Return Of Disease Activity Research Articles

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

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. 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. 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. 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. Patient-Centered Outcomes Research Institute and the National Multiple Sclerosis Society.

Natalizumab Pharmacokinetics and -Dynamics and Serum Neurofilament in Patients With Multiple Sclerosis

Background: Natalizumab (NAT) is a high-efficacy treatment for relapsing remitting multiple sclerosis (RRMS). However, it is associated with an increased risk of progressive multifocal leukoencephalopathy that sometimes requires treatment cessation with a risk of returning disease activity. The aim of this study was to characterize the pharmacokinetics and -dynamics as well as neurodestruction marker serum neurofilament light chain (sNfL) in patients with RRMS and secondary progressive MS (SPMS) stopping NAT in correlation to clinical data.Methods: In this study, 50 RRMS and 9 SPMS patients after NAT cessation were included. Five RRMS patients on NAT treatment holiday were evaluated. Clinical and radiological disease activity were systemically assessed by frequent exams after NAT stop. Free NAT concentration, cell bound NAT, α4-integrin expression and α4-integrin-receptor saturation as well as immune cell frequencies were measured for up to 4 months after NAT withdrawal. Additionally, sNfL levels were observed up to 12 months in RRMS and up to 4 months in SPMS patients.Results: NAT cessation was associated with a return of disease activity in 38% of the RRMS and 33% of the SPMS patients within 12 and 7 months, respectively. Concentration of free and cell bound NAT as well as α4-integrin-receptor saturation decreased in the RRMS and SPMS patients whereas α4-integrin expression increased over time. NAT induced increase of lymphocytes and its subsets normalized and a non-significant drop of NK and Th17 T-cells counts could be detected. All RRMS patients showed physiological sNfL levels <8pg/ml 1 month after last NAT infusion. During follow-up period sNfL levels peaked up to 16-fold and were linked to return of disease activity in 19 of the 37 RRMS patients. Treatment holiday was also associated with a return of disease activity in 4 of 5 patients and with an increase of sNfL at an individual level.Conclusions: We demonstrate the reversibility of NAT pharmacodynamic and -kinetic markers. sNfL levels are associated with the recurrence of disease activity and can also serve as an early marker to predict present before onset of clinical or radiological disease activity on the individual level.

Clinical outcomes in patients who discontinue natalizumab therapy after 2 years in the Tysabri® Observational Program (TOP)

Background: Natalizumab is a highly efficacious therapy for relapsing–remitting multiple sclerosis (RRMS). Patients who discontinue natalizumab may experience return of MS disease activity. Objective: The aim of this study was to analyze predictors of post-natalizumab disease activity return. Methods: The Tysabri® Observational Program (TOP) is an ongoing observational study of natalizumab-treated RRMS patients. Patients discontinuing natalizumab are encouraged to remain in TOP. Results: Analyses included 3221 TOP patients. After ⩾2 years on natalizumab, relapse risk was twice as high for patients who switched to an oral therapy (n = 660, hazard ratio (HR) = 2.18, p < 0.001) and three times as high for patients who switched to an injectable therapy (n = 95, HR = 3.02, p < 0.001) as for those who stayed on natalizumab (n = 2466). Relapse rates after switching remained below pre-natalizumab rates. In patients who switched to an oral therapy, higher relapse risk was predicted by longer washout time, more pre-natalizumab relapses, higher Expanded Disability Status Scale score at natalizumab initiation, and shorter natalizumab treatment duration. Conclusion: Patients who stayed on natalizumab had better clinical outcomes than those who switched to an oral or injectable therapy after ⩾2 years on natalizumab. These results highlight modifiable risk factors for disease activity return (e.g. natalizumab treatment duration and washout duration) to consider when making treatment decisions.

Effect of short-term methotrexate discontinuation on rheumatoid arthritis disease activity: post-hoc analysis of two randomized trials

To investigate the effects of short-term discontinuation of methotrexate (MTX) on disease activity in patients with rheumatoid arthritis (RA) taking a stable dose of MTX. A post-hoc analysis of two randomized controlled trials was used to investigate the effects of temporary MTX discontinuation (for 2weeks or 4weeks) on responses to seasonal influenza vaccination. The impact of MTX discontinuation on the RA disease activity score (DAS28) and RA flare rate during discontinuation and after reintroduction was examined. The DAS28 increased during the 4-week MTX discontinuation period, before returning to baseline after reintroduction. The overall flare-free survival period did not differ between the groups (log rank p = 0.142). However, during the 4-week MTX discontinuation period, more patients in the MTX-hold group than in the MTX-continue group experienced a flare (20.5% vs. 7.4%, respectively; p = 0.058). After resumption of MTX, the flare rate did not differ between groups. The flare rates in the MTX-continue group and the 2-week and 4-week MTX-hold groups were 5.8%, 10.8% and 20.5%, respectively (p < 0.01). The change in the DAS28 from baseline did not differ significantly between the MTX-continue and the 2-week MTX-discontinue groups. However, there was a significant difference between the 4-week MTX-hold group and the MTX-continue group (p = 0.005). Short-term discontinuation of MTX for up to 2weeks is safe, whereas discontinuation for 4weeks is associated with a transient increase in disease flares and activity in RA patients taking a stable MTX dose.Key Points• Methotrexate discontinuation for 2weeks is safe.• Methotrexate discontinuation for 4weeks transiently increases flare risk and disease activity.• Disease flare risk and disease activity return to baseline after restarting methotrexate treatment.

Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab

ObjectiveTo examine the association between peripheral blood lymphocyte pharmacodynamics and autoimmune adverse events (AEs) or return of disease activity in alemtuzumab-treated patients with relapsing-remitting MS.MethodsPatients received 2 alemtuzumab courses (12 mg/d IV; 5 days at baseline, 3 days 12 months later) in the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis studies (NCT00530348 and NCT00548405) and could then receive as-needed alemtuzumab or other disease-modifying therapy in a 4-year extension (NCT00930553). Lymphocytes were phenotyped quarterly over 2 years using fluorescence-activated cell sorting. Pharmacodynamic assessments included counts of total lymphocytes, CD3+ T cells, CD4+/CD8+ T cells (total/naive/memory/regulatory [Treg]), and CD19+ B cells (total/immature/mature/memory) and ratios of CD19+ (total/immature/mature/memory) to Treg (CD4+/CD8+) counts. Assessed autoimmune AEs included immune thrombocytopenia, nephropathies, and thyroid events. Efficacy assessments included relapses, 6-month confirmed disability worsening (CDW), and MRI disease activity.ResultsLymphocyte repopulation patterns, including ratios between distinct lymphocyte subsets (e.g., CD19+ to Treg cell count ratios), showed no significant differences over 2 years in patients developing/not developing autoimmune AEs, relapses, CDW, or MRI activity through 6 years following alemtuzumab. Lymphocyte kinetics were also unrelated to multiple autoimmune AEs or extreme clinical phenotypes.ConclusionsRepopulation kinetics of the evaluated peripheral lymphocyte subsets did not predict autoimmune AE occurrence or disease activity, including return of disease activity after 2 alemtuzumab courses. Further study is needed to investigate potential antigen-level markers of treatment response.

Analysis of disease activity return after natalizumab withdrawal in multiple sclerosis (P3.2-069)

Analysis of disease activity return after natalizumab withdrawal in multiple sclerosis (P3.2-069)

Reducing return of disease activity in patients with relapsing multiple sclerosis transitioned from natalizumab to teriflunomide: 12-month interim results of teriflunomide therapy.

BackgroundNatalizumab is an effective treatment for relapsing multiple sclerosis. Return of disease activity upon natalizumab discontinuance creates the need for follow-up therapeutic strategies.ObjectiveTo assess the efficacy of teriflunomide following natalizumab discontinuance in relapsing multiple sclerosis patients.MethodsClinically stable relapsing multiple sclerosis patients completing 12 or more consecutive months of natalizumab, testing positive for anti-John Cunningham virus antibody, started teriflunomide 14 mg/day, 28 ± 7 days after their final natalizumab infusion. Physical examination, Expanded Disability Status Scale, laboratory assessments, and brain magnetic resonance imaging were performed at screening and multiple follow-up visits.ResultsFifty-five patients were enrolled in the study. The proportion of patients relapse-free was 0.94, restricted mean time to first gadolinium-enhancing lesion was 10.9 months and time to 3-month sustained disability worsening was 11.8 months. The mean number of new or enlarging T2 lesions per patient at 12 months was 0.42. Exploratory analyses revealed an annualized relapse rate of 0.08, and a proportion of patients with no evidence of disease activity of 0.68. Forty-seven patients (85.5%) reported adverse events, 95% of which were mild to moderate.ConclusionsTeriflunomide therapy initiated without natalizumab washout resulted in a low rate of return of disease activity. Clinicians may consider this a worthwhile strategy when transitioning clinically stable patients off natalizumab to another therapy.ClinicalTrials.gov Identifier: NCT01970410

Longer duration of natalizumab exposure may lessen return of disease activity following a switch from natalizumab to an oral therapy: modelling real-world data from relapsing-remitting multiple sclerosis (RRMS) patients in the TYSABRI® Observational Program (TOP) (P6.379)

Longer duration of natalizumab exposure may lessen return of disease activity following a switch from natalizumab to an oral therapy: modelling real-world data from relapsing-remitting multiple sclerosis (RRMS) patients in the TYSABRI® Observational Program (TOP) (P6.379)

α4-integrin receptor desaturation and disease activity return after natalizumab cessation.

Objective:To describe the time course of α4-integrin receptor desaturation and disease activity return in patients with relapsing-remitting MS who discontinued natalizumab and to investigate baseline and on-study predictors for the recurrence of disease activity.Methods:In the course of TOFINGO, a 32-week, patient- and rater-blinded multicenter, parallel-group study, we performed MRI, counted relapses, and measured α4-integrin receptor occupancy (RO) at baseline and 8, 12, 16, 20, and 24 weeks. The relationship between RO and total number of new T1 gadolinium-enhancing (Gd+) lesions was modeled using Poisson linear regression.Results:Patients (N = 142) were randomized (1:1:1) to 8-, 12-, or 16-week washout (WO) groups. At randomization, the median RO in the 8-, 12-, and 16-week WO groups was 94.5%, 92.4%, and 90.9%, which declined to 79.8%, 30.7%, and 8.7% after 8, 12, and 16 weeks of WO, respectively. The percentage of patients with new T1 Gd+ lesions increased with longer WO period before commencing fingolimod: 2.1% (8 weeks), 9.1% (12 weeks), and 50.0% (16 weeks). Overall, 71% of patients with first relapse between weeks 6 and 18 had RO values below the time-matched population median. Higher T2 lesion volume (LV) at baseline predicted a higher number of new T1 Gd+ lesions.Conclusions:A faster decline in natalizumab RO, longer WO period, and higher T2 LV at baseline were associated with an increased risk for return of inflammatory disease activity. These results provide a mechanistic rationale and, together with the main outcomes of the TOFINGO study, support initiation of fingolimod within 8 weeks of natalizumab discontinuation.ClinicalTrials.gov identifier:NCT01499667.

Rescue of severe brain and cervical cord IRIS by restarting natalizumab in a pregnant MS patient

Natalizumab inhibits lymphocyte trafficking across the blood–brain barrier, reducing relapse rates by up to 70% in patients with relapsing-remitting multiple sclerosis (RRMS). Discontinuation of the drug, usually due to pregnancy or risk of progressive multifocal leukoencephalopathy (PML), can trigger the return of disease activity or, occasionally, a fulminant immune reconstitution inflammatory syndrome (IRIS) as lymphocytes re-enter the CNS.1–3 Acknowledgment: The authors thank the patient and her family for their assistance with this report.

SP0187 How do we combine modern imaging in the RA remission criteria?

The above title, (kindly provided by the planning committee) carries some duplicity. Two main topics come to mind:“Is better classification of remission possible if we use modern imaging techniques?” And:“How...

FRI0217 Extended drug interval trial to clarify the efficacy of tocilizumab after stable status in

BackgroundWe previously used MMP3 and CDAI, composite measures that do not include acute-phase protein – thatis, CRP/ESR – to study the results of 52 weeks of routine clinical treatment with...

AB0514 Extended drug interval trial to clarify the efficacy of tocilizumab after stable status in patients with rheumatoid arthritis

BackgroundWe previously used MMP3 and CDAI, composite measures that do not include acute-phase protein – that is, CRP/ESR – to study the results of 52 weeks of routine clinical treatment...

Natalizumab Discontinuation: Observational Study of University of Colorado Patients with Relapsing-Remitting Multiple Sclerosis (P06.170)

Objective: Evaluate disease activity among relapsing remitting multiple sclerosis patients during transition off natalizumab therapy. Background Natalizumab (NTZ) is an effective disease modifying drug (DMD) for treatment of relapsing-remitting multiple sclerosis (RRMS)¹. Patients discontinue NTZ for many reasons, including increased risk of progressive multifocal leukoencephalopathy (PML)². Many studies have demonstrated marked increases in gadolinium enhancing (Gd+) lesions and clinical activity among a subset of patients after NTZ withdrawal³. In our retrospective study, we characterized disease activity among patients with RRMS who transitioned off of NTZ. Design/Methods: Seventy-six patients were followed clinically and radiographically over 6 months following NTZ withdrawal. Decision to discontinue NTZ included increased or continued disease activity, adverse events, JCV seropositive status, and the decision to become pregnant. Alternative treatments were initiated after NTZ discontinuation (interferon-β 1a or -β 1b, glatiramer acetate, fingolimod, rituximab, pulsed steroids, or none). Intervals between NTZ discontinuation and start of alternative therapies were documented. Results: Thirty-seven subjects had return of clinical activity (relapse) following NTZ withdrawal. Median time to relapse after NTZ discontinuation was 3 months. Among relapses, the median time between NTZ discontinuation and initiation of an alternative DMD was 0.5 months. Nine severe relapses, defined as disease activity more than 2-fold higher than pre-NTZ were observed (MRI: average pre-NTZ = 0.5 Gd+ lesions; average post-NTZ withdrawal = 7.6 Dd+ lesions). Conclusions: Return of disease activity was noted clinically and radiographically. Disease activity increases within the first 3 months after NTZ discontinuation and is associated with increased time to alternative therapy. More studies are needed to identify patients at risk for increased disease activity in order to develop protocols that minimize disease burden following NTZ discontinuation. We will continue to evaluate the association of disease activity and choice of alternative DMD, duration of NTZ therapy, and interval between discontinuation of NTZ and initiation of alternative therapy. Disclosure: Dr. Nnunukwe has nothing to disclose. Dr. Schreiner has nothing to disclose.

Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis

The correspondence this week highlights controversial points in 2 recently published articles. Dr. Rammohan and colleagues disagree with the findings of Dr. O'Connor et al. that, after discontinuation of natalizumab therapy, multiple sclerosis (MS) disease activity returns to baseline levels without rebound, based partly on methodologic concerns. In his response, Dr. O'Connor clarifies the study's methodology and justifies the conclusions. In reference to another study, Drs. Mascitelli and Goldstein question the conclusion that statins are beneficial in young patients with strokes of unknown etiology based on other literature showing that higher cholesterol is associated with decreased stroke severity and poststroke mortality. Putaala et al. contend that their study focused on reducing future vascular events rather than stroke outcomes and that their data show a …

Pulse monthly steroids during an elective interruption of natalizumab: a post‐marketing study

Temporary discontinuation of natalizumab is sometimes considered as the observed risk of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS). However, interruption of natalizumab may result in a re-start of disease activity. In this prospective post-marketing study, 23 patients with MS treated with natalizumab elected a trial of treatment interruption (90-150 days) because of safety concerns on the risk of developing PML. To reduce the risk of disease activity return, patients received monthly intravenous (i.v.) steroid pulses before natalizumab re-start. Despite the steroid coverage, seven patients (30.4%) had an active scan during the natalizumab interruption period; of these, four also had a concomitant clinical exacerbation. Our findings suggest that i.v. steroids are not currently recommendable as drug coverage during a scheduled treatment interruption period.

What happens when natalizumab therapy is stopped?

Evaluation of: O’Connor PW, Goodman A, Kappos L et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 76(22), 1858–1865 (2011).Natalizumab is an α-4 integrin antagonist used for the treatment of relapsing multiple sclerosis (MS). Concerns with the drug have a risen owing to a heightened risk of progressive multifocal leukoencephalopathy, which has caused some physicians to interrupt or stop treatment altogether. The article under review evaluates the safety of natalizumab treatment interruption, including the rate and magnitude of the return of MS disease activity toward baseline levels by clinical and MRI measures. The investigators found that by 4–7 months after natalizumab treatment interruption, MS disease activity began to reach baseline levels, which is consistent with the known elimination kinetics of natalizumab. The duration of prior natalizumab exposure or alternate MS treatments during interruption was demonstrated to not affect return of disease activity. Despite nearly similar disease activity after natalizumab treatment, patients with highly active disease prior to treatment had a return of disease activity that was greater in magnitude when compared with those with less active disease. Most significantly, the study did not show evidence of rebound following natalizumab cessation. We agree with these conclusions, but note that a subgroup of MS patients may demonstrate highly active disease after natalizumab cessation.

Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis

Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some physicians interrupt treatment of patients with multiple sclerosis (MS) despite a lack of data regarding the safety of treatment interruption, the rate and severity of MS disease activity return after treatment interruption, or alternative treatment strategies. To determine the effects of natalizumab treatment interruption on clinical and MRI measures of disease activity in relapsing patients with MS. Clinical relapses and gadolinium-enhanced (Gd+) lesions were analyzed over an 8-month period in patients from the AFFIRM, SENTINEL, and GLANCE studies of natalizumab, and their respective safety extension studies, following the voluntary suspension of natalizumab dosing that occurred in February 2005. Relapses were analyzed in 1,866 patients, and Gd+ lesions were analyzed in 341 patients. Annualized relapse rates and Gd+ lesions both increased shortly after natalizumab interruption and peaked between 4 and 7 months. A consistent return of disease activity was observed regardless of overall natalizumab exposure, whether or not patients received alternative MS therapies, and in patients with highly active MS disease. A rebound of relapse or Gd+ lesion activity, beyond placebo-treated levels from the clinical studies, was not observed in any of the analyses conducted. Following interruption of natalizumab treatment, MS disease activity returned in a pattern that was consistent with known pharmacokinetic and pharmacodynamic properties of natalizumab, and did not show evidence of rebound.

Observations during an elective interruption of natalizumab treatment: a post-marketing study

In this prospective post-marketing study, 21 patients with multiple sclerosis treated with natalizumab for 24 consecutive months elected a trial of treatment interruption (90–180 days). During a mean duration of treatment interruption of 111.5 days 4 patients (19.0%) experienced a relapse and 9 out of 19 (47.4%) had MRI activity. Number of contrast-enhancing lesions at baseline was lower than during treatment interruption, but the difference was not significant. These findings suggest that disease activity may return after the last infusion of natalizumab. Patients should have regular MRI assessment during treatment interruption to rapidly identify any return of disease activity. The aim of this study was to determine the optimal duration for temporary interruption of natalizumab therapy in patients who have received continuous therapy with natalizumab for 24 months.

Rituximab Pharmacokinetics in Patients With Rheumatoid Arthritis: B‐Cell Levels Do Not Correlate With Clinical Response

This study characterized the relationship between clinical response, serum rituximab concentrations, and peripheral B-cell levels in patients with rheumatoid arthritis treated with rituximab. Data were analyzed from a double-blind, phase IIa trial in which 161 patients with active rheumatoid arthritis despite continuing methotrexate were randomized to methotrexate alone (10-25 mg/wk), rituximab alone (single course: 1000 mg administered intravenously on days 1 and 15), rituximab plus cyclophosphamide (750 mg administered intravenously on days 3 and 17), or rituximab plus methotrexate. Serum samples for pharmacokinetic analysis were collected through 24 weeks, and peripheral circulating CD19+ B-cell levels were measured through 48 weeks. All treatments were generally well tolerated, with no clinically relevant excess of adverse events leading to withdrawal among patients who received rituximab compared with those who received methotrexate alone. The proportions of patients who achieved an American College of Rheumatology score of 50 at week 24 were 13% (methotrexate alone), 33% (rituximab alone), 41% (rituximab plus cyclophosphamide), and 43% (rituximab plus methotrexate). Peripheral B-cell depletion occurred by day 15 in all patients treated with rituximab. There was no relationship between B-cell depletion and clinical response. Recovery of peripheral B cells was variable and showed no relationship with return of disease activity in patients who responded to rituximab. The mean terminal half-life of rituximab was 19 to 22 days; pharmacokinetic parameters were similar whether rituximab was administered alone or with methotrexate or cyclophosphamide. Because the level of peripherally circulating B cells does not appear to correlate with a maintained clinical response in patients with rheumatoid arthritis, the timing of rituximab retreatment should be based on clinical symptoms rather than peripheral B-cell levels.