M. Vis

Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFκB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis

Objectives: To examine whether treatment with anti-tumour necrosis factor (TNF) α prevents loss of bone mineral density (BMD) at the spine and hip (generalised) and in the hands (local) of patients with rheumatoid arthritis, and to study the changes in markers of bone metabolism, including receptor activator of the NFκB ligand (RANKL) and osteoprotegerin (OPG), during anti-TNF treatment. Patients and methods: 102 patients with active rheumatoid arthritis, who were treated with infliximab during 1 year, were included in this open cohort study. The BMD of the spine and hip (dual x ray absorptiometry) and hands dual x ray radiogrammetry was measured before the start of treatment and after 1 year. Changes in osteocalcin formation, β-isomerised carboxy terminal telopeptide of type 1 collagen (β-CTx, resorption), RANKL and OPG were determined at 0, 14, 30 and 46 weeks. Results: The BMD of the spine and hip was unchanged during treatment with infliximab, whereas BMD of the hand decreased significantly by 0.8% (p<0.01). The BMD of the hip in patients with a good European League Against Rheumatism response showed a favourable change compared with patients not achieving such a response. Serum β-CTx and RANKL were both considerably decreased compared with baseline at all time points. The decrease in β-CTx was associated with the decrease in Disease Activity Score of 28 joints and C reactive protein during the 0–14 weeks interval. Conclusion: In patients with rheumatoid arthritis treated with infliximab, spine and hip bone loss is arrested, whereas metacarpal cortical hand bone loss is not stopped. The outcome of the study also supports a relationship between clinical response, in terms of reduced inflammatory activity, and changes in bone loss of the spine, hip and hands.

Changes in lipid profile during infliximab and corticosteroid treatment in rheumatoid arthritis

Objective: To evaluate the effects of infliximab and corticosteroid treatment on the lipid profile in patients with active rheumatoid arthritis (RA). Methods: Infliximab infusions were given at weeks 0, 2, 6 and then every 8 weeks. Before each infusion, disease activity parameters (Disease Activity Index 28-Joint Score (DAS28)) C reactive protein (CRP) and lipid levels (total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, apolipoprotein A1 (apo A1) and apolipoprotein B) were measured in 80 consecutive patients with RA, who completed the study period of 48 weeks. Longitudinal analyses were used to investigate (1) the course of lipid levels over a period of time and (2) the relationship between lipids, prednisone dose and disease activity. Results: Infliximab treatment causes a significant reduction in disease activity and a concomitant decrease in prednisone dose. Although they initially improved significantly, all lipid levels had returned to baseline levels after 48 weeks, except for apo A1. Longitudinal analyses revealed significant yet opposite associations between lipid levels and disease activity and between lipid levels and prednisone dose. DAS28 improvement by 1 point was associated with an increase of 0.016 mmol/l (0.618 mg/dl) total cholesterol and 0.045 mmol/l (1.737 mg/dl) HDL-cholesterol. Reduction of 10 mg prednisone was associated with a decrease of 0.04 mmol/l (1.544 mg/dl) total cholesterol and 0.16 mmol/l (6.177 mg/dl) HDL-cholesterol. Conclusion: Overall, no changes in serum lipid levels were observed after 48 weeks of infliximab treatment. The initial beneficial effects of infliximab on the lipid profile, by means of a reduction of disease activity, are attenuated by a concomitant decrease in prednisone dose.

Inflammatory Rheumatic Disorders and Bone

Inflammatory joint diseases such as rheumatoid arthritis, as well as other rheumatic conditions, such as systemic lupus erythematosus (SLE) and ankylosing spondylitis, comprise a heterogeneous group of joint disorders that are all associated with extra-articular side effects, including bone loss and fractures. The concept of osteoimmunology is based on growing insights into the links between the immune system and bone. The pathogenesis of osteoporosis in these patients is multifactorial. We have, more or less as an example, described this extensively for patients with SLE. High disease activity (inflammation) and immobility are common factors that substantially increase fracture risk in these patients, on top of the background fracture risk based on, among other factors, age, body mass index, and gender. Although no fracture reduction has been shown in intervention studies in patients with inflammatory rheumatic diseases, we present treatment options that might be useful for clinicians who are treating these patients.

Can bone loss in rheumatoid arthritis be prevented

Rheumatoid arthritis (RA) is a systemic inflammatory disease that can lead to local joint deformations (bone erosions and joint space narrowing) and to extra-articular phenomena, including generalized osteoporosis. In addition, in patients with RA, the risk of vertebral and nonvertebral fractures is doubled. High disease activity (inflammation), immobility, and glucocorticoid use are common factors that substantially increase fracture risk in these patients, on top of the background fracture risk based on classical risk factors such as high age, low body mass, and female gender. New insights on the links between the immune system and the bone system, the field of osteoimmunology, have shown that local and generalized bone loss share common pathways. The receptor activator of nuclear factor κB ligand/osteoprotegerin pathway (RANKl/OPG) is one of the most important pathways, as it is (strongly) upregulated by inflammation. In modern treatment of RA with biologics, for example, TNFα-blocking agents and combination therapy of conventional disease-modifying antirheumatic drugs (DMARDs), clinical remission is a realistic treatment goal. As a consequence, in recent studies, it has been documented that both local and generalized bone loss is absent or minimal in those patients who are in clinical remission.

Stable bone mineral density in lumbar spine and hip in contrast to bone loss in the hands during long-term treatment with infliximab in patients with rheumatoid arthritis

Osteoporosis is a well-known complication of rheumatoid arthritis (RA), related to disease activity, steroid use and immobility.1,–,6 In a 1-year observational study it has been suggested that infliximab can have a positive effect on bone mineral density (BMD) in patients with RA.6 In the present study, patients with RA who had been treated with infliximab for 2 years and more in the Slotervaart Hospital or the VU University Medical Center were included if BMD measurements at baseline and at 2-year intervals had been performed. Patients fulfilled the American College of Rheumatology 1987 criteria and had a disease activity score in 28 joints greater than 3.2 at baseline. Infliximab (3 mg/kg) was given at 0, 2, 6 and 14 weeks and thereafter every 8 weeks. BMD measurements of the spine (L1–L4) …

Adverse events in patients with rheumatoid arthritis treated with infliximab in daily clinical practice

Infliximab is highly effective and relatively safe for the treatment of patients with rheumatoid arthritis (RA) in clinical trials.1–5 This prospective cohort study was undertaken to determine adverse events, in particular, infections in patients with RA treated with infliximab in daily clinical practice. We treated 168 patients with RA between 1 April 2000 and 1 October 2002, 82% female, with a median disease duration of 10 years (range 1–49). Inclusion criteria were 28 joint count Disease Activity Score (DAS28) of >3.5 and failure of two disease modifying antirheumatic drugs, including methotrexate. Patients with heart failure or with a malignancy 5 years before screening were excluded. After the alert about tuberculosis,6 patients starting with infliximab treatment were screened for that disease. All patients …

Preferential decrease in IgG4 anti-citrullinated protein antibodies during treatment with tumour necrosis factor blocking agents in patients with rheumatoid arthritis

Objective: To investigate the dynamics of IgG1 and IgG4 anti-citrullinated protein antibody (ACPA) subclasses during anti-tumour necrosis factor (TNF) treatment in patients with rheumatoid arthritis (RA). Methods: IgG, IgG1 and IgG4 ACPA levels were determined by ELISA on anti-citrullinated fibrinogen (ACF) and IgG1 : IgG4 ACPA ratios were calculated. A pilot study was performed in 28 ACF-positive patients treated with infliximab for one year. Confirmation of the results was obtained using a cohort of 180 consecutive patients treated with adalimumab for 28 weeks. Results: The median reduction in ACF levels was 31% for total IgG, 29% for IgG1, 40% for IgG4 and 22% for the IgG4 : IgG1 ACF ratio in the infliximab cohort. In adalimumab-treated patients, ACF levels declined 14% for total IgG and IgG1, and 36% for IgG4 ACF; the IgG4 : IgG1 ratio was reduced by 24% (all percentage values p<0.05). The decrease in antibody levels was correlated with the clinical response; European League Against Rheumatism good responders had the greatest decline in antibody levels and this effect was most pronounced for IgG4 (48% reduction). The IgG4 : IgG1 ACF ratio preferentially decreased in patients with adequate therapeutic adalimumab levels. Conclusion: ACPA subclass distribution is modulated by effective anti-inflammatory treatment. The preferential decline of IgG4 ACPA, reflected by the decreased IgG4 : IgG1 ratio, suggests a beneficial effect of anti-TNF treatment on chronic antigenic stimulation by citrullinated proteins. This effect may be directly anti-TNF mediated or the result of effective dampening of the inflammation in the rheumatoid joint.

Prevalence of Psoriatic Arthritis in Primary Care Patients with Psoriasis

To estimate the prevalence of psoriatic arthritis (PsA) in primary care patients diagnosed as having psoriasis and to estimate the prevalence of musculoskeletal symptoms in psoriasis patients in primary care.

Treatment with intravenous pamidronate is a good alternative in case of gastrointestinal side effects or contraindications for oral bisphosphonates.

BackgroundIn case of contraindications or intolerance during treatment with oral bisphosphonates (OB), administration of pamidronate intravenously is a widely used alternative.In this study we compared the effect on change in bone mineral density (BMD) of the spine and hip during long term treatment with pamidronate iv in comparison to OB.MethodsWe studied 61 patients receiving treatment for at least two years. In case of contraindications or intolerance (within 3 months) of an OB, pamidronate iv was started. BMD was measured on a Hologic 4500 and a Lunar DPX-IQ at the spine (L1-L4) and total hip.ResultsThirty-one patients were enrolled in the OB group and 30 in the intravenous pamidronate group. Mean follow-up duration (SD) was 4.3 (1.3) years. We observed a significant increase (p < 0.001) in spinal BMD, both in the OB group (8.3%) as well as in the pamidronate iv group (6.1%), but no significant difference in BMD change between the OB and pamidronate iv groups. At the hips, we observed a tendency to increased BMD in both groups, 1.1% in the OB and 1.4% in the pamidronate iv group.ConclusionWe conclude that intravenous pamidronate is a good alternative for oral bisphosphonates in the treatment of osteoporosis in patients with contraindications or intolerance during treatment with oral bisphosphonates.

Hydroxychloroquine affects bone resorption both in vitro and in vivo

We recently showed that patients with primary Sjögren syndrome (pSS) have significantly higher bone mineral density (BMD) compared to healthy controls. The majority of those patients (69%) was using hydroxychloroquine (HCQ), which may have favorable effects on BMD. The aim of the study was to evaluate whether HCQ modulates osteoclast function. Osteoclasts were cultured from PBMC‐sorted monocytes for 14 days and treated with different HCQ doses (controls 1 and 5 μg/ml). TRAP staining and resorption assays were performed to evaluate osteoclast differentiation and activity, respectively. Staining with an acidification marker (acridine orange) was performed to evaluate intracellular pH at multiple timepoints. Additionally, a fluorescent cholesterol uptake assay was performed to evaluate cholesterol trafficking. Serum bone resorption marker β‐CTx was evaluated in rheumatoid arthritis patients. HCQ inhibits the formation of multinuclear osteoclasts and leads to decreased bone resorption. Continuous HCQ treatment significantly decreases intracellular pH and significantly enhanced cholesterol uptake in mature osteoclasts along with increased expression of the lowdensity lipoprotein receptor. Serum β‐CTx was significantly decreased after 6 months of HCQ treatment. In agreement with our clinical data, we demonstrate that HCQ suppresses bone resorption in vitro and decreases the resorption marker β‐CTx in vivo. We also showed that HCQ decreases the intracellular pH in mature osteoclasts and stimulates cholesterol uptake, suggesting that HCQ induces osteoclastic lysosomal membrane permeabilization (LMP) leading to decreased resorption without changes in apoptosis. We hypothesize that skeletal health of patients with increased risk of osteoporosis and fractures may benefit from HCQ by preventing BMD loss.