The effect of gender on methotrexate prescription attitudes in Italian rheumatoid arthritis patients: the MARI study.

OBJECTIVES: The MARI study investigated the prescription patterns of methotrexate (MTX) in patients presenting with rheumatoid arthritis (RA) in Italy. The primary aims of this cross-sectional analysis from the MARI study were to investigate the effect of gender on the prescription patterns and safety of MTX therapy. METHODS: The study enrolled 1336 patients with RA. Retrospective data included patients' clinical history, previous treatment with MTX and other DMARDs, and MTX modifications in the previous 12-month period. Cross-sectional data included information about current treatment with MTX (dose and route of administration, and adverse events), concomitant medications, disease activity, and modifications of MTX treatment at study entry. The prescription patterns of MTX, rates and causes of MTX modifications were analysed according to gender. RESULTS: There were no significant differences related to gender in the prescription patterns of MTX, either at 6 months after starting MTX or at the time of study entry. In the 12 months prior to study entry, women (4%) were more likely to undergo MTX modifications (dose or route of administration) compared to men (2%, p=0.032), due to subjective intolerance, but this difference was no longer significant after controlling for confounders. At study entry, a higher proportion of women (27%) reported tolerability issues (nausea and weakness) related to MTX compared to men (14%, p=0.001). Although a similar percentage of males and females changed dose or route of administration of MTX at the time of study entry, the reasons for such modifications were dissimilar between genders. Particularly, a higher proportion of women underwent MTX modification due to intolerance (women 6% vs. men 1%, p=0.002). CONCLUSIONS: In Italy, prescription patterns of MTX do not differ between genders. However, women seem to be at higher risk of adverse events leading to MTX modifications.

Clodronate news of efficacy in osteoporosis.

Clodronate belongs to Bisphosphonates family and it has been studied especially for osteoporosis treatment, Paget's disease, osteolytic metastases, hypercalcemia malignancy and some childhood skeletal diseases. Besides the osteoporosis treatment, it has been successfully used for treating tumoral osteolysis and for bone localization of multiple myeloma, hypercalcemia malignancy, primary hyperparathyroidism, Paget's disease and algodystrophy. Filipponi study showed a statistically significant reduction of the incidence of vertebral fractures after 4 years of treatment with clodronate, intravenously administered at a dose of 200 mg every three weeks. Frediani study, published in 2003 on BONE, proved the clodronate efficacy in the prevention of fractures caused by glucocorticoid-induced osteoporosis (GIO). Clodronate doses of 800 mg/day per os and 100 mg i.m./week are substantially equivalent, because the oral absorption is about 1,9%. A higher efficacy on BMD was documented in various works, especially in cohorts of patients with a greater fracture risk, using higher doses (1600 mg per os). This has led to the hypothesis of using clodronate 200 mg i.m. formulation. Clodronate is an osteoporosis drug that can be assumed in different doses (100 mg i.m./week, clodronate 200 mg i.m. every 2 weeks) considering the risk band, identified by algorithms (FRAX o DeFRA), by BMD and by the presence of at least one risk factor. That means that it is possible to envisage a differentiated use of clodronate adapting the doses to the fracture risk and to the severity of pain symptoms, thus promoting a greater adherence to the therapy. To conclude clodronate is helpful in reducing fracture risk, is safe, well tolerated, and has a good rate cost/effectiveness in patients with fracture risk over 7% established with FRAX.

Synovial biomarkers in psoriatic arthritis.

OBJECTIVE: To find candidate biomarkers of psoriatic arthritis (PsA). A panel of synovial fluid (SF) and synovial tissue (ST) biomarkers was analyzed in patients with resistant peripheral PsA, in relation to clinical and imaging outcomes of synovitis response following serial intraarticular (IA) etanercept injections (12.5 mg). METHODS: Fourteen PsA patients with resistant knee joint synovitis were treated with 4 IA etanercept injections in a single knee joint, once every 2 weeks. Primary outcome (Thompson's knee index: THOMP) and secondary outcomes were assessed at baseline and end of study: C-reactive protein, Knee Joint Articular Index (KJAI), Health Assessment Questionnaire disability index, maximal synovial thickness (MST) by gray-scale ultrasonography, contrast-enhanced magnetic resonance imaging (C+MRI), ST-cluster differentiation (CD)45+ mononuclear cell, ST-CD31+ vessels, and ST-CD105+ angiogenic endothelial cells, along with levels of SF interleukin 1ß (IL-1ß), IL-1 receptor antagonist (Ra), and IL-6. RESULTS: At the end of the study, clinical and imaging outcomes, ST and SF biological markers were significantly reduced compared to baseline. There was a significant association between IL-6 and either THOMP or KJAI; between either ST-CD31+ or ST-CD105+ or ST-CD45+; between ST and SF biomarkers expression (CD45+ and IL-1ß) and between ST-CD45+ and both KJAI and MRI-MST. Comparing pre- versus post-IA etanercept injection changes (Δ), Δ IL-1ß was significantly correlated with both Δ IL-6 and with Δ IL-1Ra and Δ IL-6 with Δ IL-1Ra. CONCLUSION: The association to disease activity and the changes following IA treatment indicate that ST-CD45+ and ST-CD31+, along with SF-IL-6 and SF-IL-1ß, may represent candidate biomarkers of the knee synovitis response to IA tumor necrosis factor-α blockade.

Vascular perfusion kinetics by contrast-enhanced ultrasound are related to synovial microvascularity in the joints of psoriatic arthritis.

The purpose of the study was to assess the relationship of the continuous mode contrast-enhanced harmonic ultrasound (CEUS) imaging with the histopathological and immunohistochemical (IHC) quantitative estimation of microvascular proliferation on synovial samples of patients affected by sustained psoriatic arthritis (PsA). A dedicated linear transducer was used in conjunction with a specific continuous mode contrast enhanced harmonic imaging technology with a second-generation sulfur hexafluoride-filled microbubbles C-agent. The examination was carried out within 1 week before arthroscopic biopsies in 32 active joints. Perfusional parameters were analyzed including regional blood flow (RBF); peak (PEAK) of the C-signal intensity, proportional to the regional blood volume (RBV); beta (ß) perfusion frequency; slope (S), representing the inclination of the tangent in the origin; and the refilling time (RT), the reverse of beta. Arthroscopic synovial biopsies were targeted in the hypervascularity areas, as in the same knee recesses assessed by CEUS; the synovial cell infiltrate and vascularity (vessel density) was evaluated by IHC staining of CD45 (mononuclear cell) and CD31, CD105 (endothelial cell) markers, measured by computer-assisted morphometric analysis. In the CEUS area examined, the corresponding time-intensity curves demonstrated a slow rise time. Synovial histology showed slight increased layer lining thickness, perivascular lymphomonocyte cell infiltration, and microvascular remodeling, with marked vessel wall thickening with reduction of the vascular lumen. A significant correlation was found between RT and CD31+ as PEAK and CD105+ vessel density; RT was inversely correlated to RBF, PEAK, S, and ß. The study demonstrated the association of the CEUS perfusion kinetics with the histopathological quantitative and morphologic estimation of synovial microvascular proliferation, suggesting that a CEUS imaging represents a reliable tool for the estimate of the synovial hypervascularity in PsA.

Blockade of intra-articular TNF in peripheral spondyloarthritis: its relevance to clinical scores, quantitative imaging and synovial fluid and synovial tissue biomarkers.

OBJECTIVES: This open-label study is based on a translational approach with the aim of detecting changes in the clinical condition as well as in imaging and synovial biological markers in both synovial fluid (SF) and synovial tissue (ST) in peripheral spondyloarthritis (SpA) patients following intra-articular (IA) blockade of TNF-α by serial etanercept injections. METHODS: Twenty-seven SpA patients with resistant knee synovitis underwent four biweekly IA injections of etanercept (E) (12.5 mg). The primary outcome of Thompson's Knee Index (THOMP), and secondary outcomes of Knee Joint Articular Index (KJAI), C-reactive protein (CRP), HAQ-Disability Index (HAQ-DI), maximal synovial thickness (MST) according to ultrasonography (US) and contrast-enhanced magnetic resonance (C+MR) imaging, ST-CD45+ mononuclear cells (MNC) and ST-CD31+ vessels, IL-1ß, IL-1Ra and IL-6 levels in SF were assessed at baseline and at the end of the study. RESULTS: At the study end, clinical and imaging outcomes as well as ST and SF biological markers were significantly reduced compared to baseline. There were significant correlations between clinical, imaging and biological markers (CRP with either THOMP, or KJAI, or HAQ-DI or SF-IL-1Ra; US-MST with KJAI, ST-CD45+ with either THOMP, or KJAI, or ST-CD31+, or SF-IL-1ß; SF-IL-6 with either THOMP, or KJAI, or SF-IL-1ß, or IL-1Ra). CONCLUSIONS: The proof of concept study revealed early improvement either in local and systemic clinical scores, in synovial thickness measures by C+MR and US, or expression of synovial biological markers. CD45+, CD31+ in ST and IL-6 and IL-1ß in SF may be considered potential biomarkers of the peripheral SpA response to IA TNF-α blocking.

Domino Effect: mechanic factors role.

The rapid onset of the Domino Effect following the first Vertebral Compression Fracture is a direct consequence of the mechanical variations that affect the spine when physiological curves are modified. The degree of kyphosis influences the intensity of the Flexor Moment; this is greater on vertebrae D7, D8 and on vertebrae D12, L1 when the spine flexes. Fractures of D7, D8, D12 and L1 are, by far, the most frequent and also the main cause of the mechanical alterations that can trigger the Domino Effect. For these considerations vertebrae D7, D8, D12 and L1 have to be taken in consideration as "critical". In the case of critical clinical vertebral fractures it is useful to provide an indication for minimally invasive surgical reduction or intrasomatic stabilization. When occurs a fracture of a "critical vertebra", prompt restoration of the heights leads to a reduction in the Kyphosis Index and therefore in the Flexor Moment, not only of the fractured vertebra but also, in turn, of all the other metameres which, even if morphologically still intact, are structurally fragile; so, through the restoration of the mechanical vertebral proprieties, we can reduce the risk of the Domino Effect. At the same time the prompt implementation of osteoinductive therapy is indispensable in order to achieve rapid and intense reconstruction of the trabecular bone, the strength of which increases significantly in a short period of time. Clinical studies are necessary to confirm the reduction of the domino effect following a fragility fracture of "critical vertebrae" with the restoration of the mechanical properties together with anabolic therapy.

Synovial effusion and synovial fluid biomarkers in psoriatic arthritis to assess intraarticular tumor necrosis factor-α blockade in the knee joint.

INTRODUCTION: The purpose of this study was the evaluation of synovial effusion (SE), synovial fluid (SF) and synovial tissue (ST) biomarkers in relation to disease activity indexes to assess the response to intraarticular (IA) tumor necrosis factor (TNF)-α blockers in psoriatic arthritis (PsA). METHODS: Systemic and local disease activity indexes (disease activity score (DAS); the Ritchie articular index (mRAI), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); Thompson articular (THOMP) and joint articular (KJAI)-Index ) and ST samples were assessed at baseline, throughout treatment, and during the follow-up in 14 patients affected with PsA who underwent IA injections (0.5 ml to 12.5 mg) in the knee joint of etanercept (E) or placebo (P) once every two weeks for a 10-week period. Total SF white blood cell (WBC) counts (WBC/µl) and SF cytokine/chemokine (CK/CCK) levels were measured before IA-E at baseline, after IA-E, and as long as there were adequate amounts of SF for knee aspiration (post). Characterization of synovial mononuclear cell infiltration and synovial vessels was carried out in 8 out of 14 knees by staining serial sections of synovial tissue biopsies for CD45, CD3, CD68, CD31 and CD105. RESULTS: At baseline, CRP and/or ESR were significantly correlated with SF-CK (interleukin- (IL-)1ß, IL-1Ra, IL-6, IL-8) and CCK (CCL3). Post-IA injections, there was a decrease in SE in the knees in which aspiration following IA-E injection was possible as well as a significant reduction in SF WBC/µl and in SF-CK (IL-1ß, IL-1Ra, IL-6 and IL-22). Pre- and post-IA-E injections, there were significant correlations between ST markers and SF-CK (IL-1ß with CD45; IL-1ß and IL-6 with CD31) and between SF-CCK (CCL4 and CCL3 with CD3). At the end of the study, there was a significant reduction in disease activity indexes (CRP, DAS, RAI, THOMP, KJAI) as well as in the ST markers (CD45; CD3). CONCLUSIONS: Synovial effusion regression is a reliable indicator of the response to IA TNF-α blockers in PsA patients as it is confirmed by the correlation between SF biomarkers to disease activity and synovial tissue inflammation.

Co-stimulatory modulation in rheumatoid arthritis: the role of (CTLA4-Ig) abatacept.

Associations between rheumatoid arthritis (RA) susceptibility and polymorphism in multiple immunoregulatory genes suggest a role of altered T cell function in the disease. The growing relevance of the oxidative stress in RA synovitis, which results in a number of T cell signalling abnormalities, is reinforced by the demonstration of a direct NO inducing activity through the shared epitope of the HLA class II molecules HLA-DRbeta1, with secondary lymphocytes oxidative damage. Direct T cell/macrophage contact-dependent activation, one of the driving mechanisms of synovitis, is mediated by co-stimulatory molecules as well as cell membrane cytokines and may also result in an impaired suppressive function of T regulatory cells (Treg) in RA joints. The fusion of CTLA4 extracellular binding domain to the Fcgamma1 allows to obtain a soluble CTLA4 receptor, the dimeric recombinant human fusion protein abatacept (CTLA4-Ig). The improved knowledge of the CTLA4-B7 co-stimulation regulatory mechanisms by signals delivered into DCs and Tregs provides multiple potential targets for the abatacept treatment. CTLA4-Ig shows the capacity, either ex vivo or in vivo, to interrupt at multiple steps the ongoing inflammatory and destructive process, and to concur in restoring the immunoregulatory balance in RA.

Contrast medium in power Doppler ultrasound for assessment of synovial vascularity: comparison with arthroscopy.

OBJECTIVE: To evaluate the reliability of contrast-unenhanced power Doppler (CUPD) and contrast-enhanced power Doppler (CEPD) ultrasound (US) assessment of synovial vascularity of knee joint synovitis by prospective comparison with the "gold standard," arthroscopy. METHODS: A total of 18 knees of 17 patients with refractory rheumatoid and psoriatic knee joint synovitis were examined by US. Recognition of PD synovial vessel flow and its spatial arrangement in relation to the pannus/cartilage interface (P/CI) or fluid/synovium interface (F/SI) were studied by CUPD- and CEPD-US after a single intravenous bolus of galactosel palmitic acid (Levovist). Arthroscopy video recordings were reanalyzed by computer image analysis to assess synovial vascular marking. CUPD and CEPD flow signal scores were compared with each other and with corresponding vascular marking scores. Using villous vascular marking as reference, CUPD and CEPD sensitivity and specificity were measured. Interobserver variability was evaluated. RESULTS: Compared with the unenhanced PD method, contrast administration increased the PD flow signal score in 13/18 knees (72.2%), allowing increased detection of F/SI PD flow signal configuration (p < 0.018) and of the coexistence of P/CI and F/SI PD imaging (p < 0.0078). With arthroscopy as reference, contrast-enhanced PD was found to be more useful than the unenhanced method, showing more reproducible PD signal scores (p = 0.05 vs p = nonsignificant), as well as higher sensitivity (80% vs 30%), but lower specificity (62% vs 87%), in the recognition of increased vascularity of synovial villi. Interobserver agreement was 100%. CONCLUSION: The prospective comparison with arthroscopy showed the reliability of the CEPD method in synovial vessel recognition and its potential clinical usefulness in assessment of knee joint synovitis.