Intracellular Mechanisms of Cyclosporin A–Induced Tubular Cell Apoptosis
Authors: Pilar Justo, Corina Lorz, Ana Sanz, Jesus Egido, Alberto Ortiz
Journal: Journal of the American Society of Nephrology (2003)

<b>Objective:</b> To investigate the effects of cladribine on MRI disease activity measures in RRMS patients treated for 2 additional years beyond the initial 2-year regimen (CLARITY). <b>Background:</b> In CLARITY, cladribine significantly reduced relapse rates, MRI disease-activity measures and slowed disability progression. After a treatment gap (median 40 weeks), the effects of 2 additional years of cladribine treatment vs. placebo were investigated in CLARITY-Extension (EXT); MRI outcomes are described here. <b>Methods:</b> CLARITY patients were randomized to 2 years' treatment with placebo or cladribine (3.5 or 5.25mg/kg bodyweight). In CLARITY-EXT, placebo recipients in CLARITY received cladribine 3.5mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5mg/kg or placebo (5 groups total). <b>Results:</b> The proportion of patients with no new T1 gadolinium enhanced (Gd+) lesions was 85.1-89.9[percnt] in cladribine-treated groups during CLARITY-EXT vs. 73.0-80.2[percnt] in placebo-treated groups. Respectively, the proportions with no active T2 lesions were 37.6-43.7[percnt] vs. 27.6-34.4[percnt]; proportions with no combined unique lesions were similar. Mean numbers of new T1 Gd+ lesions/subject/scan were 0.03-0.17 and 0.28-0.29, respectively, being significantly lower in patients treated with cladribine 3.5mg/kg in both CLARITY and CLARITY-EXT (0.03±0.08) vs. treatment with cladribine 3.5mg/kg in CLARITY and placebo in CLARITY-EXT (0.28±0.87, P&lt;0.001). Of note, mean numbers of new T1 Gd+ lesions/subject/scan were &lt;1 in 88.4[percnt] of patients in the latter group. <b>Conclusions:</b> Overall, mean numbers of new T1 Gd+ lesions in CLARITY-EXT were low. Considering the favourable relapse-rate response seen in CLARITY-EXT, these findings suggest that the clinical benefits of 2 years' cladribine treatment were maintained for up to 4 years in the majority of patients. A small subgroup of patients treated with cladribine 3.5mg/kg in CLARITY and placebo in CLARITY-EXT showed some evidence of T1-Gd+ activity; decisions on further treatment could be based upon monitoring. Study supported by: Merck KGaA, Darmstadt, Germany <b>Disclosure:</b> Dr. Giancarlo has received research support from Novartis, Teva Pharmaceutical, Sanofi-Aventis, Merck Serono, Biogen Domp, and Bayer Schering. Dr. Giovannoni has received personal compensation for activities with AbbVie Biotherapeutics Inc., Biogen, Bayer HealthCare, Genzyme, Merck Serono, Sanofi-Aventis, Teva, Ironwood, and Novartis. Dr. Cook has received personal compensation for activities with Merck Serono, Bayer HealthCare, Sanofi-Aventis, Neurology Reviews, Biogen Idec, Teva Pharmaceuticals, and Actinobac Biomed Inc. Dr. Rammohan has received personal compensation for activities with EMD Serono, Biogen Idec, Sanofi-Aventis, Genzyme Corporation, Novartis, Teva Neurosciences, Acorda and Roche/Genentech Inc. as a speaker and committee member. Dr. Soelberg-Sorensen has received personal compensation for activities with Biogen Idec, Merck Serono, Novartis, Genmab, Teva, Elan, and GlaxoSmithKline, Inc. Dr. Vermersch has received personal compensation for activities with Biogen Idec, Sanofi, Bayer, Novartis, Merck Serono, GlaxoSmithKline, and Almirall. Dr. Vermersch has received research support from Biogen Idec, Sanofi, Bayer, and Merck Serono. Dr. Martin has received personal compensation for activities with EMD Serono, Inc. as an employee. Dr. Dangond has received personal compensation for activities with EMD Serono, Inc. as an employee. Dr. Rieckmann has received personal compensation for activities with Merck Serono, Biogen Idec, Bayer Schering Pharma, Boehringer-Ingelheim, Sanofi-Aventis, Genzyme, Novartis, and Teva Pharmaceutical Industries.