Arthritis Research & Therapy - Latest Articles

Vaccination under TNF blockade: less effective, but worthwhile

Martin Aringer — 2012-05-14T00:00:00Z

Only after biological response modifiers have become available have we begun to understand some of the complex functions of TNF in the human immune system. TNF is clearly essential for fighting intracellular pathogens, but probably not essential for fighting tumors. TNF influence on the humoral immune response, in contrast, has been more complicated to decipher, since TNF blockade is associated with both autoantibody formation and (somewhat) reduced responses to vaccination. Novel data now show that TNF is good for the humoral immune response. Vaccinations still work, however, and should be strongly recommended.

High-density lipoprotein cholesterol subfractions HDL2 and HDL3 are reduced in women with rheumatoid arthritis and may augment the cardiovascular risk of women with RA: a cross-sectional study

Elke Arts — 2012-05-14T00:00:00Z

IntroductionHigher levels of HDL subfractions HDL3-chol and particularly HDL2-chol protect for cardiovascular disease (CVD), but inflammation reduces HDL level and may impair its anti-atherogenic effect. Changed HDL composition through the impact of inflammation on HDL subfractions may contribute to the excess risk of CVD in RA. In this study, we investigated whether HDL2-chol and HDL3-chol concentrations differ between RA patients and healthy controls, and whether these levels are related to the level of RA disease activity. Methods: Non-fasting blood samples were collected from 45 RA patients and 45 healthy controls. None of the participants had a history of CVD, diabetes, or used lipid-lowering drugs. HDL2-chol and HDL3-chol concentrations were obtained by ultracentrifugation. Regression modeling was used to compare HDL subfraction levels between RA patients and healthy controls, and to analyze the effect of disease activity on HDL2-chol and HDL3-chol. Results: HDL2-chol and HDL3-chol were significantly lower in RA patients compared to healthy controls (p=0.01, p=0.005). The HDL2:HDL3 ratio was significantly lower in patients compared to controls (p=0.04). Reduced HDL2-chol and HDL3-chol levels were primarily present in female RA patients and not in male RA patients. A modest effect of DAS28 on HDL2-chol concentrations was found, after correction for disease duration, glucocorticosteroid use and BMI, with a 0.06 mmol/L decrease with every point increase in DAS28 (p=0.05). DAS28 did not significantly affect HDL3-chol concentrations (p=0.186). Conclusions: Both HDL subfractions but particularly HDL2-chol concentrations were decreased in RA, primarily in women. This seems to be associated with disease activity and is of clinical relevance. The reduction of the HDL subfraction concentrations, particularly the supposedly beneficial HDL2-chol, may negatively impact the cardiovascular risk profile of women with RA.

Body mass index influences the response to infliximab in ankylosing spondylitis

Sebastien Ottaviani — 2012-05-14T00:00:00Z

IntroductionThe excess of adipose tissue in obese individuals may have immunomodulating properties and pharmacokinetic consequences. The aim of this study was to determine whether body mass index (BMI) affects response to infliximab (IFX) in ankylosing spondylitis (AS) patients. Methods: In 155 patients retrospectively included with active AS, the BMI was calculated before initiation of IFX treatment (5 mg/kg intravenously). After 6 months of treatment, changes from baseline in BASDAI, Visual Analogue Scale (VAS) pain, C-reactive protein (CRP) level and total dose of Nonsteroidal anti-inflammatory drug (NSAID) was dichotomized with a threshold corresponding to a decrease of 50% of initial level of the measure, into binary variables assessing response to IFX (BASDAI50, VAS50, CRP50, NSAID50). Whether BMI was predictive of response to IFX therapy according to these definitions was assessed with logistic regression. Results: Multivariate analysis found a higher BMI was associated with a lower response for BASDAI50 (P=0.0003, OR 0.87 95%CI0.81-0.94VAS50 (P<0.0001, OR 0.87 95%CI[0.80-0.93]), CRP50 (P=0.0279, OR 0.93 95%CI0.88-0.99) and NSAID50 (P=0.0077, OR 0.91 95%CI0.85-0.97criteria. According to the 3 WHO BMI categories, similar results were found for BASDAI50 (77.6%, 48.9% and 26.5%, P<0.0001), VAS50 (72.6%, 40.4% and 16.7%, P<0.0001), CRP50 (87.5%, 65.7% and 38.5%, P=0.0001) and NSAID50 (63.2%, 51.5% and 34.6%, P=0.06). Conclusions: This study provides the first evidence that a high BMI negatively influences the response to IFX in AS. Further prospective studies, including assessment of the fat mass, pharmacokinetics and adipokines dosages are mandatory to elucidate the role of obesity in AS IFX response.

Elevated levels of fibrinogen-derived endogenous citrullinated peptides in synovial fluid of rheumatoid arthritis patients

Reinout Raijmakers — 2012-05-14T00:00:00Z

IntroductionRheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of the joints and the presence of autoantibodies directed against proteins containing the non-standard arginine-derived amino acid citrulline. The protein fibrinogen, which has an essential role in blood clotting, is one of the most prominent citrullinated autoantigens in RA, particularly because it can be found in the inflamed tissue of affected joints. Here, we set out to analyze the presence of citrullinated endogenous peptides in the synovial fluid of RA and arthritic control patients. Methods: Endogenous peptides were isolated from the synovial fluid of RA patients and controls by filtration and solid phase extraction. The peptides were identified and quantified using high resolution liquid chromatography-mass spectrometry. Results: Our data reveal that the synovial fluid of RA patients contains soluble endogenous peptides derived from fibrinogen, containing significant amounts of citrulline residues and in some cases also phosphorylated serine. Several citrullinated peptides are found to be more abundantly present in the synovial fluid of RA patients compared to patients suffering from other inflammatory diseases affecting the joints. Conclusions: The increased presence of citrullinated peptides in RA patients points towards a possible specific role of these peptides in the immune response at the basis of the recognition of citrullinated peptides and proteins by RA patient autoantibodies.

Increased type II collagen cleavage by cathepsin K and collagenase activities with aging and osteoarthritis in human articular cartilage

Valeria Dejica — 2012-05-14T00:00:00Z

IntroductionThe intra-helical cleavage of type II collagen by proteases including collagenases and cathepsin K is increased with aging and osteoarthritis (OA) in cartilage as determined by immunochemical assays. The distinct sites of collagen cleavage generated by collagenases and cathepsin K in healthy and OA human femoral condylar cartilages were identified and compared. Methods: Fixed frozen cartilage sections were examined immunohistochemically, using antibodies that react with the collagenase-generated cleavage neoepitopes, C2C and C1,2C, and the primary cleavage neoepitope (C2K) generated in type II collagen by the action of cathepsin K and possibly by other proteases but not by any collagenases studied to date. Results: In most cases the staining patterns for collagen cleavage were similar for all three epitopes: weak to moderate mainly pericellular staining in non-OA cartilage from younger individuals and stronger, more widespread staining in ageing and OA cartilages that often extended from the superficial to the mid/deep zone of the tissue. In very degenerate OA specimens, with significant disruption of the articular surface, staining was distributed throughout most of the cartilage matrix. Conclusions: Cleavage of collagen by proteases usually arises pericellularly around chondrocytes at and near the articular surface, subsequently becoming more intense and extending progressively deeper into the cartilage with ageing and OA. The close correspondence between the distributions of these products suggests that both collagenases and cathepsin K, and other proteases that may generate this distinct cathepsin K cleavage site, are usually active in the same sites in the degradation of type II collagen.

Low-dose oral prednisone improves clinical and ultrasonographic remission rates in early rheumatoid arthritis. Results of a 12 month open-label randomized study.

Carlomaurizio Montecucco — 2012-05-14T00:00:00Z

IntroductionIn early rheumatoid arthritis (RA), low-dose oral prednisone (PDN) co-medication yields better clinical results than monotherapy with disease modifying antirheumatic drugs (DMARDs). In addition, ultrasonographic (US) evaluation reveals rapid and significative effects of glucocorticosteroids on subclinical synovitis. No data currently exists which examines the clinical and US results offered by GC co-medication over DMARD monotherapy in early RA patients. Methods: Two hundred and twenty (220) patients with early RA (<1 year from clinical onset) were treated according to a low disease activity (LDA) targeted step-up protocol including methotrexate (MTX) and, in the active treatment arm, low-dose (6.25 mg/d) oral PDN over 12 months. Clinical disease activity measures were collected at baseline, 2, 4, 6, 9 and 12 months, and US examination of hands was performed at baseline, 6 and 12 months. Grey-scale (GS) and power Doppler (PD) synovitis were scored (0 to 3) for each joint. At 12 months, clinical remission, according to disease activity score 28 (DAS28), was defined as clinical outcome, and total joint PD score=0 (PD negativity) as imaging outcome. Results: Each group included 110 patients with comparable demographic, clinical, laboratory and US characteristics. At 12 months, LDA rate was similar in the 2 groups, whilst clinical remission rate (RR 1.61 [95%CI 1.08, 2.04]) and PD negativity rate (RR 1.31 [95%CI 1.04, 1.64]) were significantly higher in MTX+PDN group. Conclusions: In early RA, despite a similar response rate in terms of LDA, low-dose oral PDN co-medication led to a higher proportion of clinical remission and PD negativity compared to MTX monotherapy, thus ensuring a better disease activity control.Trial Registration: Current Controlled Trials ISRCTN2486111

Resistin in idiopathic inflammatory myopathies

Maria Filkova — 2012-05-11T00:00:00Z

IntroductionTo evaluate and compare the serum levels and local expression of resistin in patients with idiopathic inflammatory myopathies to controls, and to determine the relationship between resistin levels, inflammation and disease activity. Methods: Serum resistin levels were determined in 42 patients with inflammatory myopathies and 27 healthy controls. The association between resistin levels, inflammation, global disease activity and muscle strength was examined. The expression of resistin in muscle tissues from patients with inflammatory myopathies and healthy controls was evaluated. Gene expression and protein release from resistin-stimulated muscle and mononuclear cells were assessed. Results: In patients with inflammatory myopathies, the serum levels of resistin were significantly higher than those observed in controls (8.53+/-6.84 vs. 4.54+/-1.08 ng/ml, P<0.0001) and correlated with CRP levels (r=0.328, P=0.044) and global disease activity score MYOACT (r=0.382, P=0.026). Stronger association was observed between the levels of serum resistin and C-reactive protein (CRP) levels (r=0.717, P=0.037) as well as myositis disease activity assessment visual analogue scales (MYOACT; r=0.798, P=0.007), and there was a trend towards correlation between serum resistin and myoglobin levels (r=0.650, P=0.067) in anti-Jo-1 positive patients. Furthermore, in patients with DM, serum resistin levels significantly correlated with MYOACT (r=0.667, P=0.001), creatine kinase (r=0.739, P=0.001) and myoglobin levels (r=0.791, P=0.0003) and showed a trend towards correlation with CRP levels (r=0.447, P=0.067). Resistin expression in muscle tissue was significantly higher in patients with inflammatory myopathies compared to controls, and resistin induced the expression of interleukins (IL)-1beta and IL-6 and monocyte chemoattractant protein (MCP)-1 in mononuclear cells but not in myocytes. Conclusions: The results of this study indicate that higher levels of serum resistin are associated with inflammation, higher global disease activity index and muscle injury in patients with myositis-specific anti-Jo-1 antibody and patients with dermatomyositis. Furthermore, up-regulation of resistin in muscle tissue and resistin-induced synthesis of pro-inflammatory cytokines in mononuclear cells suggest a potential role for resistin in the pathogenesis of inflammatory myopathies.

Nothing lasts forever - a critical look at sustained remission

Daniel Aletaha — 2012-05-09T00:00:00Z

Remission is key to prevent progression of rheumatoid arthritis, but it is still rarely seen in clinical practice, not to speak of sustained remission, which is the best possible disease outcome of rheumatoid arthritis. New strategies and recommendations focus on achievement of remission, but it is unclear how long remission can actually be maintained in clinical practice. A study by Prince and colleagues gives insights into this question, and raises some other questions for the future.

Mycophenolic acid counteracts B cell proliferation and plasmablast formation in patients with systemic lupus erythematosus

Sebastian Eickenberg — 2012-05-09T00:00:00Z

IntroductionClinical trials revealed a high efficacy of mycophenolate mofetil (MMF) in inducing and maintaining remission in patients with class III-V-lupus nephritis. Also extrarenal manifestations respond to MMF treatment. However, few attempts have been undertaken to delineate its mechanism of action in systemic lupus erythematosus (SLE) a disease characterized by enhanced B cell activation. Methods: Clinical and paraclinical parameters of 107 patients with SLE were recorded consecutively and analyzed retrospectively. Patients were divided into treatment groups (MMF: n=39, azathioprine (AZA) n=30 and controls without immunosuppressive therapy n=38). To further delineate the effect of mycophenolic acid (MPA) on naive and memory B cells in vitro assays were performed. Results: Although patients taking AZA flared more frequently than patients on MMF or controls, the analysis of clinical parameters did not reveal significant differences. However, profound differences in paraclinical parameters were found. B cell frequencies and numbers were significantly higher in patients taking MMF compared to those on AZA but lower numbers and frequencies of plasmablasts were detected compared to AZA-treated patients or controls. Notably, MMF treatment was associated with a significantly higher frequency and number of transitional B cells as well as naive B cells compared to AZA treatment. Differences in T cell subsets were not significant. MPA abrogated in vitro proliferation of purified B cells completely but had only moderate impact on B cell survival. Conclusions: The thorough inhibition of B cell activation and plasma cell formation by MMF might explain the favorable outcomes of previous clinical trials in patients with SLE, since enhanced B cell proliferation is a hallmark of this disease.

Long-term stability of anti-cyclic citrullinated peptide antibody status in patients with early inflammatory polyarthritis

Marian Burr — 2012-05-09T00:00:00Z

IntroductionThe utility of reassessing anti-cyclic citrullinated peptide (anti-CCP) antibody status later in disease in patients presenting with early undifferentiated inflammatory polyarthritis, particularly in those who test negative for both anti-CCP and rheumatoid factor (RF) at baseline, remains unclear. We aimed therefore to determine the stability of CCP antibody status over time and the prognostic utility of repeat testing in subjects with early inflammatory polyarthritis (IP). Methods: Anti-CCP and RF were measured at baseline and 5 years in 640 IP patients from the Norfolk Arthritis Register, a primary care based inception cohort. The relationship between change in anti-CCP status/titre and the presence of radiological erosions, the extent of the Larsen score and Health Assessment Questionnaire (HAQ) score by 5 years was investigated. Results: Using a cut-off of 5 U/ml, 28% subjects tested positive for anti-CCP antibodies, 29% for RF and 21% for both at baseline. Nine (2%) anti-CCP negative patients seroconverted to positive and 9 (4.6%) anti-CCP positive individuals became negative between baseline and 5 years. In contrast, RF status changed in 17% of subjects. However, change in RF status was strongly linked to baseline anti-CCP status and was not independently associated with outcome. Ever positivity for anti-CCP antibodies by 5 years did not improve prediction of radiographic damage compared to baseline status alone (accuracy 75% vs 74%). A higher baseline anti-CCP titre (but not change in anti-CCP titre) predicted worse radiological damage at 5 years (P <0.0001), even at levels below the cut-off for anti-CCP positivity. Thus, a titre of 2-5U/ml was strongly associated with erosions by 5 years (odds ratio 3.6 (1.5,8.3); P = 0.003). Conclusions: Repeat testing of anti-CCP antibodies or RF in patients with IP does not improve prognostic value and should not be recommended in routine clinical practice.