Original Article
A Placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis
N Engl J Med 2010; 362:416-426February 4, 2010
- Abstract
Background
Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-course oral tablet therapy in patients with relapsing–remitting multiple sclerosis.
Methods
We randomly assigned 1326 patients in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo, given in two or four short courses for the first 48 weeks, then in two short courses starting at week 48 and week 52 (for a total of 8 to 20 days per year). The primary end point was the rate of relapse at 96 weeks.
Results
Among patients who received cladribine tablets (either 3.5 mg or 5.25 mg per kilogram), there was a significantly lower annualized rate of relapse than in the placebo group (0.14 and 0.15, respectively, vs. 0.33; P<0.001 for both comparisons), a higher relapse-free rate (79.7% and 78.9%, respectively, vs. 60.9%; P<0.001 for both comparisons), a lower risk of 3-month sustained progression of disability (hazard ratio for the 3.5-mg group, 0.67; 95% confidence interval [CI], 0.48 to 0.93; P=0.02; and hazard ratio for the 5.25-mg group, 0.69; 95% CI, 0.49 to 0.96; P=0.03), and significant reductions in the brain lesion count on magnetic resonance imaging (MRI) (P<0.001 for all comparisons). Adverse events that were more frequent in the cladribine groups included lymphocytopenia (21.6% in the 3.5-mg group and 31.5% in the 5.25-mg group, vs. 1.8%) and herpes zoster (8 patients and 12 patients, respectively, vs. no patients).
Conclusions
Treatment with cladribine tablets significantly reduced relapse rates, the risk of disability progression, and MRI measures of disease activity at 96 weeks. The benefits need to be weighed against the risks. (ClinicalTrials.gov number, NCT00213135.)
Media in This Article
Figure 1
Efficacy Outcome Measures Relating to Relapse and Progression of Disability during the 96-Week Study Period (Intention-to-Treat Population).Table 1
Demographic and Clinical Characteristics of the Patients at Baseline (Intention-to-Treat Population).Article Activity
- Article
Multiple sclerosis is a chronic and debilitating autoimmune disorder of the central nervous system, in which T and B cells are believed to play a major pathophysiological role.1-3 Treatment benefits and disease modification can be obtained with the currently approved parenteral immunomodulatory and immunosuppressant therapies: interferon beta, glatiramer acetate, mitoxantrone, and natalizumab. However, treatment responses are often less than complete, and concern regarding safety and side-effect profiles may limit the general use of these drugs. The need for parenteral administration may present relative or absolute barriers to access, limiting treatment adherence and long-term outcomes.4
Intracellular accumulation of the active metabolite of cladribine, 2-chlorodeoxyadenosine triphosphate, results in the disruption of cellular metabolism, the inhibition of DNA synthesis and repair, and subsequent apoptosis.5 Cladribine preferentially affects lymphocytes because these cells have a relatively high ratio of deoxycytidine kinase to 5′-nucleotidase and are dependent on adenosine deaminase activity to maintain the equilibrium of cellular concentrations of triphosphorylated nucleotides. The accumulation of the cladribine nucleotide produces rapid and sustained reductions in CD4+ and CD8+ cells and rapid, though more transient, effects on CD19+ B cells, with relative sparing of other immune cells.5-8 Cladribine also has been shown to cause a reduction in the levels of proinflammatory cytokines and serum and cerebrospinal fluid chemokines, in adhesion molecule expression, and in mononuclear-cell migration.5,9-13
In the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study, we investigated the efficacy and safety of cladribine in a 96-week, phase 3, double-blind, placebo-controlled, multicenter trial involving patients with relapsing–remitting multiple sclerosis. The two doses of cladribine that we evaluated were based on the results of previous clinical studies that used a parenteral formulation of the drug in various regimens.7,14-16 In order to provide an extended interim hematopoietic recovery period before subsequent retreatment, we administered cladribine in short courses within separate 48-week periods rather than administering the aggregate treatment as six to eight consecutive monthly courses.
Methods
Patients
From April 20, 2005, to January 18, 2007, we recruited patients from 155 clinical centers in 32 countries (for details, see the Supplementary Appendix, available with the full text of this article at NEJM.org). Patients were eligible if they had received a diagnosis of relapsing–remitting multiple sclerosis (according to the McDonald criteria),17 had lesions consistent with multiple sclerosis on magnetic resonance imaging (MRI) (according to the Fazekas criteria),18 had had at least one relapse within 12 months before study entry, and had a score of no more than 5.5 on the Kurtzke Expanded Disability Status Scale (EDSS, which ranges from 0 to 10, with higher scores indicating a greater degree of disability).19
Patients were excluded from the study if two or more previous disease-modifying therapies had failed or if they had received immunosuppressive therapy at any time before study entry or cytokine-based therapy, intravenous immune globulin therapy, or plasmapheresis within 3 months before study entry. Patients were also excluded if they had abnormal results on hematologic testing (a platelet or neutrophil count below the lower limit of the normal range or a leukocyte count of half the lower limit of the normal range) within 28 days before study entry, had a disorder that could compromise immune function (including systemic disease or infection with the human immunodeficiency virus or human T-cell lymphotropic virus), or had had a relapse within 28 days before study entry. For any patient who had received a disease-modifying drug for multiple sclerosis, a washout period of at least 3 months before study entry was required.
Study Design
Eligible patients were assigned in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine over 96 weeks (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo. Randomization was performed with the use of a central system and a computer-generated treatment randomization code, with dynamic allocation by site in permuted blocks of six. The study drugs were administered orally as short courses, each consisting of one or two 10-mg cladribine tablets or matching placebo given once daily for the first 4 or 5 days of a 28-day period.
In the first 48-week treatment period, patients received either two courses of cladribine, followed by two courses of placebo (in the 3.5-mg group); four courses of cladribine (in the 5.25-mg group); or four courses of placebo (in the placebo group), starting at day 1 and at weeks 5, 9, and 13 (8 to 20 days of treatment). In the second 48-week period, both cladribine groups received two courses of cladribine, and the placebo group received two courses of placebo, starting at weeks 48 and 52 (8 to 10 days of treatment) (Fig. 1 in the Supplementary Appendix). After week 24, rescue therapy with subcutaneous interferon beta-1a (at a dose of 44 μg three times per week) was available if a patient had more than one relapse or a sustained increase in the EDSS score.
The study was conducted in accordance with relevant clinical guidelines (see the Supplementary Appendix). All patients provided written informed consent.
Study Oversight
The protocol was reviewed and approved by the local review board or ethics committee at each study center. An independent data and safety monitoring board reviewed the study conduct and all safety data. Data were gathered by an independent commercial research organization and analyzed by the sponsor (Merck Serono) in accordance with the statistical plan. MRI data were analyzed by an independent commercial research organization at a central reading center. The authors were involved in all stages of development and finalization of the manuscript and were assisted by an independent medical-writing-services agency paid by Merck Serono. The first draft of the manuscript was cowritten by the lead academic author and a representative of the sponsor, with the medical-writing-services agency providing support as directed. The authors vouch for the completeness and accuracy of the data and analyses.
Study Procedures
To maintain the double-blind nature of the study, all patients within a weight range received the same number of tablets (cladribine or matched placebo). In addition, at each study site, a treating physician reviewed clinical laboratory results and assessed treatment-emergent adverse events and safety information, and an independent evaluating physician who was unaware of study-group assignments performed neurologic examinations and determined whether a clinical event fulfilled criteria consistent with a relapse. Evaluators at a central neuroradiology center assessed MRI evaluations in a blinded fashion.
Neurologic examinations included the EDSS evaluation,19 which was conducted at the prestudy evaluation and at day 1 and at weeks 13, 24, 36, 48, 60, 72, 84, and 96. MRI scans were obtained at the prestudy evaluation and at weeks 24, 48, and 96. Clinical laboratory tests, including chemical and hematologic analyses and urinalysis, were performed by a central laboratory at frequent intervals during the 96-week study (for details, see the Supplementary Appendix). For suspected relapses occurring between study visits, patients were required to attend the study site within 7 days after the onset of neurologic symptoms for objective assessment by the evaluating physician in a blinded fashion. Relapses could be treated with intravenous corticosteroids at the discretion of the treating physician.
Primary and Secondary End Points
The primary end point was the rate of relapse at 96 weeks. A relapse was defined as an increase of 2 points in at least one functional system of the EDSS or an increase of 1 point in at least two functional systems (excluding changes in bowel or bladder function or cognition) in the absence of fever, lasting for at least 24 hours and to have been preceded by at least 30 days of clinical stability or improvement.
Key clinical secondary efficacy end points were the proportion of patients who were relapse-free and the time to sustained progression of disability, which was defined as the time to a sustained increase (for at least 3 months) of at least 1 point in the EDSS score or an increase of at least 1.5 points if the baseline EDSS score was 0. Additional clinical efficacy end points included the time to the first relapse and the proportion of patients receiving rescue therapy with interferon beta-1a. Secondary MRI end points were the mean number of lesions per patient per scan at 96 weeks for gadolinium-enhancing T1-weighted lesions, active T2-weighted lesions, and combined unique lesions, which were defined as new gadolinium-enhancing T1-weighted lesions or new nonenhancing or enlarging T2-weighted lesions (without double-counting).
The safety assessment included a review of the incidence of treatment-emergent adverse events in each study group, physical examination, and laboratory measurements. A strict protocol was established for the management of hematologic events (see the Supplementary Appendix).
Statistical Analysis
We determined that 1290 patients (approximately 430 in each group) were required to provide a power of 90% to detect a clinically meaningful relative reduction of 25% in the relapse rate in the cladribine groups, as compared with the placebo group, at 96 weeks (the primary end point). This was calculated with the use of a two-sided t-test on the assumption that a mean number of 2.1 relapses would occur in the placebo group, that the standard deviation for the number of relapses in each group would be 2.02, that the proportion of patients who could not be evaluated would be 10%, and that the two-sided type I error rate for the comparison between each cladribine group and the placebo group would be 2.5%.
The intention-to-treat population included all patients who underwent randomization, and the safety population included all patients who received at least one dose of a study drug and for whom follow-up safety data were available. The primary efficacy measurement was analyzed with the use of a Poisson regression model including effects for treatment and region and the log of time in the study as the offset variable. The study groups were compared by means of an approximate chi-square test on the basis of Wald statistics and Hochberg's step-up method for multiple comparisons to protect the type I error.
For patients who received rescue therapy, the primary and secondary efficacy analyses included the prerescue data and imputed data from the time of rescue onward, according to prespecified methods in the statistical analysis plan. For the primary end point, imputed data were derived only from patients in the placebo group.
In the analysis of secondary end points, the proportions of patients who were relapse-free and progression-free were analyzed with the use of a logistic-regression model that included study-group and region effects, and odds ratio and 95% confidence intervals were estimated for each study group. The three study groups were compared with the use of an approximate chi-square test on the basis of Wald statistics. The time to the first relapse and the time to a 3-month sustained change in the EDSS score were analyzed with the use of a Cox proportional-hazards model that included study-group and region effects, and the hazard ratio for the time to the first relapse and the time to a 3-month sustained change in the EDSS score in each group and associated 95% confidence intervals were estimated. Kaplan–Meier plots of the time to the first relapse and the time to a 3-month sustained change in the EDSS score were also generated.
Secondary end points that were related to lesion counts on MRI were analyzed with the use of a nonparametric analysis-of-covariance model on ranked data with effects for study group and region adjusted for baseline counts of gadolinium-enhancing T1 lesions. To protect the overall family-wise type I error rate of 5%, dose groups that differed significantly from placebo for the primary efficacy measures were compared with placebo for the three secondary MRI measurements with the use of a hierarchical testing procedure that was based on the Hochberg procedure. The sequential testing of the measurements was carried out only if the test for the previous measurement was significant.
Sensitivity analyses were conducted to assess the effect of baseline differences in disease characteristics on efficacy outcome measures. The results of these analyses are not reported here, since no material effects were shown. No interim analyses were conducted for this study.
Results
Patients
The demographic and clinical characteristics of the intention-to-treat population of 1326 patients was generally well balanced across the three study groups, although patients receiving 3.5 mg of cladribine per kilogram had a shorter mean duration of disease (P=0.005 for the overall comparison) (Table 1Table 1
Demographic and Clinical Characteristics of the Patients at Baseline (Intention-to-Treat Population).). Almost one third of patients had previously received disease-modifying therapy. Overall, 1184 patients (89.3%) completed the 96-week study (91.9% in the cladribine 3.5-mg group, 89.0% in the cladribine 5.25-mg group, and 87.0% in the placebo group) (Fig. 2 in the Supplementary Appendix). A total of 1165 patients (87.9%) completed treatment (91.2%, 86.2%, and 86.3%, respectively). The mean time of participation in the study was 89.4 weeks (91.0, 89.4, and 87.8 weeks, respectively).Primary and Secondary End Points
The annualized relapse rate at 96 weeks was significantly reduced in both cladribine groups, as compared with the placebo group (0.14 in the cladribine 3.5-mg group and 0.15 in the cladribine 5.25-mg group, vs. 0.33 in the placebo group), for relative reductions of 57.6% and 54.5%, respectively (P<0.001 for both comparisons) (Table 2Table 2
Clinical and Imaging End Points and Relapses during the 96-week Study (Intention-to-Treat Population). and Figure 1A and 1CFigure 1Efficacy Outcome Measures Relating to Relapse and Progression of Disability during the 96-Week Study Period (Intention-to-Treat Population).). The proportion of patients who remained relapse-free at 96 weeks was significantly higher in both cladribine groups (79.7% and 78.9%, respectively), as compared with the placebo group (60.9%) (P<0.001 for both comparisons) (Table 2). In addition, the time to the first relapse was longer in both cladribine groups (hazard ratio in the 3.5-mg group, 0.44; 95% confidence interval [CI], 0.34 to 0.58; P<0.001; and hazard ratio in the 5.25-mg group, 0.46; 95% CI, 0.36 to 0.60; P<0.001 for both comparisons) (Table 2 and Figure 1B). These improvements were achieved with a reduction in the odds of receiving rescue therapy with interferon beta-1a in the cladribine 3.5-mg group (60%) and the cladribine 5.25-mg group (69%), as compared with placebo (P=0.01 and P=0.003, respectively) (Table 2).During the 96-week study, there was a relative reduction in the risk of 3-month sustained progression of disability in both cladribine groups, as compared with placebo, with a 33% reduction in the cladribine 3.5-mg group (hazard ratio, 0.67; 95% CI, 0.48 to 0.93; P=0.02) and a 31% reduction in the cladribine 5.25-mg group (hazard ratio, 0.69; 95% CI, 0.49 to 0.96; P=0.03) (Table 2 and Figure 1D). There were corresponding increases in the odds for remaining free of 3-month sustained disability progression in both cladribine groups, as compared with placebo (P=0.02 for the 3.5-mg group and P=0.03 for the 5.25-mg group) (Table 2).
Cladribine treatment resulted in significant reductions in measures of MRI activity, as compared with placebo. Patients in the cladribine 3.5-mg group and cladribine 5.25-mg group had fewer lesions per patient per scan than those in the placebo group for gadolinium-enhancing T1 lesions (mean number, 0.12 and 0.11, respectively, vs. 0.91), active T2 lesions (mean number, 0.38 and 0.33, respectively, vs. 1.43), and combined unique lesions (mean number, 0.43 and 0.38, respectively, vs. 1.72) (P<0.001 for all comparisons vs. placebo) (Table 2).
Adverse Events
Lymphocytopenia (mostly graded as mild or moderate) was reported more frequently among patients receiving cladribine than among those receiving placebo (Table 3Table 3
Adverse Events and Investigator-Assessed Severity at 96 Weeks (Safety Population).). Severe neutropenia (as rated by the investigators) was reported in three patients receiving cladribine (one in the 3.5-mg group and two in the 5.25-mg group), with severe thrombocytopenia and pancytopenia in one of the patients in the latter group, who also had an exacerbation of latent tuberculosis (see the Supplementary Appendix). There were no cases of severe anemia. The effects of cladribine on lymphocyte counts in the first and second 48-week periods are presented in Table 4Table 4
Effects of Cladribine on Lymphocyte Counts, According to Time Point (Safety Population).. Fig. 3 in the Supplementary Appendix shows the effects of therapy on lymphocyte and neutrophil counts over the duration of the study. Maximal effects on lymphocyte, neutrophil, and platelet counts and hemoglobin levels are presented, according to laboratory criteria of the National Cancer Institute's Common Terminology Criteria for Adverse Events, in Table 1 in the Supplementary Appendix.Infections or infestations were reported in 47.7% of the patients in the cladribine 3.5-mg group, 48.9% of those in the cladribine 5.25-mg group, and 42.5% of those in the placebo group, with most of the events graded as mild or moderate by investigators (99.6% and 98.6%, respectively, vs. 99.0%). Herpes zoster infections developed in 20 patients who received cladribine (including 1 with herpes zoster oticus): 8 patients in the 3.5-mg group and 12 in the 5.25-mg group. All cases of herpes zoster were restricted and dermatomal in nature. There were three cases of primary varicella (one in each study group), all of which resolved without complication. Correlation analysis suggested that the lowest absolute lymphocyte counts in patients receiving cladribine were inversely correlated with the occurrence of infection (Spearman's correlation coefficient for both cladribine groups combined, –0.10; P=0.003).
Adverse events led to treatment discontinuation for 3.5% of patients in the cladribine 3.5-mg group, 7.9% of those in the cladribine 5.25-mg group, and 2.1% of those in the placebo group. The occurrence of lymphocytopenia and leukocytopenia led to treatment discontinuation in 0.9%, 4.2%, and no patients, respectively. The three study groups had similar rates of other events leading to the discontinuation of a study drug.
The incidence of serious adverse events was 8.4% in the cladribine 3.5-mg group, 9.0% in the cladribine 5.25-mg group, and 6.4% in the placebo group (Table 3, and Table 2 in the Supplementary Appendix). Infections or infestations were reported as serious adverse events in 2.3%, 2.9%, and 1.6% of patients, respectively. Herpes zoster was reported as a serious adverse event for three patients receiving cladribine (two in the 5.25-mg group). The occurrence of neoplasms (including those that were found to be benign, malignant, or unspecified) was reported as a serious adverse event in 1.4% of patients in the cladribine 3.5-mg group and in 0.9% of those in the cladribine 5.25-mg group, as compared with no patients in the placebo group. These included five benign uterine leiomyomas that required inpatient hospital visits for treatment. There were three cases of cancer in the cladribine 3.5-mg group: a melanoma and carcinomas of the pancreas and ovary. A case of stage 0 cervical carcinoma in situ (considered a precancerous condition) was also reported in the cladribine 5.25-mg group. The time from the last course of therapy to diagnosis in these four patients was 2 months, 6 months, <9 months, and 7 months, respectively. For the patient with cervical carcinoma in situ, the relevant medical history included a positive test for human papillomavirus type 16 at 3 years before diagnosis. A choriocarcinoma was diagnosed in one patient in the cladribine 5.25-mg group approximately 9 months after completion of the study.
There were four deaths during the study and two after study discontinuation, equally distributed across the three study groups. Causes of death were acute myocardial infarction and metastatic pancreatic carcinoma in the cladribine 3.5-mg group, drowning and cardiopulmonary arrest that was considered secondary to exacerbation of latent tuberculosis in the cladribine 5.25-mg group, and suicide and hemorrhagic stroke in the placebo group (for details, see the Supplementary Appendix).
Discussion
Our study showed that short-course therapy with cladribine tablets provided rapid and sustained treatment benefits for patients with relapsing–remitting multiple sclerosis during a 96-week period. As compared with placebo, treatment with cladribine resulted in reductions in the rates of clinical relapse and in the risk of disability progression and in the suppression of active inflammatory lesions, as visualized on MRI. Both the regimens of 3.5 mg and 5.25 mg per kilogram appeared to be equally efficacious.
The most commonly reported adverse event was lymphocytopenia. There was an inverse correlation between the incidence of infection and a patient's lowest absolute lymphocyte count in the combined cladribine groups. Activation of latent herpes zoster occurred in 20 cladribine-treated patients. One patient who was treated with cladribine had reactivation of latent tuberculosis and died. The use of cladribine may have contributed to this reactivation, and tuberculosis screening measures were subsequently implemented in ongoing clinical trials to rule out latent or active infection before treatment or retreatment. Cancers were isolated cases across different organ systems, and given the small number, it is not possible to establish a risk for the use of cladribine.
In conclusion, our study showed that short-course treatment with cladribine tablets for only 8 to 20 days per year provided a significant benefit for patients with relapsing–remitting multiple sclerosis with respect to the rate of relapse, disability progression, and MRI measures of disease activity during the 96-week study period. The benefits of treatment will need to be weighed against the risks.
Supported by Merck Serono, with editorial assistance provided by Acumed, which was funded by Merck Serono.
Dr. Giovannoni reports receiving consulting fees from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Teva-Aventis, UCB Pharma, and Vertex Pharmaceuticals, lecture fees from Bayer Schering Pharma, Biogen Idec, Merck Serono, and Vertex Pharmaceuticals, and grant support from Bayer Schering Pharma, Biogen Idec, Ironwood Pharmaceuticals, Merck Serono, Merz, Novartis, and Teva-Aventis; Dr. Comi, receiving consulting fees from Novartis, Teva Pharmaceuticals, Sanofi-Aventis, Merck Serono, and Bayer Schering and lecture fees from Novartis, Teva Pharmaceuticals, Sanofi-Aventis, Merck Serono, Biogen-Dompé, and Bayer Schering; Dr. Cook, receiving consulting fees from Merck Serono, Bayer Healthcare, and Genmab and lecture fees from EMD Serono and Bayer Healthcare; Dr. Rammohan, receiving consulting fees from Bayer Pharmaceuticals, EMD Serono, Pfizer, Teva, Genentech, and Novartis, lecture fees from Bayer, EMD Serono, Pfizer, and Teva, and grant support from Bayer, EMD Serono, Pfizer, Teva, Acorda, Biogen, Genzyme, UCB Pharma, and Novartis; Dr. Rieckmann, receiving consulting fees from Merck Serono, Biogen Idec, Teva, Bayer, and Novartis, lecture fees from Merck Serono, Biogen Idec, and Teva, and grant support from Merck Serono, Bayer, Teva, the MS Society of Canada, and the Ilich Foundation; Dr. Soelberg Sørensen, receiving consulting fees from Merck Serono, Biogen Idec, Teva, Bayer Schering, Genmab, and Novartis, lecture fees from Merck Serono, Biogen Idec, and Teva, and grant support from Biogen Idec; Dr. Vermersch, receiving consulting fees from Merck Serono, Bayer Schering, Teva-Aventis, Biogen Idec, and Novartis, lecture fees from Merck Serono, Biogen Idec, Bayer Schering, and Novartis, and grant support from Biogen Idec, Merck Serono, and Teva-Aventis; and Drs. Chang, Hamlett, Musch, and Greenberg, being employees of Merck Serono. No other potential conflict of interest relevant to this article was reported.
This article (10.1056/NEJMoa0902533) was published on January 20, 2010, at NEJM.org.
We thank Rehan Verjee of Merck Serono and Mary Goodsell of Acumed for their contributions to the preparation of the manuscript.
Source Information
From Queen Mary University London, the Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London (G.G.); the Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Milan (G.C.); the University of Medicine and Dentistry, New Jersey Medical School, Newark (S.C.); Ohio State University, Columbus (K.R.); the University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada (P.R.); Copenhagen University Hospital, Rigshospitalet, Copenhagen (P.S.S.); the University of Lille–Nord de France, Lille, France (P.V.); and Merck Serono, Geneva (P.C., A.H., B.M., S.J.G.).
Address reprint requests to Dr. Giovannoni at the Neuroscience Centre, Blizard Institute of Cell and Molecular Science, 4 Newark St., Whitechapel, London E1 2AT, United Kingdom, or at g.giovannoni@qmul.ac.uk.
Other members of Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study group are listed in the Supplementary Appendix, available with the full text of this article at NEJM.org.
- References
References
1
Chitnis T . The role of CD4 T cells in the pathogenesis of multiple sclerosis. Int Rev Neurobiol 2007;79:43-72
CrossRef | Web of Science | Medline2
Franciotta D ,Salvetti M ,Lolli F ,Serafini B ,Aloisi F . B cells and multiple sclerosis. Lancet Neurol 2008;7:852-858
CrossRef | Web of Science | Medline3
Kleinschnitz C ,Meuth SG ,Kieseier BC ,Wiendl H . Immunotherapeutic approaches in MS: update on pathophysiology and emerging agents or strategies 2006. Endocr Metab Immune Disord Drug Targets 2007;7:35-63
Medline4
Cohen BA ,Rieckmann P . Emerging oral therapies for multiple sclerosis. Int J Clin Pract 2007;61:1922-1930
CrossRef | Web of Science | Medline5
Beutler E . Cladribine (2-chlorodeoxyadenosine). Lancet 1992;340:952-956
CrossRef | Web of Science | Medline6
Guarnaccia JB, Rinder H, Smith B. Preferential depletion of lymphocyte subpopulations by cladribine in a phase III clinical trial in multiple sclerosis. In: Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis, Montreal, September 17–20, 2008 (poster).
7
Rice GP ,Filippi M ,Comi G . Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Neurology 2000;54:1145-1155
Web of Science | Medline8
Leist T, Weissert R. The mechanism of action of cladribine and its implications for oral therapy in multiple sclerosis. Presented at the 23rd Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC), Atlanta, May 27–30, 2009.
9
Bartosik-Psujek H ,Belniak E ,Mitosek-Szewczyk K ,Dobosz B ,Stelmasiak Z . Interleukin-8 and RANTES levels in patients with relapsing-remitting multiple sclerosis (RR-MS) treated with cladribine. Acta Neurol Scand 2004;109:390-392
CrossRef | Web of Science | Medline10
Janiec K ,Wajgt A ,Kondera-Anasz Z . Effect of immunosuppressive cladribine treatment on serum leucocytes system in two-year clinical trial in patients with chronic progressive multiple sclerosis. Med Sci Monit 2001;7:93-98
Medline11
Kopadze T ,Dobert M ,Leussink VI ,Dehmel T ,Kieseier BC . Cladribine impedes in vitro migration of mononuclear cells: a possible implication for treating multiple sclerosis. Eur J Neurol 2009;16:409-412
CrossRef | Web of Science | Medline12
Laugel B, Challier J, Siegfried C, Chvatchko Y, Weissert R, Galibert L. Cladribine exerts a modulatory effect on T-cell activation In: Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis, Montreal, September 17–20, 2008 (poster).
13
Niezgoda A ,Losy J ,Mehta PD . Effect of cladribine treatment on beta-2 microglobulin and soluble intercellular adhesion molecule 1 (ICAM-1) in patients with multiple sclerosis. Folia Morphol (Warsz) 2001;60:225-228
Medline14
Beutler E ,Sipe JC ,Romine JS ,Koziol JA ,McMillan R ,Zytroff J . The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci U S A 1996;93:1716-1720
CrossRef | Web of Science | Medline15
Romine JS ,Sipe JC ,Koziol JA ,Zyroff J ,Beutler E . A double-blind, placebo-controlled, randomized trial of cladribine in relapsing-remitting multiple sclerosis. Proc Assoc Am Physicians 1999;111:35-44
CrossRef | Medline16
Sipe JC ,Romine JS ,Koziol JA ,McMillan R ,Zyroff J ,Beutler E . Cladribine in treatment of chronic progressive multiple sclerosis. Lancet 1994;344:9-13
CrossRef | Web of Science | Medline17
McDonald WI ,Compston A ,Edan G , et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-127
CrossRef | Web of Science | Medline18
Fazekas F ,Barkhof F ,Filippi M , et al. The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis. Neurology 1999;53:448-456
Web of Science | Medline19
Kurtzke JF . Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 1983;33:1444-1452
Web of Science | Medline
- Citing Articles (94)
Citing Articles
1
Daniel Ontaneda, Megan Hyland, Jeffrey A. Cohen. (2012) Multiple Sclerosis: New Insights in Pathogenesis and Novel Therapeutics. Annual Review of Medicine 63:1, 389-404
CrossRef2
Jin Nakahara, Michiko Maeda, Sadakazu Aiso, Norihiro Suzuki. (2012) Current Concepts in Multiple Sclerosis: Autoimmunity Versus Oligodendrogliopathy. Clinical Reviews in Allergy & Immunology 42:1, 26-34
CrossRef3
Fred D. Lublin. (2012) Disease activity free status in MS. Multiple Sclerosis and Related Disorders 1:1, 6-7
CrossRef4
David Baker, Gareth Pryce, Samuel J. Jackson, Chris Bolton, Gavin Giovannoni. (2012) The biology that underpins the therapeutic potential of cannabis-based medicines for the control of spasticity in multiple sclerosis. Multiple Sclerosis and Related Disorders
CrossRef5
R. Alroughani, A. Ashkanani, S. Lamdhade. (2012) Clinical Characteristics of Multiple Sclerosis in Kuwait: Data From the New MS Registry of Amiri Hospital. International Journal of Neuroscience 122:2, 82-87
CrossRef6
Sarah Al-Izki, Gareth Pryce, Janet K. O'Neill, Colin Butter, Gavin Giovannoni, Sandra Amor, David Baker. (2012) Practical guide to the induction of relapsing progressive experimental autoimmune encephalomyelitis in the Biozzi ABH mouse. Multiple Sclerosis and Related Disorders 1:1, 29-38
CrossRef7
Shyi-Jou Chen, Yen-Ling Wang, Hueng-Chuen Fan, Wen-Tsung Lo, Chih-Chien Wang, Huey-Kang Sytwu. (2012) Current Status of the Immunomodulation and Immunomediated Therapeutic Strategies for Multiple Sclerosis. Clinical and Developmental Immunology 2012, 1-16
CrossRef8
Kottil Rammohan, Gavin Giovannoni, Giancarlo Comi, Stuart Cook, Peter Rieckmann, Per Soelberg Sørensen, Patrick Vermersch, Anthony Hamlett, Nuwan Kurukulasuriya. (2012) Cladribine tablets for relapsing–remitting multiple sclerosis: Efficacy across patient subgroups from the phase III CLARITY study. Multiple Sclerosis and Related Disorders 1:1, 49-54
CrossRef9
Shehzad Ali, Noman Paracha, Stuart Cook, Gavin Giovannoni, Giancarlo Comi, Kottil Rammohan, Peter Rieckmann, Per Soelberg Sørensen, Patrick Vermersch, Steven Greenberg, David A. Scott, Alexandre Joyeux. (2012) Reduction in Healthcare and Societal Resource Utilization Associated with Cladribine Tablets in Patients with Relapsing-Remitting Multiple Sclerosis. Clinical Drug Investigation 32:1, 15-27
CrossRef10
Shiv Saidha, Christopher Eckstein, Peter A. Calabresi. (2012) New and emerging disease modifying therapies for multiple sclerosis. Annals of the New York Academy of Sciencesno-no
CrossRef11
Per Soelberg Sørensen. (2011) Balancing the benefits and risks of disease-modifying therapy in patients with multiple sclerosis. Journal of the Neurological Sciences 311, S29-S34
CrossRef12
Bruno Laugel, Frédéric Borlat, Laurent Galibert, Alain Vicari, Robert Weissert, Yolande Chvatchko, Denis Bruniquel. (2011) Cladribine inhibits cytokine secretion by T cells independently of deoxycytidine kinase activity. Journal of Neuroimmunology 240-241, 52-57
CrossRef13
Xavier Montalban. (2011) Review of methodological issues of clinical trials in multiple sclerosis. Journal of the Neurological Sciences 311, S35-S42
CrossRef14
Alan M. Palmer. (2011) Immunomodulatory medicines for multiple sclerosis: Progress and prospects. Drug Development Research 72:8, 664-673
CrossRef15
Claudio Gasperini, Serena Ruggieri. (2011) Emerging oral drugs for relapsing–remitting multiple sclerosis. Expert Opinion on Emerging Drugs 16:4, 697-712
CrossRef16
Ruth Dobson, Ute C. Meier, Gavin Giovannoni. (2011) More to come: Humoral immune responses in MS. Journal of Neuroimmunology 240-241, 13-21
CrossRef17
Catherine Larochelle, Jorge Ivan Alvarez, Alexandre Prat. (2011) How do immune cells overcome the blood–brain barrier in multiple sclerosis?. FEBS Letters 585:23, 3770-3780
CrossRef18
Oscar Fernández. (2011) Nuevos fármacos para el tratamiento de la esclerosis múltiple. FMC - Formación Médica Continuada en Atención Primaria 18:9, 582-588
CrossRef19
Jeremy Chataway, David H Miller. (2011) Multiple sclerosis—quenching the flames of inflammation. The Lancet 378:9805, 1759-1760
CrossRef20
Ludwig Kappos, David Li, Peter A Calabresi, Paul O'Connor, Amit Bar-Or, Frederik Barkhof, Ming Yin, David Leppert, Robert Glanzman, Jeroen Tinbergen, Stephen L Hauser. (2011) Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. The Lancet 378:9805, 1779-1787
CrossRef21
Joep Killestein, Richard A Rudick, Chris H Polman. (2011) Oral treatment for multiple sclerosis. The Lancet Neurology 10:11, 1026-1034
CrossRef22
T. Menge, B.C. Kieseier, C. Warnke, O. Aktas, H.-P. Hartung. (2011) Alemtuzumab: eine weitere Chance zur Therapie der Multiplen Sklerose. Der Nervenarzt
CrossRef23
Yossan
Var Tan, James A Waschek. (2011) Targeting VIP and PACAP receptor signalling: new therapeutic strategies in multiple sclerosis. ASN NEURO 3:4, 195-212
CrossRef24
O'Connor, Paul, Wolinsky, Jerry S., Confavreux, Christian, Comi, Giancarlo, Kappos, Ludwig, Olsson, Tomas P., Benzerdjeb, Hadj, Truffinet, Philippe, Wang, Lin, Miller, Aaron, Freedman, Mark S., . (2011) Randomized Trial of Oral Teriflunomide for Relapsing Multiple Sclerosis. New England Journal of Medicine 365:14, 1293-1303
Full Text25
Dorothea Buck, Bernhard Hemmer. (2011) Treatment of multiple sclerosis: current concepts and future perspectives. Journal of Neurology 258:10, 1747-1762
CrossRef26
Marloes T Bazelier, Tjeerd van Staa, Bernard MJ Uitdehaag, Cyrus Cooper, Hubert GM Leufkens, Peter Vestergaard, Joan Bentzen, Frank de Vries. (2011) The risk of fracture in patients with multiple sclerosis: The UK general practice research. Journal of Bone and Mineral Research 26:9, 2271-2279
CrossRef27
Bernard M.J. Uitdehaag, Frederik Barkhof, Patricia K. Coyle, Jason D. Gardner, Douglas R. Jeffery, Daniel D. Mikol. (2011) The changing face of multiple sclerosis clinical trial populations. Current Medical Research and Opinion 27:8, 1529-1537
CrossRef28
R. Hohlfeld, K.V. Toyka. (2011) Multiple Sklerose: Updates zu Pathogenese und Therapie. Der Nervenarzt 82:8, 1026-1035
CrossRef29
Reinhard Hohlfeld. (2011) Multiple sclerosis: Cladribine—a contentious therapeutic contender for MS. Nature Reviews Neurology 7:8, 425-427
CrossRef30
Esther V Hobson, Basil Sharrack. (2011) Emerging oral disease-modifying therapies in multiple sclerosis: a review of the latest clinical evidence. Clinical Investigation 1:7, 1049-1058
CrossRef31
Christine Lebrun, Patrick Vermersch, David Brassat, Gilles Defer, Lucien Rumbach, Pierre Clavelou, Marc Debouverie, Jérôme Seze, Sandrine Wiertlevsky, Olivier Heinzlef, Ayman Tourbah, Agnes Fromont, Marc Frenay. (2011) Cancer and multiple sclerosis in the era of disease-modifying treatments. Journal of Neurology 258:7, 1304-1311
CrossRef32
Christoph Heesen, Alessandra Solari, Andrea Giordano, Jürgen Kasper, Sascha Köpke. (2011) Decisions on multiple sclerosis immunotherapy: New treatment complexities urge patient engagement. Journal of the Neurological Sciences 306:1-2, 192-197
CrossRef33
D Sean Riminton, Hans-Peter Hartung, Stephen W Reddel. (2011) Managing the risks of immunosuppression. Current Opinion in Neurology 24:3, 217-223
CrossRef34
Bernd C Kieseier, Heinz Wiendl, Hans-Peter Hartung, Verena-Isabell Leussink, Olaf Stüve. (2011) Risks and benefits of multiple sclerosis therapies: need for continual assessment?. Current Opinion in Neurology 24:3, 238-243
CrossRef35
Gunnar Juliusson, Henrik Samuelsson. (2011) Hairy cell leukemia: epidemiology, pharmacokinetics of cladribine, and long-term follow-up of subcutaneous therapy. Leukemia & Lymphoma 52:S2, 46-49
CrossRef36
Jordi Río, Manuel Comabella, Xavier Montalban. (2011) Multiple sclerosis: current treatment algorithms. Current Opinion in Neurology 24:3, 230-237
CrossRef37
Clemens Warnke, Verena I. Leussink, Norbert Goebels, Orhan Aktas, Alexey Boyko, Bernd C. Kieseier, Hans-Peter Hartung. (2011) Cladribine as a therapeutic option in multiple sclerosis. Clinical Immunology
CrossRef38
Adil Javed, Betty Soliven. (2011) Fingolimod: a novel oral immunomodulatory treatment for multiple sclerosis. Future Neurology 6:3, 315-325
CrossRef39
Tanuja Chitnis, Lauren Krupp, Ann Yeh, Jennifer Rubin, Nancy Kuntz, Jonathan B. Strober, Dorothee Chabas, Bianca Weinstock-Guttmann, Jayne Ness, Moses Rodriguez, Emmanuelle Waubant. (2011) Pediatric Multiple Sclerosis. Neurologic Clinics 29:2, 481-505
CrossRef40
Bernd C. Kieseier, Olaf Stüve. (2011) A critical appraisal of treatment decisions in multiple sclerosis—old versus new. Nature Reviews Neurology 7:5, 255-262
CrossRef41
Martin Duddy, Aiden Haghikia, Eleonora Cocco, Christian Eggers, Jelena Drulovic, Olga Carmona, Helene Zéphir, Ralf Gold. (2011) Managing MS in a changing treatment landscape. Journal of Neurology 258:5, 728-739
CrossRef42
Gavin Giovannoni. (2011) Promising Emerging Therapies for Multiple Sclerosis. Neurologic Clinics 29:2, 435-448
CrossRef43
E. Ann Yeh, B. Weinstock-Guttman. (2011) Fingolimod: an oral disease-modifying therapy for relapsing multiple sclerosis. Advances in Therapy 28:4, 270-278
CrossRef44
Gavin Giovannoni, Stuart Cook, Kottil Rammohan, Peter Rieckmann, Per Soelberg Sørensen, Patrick Vermersch, Anthony Hamlett, Vissia Viglietta, Steven Greenberg. (2011) Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. The Lancet Neurology 10:4, 329-337
CrossRef45
Hans-Peter Hartung, Orhan Aktas. (2011) Evolution of multiple sclerosis treatment: next generation therapies meet next generation efficacy criteria. The Lancet Neurology 10:4, 293-295
CrossRef46
Joep Killestein, Chris H. Polman. (2011) Determinants of interferon β efficacy in patients with multiple sclerosis. Nature Reviews Neurology 7:4, 221-228
CrossRef47
Aaron E. Miller. (2011) Multiple Sclerosis: Where Will We Be in 2020?. Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine 78:2, 268-279
CrossRef48
Victoria J. Muir, Greg L. Plosker. (2011) Cladribine Tablets. CNS Drugs 25:3, 239-249
CrossRef49
Hans-Peter Hartung, Xavier Montalban, Per Soelberg Sorensen, Patrick Vermersch, Tomas Olsson. (2011) Principles of a new treatment algorithm in multiple sclerosis. Expert Review of Neurotherapeutics 11:3, 351-362
CrossRef50
Stephen Krieger. (2011) Multiple Sclerosis Therapeutic Pipeline: Opportunities and Challenges. Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine 78:2, 192-206
CrossRef51
Cris S Constantinescu, Nasr Farooqi, Kate O'Brien, Bruno Gran. (2011) Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). British Journal of Pharmacologyno-no
CrossRef52
Henry McFarland. (2011) The importance of clinical trials in unraveling the mysteries of multiple sclerosis. Journal of Neuroimmunology 231:1-2, 3-6
CrossRef53
Colleen E. Miller, Margaret A. Umhauer. (2011) Emerging Oral Therapies for Multiple Sclerosis. Journal of Neuroscience Nursing 43:1, 3-14
CrossRef54
Jacek Losy, Alicja Kalinowska-Łyszczarz. (2011) Emerging disease-modifying oral therapies for multiple sclerosis. Journal of Neuroimmunology 231:1-2, 15-22
CrossRef55
Massimo Filippi. (2011) Multiple sclerosis in 2010: Advances in monitoring and treatment of multiple sclerosis. Nature Reviews Neurology 7:2, 74-75
CrossRef56
Jeffrey K. Huang, Robin J.M. Franklin. (2011) Regenerative medicine in multiple sclerosis: Identifying pharmacological targets of adult neural stem cell differentiation. Neurochemistry International
CrossRef57
Karen Schreiber, Per Soelberg Sorensen. (2011) Cladribine in the treatment of multiple sclerosis. Clinical Investigation 1:2, 317-326
CrossRef58
Ralf Gold. (2011) Oral Therapies for Multiple Sclerosis. CNS Drugs 25:1, 37-52
CrossRef59
Francesco Patti, Salvatore Lo Fermo. (2011) Lights and Shadows of Cyclophosphamide in the Treatment of Multiple Sclerosis. Autoimmune Diseases 2011, 1-14
CrossRef60
Trygve Holmøy, Elisabeth Celius. (2011) Utvikling av ny behandling for multippel sklerose. Tidsskrift for Den norske legeforening 131:8, 832-836
CrossRef61
Hitoshi Nakano, Rie Motoyama, Keiko Tanaka, Masami Tanaka. (2011) A case of neuromyelitis optica with varicella zoster virus meningitis during mitoxantrone treatment. Rinsho Shinkeigaku 51:9, 703-705
CrossRef62
Thomas P. Leist, Robert Weissert. (2011) Cladribine. Clinical Neuropharmacology 34:1, 28-35
CrossRef63
Paul Wicks, Michael Massagli, Amit Kulkarni, Homa Dastani. (2011) Use of an Online Community to Develop Patient-Reported Outcome Instruments: The Multiple Sclerosis Treatment Adherence Questionnaire (MS-TAQ). Journal of Medical Internet Research 13:1,
CrossRef64
Peter Wipfler, Andrea Harrer, Georg Pilz, Katrin Oppermann, Eugen Trinka, Jörg Kraus. (2011) Recent developments in approved and oral multiple sclerosis treatment and an update on future treatment options. Drug Discovery Today 16:1-2, 8-21
CrossRef65
Amy Perrin Ross, Ben W. Thrower. (2010) Recent Developments in the Early Diagnosis and Management of Multiple Sclerosis. Journal of Neuroscience Nursing 42:6, 342-353
CrossRef66
Lawrence Steinman, Scott S. Zamvil. (2010) Delivery of myelin peptides through the first line of defense, skin, to counter autoimmunity in multiple sclerosis. Annals of Neurology 68:5, 567-569
CrossRef67
Nasr Farooqi, Bruno Gran, Cris S. Constantinescu. (2010) Are current disease-modifying therapeutics in multiple sclerosis justified on the basis of studies in experimental autoimmune encephalomyelitis?. Journal of Neurochemistry 115:4, 829-844
CrossRef68
Eilhard Mix, Hans Meyer-Rienecker, Hans-Peter Hartung, Uwe K. Zettl. (2010) Animal models of multiple sclerosis—Potentials and limitations. Progress in Neurobiology 92:3, 386-404
CrossRef69
Rex D. Simmons. (2010) Life issues in multiple sclerosis. Nature Reviews Neurology 6:11, 603-610
CrossRef70
Clare J. Fowler, Catherine Dalton, Jalesh N. Panicker. (2010) Review of Neurologic Diseases for the Urologist. Urologic Clinics of North America 37:4, 517-526
CrossRef71
D. S. Sigal, H. J. Miller, E. D. Schram, A. Saven. (2010) Beyond hairy cell: the activity of cladribine in other hematologic malignancies. Blood 116:16, 2884-2896
CrossRef72
Rachel A. Farrell, Gavin Giovannoni. (2010) Current and Future Role of Interferon Beta in the Therapy of Multiple Sclerosis. Journal of Interferon & Cytokine Research 30:10, 715-726
CrossRef73
S. Schmidt. (2010) Cladribin-Tabletten bei schubförmiger Multipler Sklerose. Der Nervenarzt 81:10, 1231-1241
CrossRef74
Clare E. Buckley, Anita Marguerie, Alan G. Roach, Paul Goldsmith, Angeleen Fleming, Wendy K. Alderton, Robin J.M. Franklin. (2010) Drug reprofiling using zebrafish identifies novel compounds with potential pro-myelination effects. Neuropharmacology 59:3, 149-159
CrossRef75
Vijayshree Yadav, Dennis Bourdette. (2010) Oral Disease-Modifying Therapies for Multiple Sclerosis: Are We There Yet?. Current Neurology and Neuroscience Reports 10:5, 333-335
CrossRef76
K. Rejdak, S. Jackson, G. Giovannoni. (2010) Multiple sclerosis: a practical overview for clinicians. British Medical Bulletin 95:1, 79-104
CrossRef77
Rina Aharoni. (2010) Immunomodulatory drug treatment in multiple sclerosis. Expert Review of Neurotherapeutics 10:9, 1423-1436
CrossRef78
Junger Tang, Moses Rodriguez. (2010) Dalfampridine for the treatment of ambulatory impairment in multiple sclerosis. Future Neurology 5:5, 637-643
CrossRef79
Devon Conway, Jeffrey A. Cohen. (2010) Emerging Oral Therapies in Multiple Sclerosis. Current Neurology and Neuroscience Reports 10:5, 381-388
CrossRef80
G.F. Hamann, M. Dieterich. (2010) Bericht vom 2. NeuroUpdate der MedUpdate-Reihe in Wiesbaden. Der Nervenarzt 81:8, 998-1002
CrossRef81
Natalie J. Carter, Gillian M. Keating. (2010) Glatiramer Acetate. Drugs 70:12, 1545-1577
CrossRef82
Eppie M Yiu, Brenda Banwell. (2010) Update on emerging therapies for multiple sclerosis. Expert Review of Neurotherapeutics 10:8, 1259-1262
CrossRef83
Tom Valeo. (2010) Trialists Debate: Are Randomized Placebo Controlled Trials Always Ethical?. Neurology Today 10:14, 20-21
CrossRef84
Reza Vosoughi, Mark S. Freedman. (2010) Therapy of MS. Clinical Neurology and Neurosurgery 112:5, 365-385
CrossRef85
(2010) Oral Cladribine and Fingolimod for Relapsing Multiple Sclerosis. New England Journal of Medicine 362:18, 1738-1740
Full Text86
Hans-Peter Hartung, Orhan Aktas. (2010) Oral therapies for multiple sclerosis: are we there yet?. The Lancet Neurology 9:5, 454-457
CrossRef87
Mathias Buttmann. (2010) Treating multiple sclerosis with monoclonal antibodies: a 2010 update. Expert Review of Neurotherapeutics 10:5, 791-809
CrossRef88
Darran Yates. (2010) Multiple sclerosis: Orally administered cladribine displays efficacy in multiple sclerosis trial. Nature Reviews Neurology 6:4, 182-182
CrossRef89
Devon Conway, Jeffrey A Cohen. (2010) Combination therapy in multiple sclerosis. The Lancet Neurology 9:3, 299-308
CrossRef90
(2010) New drugs may improve, complicate treatment for multiple sclerosis. Nature Medicine 16:3, 272-272
CrossRef91
Tom Button, Alasdair J Coles. (2010) Alemtuzumab for the treatment of multiple sclerosis. Future Neurology 5:2, 177-188
CrossRef92
Jack C Sipe. (2010) Cladribine tablets: a potential new short-course annual treatment for relapsing multiple sclerosis. Expert Review of Neurotherapeutics 10:3, 365-375
CrossRef93
Gavin Giovannoni. (2010) Recent developments in oral medications for the treatment of multiple sclerosis. Future Neurology 5:2, 167-172
CrossRef94
Carroll, William M., . (2010) Oral Therapy for Multiple Sclerosis — Sea Change or Incremental Step?. New England Journal of Medicine 362:5, 456-458
Full Text
