Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg.

SUMMARY: Patients treated with intravenous zoledronic acid 5 mg for osteoporosis may experience post-dose influenza-like symptoms. Oral acetaminophen/paracetamol or ibuprofen administered 4 h post-infusion reduced the proportion of patients with increased oral temperature and worsening post-infusion symptom scores vs. placebo, thus providing an effective strategy for the treatment of such symptoms. INTRODUCTION: Once-yearly intravenous zoledronic acid 5 mg is a safe and effective treatment for postmenopausal osteoporosis. This study assessed whether transient influenza-like post-dose symptoms associated with intravenous infusion of zoledronic acid can be reduced by post-dose administration of acetaminophen/paracetamol or ibuprofen. METHODS: In an international, multicenter, randomized, double-blind, double-dummy parallel-group study, bisphosphonate-naïve postmenopausal women with osteopenia (n = 481) were randomized to receive zoledronic acid 5 mg + acetaminophen/paracetamol (n = 135), ibuprofen (n = 137) or placebo (n = 137), or placebo + placebo (n = 72). Acetaminophen/paracetamol and ibuprofen were administered every 6 h for 3 days beginning 4 h post-infusion. RESULTS: The proportion of patients with increased oral temperature (≥1°C above 37.5°C) and with worsening post-infusion symptom scores over 3 days was significantly lower in patients receiving ibuprofen (36.8% and 48.5%) or acetaminophen/paracetamol (37.3% and 46.3%) vs. those receiving placebo (63.5% and 75.9%, respectively; all p < 0.0001) compared with background rates of 11.1% and 16.7%, respectively, in the absence of any active treatment. Overall incidence of adverse events was comparable for patients receiving acetaminophen/paracetamol or ibuprofen. CONCLUSION: Oral acetaminophen/paracetamol or ibuprofen effectively managed the transient influenza-like symptoms associated with zoledronic acid 5 mg.

Once-daily, controlled-release tramadol and sustained-release diclofenac relieve chronic pain due to osteoarthritis: a randomized controlled trial.

OBJECTIVE: The present study was a randomized, parallel, double-blind comparison between controlled-release (CR) tramadol and sustained-release (SR) diclofenac in patients with chronic pain due to osteoarthritis of the hips and/or knees. METHODS: Patients with at least moderate pain intensity, and having received analgesics over the past three months, underwent a two- to seven-day washout of current analgesics before initiation of 200 mg CR tramadol or 75 mg SR diclofenac. During the eight-week study, patients returned to the clinic biweekly. CR tramadol doses were titrated to a maximum of 200 mg, 300 mg or 400 mg per day. SR diclofenac doses were titrated to 75 mg or 100 mg once daily, or 75 mg twice a day based on pain relief and the presence of side effects. For rescue analgesic, patients took acetaminophen as needed, up to 650 mg three times a day. RESULTS: Forty-five patients on CR tramadol and 52 patients on SR diclofenac were evaluable. Significant improvements from prestudy treatment were shown for visual analogue scale pain (P=0.0001), stiffness (P<0.0005) and physical function (P=0.0001) scores for both treatments. There were no significant differences between the two treatments in the Western Ontario and McMaster Universities subscales, overall pain, pain and sleep, or the clinical effectiveness evaluation. Overall incidence of adverse events was similar in both groups, with more opioid-related adverse events with CR tramadol, and two serious adverse events occurring with the use of SR diclofenac. CONCLUSIONS: CR tramadol is as effective as SR diclofenac in the treatment of pain due to knee or hip osteoarthritis, with the potential for fewer of the serious side effects that characterize nonsteroidal anti-inflammatory drug administration.

Evaluation of easily measured risk factors in the prediction of osteoporotic fractures.

BACKGROUND: Fracture represents the single most important clinical event in patients with osteoporosis, yet remains under-predicted. As few premonitory symptoms for fracture exist, it is of critical importance that physicians effectively and efficiently identify individuals at increased fracture risk. METHODS: Of 3426 postmenopausal women in CANDOO, 40, 158, 99, and 64 women developed a new hip, vertebral, wrist or rib fracture, respectively. Seven easily measured risk factors predictive of fracture in research trials were examined in clinical practice including: age (< 65, 65-69, 70-74, 75-79, 80+ years), rising from a chair with arms (yes, no), weight (< 57, > or = 57 kg), maternal history of hip fracture (yes, no), prior fracture after age 50 (yes, no), hip T-score (> -1, -1 to > -2.5, < or = -2.5), and current smoking status (yes, no). Multivariable logistic regression analysis was conducted. RESULTS: The inability to rise from a chair without the use of arms (3.58; 95% CI: 1.17, 10.93) was the most significant risk factor for new hip fracture. Notable risk factors for predicting new vertebral fractures were: low body weight (1.57; 95% CI: 1.04, 2.37), current smoking (1.95; 95% CI: 1.20, 3.18) and age between 75-79 years (1.96; 95% CI: 1.10, 3.51). New wrist fractures were significantly identified by low body weight (1.71, 95% CI: 1.01, 2.90) and prior fracture after 50 years (1.96; 95% CI: 1.19, 3.22). Predictors of new rib fractures include a maternal history of a hip fracture (2.89; 95% CI: 1.04, 8.08) and a prior fracture after 50 years (2.16; 95% CI: 1.20, 3.87). CONCLUSION: This study has shown that there exists a variety of predictors of future fracture, besides BMD, that can be easily assessed by a physician. The significance of each variable depends on the site of incident fracture. Of greatest interest is that an inability to rise from a chair is perhaps the most readily identifiable significant risk factor for hip fracture and can be easily incorporated into routine clinical practice.

The relationship of antiphospholipid antibodies to thromboembolic disease in systemic lupus erythematosus: a cross-sectional study.

In order to determine whether an association exists between antiphospholipid antibodies (APLA) and thromboembolic events in patients with systemic lupus erythematosus (SLE), we performed a cross-sectional study of consecutive unselected SLE patients. The occurrence of previous thromboembolic events was determined by investigators blinded to the APLA status of the patients by critical review of objective tests that had been performed at the time of symptomatic presentation and by performing venous Doppler ultrasound of the legs to elicit venous reflux as an indication of previous venous thrombosis. The presence of APLA was determined by coagulation assays for the lupus anticoagulant (LA) using five tests with well-defined control ranges and by ELISA assay for anticardiolipin antibodies (ACLA). These tests were measured on two separate occasions. The results of the study demonstrate a statistically significant association between persistently abnormal ACLA assays and thromboembolic events and a non-significant trend between persistently abnormal LA and thromboembolic events. Transient abnormalities of LA and ACLA were less strongly associated with thromboembolic events. We conclude that in patients with SLE, there is a significant association between thromboembolism and APLA.

Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial.

OBJECTIVE: To compare the efficacy and safety of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, with those of naproxen, a nonsteroidal anti-inflammatory drug (NSAID), and placebo in the treatment of osteoarthritis of the knee. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 1003 patients with symptomatic osteoarthritis of the knee were randomly assigned to receive celecoxib at doses of 50, 100, or 200 mg twice a day; naproxen, 500 mg twice a day; or placebo for 12 weeks. Patients were evaluated with standard measures of efficacy 2 to 7 days after discontinuing previous NSAID or analgesic therapy and after 2, 6, and 12 weeks of treatment with the study drug. RESULTS: Celecoxib treatment led to significant improvement in the signs and symptoms of osteoarthritis as determined by all efficacy measures. Significant pain relief occurred within 2 days of the initiation of treatment, and maximum anti-inflammatory and analgesic activity, evident within 2 weeks, was sustained throughout the 12-week study. All celecoxib doses were efficacious compared with placebo, although the 50-mg twice-daily dosage regimen was minimally effective. The higher doses of celecoxib (100 and 200 mg twice a day) were similarly efficacious, and the magnitude of improvement observed with these dosing regimens was comparable to that seen with naproxen at a dose of 500 mg twice a day. All doses of celecoxib and naproxen were well tolerated. CONCLUSION: COX-2 inhibition with celecoxib is an effective approach for the treatment of osteoarthritis, as seen by clinical improvement in signs and symptoms comparable to treatment with naproxen.

Corticosteroid-induced osteoporosis.

Corticosteroid-induced osteoporosis is a major problem faced by rheumatologists, with up to 50% of patients at increased risk for vertebral fractures. Our current understanding of the pathophysiology of corticosteroid-induced osteoporosis suggests two basic problems: a reduction in bone formation and an increase in bone resorption leading to an overall reduction in bone mass. Adequate calcium and vitamin D intake, calcitonin, hormone-replacement therapy, and thiazide diuretics are of benefit in preventing corticosteroid-induced bone loss. Other therapies such as the bisphosphonates, fluoride, and anabolic steroids should be considered when fractures occur or ongoing bone loss is evident. A review of the literature outlining the pathophysiology, clinical features, assessment, and treatment is presented.

Gold induced thrombocytopenia: 12 cases and a review of the literature.

Gold induced thrombocytopenia is immune mediated, with the production of platelet associated IgG leading to peripheral platelet destruction. An association with HLA-DR3 has been demonstrated. Corticosteroid therapy is effective in treatment, although other modes of therapy may be as efficacious.

Aim for remission or "personal best" using combination DMARD therapy with methotrexate and hydroxychloroquine.

Combination disease-modifying antirheumatic drug therapy with methotrexate and hydroxychloroquine has changed the course of rheumatoid arthritis. Better management requires "front of the line" care, effective drug combinations, and a goal of "Personal Best." The Pincus phenomenon--the discrepancy between subjective satisfaction and objective progression--may be minimized in clinical practice by questionnaires and Snapshot.

Positive effect of etidronate therapy is maintained after drug is terminated in patients using corticosteroids.

Following a 52-wk randomized controlled trial of intermittent cyclic etidronate therapy in patients using corticosteroids, we performed a 52-wk open-label trial of calcium alone in 114 corticosteroid-treated patients to determine whether the beneficial effect of etidronate is maintained after the drug is discontinued. All patients were given 500 mg/d of elemental calcium. Sixty-one and 53 patients made up the former placebo and etidronate groups, respectively. A total of 89 (98%) of patients in the former placebo and etidronate groups remained on corticosteroids throughout the second year. The mean (SE) percentage change in bone mineral density of the lumbar spine, femoral neck, and trochanter were compared between groups. The difference between groups in mean percentage change from baseline (wk 0, initiation of etidronate or placebo therapy) in the bone density of the lumbar spine, femoral neck, and trochanter, following 104 wk, was 3.8 (0.9), 3.0 (1.1), and 4.3 (1.1), respectively (p < 0.05, all sites), in favor of the former etidronate group. While not significant, the former placebo group demonstrated a slightly larger rate of decline in bone density over the second year than the former etidronate group at all three sites. Following the discontinuation of etidronate therapy, there was no accelerated bone loss and there was evidence of a residual protective effect in both the lumbar spine and femoral neck for up to 1 yr posttreatment.

Antiinflammatory and analgesic efficacy of COX-2 specific inhibition: from investigational trials to clinical experience.

Research strongly indicates that increased expression of the isoenzyme cyclooxygenase-2 (COX-2) is responsible for elevated production of prostaglandins in inflamed joint tissues and is involved in the mediation of pain. In contrast, COX-1 is a constitutively produced isoenzyme that is involved in the synthesis of eicosanoids that have important homeostatic functions, for example, in the gastric mucosa and platelets. This new knowledge led to the development of drugs that are highly specific inhibitors of COX-2 while not inhibiting COX-1 at maximally efficacious dosages. The first COX-2 specific agent approved for clinical use in the United States was celecoxib. Large multicenter trials have shown that celecoxib at dosages of 100 mg BID and 200 mg BID is as effective as naproxen 500 mg BID in patients with osteoarthritis of the knee or hip. Another large multicenter trial also demonstrated that celecoxib 200 mg BTD and 400 mg BID is as effective as naproxen 500 mg BID in patients with rheumatoid arthritis (RA). A comparative trial showed that celecoxib 200 mg BID is as effective as diclofenac SR 75 mg BID in patients with RA. The potential of COX-2 specific inhibitors to provide antiinflammatory and analgesic efficacy equivalent to that of conventional nonsteroidal antiinflammatory drugs without the adverse gastrointestinal mucosal and platelet effects associated with nonspecific COX inhibitors promises to revolutionize the clinical care of arthritis patients.

Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the clinical response, safety, and tolerability of a single intraarticular injection of anakinra in patients with symptomatic osteoarthritis (OA) of the knee. METHODS: Patients with OA of the knee were enrolled in a multicenter, double-blind, placebo-controlled study and randomized 2:1:2 to receive a single intraarticular injection of placebo, anakinra 50 mg, or anakinra 150 mg in their symptomatic knee. Patients were evaluated for 12 weeks postinjection. The primary end point was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score from baseline to week 4. Safety assessments included the evaluation of adverse events (AEs), laboratory tests, and vital signs. Pharmacokinetic parameters were assessed in a subset of patients. RESULTS: Of 170 patients who enrolled, 160 (94%) completed the study. The mean improvements from baseline to week 4 in the WOMAC score were not statistically different between the placebo group and the patients who received 50 mg of anakinra (P = 0.67) or 150 mg of anakinra (P = 0.77). Anakinra was well tolerated. No withdrawals due to AEs or serious AEs, and no serious infections or deaths were reported. No clinically significant trends were noted in laboratory values or vital signs. Pharmacokinetic parameters demonstrated that the mean terminal half-life of anakinra in serum after intraarticular injection was approximately 4 hours. CONCLUSION: Anakinra was well tolerated as a single 50-mg or 150-mg intraarticular injection in patients with OA of the knee. However, anakinra was not associated with improvements in OA symptoms compared with placebo.

Articular manifestations of systemic diseases.

Many systemic diseases present with articular manifestations. An understanding of the clinical, laboratory and radiological features of these diseases can lead to early diagnosis and appropriate therapy. This article describes the articular presentation and management of four generalized disorders: idiopathic hemachromatosis; sarcoidosis; hepatitis-B virus-induced arthritis, and polymyositis-dermatomyositis induced arthritis.

Back to the future: the pyramids of rheumatoid arthritis.

The management treatment pyramid, treatment target and treatment pyramids provide a framework for RA management and treatment. This model brings back the traditional pyramid, which was widely accepted, and adapts it to our newer understanding of RA treatment. It provides a focus for care, as well as the flexibility to apply selective treatments to different temperaments of disease. We hope that these models will fill the void left by the abandonment of the traditional pyramid. We certainly need a model to refocus the patient and physician to the importance of RA and bring "order out of chaos". With our current knowledge, resources, and drugs, we could be making a far greater impact on this serious, expensive, and crippling disease. We must re-excite and re-educate the public, the patient, and the profession to the remarkable progress we have made with incurable but very treatable arthritis.

Newer, safer nonsteroidal anti-inflammatory drugs. Rational NSAID selection for arthritis.

OBJECTIVE: To summarize current evidence that three new additions to nonsteroidal anti-inflammatory drugs (NSAIDs) offer comparable efficacy with fewer adverse effects than established NSAIDs. QUALITY OF EVIDENCE: No large randomized controlled trials (RCTs) have compared all important NSAIDs. Several RCTs have shown that H2 antagonists do not protect against NSAID side effects, but some RCTs compared the protective effect of misoprostol (Cytotec) used with other NSAIDs; others have compared etodolac (Ultradol) or nabumetone (Relafen) with placebo and naproxen (eg, Naprosyn). Postmarketing surveys have been used to support claims that the new NSAIDs have few gastric or renal side effects. MAIN FINDINGS: Using misoprostol in conjunction with traditional NSAIDs reduces gastric and renal adverse effects. Misoprostol can be taken at the same time as NSAIDs or in a combination tablet. Two new NSAIDS, etodolac and nabumetone, do not inhibit cyclooxygenase 1 prostaglandins, which occur in the stomach and kidneys, but more selectively block cyclooxygenase 2 prostaglandins, which cause arthritic inflammation. These two NSAIDs have efficacy profiles comparable to older NSAIDs but have markedly fewer side effects. CONCLUSIONS: Safer treatment for arthritis can be achieved by combining misoprostol with traditional NSAIDs or by using one of two new agents, nabumetone or etodolac.

Which Anti-inflammatory?

Over the past ten years clinicians have been stampeded by the introduction of newer non-steroidal anti-inflammatory drugs. These drugs share analgesic, antipyretic and, most importantly, clinical anti-inflammatory activity and are therefore useful in treating rheumatic diseases. These medications often have less frequent adverse reactions than aspirin and offer alternatives to patients who are intolerant to the more conventional NSAID. The authors review some of the principles which determine choice of the non-steroidal anti-inflammatory drugs, list some specifics on each of the currently available medications, and recommend drugs of choice in a number of specific rheumatic processes.

Is HLA-B27 the ankylosing spondylitis susceptibility gene?

We studied a family in which the mother and her son had primary ankylosing spondylitis (AS). The mother carried the HLA-B27 allele, but did not pass this to her son. It is possible that the son is a coincidental, sporadic, non-B27 patient with spondylitis and the presence of B27 in the mother is relevant to the disease. Alternatively, it is possible that B27 in the mother is coincidental and the non-B27 haplotype, inherited by the son, carries the disease susceptibility gene. The results would then support the hypothesis that the B27 antigen may not be the AS gene, but rather a marker for another closely linked AS gene.

Bilateral retinal detachment in a case of Reiter's disease.

A patient is described who developed co-existent Reiter's disease and bilateral non-traumatic retinal detachment. Although numerous ophthalmological disorders are associated with Reiter's disease and HLA-B27, to our knowledge this is the first report of co-existent retinal detachment. Although this relationship may be fortuitous, there are a number of immunological mechanisms common to both entities. Retinal detachment, unlike bilateral conjunctivitis and acute anterior uveitis, may be clinically asymptomatic and its sequelae prevented by appropriate ophthalmological assessment.

Corticosteroid-induced osteoporosis.

Corticosteroid-induced osteoporosis is a serious disorder that results in significant morbidity. A summary of our understanding of the pathophysiology is provided and highlights some of the controversy the exists. Clinical trials for the prevention and treatment of corticosteroid-induced osteoporosis are reviewed.

Pauciarticular juvenile rheumatoid arthritis presenting in an adult.

Type I pauciarticular juvenile rheumatoid arthritis (PA-JRA) is characterized by a female predominance, chronic iridocyclitis and a positive antinuclear antibody (ANA) test. In contrast, patients with type II PA-JRA are usually male, have a negative ANA test, but are HLA-B27 positive. We report a patient with longstanding iridocyclitis who presented at age 20 with oligoarthritis, whom we believe has Type I PA-JRA. Slit lamp examination should be considered in patients with oligoarthritis; the detection of asymptomatic chronic iridocyclitis may aid in the diagnosis. Untreated, this condition may cause irreversible ocular damage.