| 1. |
- Alping, Peter, et al.
(författare)
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Cancer Risk for Fingolimod, Natalizumab, and Rituximab in Multiple Sclerosis Patients
- 2020
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Ingår i: Annals of Neurology. - : John Wiley & Sons. - 0364-5134 .- 1531-8249. ; 87:5, s. 688-699
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking.METHODS: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer.RESULTS: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7-48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2-63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1-41.6). The general population IR was 31.0 (95% CI = 27.8-34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98-2.38) and rituximab (HR = 1.68, 95% CI = 1.00-2.84).INTERPRETATION: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings.
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| 2. |
- Englund, Simon, et al.
(författare)
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Predictors of patient-reported fatigue symptom severity in a nationwide multiple sclerosis cohort
- 2023
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Ingår i: Multiple Sclerosis and Related Disorders. - : Elsevier. - 2211-0348 .- 2211-0356. ; 70
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Fatigue is a debilitating symptom of multiple sclerosis (MS), but its relation to sociodemographic and disease-related characteristics has not been investigated in larger studies. The objectives of this study were to evaluate predictors of self-reported fatigue in a Swedish nationwide register-based MS cohort.METHODS: Using a repeated cross-sectional design, we included 2,165 persons with relapsing- remitting and secondary progressive MS with one or multiple Fatigue Scale for Motor and Cognitive Functions (FSMC) scores, which was modelled using multivariable linear regressions for multiple predictors.RESULTS: Only associations to expanded disability status scale (EDSS) and Symbol Digit Modalities Test (SDMT) were considered clinically meaningful among MS-associated characteristics in our main model; compared to mild disability (EDSS 0-2.5), those with severe disability (EDSS ≥6) scored 17.6 (95% CI 13.1-22.2) FSMC points higher, while the difference was 10.7 (95% CI 8.0-13.4) points for the highest and lowest quartiles of SDMT. Differences between highest and lowest quartiles of health-related quality of life (HRQoL) instruments were even greater and considered clinically meaningful; EuroQoL Visual Analogue Scale (EQ-VAS) 31.9 (95% CI 29.9-33.8), Multiple Sclerosis Impact Scale (MSIS-29) psychological component 35.6 (95% CI 33.8-37.4) and MSIS-29 physical component 45.5 (95% CI 43.7-47.4).CONCLUSION: Higher self-reported fatigue is associated with higher disability level and worse cognitive processing speed, while associations to other MS-associated characteristics including MS type, line of disease modifying therapy (DMT), MS duration, relapse and new cerebral lesions are weak. Furthermore, we found a strong correlation between high fatigue rating and lower ratings on health-related quality of life instruments.
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| 3. |
- Longinetti, Elisa, et al.
(författare)
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Trajectories of cognitive processing speed and physical disability over 11 years following initiation of a first multiple sclerosis disease-modulating therapy
- 2024
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 95:2, s. 134-141
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of processing speed and physical disability after disease-modulating therapy (DMT) start.METHODS: Using a group-modelling approach, we assessed trajectories of processing speed with oral Symbol Digit Modalities Test (SDMT) and physical disability with Expanded Disability Status Scale, from first DMT start among 1645 patients with RRMS followed during 2011-2022. We investigated predictors of trajectories using group membership as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories.RESULTS: We identified 5 stable trajectories of processing speed: low SDMT scores (mean starting values=29.9; 5.4% of population), low/medium (44.3; 25.3%), medium (52.6; 37.9%), medium/high (63.1; 25.8%) and high (72.4; 5.6%). We identified 3 physical disability trajectories: no disability/stable (0.8; 26.8%), minimal disability/stable (1.6; 58.1%) and moderate disability (3.2; 15.1%), which increased to severe disability. Older patients starting interferons were more likely than younger patients starting rituximab to be on low processing speed trajectories. Older patients starting teriflunomide, with more than one comorbidity, and a history of pain treatment were more likely to belong to the moderate/severe physical disability trajectory, relative to the no disability one. There was a strong association between processing speed and physical disability trajectories.CONCLUSIONS: In this cohort of actively treated RRMS, patients' processing speed remained stable over the years following DMT start, whereas patients with moderate physical disability deteriorated in physical function. Nevertheless, there was a strong link between processing speed and disability after DMT start.
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| 4. |
- Luna, Gustavo, et al.
(författare)
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Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies
- 2020
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Ingår i: JAMA Neurology. - : American Medial Association. - 2168-6149 .- 2168-6157. ; 177:2, s. 184-191
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden.Objective: To examine the risk of serious infections associated with disease-modifying treatments for MS.Design, Setting, and Participants: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included.Exposures: Treatment with rituximab, natalizumab, fingolimod, and interferon beta and GA.Main Outcomes and Measures: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions.Results: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]).Conclusions and Relevance: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.
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| 5. |
- Piehl, Fredrik, et al.
(författare)
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COMBAT-MS : A Population-Based Observational Cohort Study Addressing the Benefit-Risk Balance of Multiple Sclerosis Therapies Compared with Rituximab
- 2024
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Ingår i: Annals of Neurology. - : John Wiley & Sons. - 0364-5134 .- 1531-8249.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess comparative effectiveness, safety, and tolerability of off-label rituximab, compared with frequently used therapies approved for multiple sclerosis (MS).METHODS: A Swedish cohort study of persons with relapsing-remitting MS, age 18 to 75 years at inclusion and with a first therapy start or a first therapy switch between 2011 and 2018. Low-dose rituximab was compared with MS-approved therapies. Primary outcomes were proportions with 12 months confirmed disability worsening and change in MS Impact Scale-29 (MSIS-29) scores, respectively. Secondary endpoints included relapses, therapy discontinuation, and serious adverse events. Analyses used an intention-to-treat approach and were adjusted for demographics, MS features, and health characteristics.RESULTS: We included 2,449 participants as first therapy start and 2,463 as first therapy switch. Proportions with disability worsening at 3 years were 9.1% for rituximab as first therapy and 5.1% after therapy switch, with no differences to MS-approved comparators. Worsening on rituximab was mostly independent of relapses. MSIS-29 with rituximab at 3 years improved by 1.3/8.4 points (physical/psychological) for first disease-modifying therapy (DMT) and 0.4/3.6 for DMT switch, and was mostly similar across therapies. Rituximab had lower relapse rates and higher therapy persistence in both groups. The rate of hospital-treated infections was higher with rituximab after a therapy switch, but not as a first therapy.INTERPRETATION: This population-based real-world cohort study found low rates of disability progression, mostly independent of relapses, and without significant differences between rituximab and MS-approved comparators. Rituximab led to lower rates of inflammatory activity and higher treatment persistence, but was associated with an increased rate of serious infections. ANN NEUROL 2024.
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| 6. |
- Alkner, Sara, et al.
(författare)
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Quality assessment of radiotherapy in the prospective randomized SENOMAC trial
- 2024
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Ingår i: Radiotherapy and Oncology. - : Elsevier. - 0167-8140 .- 1879-0887. ; 197
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Recommendations for regional radiotherapy (RT) of sentinel lymph node (SLN)-positive breast cancer are debated. We here report a RT quality assessment of the SENOMAC trial. Materials and Methods: The SENOMAC trial randomized clinically node-negative breast cancer patients with 1-2 SLN macrometastases to completion axillary lymph node dissection (cALND) or SLN biopsy only between 2015-2021. Adjuvant RT followed national guidelines. RT plans for patients included in Sweden and Denmark until June 2019 were collected (N = 1176) and compared to case report forms (CRF). Dose to level I (N = 270) and the humeral head (N = 321) was analyzed in detail.
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| 7. |
- Alping, Peter, et al.
(författare)
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Safety of Alemtuzumab and Autologous Hematopoietic Stem Cell Transplantation Compared to Noninduction Therapies for Multiple Sclerosis
- 2021
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Ingår i: Neurology. - : Wolters Kluwer. - 0028-3878 .- 1526-632X. ; 96:11, s. E1574-E1584
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Tidskriftsartikel (refereegranskat)abstract
- Objective To assess safety outcomes for the induction therapies alemtuzumab and autologous hematopoietic stem cell transplantation (AHSCT) compared to noninduction disease-modifying therapies.Methods We performed a population-based cohort study linking the Swedish Multiple Sclerosis Register to national health care registers. Alemtuzumab, AHSCT, and a matched reference group of noninduction therapies (natalizumab, dimethyl fumarate, rituximab, fingolimod) were included if started between 2008 and 2017. Main outcomes were death, thyroid disease, nonthyroid autoimmune disease, and infection.Results We identified 132 alemtuzumab-treated and 139 AHSCT-treated (68% high-dose cyclo-phosphamide and anti-thymocyte globulin [ATG], 32% BCNU, etoposide, cytosine-arabinoside, and melphalan/ATG) patients, together with 2,486 matched patients treated with noninduction therapies. Four patients in the alemtuzumab group died (incidence rate [IR] per 1,000 person-years 8.6, 95% confidence interval [CI] 2.3-22.0) compared to 1 patient in the AHSCT group (IR 1.7, 95% CI 0.0-9.6), and the mortality rate in the reference group was 0.7 (95% CI 0.3-1.3). Thyroid disease was most frequent in the alemtuzumab group (IR 109, 95% CI 75-154) but also occurred more often for AHSCT (IR 34, 95% CI 18-56) compared to the reference (IR 5.3 95% CI 3.9-7.1). The incidence of nonthyroid autoimmune disease was similar in all groups. IR for infection diagnosed >= 6 months from therapy initiation was 53 (95% CI 30-87) for alemtuzumab, 108 (95% CI 75-150) for AHSCT, and 51 (95% CI 46-57) for the reference.Conclusion We confirmed a high incidence of thyroid disease in alemtuzumab- and, to a smaller extent, AHSCT-treated patients and found a higher incidence of infection for AHSCT compared to both alemtuzumab and noninduction therapies. The incidence of nonthyroid autoimmune disease was low for both therapies.Classification of evidence This study provides Class III evidence of an increased risk of thyroid disease with alemtuzumab and an increased risk of infection with AHSCT treatment.
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| 8. |
- Alping, Peter, et al.
(författare)
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Safety of Alemtuzumab and Autologous Hematopoietic Stem Cell Transplantation Compared to Noninduction Therapies for Multiple Sclerosis
- 2021
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 96:11
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Tidskriftsartikel (refereegranskat)abstract
- Objective To assess safety outcomes for the induction therapies alemtuzumab and autologous hematopoietic stem cell transplantation (AHSCT) compared to noninduction disease-modifying therapies. Methods We performed a population-based cohort study linking the Swedish Multiple Sclerosis Register to national health care registers. Alemtuzumab, AHSCT, and a matched reference group of noninduction therapies (natalizumab, dimethyl fumarate, rituximab, fingolimod) were included if started between 2008 and 2017. Main outcomes were death, thyroid disease, nonthyroid autoimmune disease, and infection. Results We identified 132 alemtuzumab-treated and 139 AHSCT-treated (68% high-dose cyclo-phosphamide and anti-thymocyte globulin [ATG], 32% BCNU, etoposide, cytosine-arabinoside, and melphalan/ATG) patients, together with 2,486 matched patients treated with noninduction therapies. Four patients in the alemtuzumab group died (incidence rate [IR] per 1,000 person-years 8.6, 95% confidence interval [CI] 2.3-22.0) compared to 1 patient in the AHSCT group (IR 1.7, 95% CI 0.0-9.6), and the mortality rate in the reference group was 0.7 (95% CI 0.3-1.3). Thyroid disease was most frequent in the alemtuzumab group (IR 109, 95% CI 75-154) but also occurred more often for AHSCT (IR 34, 95% CI 18-56) compared to the reference (IR 5.3 95% CI 3.9-7.1). The incidence of nonthyroid autoimmune disease was similar in all groups. IR for infection diagnosed >= 6 months from therapy initiation was 53 (95% CI 30-87) for alemtuzumab, 108 (95% CI 75-150) for AHSCT, and 51 (95% CI 46-57) for the reference. Conclusion We confirmed a high incidence of thyroid disease in alemtuzumab- and, to a smaller extent, AHSCT-treated patients and found a higher incidence of infection for AHSCT compared to both alemtuzumab and noninduction therapies. The incidence of nonthyroid autoimmune disease was low for both therapies. Classification of evidence This study provides Class III evidence of an increased risk of thyroid disease with alemtuzumab and an increased risk of infection with AHSCT treatment.
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| 9. |
- de Boniface, Jana, et al.
(författare)
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Completion axillary lymph node dissection for the identification of pN2–3 status as an indication for adjuvant CDK4/6 inhibitor treatment : a post-hoc analysis of the randomised, phase 3 SENOMAC trial
- 2024
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Ingår i: The Lancet Oncology. - : Elsevier. - 1470-2045 .- 1474-5488. ; 25:9, s. 1222-1230
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Tidskriftsartikel (refereegranskat)abstract
- Background: In luminal breast cancer, adjuvant CDK4/6 inhibitors (eg, abemaciclib) improve invasive disease-free survival. In patients with T1–2, grade 1–2 tumours, and one or two sentinel lymph node metastases, completion axillary lymph node dissection (cALND) is the only prognostic tool available that can reveal four or more nodal metastases (pN2–3), which is the only indication for adjuvant abemaciclib in this setting. However, this technique can lead to substantial arm morbidity in patients. We aimed to pragmatically describe the potential benefit and harm of this strategy on the individual patient level in patients from the ongoing SENOMAC trial.Methods: In the randomised, phase 3, SENOMAC trial, patients aged 18 years or older, of any performance status, with clinically node-negative T1–T3 breast cancer and one or two sentinel node macrometastases from 67 sites in five European countries (Denmark, Germany, Greece, Italy, and Sweden) were randomly assigned (1:1), via permutated block randomisation (random block size of 2 and 4) stratified by country, to either cALND or its omission (ie, they had a sentinel lymph node biopsy only). The primary outcome is overall survival, which is yet to be reported. In this post-hoc analysis, patients from the SENOMAC per-protocol population, with luminal oestrogen-receptor positive, HER2-negative, T1–2, histological grade 1–2 breast cancer, with tumour size of 5 cm or smaller were selected to match the characteristics of cohort 1 of the monarchE trial who would only have an indication for adjuvant abemaciclib if found to have 4 or more nodal metastases. The primary study objective was to determine the number of patients who developed patient-reported severe or very severe impairment of physical arm function after cALND (as measured by the Lymphedema Functioning, Disability, and Health [Lymph-ICF] Questionnaire) 1 year after surgery to avoid one invasive disease-free survival event at 5 years with 2 years of adjuvant abemaciclib, using invasive disease-free survival event data from cohort 1 of the monarchE trial. The SENOMAC trial is registered with ClincialTrials.gov, NCT02240472, and is closed to accrual and ongoing.Findings: Between Jan 31, 2015, and Dec 31, 2021, 2766 patients were enrolled in SENOMAC and randomly assigned to cALND (n=1384) or sentinel node biopsy only (n=1382), of whom 2540 were included in the per-protocol population. 1705 (67%) of 2540 patients met this post-hoc study's eligibility criteria, of whom 802 (47%) had a cALND and 903 (53%) had a sentinel lymph node biopsy only. Median age at randomisation was 62 years (IQR 52–71), 1699 (>99%) of 1705 patients were female, and six (<1%) were male. Among 1342 patients who responded to questionnaires, after a median follow-up of 45·2 months (IQR 25·6–59·8; data cutoff Nov 17, 2023), patient-reported severe or very severe impairment of physical arm function was reported in 84 (13%) of 634 patients who had cALND versus 30 (4%) of 708 who had sentinel lymph node biopsy only (χ2 test p<0·0001). To avoid one invasive disease-free survival event at 5 years with adjuvant abemaciclib, cALND would need to be performed in 104 patients, and would result in nine patients having severe or very severe impairment of physical arm function 1 year after surgery.Interpretation: As a method to potentially identify an indication for abemaciclib, and subsequently avoid invasive disease-free survival events at 5 years with 2 years of adjuvant abemaciclib, cALND carries a substantial risk of severe or very severe arm morbidity and so cALND should be discouraged for this purpose. Funding: Swedish Research Council, the Swedish Cancer Society, the Nordic Cancer Union, and the Swedish Breast Cancer Association.
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| 10. |
- Gahm, Jessica, et al.
(författare)
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Effectiveness of single vs multiple doses of prophylactic intravenous antibiotics in implant-based breast reconstruction : A randomized clinical trial
- 2022
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Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 5:9
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Multiple-dose antibiotic prophylaxis is widely used to prevent infection after implant-based breast reconstruction despite the lack of high-level evidence regarding its clinical benefit.Objective: To determine whether multiple-dose antibiotic prophylaxis is superior to single-dose antibiotic prophylaxis in preventing surgical site infection (SSI) after implant-based breast reconstruction.Design, Setting, and Participants: This prospective, multicenter, randomized clinical superiority trial was conducted at 7 hospitals (8 departments) in Sweden from April 25, 2013, to October 31, 2018. Eligible participants were women aged 18 years or older who were planned to undergo immediate or delayed implant-based breast reconstruction. Follow-up time was 12 months. Data analysis was performed from May to October 2021.Interventions: Multiple-dose intravenous antibiotic prophylaxis extending over 24 hours following surgery, compared with single-dose intravenous antibiotic. The first-choice drug was cloxacillin (2 g per dose). Clindamycin was used (600 mg per dose) for patients with penicillin allergy.Main Outcomes and Measures: The primary outcome was SSI leading to surgical removal of the implant within 6 months after surgery. Secondary outcomes were the rate of SSIs necessitating readmission and administration of intravenous antibiotics, and clinically suspected SSIs not necessitating readmission but oral antibiotics.Results: A total of 711 women were assessed for eligibility, and 698 were randomized (345 to single-dose and 353 to multiple-dose antibiotics). The median (range) age was 47 (19-78) years for those in the multiple-dose group and 46 (25-76) years for those in the single-dose group. The median (range) body mass index was 23 (18-38) for the single-dose group and 23 (17-37) for the multiple-dose group. Within 6 months of follow-up, 30 patients (4.3%) had their implant removed because of SSI. Readmission for intravenous antibiotics because of SSI occurred in 47 patients (7.0%), and 190 women (27.7%) received oral antibiotics because of clinically suspected SSI. There was no significant difference between the randomization groups for the primary outcome implant removal (odds ratio [OR], 1.26; 95% CI, 0.69-2.65; P = .53), or for the secondary outcomes readmission for intravenous antibiotics (OR, 1.18; 95% CI, 0.65-2.15; P = .58) and prescription of oral antibiotics (OR, 0.72; 95% CI, 0.51-1.02; P = .07). Adverse events associated with antibiotic treatment were more common in the multiple-dose group than in the single-dose group (16.4% [58 patients] vs 10.7% [37 patients]; OR, 1.64; 95% CI, 1.05-2.55; P = .03).Conclusions and Relevance: The findings of this randomized clinical trial suggest that multiple-dose antibiotic prophylaxis is not superior to a single-dose regimen in preventing SSI and implant removal after implant-based breast reconstruction but comes with a higher risk of adverse events associated with antibiotic treatment.Trial Registration: EudraCT 2012-004878-26.
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