Immune response to immunotherapy: the role of neutralising antibodies to interferon beta in the treatment of multiple sclerosis

Interferon beta was the first therapy to be approved for the treatment of relapsing-remitting multiple sclerosis (MS) more than 10 years ago. Interferon beta reduces relapse rates and disease burden and activity, and it may have beneficial effects on the progression of long-term disease disability. The occurrence of neutralising interferon-beta antibodies has been postulated as a possible cause of the failure of interferon beta in some patients with MS. Here we discuss the basic mechanisms that may account for the generation of an interferon-beta antibody response and its biological implications. We review the evidence for neutralising antibodies as a consequence of interferon-beta treatment, and discuss the implications for the treatment of MS. Strategies to assess and manage the long-term impact of neutralising antibodies will be outlined.     

Immunomodulatory therapy in multiple sclerosis

During the past decade, several disease-modifying agents have been established and have become available for the treatment of multiple sclerosis. The disease-modifying agents could be grouped into immunomodulatory and immunosuppressive therapies altering the long-term course of multiple sclerosis. Therapy is now available for relapsing-remitting, secondary progressive and progressive-relapsing multiple sclerosis. Different disease-modifying agents became also available for the treatment of relapsing-remitting multiple sclerosis in Hungary which makes the therapeutic decision difficult. This overview might help to give an answer for different questions in the management of multiple sclerosis: Which agent to choose? When to initiate the therapy? Which dose to apply? Are the drugs safe? How long to treat the patients with immunomodulatory drugs? We give a review from the literature to assess the efficacy of disease-modifying therapies and to compare the data from phase three trials of interferon beta1b, two preparations of interferon beta1a or glatiramer acetate for the treatment of multiple sclerosis. We analyzed the efficacy and safety of these agents on physical, inflammatory and cognitive measures of disease activity. Comparison of study results indicated similar effects of immunomodulatory agents on relapse-related and inflammatory measures in relapsing multiple sclerosis. Interferon beta1a slowed the progression of disability in relapsing multiple sclerosis. One interferon beta1a preparation (intramuscularly injected) demonstrated efficacy in slowing progression of cognitive dysfunction. The interferons reduced relapses at early phase of secondary progressive multiple sclerosis, but their efficacy have not yet been proven in the later phase of secondary progressive multiple sclerosis without relapses. Mitoxantrone demonstrated efficacy in slowing the progression of disability in secondary progressive multiple sclerosis. All of the disease modifying agents are safe and tolerable, if the indication is correct and the patients are strictly controlled.     

Clinical markers of therapeutic response to disease modifying drugs

Interferon beta (IFNβ) and glatiramer acetate (GA) showed a relevant impact in modifying the clinical course of relapsing-remitting multiple sclerosis. However, not all treated patients experience a satisfied response to therapy in terms of suppression of relapse and slowing disability progression.At the present time none of the proposed criteria of response to disease modifying therapies (DMTs) have been validated. Clinical parameters, such as relapse rate and disability progression assessing with EDSS scale, may represent two useful indicators of therapeutic response, but their value in predicting the long-term response to DMTs is weak.     

Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Most patients undergo an initial relapsing-remitting (RR-MS) course that transforms into a relentless neurodegenerative disorder, termed secondary progressive (SP)-MS. Reversible inflammation and demyelination account readily for the pattern of RR-MS but provide an unsatisfactory explanation for irrevocable decline in SP-MS. Axon loss is thought to be responsible for progressive, non-remitting neurological disability during SP-MS. There is considerable potential for neuroprotective therapies in MS, but their application awaits animal models in which axonal loss correlates with permanent neurological disability. In this report, we describe quantitative immunohistochemical methods that correlate inflammation and axonal loss with neurological disability in chronic-relapsing experimental autoimmune encephalomyelitis (EAE). At first attack, CNS inflammation, but not axon loss, correlated with the degree of neurological disability. In contrast, fixed neurological impairment in chronic EAE correlated with axon loss that, in turn, correlated with the number of symptomatic attacks. As proposed for MS, these observations imply a causal relationship between inflammation, axon loss, and irreversible neurological disability. This chronic-relapsing EAE model provides an excellent platform for 2 critical objectives: investigating mechanisms of axon loss and evaluating efficacy of neuroprotective therapies.     

Are statins a treatment option for multiple sclerosis?

BACKGROUND: Treatment options for multiple sclerosis (MS) are limited. The immunomodulatory drugs interferon beta and glatiramer acetate are only partly effective in reducing the relapse rate, slowing disease progression, and diminishing the number and volume of lesions on MRI. Mitoxantrone is an immunosuppressant approved for the treatment of active forms of relapsing-remitting or secondary progressive MS, but is dose-limited owing to its potential cardiotoxicity. Thus, identifying new effective therapeutic options with few side-effects is highly desirable. RECENT DEVELOPMENTS: Evidence has emerged that statins, which are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, have immunomodulatory effects. Recent reports showed that statins prevent and reverse chronic and relapsing experimental autoimmune encephalomyelitis, an animal model of MS. Furthermore, in vitro experiments with human immune cells have shown an immunomodulatory profile of statins comparable to that of interferon beta. An open label clinical trial of simvastatin for MS revealed a significant decrease in the number and volume of new MRI lesions and a favourable safety profile. WHERE NEXT?: The obvious advantage of statins over existing MS therapies is their oral route of dosing. Statins might be beneficial for MS patients as monotherapy or as an add-on to established disease modifying drugs. As the evidence of the benefit of statins in MS is currently insufficient, large controlled clinical trials are needed. The first of these trials is about to start.     

Primary headache and multiple sclerosis: preliminary results of a prospective study

The aim of this study was to explore the association between different types of headache (HA) and the clinical features of multiple sclerosis (MS). The relationship between HA and MS-specific therapies was also analysed. A total of 102 MS patients were recruited at the MS Centre of S. Andrea Hospital in Rome. According to International Headache Society criteria, the lifetime prevalence of primary HA was 61.8%. Migraine was observed more often in young relapsing-remitting MS patients, whilst tension-type HA was associated with older age, male gender and a secondary progressive course. Sixty-four patients had a history of ongoing or past interferon beta (IFNb) exposure. Of these, 17 subjects did not have a history of HA, while 24 complained of an increase in frequency of migraine attacks and 7 reported an IFNb-induced HA. Investigating and treating HA in MS patients starting IFNb therapy may improve MS-specific medication compliance.

     

The role of intravenous immunoglobulin in the treatment of multiple sclerosis

Intravenous immunoglobulin (IVIG) has several effects on the immune system that could have a beneficial influence on disease processes in multiple sclerosis (MS). Owing to its anti-inflammatory properties, IVIG may be beneficial in the treatment of acute relapses and in prevention of new relapses. By promoting remyelination, IVIG could have a beneficial effect on disability and disease progression. Four double-blind trials in relapsing-remitting MS have demonstrated that IVIG reduces the relapse rate and the number of gadolinium enhancing lesions, and in this respect seems comparable to established therapies in relapsing-remitting MS, i.e. interferon-beta and glatiramer acetate. The doses of IVIG that have been used for treatment in relapsing-remitting have varied 10-fold, and the ideal dosage of IVIG for treating MS still needs to be determined. Three studies have been performed to assess the effect of IVIG on chronic visual impairment or established motor symptoms in MS. None of these trials could confirm that established symptoms in MS can be reversed by IVIG. In secondary progressive MS, a large randomized placebo-controlled trial has recently shown that IVIG is without beneficial effects in this phase of the disease. In conclusion, IVIG is a valuable alternative for treatment of relapsing-remitting MS in patients who do not tolerate or are unwilling to take the approved injectable medications, but additional studies are needed to establish the role of IVIG in the management of multiple sclerosis.     

A double blind, placebo-controlled, phase II, add-on study of cyclophosphamide (CTX) for 24 months in patients affected by multiple sclerosis on a background therapy with interferon-beta study denomination: CYCLIN

The authors present and discuss a new protocol for active multiple sclerosis (MS) patients. A double blind randomized controlled multicenter study was planned to study the effects of a combination regimen therapy: cyclophosphamide plus beta interferon versus beta interferon alone on both relapsing-remitting and secondary MS patients with active disease. The primary endpoint of this study is the number of new gadolinium enhancing lesions at MRI evaluation. Secondary endpoints are new T2 lesions, new T1 lesions, T2 lesion load, T1 lesion load, cerebral atrophy, number of patients who were relapse-free, number of patients who improved, yearly relapses, quality of life, disability and cognitive impairment, frequency of neutralizing antibodies, safety of the combination therapy (cyclophosphamide + beta interferon). The study will enroll 225 patients in 25 Italian MS centers. Eligible for the study are patients with either relapsing-remitting or secondary MS according McDonald criteria on 6-24 months beta interferon treatment with active disease (new gadolinium enhancing lesion or who experienced a new relapse on beta interferon treatment). Clinical evaluation will be performed every 4 months, MRI yearly. Vital signs and eventual adverse events will be collected monthly. The study will last 36 months, 12 for the enrollment phase and 24 for the treatment phase. The study will start on April 2004.     

Serial magnetic resonance imaging in multiple sclerosis: correlation with attacks, disability, and disease stage

Serial MRI and clinical testing was performed on 45 well-defined untreated multiple sclerosis patients in different categories of disease (relapsing-remitting, progressive, stable). Up to 24 MRIs were scheduled over a 1-year period for each patient. Clinical evaluation was performed monthly and at times of attacks using the Expanded Disability Status Scale (EDSS) and the Ambulation Index (AI). MRI scans were performed both with and without gadolinium enhancement. MRI lesion volume was determined by computerized analysis and gadolinium-enhancing lesions were counted by radiologists. We observed an increase in lesion volume over 1 year in all patient groups except those classified clinically as stable. In relapsing-remitting patients there were correlations between increases in the number of gadolinium enhancing lesions and increases in EDSS and the occurrence of attacks. In chronic progressive patients, increases in lesion volume were correlated with both increases in EDSS and AI. These results demonstrate a linkage between MRI and clinical disease that depends both on the stage of MS and the MRI measures used and support the use of MRI as a surrogate marker of clinical disability in the study of multiple sclerosis.     

A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis

BACKGROUND: Epidemiological and ecological studies suggest links between vitamin D deficiency and increased multiple sclerosis (MS) prevalence. OBJECTIVE: To evaluate the safety and tolerability of oral calcitriol therapy in an open label pilot study. METHODS: 15 ambulatory patients with relapsing-remitting MS and at least one clinical relapse within the previous 12 months received oral calcitriol (target dose: 2.5 microg/d) for 48 weeks. Dietary calcium was restricted to 800 mg/d. Patients were monitored using frequent clinical and laboratory examinations, the expanded disability status scale (EDSS), and brain magnetic resonance imaging (MRI). RESULTS: Two patients withdrew because of symptomatic hypercalcaemia (serum calcium >3.35 mmol/l in each case) resulting from persistent dietary indiscretion. Two diet compliant patients required temporary dose adjustments for mild asymptomatic hypercalcaemia. Diet compliant patients experienced mild adverse effects. The on-study exacerbation rate (27%) was less than baseline. Four patients experienced five clinical relapses but only one patient worsened by >1 EDSS point. Brain MRI revealed enhancing lesions in five patients at baseline (33%) and in four (29%) at both 24 and 48 weeks. CONCLUSIONS: Oral calcitriol is safe and well tolerated for up to one year by diet compliant relapsing-remitting MS patients. Further study of vitamin D related mechanisms is warranted in MS.     

The pathogenesis of primary progressive multiple sclerosis: antibody-mediated attack and no repair?

Primary progressive multiple sclerosis (MS) differs from the more common form of MS which has an initial relapsing-remitting course in a number of ways, including pathological features, clinical course, differential diagnosis and response to treatment. The lesions in primary progressive MS tend to be more diffuse, less inflammatory and less likely to remyelinate than those occurring in relapsing-remitting MS and secondary progressive MS; there are also fewer focal lesions in the brain in primary progressive MS. Recent evidence suggests that antibodies to central nervous system (CNS) antigens have an important role in disease progression. Such antibodies could cause demyelination, inhibit remyelination and cause axonal destruction. Ongoing immune attack by autoantibody and lack of CNS repair could be responsible for the gradually increasing disability in primary progressive MS. Further research on the B-cell and autoantibody response in primary progressive MS might lead to advances in diagnosis and treatment. Inhibition of autoantibody production by inducing B-cell apoptosis with rituximab is a potential new therapy for primary progressive MS.     

Drug Insight: interferon treatment in multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS. Between 1987 and 1997, clinical trials of three preparations of recombinant interferon-beta were conducted in patients with MS, ushering in a new therapeutic era. These medications have demonstrable benefits and seem to be safe; they represent an important advance in MS treatment. All three formulations of interferon-beta had modest effects on relapses and short-term progression of disability, but the effects on MRI lesion parameters were more substantial. The benefits were greater in clinically isolated syndromes and relapsing-remitting MS than in secondary progressive MS. Although these drugs have been shown to be effective, however, their long-term impact on clinically relevant disability progression is uncertain, and there are many areas of controversy in the MS field regarding the use of these products. There is still a need for more effective treatments, which might include new agents or combination therapies.     

Autonomic dysfunction in multiple sclerosis: cervical spinal cord atrophy correlates

Autonomic dysfunction has rarely been studied in patients suffering from multiple sclerosis (MS). Some hypotheses have concerned the pathophysiology, especially with regard to a possible spinal cord origin. However, there have been no previous studies on autonomic dysfunction in MS and spinal cord lesions. This study assessed the frequency of autonomic dysfunction (AD) in MS and the correlation to spinal cord magnetic resonance imaging (MRI) findings. We prospectively studied 75 MS patients (25 with relapsing-remitting forms, 25 with secondary progressive forms and 25 with primary progressive forms). We performed sympathetic skin response, R-R interval variability and orthostatic hypotension testing. Spinal cord MRI was performed to detect demyelinating lesions (sagittal and axial plane) or spinal cord atrophy. Clinical and laboratory evidence of AD was found in 84 % and 56 % of MS patients, respectively. The correlation of the latter with disability was evaluated using the Extended Disability Status Scale. AD was more frequent in primary progressive MS than in the other two forms. AD was correlated with spinal cord cross-sectional area reduction but not with spinal cord hyperintensities. This study confirms that the frequency of AD in MS, especially in primary progressive forms, has until now been underestimated. Furthermore, AD appears to be more closely related to axonal loss, as demonstrated by spinal cord atrophy, than to demyelinating lesions. Received: 20 March 2000, Received in revised form: 13 October 2000, Accepted: 29 October 2000     

Correlation between brain MRI lesion volume and disability in patients with multiple sclerosis

In this study we evaluated the relationships between clinical variables and lesion volumes measured from magnetic resonance imaging (MRI) scans in a large cohort of multiple sclerosis (MS) patients. One hundred and thirty patients with MS entered the study: 36 patients had relapsing-remitting (RR), 39 benign (B), 42 secondary progressive (SP) and 13 primary progressive (PP) courses. There was a significant correlation (r=0.3; p=0.0006) between the total lesion load and the EDSS score when the whole cohort of patients was considered. This correlation increased (r=0.5) when only patients with RRMS and SPMS were considered. Our data indicate that a correlation between disability and MRI lesion volume in MS exists, but its strength is moderate.     

Short-term ventricular volume changes on serial MRI in multiple sclerosis

Axonal loss is likely to be an important component of atrophy and the pathological substrate for the fixed disability of MS. To estimate the rate of central white matter reduction we investigated ventricular volume change and disease activity on monthly MRI in 19 patients over 6 months. At baseline, ventricular volumes were largest in primary progressive MS and smallest in relapsing-remitting MS. Over the study period ventricular volumes increased overall by 0.2% (F= 2.75, P = 0.02), but the percentage changes in relapsing-remitting MS were much larger (median increase 14.9%). Lesion volumes were also highest at baseline in relapsing-remitting MS, but serial changes in ventricular volumes were not correlated with serial changes in lesions. This study shows that ventricular enlargement in MS may occur over short epochs, particularly in relapsing-remitting cases. However, the loss of central white matter volume observed in any brief period may be related to inflammatory activity that occurred in a preceding or earlier epoch, a delayed post-inflammatory degenerative process, or most likely, a combination of both.     

Cyclophosphamide therapy for MS

Cyclophosphamide has been widely studied for the treatment of MS and the effective stabilization of selected patients on therapy has been suggested in several studies. This drug has selective effects on the immune response, such as suppression of helper Th1 activity and enhancement of helper Th2 responses; both of these processes are thought to be involved in the beneficial effect of cyclophosphamide in MS. Over the years, especially with the advent of magnetic resonance imaging (MRI), there has been an improved understanding of the profound anti-inflammatory effect of cyclophosphamide, evidenced by its effect on clinical relapses and contrast-enhancing lesions on MRI. Toxic effects on the bladder and the risk of malignancy prevent the widespread use of cyclophosphamide in early MS; however, it can be dosed safely and is usually well tolerated in actively progressing relapsing-remitting or early secondary progressive MS cases that are unresponsive to beta interferon and glatiramer acetate.     

Intravenous polyclonal human immunoglobulins in multiple sclerosis

Intravenous immunoglobulin (IVIG) is an established therapy for demyelinating diseases of the peripheral nervous system. IVIG exerts a number of effects that may be beneficial in multiple sclerosis (MS). Four double-blind IVIG trials have been performed in relapsing-remitting MS. A meta-analysis of the four trials has shown that IVIG reduces the relapse rate and, possibly, disease progression. In patients with a first episode of demyelinating disease, IVIG delays the time to the second relapse and thereby to the diagnosis of definite MS. In patients with an acute MS relapse, IVIG as add-on therapy to methylprednisolone does not make remission of symptoms faster or more complete. IVIG does not seem to be of any benefit to chronic visual or motor symptoms in MS. In secondary progressive MS, IVIG has not shown any effect on disease progression, relapses or new magnetic resonance imaging lesions. Experimental studies in the MS model experimental autoimmune encephalomyelitis in rats demonstrate that IVIG has to be administered at the time of induction of a relapse in order to be effective. In conclusion, IVIG can be considered as a second-line treatment to approved therapies for relapsing-remitting MS, but the ideal dosage of IVIG still needs to be determined. In order to be a first-line treatment for MS, the beneficial effect should be confirmed in a large-scale placebo-controlled survey, or in a study comparing the effect with approved therapies for relapsing-remitting MS using appropriate clinical and magnetic resonance imaging outcome measures.     

Corticosteroids treatment

Corticosteroids (Cs) are widely used for treatment of multiple sclerosis (MS) acute relapses because of the potent immunosuppressive and anti-inflammatory properties. As for patients with relapsing-remitting (RR) MS, short-term administrations of Cs markedly less severity of symptoms and promote faster recovery of clinical attacks. Chronic administrations of Cs significantly diminish the formation of T1 hypointense lesions and the progression of brain atrophy. As for patients with secondary progressive MS treatment with Cs delays the time to onset of sustained disability. Finally the association between methylprednisolone and interferon beta (IFNbeta) leads the recovery of active lesions at greater extent and reduces the formation of neutralizing antibodies (NABs) against IFNbeta in patients with RRMS.     

Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis

Predicting clinical outcome is one of the major and most interesting issues in MS patients. If the global evolution of disability (usually chosen levels on the Kurtzke's Disability Status Scale) has been widely studied, much less is known about the progression of disability during the secondary progressive phase of the disease. It is usually said that there is a poorer prognosis once patients enter a progressive phase, whether from onset (like in primary progressive MS) or after an initial relapsing-remitting phase. The secondary progressive phase of multiple sclerosis (MS) is the one most often associated with the development of severe and irreversible disability. Despite this fact, there is a lot of information about the initial relapsing-remitting phase in the literature, but much less about the secondary progressive one. We review here information available from the literature and from the Lyon MS database about this secondary progressive phase.