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Doi:10.1016/s1474-4422(08)70020-6Intense immunosuppression in patients with rapidly
worsening multiple sclerosis: treatment guidelines for the
Aaron Boster, Gilles Edan, Elliott Frohman, Adil Javed, Olaf Stuve, Alexandros Tselis, Howard Weiner, Bianca Weinstock-Guttman, Omar Khan Several lines of evidence link immunosuppression to inﬂ ammation in patients with multiple sclerosis (MS) and Lancet Neurol 2008; 7: 173–183
provide a rationale for the increasing use of immunosuppressive drugs in the treatment of MS. Treatment-refractory, The Multiple Sclerosis Clinical
clinically active MS can quickly lead to devastating and irreversible neurological disability and treating these patients Research Center, Department
can be a formidable challenge to the clinician. Patients with refractory MS have been treated with intense of Neurology, Wayne State
University School of Medicine,
immunosuppression, such as cyclophosphamide or mitoxantrone, or with autologous haematopoeitic stem cell and The Detroit Medical Center,
transplants. Evidence shows that intense immunosuppression might be eﬀ ective in patients who are unresponsive to Detroit, MI, USA (A Boster MD,
immunomodulating therapy, such as interferon beta and glatiramer acetate. Natalizumab, a new addition to the A Tselis PhD, O Khan MD);
armamentarium for treating MS, might also have a role in the treatment of this MS phenotype. This Review describes Clinique Neurologique, CHU,
Rennes, France (G Edan MD);
the use of intense immunosuppressant drugs and natalizumab in patients with rapidly worsening MS and provides Department of Neurology,
clinicians with guidelines for the use of these drugs in this patient group.
University of Texas
Southwestern Medical Center,
concentrations of IL-12 are linked to clinical activity.11 The Dallas, TX, USA (E Frohman MD,
O Stuve MD); Department of
Several immunomodulatory treatments can partially alter cyclophosphamide-induced shift from a Th1-type to a Neurology, University of
the course of relapsing-remitting multiple sclerosis Th2-type cytokine proﬁ le might, therefore, positively Chicago, Chicago, MI, USA
(MS).1 By contrast, the eﬀ ect of immunomodulatory aﬀ ect the course of MS.12
(A Javid MD); Center for
treatments on the course of progressive MS phenotypes Neurologic Diseases, Brigham
and Women’s Hospital and
is modest at best.2–4 Treating patients with rapidly Early studies Harvard Medical School,
worsening or fulminant MS who have frequent relapses The results of early, open-label studies with cyclo- Boston, MA, USA
that result in sustained clinical worsening despite phosphamide were encouraging. In an uncontrolled, (H Weiner MD); and Jacobs
immunomodulatory treatments and repeated pulses of open-label trial in 1975, Hommes and co-workers showed Neurological Institute, State
University of New York,
intravenous methylprednisolone is an even greater stabilisation of the disease for 1–5 years in 69% of patients Buﬀ alo, NY, USA
challenge. Placebo-controlled trials in these patients are after a short course of cyclophosphamide (400 mg (B Weinstock-Guttman MD)
ethically tenuous because patients are likely to accumulate
cyclophosphamide and 1 g prednisone per day) to Correspondence to: permanent disability without treatment, and patients 86 patients with chronic progressive MS.13 Hauser and Omar Khan, Department of whose condition rapidly worsens during clinical studies co-workers conducted an open-label, prospective, Neurology, Wayne State are deemed treatment failures. Intense immuno- randomised trial in 58 patients with progressive MS, and 4201 St Antoine, 8D-UHC, suppression might be an option for such rapidly worsening compared a short course of high-dose intravenous Detroit, MI 48201, USA patients. In this Review, we will assess the eﬀ ectiveness cyclophosphamide and ACTH (adrenocorticotrophin [email protected]
and safety of intense immunosuppression in patients with
hormone) with ACTH alone and with low-dose rapidly worsening MS, and provide clinicians with cyclophosphamide with ACTH and plasma exchange.14 guidelines for the use of intense immunosuppression in The authors reported 80% disease stabilisation or patients with this MS phenotype. improvement in patients in the high-dose cyclo-phosphamide and ACTH arm compared with 20% and Immunosuppressant drugs used in MS
50% disease stabilisation in the ACTH alone and ACTH Cyclophosphamide
and low-dose cyclophosphamide groups, respectively.
The authors of two large trials published in the 1990s Cyclophosphamide is an alkylating drug, which is related reported contrasting results with regard to the use of to nitrogen mustards, that binds to DNA and interferes cyclophosphamide in patients with MS. The Northeast with mitosis, cell replication, and causes suppression of Cooperative Multiple Sclerosis Treatment Group cell-mediated and humoral immunity through its eﬀ ects conducted a randomised trial of 256 patients with on B cells and T cells.5 Cyclophosphamide is commonly progressive MS15 who were randomly assigned to one of used as an antineoplastic drug to treat several autoimmune four arms: intravenous cyclophosphamide and ACTH disorders, including immune-mediated neuropathies and given according to an established induction regimen, lupus nephritis.6,7 Treatment with cyclophosphamide has with or without intravenous boosters of cyclophosphamide been shown to decrease the secretion of interferon γ and every other month; or intravenous cyclophosphamide and IL-12 by monocytes8 and increase secretion of IL-4 and ACTH given according to a modiﬁ ed induction regimen IL-10 from peripheral blood mononuclear cells.9 Increased (600 mg intravenous cyclophosphamide per m2 on days 1, secretion of interferon γ and IL-12 has been reported in 2, 4, 6, and 8), with or without intravenous boosters of patients with secondary progressive MS,10 and increased cyclophosphamide every other month. Initially, the http://neurology.thelancet.com Vol 7 February 2008
authors found no diﬀ erences in disease stabilisation were treated monthly with intravenous cyclophosphamide between the two induction regimens; however, the patients and intravenous prednisone for 1 year then alternate who received maintenance boosters of cyclophosphamide months for a second year.21 Zephir and co-workers did a had a signiﬁ cant delay in reaching time-to-treatment retrospective, open-label review of 362 patients with failure—deﬁ ned as a one-point increase on the Expanded secondary-progressive MS and 128 patients with primary-Disability Status Scale (EDSS) score that lasted for progressive MS who were given 12 monthly pulses of 2 months—compared with the patients who did not receive intravenous cyclophosphamide.22 Compared with baseline, boosters. Furthermore, amelioration of disease progression the EDSS score stabilised or improved at month 12 in occurred mostly in patients of a younger age. 78·6% of patients with secondary-progressive MS and The Northeast Cooperative Study results were 73·5% of patients with primary-progressive MS, and a challenged by the results of a clinical trial by the Canadian shorter progressive disease course predicted the response Cooperative Multiple Sclerosis group.16 This single- to therapy. A report of a single patient with relapsing- blinded, placebo-controlled, multicentre trial randomly remitting MS who, on one occasion, accidentally received assigned 168 patients with progressive MS to receive a dose of 3800 mg (3·8-times the normal dose) of intravenous cyclophosphamide and oral prednisone, oral cyclophosphamide showed no evidence of clinical or MRI cyclophosphamide and oral prednisone on alternate days, disease activity for the next 7 years.23 An open-label study with weekly plasma exchange, or oral placebo and sham by Gladston and co-workers of 200 mg per kg plasma exchange. The investigators found no signiﬁ cant cyclophosphamide over 4 days in 15 patients with between-group diﬀ erences in time-to-treatment failure— treatment-refractory MS patients showed signiﬁ cant deﬁ ned as a worsening of one or more points on the stability of disease and improvement in quality of life after EDSS on two consecutive examinations that were 15 months.24 separated by at least 6 months. As a result of the conﬂ icting data, a prolonged debate about the use of Combination studiescyclophosphamide in patients with MS ensued.
In a randomised, multi-centre trial of 59 patients with relapsing-remitting MS who did not respond to interferon beta, the combination of cyclophosphamide and interferon Since the early 1990s there have been numerous trials of beta-1a reduced clinical disease activity and gadolinium-cyclophosphamide in patients with rapidly worsening or enhancing MRI lesions in the brain.25 In 10 patients who treatment-refractory MS. Weinstock-Guttman reported an had frequent and severe attacks despite interferon beta open-label series of 17 consecutive patients with fulminant therapy, the addition of intravenous cyclophosphamide MS—deﬁ ned as a deterioration of more than one and a every month led to a signiﬁ cant reduction in the number half points on the EDSS for more than 3 months—who of relapses, EDSS score, and number of T2-weighted were treated with cyclophosphamide;17 after 24 months, lesions; these benﬁ ts were maintained for 36 months 69% of patients were stable or had improved. In an open- label observational study of 95 patients with progressive MS, Hohol and co-workers found that 80% of patients with secondary-progressive MS who had monthly Collectively, these data from several open-label studies cyclophosphamide with intravenous pulses of prednisone indicate that patients with rapidly worsening, treatment-had stable or improved EDSS scores at 12 months.18 refractory, relapsing-remitting MS might beneﬁ t from Gobbini and co-workers reported a rapid reduction in treatment with intravenous cyclophosphamide. The gadolinium-enhancing lesions, seen with monthly brain beneﬁ cial eﬀ ect of cyclophosphamide in patients with MRI scans, and clinical stability in ﬁ ve patients with rapidly secondary-progressive MS without superimposed relapses deteriorating, relapsing-remitting MS who were treated is unclear, as shown by the contrasting results of the with monthly cyclophosphamide for 6 months followed by Northeast Cooperative and Canadian Cooperative studies. cyclophosphamide on alternate months.19 Khan and co- Factors that confound assessment of the response to cyclo- workers reported an open-label study of intravenous phosphamide in patients with secondary-progressive MS cyclophosphamide given monthy to 14 patients with include the treatment regimens, outcome measures, and relapsing-remitting MS who were rapidly deteriorating the heterogeneity of disease progression. Nonetheless, (deﬁ ned as a greater than three-point increase in EDSS score despite the limitations of the open-label observations, in the previous 12 months despite immunomodulating cyclop hosphamide appears to beneﬁ t appropriately selected therapy and intravenous prednisone).20 Compared with patients with the rapidly worsening MS phenotype. baseline scores, the mean EDSS scores were signiﬁ cantly lower at follow-up (up to 18 months) and no relapses were Mitoxantrone
reported. In an open-label study of 24 patients with Mechanism of actionclinically active and treatment-refractory MS, Perini and Mitoxantrone is an anthracendione drug that was co-workers reported signiﬁ cant improvement in EDSS developed to treat malignancies by intercalating into scores, relapse rate, and MRI measures in patients who DNA and inhibiting topoisomerase II enzyme, thereby http://neurology.thelancet.com Vol 7 February 2008
delaying cell-cycle progression by preventing ligation of Weinstock-Guttman and co-workers conducted a 2-year, DNA strands. Mitoxantrone also inhibits B-cell functions, prospective, open-label trial to assess the use of including antibody secretion, abates helper and cytotoxic mitoxantrone (12 mg per m2) and intravenous prednisone T-cell activity, and decreases the secretion of Th1 (1 g) given monthly for 6 months followed by three cytokines, such as interferon γ, TNF, and IL-2.27 additional infusions every 3 months.36 Four of the ﬁ ve Mitoxantrone is released slowly from tissues and has a patients showed a remarkable reduction in relapse rate terminal half-life of between 8·9 hours and 9 days.28 and the resolution of longitudinally extensive spinal cord Mitoxantrone can persist in the body for up to 272 days lesions. Le Page and co-workers reported an observational after treatment stops,29 and it eﬀ ectively suppresses study of 100 patients with aggressive relapsing-remitting experimental autoimmune encephalomyelitis.30 MS who were induced with 20 mg intravenous mitoxantrone and 1 g intravenous prednisone every month for 6 months.37 This was followed by maintenance The authors of an open-label study of 13 patients with therapy of either mitoxantrone every 3 months, interferon progressive MS reported on the eﬀ ects of intravenous beta, glatiramer acetate, azathioprine, or methotrexate in mitoxantrone (8 mg per m2) given every 3 weeks for a total 57 patients, with a mean follow-up of 3·8 years. In the of seven infusions.31 Although the disease did not progress year after induction, relapse rate, EDSS score, and MRI in most patients, compared with untreated historical activity were signiﬁ cantly decreased, and this decrease control groups there was no statistically signiﬁ cant was sustained for up to 5 years. diﬀ erence. The ﬁ rst placebo-controlled trial of mitoxantrone, in which 51 patients with relapsing-remitting MS were Combination studiesrandomly assigned to either monthly infusions of Jeﬀ ery and co-workers did an open-label, add-on, pilot mitoxantrone (8 mg per m2) or saline for 1 year, showed a study in 10 patients with MS who had active disease despite signiﬁ cant reduction in the annual relapse rate and an at least 6 months of interferon beta therapy.38 With the increase in the proportion of patients who were relapse-free addition of mitoxantrone (12 mg per m2 for the ﬁ rst month, in the mitoxantrone group at the end of years one and two, then 5 mg per m2 every month for 2 months, then 5 mg but no mean change in EDSS score.32 There was a trend in per m2 every third month), the mean frequency and volume the treatment group towards a reduction in the number of of gadolimium-enhancing lesions decreased by 90% and new brain MRI T2-weighted lesions. Edan and co-workers, 96%, respectively, after 7 months, and the relapse rate was in an unblinded, multi-centre trial of 42 patients with reduced by 64%. In an open-label study, 27 consecutive worsening relapsing-remitting MS and secondary- patients with clinically active relapsing-remitting MS were progressive MS found that monthly infusions of intravenous treated with variable dose regimens of mitoxantrone, mitoxantrone (20 mg) and intravenous prednisone (1 g) including monthly infusions for 3–6 months followed by improved the clinical and MRI indices of disease activity mitoxantrone every 3 months, in combination with over 6 months, whereas no change was seen in these glatiramer acetate.39 At a mean follow-up of 36 months indices in the group on intravenous prednisone alone.33 In (range 16–66 months) from the ﬁ rst dose of mitoxantrone, a double-blind trial of 49 patients with secondary-progressive EDSS scores and relapse rate were signiﬁ cantly reduced MS with superimposed relapses who were randomly compared with baseline.
assigned to receive 13 infusions of either mitoxantrone (12 mg per m2) or intravenous prednisone (1 g) over Conclusions32 months, neurological disability, relapse rate, and the During a phase III trial, mitoxantrone decreased relapse number of gadolinium-enhancing lesions seen in the brain rate by 68% compared with placebo and signiﬁ cantly with MRI were signiﬁ cantly reduced in the group taking prolonged the time to conﬁ rmed progression.35 Similar to mitoxantrone.34 A phase III trial of 194 patients with cyclophosphamide, mitoxantrone also appears to be an worsening relapsing-remitting or secondary-progressive eﬀ ective treatment to stabilise rapidly worsening, MS were randomly assigned to receive either placebo or treatment-refractory MS. However, unlike cyclophos-intravenous mitoxantrone (12 mg per m2 or 5 mg per m2) phamide, the use of mitoxantrone is limited by dose-related every 3 months for 2 years.35 The higher dose of cardiotoxicity and treatment-related acute leukaemia.40
mitoxantrone had signiﬁ cantly more eﬀ ect than placebo on
the combined primary end point, which consisted of ﬁ ve Autologous haematopoietic stem cell transplantation
clinical measures, including change from baseline EDSS Mechanism of action
score at 24 months, change from baseline ambulation index
Intense immunosuppression followed by autologous at 24 months, number of treated relapses, time to ﬁ rst haematopoietic stem cell transplantation has been treated relapse, and change from baseline standardised investigated as a treatment for severe autoimmune neurological status at 24 months. The results of this trial disorders such as MS.41 This treatment requires the led to the regulatory approval of mitoxantrone as the ﬁ rst mobilisation and collection of haematopoietic stem cells immunosuppressive chemotherapy drug for patients with from peripheral blood followed by ablation of the immune MS. system with a regimen of chemotherapeutic drugs, and http://neurology.thelancet.com Vol 7 February 2008
then reinfusion of the stem cell graft. Autologous grafts cell transplantation have recently been reported. Saiz and have a lower mortality rate (3–10%) than allogenic co-workers found that ﬁ ve patients with MS who had transplants (15–35%).42 The aim of autologous haemato- autologous haematopoietic stem cell transplantation had poietic stem cell transplantation for patients with MS is to atrophy of the corpus callosum at 1 year, with more than ablate their aberrant immune system and reconstitute one 50% of the reduction in volume seen in the ﬁ rst 3 months that is more tolerant to self-antigens, thereby stabilising or after autologous haematopoietic stem cell transplantation.51 possibly curing the disease altogether.43 All patients had oligoclonal bands in the CSF before autologous haematopoietic stem cell transplantation, and the four patients who were retested after 1 year all had Disease stabilisation in patients with MS after autologous persistent oligoclonal bands, which suggests that the B haematopoietic stem cell transplantation was ﬁ rst cells that secrete IgG in the CNS had survived. Chen and described in several case reports of individual MS patients co-workers reported a signiﬁ cant decrease in brain who were treated for concurrent malignancies.44–46 These volume compared with baseline (3·2% over a median observations and favourable results from autologous time of 2·4 months) that was not accounted for by the haematopoietic stem cell transplantation in the resolution of oedema or a decrease in the size of T2-experimental autoimmune encephalomyelitis animal weighted lesions in nine patients who had immunoablation model have encouraged further investigation of and autologous haematopoietic stem cell transplantation.52 autologous haematopoietic stem cell transplantation in Similar changes in brain volume were seen in a patient patients with MS.46,47 with non-CNS lymphoma who had autologous haematopoietic stem cell transplantation, which suggests a direct neurotoxic eﬀ ect of this therapy.
Fassas and colleagues treated 24 patients with chronic progressive MS with autologous haematopoietic stem cell transplantation, with a median follow-up of 40 months:47 Autologous haematopoietic stem cell transplantation 18 patients either improved or stabilised, ﬁ ve patients might lead to prolonged periods of stable disease in progressed, and one died of aspergillosis 65 days after patients with treatment-refractory, rapidly deteriorating transplantation. Of those who stabilised or improved, MS. Important questions with regard to patient selection, nine later developed relapses or slowly resumed toxicity, and treatment-related brain atrophy require progression. The probability of progression-free survival further investigation and long-term follow-up, which at 3 years compared with entry status was 92% for patients currently limit autologous haematopoietic stem cell with secondary-progressive MS and 39% for patients with transplantation to specialised centres in controlled study primary-progressive MS. Nash and co-workers enrolled settings. 26 patients with MS of various phenotypes (relapsing-remitting MS, secondary-progressive MS, and primary- Other immunosuppressive drugs
progressive MS) into an open-label, multi-centre study to Several other immunosuppressive drugs, including assess the safety of high-dose immunosuppressive cladribine, mycophenolate cellcept, methotrexate, therapy followed by autologous haematopoietic stem cell azathioprine, and cyclosporin, have been studied in transplantation.48 The Kaplan–Meier 3-year estimates for patients with MS. However, there are no data on the progression of one or more points on the EDSS score and eﬀ ects of these drugs in patients with rapidly worsening survival were 27% and 91%, respectively. A pilot study was MS, which precludes further discussion of them in this done by Saiz and co-workers to evaluate prospectively the Review. Although these drugs might be useful as add-on disease course after autologous haematopoietic stem cell therapies in patients with treatment-refractory MS or transplantation in 14 patients with relapsing-remitting patients with breakthrough disease, recent data appear to MS or secondary-progressive MS with severe treatment- refractory disease.49 The 3-year probability of progression-
free survival was 85·7%, and the 3-year probability of Immunomodulation with humanised
disease-free survival was 46·4%. Brain MRI gadolinium-
enhancing lesions were completely resolved during the Although monoclonal antibodies are not immuno-3-year period, and T2-weighted lesion load decreased by suppressive agents, they are highly promising therapies 20%; no deaths or serious complications were reported. that selectively bind to speciﬁ c antigens on targeted cells. The European Group for Blood and Marrow Humanised monoclonal antibodies, which have a limited Transplantation reported an overall transplant-related murine component, substantially decrease immuno-mortality of 5·3% in 178 patients with MS who received genicity compared with purely non-human monoclonal autologous haematopoietic stem cell transplantation antibodies.54 Several humanised monoclonal antibodies before 2000.50 are currently being investigated as therapies for MS but Data on brain atrophy and the persistence of CSF only one has been approved for use in patients with MS. oligoclonal bands after autologous haematopoietic stem A brief discussion follows to provide clinicians with the http://neurology.thelancet.com Vol 7 February 2008
potential options of monoclonal antibodies in patients 0·1%, and unknown complications, such as other with rapidly worsening MS.
opportunistic infections, must also be considered. As such, the current guidelines for treatment with Natalizumab
natalizumab, which are based on expert opinion, include Natalizumab is the most recent addition to the careful patient selection, pretreatment brain MRI, the armamentarium of disease-modifying drugs for patients use of natalizumab as monotherapy, and an appropriate with MS. Although not a form of immunosuppression, washout period of other immunomodulators or immuno-treatment with natalizumab is increasingly considered for suppressants (panel);63 algorithms to diagnose progressive patients with rapidly worsening MS on the basis of the multifocal leukoencephalopathy in patients with MS on data available from clinical trials. Natalizumab is a selective natalizumab have been proposed.63 Natalizumab should adhesion-molecule-inhibitor humanised monoclonal anti- be used in strict accordance with the TOUCH programme body against α4 integrin that prevents adherence of initiated by the drug manufacturor, which registers all activated leukocytes to the endothelium, thereby blocking patients and prescribers and helps to monitor patients an important step in the formation of MS lesions.55 In the phase III AFFIRM trial, monotherapy with natalizumab decreased annual relapse rate by 68%, the rate of disability Alemtuzumab
progression by 42%, the number of brain T2-weighted Alemtuzumab is a humanised monoclonal antibody MRI lesions by 83%, and the number of brain gadolinium- against the CD52 antigen on T lymphocytes and enhancing MRI lesions by 92%, compared with placebo.56 B lymphocytes64 that produces rapid and sustained In the phase III SENTINEL trial, natalizumab and lymphocyte depletion and is an approved therapy for B-intramuscular interferon beta-1a improved clinical outcome cell chronic lymphocytic leukaemia. Coles and co- compared with intramuscular interferon beta-1a alone.57 workers conducted a rater-blinded phase II trial to Natalizumab was temporarily suspended, however, after compare two doses of alemtuzumab given once a year two cases of progressive multifocal leuko encephalopathy with interferon beta-1a (44 µg subcutaneously, three were diagnosed in patients with MS who received times a week) in treatment-naive patients with relapsing-natalizumab in combination with interferon beta-1a.58,59 A remitting MS.65 The 2-year interim results showed third case of progressive multifocal leukoencephalopathy superiority of alemtuzumab over interferon beta-1a for was later diagnosed in a patient treated with natalizumab EDSS score, multiple sclerosis functional composite, for Crohn’s disease.60 The US Food and Drug Administration relapse rate, time to ﬁ rst relapse, and MRI outcomes. subsequently reapproved natalizumab as a second-line Two large phase III trials are underway to establish the monotherapy for patients with relapsing forms of MS who cacy and safety of alemtuzumab in treatment-naive have not responded to other immunomodulating therapies. patients and patients with relapsing-remitting MS with Currently, there are no data on the use of natalizumab in breakthrough disease. Alemtuzumab might be a highly patients with rapidly worsening MS phenotypes, and only eﬀ ective therapy in patients with MS; however, at this the phase II trial included patients with a secondary- time, the use of alemtuzumab is restricted to clinical progressive MS phenotype.61 Compared with placebo, a trials. Oﬀ -label use of alemtuzumab in clinical practice signiﬁ cantly lower proportion of patients treated with should be avoided until ongoing problems related to the natalizumab had on-study relapses and new gadolinium- incidence of autoimmune thrombocytopenia and enhancing brain MRI lesions. These diﬀ erences were thyroiditis are clariﬁ ed65,66 and phase III trials are most appreciable in patients with a more active disease at completed.
study entry (more than three relapses in the 2 years before study entry and more than two new gadolinium-enhancing MRI lesions at month 0). On the basis of highly impressive Panel: Proposed recommendations for the prescription of natalizumab
imaging results and a reduction in relapse rate, natalizumab Patient selection
is gaining popularity as an alternative treatment in patients Conﬁ rmed diagnosis of relapsing form of MS with frequent relapses or rapidly worsening MS who have Active disease course despite the use of immunomodulating therapy failed to respond to other therapies. Recently, the UK Patient understands the risks of opportunistic infections National Institute for Health and Clinical Excellence No history of haematological malignancy or HIV approved natalizumab for use in patients with rapidly evolving, severe, replapsing-remitting MS—deﬁ ned as two Pretreatment tests
or more disabling relapses in 1 year and one or more MRI of brain within 6 months before the ﬁ rst infusion gadolinium-enhancing lesions or a signiﬁ cant increase in Full blood count in all patients, and CD4:CD8 in selected patients T2-weighted lesion load seen on brain MRI—which further Washout period
highlights natalizumab as a potential therapy for these Discontinue immunomodulating therapy 1 month before natalizumab The current estimated risk of progressive multifocal Discontinue immunosuppressants at least 6 months before natalizumab leukoencephalopathy associated with natalizumab is http://neurology.thelancet.com Vol 7 February 2008
Reported by 55–71% of patients,71 occurs between 4–6 h after infusion, Begins 4–6 h after infusion and lasts up to 24 h; managed eﬀ ectively and lasts up to 48 h; eﬀ ectively managed with medications Haemorrhagic Reported by 7–15% of patients,72,73 occurs within 24 h of infusion, with haematuria or irritative voiding,74 and can be prevented by good hydration Monitor white blood cell count and adjust dose accordingly; promptly Monitor white blood cell count; promptly investigate fever, rash, or investigate fever, rash, or signs of infection Reversible amenorrhea reported in 33·3% of young women;75 7% women younger than 35 y had prolonged amenorrhea; permanent infertility is less common and associated with older age;75,76 permanent amenorrhea is more likely to occur in older women (only patients might consider ova donation or storage77 14% of women younger than 35 y78); patients might consider ova donation or storage77 1·0–1·5% risk of secondary leukaemia in chemotherapeutic treatment of cancers;80 also reported in chemotherapeutic treatment of other autoimmune disorders;81–83 bladder carcinomas have been reported in patients with MS84 Reported in 14 patients: 13 with acute myelocytic and promyelocytic leukaemia and one with acute lymphoblastic leukaemia;85,86 0·23% relative risk, calculated on the basis of two prospective cohort studies87,88 Reported in patients who received the high doses (4 g per m2) used for Risk increases with cumulative doses to a lifetime total dose of mobilisation regimens in patients with multiple myeloma;89 not 140 mg per m2;76,90 cardiotoxicity reported after only 1–2 doses;91 see Table: Adverse reactions and complications of intense immunosuppression
Rituximab is a humanised monoclonal antibody against Humanised monoclonal antibodies have promise as the CD20 antigen on B cells that has shown a signiﬁ cant powerful additions to the therapeutic armamentarium reduction in inﬂ ammation in several autoimmune for the treatment of patients with MS. Natalizumab has disorders, such as systemic lupus erythematosus and already shown impressive results in phase III clinical rheumatoid arthritis.67 In a randomised, double-blind, and MRI outcomes that have led to its approval in several placebo-controlled phase II trial of 104 patients with countries. Currently, the use of alemtuzumab, rituximab, relapsing-remitting MS, rituximab given once every and daclizumab in patients with MS is limited to clinical 6 months led to a signiﬁ cant reduction in gadolinium- trials, and the outcomes of deﬁ nitive phase III trials are enhancing lesions seen on MRI, T2-weighted lesion eagerly anticipated. Moreover, the role of monoclonal volume, and the number of patients with relapses, antibodies in patients with rapidly worsening MS will compared with placebo.68 Phase III trials of rituximab in patients with primary-progressive MS are ongoing, and
phase III trials in patients with relapsing-remitting MS Clinical guidelines for the treatment of rapidly
are underway. The current use of rituximab is largely worsening MS
restricted to clinical trials; however, it is anticipated that
Identiﬁ cation of appropriate patients
rituximab might be a highly eﬀ ective and unique therapy The factors that might predict the response to intense that is directed against B-cell-driven eﬀ ector immunosuppression with cyclophosphamide or mechanisms.
mitoxantrone are given (table, ﬁ gure). In summary, younger ambulatory patients with active progression Daclizumab
and frequent relapses are good candidates for Daclizumab is a humanized monoclonal antibody against intervention with intense immunomodulating therapy or the CD25 antigen that has proven eﬀ ectiveness in natalizumab.17,20,21,22,32,72,79,80,81,82,83,84 preventing the rejection of several diﬀ erent solid organ transplants.69 In a randomised, double-blind, placebo- When to initiate therapy
controlled, phase II trial of the addition of subcutaneous The identiﬁ cation of the window of opportunity when weekly or alternate week daclizumab to interferon beta treatment with intense immunosuppression is most therapy in 230 patients with relapsing-remitting MS, the eﬀ ective is as important as the determination of a good combination therapy was associated with a signiﬁ cant recipient. Delays in treatment might result in a reduction in gadolinium-enhancing lesions.70 Phase III suboptimal response. Treatment-refractory patients, trials are needed to establish the eﬃ cacy and safety of who are deﬁ ned as those with frequent attacks with daclizumab as monotherapy and combination therapy in immunomodulating therapy and pulsed steroids, http://neurology.thelancet.com Vol 7 February 2008
Characteristics of patients who are likely to respond to intense Characteristics of patients who are unlikely to respond to intense • active progression during the past several months or frequent and severe • long-standing, stable disability92,93 • aged younger than 40 years17,21,92,93 • profound or only cerebellar symptoms due to disability94,95 • ﬁxed, long-standing motor deﬁcits94 • earlier disease course (relapsing-remitting MS or secondary-progressive MS)22,32,93 • recovery from relapses is incomplete92 • frequent relapses, which lead to disability93 • persistence of multiple enhancing lesions92,93 Consider intense immunosuppression or natalizumab Avoid intense immunosuppression or natalizumab Natalizumab*,†,‡
Given intravenously every 4 weeks for 2 years, with clinical assessment and • take baseline laboratory investigations evaluations for opportunistic infections every 3 months, and an annual MRI Cyclophosphamide
Given intravenously every month for 6 months, with laboratory MUGA scan or 2D echocardiogram at baseline, then given intravenously every investigations 2 days before and 2 weeks after each infusion (dose should month, with laboratory investigations 2 days before and 2 weeks after each be adjusted as indicated) and clinical evaluation every 3 months infusion and a MUGA scan or echocardiogram before each infusion, and clinical evaluation every 3 months than 50% at any time, a decreasein left ventricular ejection fraction of 10% or more, or lifetime cumulative dose of mitoxantrone reached Stop mitoxantrone and resume immunomodulating therapy; re-evaluate at 3 months with follow-up Stop mitoxantrone and consider cyclophosphamide Figure: Algorithm to identify appropriate patients with rapidly worsening MS who are suitable for intense immunosuppression or natalizumab
*Limited data available from the phase II61 and AFFIRM56 trials for the use of natalizumab. †Suggested recommendations. ‡See panel for further uses of natalizumab.
should be considered for intense immunosuppression. immuno suppression or controlled trials to determine their Patients with fulminant MS from the onset,17 which is eﬃ highly uncommon, can be treated with intense immuno- Despite these major limitations, it is reasonable to suppression as a ﬁ rst-line therapy. However, there is a consider either natalizumab or intense immuno-lack of published data on intense immuno suppression suppression for patients with MS who rapidly accumulate as an initial therapy, and further studies are needed. disabilities despite treatment with intravenous prednisone and immunomodulating therapy; however, the risks and Selection of the most appropriate therapy
beneﬁ ts of each option must be assessed. So-called The drugs available to treat patients with rapidly worsening induction with intense immunosuppression has the MS are cyclophosphamide, mitoxantrone, or natalizumab. ﬂ exibility of concomitant use with immuno modulating However, the decision whether to use natalizumab or treatment, whereas natalizumab can be used only as intense immunosuppression (cyclo phosphamide or monotherapy. Infertility and transient cytopenia, with a cult because of the lack of evidence to risk of infection, are risks associated with intense support the use of natalizumab in patients with rapidly immunosuppression. Treatment with natalizumab carries worsening MS. Limited information can be obtained from the risk of opportunistic infections, such as progressive the phase II trial of natalizumab61 and from patients from multifocal leukoencephalopathy; as more data emerge, the AFFIRM trial who had frequent relapses.56 Furthermore, our understanding of the risk of opportunistic infections there are no head-to-head trials of natalizumab and intense for patients on natalizumab monotherapy might change, http://neurology.thelancet.com Vol 7 February 2008
and lead to natalizumab as the prefered ﬁ rst-line therapy cyclophosphamide can be discontinued and immuno-over intense immuno suppression. For now, however, the modulating therapy resumed. If the disease has not risks of intense immuno suppression and natalizumab stabilised, cyclophosphamide pulses should be continued, must be considered on an individual basis.
either monthly or bi-monthly, for a further 6 months. There are no large-scale, head-to-head studies that Factors such as the patient’s age, neurological disability, compare cyclophosphamide with mitoxantrone. Caon and ability to tolerate cyclophosphamide must all be and co-workers reported a 2-year, open label, observational considered when deciding to extend the duration of study that compared monthly intravenous cyclo- treatment. Brain MRI scans that show stable disease (no phosphamide and intravenous m itoxantrone every new or enlarging T2-weighted lesions and no gadolinium-3 months in 51 patients with relapsing-remitting MS.98 All enhancing lesions) might also be useful to determine the patients had at least a one-point increase in EDSS score response to therapy. despite at least 1 year of treatment with immunomodulating therapy and at least two courses of intravenous prednisone. The demographics of the patients and their baseline Several mitoxantrone regimens have been used in EDSS scores were similar in both groups patients with MS.40,101 The dose approved by the US Food (cyclophosphamide 5·3 vs mitoxantrone 5·4). Mean EDSS and Drug Administration is 12 mg per m2, given every scores after 24 months were statistically lower in the 3 months. Unlike cyclophosphamide, the dose of cyclophosphamide group compared with the mitoxantrone mitoxantrone is ﬁ xed, and white blood cell counts are group (cyclophosphamide 4·3 vs mitoxantrone 5·3, primarily used to monitor myelosuppression. p=0·02). Perini and co-workers compared intravenous An alternative mitoxantrone regimen used in patients venous prednisone (1 g), with MS that rapidly progresses comprises six monthly given monthly for 1 year and then every other month for a infusions of 20 mg.37 For patients who receive monthly second year, with intravenous mitoxantrone (8 mg per mitoxantrone, blood counts are monitored, similar to m2) plus intravenous prednisone (1 g) given every patients who have monthly infusions of cyclo-2 months for 2 years to 50 patients with secondary- phosphamide. The adverse reactions and complications progressive MS who had recent sustained progression of treatment with mitoxantrone are given (table).
and relapses.91 Both regimens reduced the relapse rate, The duration of treatment with mitoxantrone is largely EDSS score, and MRI activity, with no signiﬁ cant between- determined by two factors: the lifetime maximum dose, group diﬀ erences, including in the safety data, at 2 years. and the type of dose regimen. In general, most patients Larger trials are needed to conﬁ rm these ﬁ ndings. will receive mitoxantrone therapy for 1–2 years before Cyclophosphamide might have advantages over they reach the lifetime maximum of 140 mg per m2.102 mitoxantrone, including no risk of cardiotoxicity, no Current recommendations to monitor left ventricular lifetime maximum dose, and no therapy-related acute ejection fraction include a MUGA (multiple gated leukaemia.99 Conversely, mitoxantrone has no risk of acquisition) scan or echocardiogram at baseline and haemorrhagic cystitis and might have a lower risk of late An echocardiogram might be preferable with monthly cycles of mitoxantrone because monthly MUGA scans lead to excessive exposure to radiation. Therapy with Several cyclophosphamide regimens for patients with mitoxantrone should be started only in patients with a MS have been published;12,17,19,20,24 however, there are no baseline left ventricular ejection fraction of 50% or more data that compare the eﬃ cacies of these regimens. One and no cardiac disease. Mitoxantrone therapy should be of the most commonly used outpatient cyclophosphamide discontinued if the left ventricle ejection fraction regimens for patients with MS is monthly intravenous decreases by 10% or more at any time, if clinical signs of
infusions: patients initially receive intravenous cardiac failure develop, or if the left ventricular ejection
cyclophosphamide at a dose of 1 g per m2, and a 2-week fraction is below 50%.35
post-infusion white blood cell count nadir of
2000–2500 cells per mm3 (or decreased absolute Resumption of immunomodulating therapy after
lymphocyte count) is a reasonable outcome. Subsequent immunosuppression
doses can be increased or decreased by 100–200 mg per Clinical stability can be sustained for prolonged periods
m2, accordingly. The adverse reactions and complications
after intense immunosuppression is stopped.17,20,35,37 That of treatment with cyclophosphamide are given (table).
eﬀ ect, however, is unlikely to continue indeﬁ nitely; in a No study has assessed the optimum duration of study by Carter and co-workers, 69% of patients treated treatment with cyclophosphamide in patients with MS; with cyclophosphamide and ACTH reprogressed at a however, an initial course of six monthly infusions with mean interval of 17·6 months after intense immuno-close monitoring might be reasonable. If the 6-month suppression was stopped, which suggests that assessment indicates disease stabilisation (a decrease in maintenance therapy is required.103 Therefore immuno-relapse frequency or stable or improved EDSS score), modulating therapy can be reasonably reinstituted after http://neurology.thelancet.com Vol 7 February 2008
Medical School through an educational grant provided by EMD Serono. Search strategy and selection criteria
OK has received grant support and/or lecture honoraria from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Bayer Pharmaceuticals, References for this Review were identiﬁ ed through searches of Genentech, Genzyme, and Protein Design Laboratories. AT has received PubMed from 1950 to June 2007, with the term “multiple lecture honoraria from Teva Pharmaceuticals and EMD Serono. HW has sclerosis” in combination with “fulminant”, “rapidly received grant support and/or lecture honoraria from Biogen Idec, Teva Pharmaceuticals, EMD Serono, Bayer Pharmaceuticals, Genentech, worsening”, “rapidly progressive”, “immunosuppression”, and Genzyme, and Protein Design Laboratories. EF has received grant support “immunomodulation”. Articles were also identiﬁ ed through and lecture honoraria from Biogen Idec and Teva Pharmaceuticals. BWG searches of the references of articles and the authors’ own ﬁ les. has received grant support from Biogen Idec, Teva Neurosciences, EMD Only papers in English were reviewed. Case reports were Serono, Pﬁ zer, Acorda Pharmaceuticals, Aspreva, Cognition, and Avanir Pharmaceuticals. She has also received consultancy fees and/or lecture included if they contained outstanding new data that are honoraria and has served on advisory boards for Biogen Idec, Teva otherwise not available. Abstracts and reports from meetings Neurosciences, EMD Serono, and Novartis. OS has received grant support were included only if they presented new relevant information. and/or lecture honoraria from Biogen Idec, Teva Pharmaceuticals, and Genentech. AJ has received grant support and lecture honoraria from Teva Pharmaceuticals, EMD Serono, and Bayer Pharmaceuticals. GE has received grant support and/or lecture honoraria from Biogen Idec, Teva intense immunosuppression, and several reports indicate Pharmaceuticals, EMD Serono, and Bayer Pharmaceuticals. that patients respond well to immunomodulating therapy Acknowledgments
after intense immunosuppression.17,20,39,104 In many series, The authors thank Stephen L Hauser for helpful comments during the patients restarted the same immunomodulating therapy preparation of this manuscript. AB is supported by a fellowship grant that was deemed a failure before intense immuno- from the Partners Multiple Sclerosis Program at Brigham and Women’s References
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EDUCATION Ed.D., Doctor of Education in Higher and Adult Education. Teachers College, Columbia University, New York, New York, 1990. Doctoral Dissertation Title: Facilitating Adult Learning Through Technology Based Distance Education. M.A., Master of Arts in Higher and Adult Education. Teachers College, Columbia University, New York, New York, 1990. Masters Degree Essay: Philosophi