Novel glucocorticoids: where are we now and where do we want to go?

Glucocorticoid (GC) therapy is widely accepted as effective treatment for many inflammatory conditions. However, the potential of GC to produce adverse effects may prompt both patients and prescribing doctors to take a critical view on these important drugs. The increasing awareness of potential side effects suggests that the improvement of the benefit:risk ratio represents both a current need and an ongoing challenge. The developing and detailed knowledge on mechanisms of GC action has resulted in exploration of numerous approaches to optimise treatments with these important drugs. Most advanced is a chronotherapeutic formulation of prednisone (termed modified- or delayed-release prednisone) that has been recently approved in many European and other countries, and very recently also in the United States. Another interesting example is the development of selective GC receptor (GR) agonists, with clinical studies being currently underway. The development of so called liposomal GC is ongoing. However, another approach, the synergistic combination of prednisolone and dipyridamole, has been recently discontinued because a phase 2b study with the treatment in patients with rheumatoid arthritis showed a statistically significant improvement in disease activity score measured in 28 joints (DAS28) compared with placebo, but not compared with prednisolone alone. Other interesting developments and promising concepts include the development of nitrosteroids, targeting the membrane-bound GR and the use of extracts of the medicinal plant Tripterygium wilfordii Hook F.

Increase in prophylaxis of glucocorticoid-induced osteoporosis by pharmacist feedback: a randomised controlled trial.

UNLABELLED: The aim of this study was to determine whether feedback by pharmacists to prescribers of patients eligible for glucocorticoid-induced osteoporosis prophylaxis would stimulate the prescribing of osteoporosis prophylaxis. The intervention did not significantly increase the prescribing of bisphosphonates in the total study population, but a significant increase was seen in men and in the elderly. However, the proportion of bisphosphonate-treated patients remained low. INTRODUCTION: The aim of this study was to determine whether feedback by pharmacists to prescribers of patients eligible for glucocorticoid-induced osteoporosis prophylaxis (GIOP) would stimulate the implementation of the Dutch GIOP guideline. METHODS: This randomised controlled trial included 695 patients who were dispensed ≥675 mg prednisone equivalents without a concomitant bisphosphonate prescription within 6 months before baseline. Pharmacists were asked to contact the physicians of GIOP-eligible patients in the intervention group to suggest osteoporosis prophylaxis. The primary endpoint was a bisphosphonate prescription. Secondary endpoints were a prescription of calcium supplements, vitamin D or any prophylactic osteoporosis drug (bisphosphonate, calcium supplements, vitamin D). RESULTS: The group assigned to the intervention was slightly younger than the control group (68.7 ± 15.4 vs. 65.9 ± 16.9 years, p = 0.02) and used hydrocortisone more often (7.0% vs. 3.1%, p = 0.02). Within 6 months, the intervention did not significantly increase the prescribing of bisphosphonates (11.4% after intervention vs. 8.0% for controls; hazard ratio [HR] 1.47, 95% confidence interval [CI] 0.91-2.39). However, subgroup analyses showed a significant increase for the primary endpoint in men (12.8% vs. 5.1%, HR 2.53, 95% CI 1.11-5.74) and patients ≥70 years (13.4% vs. 4.9%, HR 2.88, 95% CI 1.33-6.23). The prescribing of calcium and vitamin D was not significantly altered. CONCLUSION: This study showed that active identification of patients eligible for GIOP by pharmacists did not significantly increase the prescribing of bisphosphonates in the total study population, but there was an increase in men and the elderly. However, the proportion of GIOP-treated patients remained low.

The intra-articular distribution of 90yttrium does not influence the clinical outcome of radiation synovectomy of the knee.

OBJECTIVES: To assess the impact of the intra-articular distribution of (90)yttrium-citrate ((90)Y) on the clinical effect of radiosynoviorthesis (RSO) of the knee and on (90)Y leakage from this joint. METHODS: Patients with arthritis of the knee received 185 MBq (90)Y combined with a glucocorticoid, followed by clinical bed rest. Intra-articular (90)Y distribution, measured with a dual-head gamma camera immediately or after 24 hours, was scored as mainly diffuse or mainly focal. Leakage to regional lymph nodes, the liver and spleen was assessed with a dual-head gamma camera after 24 hours. Clinical effect was scored after 6 months by a composite change index (CCI), range 0-12; responders were defined as having a CCI > or =6. RESULTS: Seventy-eight knees of 69 patients, mostly suffering from undifferentiated arthritis (42%) or RA (28%), were treated. (90)Y distribution was mainly diffuse in 54% and mainly focal in 46% with clinical response rates of 40% versus 56%, respectively, p = 0.3. CCI was not correlated with distribution. (90)Y leakage was found only to the liver and the spleen (mean leakage 0.4% and 1.1%, respectively). Leakage was significantly less in case of diffuse intra-articular (90)Y distribution, whereas leakage to the liver was correlated with distribution (r = 0.68, p<0.001). (90)Y leakage was not correlated with CCI. CONCLUSIONS: Intra-articular (90)Y distribution does not influence the clinical effect of RSO of the knee. Although (90)Y leakage from the joint is less if (90)Y distributes diffusely in the joint cavity, leakage does not seem to hamper the clinical effect.

[Effectiveness of dietary supplements in patients with osteoarthritis: the doubt persists]. / Effectiviteit van voedingssupplementen bij artrose: de twijfel blijft.

Earlier studies with glucosamines in patients with osteoarthritis have shown conflicting results. A placebo-controlled randomised trial was now carried out in 1583 patients with osteoarthritis. The primary endpoint was a 20% reduction in knee pain between baseline and week 24 according to the 'Western Ontario and McMaster Universities arthritis index'(WOMAC)-score. No statistically significant difference was found between the groups using placebo (60% response), glucosamine (64%), chondroitin sulphate (65%) or combination therapy (67%). The results of this trial do not support the hypothesis that glucosamines have a positive effect on symptoms in patients with osteoarthritis of the knee. However, (a) the chance of a statistically significant difference decreases with increasing magnitude of the placebo response, (b) there was a statistically significant reduction in the patients with moderate to severe pain, (c) when the pain was assessed with the more sensitive 'Outcome measures in rheumatology clinical trials'(OMERACT)-'Osteoarthritis Research Society International'(OARSI)-score, there was a better response in the group given combined treatment, (d) the data on radiological progression and the effects on cartilage markers must still come in, and (e) the efficacy may have been higher ifa different dietary supplement had been used. These questions on the design and the robustness of the study indicate that further studies are necessary.

Positive effect of alendronate on bone mineral density and markers of bone turnover in patients with rheumatoid arthritis on chronic treatment with low-dose prednisone: a randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Alendronate has been described to have a bone-sparing effect in patients treated with moderate and high dosages of prednisone for heterogeneous diseases, however no data are available on groups of patients with the same underlying diseases who receive chronic low-dose prednisone treatment. The objective of the investigation reported here was, therefore, to study the effect of alendronate on bone mineral density (BMD) of the lumbar spine and hips in patients with rheumatoid arthritis (RA) who are on chronic low-dose prednisone treatment. METHODS: A total of 163 patients with RA, according to the ACR-criteria, were enrolled in a double-blind, placebo-controlled trial. The patients were treated with low-dose prednisone (

[Polymyalgia rheumatica and temporal arteritis]. / Polymyalgia rheumatica en arteriitis temporalis.

Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are closely related and frequently occurring inflammatory diseases with an incidence of 50 and 18 per 100,000 per year, respectively, in people aged 50 years or over. The most frequent symptom of PMR is aching and morning stiffness lasting more than 1 month and exacerbated by movement, occurring in the shoulder and pelvic girdles and in the neck region. GCA is vasculitis of the large and medium-sized arteries that originate from the aortic arch, causing new and marked headache localised over the temporal or occipital areas, jaw claudication, visual impairment or claudication of the arms. GCA is characterised by histopathological panarteritis with a predominantly lymphohistiocytic cell infiltrate. Activation of macrophages is central to the arteritis. Standard treatment for PMR and GCA is glucocorticoids, which may consist of prednisone 10-20 mg/day or its equivalent for PMR patients and prednisone 30-40 mg to 1 mg/kg body weight for GCA patients. For GCA patients with recently impaired vision, treatment should start with high doses of intravenously administered glucocorticoids, such as methylprednisolone 1 g/day for 3 consecutive days. A treatment duration of 1-2 years is often required for patients with PMR or GCA; because of the side effects associated with long-term use of glucocorticoids, osteoporosis prophylaxis with oral calcium supplementation, vitamin D and bisphosphonates is appropriate.

Low-dose glucocorticoids in early rheumatoid arthritis: discordant effects on bone mineral density and fractures?

OBJECTIVE: To investigate the incidence of osteoporotic fractures and effects on bone of low-dose glucocorticoid (GC) monotherapy in a group of previously untreated patients with early active RA we performed a double blind, randomised, placebo-controlled clinical trial. The study duration was 2 years, with an open follow-up during the third year. Patients were randomly allocated to receive 10 mg prednisone or placebo. METHODS: Non-steroidal anti-inflammatory drugs (NSAIDs) were allowed in both groups. After 6 months sulphasalazine (2 gr daily) could be prescribed as rescue therapy in both groups. Except for 500 mg calcium supplement daily, no specific preventive measures were taken. This was a normal procedure at the time the study was designed (1989-1991). At the start of the study and every 6 months, X-rays of the twelfth thoracic and of all lumbar vertebrae were scored using the Kleerekoper method, and every year biochemical parameters of bone metabolism and bone mineral density (BMD, expressed in T-scores) and bone mineral content (BMC, expressed in g/cm) were assessed. RESULTS: In the prednisone group there was a higher incidence during the study of lumbar vertebral fractures than in the placebo group: 7 vs 4 respectively. This difference did not reach statistical significance however, probably because of the small numbers. One patient of the prednisone group suffered an osteoporotic fracture of the pelvis. In the 2-year study and the subsequent follow-up year, no other peripheral fractures were seen in either group. No significant changes from baseline in BMD and BMC of the hips were seen in either group during the study and the follow-up year. In the lumbar spine, BMD in the prednisone group decreased although not statistically significantly during the whole study. No correlation between changes in serum osteocalcin and BMD was observed. CONCLUSION: Low-dose prednisone monotherapy for patients with early active previously untreated RA seems to increase the risk of fractures not only by reducing the BMD but also by changes in bone strength and structure.

[Glucosamine and chondroitin sulfate as a possible treatment for osteoarthritis]. / Glucosamine en chondroïtinezwavelzuur als mogelijke behandeling van artrose.

The nutritional supplements glucosamine and chondroitine sulphate are widely used in the treatment of osteoarthritis. In published studies, glucosamine used in a dosage of 1.5 gram daily is, after a period of 2 to 4 weeks, just as effective as low doses of NSAIDs in alleviating pain. Chondroitine sulphate has been less well investigated. There are indications that it affects the symptoms of osteoarthritis, even though this effect only occurs after a longer period of time. The side effects for both substances are minor. A disease-modifying effect (defined as delay of radiological progression of osteoarthritis) has not been proven.