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Apreciados Colegas: En está entrega tenemos en Noticias; la advertencia de la oficina oficial de aprobación de medicamentos europea sobre los reportes de posible hepatotoxicidad severa con leflunamida y la recomendación perentoria de realizar chequeos mensuales por los seis primeros meses con el medicamentos y luego cada 2 meses. .

En esta edición hemos incluido una revisión del Dr. Paul Tak de la Academia de Medicina de Holanda sobre el estudio CLASS de Silverstein y colaboradores publicado en JAMA en Septiembre del 2000 (JAMA Sep 13;284(10):1247-55) y en el siguiente boletín una revisión similar por Larry Moreland sobre el estudio VIGOR. Además nuestras secciones usuales de sitios recomendados y eventos .No olviden la fecha de entrega de los trabajos para el Congreso de la Asociación antes del 31 de Marzo.

LONDON (Reuters Health) - Severe liver reactions--some with fatal outcomes--have occurred in patients treated with Aventis' novel rheumatoid arthritis drug Arava (leflunomide), according to the European Medicines Evaluation Agency (EMEA).

In a public statement on its Web site, the agency said a total of 296 liver reactions had been reported.

``Of these, 129 cases were considered as serious, including two cases of liver cirrhosis and 15 cases of liver failure, nine with a fatal outcome.'' The statement warns that ``although confounding factors were present in many cases, a causal relationship to leflunomide cannot be excluded.''

Arava, a so-called ``disease-modifying antirheumatic drug,'' is the first new treatment for rheumatoid arthritis in more than 10 years. Rheumatoid arthritis is an autoimmune disease in which progressive damage to the joints leads to increasing disability. The EMEA's statement, dated March 12, reports that most side effects occurred within 6 months of starting therapy.

The agency said that, in view of the seriousness of the reactions, it wished to point out that the drug is contraindicated in patients with impaired liver function. It added that combining drugs such as leflunomide and methotrexate or other medications that can be toxic to the liver is associated with an increased risk of serious liver reactions and is not advisable.

A spokesman for Aventis told Reuters Health that the firm is sending out a ``Dear Doctor'' letter and reinforcing the drug's labeling about liver injury in the EU. In the United States, talks are underway with the Food and Drug Administration (news - web sites) to determine whether similar steps are necessary, he added.

The spokesman said that 200,000 patients have used the drug since it was launched in the US in September 1998 and in the EU in September 1999. He stressed that a causal relationship between the drug and liver injury has not been established. ``We are confident that in most patients, these rare reports do not in any way alter the benefit-risk profile,'' he said.

The new labeling states that liver enzyme function must be checked before therapy is started, at least monthly during the first 6 months of treatment, and then every 8 weeks thereafter.

If liver enzymes are between two and three times the normal upper limit, the drug dose can be reduced from 20 milligrams to 10 milligrams and monitoring should be performed weekly. If elevations of more than twice the normal upper limit persist, or if they increase to more than three times the normal upper limit, leflunomide must be stopped and ``wash-out'' procedures implemented to reduce drug levels in the body.

The EMEA statement makes clear that 78% of the patients experiencing serious reactions were also taking other medications known to be toxic to the liver. ``In addition, in 33 of these serious cases (27%) other risk factors were reported, including a history of alcohol abuse and liver function disturbance,'' the statement reports. ``Preliminary data on the prescribing profile of leflunomide suggest that monitoring of liver function tests and wash-out procedures might not have been fully adhered to,'' the EMEA added.

NUEVOS MEDICAMENTOS PARA LA ARTRITIS Y LA OSTEOPOROSIS EN BUSCA DE APROBACION POR LA FDA

Las compañias farmaceúticas y biotecnológicas recibierón aprobación para 32 medicamentos nuevos en el año 2000. Hubo aprobación para 19 medicamentos para la artritis y 14 para la osteoporosis. El 79% de las personas mayores de 65 años toman al menos un medicamento de prescripción diario y 28% multiples medicamentos.

REVISION POR EXPERTOS: Tomado de DiseaseRef Online Journal - Volume I, Issue 09

Article Title: Are COX-2 specific inhibitors associated with a lower incidence of adverse effects?

Journal Title: Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study (CLASS). JAMA 2000 Sep 13;284(10):1247-55

QUESTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with gastrointestinal effects due to inhibition of cyclooxygenase (COX)-1. Celecoxib and rofecoxib are COX-2 selective inhibitors. It has been shown previously that celecoxib induces clinical improvement in patients with rheumatoid arthritis (RA) comparable with naproxen, but with a lower incidence of gastrointestinal ulcers identified by endoscopy. The aim of this study was to determine whether COX-2 specific inhibitors are associated with fewer clinical signs of gastrointestinal adverse toxicity.

METHODS: A total of 8059 with RA or osteoarthritis (OA) at 386 sites in the United States and in Canada were included in the study; 7968 patients received a minimum of one dose of the study drug. Patients were randomly assigned to receive celecoxib 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively), ibuprofen (800 mg 3 times per day), or diclofenac (75 mg twice per day). The treatment regimens were blinded. NSAIDs other than study medication (except for stable dosages of aspirin up to 325 mg/d) were prohibited during the study. All patients were invited to complete a minimum of 6 months of treatment; 4573 patients completed this period. All patients including patients withdrawing prior to 6 months were followed up for endpoint evaluation for 2 months or until study termination. Patients were evaluated for symptomatic upper gastrointestinal ulcers and ulcer complications.

MAIN RESULTS: The annualized incidence rate of upper gastrointestinal ulcer complications was 0.76% for celecoxib and 1.45% for NSAIDs (P=0.09). The relative risk (RR) for celecoxib compared with NSAIDs was 0.53. When combined with symptomatic ulcers the incidence rates were 2.08% versus 3.54%, respectively (P=0.02)(RR 0.59). Low-dosage aspirin had a significant effect on the incidence of upper gastrointestinal ulcer complications in patients receiving celecoxib. Within the celecoxib group, the RR of an upper gastrointestinal ulcer complication was 4.5 with low-dose aspirin use. This effect was not observed in those patients treated with NSAIDs. For the non-aspirin using cohort the annualized incidence rates of upper gastrointestinal ulcer complications was 0.44% for celecoxib compared with 1.27% for NSAIDs (P=0.04)RR 0.35). When combined with symptomatic ulcers the incidence rates were 1.40 versus 2.91%, respectively (P=0.02)(RR 0.48). In addition, overall fewer patients had chronic gastrointestinal blood loss, gastrointestinal intolerance, hepatotoxicity, or renal toxicity in the celecoxib group compared with the NSAID group. The overall incidence of cardiovascular events was similar in the celecoxib and NSAID groups.

CONCLUSION: Celecoxib, at a dosage 2-4-fold greater than the maximum therapeutic dosage, is associated with a lower rate of upper gastrointestinal adverse effects compared with conventional NSAIDs at standard dosages, especially in those patients who do not use aspirin.

Commentary: NSAIDs target COX activity, thereby inhibiting the transformation of arachidonic acid into prostaglandins, prostacyclin, and thromboxanes. There are 2 isoforms of COX. COX-1 is expressed in most tissues, with variable expression. It plays a role in physiological processes, including gastric cytoprotection. COX-2 is undetectable in most tissues under normal circumstances, but its expression is increased in response to inflammation. It has been suggested that selective COX-2 inhibitors would have comparable analgesic and anti-inflammatory effects as conventional NSAIDs, but with less upper gastrointestinal toxicity. Non-selective COX inhibitors that were available prior to approval of rofecoxib and celecoxib inhibited both COX-1 and –2. If clinical efficacy is mediated primarily through COX-2 inhibition, then one would not expect improved efficacy of the selective inhibitors (only an improved side effect profile). Neither of the two available selective COX-2 inhibitors presented sufficient data to support a claim of improved long term safety with regard to GI toxicity.

One of the previous studies revealed that celecoxib produced clinical amelioration of symptoms and signs of RA comparable with the effects of naproxen, but with a significantly lower incidence of endoscopically identified gastrointestinal ulcers ¹. Another COX-2 inhibitor, rofecoxib, exhibited efficacy that was clinically comparable to that of nonselective NSAIDs in patients with RA ² and OA ³ with significantly fewer clinically important upper gastrointestinal side effects (2). In line with these observations, the CLASS study discussed here also clearly suggests that COX-2 specific inhibitors produce fewer ulcers and ulcer complications than conventional NSAIDs. However, the benefit was diminished in patients that took concomitant aspirin and did not reach statistical significance. This is not surprising since aspirin is a non-selective COX inhibitor that irreversibly acetylates both COX-1 and –2. Any advantage of selective COX-2 inhibition could be lost by the addition of a second drug that inhibits COX-1.

Of note, the incidence of myocardial infarction was lower among patients receiving naproxen compared with patients treated with rofecoxib ². The difference in cardiovascular disease was mainly found in the subset of the study population with the highest risk, for whom low-dose aspirin is indicated. The data suggest a coronary protective effect of conventional NSAIDs, which might be relevant in patients with increased risk, such as RA patients. In the CLASS study the overall incidence of cardiovascular events was similar in the celecoxib and NSAID groups. This might be explained by the relatively high percentage of patients using low-dosage aspirin in this study. Thus, administration of low-dose aspirin is indicated for patients with high cardiovascular risk, but this will probably also attenuate the benefit of selective COX-2 inhibition.

The advantage of specific COX-2 inhibition with regard to adverse events other than gastrointestinal toxicity and other possible benefits, such as protection against colonic cancer, remain to be determined. Co-administration of aspirin diminished this benefit, although it could potentially have cardiovascular benefits that mitigate this problem.

Practica Médica: Case Management. Se puede aplicar en nuestro medio? En una práctica muy ocupada al estilo de las EPS, de pacientes con cáncer y más recientemente de otras enfermedades crónicas ¿Tienen siempre los Médicos que revisar todas las veces a sus pacientes?. En el manejo por casos el Médico es la cabeza del equipo de salud , realiza los diagnósticos y prescribe los tratamientos.Sin embargo , el uimiento o mantenimiento del paciente se hace a través de otras personas (Case Managers) menos costosas que el Médico pero entrenadas para detectar complicaciones, referir a tiempo, educar al paciente , fomentar la adhesión a la terapia y por supuesto ahorrar costos.

FELICITAMOS AL Dr. ANAYA POR LA HOJA DE REUMATOLOGÍA QUE YA RECIBIERON TODOS. Carlo Vinicio Caballero Uribe MD
Editor del Boletín Electrónico

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