Natalizumab for relapsing multiple sclerosis.
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Antibodies, Monoclonal↗
Biomedical subjects
Douglas R Jeffery
Publications and source records attributed to Douglas R Jeffery.
A pilot trial of combination therapy with mitoxantrone and interferon beta-1b using monthly gadolinium-enhanced magnetic resonance imaging.
OBJECTIVE: To examine the safety of combination therapy with mitoxantrone (MITX) and interferon beta-1b (IFNbeta-1b) in patients with multiple sclerosis (MS) and a high on-therapy relapse rate and enhancing lesions on baseline magnetic resonance imaging (MRI) scan. METHODS: Ten patients with worsening relapsing remitting or secondary progressive MS were studied using monthly MRI with triple-dose gadolinium contrast. All patients must have been on IFNbeta-1b for at least six months, have at least one enhancing lesion on a screening MRI, at least one relapse on IFNbeta-1b in the six months prior to study entry and be neutralizing antibody negative. Monthly MRI scans using triple dose contrast and a 30-minute delay between contrast administration and scanning were carried out three times over two months to obtain baseline numbers of enhancing lesions each month. At the end of the baseline phase, MITX was administered at 12 mg/m2 (month 3), and 5 mg/m2 at months 4 and 5. Dosing was continued at 5 mg/m2 every third month. Monthly MRI scanning was continued throughout the duration of MITX dosing. The primary outcome measure was the frequency of new enhancing lesions. Secondary outcome measures included relapse rate, and T1 hypointense and T2 lesion burden. RESULTS: Following the addition of MITX to IFNbeta-1b mean enhancing lesion frequency decreased 90% at month 7 (P = 0.008) and enhancing lesion volume decreased by 96% (P = 0.01). Relapse rates decreased 64% (P = 0.004). T2 lesion burden and T1 hypointense lesion burden increased slightly during the baseline phase and decreased following MITX but the difference did not reach statistical significance. There were no serious adverse events on combination therapy and no drop-outs due to toxicity. Total white blood cell count was reduced at 14 days post-MITX infusion but returned to normal levels by day 21. There were no neutropenic fevers and there was no clinically significant elevation of liver function tests. CONCLUSIONS: While the number of patients in this study was small, the results suggest that the combination is safe and well tolerated. Disease activity was substantially reduced following the addition of MITX to IFNbeta-1b.
Adjuvants, Immunologic↗
Review of mitoxantrone in the treatment of multiple sclerosis.
Mitoxantrone is a synthetic anthracenedione recently approved by the FDA for the treatment of worsening relapsing-remitting (RR), secondary progressive (SP), and progressive relapsing (PR) multiple sclerosis (MS). In experimental allergic encephalomyelitis (EAE), mitoxantrone prevented the development of the signs and decreased the frequency of relapses in relapsing EAE. Early pilot trials using mitoxantrone were carried out using vastly different dosage regimens and patient populations, which may have resulted in conflicting results. Subsequent trials of mitroxantrone in patients with active inflammatory forms of MS suggested a profound effect in decreasing relapse rates, enhancing lesion frequency, and progression of disability. These results were later confirmed in a large, randomized, double-blind trial in patients with either worsening RRMS or SPMS. Treatment with mitoxantrone brought about statistically significant decreases in relapse rates, progression of disability, gadolinium-enhancing, and new lesions on T2-weighted MRI. Although mitoxantrone is generally well tolerated, it is associated with a variety of potential toxicities. Therefore, its use should probably be restricted to those patients with a suboptimal response to high-dose interferon therapy or those with rapidly progressive disease from onset.
Animals↗
Use of combination therapy with immunomodulators and immunosuppressants in treating multiple sclerosis.
Immunomodulating agents have beneficial effects in the treatment of multiple sclerosis (MS), decreasing the frequency of relapses, the progression of disability, and MRI measures of disease activity. Despite the efficacy of these agents, many patients continue to show progression of disability, breakthrough relapses, and active disease on MRI. Therefore, clinicians have employed a variety of combinations of agents in an attempt to decrease disease activity in those with active disease despite standard immunomodulatory therapy. Although a variety of combination therapies have been used in clinical practice, there is a paucity of data available to guide clinical decision-making. A major pitfall in using combination therapy in the absence of data demonstrating safety is the possibility that the agent added to the primary therapy may have no effect or, worse, may antagonize the effect of the primary agent. The combination of mitoxantrone and interferon beta (IFNbeta) appears safe in short-term studies from a toxicity standpoint and is associated with a reduction in relapse rates, a decrease in the frequency of enhancing lesions, and a decrease in T2 lesion burden. Other combinations that appear safe in preliminary studies include IFNbeta-1a and methotrexate, IFNbeta-1a and azathioprine, and mitoxantrone plus methylprednisolone. The decision to use combination therapy in patients with a suboptimal response to monotherapy should be considered early and not be delayed until disability becomes advanced. This review discusses the available data regarding the combination of standard immunomodulatory therapy with immunosuppressive agents.
Azathioprine↗
Statin-associated exacerbation of myasthenia gravis.
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Atorvastatin↗
The argument against the use of cyclophosphamide and mitoxantrone in the treatment of multiple sclerosis.
Mitoxantrone (MITX) and cyclophosphamide (CPM) are potent immunosuppressive agents with efficacy in the treatment of multiple sclerosis (MS). Both agents appear effective in those patients with active inflammatory disease but are probably less effective in patients with a secondary progressive (SP) course dominated by a degenerative component. Given these agents are effective patients with active inflammation the question arises as to whether they are more effective than high dose interferon therapy. Interferon beta administered at high dose and high frequency suppresses enhancing lesions by as much as 90% and brings about a 35% decrease in relapse rates in addition to decreasing the progression of disability. Interferons have an excellent safety profile even after years of administration. What then is the advantage of immunosuppressive agents such as cyclophosphamide and mitoxantrone over safer and still effective treatments? The answer lies in the magnitude of effect in those with the most active and aggressive disease states. While interferons are safe and effective in those with mild or moderate inflammatory disease states, they are probably not sufficient to bring about control in disease that is highly active and resilient. Both mitoxantrone and cyclophosphamide have the ability to suppress inflammation that may be resistant to therapy with more conservative agents. Given the safety profile of these agents their use should be restricted to those patients with aggressive disease resistant to treatment with more conservative agents.
Cyclophosphamide↗
Treatment of Marburg variant multiple sclerosis with mitoxantrone.
Marburg variant multiple sclerosis (MS) is a severe, sometimes monophasic, form of MS leading to advanced disability or death within a period of weeks to months. No consistently successful treatment for Marburg variant MS has been described. The case reported here is that of a 34-year-old woman with Marburg variant MS whose magnetic resonance imaging scan showed extensive brainstem, periventricular white matter, subcortical, and cortical involvement, giving the appearance of an "MS cerebritis." The patient had no response to treatment with methylprednisolone but improved and recovered after treatment with mitoxantrone (MITX). Because MITX has potent anti-inflammatory effects and demonstrated efficacy in worsening MS, it may be an appropriate agent for the treatment of Marburg variant MS.
Adult↗
Early intervention with immunomodulatory agents in the treatment of multiple sclerosis.
Multiple sclerosis (MS) is a lifelong neurologic disease leading to moderate or severe disability in the majority of affected patients. Studies of the natural history of MS suggest that 90% of patients with relapsing-remitting MS eventually develop secondary progressive (SP) disease. Magnetic resonance imaging (MRI) studies have consistently shown a high frequency of new T2 lesions and new gadolinium enhancing lesions even in the absence of clinical relapse. Lesion burden on T2 MRI increases by 5% to 10% per year and both axonal transection and cerebral atrophy are present at the earliest stages of RR MS. A wealth of evidence suggests that MS is a disease process that is continuously active, and that irreversible damage occurs early in the disease. Despite knowledge of the natural history and the availability of treatments that reduce relapse rates, decrease the accumulation of disability, and decrease surrogate measures of disease activity, only 60% of eligible patients have been treated with immunomodulating agents. This paper reviews the available evidence suggesting that immunomodulatory therapy modifies the natural history of MS and presents an argument for early intervention in the treatment of MS.
Adjuvants, Immunologic↗