From October 2-5, 2013, the 29th ECTRIMS (Congress of the European Committee for Research and Treatment in Multiple Sclerosis) and the 18th RIMS (Annual Conference of Rehabilitation in MS) were held in Copenhagen. With almost 8000 participants, the congress had more visitors than ever before. The high number of participants indicates the great scientific effort and interest in better understanding and treating this common neurological disease with its sometimes serious medical and socioeconomic consequences. In this article, the most interesting and important aspects of this major congress from the point of view of the authors are presented in short form and without any claim to completeness.
Established therapies
Interferons and glatiramer acetate: Earliest possible diagnosis and early initiation of therapy with the approved therapies (beta-interferons 1a s.c./i.m., Rebif® and Avonex®, 1b s.c., Betaferon®, and glatiramer acetate, Copaxone®) has been shown to positively influence disease progression and reduce mortality.
Pegylated beta interferons are in development. Their efficacy and tolerability have been demonstrated in some studies. According to initial study results, the effect in MRI is better with application every two weeks than with monthly application (ADVANCE study).
Fingolimod (Gilenya®): The known therapeutic effect has now been demonstrated to be sustained over five years. 33% of patients are free of disease activity after two years (clinically, radiologically; after one year, approximately 46%). With regard to known adverse drug reactions, there are no relevant new safety data.
Natalizumab (Tysabri®): Subcutaneous injection of natalizumab may be an alternative to intravenous administration in the future (Woodworth et al., poster 529). Changes in dosage and treatment interval (e.g., Ryerson et al., poster 1068) are being investigated.
There are now more than 400 known progressive multifocal leukoencephalopathy (PML) cases worldwide in MS patients treated with natalizumab. In addition to the three known risk factors for PML (duration of therapy >2 years, immunosuppressive pretreatment, JCV-AK status by StratifyJCV™: positive), further parameters are currently being investigated for better risk assessment. The level of the JCV-AK titer (StratifyJCV™) seems to have a significance for the risk (higher titers = higher risk; [1]) and could be helpful for the diagnosis of PML (increasing titers). A significantly reduced percentage of L-selectin-expressing CD4-positive T lymphocytes may also confer a higher risk of PML [2].
To confirm the diagnosis of PML, at least three lumbar punctures with JCV-PCR in the CSF should be performed (false negative findings) before a brain biopsy is performed. Inflammatory immune reconstitution syndrome (IRIS) usually occurs three to four weeks after natalizumab is removed from the body (plasmapheresis). Prophylactically, mefloquine, mirtazapine, or cidofovir (caveat: nephroprotection needed) can be tried. Repetitive steroid pulses are recommended during IRIS. Because of the high risk of epileptic seizures, the administration of anticonvulsants should be considered. Overall, 77% of MS patients with PML survive.
New therapies
Alemtuzumab: Alemtuzumab (Lemtrada®) received approval in the EU on Sept. 17, 2013, for the treatment of active relapsing-remitting multiple sclerosis. The activity should be demonstrated clinically or radiologically, although no precise criteria have been defined for this. In Switzerland, the application for approval is pending with Swissmedic. Basis for approval was CAMMS223- (treatment-naive patients; relative reduction in annual relapse rate vs. interferon beta-1a s.c. 74%. [p<0,001]), the CARE-MS 1- (treatment-naive patients; relative reduction in annual relapse rate vs. interferon beta-1a s.c. 54.9%. [p<0,0001]) and the CARE-MS 2 trial (escalation therapy; relative reduction in annual relapse rate vs. interferon beta-1a s.c. 49.4%. [p<0,0001]).
Based on the currently available data, it can be stated that the therapeutic effect of the treatment lasts into the third year. No new aspects emerged with regard to the safety profile. Major adverse drug reactions include autoimmune thyroid disorders (hyper- and hypothyroidism), which occur in approximately 36% of treated patients within 48 months. Note cases of idiopathic thrombocytopenic purpura (ITP), which occurs in severe form in approximately 1% of treated patients generally 14-36 months after initial exposure. Nephropathies, including Goodpasture’s syndrome (anti-GBM glomerulonephritis), occur in approximately 0.3% of patients. Infusion-associated reactions should be expected during infusion (5 consecutive days in the first year, 3 consecutive days in the second year of 12 mg alemtuzumab).
Dimethyl fumarate: Dimethyl fumarate (Tecfidera®) has been approved in the U.S. since March 27, 2013, for the treatment of relapsing forms of multiple sclerosis. Approval has been applied for and is pending in Switzerland and the EU.
The basis for approval is two large pivotal trials, DEFINE (relative reduction in annual relapse rate versus placebo 47% [p<0,001]) and CONFIRM (relative reduction in annual relapse rate versus placebo 44% [p<0,001], versus glatiramer acetate 28.6% [p<0,05]), which demonstrated the safety and efficacy of dimethyl fumarate in the treatment of relapsing forms of multiple sclerosis.
Based on the currently available data, it can be concluded that the therapeutic effect continues into the fourth year. 23% of patients are free of disease activity at two years (clinically, radiologically; at one year, approximately 50%; pooled data from DEFINE and CONFIRM).
The most common adverse drug reactions include so-called “flushing” and gastrointestinal side effects. Attention should be paid to rare cases of leukopenia and renal dysfunction. In Europe, four cases of PML have been reported with dimethyl fumarate (2 MS patients, 2 patients with psoriasis). The cases have in common that the patients were previously persistently leukopenic for at least six months.
Teriflunomide: Teriflunomide (Aubagio®) was approved in Switzerland on Nov. 5, 2013, for the treatment of relapsing-remitting multiple sclerosis.
The basis for approval was two phase III studies, the TEMSO (relative reduction in annual relapse rate versus placebo 31.5% [p<0,001]) and the TOWER (relative reduction in annual relapse rate versus placebo 36.3% [p<0,001]) studies.
The most common side effects were increased liver enzymes, headache, thinning of hair, diarrhea, and paresthesias.
Initial results were available at ECTRIMS from an international phase III trial (TOPIC; Miller et al.) in patients with clinically isolated syndrome (CIS). Compared with placebo, the risk of developing clinically defined MS was reduced by 42.6%. The risk of developing another relapse or a new lesion visible on MRI was reduced by 35% (relative risk reduction).
Risk factors
Month of birth: The presumed association between month of birth and incidence of multiple sclerosis is probably due to a type 1 error. According to a paper by Willer et al. [3], it had been assumed that a birth in the spring would confer an increased and a birth in the winter a decreased risk of developing multiple sclerosis. In a poster paper by Fiddes et al. (Poster 415) showed that the month of birth in the general population varies greatly seasonally, from year to year, and from country to country. If not corrected for in the analysis, there is a high risk of a false positive result.
Alcohol, obesity, smoking, and salt consumption: Alcohol consumption and obesity have also been identified as risk factors for multiple sclerosis. Nicotine use had long been known to be a risk factor. Here, the cumulative dose of smoking determines the level of risk. After nicotine cessation, the risk only decreases again after ten years [4]. Multiple sclerosis disease activity is also thought to be dependent on salt consumption. Here, the odds ratio is 3.5 per gram of table salt consumption per day (Correale et al., poster 119).
Pathogenesis
An interesting new explanation for the development of multiple sclerosis is the retrovirus-superantigen hypothesis. As a cause for the coexistence of inflammation and degeneration, this pathogenetic concept assumes that human endogenous retroviruses (HERVs) and their encoded coat proteins contribute as superantigens to the inflammatory responses observed in multiple sclerosis [5]. Possibly, this effect extends to both T cells and B cells. It is possible that new therapeutic approaches can be developed via understanding the mechanisms of inhibition or disinhibition of HERV expression.
Jochen Vehoff, MD
Med. pract. Stefanie miller
Prof. Dr. med. Barbara Tettenborn
Source: 29th Congress of the European Committee for Research and Treatment in Multiple Sclerosis (ECTRIMS) and the 18th Annual Conference of Rehabilitation in MS (RIMS), October 2-5, 2013, Copenhagen.
Literature:
- Trampe, et al: Anti-JC virus antibodies in a large German natalizumab-treated multiple sclerosis cohort. Neurology 2012; 78(22): 1736-1742.
- Schwab N, et al: L-selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients. Neurology 2013 Sep 3; 81(10): 865-871.
- Willer CJ, et al: Timing of birth and risk of multiple sclerosis: population based study. BMJ 2005; 330: 120.
- Hedström AK, et al: Smoking and multiple sclerosis susceptibility. Eur J Epidemiol 2013 Nov; 28(11): 867-874. doi: 10.1007/s10654-013-9853-4. epub 2013 Oct 22.
- Emmer A, et al: Retrovirus superantigen hypothesis of multiple sclerosis. Neurologist 2013; 84: 1245-1246.
InFo Neurology & Psychiatry 2014; 12(1): 42-45.
