Modeling therapeutic strategies in rheumatoid arthritis: use of decision analysis and Markov models.

OBJECTIVE: The management of patients with rheumatoid arthritis (RA) is controversial, with a number of different proposed treatment strategies based on different conceptions of the natural history of the disease and different interpretations of the efficacy and effectiveness of the drugs used for treatment. We attempted to develop a theoretical framework to assess the effectiveness of different treatment regimens for RA. METHODS: We used decision analysis to structure the problem of comparing sequential monotherapy to a combination strategy. Subsequently, we used 3 different estimates of drug effectiveness: one from expert rheumatologists; a metaanalysis; and a recent nationwide survey of American rheumatologists, in a Markov model. Last, we utilized published duration of therapy data to model drug treatment over time. RESULTS: Estimates of drug effectiveness differed substantially among rheumatologists, but regardless of the estimates and the treatment strategy used, the model predicted over 90% of patients improved by the 3rd drug trial. Over time, treatment patterns in our model resemble the "sawtooth" pattern previously observed. CONCLUSION: Treatment strategies in RA are difficult to model because of uncertainty in both the structure of the model and the data needed to perform the analysis. These models tend to overestimate the effectiveness of drug sequences because of nonindependence between therapies, probably due to sequence effects, a change in responsiveness over time, or resistant subgroups. Our preliminary analysis suggests that the most effective agent, possibly methotrexate, should be used first if the objective is to get as many patients into remission as quickly as possible.

Pharmacokinetic study of the interaction between rifabutin and delavirdine mesylate in HIV-1 infected patients.

The oxidative metabolism of delavirdine, a non-nucleoside inhibitor of HIV-1 reverse transcriptase, is mediated in part by cytochrome P450 3A. The influence of rifabutin, an inducer of certain human cytochrome P450 isozymes, on the steady-state pharmacokinetics of delavirdine was investigated in 12 HIV-positive patients with CD4 counts ranging from 75 to 671/mm3. Both the control group (n = 5) and the rifabutin group (n = 7) received 400 mg delavirdine mesylate every 8 h for 30 days; subjects in the rifabutin group took a 300 mg, once-daily dose of rifabutin on study days 16-30. Harvested plasma from serial blood samples collected after dosing on days 15, 16, and 30 was assayed for delavirdine and its N-desalkyl metabolite concentrations using a reversed-phase HPLC method. Blood samples obtained on days 16 and 30 were also assayed for rifabutin by HPLC. Delavirdine mesylate alone or in combination with rifabutin was well-tolerated. On day 30, statistically significant differences between groups were observed for all delavirdine pharmacokinetic parameters (P < 0.046). After coadministration of rifabutin and delavirdine mesylate for 2 weeks, oral clearance of delavirdine increased five-fold, resulting in lower steady-state plasma delavirdine concentrations. Rifabutin pharmacokinetic parameters were similar to those previously reported. Concomitant use of delavirdine and rifabutin at the recommended dose for each drug is discouraged. Maintaining therapeutic concentrations of delavirdine in patients on both medications may require dose modification.

Differential mineralocorticoid (type 1) and glucocorticoid (type 2) receptor expression in Lewis and Fischer rats.

Lewis (LEW/N) and Fischer (F344/N) rats represent two extremes of the spectrum of corticosterone responses to stressful stimuli, from the chronical hyporesponsiveness of LEW/N to the chronical hyperresponsiveness of F344/N. It might be expected that the amount of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) binding, and the levels of their corresponding mRNAs in various tissues in LEW/N and F344/N rats might reflect the overall integrated levels of corticosterone to which these receptors have been exposed. We have found that while the binding affinity (Kd) of MR and GR varies between tissues, there was no strain difference in any tissue. Receptor binding number (Bmax), however, varied not only between tissues, but also between strains. MR Bmax in the hippocampus and pituitary was lower in LEW/N than in F344/N, whereas the GR Bmax in the LEW/N thymus was greater than that found in F344/N rats. The hippocampal levels of MR mRNAs in Adx LEW/N and F344/N rats were in good agreement with, and paralleled, the functional levels of these receptors as determined by binding assays. On the other hand, the number of hippocampal GR binding sites and the level of GR nRNA while similar were not identical in the two strains: the hippocampal GR Bmax did not differ between strains, while the hippocampal GR mRNA level was slightly, but significantly, lower in Adx LEW/N compared to F344/N rats.

Neurotransmitter-induced hypothalamic-pituitary-adrenal axis responsiveness is defective in inflammatory disease-susceptible Lewis rats: in vivo and in vitro studies suggesting globally defective hypothalamic secretion of corticotropin-releasing hormone.

The susceptibility of female Lewis (LEW/N) rats to the development of streptococcal cell wall (SCW)-induced arthritis and other autoimmune phenomena is associated with the inability of their hypothalamic-pituitary-adrenal (HPA) axis to adequately respond to inflammatory stimuli. In contrast, resistance to the development of SCW-induced arthritis and other inflammatory autoimmune manifestations in histocompatible female Fischer rats (F344/N) is related to their intact HPA axis response to inflammatory mediators. To evaluate the mechanism and the specificity of the HPA axis defect in LEW/N rats, we examined the ability of three major excitatory neurotransmitter systems to activate the HPA axis in both Lewis and Fisher rats. The responsiveness of plasma ACTH and corticosterone to the cholinergic muscarinic receptor agonist arecoline, the alpha 1-adrenergic receptor agonist methoxamine and the serotonin (5-HT) type 2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane were significantly blunted and/or abolished in LEW/N compared to F344/N rats. To localize the HPA axis defect to the hypothalamic CRH neuron, we evaluated the ability of explanted hypothalami from the two strains to secrete immunoreactive CRH in vitro, in response to acetylcholine (ACh), norepinephrine (NE), 5-HT and the 5-HT agonist quipazine. LEW/N hypothalami released less immunoreactive CRH (iCRH) in response to ACh, NE, 5-HT and quipazine than F344/N hypothalami. The dose-response curves of these compounds in the former were shifted to the right and/or abolished, suggesting decreased sensitivity of LEW/N hypothalami to these neurotransmitters.(ABSTRACT TRUNCATED AT 250 WORDS)

Arthritis-susceptible Lewis rats fail to emerge from the stress hyporesponsive period.

Susceptibility to streptococcal cell wall (SCW)-induced arthritis in 4- to 6-week-old Lewis (LEW/N) rats is associated with blunted glucocorticoid production secondary to a profound defect in inflammatory mediator-induced hypothalamic corticotropin-releasing hormone (CRH) biosynthesis and secretion. The relative SCW arthritis resistance in histocompatible Fischer (F344/N) rats, on the other hand, is associated with robust hypothalamic-pituitary-adrenal (HPA) axis responses to inflammatory mediators. In this study, we investigated HPA axis responses to SCW during the postnatal developmental period in LEW/N and F344/N rats. We found that SCW-induced plasma corticosterone (CORT) responses do not significantly increase during development in LEW/N, while such responses clearly appear at postnatal day 14 in F344/N and outbred Harlan-Sprague-Dawley (HSD) rats. Additionally, LEW/N rats fail to exhibit the normal ontogenic increase in CRH mRNA levels in the paraventricular nucleus (PVN), whereas their SCW-induced PVN CRH mRNA responses are blunted compared to F344/N at postnatal day 14. Taken together, these results suggest that LEW/N rats fail to emerge completely from their stress hyporesponsive period. This may account for the lack of stress responsiveness in young adult LEW/N rats, and consequently, for their susceptibility to SCW-induced arthritis and other inflammatory diseases.

Increased hypothalamic [3H]flunitrazepam binding in hypothalamic-pituitary-adrenal axis hyporesponsive Lewis rats.

We have previously demonstrated that susceptibility of Lewis (LEW/N) rats to inflammatory disease, compared to relatively resistant Fischer (F344/N) rats, is related to deficient glucocorticoid counter-regulation of the immune response resulting from deficient corticotropin-releasing hormone (CRH) responsiveness to inflammatory and other stress mediators. The GABA/benzodiazepine receptor complex is an important negative modulator of CRH secretion and responsiveness to excitatory stimuli. In this study, we have examined in vitro binding of [3H]flunitrazepam to hypothalamic membrane preparations from LEW/N and F344/N rats. LEW/N rats had significantly more hypothalamic benzodiazepine binding sites (Bmax) than F344/N rats, but there were no differences in benzodiazepine binding affinities (Kd) between these two strains. The differences in benzodiazepine receptor number were consistent with the respective plasma corticosterone levels in the two strains, and with previous work indicating a negative correlation between corticosterone levels and benzodiazepine binding site number. Adrenalectomy of F344/N rats increased benzodiazepine binding to levels comparable to LEW/N animals and treatment of adrenalectomized F344/N rats with DEX resulted in lowering of benzodiazepine Bmax to levels that did not differ significantly from those of intact F344/N rats. There was no significant change in receptor number in either adrenalectomized or DEX-treated LEW/N rats. These findings suggest that basal benzodiazepine receptor differences between these strains may be partially related to strain differences in corticosterone levels, however that additional factors may contribute to maintenance of these differences in LEW/N rats. Since benzodiazepines attenuate hypothalamic CRH secretion through GABAergic inhibition, we suggest that strain differences in receptor number could also augment strain differences in hypothalamic-pituitary-adrenal axis function through differential sensitivity to GABA-mediated feedback.

Corticotropin releasing hormone related behavioral and neuroendocrine responses to stress in Lewis and Fischer rats.

We have recently shown that susceptibility to streptococcal cell wall (SCW)-induced arthritis in Lewis (LEW/N) rats is related to a lack of glucocorticoid restraint of inflammation while the relative SCW arthritis resistance in histocompatible Fischer (F344/N) rats is related to their greater hypothalamic-pituitary-adrenal (HPA) axis response. The difference in pituitary-adrenal responsiveness results from decreased inflammatory mediator-induced hypothalamic corticotropin-releasing hormone (CRH) biosynthesis and secretion in LEW/N rats. Because CRH not only activates the pituitary-adrenal axis, but also is associated with behavioral responses that are adaptive during stressful situations, we wished to determine if the differential LEW/N and F344/N CRH responsiveness to inflammatory mediators could also be associated with differences in neuroendocrine and behavioral responses to physical and emotional stressors. In this study, LEW/N rats exhibited significant differences compared to F344/N rats, in plasma adrenocorticotropin hormone (ACTH) and corticosterone responses during exposure to an open field, swim stress, restraint or ether. Furthermore, hypothalamic paraventricular CRH mRNA expression was also significantly lower in LEW/N compared to F344/N rats after restraint. These differences in neuroendocrine responses were associated with differences in behavioral responses in LEW/N compared to F344/N rats in the open field. Outbred HSD rats, which have intermediate and overlapping arthritis susceptibility compared to LEW/N and F344/N rats, exhibited intermediate and overlapping plasma corticosterone and behavioral responses to stressful stimuli compared to the two inbred strains. These data suggest that the differences in CRH responses in these strains may contribute to the behavioral and neuroendocrine differences we have observed. Therefore these strains may provide a useful animal model for studying the relationship between behavior, neuroendocrine and inflammatory responses.