Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non-inferiority trial.

BACKGROUND: Multiple sclerosis typically has onset in young adults and new disease activity diminishes with age. Most clinical trials of disease-modifying therapies for multiple sclerosis have not enrolled individuals older than 55 years. Observational studies suggest that risk of return of disease activity after discontinuation of a disease-modifying therapies is greatest in younger patients with recent relapses or MRI activity. We aimed to determine whether risk of disease recurrence in older patients with no recent disease activity who discontinue disease-modifying therapy is increased compared to those who remain on disease-modifying therapy. METHODS: DISCOMS was a multicentre, randomised, controlled, rater-blinded, phase 4, non-inferiority trial. Individuals with multiple sclerosis of any subtype, 55 years or older, with no relapse within the past 5 years or new MRI lesion in the past 3 years while continuously taking an approved disease-modifying therapy were enrolled at 19 multiple sclerosis centres in the USA. Participants were randomly assigned (1:1 by site) with an interactive response technology system to either continue or discontinue disease-modifying therapy. Relapse assessors and MRI readers were masked to patient assignment; patients and treating investigators were not masked. The primary outcome was percentage of individuals with a new disease event, defined as a multiple sclerosis relapse or a new or expanding T2 brain MRI lesion, over 2 years. We assessed whether discontinuation of disease-modifying therapy was non-inferior to continuation using a non-inferiority, intention-to-treat analysis of all randomly assigned patients, with a predefined non-inferiority margin of 8%. This trial is registered at ClinicalTrials.gov, NCT03073603, and is completed. FINDINGS: 259 participants were enrolled between May 22, 2017, and Feb 3, 2020; 128 (49%) were assigned to the continue group and 131 (51%) to the discontinue group. Five participants were lost to follow-up (continue n=1, discontinue n=4). Six (4·7%) of 128 participants in the continue group and 16 (12·2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years. The difference in event rates was 7·5 percentage points (95% CI 0·6-15·0). Similar numbers of participants had adverse events (109 [85%] of 128 vs 104 [79%] of 131) and serious adverse events (20 [16%] vs 18 [14%]), but more adverse events (422 vs 347) and serious adverse events (40 vs 30) occurred in the discontinue group. The most common adverse events were upper respiratory infections (20 events in 19 [15%] participants in the continue group and 37 events in 30 [23%] participants in the discontinue group). Three participants in the continue group and four in the discontinue group had treatment-related adverse events, of which one in each group was a serious adverse event (multiple sclerosis relapse requiring admission to hospital). One participant in the continue group and two in the discontinue group died; no deaths were deemed to be related to treatment. INTERPRETATION: We were unable to reject the null hypothesis and could not conclude whether disease-modifying therapy discontinuation is non-inferior to continuation in patients older than 55 years with multiple sclerosis and no recent relapse or new MRI activity. Discontinuation of disease-modifying therapy might be a reasonable option in patients older than 55 years who have stable multiple sclerosis, but might be associated with a small increased risk of new MRI activity. FUNDING: Patient-Centered Outcomes Research Institute and the National Multiple Sclerosis Society.

Tolerability and Safety of Switching from Rituximab to Ocrelizumab: Evaluating Factors Associated with Infusion Related Reactions.

BACKGROUND: Ocrelizumab and rituximab are frequently used treatments for multiple sclerosis (MS). Data on switching from rituximab to ocrelizumab is limited. OBJECTIVES: To assess the frequency, severity, and factors of infusion related reactions (IRRs) in patients with MS who switch from rituximab to ocrelizumab, compared to those who stay on rituximab. METHODS: Prospective study on MS patients aged 18-65, on rituximab for at least 2 cycles, who either switched to ocrelizumab (switch group) or stayed on rituximab (comparator group) (n = 100 each). Participants were followed for IRRs, safety, and tolerability over 12 months. RESULTS: The proportion of IRRs in patients who continue on rituximab (14%) were similar to those who switched to ocrelizumab on Day 1 (14%; p = 1.000) and Week 24 (12%; p = 0.647) but higher than at Day 15 (4%; 0.005). The risk of IRRs for the switch group was associated with the presence of B cells (CD19 and/or CD20 counts ≥1%) increasing by 5.01 (1.49, 16.82) times on Day 1 (p = 0.007). Antidrug antibodies to ocrelizumab were not associated with IRRs. No other safety concerns were identified in switching to ocrelizumab. CONCLUSION: IRRs are similar between both groups, which suggests that it is safe to switch from rituximab to ocrelizumab.

Brain atrophy rates in patients with multiple sclerosis on long term natalizumab resembles healthy controls.

BACKGROUND: Clinically stable multiple sclerosis (MS) patients often have negligible inflammatory MRI changes. Brain atrophy may provide insight into subclinical disease progression. The objective was to compare brain atrophy rates in stable patients on long term natalizumab treatment vs. age and gender matched healthy non-MS controls (HC) prospectively over two-years examining brain volume, cognition, and patient reported outcomes (PROs). METHODS: MS patients treated with natalizumab for a minimum of 2 years, age 18-60 were recruited and compared with age- and gender-matched healthy controls (HC). Both groups were followed prospectively to obtain two years of consecutive magnetic resonance imaging, clinical and PRO data. Baseline normalized brain volume (NBV), yearly T2 lesion volume (T2LV), and percent brain volume change (PBVC) were measured using SIENAX, JIM 6.0, and SIENA respectively. Neuropsychological tests from the MACFIMS battery were selected to optimize assessments for impairments in the domains of information processing speed and memory. Patient reported outcomes (PROs) for domains of physical, mental and social quality of life were evaluated using the NeuroQol short forms. RESULTS: Forty-eight natalizumab and 62 HC completed all study visits. At baseline, unadjusted mean NBV (natalizumab=1508.80cm (Popescu et al., 2013) vs. HC=1539.23cm (Popescu et al., 2013); p=0.033) and median baseline T2LV (natalizumab=1724.62mm (Popescu et al., 2013) vs. HC=44.20mm (Popescu et al., 2013); p=<0.0001) were different. The mean PBVC at year 2, adjusted for gender and baseline age was -0.57% (CI: 0.7620, -0.3716) for natalizumab and -0.50% (-0.7208, -0.2831) for HC, but the difference between groups was not statistically significant (0.073%; p=0.62). Over the 2-year period, HC demonstrated mild improvements in some cognitive tests vs. natalizumab subjects. However, PROs were similar between the two groups. CONCLUSION: Stable MS patients on natalizumab have similar brain volume loss as people who do not have MS, suggesting normalization of brain atrophy.

Brain Atrophy Rates for Stable Multiple Sclerosis Patients on Long-Term Fingolimod versus Glatiramer Acetate.

Background: Clinically stable multiple sclerosis (MS) patients on long-term therapy often have negligible acute inflammation on MRI. Brain atrophy may provide insight into subclinical disease progression in such populations. Objective: This study aims to compare brain atrophy for age- and gender-matched MS patients treated for >2 years with fingolimod (FTY) or glatiramer acetate (GA), examining brain volume, cognition, and patient-reported outcomes (PROs). Methods: Stable relapsing-MS patients, age 18-60, on FTY or GA for >2 years were followed up for 2 years. MRI brain and lesion volumes, cognitive measures, and PROs were collected at baseline and annually. Results: Forty-four FTY and forty-three GA patients completed baseline and year 2 visits. No differences in age, gender, or education were observed. Median EDSS was 2.0GA and 2.5FTY (p = 0.22). Treatment duration was longer for GA, 6.50GA vs. 3.73FTY years (p < 0.001). Baseline geometric mean T2LV were different, GA = 1,009.29 cm3 vs. FTY = 2,404.67 cm3 (p = 0.0071). Baseline brain volumes were similar, GA = 1,508 cm3 vs. FTY = 1,489 cm3 (p = 0.2381). Annualized atrophy rates, adjusted for baseline and at mean baseline value, were GA = -0.2775% vs. FTY = -0.2967% (p = 0.7979). No differences in cognitive measures or PROs were observed. Conclusions: Stable MS patients on long-term treatment with FTY and GA have similar brain volume loss rates. Differences in baseline disease severity may suggest patients with more aggressive disease treated with FTY may achieve similar brain volume loss rates as patients with milder baseline disease on GA.

Integration of Catholic Values and Professional Obligations in the Provision of Family Planning Services: A Qualitative Study.

Importance: Religious leaders of the Catholic church created guidelines for practicing medicine, that involve reproductive care restrictions that may conflict with professional obligations. Objective: To explore how Catholic obstetrician-gynecologists integrate their religious values and professional obligations related to family planning services. Design, Setting, and Participants: In this qualitative investigation, in 2018, US-based obstetrician-gynecologists were recruited through an online survey and were invited to participate in audio-recorded telephone interviews using a semistructured interview guide. Participants were obstetrician-gynecologists who self-identified as Catholic and reported providing reproductive health care as follows: (1) provide natural family planning only (low practitioners), (2) provide additional contraceptive methods (moderate practitioners), and (3) provide family planning services including abortion (high practitioners). The study purposively sampled those with higher self-reported religiosity. Data were analyzed from November 2018 to February 2019. Main Outcomes and Measures: The primary outcome was understanding how participants describe integration of Catholic values with family planning service provision. The telephone interviews explored their integration of Catholic values and professional obligations, and 3 coders analyzed the responses using grounded theory. Results: Among the 34 Catholic obstetrician-gynecologists interviewed (27 women [79.4%]), there were 10 low, 15 moderate, and 9 high practitioners from 19 states. Participants' description of morality was consistent with Albert Bandura's Social-Cognitive Theory of Moral Thought and Action. The findings were used to create a modified framework. Within each group of physicians, 3 themes demonstrating their reconciliations between Catholic values and professional obligations emerged; each of these themes reflected one of the medical ethical principles of autonomy, beneficence, nonmaleficence, or justice. All 10 low practitioners primarily promoted natural family planning approaches to avoid iatrogenic risks and none provided abortion, reflecting nonmaleficence. Alternatively, moderate practitioners focused on nonmaleficence by offering contraception to prevent abortions. High practitioners primarily promoted patient autonomy by separating religious doctrine from medical practice. All had concerns for beneficence. In each group, 1 of the 4 medical ethical principles was underrepresented. Conclusions and Relevance: In this qualitative analysis, Catholic obstetrician-gynecologists establish their family planning care provision practices by emphasizing certain moral and/or ethical principles over others. These findings highlight how physician morality in the realm of family planning service provision often involves certain religious and/or professional reconciliations. Understanding the dilemmas Catholic obstetrician-gynecologists face can guide professional development efforts and inform ongoing discussions about conscientious objection and provision.

Validation of the functional assessment of chronic illness therapy - General treatment satisfaction (FACIT-TS-G) in multiple sclerosis.

BACKGROUND: Patient-reported treatment satisfaction is associated with medication adherence and persistence, making it increasingly important in the multiple sclerosis (MS) population, where disease modifying treatments (DMTs) can be vital in preventing accumulation of disability. Therefore, the valid assessment of treatment satisfaction is critical in MS care. The current study aimed to examine the validity of the Functional Assessment of Chronic Illness Therapy - General Treatment Satisfaction (FACIT-TS-G) in an MS population. METHODS: Patient-reported outcome (PRO) data were collected from 555 MS patients (mean age 47.99±11.57; 76.4% female; 78.7% White/Caucasian) as part of routine clinical care. The FACIT-TS-G reliability, validity, and factor structure were examined. FACIT-TS-G scores were compared between DMT administration type (oral, injection, infusion) and examined as a possible predictor of switching DMT type at 1-to-2-year follow-up. RESULTS: The FACIT-TS-G showed good internal consistency (Cronbach's α=0.836), convergent validity, and known-group validity. Confirmatory factor analyses supported a single factor. DMT infusion administration was associated with slightly greater FACIT-TS-G scores than injection (p = 0.013, 95% CI: 0.269, 2.273) and oral administration (p = 0.030, 95% CI: 0.087, 1.717). FACIT-TS-G scores did not predict the likelihood of switching DMT type at follow-up (p>0.05). CONCLUSION: Our findings support the use of the FACIT-TS-G as a PRO measure of treatment satisfaction in MS. Moreover, results suggest DMT administration via infusion is associated with greater treatment satisfaction. Future research is needed to examine treatment satisfaction in the context of other outcomes.

A pilot study on the effect of isotretinoin on serum etonogestrel concentrations in contraceptive implant users.

OBJECTIVE: To explore the pharmacokinetic interaction between isotretinoin, a cytochrome P-450 (CYP) inducer and potent teratogen, and the etonogestrel contraceptive implant. STUDY DESIGN: We enrolled healthy reproductive-age women initiating isotretinoin and using an etonogestrel implant. We compared serum etonogestrel concentrations at baseline and after four and nine weeks of isotretinoin co-administration using a validated assay. RESULTS: Among eight implant users, all serum etonogestrel concentrations remained >90 pg/mL during isotretinoin co-administration with no significant changes from baseline (p = 0.25, Friedman's test). CONCLUSION: In this exploratory study, we found that isotretinoin did not cause serum etonogestrel concentrations to fall below the threshold for ovulatory suppression (<90 pg/mL) among implant users. IMPLICATIONS: Reproductive-age women treated with isotretinoin require reliable contraception to prevent pregnancies impacted by teratogenic-effects. This small study demonstrates that contraceptive implant users maintained serum etonogestrel concentrations above the threshold for consistent ovulatory suppression during isotretinoin co-administration. The contraceptive implant remains an appropriate option for patients considering isotretinoin therapy.

Unintentional IUD expulsion with concomitant menstrual cup use: a case series.

Although reproductive-aged women use both menstrual cups and intrauterine devices (IUDs) simultaneously, it is unknown whether concomitant use reduces contraceptive effectiveness. We report seven cases wherein IUD expulsion occurred during concomitant menstrual cup use. Further research is needed to determine mechanisms of expulsion, predictors and strategies to avoid expulsions.