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Matt
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 Posted: Sat Aug 26, 2006 3:07 pm Post subject: Campath-1h |
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Clinical Neurology and Neurosurgery
Volume 106, Issue 3, Pages 147-274 (June 2004)
Campath-1H treatment of multiple sclerosis: lessons from the bedside for the bench
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Alasdair Coles*, , , Jackie Deans, Alastair Compston
Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 2QQ, UK
Keywords: Campath-1H; Humanised monoclonal antibody and Multiple sclerosis.
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Article Outline
1. Introduction
2. Methods
3. Results
4. Discussion
Acknowledgements
References
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1. Introduction
Most therapies in modern medicine have been discovered by serendipity. But there is a growing strand of medicines that have emerged from basic science into the clinic through rational design. One such is Campath-1H. The technology to produce industrial quantities of monoclonal antibodies was developed in the early 1970s by Kohler and Milstein in Cambridge [ 1 ]. One of Milstein´s students, Herman Waldmann, set about finding a rat monoclonal antibody that would lyse human lymphocytes and so treat lymphocytic malignancies. He developed the Campath-1 (from “Cambridge Pathology” department) series of antibodies. These were amongst the first monoclonal antibodies to be “humanised” by Greg Winter, another Cambridge academician, this process reduces the chances that patients mount an immune response against the therapeutic antibody [ 2 ]. So Campath-1″H″ was born. It targets the CD52 antigen present on all lymphocytes and monocytes and causes sustained depletion of T-cells. It has recently been licensed by the FDA and EMEA as a treatment for fludarabine-resistant CLL. But over the last 15 years or so, it has been trialled in transplantation and autoimmune conditions [ 3, 4, 5, 6, 7, 8, 9, 10, 11 ].
In 1991, we started to treat multiple sclerosis (MS) using Campath-1H. Our hope was that the T-cell repertoire regenerated after lymphocyte depletion by Campath-1H would exclude the aberrant autoimmune responses underlying MS. We proceeded with caution, treating one patient in 1991, six more during 1993 [ 12 ] and a total of 36 up to 1999 [ 13 ], all had SPMSs with Kurtzke scores of 6.0 or less at the time of entry into an MRI screening programme during which one gadolinium-enhancing lesion had to be present in the three months before patients were treated electively. The lessons learned from that cohort led to a change in strategy and we have since treated 22 patients earlier in the disease with activity confined to RRMS and before onset of the secondary progressive phase. Here we show how understanding the effects of this prototypical “bench to bedside” therapy have revealed aspects of the pathogenesis of MS sending us back to the bench.
2. Methods
We treated two cohorts of patients with MS, a “progressive” and a “relapsing” group. The progressive cohort consisted of 36 patients (22 women) with SPMS defined as a period of sustained increase in disability unaccompanied by identifiable relapses but following an earlier period of episodes with full or partial recovery. At the time of treatment, disease duration was 11.2 years (S.D. ±6.1 years) of which 3.6 years (±2.6 years) had been in the progressive phase, and mean EDSS was 5.8 (±0.8, range 3.5–7.0). One selection criterion for treatment was an increase in disability in the year before treatment of at least one EDSS point, during which annual relapse rate was shown to be 0.7 patient per year. Seven patients in this cohort received a second dose of Campath-1H, 2–4 years after the first treatment. The relapsing group consisted of 22 patients (17 women) with active RRMS. They received Campath-1H, either following the failure of licensed treatments to control their disease or because a high relapse rate early in the disease raised the prospect of a poor prognosis. Disease duration ranged from 9 months to 12 years (mean 2.7 ± 2.9 years) before elective treatment with Campath-1H, at which time mean EDSS was 4.8 (±2.0, range 1.0–7.5). As a group, they had experienced a total of 133 relapses over 60 patient—years of combined disease history before treatment, giving an annual relapse rate of 2.2 per patient, this rose to 2.94 per patient in the immediate year before Campath-1H. This cohort included 17 drug-naïve patients in whom disease duration ranged from 9 to 41 months (mean 1.7 ± 0.9 years). During that time, the annualised relapse rate of this group was 2.8 per year, rising to 3.4 in the year before treatment, during which disability had increased by 0–7.5 (mean 2.1 ± 2.0) EDSS points. None of these patients had received concomitant therapy with any licensed or putative disease-modifying treatment for MS. Five additional patients had failed treatment with IFN- b. Their disease duration was necessarily longer ranging from 17 months to 12 years (mean 6.3 ± 4.9 years). Their increase in EDSS ranged from 0 to 5.5 (mean 2.4 ± 2.3) EDSS points in the previous year during which the relapse rate was 2.0 per patient. Patients were assessed every 3–6 months for the first 3 years after Campath-1H treatment and then annually, but with additional visits triggered by clinical events. A sustained increase in disability was defined as an increase in the EDSS of at least 1.0 point on consecutive examinations over 6 months, if the baseline EDSS was less than 6.0, or an increase of 0.5 point on consecutive examinations over 6 months, if the baseline was 6.0 or greater. The use of Campath-1H in this off-license study was approved by a local Ethics Committee (Cambridge LREC 02/315) and the United Kingdom Medicines Control Agency. Our early experience was with Campath-1H made by the Therapeutic Antibody Centre, Oxford.
We administered 100 mg of Campath-1H as five daily doses of 20 mg given intravenously over 4 h. Most patients were pre-medicated with IV methylprednisolone, 1 g over 1 h preceding the Campath-1H doses on days 1–3. Seven of 36 patients in the progressive cohort were re-treated with Campath-1H in order to maintain or increase perceived improvements. Subsequently, we offered elective re-treatment after 12–18 months giving a fixed total dose of 60 mg over three consecutive days (20 mg per day), again pre-medicated with corticosteroids, 9/22 of the acute relapsing group have now received a second course of Campath-1H. Patients in the progressive cohort were scanned intensively for the first 18 months after treatment, as previously described [ 14 ].
3. Results
The 58 patients treated to date have received a total of 74 courses of Campath-1H and have been followed prospectively for 280 patients—years. CD4 cells were depleted for a median of 61 months and CD8 cells for 30 months (19–46). B-cell numbers rose to 124% (S.D. ±74%) of pre-treatment levels at 27 (±15) months after treatment. In 13 patients, B-cell numbers had returned to baseline when last measured, at a mean of 62 (±17) months after treatment. However, in 18 patients, the most recent B-cell count, at 63 (±20) months, was still +66 (±48%) above baseline. These elevations in B-cell count rarely rose above the upper limit of the normal range. Those treated with Campath-1H alone experienced an acute cytokine response that we have described elsewhere [ 15 ], which is very significantly reduced by pre-treatment with corticosteroids. Seven infections that might represent adverse effects of Campath-1H have occurred, all were mild and none required hospitalisation: they included spirochaetal gingivitis (at 10 days), measles (at 11 days), herpes zoster (two instances, at 6 and 9 months, respectively), varicella zoster (at 2 years), recurrent aphthous mouth ulcers (from 6 to 9 months) and pyogenic granuloma (at 22 months). The principal adverse effect of Campath-1H therapy in patients with MS is Graves´ disease [ 16 ]. One patient had experienced Graves´ disease prior to Campath-1H treatment but to date, we have observed 15 new cases in the remaining 57 patients (27%), with one additional case of autoimmune hypothyroidism. Graves´ disease developed within 5–21 months of the first treatment (14 patients) and 2 years after the second treatment (one patient). Ten of 15 cases were detected pre-symptomatically by screening for TSH. Three patients developed Graves´ ophthalmopathy. This was transient in two cases. However, one of the 15/57 patients with Graves´ disease has a permanent and cosmetically unpleasant ophthalmopathy, which has not threatened vision. All patients were initially managed using standard therapy for Graves´ disease (carbimazole in the UK, the pro-drug of methimazole) for 6 months. Nine patients relapsed after treatment and received radioactive thyroid ablation.
In the SPMS cohort, Campath-1H reduced radiological evidence of disease activity, new lesions continued to form over 4 weeks but, thereafter, radiological markers of cerebral inflammation were suppressed maximally by >90% for at least 18 months and no new clinical relapses occurred. However, even during the first 18 months after treatment, dissociation emerged between the suppression of inflammation and disease progression [ 13 ] which has become even more apparent after longer follow-up. This cohort has now been observed for a total of 243 patient—years, giving an overall mean follow-up of 6.7 (S.D. ±2.1) years from treatment. Two patients have been lost to follow-up and three others have died (one suicide, one possible suicide and one death through sepsis in a severely disabled patient 7 years after Campath-1H). The remaining patients have been systematically followed by the same investigator for a mean of 7.6 years (±1.4 years, range 6.4–11.9 years). One year after Campath-1H, 33/36 patients in our progressive cohort had maintained their pre-treatment EDSS. With time, this proportion decreased, at last follow-up, only 4/36 had no sustained worsening of disability from their pre-treatment EDSS 7.5 years (±0.5) after treatment (7/36 if the more lax criterion for disability progression of just one EDSS point confirmed at 6 months throughout the EDSS is used). As a group, the mean rate of increase in disability after treatment was +0.2 EDSS points per patient per year, with a statistically significant reduced rate of progression compared to the year before treatment ( ), and a tendency for systematic reduction in the rate of disability acquisition. There was no difference in the rate at which disability accumulated between patients with early progression after treatment and those who were initially stable. Relapse rate, expected to decline as part of the natural history of MS in the secondary progressive phase, changed from 0.7 patient per year before treatment to an annualised rate of 0.02 patient per year, over the entire follow-up period of 243 patients per year, this group of 36 patients has experienced just six episodes, of which three occurred in the first 2 months after Campath-1H treatment, none have been associated with a persistent increase in disability.
Patients who had already progressed from baseline at the first follow-up interval (18 months) showed reduced brain volume at the time of initial treatment with Campath-1H by comparison with patients showing initial stability of clinical progression [ 13 ]. When 13 patients from this original cohort were re-examined 6 years after their last scan (which was itself 18 months after Campath-1H), there was no evidence for an increase in proton density or T1 lesion volume in the intervening period. However, 11/13 patients had evidence of further cerebral atrophy. The two with stable brain volumes were both amongst the group without atrophy in the first 18 months, however, one had shown significant progression of disability. The mean absolute change in cerebral volume was -1.37 (±1.28) ml per year ( ). Five patients had new T2 lesions at follow-up and eight patients did not.
The RRMS cohort consisted of 17 drug-naïve patients and five who had failed licensed therapy, observed now for a mean of 19 months (range 6–74 months) after treatment, representing 32 patient—years of follow-up. Before treatment, their relapse rate was 2.21per patient per year (2.94 per patient in the immediate year preceding treatment). After treatment this cohort has had five confirmed episodes, giving a relapse rate of 0.14 and representing a 94% reduction in relapse rate. The extent of relapse rate reduction is the same if patients previously treated with IFN-ß are excluded, falling from 2.74 in the 28.5 patient—years before treatment (3.24 per patient in the immediate year before treatment) to 0.19 over the 26.3 patient—years of observation after treatment (93% reduction). Comparing, the accumulation of disability in the RR- and SPMS-groups in the year before treatment, the former showed a mean annual increase of +2.2 EDSS points. Mean annualised changes over the periods 0–6, 6–12 and 12–24 months were -2.4, -0.6 and -0.4 and +0.2, +0.1 and +0.3 for the RR- and SPMS-groups, respectively.
4. Discussion
This is the record of our total experience of the use of a humanised monoclonal antibody, Campath-1H, used to treat 58 patients since 1991. At first, we used this drug in patients with relatively advanced SPMS. Inflammation was suppressed but disease progression continued, suggesting the need for exposure to anti-inflammatory therapy earlier in the disease course. Despite adverse effects, we considered that safety data accumulated from this cohort were sufficiently encouraging to justify treating a group of patients with early clinically active MS.
Clinical and radiological data from our patients with SPMS suggest that just one or two pulses of Campath-1H significantly suppress cerebral inflammation for at least 6 years. Our 58 patients have together experienced only 11 episodes during 275 patient—years of follow-up during both the RR (32 years) and the SP (243 years) phases of the disease. There was no appreciable increase in the T1 hypointense, or proton density, lesion volume in a representative subgroup of patients with SP disease who agreed to an MRI scan some 6 years after treatment. However, there was evidence for progressive cerebral atrophy at a volume loss of +1.37 (±1.28) ml per year. A similar dissociation between effective suppression of new lesions and continued cerebral atrophy in progressive patients has also been seen in a trial of the lymphocytoxic drug cladribine, a purine nucleoside analogue resistant to the action of adenosine deaminase [ 17, 18 ] and of IFN-ß [ 19, 20, 21 ].
One interpretation of these observations is that axonal loss and inflammation are independent pathologies—an interpretation supported by epidemiological evidence that relapse rate during the progressive phase of MS does not alter disability outcomes [ 22 ]. If so, immunotherapy may not influence progression of disability, however, early it is deployed. However, several epidemiological studies have confirmed that relapse rate early in the course of the disease is associated with time to reach fixed disability milestones [ 23, 24 ] and a relationship has also been reported between the load of early inflammatory lesions on MRI and later disability [ 25 ]. Patients in our SP cohort who progressed had more inflammatory load before treatment, confirming our belief that inflammation and axonal injury are intimately linked. Two processes account for axonal degeneration in the post-inflammatory phase: first, acutely transected axons undergo Wallerian degeneration over the subsequent 18 months [ 26 ], but this seems not to produce a progressive clinical deficit. Secondly, axons that escape injury in the acute phase may later degenerate through a non-inflammatory mechanism, dependent on prior inflammation. Specifically, we favour the interpretation that axon degeneration results from the loss of trophic support for neurons and axons normally provided by oligodendrocytes and myelin [ 27, 28 ]. The influence of oligodendrocytes on axonal calibre and function is well described; oligodendrocytes myelinate axons, increase axonal stability and induce local accumulation and phosphorylation of neurofilaments within the axon [ 29, 30, 31 ]. Neuronal function is further influenced by oligodendrocyte-derived soluble factors that induce sodium channel clustering along axons, necessary for efficient saltatory conduction and maintain this clustering even in the absence of direct axon–glial contact [ 32 ]. We have shown that soluble factors produced by cells of the oligodendrocyte lineage support neuronal survival [ 33 ].
The lesson is clear. Once the cascade of events leading to tissue injury is established, effective suppression of inflammation does not limit brain atrophy or protect from clinical progression. It follows that there may only be an opportunity early in the disease course to suppress those components of the inflammatory process that initiate the cascade leading to loss of tissue integrity expressed as disease progression. This hypothesis is being tested in CAMMS223, a randomised single-blind trial comparing the efficacy of two doses of Campath-1H and IFN- b in the treatment of drug-naïve patients with early, active RRMS. The hope is that patients receiving effective anti-inflammatory treatment before the cascade of events leading to uncontrolled destruction of the axon–glial unit is irretrievably established will not subsequently accumulate disability, develop cerebral atrophy or enter the secondary progressive phase of the illness.
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Acknowledgements
We are grateful to the team at the Therapeutic Antibody Centre, Oxford, led by Professors Hale & Waldmann, who manufactured the CAMPATH-1H used initially in the treatment of our patients, to Dr. Shaun Seaman and Peter Holmans for statistical advice, and to Jackie Deans for invaluable assistance in patient management. MRI scans were performed at the Institute of Neurology. The Multiple Sclerosis Society provided the MRI scanner. AJC was previously supported by the Medical Research Council and is currently a Wellcome Advanced Clinical Fellow. Some aspects of the work were also supported by a grant from MuSTER.
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References
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[3]. Killick S., Marsh J., Hale G., Waldmann H., Kelly S., Gordon Smith E., "Sustained remission of severe resistant autoimmune neutropenia with Campath-1H", Br. J. Haematol., Volume: 97, (1997), pp. 306-308 Bibliographic Page Full text
[4]. Hale G., Waldmann H., "Recent results using CAMPATH-1 antibodies to control GVHD and graft rejection", Bone Marrow Trans., Volume: 17, (1996), pp. 305-308
[5]. Isaacs J., Hazleman B., Chakravarty K., Grant J., Hale G., Waldmann H., "Monoclonal antibody therapy of diffuse cutaneous scleroderma with CAMPATH-1H", J. Rheumatol., Volume: 23, (1996), pp. 1103-1106
[6]. Lockwood C., Thiru S., Stewart S., Hale G., Isaacs J., Wraight P., et al. "Treatment of refractory Wegener´s granulomatosis with humanized monoclonal antibodies", Quart. J. Med., Volume: 89, (1996), pp. 903-912
[7]. Friend P., Rebello P., Oliveira D., Manna V., Cobbold S., Hale G., et al. "Successful treatment of renal allograft rejection with a humanized antilymphocyte monoclonal antibody", Transpl. Proc., Volume: 27, (1995), pp. 869-870
[8]. Isaacs J., Hale G., Waldmann H., Dick A., Haynes R., Forrester J., et al. "Monoclonal antibody therapy of chronic intraocular inflammation using Campath-1H [3]", Br. J. Ophth., Volume: 79, (1995), pp. 1054-1055
[9]. Hale G., Waldmann H., "Campath-1 monoclonal antibodies in bone marrow transplantation", J. Hematother., Volume: 3, (1994), pp. 15-31
[10]. Lim S., Hale G., Marcus R., Waldmann H., Baglin T., "Campath-1 monoclonal antibody therapy in severe refractory autoimmune thrombocytopenic purpura", Br. J. Haem., Volume: 84, (1993), pp. 542-544
[11]. Watts R., Isaacs J., Hale G., Hazleman B., Waldmann H., "Campath-1H in inflammatory arthritis", Clin. Exp. Rheumatol., Volume: Suppl. 11, Issue: 8 (1993), pp. 165-167
[12]. Moreau T., Thorpe J., Miller D., Moseley I., Hale G., Waldmann H., et al. "Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis", Lancet, Volume: 344, (1994), pp. 298-301 [published erratum appears in Lancet 1994; 344:486] Bibliographic Page Full text
[13]. Coles A., Wing M., Molyneux P., Paolillo A., Davie C., Hale G., et al. "Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis", Ann. Neurol., Volume: 46, (1999), pp. 296-304 Bibliographic Page Full text
[14]. Paolillo A., Coles A., Molyneux P., Gawne Cain M., MacManus D., Barker G., et al. "Quantitative MRI in patients with secondary progressive multiple sclerosis treated with monoclonal antibody Campath-1H", Neurology, Volume: 53, (1999), pp. 751-757
[15]. Moreau T., Coles A., Wing M., Isaacs J., Hale G., Waldmann H., et al. "Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis", Brain, Volume: 119, (1996), pp. 225-237
[16]. Coles A., Wing M., Smith S., Corradu F., Greer S., Taylor C., et al. "Pulsed monoclonal antibody treatment and thyroid autoimmunity in multiple sclerosis", Lancet, Volume: 354, (1999), pp. 1691-1695 Bibliographic Page Full text
[17]. Filippi M., Rovaris M., Iannucci G., Mennea S., Sormani M., Comi G., "Whole brain volume changes in patients with progressive MS treated with cladribine", Neurology, Volume: 55, (2000), pp. 1714-1718
[18]. Rice G., Filippi M., Comi G., "Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group", Neurology, Volume: 54, (2000), pp. 1145-1155
[19]. Molyneux P., Kappos L., Polman C., Pozzilli C., Barkhof F., Filippi M., et al. "The effect of interferon b-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. European Study Group on Interferon b-1b in secondary progressive multiple sclerosis", Brain, Volume: 123, (2000), pp. 2256-2263 Bibliographic Page Full text
[20]. Miller D., Molyneux P., Barker G., MacManus D., Moseley I., Wagner K., "Effect of interferon- b-1b on magnetic resonance imaging outcomes in secondary progressive multiple sclerosis: results of a European multicenter, randomized, double-blind, placebo-controlled trial. European Study Group on Interferon- b-1b in secondary progressive multiple sclerosis", Ann. Neurol., Volume: 46, (1999), pp. 850-859 Bibliographic Page Full text
[21]. Leary S., Miller D., Stevenson V., Brex P., Chard D., Thompson A., "Interferon b-1a in primary progressive MS: an exploratory, randomized, controlled trial", Neurology, Volume: 60, (2003), pp. 44-51
[22]. Confavreux C., Vukusic S., Moreau T., Adeleine P., "Relapses and progression of disability in multiple sclerosis", N. Engl. J. Med., Volume: 343, (2000), pp. 1430-1438
[23]. Weinshenker B., Bass B., Rice G., Noseworthy J., Carriere W., Baskerville J., et al. "The natural history of multiple sclerosis: a geographically based study. Part II. Predictive value of the early clinical course", Brain, Volume: 112, (1989), pp. 1419-1428
[24]. Confavreux C., Vukusic S., Adeleine P., "Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process", Brain, Volume: 126, (2003), pp. 770-782 Bibliographic Page Full text
[25]. Brex P., Ciccarelli O., O´Riordan J., Sailer M., Thompson A., Miller D., "A longitudinal study of abnormalities on MRI and disability from multiple sclerosis", N. Engl. J. Med., Volume: 346, (2002), pp. 158-164
[26]. Simon J., Jacobs L., Kinkel R., "Transcallosal bands: a sign of neuronal tract degeneration in early MS", Neurology, Volume: 57, (2001), pp. 1888-1890
[27]. Meyer Franke A., Kaplan M., Pfrieger F., Barres B., "Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture", Neuron, Volume: 15, (1995), pp. 805-819
[28]. Griffiths I., Klugmann M., Anderson T., Yool D., Thomson C., Schwab M., et al. "Axonal swellings and degeneration in mice lacking the major proteolipid of myelin", Science, Volume: 280, (1998), pp. 1610-1613
[29]. Colello R., Pott U., Schwab M., "The role of oligodendrocytes and myelin on axon maturation in the developing rat retinofugal pathway", J. Neurosci., Volume: 14, (1994), pp. 2594-2605
[30]. Sanchez I., Hassinger L., Paskevich P., Shine H., Nixon R., "Oligodendroglia regulate the regional expansion of axon caliber and local accumulation of neurofilaments during development independently of myelin formation", J. Neurosci., Volume: 16, (1996), pp. 5095-5105
[31]. Brady S., Witt A., Kirkpatrick L., de Waegh S., Readhead C., Tu P., et al. "Formation of compact myelin is required for maturation of the axonal cytoskeleton", J. Neurosci., Volume: 19, (1999), pp. 7278-7288
[32]. Kaplan M., Meyer Franke A., Lambert S., Bennett V., Duncan I., Levinson S., et al. "Induction of sodium channel clustering by oligodendrocytes", Nature, Volume: 386, (1997), pp. 724-728
[33]. Wilkins A., Chandran S., Compston A., "A role for oligodendrocyte-derived IGF-1 in trophic support of cortical neurons", Glia, Volume: 36, (2001), pp. 48-57
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Matt
Joined: 21 May 2006
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| Posted: Sat Aug 26, 2006 3:21 pm Post subject: |
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From the same journal...
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Non-specific immunosuppressants in the treatment of multiple sclerosis
Christian Confavreux*, , , Sandra Vukusic
Service de Neurologie A, Hôpital Neurologique Pierre Wertheimer, 59 Boulevard Pinel, 69394 Lyon Cedex 03, France
Abstract
Immunosuppressants have been proposed as disease-modifying treatments in multiple sclerosis (MS) for almost 40 years, but only one, mitoxantrone, has recently been approved, whereas b-interferons and glatiramer acetate have been licensed since the mid-90s. Recent therapeutic trials of potent immunosuppressive agents such as Campath-1H, mitoxantrone and cyclophosphamide of MS patients with high relapse rates, rapid accumulation of disability and high degree of MRI activity, have resulted in strong suppression of clinical and MRI inflammatory activity, provided that profound and prolonged lymphopenia was achieved. Clinical experience during the past decades has amply demonstrated that some patients with MS respond to immunosuppressants. The odds ratios of relapsing-remitting MS patients to remain relapse-free after a 2-year period of treatment are similar for Betaseron®, Avonex®, Rebif®, Copaxone®, intravenous immunoglobulins or azathioprine compared to placebo. The risk of cancer induction is not significant for up to 10 years of daily usage of azathioprine. Currently available non-specific immunosuppressants are able to control inflammation and reduce relapses in MS, but cannot prevent neurodegeneration and the progression of irreversible disability; specific tools need to be developed for that purpose.
Keywords: Multiple sclerosis; Immunosuppressants; Inflammation and Degeneration.
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Article Outline
1. Introduction
2. Immunosuppressants in the pre-interferons era
3. The emergence of interferons and the re-discovery of the potential of immunosuppressants in MS
4. Immunosuppressants in future treatment strategies for MS
5. Conclusion
References
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1. Introduction
Global immunosuppressants are used in many autoimmune diseases; they are active at different stages of the pathogenic cascade and on all the clones of immunocompetent cells. They interfere with the cell´s life cycle either via a blocking, cytostatic action or by stopping DNA replication and inducing cell death, a cytotoxic effect. In contrast, immunomodulators such as b-interferons exert a limited effect by shifting the balance between immune systems, i.e. suppressor versus helper T-cells, Th1 versus Th2 type lymphocytes, or pro-inflammatory versus anti-inflammatory cytokines.
Immunosuppressants have been proposed as disease-modifying treatments for MS for almost 40 years, but their effectiveness has only recently been formally acknowledged, albeit for only one of them [ 1, 2 ]. Acceptable controlled phase III trials for similar agents are still lacking.
Admittedly, the therapeutic approach to MS changed dramatically as the result of the publication in 1993 of well-designed and well-conducted prospective multicentre randomised double-blind placebo-controlled phase III trials [ 3, 4, 5 ], leading to the approval, for some patient categories, by North-American and European regulatory agencies of interferon- b-1b (Betaseron®), interferon- b-1a (Avonex® and Rebif®) [ 6, 7, 8 ] and glatiramer acetate (Copaxone®) [ 9 ]. Nevertheless, immunosuppressants can still prove to be useful in the treatment of MS.
2. Immunosuppressants in the pre-interferons era
The first paper on the possible efficacy of immunosuppressants in MS was published by Aimard, Girard and Raveau in 1966 under the title of “Sclérose en plaques et processus d´autoimmunisation. Traitement par les anti-mitotiques” in “Le Journal de Médecine de Lyon”. This article dealt mainly with studies on the experimental allergic encephalomyelitis model and with a case of a clinically very active RRMS successfully treated with cyclophosphamide infusions (Fig. 1) [ 10 ]. The following year, the same group published another article about a series of 30 patients treated with 200 mg daily of cyclophosphamide for 4–6 weeks, and anecdotal cases treated with azathioprine. Results were considered promising [ 11 ].
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Fig. 1: Front page reproduction of the pioneer paper on non-specific immunosuppressants in MS [ 10 ].
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Since then, azathioprine has become the immunosuppressant the most widely used in MS. It is administered orally, 2.5 mg/kg per day, and is relatively safe and well-tolerated. Two meta-analyses of published blinded, placebo-controlled trials have shown that it significantly increases the likelihood of remaining relapse-free, and marginally decreases progression of disability after 2 or 3 years of treatment [ 12, 13 ]. In fact, there have been only two trials of azathioprine, one for PR- and SPMS [ 14 ], the other for RRMS only [ 15 ], using appropriate protocols (prospective, double-blind, placebo-controlled, randomised), large enough sample size and minimum number of patients withdrawn during the trial ( - Table: [ 1]). The British–Dutch trial [ 14 ] was by far the most important because of the number of patients involved; however, the mean duration of disease at entry was over 9 years, and one-third of the patients had already converted to SPMS, probably a less sensitive phase than RRMS. Disability increased but clearly less than in the placebo group, the difference between the two groups becoming statistically significant in the third year of the study, with a slower progression in the azathioprine-treated arm when using the ambulation index [ 16 ] as the outcome measure: mean change: +1.25 in the placebo-treated arm, +0.84 in the azathioprine-treated arm: ; there was a similar trend with the EDSS: mean change: +0.80 in the placebo-treated arm, +0.62 in the azathioprine-treated arm: not significant (Fig. 2).
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Table 1: Inclusion criteria, protocol, numbers of patients, and clinical results of two prospective, placebo-controlled, randomised and double-blind trials of azathioprine in MS
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Fig. 2: Mean changes in the EDSS [ 32 ] (upper) and ambulation index [ 16 ] (lower) for patients on azathioprine and placebo in the British and Dutch azathioprine trial in MS [ 14 ]. Horizontal BARS = S.E.M. Reproduced with permission from the Lancet.
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Cyclophosphamide has also been utilised in MS [ 10, 11, 17, 18 ], particularly in cases with frequent relapses and rapid worsening of disability. When administered in the chronic progressive stage according to an induction protocol producing lymphopenia, it proved to be efficient in a small open study of 58 MS patients [ 16 ]. By contrast, no beneficial effect was observed in the prospective, double-blind, placebo-controlled, randomised phase III Canadian co-operative trial (the only such effort) of 168 SPMS patients [ 19 ]. Monthly infusions of cyclophosphamide have also been tested in pilot studies. However, such protocols rapidly lead to high cumulative doses of the drug and an increasing risk of cancer induction in the long-term [ 20 ].
It should be noted that these therapeutic efforts, mostly with azathioprine and cyclophosphamide, were directed mostly at patients in advanced stages of disease, more often SP than RRMS, using low to moderate doses, all these factors conspiring to give poor or no results, and in the 1980s, leading to the conclusion that they were of little use.
3. The emergence of interferons and the re-discovery of the potential of immunosuppressants in MS
In 1993, with the disappointment in the therapeutic value of immunosuppressants as background, the first publication of the efficacy of interferon- b-1b in RRMS appeared as a major event, despite the fact that the initial clinical results were less than spectacular, only a 30% reduction in the relapse rate and no significant effect on disease progression [ 3 ]. By contrast, MRI results were much more impressive with an approximately two-third reduction in activity [ 4 ]. Results of subsequent pivotal trials with intramuscular and subcutaneous interferon- b-1a [ 6, 7 ] and with glatiramer acetate [ 8 ] were in the same range. Nevertheless, this seemed to end any possible interest in the use of immunosuppressants in MS.
Strangely enough, the popularity of the currently approved disease-modifying agents coincided with the renewal of interest in immunosuppressants in MS. This came from a better understanding of the pathophysiology of the disease. The course of MS consists of two distinct clinical phenomena, relapses and disability progression, and two different biological phenomena, inflammation and degeneration. Relapses are the clinical counterpart of the inflammation of the CNS, which is multifocal, acute and recurrent. Longitudinal MRI assessment of brain atrophy, coupled with the structural and biochemical analyses of the so-called normal appearing white matter, suggests that the long-term progression of neurological disability results from a diffuse, chronic and progressive degeneration. It would seem that global immunosuppressants might interfere with the inflammatory process, thus the occurrence of relapses, but to a much lesser extent with the neurodegenerative process and irreversible disability.
The importance of recent trials of potent immunosuppressive agents in MS is that they have focused on very active MS. The results that have been obtained with three different drugs have been very consistent. Campath-1H is a humanised monoclonal antibody with a powerful lymphocyte-depleting activity; its effect on MS patients with high relapse rate, rapid accumulation of disability and high MRI activity, resulted in the expected profound and prolonged lymphopenia, but also in the suppression of clinical and MRI inflammatory activity (Fig. 3) [ 21, 22 ].
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Fig. 3: Effect of Campath-1H on relapses (left panel) and neurological disability (right panel) in 27 patients with active MS [ 22 ]. Reproduced with permission from Annals of Neurology.
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Similar results were obtained with mitoxantrone. The French multicentre study enrolled 42 patients with very active MS defined as relapses at close intervals and/or rapidly accumulating disability, and the presence of gadolinium-enhancing lesions on brain MRI [ 1 ]. At entry, patients had to be ambulatory with an EDSS under 6.0. Patients received six monthly intravenous infusions of 20 mg of mitoxantrone, or a placebo, as well as monthly intravenous infusions of 1 g of methylprednisolone. Clinical assessments were open but MRIs interpretation was blinded. The change in the EDSS score at the end of the trial was significantly higher in the mitoxantrone-treated group: -1.1 versus +0.3: . Relapses were 4.4 times less frequent ( ), and MRI activity dramatically decreased in the treated group but remained stable in the placebo group ( ).
A trial with cyclophosphamide [ 23 ] gave similar results: it involved only 10 patients but these were highly selected, suffering from so-called “rapidly transitional MS”, i.e. a very high relapse rate, increasing disability directly related to relapses and a very high MRI activity despite having received interferon- b-1b for 12–16 months. Patients received IV infusions of cyclophosphamide as an add-on therapy, from 500 to 1500 mg/m2, to produce a chronic lymphopenia in the 600–900/mm3 range. Infusions were administered monthly for the first 12 months, and then bimonthly. Assessment of this b-interferon/cyclophosphamide combination was performed at 18 months: relapses were suppressed in most patients; the mean EDSS was reduced by more than 50% by comparison to the preceding period of interferon therapy; T2 lesion load on brain MRI was also reduced.
Clearly, intensive immunosuppression is effective in controlling inflammation in very active cases of MS; clinical practice during the past decades has shown that it is also of value in treating the classical form of RRMS. Several of our own cases enjoyed abolition of clinical activity after long-term azathioprine treatment (unpublished data). One of them exemplifies the dramatic effects of initiation, interruption and resumption of non-specific oral immunosuppressive treatments (Fig. 4). This woman born in 1954, had RRMS since the age of 24. She had experienced 11 well-documented relapses, 5 of them during the 12 months before the introduction of azathioprine, 150 mg per day, in October 1986. With the exception of a single bout in December 1986, she suffered no other neurological episodes until azathioprine treatment was stopped in October 1994 when she was contemplating a third pregnancy. Two months later, sensory and motor symptoms appeared in the lower extremities with a maximum EDSS of 4.0. Azathioprine treatment was resumed. No new relapses occurred but the treatment had to be stopped again in February 1996 due to anaemia. In April 1996, she complained of upper extremity weakness and exhibited pyramidal signs; azathioprine treatment was resumed, again with good control of the disease despite a single bout of paraparesis in June 1998 in the context of family problems. In October 1998, azathioprine was permanently discontinued because of the possible risk of cancer after a 10-year period of treatment [ 24 ], and the new availability of the b-interferons in France. Her EDSS had never been higher than 4.0 since the onset of her MS in February 1979. In December 1998, treatment with weekly intramuscular interferon- b-1a was initiated but as early as January 1999, she experienced the most severe relapse she had ever had, with spastic tetraparesis, sphincter disturbances, and oculomotor and bulbar symptoms. Her EDSS reached 7.0. In addition, her liver enzymes were elevated. Despite intensive intravenous methylprednisolone followed by oral steroids, improvement was only partial. Interferon therapy was stopped in February 1999. Another relapse with reactivation of the paraplegia and diplopia occured in June 1999. In view of the severe adverse response to b-interferon, the previous sustained former response to non-specific immunosuppression, coupled with the reactivation of the disease associated with interruption of that treatment, the patient agreed to the resumption of long-term oral immunosuppressants, being fully aware of the risks of cancer. A daily dose of 1500 mg of mycophenolate mofetil was started in July 1999. As of her last visit in December 2003, the drug has been well-tolerated, she has had no further relapses and her EDSS has returned to 2.0; she is once again able to engage in all familial and professional activities. Unfortunately, such dramatic responses to immunosuppressants are rather unique in MS; the fact that they do occur, however, favours the concept of biological heterogeneity of the disease [ 25 ].
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Fig. 4: Frequency of relapses and evolution of the DSS [ 31 ] over 24 years in a woman born in 1954 and suffering from RRMS.
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A recent open-label pilot study of six RRMS patients with continued disease activity despite interferon- b-1b treatment, showed that the addition of azathioprine decreased by 69% ( ) the number of contrast-enhancing lesions after a median period of 15 months [ 26 ]. This was yet another point in favour of immunosuppressant therapy for MS.
There has not yet been a direct comparison of the efficacy of oral immuno-suppressants with the currently approved MS-modifying agents. However, the odds ratios of RRMS patients to remain relapse-free after 2 years of treatment have been compared to those receiving placebo by using data from the pivotal phase III trials ( - Table: [ 2]) [ 13 ]. They are remarkably similar for the five drugs under study, and the beneficial effect of the active drug by comparison to placebo becomes significant only for Betaseron®[ 3 ], intravenous immunoglobulins [ 27 ] and azathioprine [ 14 ].
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Table 2: Odds ratios of drug-treated RRMS patients for remaining relapse-free at the end of 2 years compared to placebo-treated
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It has also been possible, after years of use, to better assess the risks of cancer in patients receiving azathioprine. A first report based on a series of cases was rather alarming [ 28 ] but a systematic epidemiological study was more reassuring [ 24 ] ( - Table: [ 3]). There is indeed a dose-related effect associated with azathioprine, especially after 10 years of continuous treatment, but it does not reach statistical significance; we consider that in patients without any other cancer risk factors, it constitutes an acceptable risk for those who seem to gain some benefit from the therapy.
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Table 3: Risk of cancer from azathioprine therapy in 1191 patients with MS from the Lyon Cohort
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4. Immunosuppressants in future treatment strategies for MS
Unexpected findings have recently emerged from the studies of the Lyon Natural History MS Cohort [ 29, 30 ]. One is that the progression of irreversible disability is not seriously affected by relapses; more precisely, the rate of progression from the date of reaching an EDSS of 4 is similar for both RR and SPMS [ 31, 32 ]. This suggests that the presence or absence of relapses before the change from RR to SPMS does not influence this progression. Furthermore, in the subgroup of PPMS, the rate of disability progression is similar, regardless of the presence or absence of relapses; it is also the same in cases of SPMS, with or without relapses. Therefore, it would seem that the contribution of relapses. i.e. inflammation, to the accumulation of disability, i.e. degeneration, is only marginal at best.
The observations from immunoactive treatment trials in general and immunosuppressive treatment trials in particular, are in agreement with natural history data. A first example comes from the experience accumulated with b-interferon treatments: they result in a 30% reduction in the relapse rate and to more than 50% reduction in conventional MRI activity. Despite this documented effect on inflammation, their effect on disability [ 3, 4, 5, 6, 7, 8, 33, 34 ] and brain atrophy [ 35, 36 ] is nil or only marginal. Furthermore, not all patients respond to interferon therapy [ 37 ]. Unfortunately, the results obtained with potent immunosuppressants show the same dissociation of effect on the disease; this was first seen with Campath-1H which resulted in the suppression of clinical and MRI inflammatory activity, but failed to halt the progression of disability and cerebral atrophy (Fig. 3) [ 22 ]. The same situation applies to mitoxantrone which has been in use for more than 10 years in our department. More than 150 patients have been treated to date (unpublished data). We have observed a strong anti-inflammatory effect as shown by clinical and MRI assessments in both RR and SPMS patients, but it has not been unusual to witness secondary progression of disability some months later. Furthermore, in our experience as well as that of others, the administration of mitoxantrone or cyclophosphamide in SPMS with or without relapses is futile. Finally, progression of cerebral atrophy continued in a small series of MS patients in the 24-month period following autologous hematopoietic stem cell transplantation (G. Mancardi, personal communication). All of these observations indicate that non-specific immunosuppressants and, more generally, immunoactive drugs, are capable of controlling inflammation in MS if used aggressively, but are unable to prevent the progression of neurodegeneration and irreversible disability.
5. Conclusion
Currently available immunoactive drugs, including non-specific immunosuppressants, can control inflammation and relapses in MS, but even powerful agents such as Campath-1H, mitoxantrone and cyclophosphamide, do not prevent neurodegeneration and its clinical counterpart, the progression of irreversible disability. In the future, major efforts must be made to foster the utilisation of these alternate therapeutic agents. Along with the anti-inflammatory agents, efficient tools for protecting the CNS from degeneration, and for the promotion of repair must be made to address this second component of the disease. In this respect, some advances have already been made: premyelinating oligodendrocytes are present in MS plaques [ 38 ]; but, while capable of remyelination, they remain quiescent, and it is critical that means for making them actively remyelinate be found. The demonstration that autologous stem cells can be used for protecting and remyelinating the CNS in mice is a promising step for the future of therapeutics in MS [ 39 ].
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