs. During this same period, TUG test, range of motion extension and left knee flexion improved when compared with the control group, although these improvements had little clinical relevance. Conclusions: Participants in the OAK program recorded statistically significant improvements in pain, quality of life and function as demonstrated by WOMAC and SF-36 at 8 weeks and 6 months compared with a control group.

Local administration of glucocorticoids decrease synovial citrullination in rheumatoid arthritis

Dimtrios Makrygiannakis — 2012-01-27T00:00:00Z

IntroductionProtein citrullination is present in the rheumatoid synovium, presumably contributing to the perpetuation of chronic inflammation in the presence of specific autoimmunity. As a result, the present study examines the possibility that effective anti rheumatic treatment will decrease the level of synovial citrullination. Methods: Synovial biopsies were obtained from 11 rheumatoid arthritis (RA) patients before and after 8 weeks of treatment with 20 mg methotrexate weekly, 15 RA patients before and 2 weeks after an intra-articular glucocorticoid injection, 8 healthy individuals and 5 patients with osteoarthritis. Synovial inflammation was assessed by double blind semi quantitative analysis of lining thickness, cell infiltration and vascularity using a 4 points scale. Expression of citrullinated proteins (CP) with the monoclonal antibody F95 and peptidylarginine deiminase (PAD) 2 and 4 was assessed immunohistochemically by double blind semi-quantitative analysis. In vitro synovial fluid (SF), peripheral blood (PB) mononuclear cells (MC) and synovial explants obtained from RA patients were incubated with dexamethasone and analyzed by immunhistochemistry for expression of CP as well as PAD2 and PAD4 enzymes. Results: Presence of synovial CP was almost exclusive in RA compared to healthy synovium and correlated with the degree of local inflammation. Treatment with glucocorticoids but not methotrexate alters expression of synovial CP and PAD enzymes, in parallel with a decrease of synovial inflammation. Ex vivo and in vitro studies suggest also a direct effect of glucocorticoids on citrullination as demonstrated by the decrease in the level of citrullination and PAD expression following incubation of SFMC and synovial explants with dexamethasone. Conclusion: Synovial citrullination and PAD expression is depended on local inflammation and targeted by glucocorticoids.

Restrictive pulmonary function is more prevalent in patients with ankylosing spondylitis than in matched population controls and is associated with impaired spinal mobility: a comparative study

Gunnhild Berdal — 2012-01-25T00:00:00Z

IntroductionPulmonary involvement is a known manifestation in patients with ankylosing spondylitis (AS). However, previous studies have been based on small samples and the reported prevalence and associations with typical clinical features vary. The purpose of this study was to compare pulmonary function (PF) in patients with AS and population controls, and to study associations between PF and disease related variables, cardio-respiratory fitness and demographic variables in patients with AS. Methods: In a cross-sectional controlled study, 147 AS patients and 121 controls underwent examinations including demographic variables, laboratory (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) and clinical measures (disease activity ankylosing spondylitis disease activity score, ASDAS), physical function (Bath ankylosing spondylitis functional index, BASFI), spinal mobility (Bath ankylosing spondylitis metrology index, BASMI), chest expansion, cardio-respiratory fitness (peak oxygen uptake, VO2peak ) and pulmonary function test (PFT) (spirometry)). Cumulative probability plots were used to visualize associations between the ASDAS and BASMI scores and the corresponding forced vital capacity (FVC%, percentage of predicted value controlled for the influence of confounding factors) score for each patient. Univariate ANCOVAs were performed to explore group differences in PF adjusting for relevant variables, and a multiple regression model was used to estimate the explanatory power of independent variables (demographic, disease related, VO2peak) on restrictive ventilatory impairment (FVC%). Results: AS patients showed significantly lower PF values compared with controls, and significantly more patients were categorized with restrictive pattern (18% vs. 0%, P<0.001). Cumulative probability plots showed significant associations between spinal mobility measures (BASMI) and FVC% for individual patients. BASMI, chest expansion and male gender contributed significantly and independently in a multiple regression model predicting the variation of FVC% in AS patients, whereas disease activity, physical function and VO2peak did not contribute significantly. The final model explained 45% of the variance in FVC% (P<0.001). Conclusions: This study showed significantly impaired pulmonary function in the AS patients compared to controls and reference data, and demonstrated a clear relationship between reduced spinal mobility and restrictive PF in AS patients. The results support the assumption of an association between musculoskeletal limitations and restrictive respiratory impairment in AS, emphasizing the importance of maintained spinal flexibility in the management of the disease. Further, patients with severely reduced spinal mobility should be referred to pulmonary function examination and relevant follow-up treatment.