Daniel Albert

B-cell targeted therapies in rheumatoid arthritis and systemic lupus erythematosus

B cells appear to have a central role in the immunopathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE); both autoantibody production and B-cell anomalies are characteristic of these diseases. With the recent availability of biologic agents that can deplete B cells or block their function in vivo, it has become possible to target B cells therapeutically. Evidence strongly suggests that novel B-cell targeting agents are effective. In addition, the mechanistic specificity of B-cell targeted approaches, combined with the ability to test them in large randomized controlled trials, will provide an unprecedented opportunity to study the precise roles of B cells in the immunopathogenesis of RA and SLE. The largest volume of information is available for rituximab, a chimeric monoclonal antibody that depletes B cells by binding to the CD20 cell-surface antigen. Information from multiple investigator-sponsored trials and from off-label use suggests efficacy of this antibody in RA, SLE, and other autoimmune syndromes. Randomized controlled trials have also provided solid evidence for the efficacy of rituximab in RA and are ongoing in SLE. Other therapeutic agents supported by controlled data include cytotoxic T-lymphocyte-associated protein 4 immunoglobulin and antibodies against the interleukin-6 receptor and the B-cell survival molecule BLyS. Additional agents and targets are in earlier stages of development. The concerns about infectious complications have so far not proven to be justified. We can reasonably expect important advances in the understanding and treatment of RA and SLE in the next 5–10 years, as B-cell targeting methods become more widespread and sophisticated.

Cost‐effectiveness of prophylaxis against Pneumocystis carinii pneumonia in patients with Wegener's granulomatosis undergoing immunosuppressive therapy

OBJECTIVE To assess the incremental cost-effectiveness of 3 Pneumocystis carinii pneumonia (PCP) prophylaxis strategies in patients with Wegeners granulomatosis (WG) receiving immunosuppressive therapies: 1) no prophylaxis; 2) trimethoprim/sulfamethoxazole (TMP/SMX) 160 mg/800 mg 3 times a week, which is discontinued if patients experience an adverse drug reaction (ADR); and 3) TMP/SMX 160 mg/800 mg 3 times a week, which is replaced by monthly aerosolized pentamidine (300 mg) if patients experience an ADR. METHODS A Markov state-transition model was developed to follow a hypothetical cohort of WG patients over their lifetimes starting from the time of initial exposure to the immunosuppressive therapy. The effect of PCP prophylaxis on life expectancy, quality-adjusted life expectancy, average discounted lifetime cost (ADLC), and incremental cost-effectiveness was estimated based on data obtained from a literature review. Direct medical costs were examined from a societal perspective, and costs and benefits were discounted at 3% annually. RESULTS No prophylaxis resulted in a life expectancy of 13.36 quality-adjusted life years (QALY) at an ADLC of

Diagnosis of crystal-induced arthritis by synovial fluid examination for crystals : Lessons from an imperfect test

4,538. In comparison, prophylaxis with TMP/ SMX alone increased the QALY to 13.54 and was cost saving, with an ADLC of

Cost-effectiveness of raloxifene and hormone replacement therapy in postmenopausal women: Impact of breast cancer risk

3,304. The addition of pentamidine in patients who had an ADR to TMP/SMX resulted in 13.61 QALY, with an ADLC of

Acute onset of Wegener's granulomatosis and diffuse alveolar hemorrhage treated successfully by extracorporeal membrane oxygenation.

7,428. Compared with TMP/SMX alone, TMP/SMX followed by pentamidine increased the QALY by 0.07 at an incremental cost of

Wegener's granulomatosis: Possible role of environmental agents in its pathogenesis

58,037 per QALY. Both TMP/SMX alone and TMP/SMX followed by pentamidine prophylaxis strategies dominated the no prophylaxis strategy until the incidence of PCP fell below 0.2% and 2.25%, respectively. Institution of pentamidine therapy for patients with a TMP/SMX ADR increased quality-adjusted life expectancy compared with that with TMP/ SMX alone until the incidence of PCP rose above 7.5%. CONCLUSION Prophylaxis using TMP/SMX alone increased life expectancy and reduced cost for patients with WG receiving immunosuppressive therapy. Replacing TMP/SMX with monthly aerosolized pentamidine in cases of ADR further increased life expectancy, although at an increased cost.

Transgenic mice with pigmented intraocular tumors: tissue of origin and treatment.

OBJECTIVE Diagnosis of the crystal-induced arthritides is primarily based on microscopic identification of crystals in synovial fluid. Therefore, we aimed to estimate the operating characteristics of this test and demonstrate its clinical use. METHODS Medline was searched for relevant studies. Sensitivity and specificity of identification of crystals were calculated, as were measures of interobserver agreement. Likelihood ratios were calculated and curves constructed using the solutions to the Bayesian equations. RESULTS Four studies were identified. The rates of interobserver agreement were low; the false-negative rates in identifying calcium pyrophosphate crystals were particularly high. Only one study allowed calculation of the test operating characteristics, and this was a study that used synthetic crystals and therefore may not be directly useful in a clinical setting. CONCLUSION There is a paucity of data about the accuracy of crystal identification. As it is clearly not a perfectly sensitive and specific test, the most prudent diagnostic strategy, as with essentially all diagnostic tests, is to establish a posterior probability of disease from a prior probability, based on the clinical features of the patient. Determining the operating characteristics of this test in conventional and reference laboratories should be a research priority for high quality clinical research on crystal arthropathies.

Resolving the Paradox of Interdependency and Strategic Renewal in Activity Systems

OBJECTIVE To examine the life expectancy and cost‐effectiveness of hormone replacement therapy (HRT) and raloxifene therapy in healthy 50‐year‐old postmenopausal women. METHODS We performed a cost‐effectiveness analysis using a Markov model, discounting the value of future costs and benefits to account for their time of occurrence. RESULTS Both HRT and raloxifene therapy increase life expectancy and are cost‐effective relative to no therapy for 50‐year‐old postmenopausal women. For women at average breast cancer and coronary heart disease risk, lifetime HRT increases quality‐adjusted life expectancy more (1.75 versus 1.32 quality‐adjusted life years) and costs less (

Temporal Myopia in Strategic Search

3802 versus

Strategy as Activity System: A Review and Conceptualization

12,968) than lifetime raloxifene therapy. However, raloxifene is more cost‐effective than HRT for women at average coronary risk who have a lifetime breast cancer risk of 15% or higher or who receive 10 years or less of postmenopausal therapy. Raloxifene is also the more cost‐effective alternative if HRT reduces coronary heart disease risk by less than 20%. CONCLUSIONS Assuming the benefit of HRT in coronary heart disease prevention from observational studies, long‐term HRT is the most cost‐effective alternative for women at average breast cancer and coronary heart disease risk seeking to extend their quality‐adjusted life expectancy after menopause. However, raloxifene is the more cost‐effective alternative for women at average coronary risk with one or more major breast cancer risk factors (first‐degree relative, prior breast biopsy, atypical hyperplasia or BRCA1/2 mutation). These results can help inform decisions about postmenopausal therapy until the results of large scale randomized trials of these therapies become available.