Prevention of adjuvant arthritis by cyclosporine in rats

The effect of cyclosporine A during the development phase of adjuvant arthritis was studied in 40 female rats. Five groups of eight animals each received oral cyclosporine, 2.5, 5, 10, 20, or 30 mg/kg daily for 30 days. Also, eight normal and eight diseased rats served as placebo controls. At the time of inoculation of the adjuvant suspension on day 0, measurement of disease parameters (paw swelling and vertebral density) was started concomitantly with beginning of therapy. On completion of the study, the animals were killed, and after measurement of total skeletal and segmental (hind legs and caudal spine plus two caudal vertebrae) calcium, the two assessed vertebrae and both femoral condyles were removed for histomorphometric evaluation (vertebrae) and for estimation of glycosaminoglycan (GAG) content of cartilage. Blood for osteocalcin determinations also was taken at term from control and untreated arthritic rats and from animals that had received 10 mg/kg cyclosporine. Treatment with 2.5 mg/kg was ineffective, but doses between 5 and 20 mg/kg prevented the development of articular and osseous lesions. The 20 mg/kg dose showed no better effect than 10 mg/kg. This was shown by the absence of inflammation and the presence of normal condylar GAG and total mineral content in the areas screened. Untreated animals showed marked reductions in all of these parameters. The 30 mg/kg dose was effective in blocking the GAG loss, but significant reductions in bone density and trabecular volume were seen. There was a close correlation between GAG and bone density values, suggesting a common causal relationship. Circulating osteocalcin was significantly elevated in the untreated animals with adjuvant arthritis.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental arthritis: effect on growth parameters and total skeletal calcium

Aim of the study was to investigate the possible mechanisms leading to stunted growth and osteoporosis in experimental arthritis. Fourty-two female rats of 7-8 weeks of age were randomly assigned to three groups of 14 animals each: (a) controls; (b) adjuvant-inoculated (AA); and (c) adjuvant-inoculated rats receiving 10 mg cyclosporin A (CsA) orally for 30 days. Biological parameters studied were: hindpaw swelling; vertebral length progression expressed as Delta increments between days 1 and 30 as a parameter of skeletal growth, and estimation of total skeletal mineral content by dual energy X-ray absorptiometry (n=10 each group) on day 30. Endocrine parameters measured were pulsatile release of growth hormone (rGH) on day 30 following jugular cannulation and measurement of insulin-like growth factor (IGF-1) in pooled plasma from rGH profiles. Results can be summarized as follows: Untreated AA rats exhibited local signs of inflammation in comparison with controls (hindpaw diameter 8.1-8.9 mm vs. 5.3-5.6 mm in controls). Treatment with CsA normalized this parameter (4.9-5.6 mm). Vertebral growth was significantly retarded in AA rats in comparison with controls (214+/-32 vs. 473+/-33 microm; p<0.001). Administration of CsA normalized vertebral size increment with a clear tendency to overgrowth (523+/-43 microm, n.s.). There was also a marked reduction in total skeletal mineral content in diseased (AA) rats as compared to controls (5.8+/-0.1 vs. 7.5+/-0.1g [OH-apatite]; p<0.001), and a moderate but significant increment above controls in the group receiving CsA (8.0+/-0.1 vs. 7.5+/-0.1g [OH-appatite]; p<0.04). Integrated rGH profiles exhibited a significant fall in arthritic rats and were completely restored to normal under CsA treatment. A trend toward higher rGH values was observed in the latter group (2908+/-554 in AA vs. 8317+/-1492 ng/ml/240 min in controls; p<0.001, and 10940+/-222 ng/ml/240 min, n.s. in the CsA group). There was a good correlation between skeletal growth and rGH pulsatility (r=0.81; p<0.001). IGF-1 followed a similar pattern (630+/-44 in AA vs. 752+/-30 ng/ml in controls; p<0.04, and 769+/-59 ng/ml in the CsA group, n.s. vs. controls). Thus, a clear tendency to skeletal overgrowth following treatment was observed in agreement with the hormonal data. It can therefore be concluded that, in experimental arthritis, attenuated GH-spiking and reduced circulating IGF-1 appear to be causally related to growth retardation, probably mimicking signs and symptoms observed in juvenile arthritis. Therapy with CsA is followed by normalization of hormonal and biological parameters accompanied by a catch up phenomenon in skeletal growth which is also observed clinically in juvenile arthritis. Generalized osteopenia is a prominent feature seemingly connected with the growth abnormalities as they parallel each other during the evolution of the disease and respond equally to therapy.

Hepatoprotective effect of tumour necrosis factor alpha blockade in psoriatic arthritis: a cross-sectional study

Objective To evaluate the impact of tumour necrosis factor α (TNFα) blockers on the presence of liver fibrosis in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with methotrexate (MTX). Methods Participants were consecutive patients with RA and PsA who had undergone MTX treatment for at least 1 year ± TNF blockade for over 6 months. Liver fibrosis was assessed using non-invasive transient elastography (FibroScan). Regression models were used to compare FibroScan values of patients with RA and patients with PsA receiving TNFα blockers with those who were not. Results FibroScan assessments were performed on 51 patients with RA and 43 patients with PsA. Compared to patients with RA, those with PsA were predominantly young men, received lower cumulative dosages of MTX and exhibited a higher incidence of liver steatosis and hyperlipidaemia. An abnormal result was observed in 7.1% of the anti-TNFα-naïve and in 13% of the anti-TNFα-treated patients in the RA group and in 30% of the anti-TNFα-naïve and 4.3% of the anti-TNFα-treated patients in the PsA group (OR=0.11, 95% CI 0.02 to 0.98). Results of the PsA group were robust when adjusted for baseline characteristics. Conclusion The results suggest a protective effect of TNFα inhibitors against the development of liver fibrosis in patients with PsA.

Inter- and intraobserver reliability of the COFAS end-stage ankle arthritis classification system

End-stage ankle arthritis should have an appropriate classification to assist surgeons in the management of end-stage ankle arthritis. Outcomes research also requires a classification system to stratify patients appropriately.

Metacarpophalangeal joints in rheumatoid arthritis: delayed gadolinium-enhanced MR imaging of cartilage - a feasibility study

To evaluate the feasibility of delayed gadolinium-enhanced magnetic resonance (MR) imaging of the cartilage of metacarpophalangeal (MCP) joints in patients with rheumatoid arthritis (RA) compared with that in control subjects.

Postmortem imaging-guided biopsy as an adjuvant to minimally invasive autopsy with CT and postmortem angiography: a feasibility study

Although postmortem CT suffices for diagnosing most forms of traumatic death, the examination of natural death is, to date, very difficult and error prone. The introduction of postmortem angiography has led to improved radiologic diagnoses of natural deaths. Nevertheless, histologic changes to tissues, an important aspect in traditional examination procedures, remain obscure even with CT and CT angiography. For this reason, we examined the accuracy of a minimally invasive procedure (i.e., CT angiography combined with biopsy) in diagnosing major findings and the cause of death in natural deaths.

Cardiovascular complications of conventional and targeted adjuvant breast cancer therapy

Adjuvant therapy has improved the survival of women with early breast cancer (BC). Meta-analyses suggest that anthracycline-based regimens reduced the annual BC death rate by 40% in women below the age of 50 and 20% in older women. Novel agents designed to modulate abnormal growth factor signaling in and around the BC cell further increase patients' chances of survival. However, both conventional chemotherapeutic agents as well as some of the novel signaling inhibitors can induce important cardiovascular side-effects, potentially attenuating the progress made in recent years. The mechanism of cancer drug-induced cardiovascular complications varies greatly with some compounds inducing irreversible myocardial cell damage, while others lead to temporary cell dysfunction. The challenge of the future will be to prospectively discriminate between irreversible damage which can lead to progressive cardiovascular disease and reversible cardiovascular dysfunctions without further prognostic implications. Since adjuvant therapy for BC is potentially curative, emphasis must be placed on finding treatments combining maximum efficacy with the minimum of long-term side-effects in order to achieve survival with preserved quality of life.

Abnormal bone geometry at the metacarpal bone shaft of rheumatoid arthritis patients with maintained muscle-bone relationship

OBJECTIVES:: Metacarpal juxta-articular bone is altered in Rheumatoid Arthritis (RA). However, a detailed analysis of disease related geometrical adaptations of the metacarpal shaft is missing. The aim of the present study was to assess the role of RA disease, forearm muscle cross-sectional area (CSA), age and sex on bone geometry at the metacarpal shaft. METHODS:: In 64 RA patients and 128 control subjects geometric properties of the third metacarpal bone mid-shaft and forearm muscle CSA were measured by peripheral quantitative computed tomography (pQCT). Linear models were performed for cortical CSA, total bone CSA, polar stress-strain Index (polar SSI, a surrogate for bone's resistance to bending and torsion), cortical thickness and Metacarpal Index (MI=cortical CSA/total CSA) with explanatory variables muscle CSA, age, RA status and sex. RESULTS:: Forearm muscle CSA was associated with cortical and total metacarpal CSA, and polar SSI. RA group status was associated with all bone parameters except cortical CSA. There was a significant interaction between RA status and age, indicating that the RA group had a greater age-related decrease in cortical CSA, cortical thickness and MI. CONCLUSIONS:: Bone geometry of the metacarpal shaft is altered in RA patients compared to healthy controls. While bone mass of the metacarpal shaft is adapted to forearm muscle mass, cortical thickness and MI are reduced but outer bone shaft circumference and polar SSI increased in RA patients. These adaptations correspond to an enhanced aging pattern in RA patients.

Do new biologics meet the unmet medical need in rheumatoid arthritis? Safety and efficacy of abatacept following B-cell depletion

Sir, anti TNF-α agents (aTNFs) are the most commonly prescribed biological agents in RA. More recently abatacept (ABA), a T-cell costimulation modulator, and rituximab (RTX), a monoclonal antibody directed against CD20, have become available. Observational studies suggest that switching to a new drug class may be more effective in uncontrolled RA than switching to a class of biologics to which the patient had unsuccessfully been exposed [1]. Information about the efficacy and safety of cycling strategies through third-line biologics is lacking. This study aimed to analyse the effectiveness and safety of switching patients to ABA as the third biological class after failure of aTNF plus RTX. The Swiss Clinical Quality Management (SCQM) programme for RA is a longitudinal population-based cohort, which has been approved by the local ethics committees of all participating centres [2]. For this analysis, we collected all the …

Reduced trabecular bone mineral density and cortical thickness accompanied by increased outer bone circumference in metacarpal bone of rheumatoid arthritis patients: a cross-sectional study

Introduction The objective of this study was to assess three-dimensional bone geometry and density at the epiphysis and shaft of the third meta-carpal bone of rheumatoid arthritis (RA) patients in comparison to healthy controls with the novel method of peripheral quantitative computed tomography (pQCT). Methods PQCT scans were performed in 50 female RA patients and 100 healthy female controls at the distal epiphyses and shafts of the third metacarpal bone, the radius and the tibia. Reproducibility was determined by coefficient of varia-tion. Bone densitometric and geometric parameters were compared between the two groups and correlated to disease characteristics. Results Reproducibility of different pQCT parameters was between 0.7% and 2.5%. RA patients had 12% to 19% lower trabecular bone mineral density (BMD) (P ≤ 0.001) at the distal epiphyses of radius, tibia and metacarpal bone. At the shafts of these bones RA patients had 7% to 16% thinner cortices (P ≤ 0.03). Total cross-sectional area (CSA) at the metacarpal bone shaft of pa-tients was larger (between 5% and 7%, P < 0.02), and relative cortical area was reduced by 13%. Erosiveness by Ratingen score correlated negatively with tra-becular and total BMD at the epiphyses and shaft cortical thickness of all measured bones (P < 0.04). Conclusions Reduced trabecular BMD and thinner cortices at peripheral bones, and a greater bone shaft diameter at the metacarpal bone suggest RA spe-cific bone alterations. The proposed pQCT protocol is reliable and allows measuring juxta-articular trabecular BMD and shaft geometry at the metacarpal bone.

Is IgG galactosylation the relevant factor for pregnancy-induced remission of rheumatoid arthritis?

During pregnancy, most patients with rheumatoid arthritis (RA) experience spontaneous improvement of their disease activity. Among the soluble candidates that have been investigated in search for the most relevant disease-remitting factor are the galactosylation levels of immunoglobulin G (IgG). In RA, a higher percentage of IgG lacking the terminal galactose residues, thought to play a pro-inflammatory role, is found. During pregnancy, however, IgG galactosylation levels increase and correlate with improved disease activity. The question remains whether the increase in IgG galactosylation during pregnancy is a mere epiphenomenon or a true remission-inducing factor.

Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant chemotherapy trials

Pathological complete response (pCR) to neoadjuvant treatment correlates with outcome in breast cancer. We determined whether characteristics of neoadjuvant therapy are associated with pCR. We used multi-level models, which accounted for heterogeneity in pCR across trials and trial arms, to analyze individual patient data from 3332 women included in 7 German neoadjuvant trials with uniform protocols. PCR was associated with an increase in number of chemotherapy cycles (odds ratio [OR] 1.2 for every two additional cycles; P = 0.009), with higher cumulative anthracycline doses (OR 1.6; P = 0.002), higher cumulative taxane doses (OR 1.6; P = 0.009), and with capecitabine containing regimens (OR 1.62; P = 0.022). Association of pCR with increase in number of cycles appeared more pronounced in hormone receptor (HR)-positive tumors (OR 1.35) than in HR-negative tumors (OR 1.04; P for interaction = 0.046). Effect of anthracycline dose was particularly pronounced in HER2-negative tumors (OR 1.61), compared to HER2-positive tumors (OR 0.83; P for interaction = 0.14). Simultaneous trastuzumab treatment in HER2-positive tumors increased odds of pCR 3.2-fold (P < 0.001). No association of pCR and number of trastuzumab cycles was found (OR 1.20, P = 0.39). Dosing characteristics appear important for successful treatment of breast cancer. Longer treatment, higher cumulative doses of anthracyclines and taxanes, and the addition of capecitabine and trastuzumab are associated with better response. Tailoring according to breast cancer phenotype might be possible: longer treatment in HR-positive tumors, higher cumulative anthracycline doses for HER2-negative tumors, shorter treatment at higher cumulative doses for triple-negative tumors, and limited number of preoperative trastuzumab cycles in HER2-positive tumors.