Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 23, 2023
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Interferons are glycoproteins secreted in the body in response to viral infections and are presumed to provide protection to other cells against viral infection. The name derives from the term "viral interference" used in the first description of these proteins by their discoverers (18). In addition to the antiviral properties, immunomodulatory and antineoplastic properties of interferons were discovered later (05). Use of interferons in multiple sclerosis was based on the belief that the disease may be due to a latent virus infection of the brain in persons with impairment of the immune system (07). Trials with interferon have been conducted in various diseases of the nervous system including multiple sclerosis (11). Two types of interferons have been identified: type 1 (interferon alpha and interferon beta) and type 2 (interferon gamma). Type 2 is synthesized mainly by lymphocytes and type 1 beta by fibroblasts, but both have a similar amino acid composition and genetic coding. Gamma interferon differs from type 1 interferons by its amino acid composition and cell surface receptor. Interferon alpha has been developed mostly for applications in virology and oncology. Interferon beta has a beneficial effect on the course of multiple sclerosis, and interferon alpha has an equivocal effect, whereas interferon gamma exacerbated the disease. Reasons for these varying effects are not well understood.
Interferons are now manufactured commercially in large quantities by recombinant DNA technology. Interferon beta 1b was approved for the treatment of multiple sclerosis by the United States Food and Drug Administration in 1993. Interferon beta 1a is described elsewhere in MedLink Neurology.
Interferons are cytokines that mediate antiviral, antiproliferative, and immunomodulatory activities in response to viral infections and other biological inducers.
Pharmacodynamics. Interferon beta exerts its effect by binding to specific receptors on human cells. This leads to a complex chain of events that, in turn, lead to expression of various interferon-induced gene products that are believed to be the mediators of the biological actions of interferon beta 1b. The exact mechanism of action is not fully understood, but it may decrease the synthesis of inflammatory cytokines interferon gamma and tumor necrosis factor alpha.
Interferon beta 1b stabilizes the blood-brain barrier, which is damaged in multiple sclerosis. This might help improve the management of multiple sclerosis. Interferon beta 1b achieves this by blocking apoptosis of the endothelial cells of the blood-brain-barrier that is induced by serum from multiple sclerosis patients (15). Measurement of immunological biomarkers such as cytokines and neurotrophic factors in patients treated with interferon beta 1b for 1 year indicate their usefulness as indicators of clinical response (08).
Pharmacokinetics. Because serum concentrations of interferon beta 1b are low or undetectable following subcutaneous administration of 0.25 mg or less, pharmacokinetic information in patients with multiple sclerosis receiving the recommended dose of the drug is not available. In healthy volunteers, serum interferon beta 1b concentrations are generally below 100 IU/mL following single and multiple daily subcutaneous administrations of 0.5 mg of the drug. Peak serum interferon beta 1b concentrations occur between 1 and 8 hours. The pharmacokinetic profile is similar after intravenous administration. In patients receiving single intravenous doses up to 2.0 mg, increases in serum concentrations are dose proportional. Mean terminal elimination half-life values ranged from 8.0 minutes to 4.3 hours. Prolonged treatment does not result in accumulation of interferon beta 1b in the serum of patients.
Formulations. A refrigeration-free formulation of interferon beta 1b, based on mannitol, is stable at room temperature for up to 2 years. The safety and efficacy of the refrigeration-free formulation of interferon beta 1b is comparable with that of the original glucose.
Pharmacogenetics/pharmacogenomics. Nonresponder and responders to interferon beta differ in their ex vivo gene expression profile as determined by cDNA microarrays, longitudinal gadolinium-enhanced MRI scans, and clinical disease activity. These findings will help to better understand the mechanism of action of interferon beta in relation to different disease patterns and enable optimized therapy. Several differentially regulated genes have been identified in healthy volunteers in response to interferon beta 1b, and this biomarker panel may become a valuable tool for assessment of clinical drug effects.
Several clinical trials have been conducted with interferon beta 1b. Some of these are shown in Table 1.
Method and reference
Multicenter, randomized, placebo-controlled trial in patients in secondary progressive phase of multiple sclerosis receiving 8 million IU interferon beta 1b every other day subcutaneously for up to 3 years (02).
Treatment with interferon beta 1b delayed sustained neurologic deterioration.
Randomized, placebo-controlled trial of interferon beta 1b in patients with secondary progressive multiple sclerosis in the European Study Group with MRI studies (27).
Interferon beta 1b reduced the accumulation of new inflammatory disease foci, which might be the mechanism of positive clinical benefits of treatment.
A prospective European multicenter, double-blind, randomized, placebo-controlled trial with patients treated for up to 36 months (21).
Interferon beta 1b treatment delays neurologic deterioration in patients with secondary progressive multiple sclerosis.
An open pilot study of the safety of combining mitoxantrone with interferon in patients with worsening relapsing-remitting or secondary progressive multiple sclerosis (19).
The combination was safe and enhanced the effect of interferon on disease progression.
A randomized, multicenter study in Japanese patients with relapsing-remitting multiple sclerosis (37).
Interferon beta 1b significantly reduced relapse rates and change in MRI lesion area in classical as well as optic-spinal multiple sclerosis.
Examination of detailed MRI findings from the first 2 years of Betaseron/Betaferon in the Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) study, which is a double-blind, placebo-controlled, randomized, parallel-group, multicenter, phase 3 study.
Interferon beta 1b treatment had a robust effect on MRI measures, supporting its value as an early intervention in this patient group (04).
Interferon beta 1b treatment effect was analyzed by Cox proportional hazards regression in a subgroup of the BENEFIT study.
Interferon beta 1b treatment effect was robust across the study population, including patients without MRI disease activity and patients not receiving steroids for the clinically isolated syndrome (33).
The 5-year active treatment extension of the BENEFIT study compared effects of early and delayed treatment with interferon beta 1b on time to clinically definite multiple sclerosis and other disease outcomes (20).
Favorable long-term safety support with early initiation of treatment with interferon beta 1b, although delay in treatment by up to 2 years did not affect long-term disability outcomes.
Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) trial, compared efficacy, safety, and tolerability of 250 microg or 500 microg interferon beta-1b with glatiramer acetate for treating relapsing-remitting multiple sclerosis (OConnor et al 2009).
500 microg interferon beta-1b was not more effective than the standard 250 microg dose, and both doses had similar clinical effects to glatiramer acetate.
Modest but beneficial effects of interferon beta 1b on clinical variables and brain atrophy development were observed 5 years after termination of a 2-year clinical trial of interferon beta 1b for the treatment of primary progressive multiple sclerosis (41).
In the BENEFIT study, the impact of interferon beta-1b on cognitive performance at the clinically isolated stage of multiple sclerosis was evaluated by Paced Auditory Serial Addition Test-3 scores (31). IFNβ-1b treatment had a sustained positive effect on the test scores over the 5-year duration of the study. A 16-year longitudinal study has shown beneficial effects of interferon beta-1b on cognition outcomes in multiple sclerosis (23). In a randomized placebo-controlled trial of clinically isolated syndrome with follow-up of 5 years, interferon beta-1b was shown to reduce the number of black holes (ie, persisting T1 hypointensities on MRI) (28).
Regression analysis of patients with relapsing-remitting multiple sclerosis from BEYOND clinical trial has examined the predictive value of patient characteristics at baseline and after 1 year of treatment with interferon beta-1b 250 μg every other day (16). Higher number of relapses in year 1 predicted the future occurrence of relapses, whereas age, MRI activity, and the presence of neutralizing antibodies in the first year were mainly predictive of future MRI activity.
A 2-year prospective cohort study assessed serum 25-hydroxyvitamin D levels to determine association of interferon beta-1 treatment with the course of multiple sclerosis in participants of BEYOND clinical trial because low 25-hydroxyvitamin D levels indicate increased disease activity and rate of progression (10). Results showed that in patients treated with interferon beta-1b, higher 25-hydroxyvitamin D levels were associated with lower rates of disease activity observed on MRI.
A 2-year longitudinal study was conducted to estimate the prevalence of growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in clinically isolated syndrome (CIS) patients and their correlation with conversion to multiple sclerosis in interferon beta 1b treated patients (24). GH/IGF-1 axis function was found to be frequently altered in CIS patients, but this was not related to conversion to multiple sclerosis despite improvement of growth hormone deficiency during interferon therapy.
Interferon beta 1b is indicated for use in ambulatory patients with relapsing-remitting multiple sclerosis. An extension of the indication to include the treatment of patients with a first clinical event suggestive of multiple sclerosis has been approved in all 27 European member states, as well as in Iceland and Norway.
A multicenter, prospective, open-label, randomized, phase 2 trial in adults with COVID-19 showed that triple antiviral therapy (interferon beta-1b, lopinavir-ritonavir, and ribavirin) was safe and superior to lopinavir-ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19 (17). A randomized clinical trial showed that interferon-beta 1b was effective in shortening the time to clinical improvement without serious adverse events in patients with severe COVID-19 (34).
Interferon beta 1b is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, human albumin, or other components of the formulation.
The aim is to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations. It is not a curative treatment. The therapy can be continued for an indefinite period. A 21-year follow-up of multiple sclerosis patients treated with interferon beta-1b has reported better life (22).
An MRI study has shown that lack of size decrease of contrast enhancing lesions, which represent inflammatory events during interferon beta 1a therapy, suggests a limited therapeutic effect of the drug due to increased severity of brain tissue damage associated with blood-brain barrier breakdown (12).
In an observational extension study of the BENEFIT clinical trial, 8-year results provide further evidence supporting early initiation of treatment with interferon beta 1b in patients with a first event suggestive of multiple sclerosis (09). Patients originally randomized to interferon beta 1b had a reduced risk of developing clinically definite multiple sclerosis by 32.2% over the 8-year observation period.
A study on patients with relapsing-remitting multiple sclerosis showed that serum neutralizing antibodies (Nabs) were more frequent in patients receiving interferon beta 1b treatment than in those treated with subcutaneous or intramuscular interferon beta 1a, supporting Nabs as a biomarker to identify multiple sclerosis patients with a high probability of showing an optimal response to interferon beta 1b (01).
Predictive validity for negative disability outcomes at 16 years and survival at 21 years postrandomization were assessed in a follow-up of a randomized trial of interferon beta 1b for no evidence of disease activity (13). Clinical assessment of no disease activity predicted long-term disability outcome, whereas MRI variables did not increase the predictive validity.
The goal of a digital observational study, which was a mixed prospective and retrospective study, conducted among users of autoinjector BETACONNECT® (80% of the patients) was to establish a method that enables the collection of medication usage data on a medical app (myBETAapp) and to assess medication usage among patients with multiple sclerosis treated with interferon beta 1b (ClinicalTrials.gov NCT03134573). This study provides important information on interferon beta 1b usage among patients with multiple sclerosis as well as on the consenting behavior of patients in digital studies, and in future clinical studies, this approach may enable patients' feedback to be rapidly implemented in existing digital solutions (26).
Following the introduction of BETACONNECT® (an electronic autoinjector), an exploratory study suggested that persons with multiple sclerosis taking interferon beta 1b were more adherent compared with those taking interferon beta 1a, with higher persistence (06). More than 90% reached a medication possession ratio of 80%, a threshold commonly used to define good adherence.
The recommended dose of interferon beta 1b for the treatment of ambulatory relapsing-remitting multiple sclerosis is 0.25 mg injected subcutaneously per day. Higher doses have been given on alternate days in clinical trials, and this was found to be more effective than once weekly interferon beta 1a.
All patients should have blood chemistry and hematology tests prior to initiating interferon beta 1b therapy and at periodic intervals thereafter: hemoglobin, complete and differential white blood cell counts, platelet counts, and blood chemistries including liver function tests. In the controlled clinical trials, patients were monitored every 3 months. The study protocol stipulated that interferon beta 1b therapy should be discontinued in the event the absolute neutrophil count fell below 750/mm3. When the absolute neutrophil count had returned to a value greater than 750/mm3, therapy could be restarted at a 50% reduced dose. Similarly, if hepatic transaminase levels exceeded 10 times the upper limit of normal or if the serum bilirubin exceeded 5 times the upper limit of normal, therapy was discontinued. In each instance during the controlled trials, hepatic enzyme abnormalities returned to normal following discontinuation of therapy.
Caution should be exercised in giving interferon beta 1b to patients with depression and patients with seizure disorders. Patients with cardiac disease should be closely monitored.
Anesthesia. No relevant information is available.
Pregnancy. Interferon beta 1b is contraindicated for pregnant women. It is not known if interferon beta is excreted in human milk. Nursing mothers should either discontinue nursing or interferon beta treatment. The rates of spontaneous abortions and birth defects in a study with the largest number of interferon beta 1bexposed pregnancies do not differ from available population estimates, and no pattern of specific birth defects was observed (36). However, the number of cases is not large enough to make a final assessment of the safety of interferon beta 1b during pregnancy.
Pediatric. Safety and efficacy in patients below the age of 18 years has not been established. A retrospective study, however, supports the safety and tolerability of interferon beta 1b in children with multiple sclerosis and related diseases, but regular monitoring of liver function is recommended (03).
Geriatric. No relevant information is available.
There are no clinically significant interactions.
Adverse events reported during clinical trials and postmarketing experience are listed in the Physicians Desk Reference. Some of the adverse reactions are:
• Flu-like symptoms, which include fever, chills, myalgias, and arthralgias. These symptoms can be reduced by slower titration of the drug.
• Injection-site inflammation. This can be reduced by use of an autoinjector.
• Interferon beta 1b subcutaneous has been reported to result in ulceration due to multiple superficial thrombosed vessels.
• Neutralizing antibodies to interferon beta occur in some multiple sclerosis patients, particularly during the first year of treatment, and may be associated with an attenuation of the therapeutic effect. However, another study shows that most patients with poor clinical response are negative for neutralizing bodies, suggesting that this explains only partially the suboptimal response to interferon beta (38). The IDEA (Interferon Dose Escalation Assessment) extension study demonstrated that when neutralizing antibodies develop in patients receiving higher doses of interferon beta 1b they tend to persist for a prolonged period, although neutralizing antibody titers tend to decrease over time and some patients may revert to neutralizing antibody-negative status (14). In 1 study, patients who produced neutralizing antibodies differed from those who did not by higher incidence of cognitive deficit and higher lesion load, and this might be a biomarker of a more aggressive form of multiple sclerosis (25). Methylprednisolone combined with interferon beta 1b reduces the incidence of neutralizing bodies during the first year of treatment. Neutralizing antibodies to interferon beta are linked to aggregation of the peptide during manufacturing and storage. Dodecylmaltoside, a nontoxic alkylsaccharide surfactant, reduces aggregation of interferon beta in vitro and reduces its immunogenicity in vivo in rodent models (35).
• Interferon syndrome.
• Exacerbation of multiple sclerosis may occur in some cases. It is difficult to ascertain if this is the natural progression of the disease with a lack of efficacy of treatment or an adverse reaction to the drug.
• Drug-induced systemic lupus erythematosus has been reported in a patient suffering from multiple sclerosis after 8-year use of interferon beta 1b, and the symptoms gradually resolved after discontinuation of the drug (40).
• Postmenopausal bleeding has been reported in a patient with the use of interferon beta 1b therapy, which could be due to elevated serum estradiol levels (32).
• Thrombotic microangiopathy manifested by headache, thrombocytopenia, renal dysfunction, severe hypertension, posterior reversible encephalopathy syndrome, and gastrointestinal involvement has been reported in a patient after 8 years of therapy with interferon beta 1b (30). Rapid improvement followed discontinuation of the medication and initiation of antihypertensive treatment.
• Severe active pulmonary tuberculosis has been reported in patients with multiple sclerosis undergoing interferon beta-1b therapy due to impact on cellular immunity. Screening is recommended for latent infection with Mycobacterium tuberculosis prior to interferon beta-1b therapy (39).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.See Profile
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