Effects of concomitant immunomodulators on the pharmacokinetics, efficacy and safety of adalimumab in patients with Crohn's disease or ulcerative colitis who had failed conventional therapy.

BACKGROUND: Adalimumab is approved for use in patients with moderate to severe Crohn's disease (CD) or ulcerative colitis (UC) who have not achieved disease control with conventional therapies including corticosteroids and/or immunomodulators (IMM). AIM: To analyse six studies that examined efficacy, pharmacokinetics and safety of combination IMM/adalimumab therapy, compared with adalimumab monotherapy in patients with inadequate disease control on conventional therapy. METHODS: Patients with moderate to severe CD or UC from randomised, double-blind, placebo-controlled trials were analysed. Adalimumab was added to background therapy; patients were categorised as receiving adalimumab monotherapy (CD induction, n = 245, maintenance, n = 185; UC induction, n = 213, maintenance, n = 157) or combination therapy (CD induction, n = 139, maintenance, n = 139; UC induction, n = 140, maintenance, n = 100) according to baseline immunomodulator use. Efficacy was reported for the intent-to-treat populations from each study, with remission defined as CD activity index <150 for CD and Mayo score ≤2 with no subscore >1 for UC. Safety was assessed via adverse events. RESULTS: The proportions of patients achieving remission were similar for adalimumab monotherapy and immunomodulator combination therapy in all studies. Median adalimumab concentrations at week 4 or 8 were numerically but not significantly higher with adalimumab combination therapy vs. monotherapy in the CD and UC studies respectively. Incidence and rate of adverse events was similar for adalimumab monotherapy and combination therapy. CONCLUSIONS: Post hoc analysis of six randomised, controlled trials demonstrated no efficacy benefits with immunomodulator/adalimumab combination therapy, compared with adalimumab monotherapy in CD and UC patients with inadequate disease control on conventional therapy; the safety of the two treatment approaches was comparable.

Randomised clinical study: discrepancies between patient-reported outcomes and endoscopic appearance in moderate to severe ulcerative colitis.

BACKGROUND: Associations between patient-reported outcomes and mucosal healing have not been established in ulcerative colitis (UC). AIM: To evaluate relationships of rectal bleeding and stool frequency with mucosal healing and quality of life (QoL) in patients with UC in two Phase 3 studies (ULTRA 1 and 2). METHODS: Associations of patient-reported rectal bleeding and stool frequency subscores with mucosal healing (Mayo endoscopy subscore = 0 or 0/1) and QoL [inflammatory bowel disease questionnaire (IBDQ)] were assessed in adalimumab-randomised patients (160/80 mg at Weeks 0/2 followed by 40 mg biweekly or weekly) at Weeks 8 (n = 433) and 52 (n = 299), and in patients with mucosal healing [endoscopy subscore = 0 (n = 17); 0/1 (n = 52)] at Weeks 8 and 52. RESULTS: At Week 8, the positive predictive values (PPVs) of rectal bleeding subscore = 0, stool frequency subscore = 0 or both scores = 0 for endoscopy subscore = 0/1 were 69%, 84% and 90% respectively; all proportions increased at Week 52. Equivalent PPVs for these subscores in patients with endoscopy subscore = 0 were 26%, 37% and 46% respectively. Among patients with endoscopy subscore = 0 at Week 8, 87% reported no rectal bleeding, while only 29% reported normal stool frequency; these proportions had increased to 94% and 41% respectively, at Week 52. Among patients with mucosal healing, IBDQ scores trended highest for patients with both rectal bleeding and stool frequency subscores = 0. CONCLUSIONS: Absence of rectal bleeding and normal stool frequency are often predictive of mucosal healing and QoL, but complete normalisation of stool frequency is encountered rarely in patients with mucosal healing.

Escalation to weekly dosing recaptures response in adalimumab-treated patients with moderately to severely active ulcerative colitis.

BACKGROUND: Patients with moderately to severely active ulcerative colitis occasionally do not respond to or lose initial response to maintenance dosing of anti-TNF therapy. AIM: To report the efficacy of escalation from every other week (EOW) to weekly adalimumab dosing in patients from the clinical trial ULTRA 2 (NCT00408629), by week 8 response (i.e. response after adalimumab induction therapy). METHODS: Week 52 remission, response, and mucosal healing rates were assessed in ULTRA 2 adalimumab-randomised patients who escalated to weekly dosing. Patients were stratified by week 8 response per partial Mayo score. Kaplan-Meier and logistic regression analyses estimated time to weekly dosing and defined predictors of escalation to weekly dosing, respectively. Adverse events were reported for patients receiving open-label adalimumab. RESULTS: The rate of escalation to weekly dosing was 16.3% (20/123) for week 8 responders and 38.4% (48/125) for week 8 nonresponders. Week 52 remission, response and mucosal healing rates with weekly dosing were 20%, 45%, and 45% for week 8 responders and 2.1%, 25% and 29.2% for nonresponders, respectively (NRI). The median time to weekly dosing was 288 days for week 8 nonresponders and not estimable for responders. Prior anti-TNF use was a significant predictor of escalation to weekly dosing. Treatment-emergent adverse event rates were similar for patients receiving open-label EOW or weekly adalimumab. CONCLUSIONS: Escalation to weekly adalimumab dosing demonstrated clinical benefits for patients who lost response to therapy and may be beneficial for patients not initially responding to induction therapy. No new safety risks were identified with weekly dosing.

Adalimumab maintains remission of Crohn's disease after up to 4 years of treatment: data from CHARM and ADHERE.

BACKGROUND: Therapies that maintain remission for patients with Crohn's disease are essential. Stable remission rates have been demonstrated for up to 2 years in adalimumab-treated patients with moderately to severely active Crohn's disease enrolled in the CHARM and ADHERE clinical trials. AIM: To present the long-term efficacy and safety of adalimumab therapy through 4 years of treatment. METHODS: Remission (CDAI <150), response (CR-100) and corticosteroid-free remission over 4 years, and maintenance of these endpoints beyond 1 year were assessed in CHARM early responders randomised to adalimumab. Corticosteroid-free remission was also assessed in all adalimumab-randomised patients using corticosteroids at baseline. Fistula healing was assessed in adalimumab-randomised patients with fistula at baseline. As observed, last observation carried forward and a hybrid nonresponder imputation analysis for year 4 (hNRI) were used to report efficacy. Adverse events were reported for any patient receiving at least one dose of adalimumab. RESULTS: Of 329 early responders randomised to adalimumab induction therapy, at least 30% achieved remission (99/329) or CR-100 (116/329) at year 4 of treatment (hNRI). The majority of patients (54%) with remission at year 1 maintained this endpoint at year 4 (hNRI). At year 4, 16% of patients taking corticosteroids at baseline were in corticosteroid-free remission and 24% of patients with fistulae at baseline had healed fistulae. The incidence rates of adverse events remained stable over time. CONCLUSIONS: Prolonged adalimumab therapy maintained clinical remission and response in patients with moderately to severely active Crohn's disease for up to 4 years. No increased risk of adverse events or new safety signals were identified with long-term maintenance therapy. (clinicaltrials.gov number: NCT00077779).

Association of baseline C-reactive protein and prior anti-tumor necrosis factor therapy with need for weekly dosing during maintenance therapy with adalimumab in patients with moderate to severe Crohn's disease.

OBJECTIVE: A post hoc analysis of data from the adalimumab Crohn's disease (CD) maintenance trial (CHARM, NCT00077779), examining the relationship between adalimumab dosing and maintenance of remission and response in subgroups stratified by previous anti-TNF use and baseline CRP. METHODS: All patients received open-label induction (adalimumab: 80 mg, week [wk] 0; 40 mg, wk 2). At wk 4, all patients were randomized to double-blind maintenance adalimumab (40 mg weekly or every other week [eow]) or placebo for 52 weeks. In this analysis, clinical remission (CDAI <150) and clinical response (CR-100) at wk 26 and wk 56 by baseline CRP (high: ≥ 10 mg/L, or low: <10 mg/L) and prior anti-TNF use were determined for patients with CR-70 at wk 4. RESULTS: Of 498 patients in this analysis, 260 (52.2%) were anti-TNF-naïve. For anti-TNF-naïve patients, the wk 56 remission rates in the adalimumab groups were significantly greater than placebo (P < 0.05) for both high and low CRP cohorts, with no statistically significant differences between remission rates with eow and weekly dosing within each CRP cohort (high: 52.8% eow, 53.5% weekly; low: 34.7% eow, 41.9% weekly). For anti-TNF-exposed patients, wk 56 remission rates were higher than placebo with both eow and weekly dosing within each cohort; weekly dosing in the high CRP cohort and eow dosing in the low CRP cohort achieved statistical significance (P < 0.05). In the high CRP cohort, remission rate with weekly dosing (46.9%) was statistically significantly greater compared with eow dosing (22.5%). There were no significant differences between eow (23.1%) and weekly (37.0%) dosing in the low CRP group. For all subgroups, clinical remission (wk 26) and clinical response (wk 26 and wk 56) patterns were similar to those observed for wk 56 remission. CONCLUSIONS: These subgroup analyses suggest that in patients with moderately to severely active CD, weekly dosing may be most effective in the anti-TNF-experienced patients with elevated CRP at baseline.

What do international guidelines say about therapy?

PURPOSE: We will discuss the treatment guidelines from the British Hypertension Society, Canadian Medical Association, Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, the sixth report, and the World Health Organization-International Society of Hypertension. Our emphasis will be on blood pressure thresholds, goals of therapy, non-pharmacologic interventions, choice of first-line agents in uncomplicated patients, individualized therapeutic choices, adjunctive therapy, and future considerations. DATA IDENTIFICATION: Specific recommendations in international guidelines regarding antihypertensive therapy, that are written in English, easily accessible (i.e., found on the World Wide Web), and current (published in 1997 or later). CONCLUSIONS: The reviewed hypertension guidelines strongly favor lifestyle modifications in all patients diagnosed with hypertension, and a trial of lifestyle modification for a specified time period prior to initiating drug therapy is advocated. Pharmacologic therapy should be based on the patient profile: presence of major cardiovascular risk factors, cardiovascular disease, target-organ damage, and concomitant medical conditions, thus allowing for the tailoring of antihypertensive therapy to the individual patient. Thiazide diuretics are the most commonly recommended antihypertensive drug class, based on numerous outcome trials. Finally, new strategies such as low-dose combination therapy are recommended as initial treatment in some patients.

Primary aldosteronism: a practical approach to diagnosis and treatment.

Primary aldosteronism (PA) may account for as many as 10%-14% of hypertension cases. The plasma aldosterone concentration/plasma renin activity ratio is a simple screening test for PA that should be performed in all patients with refractory/severe hypertension, spontaneous or provoked (by diuretics) hypokalemia, or a requirement for excessive potassium supplementation to maintain normokalemia. PA can be confirmed by a fludrocortisone suppression test or 24-hour urine collection for aldosterone. Confirmatory testing should be followed by high-resolution computerized tomography of the adrenal glands to distinguish bilateral hyperplasia or an adenoma. A solitary tumor greater than 1 cm in size in a younger patient is an indication for surgery; all other (nondiagnostic) findings should be followed by bilateral adrenal venous sampling (if available) to identify a unilateral cause of PA. Treatment for a lateralizing positive study is surgical; spironolactone or another mineralocorticoid receptor antagonist is the treatment of choice for a nonlateralizing study. If adrenal venous sampling is not readily available, patients may be successfully treated pharmacologically.