Background
The association between multiple sclerosis and malignancy is controversial and a current appraisal is needed.
Objective
To determine the incidence of malignancy in patients with multiple ...sclerosis compared with the general population and in relation to disease-modifying therapy.
Methods
Patients with multiple sclerosis (1995 – 2015) were matched by birth year and sex to individuals without multiple sclerosis in the general population. Patients with multiple sclerosis initiating disease-modifying therapy were evaluated using landmark period analysis. Malignancy risk was assessed by incidence rates, incidence rate ratios, and standardised incidence ratios.
Results
The standardised incidence ratio of any malignancy (excluding non-melanoma skin cancer) in patients with multiple sclerosis (n = 10,557) was 0.96 (95% CI 0.88 – 1.06), and there was no increased incidence of specific malignancy types compared with the general population cohort (n = 103,761). At the 48-month landmark period, the age-adjusted incidence per 100,000 person-years of any malignancy (excluding non-melanoma skin cancer) was 436.7 (95% CI 361.0 – 512.4) in patients newly treated with immunomodulator-only and 675.1 (95% CI 130.4 – 1219.9) in patients newly treated with immunosuppressant-only.
Conclusions
There was no increased incidence of malignancy overall or by type in patients with multiple sclerosis compared neither with the general population nor in relation to disease-modifying therapy.
Neurofilaments are structural proteins, and neurofilament light chain (NfL) is released after neuroaxonal injury.1 NfL can be measured in blood by ultrasensitive assays, with good correlation between ...blood and CSF levels.1,2 In healthy individuals, blood concentrations of NfL increase with age. ...it should be noted that NfL concentrations measured with methods other than the one used in this study might not provide valid Z scores for the app. ...NfL concentrations in plasma tend to be lower than those in serum5,8 and, therefore, might also not be valid with the app. ...the use of NfL Z scores to estimate risk of progression independent of relapses and MRI activity in multiple sclerosis remains to be established.10 FS declares grants from Biogen, Merck, Novartis, Roche, and Sanofi Genzyme; consulting fees from Novartis; speaking fees from Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, and Sanofi Genzyme; travel support from Biogen and Roche; and fees for participating on a Data Safety Monitoring Board from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, and Sanofi Genzyme.
Whereas drugs used for maintenance/escalation therapy do not maintain their beneficial effect after cessation of therapy, some new highly effective therapies can show prolonged treatment effects ...after a short treatment course. Such therapies have been named pulsed immune reconstitution therapies or pulsed immunosuppressive therapies, and typical representatives are alemtuzumab and cladribine. Autologous haematopoietic stem cell transplantation could be considered as the strongest immune reconstitution therapy. Both alemtuzumab and cladribine induce depletion of lymphocytes, and a common mechanism of action is preferential depletion of class-switched and unswitched memory B-cells. Whereas CD-19+ B-lymphocytes repopulate within 6 months, CD4+ T-cells repopulate at a slower rate, taking 1–2 years to reach the lower level of normal. In general, the depletion of lymphocytes is more profound and the repletion of T-cells is slower after alemtuzumab than after cladribine treatment. Both drugs have a strong effect on relapses and magnetic resonance imaging (MRI) activity, and reduce disability worsening. The therapeutic effect is maintained beyond the period of active treatment in a large proportion of patients, which is best documented for alemtuzumab. Adverse effects include reactivation of latent infections such as tuberculosis and risk of herpes zoster. The main disadvantage in alemtuzumab-treated patients is the risk of secondary immune-mediated disorders. Pulsed immune reconstitution therapy is an option as initial therapy in relapsing-remitting multiple sclerosis patients with high disease activity and in patients on treatment with another disease-modifying therapy with significant relapse and/or MRI activity.
ObjectiveWe investigated whether clinical rebound occurred after fingolimod discontinuation in a complete population of patients with relapsing-remitting multiple sclerosis (RRMS) in Denmark. We ...further identified clinical and demographical factors associated with disease reactivation after fingolimod discontinuation.MethodsThe population comprised 992 RRMS patients treated with fingolimod for 6 months or more. We estimated annualised relapse rates (ARR) before, during and after treatment. We estimated overall ARRs and ARRs stratified by disease activity before discontinuation. We calculated the proportion of patients with a higher clinical disease activity after discontinuation than before treatment start. Finally, we analysed the association between variables at discontinuation and time to first relapse after discontinuation.ResultsThe ARR 3 months after discontinuation (ARR=0.56; 95% CI=0.47 to 0.66) was statistically significantly lower (p<0.01) than the ARR 1 year before treatment (ARR=0.74; 95% CI=0.69 to 0.80). Results were similar when repeating analyses in patients with and without disease activity before discontinuation. In total, 124 patients (12.5%) had clinical rebound. Of those, 36 had no disease breakthrough before discontinuation (3.6% of total population). On treatment disease activity (HR=1.98, p<0.01), lower age (HR=0.98, p=0.01) and female sex (HR=1.68, p=0.02) were associated with a higher relapse risk after discontinuation.ConclusionsBased on average ARR levels, there was no evidence of clinical rebound after fingolimod discontinuation. In total, 12.5% of patients had clinical rebound. Only 3.6%, however, had clinical rebound without disease activity before discontinuation. Disease activity before discontinuation, female sex and younger age were statistically significantly associated with a higher relapse risk after discontinuation.
Background and purpose
Data on pregnancy outcomes following fetal exposure to disease‐modifying drugs (DMDs) in women with multiple sclerosis (MS) are sparse although growing.
Methods
Data from the ...Danish Multiple Sclerosis Registry were linked with nationwide registries enabling an investigation of adverse pregnancy outcomes in newborns of women with MS following fetal exposure to injectable first‐line treatments, dimethyl fumarate, glatiramer acetate, or natalizumab. Logistic regression models accounting for clustered data were used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for individual and composite adverse outcomes after adjusting for relevant covariates.
Results
A total of 1009 DMD‐exposed pregnancies were compared with 1073 DMD‐unexposed pregnancies as well as 91,112 pregnancies from the general population. No association of an increased risk of any perinatal outcome was found when comparing newborns with fetal exposure with the general population, including preterm birth (OR = 1.19, 95% CI = 0.86–1.64), small for gestational age (OR = 1.38, 95% CI = 0.92–2.07), spontaneous abortion (OR = 1.04, 95% CI = 0.84–1.27), congenital malformation (OR = 0.99, 95% CI = 0.68–1.45), low Apgar score (OR = 0.62, 95% CI = 0.23–1.65), stillbirth (OR = 1.05, 95% CI = 0.33–3.31), placenta complication (OR = 0.53, 95% CI = 0.22–1.27), and any adverse event (OR = 1.10, 95% CI = 0.93–1.30). Similar results were found when comparing DMD‐exposed pregnancies with DMD‐unexposed pregnancies.
Conclusions
We found no increased association of adverse pregnancy outcomes in newborns with fetal exposure to DMDs when compared with either DMD‐unexposed pregnancies or the general population.
Pathology studies of progressive multiple sclerosis (MS) indicate a major role of inflammation including Th17-cells and meningeal inflammation with ectopic lymphoid follicles, B-cells and plasma ...cells, the latter indicating a possible role of the newly identified subset of follicular T-helper (TFH) cells. Although previous studies reported increased systemic inflammation in progressive MS it remains unclear whether systemic inflammation contributes to disease progression and intrathecal inflammation. This study aimed to investigate systemic inflammation in progressive MS and its relationship with disease progression, using flow cytometry and gene expression analysis of CD4(+) and CD8(+)T-cells, B-cells, monocytes and dendritic cells. Furthermore, gene expression of cerebrospinal fluid cells was studied. Flow cytometry studies revealed increased frequencies of ICOS(+)TFH-cells in peripheral blood from relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients. All MS subtypes had decreased frequencies of Th1 TFH-cells, while primary progressive (PPMS) MS patients had increased frequency of Th17 TFH-cells. The Th17-subset, interleukin-23-receptor(+)CD4(+)T-cells, was significantly increased in PPMS and SPMS. In the analysis of B-cells, we found a significant increase of plasmablasts and DC-SIGN(+) and CD83(+)B-cells in SPMS. ICOS(+)TFH-cells and DC-SIGN(+)B-cells correlated with disease progression in SPMS patients. Gene expression analysis of peripheral blood cell subsets substantiated the flow cytometry findings by demonstrating increased expression of IL21, IL21R and ICOS in CD4(+)T-cells in progressive MS. Cerebrospinal fluid cells from RRMS and progressive MS (pooled SPMS and PPMS patients) had increased expression of TFH-cell and plasmablast markers. In conclusion, this study is the first to demonstrate the potential involvement of activated TFH-cells in MS. The increased frequencies of Th17-cells, activated TFH- and B-cells parallel findings from pathology studies which, along with the correlation between activated TFH- and B-cells and disease progression, suggest a pathogenic role of systemic inflammation in progressive MS. These observations may have implications for the treatment of progressive MS.
IMPORTANCE: Treatment strategies for relapsing-remitting multiple sclerosis (RRMS) vary markedly between Denmark and Sweden. The difference in the association of these national strategies with ...clinical outcomes is unknown. OBJECTIVE: To investigate the association of national differences in disease-modifying treatment (DMT) strategies for RRMS with disability outcomes. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data on 4861 patients from the Danish and Swedish national multiple sclerosis (MS) registries from the date of index DMT initiation (between January 1, 2013, and December 31, 2016) until the last recorded visit at time of data extraction (October 2, 2019). EXPOSURES: All MS-specific DMTs initiated during the observation period were included in the analysis. MAIN OUTCOMES AND MEASURES: The primary study outcome was time to 24-week confirmed disability worsening. Secondary outcomes were 24-week confirmed disability improvement, milestone Expanded Disability Status Scale scores of 3 and 4, annualized relapse rate, time to first relapse, and treatment switching. Data were analyzed using inverse probability of treatment weighting–based models using a propensity score to weight and correct the comparison for the imbalance of confounders observed at baseline between the 2 countries. RESULTS: A total of 2700 patients from the Swedish MS registry (1867 women 69.2%; mean SD age, 36.1 9.5 years) and 2161 patients from the Danish MS registry (1472 women 68.1%; mean SD age, 37.3 9.4 years) started a first DMT between 2013 and 2016, were included in the analysis, and were observed for a mean (SD) of 4.1 (1.5) years. A total of 1994 Danish patients (92.3%) initiated a low to moderately effective DMT (teriflunomide, 907 42.0%) and 165 (7.6%) initiated a highly effective DMT, whereas a total of 1769 Swedish patients (65.5%) initiated a low to moderately effective DMT (teriflunomide, 64 2.4%) and 931 (34.5%) initiated a highly effective DMT. The Swedish treatment strategy was associated with a 29% reduction in the rate of postbaseline 24-week confirmed disability worsening relative to the Danish treatment strategy (hazard ratio, 0.71; 95% CI, 0.57-0.90; P = .004). The Swedish treatment strategy was also associated with a 24% reduction in the rate of reaching an expanded disability status scale score of 3 (hazard ratio, 0.76; 95% CI, 0.60-0.97; P = .03) and a 25% reduction in the rate of reaching an expanded disability status scale score of 4 (hazard ratio, 0.75; 95% CI, 0.61-0.96; P = .01) relative to Danish patients. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that there is an association between differences in treatment strategies for RRMS and disability outcomes at a national level. Escalation of treatment efficacy was inferior to using more efficacious DMT as initial treatment.
PDF
