Early treatment responses to peginterferon beta-1a are associated with longer-term clinical outcomes in patients with relapsing-remitting multiple sclerosis: Subgroup analyses of ADVANCE and ATTAIN.

BACKGROUND: Early intervention with well-tolerated disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) is recommended in order to delay disease progression, reduce neurologic damage, preserve brain volume, and optimize long-term patient outcomes. Lack of conversion of new/newly enlarging T2 (NET2) or gadolinium-enhancing (Gd+) lesions to chronic hypointensities (black hole conversion) and achievement of no evidence of disease activity (NEDA) early in the course of treatment are considered potential indicators of treatment effect and predictors of longer-term clinical outcomes. METHODS: Patients with RRMS who were treated with peginterferon beta-1a in the 2-year ADVANCE phase 3 clinical trial (NCT0090639) and its 2-year open-label extension study, ATTAIN (NCT01332019), were grouped as newly diagnosed (diagnosed ≤1 year prior to enrollment and DMT naive) or non-newly diagnosed. For analyses of the impact of early treatment and disease activity control, the newly diagnosed and non-newly diagnosed subgroups were further divided based on whether they initiated peginterferon beta-1a every 2 weeks (Q2W) starting in study year 1 (continuously treated) or peginterferon beta-1a Q2W or every 4 weeks in study year 2 (delayed treatment). Patient subgroups were evaluated for conversion of NET2 or Gd+ lesions to persistent black holes (PBHs), brain atrophy (percentage change in whole brain volume [WBV]), achievement of NEDA composite outcomes, and the association of these disease activity measures with longer-term clinical outcomes (annualized relapse rate [ARR] and confirmed disability worsening [CDW]). RESULTS: At 2 years, significantly fewer PBHs developed from NET2 lesions or Gd+ lesions in newly diagnosed and non-newly diagnosed patients continuously treated with peginterferon beta-1a than in the corresponding delayed-treatment groups (all p<0.0001). Percentage decrease in WBV from 6 months (rebaselined) to 2 years was significantly lower for newly diagnosed and non-newly diagnosed patients who received continuous peginterferon beta-1a treatment than for patients who received delayed treatment (both p ≤ 0.0442). In study year 1, a higher proportion of newly diagnosed and non-newly diagnosed patients treated with peginterferon beta-1a than those treated with placebo achieved NEDA (newly diagnosed: 28.3% vs 13.5% [p = 0.0010]; non-newly diagnosed: 40.8% vs 15.8% [p<0.0001]). NEDA rates remained stable over study years 2-4 for the newly diagnosed (range: 50.0%-53.9%) and non-newly diagnosed (range: 54.4%-57.0%) subgroups. Patients without PBH conversion had significantly lower ARR at 2 years (newly diagnosed: p = 0.0109; non-newly diagnosed: p = 0.0044) and a lower proportion of patients with 12-week CDW at 2 years (newly diagnosed: p = 0.2787; non-newly diagnosed: p = 0.0045) than the corresponding patient subgroups with PBH conversion. Patients who achieved NEDA in ADVANCE (study years 1-2) had a significantly lower ARR in ATTAIN (study years 3-4) than patients who did not achieve NEDA (newly diagnosed, p = 0.0003; non-newly diagnosed, p = 0.0001). Over 4 years, safety outcomes did not differ for the newly diagnosed and non-newly diagnosed patient subgroups. CONCLUSIONS: These results indicate that newly diagnosed and non-newly diagnosed patients treated continuously with peginterferon beta-1a Q2W experienced better disease control over time than those who received delayed treatment. Patients with NEDA or evidence of less radiological disease activity in the first 2 years of treatment had better longer-term clinical outcomes than those with evidence of greater disease activity.

Neurosarcoidosis mimicry of MS: Clues from cases with CNS tissue diagnosis.

The clinical picture of neurosarcoidosis (NS) shares many aspects with multiple sclerosis (MS). I examine whether or not clinical measures can reliably distinguish NS mimicking MS from NS coexisting with MS, and the informative role biopsy and autopsy evidence may play in understanding these two disorders. Uniquely challenging, I explore the rare patients presenting with the differential of MS or acute disseminated encephalomyelitis (ADEM) versus NS, including MS or ADEM as an associated illness in patients with systemic sarcoidosis. In most but not all NS patients, red flags against a diagnosis of MS are strong enough to rule out this more common disorder. Biopsy and autopsy findings indicate a tendency of NS granulomatous changes in the CNS to involve the same deep white matter perivascular spaces as expected to occur in MS, and hence correlate with a tendency of NS involving white matter to produce classic MRI findings of MS. The spectrum of NS includes some cases limited to a single anatomical site, including sites classically involved in demyelinating CIS (optic nerve, brainstem, and transverse myelitis). Asymptomatic "non-specific" periventricular MRI changes are described in many studies as "MS-like". No biopsied or autopsied cases have yet proven associated classic pathological changes of MS in patients with NS.

Real world prognosis in MS: does early versus late diagnosis matter?

BACKGROUND: Multiple sclerosis (MS) often presents soon after the onset of a recognized clinically isolated syndrome (CIS). In order to interpret data from CIS trials, it is important to know whether patients presenting as classical CIS provide group data representative of RRMS. OBJECTIVE: We aimed to determine whether or not MS patients presenting soon after the onset of symptoms with clinically isolated syndromes have an identifiable clinical profile, including worse outcomes, versus MS patients presenting later. METHODS: Chart review of consecutive patients with newly diagnosed relapsing MS, diagnosed in our clinic between 1989 and 2005. We divided patients into an early presentation group (EP), versus the remaining late presenting group (LP), and analyzed the impact of delay in presentation on 10- and 15-year disability outcomes. We also sought to identify reasons for later presentation. RESULTS: The two groups were similar in terms of many demographics, clinical risk factors, and long-term disability outcomes (median EDSS 2.25 versus EDSS 2.0 at 10 years). Exceptionally, patients in the EP group had more frequent attacks in the first few years after onset and were diagnosed and treated earlier. CONCLUSIONS: Patients in our MS clinic with EP versus LP were more likely to have multiple attacks in the first 2 years after onset and were treated earlier, but did not have a better 10- or 15-year outcome.

Matching comparisons of therapeutic efficacy suggest better clinical outcomes for patients treated with peginterferon beta-1a than with glatiramer acetate.

BACKGROUND: Peginterferon beta-1a and glatiramer acetate (GA) are approved first-line therapies for the treatment of relapsing forms of multiple sclerosis, but their therapeutic efficacy has not been compared directly. METHODS: Clinical outcomes at 2 years, including no evidence of disease activity (NEDA), for patients receiving peginterferon beta-1a 125 mcg every 2 weeks (Q2W) or GA 20 mg/ml once daily (QD) were compared by propensity score matching analysis using individual patient data from ADVANCE and CONFIRM phase III clinical trials. In addition, clinical outcomes at 1-3 years for patients receiving peginterferon beta-1a Q2W or GA 40 mg/ml three times a week (TIW) were evaluated using a matching-adjusted comparison analysis of individual patient data from ADVANCE and the ADVANCE extension study, ATTAIN, and aggregate patient data from the phase III GALA and the GALA extension studies. RESULTS: Propensity-score-matched peginterferon beta-1a patients (n = 336) had a significantly lower annualized relapse rate [ARR (0.204 versus 0.282); rate ratio = 0.724; p = 0.045], a significantly lower probability of 12-week confirmed disability worsening (10.0% versus 14.6%; hazard ratio = 0.625; p = 0.048), and a significantly higher rate of NEDA (20.3% versus 11.5%; p = 0.047) compared with GA 20 mg/ml QD patients after 2 years of treatment. Matching-adjusted peginterferon beta-1a patients (effective n = 276) demonstrated a similar ARR at 1 year (0.278 versus 0.318; p = 0.375) and significantly lower ARR at 2 years (0.0901 versus 0.203; p = 0.032) and 3 years (0.109 versus 0.209; p = 0.047) compared with GA 40 mg/ml TIW patients (n = 834). CONCLUSION: Results from separate matching comparisons of phase III clinical trials and extension studies suggest that peginterferon beta-1a 125 mcg Q2W may provide better clinical outcomes than GA (20 mg/ml QD or 40 mg/ml TIW).

Outcomes in a Modern Cohort of Treated Patients with Multiple Sclerosis from Diagnosis Up to 15 Years.

BACKGROUND: Before disease-modifying therapies (DMTs) were available, the natural history of multiple sclerosis (MS) regarding attainment of accepted disability milestones was reported with fairly wide variance comparing outcomes across studies. The influence of DMTs on these outcomes is unknown. This study aimed to calculate attainment of disability milestones during the first 15 years after onset of DMT-treated relapsing forms of MS (RMS). METHODS: As a retrospective study, all available disability data (collected routinely) on all newly diagnosed patients with RMS seen and initially diagnosed in a single clinic between 1989 and 2006 were reviewed. Times from first symptoms and diagnosis until first treatment with DMTs were also reviewed. Time-to-event statistics were applied using disability milestones. RESULTS: Mean follow-up of 184 adult patients from symptom onset was 13.7 years. Of patients followed up for 15 years after onset, 16 of 86 (19%) reached an Expanded Disability Status Scale (EDSS) score of 6.0. Estimated median time to reach an EDSS score of 3.0 was 10.7 years and to reach an EDSS score of 4.0 was 18.1 years. CONCLUSIONS: There were striking differences between the present results and older data sets and similar results to the few available modern data sets. This analysis of a modern treated RMS cohort provides outcomes data that may be compared favorably with the natural history of RMS.

The impact of multiple sclerosis relapses on worsening over the long term; insights in the treatment era.

Relapses of multiple sclerosis (MS) are the clinical manifestations of inflammatory events involving eloquent anatomical structures within the central nervous system. Relapses are associated with worsening disability of MS patients in both early and later disease, even after progressive features are seen. The impact of relapses on the long-term course of the disease is now being realized as a generation of treated patients is now elderly. New MRI brain lesions can be viewed as a radiologic manifestation of acute inflammation and are associated with similar prognostic value. The complex relationship between clinical relapse activity and later slow progressive worsening remains incompletely understood, however, there is increasing biological plausibility for a causative association between relapse activity and lifelong disability.

Is baseline routine renal ultrasound indicated for all MS patients?

BACKGROUND: Most patients with multiple sclerosis (MS) develop multiple urological complaints due to hyperactive or hypoactive bladder, and may have detrusor-sphincter dyssynergia. Routine renal ultrasound (RUS) screening has been recommended for both symptomatic and asymptomatic MS patients; however, there is little data to support this practice. METHODS: Prospectively screened consecutive MS clinic patients in 2016-2017 with functional systems scores (FSS) indicating moderate to severe neurogenic bladder symptoms (FSS bladder ≥2) were sent for RUS. We also screened for history of urinary tract infections. RESULTS: 872 patients were screened between 3 September 2016 and 13 April 2017. 58 patients met inclusion criteria for RUS. 6 were excluded due to non-compliance with testing or unavailability of results; 52 patients were imaged. Only 3/52 patients were found to have renal pathology requiring follow-up. Of those three, one had known symptomatic nephrolithiasis, and one had subsequently normal findings, leaving one patient newly found to have valid abnormal upper urinary tract (UUT) findings. Multiple incidental findings were also discovered. CONCLUSION: The minimal yield for significant UUT pathology found in this enriched group of symptomatic MS patients indicates that RUS screening for asymptomatic MS patients without clear risk factors is not indicated. Red flags for high risk of UUT complications should be used as triggers for baseline RUS screening in MS patients.

Multiple sclerosis relapses contribute to long-term disability.

BACKGROUND: Treatments affect both relapse-related disability and short-term disability change, but measurements of their impact on long-term outcomes remain a challenge. OBJECTIVE: To ascertain the contribution of relapse-associated disability to overall disability in relapse-onset multiple sclerosis (RMS) using long-term data collected in our clinic. MATERIALS AND METHODS: Retrospective study of a cohort of newly diagnosed patients with RMS, (n = 176) was undertaken, measuring all confirmed changes in disability up to 15 years after onset. Worsening was assessed yearly and in 5-year epochs and was attributed to either relapse (RW) or slow progression (PW). RESULTS: At data lock, 139/176 (81%) of patients were still actively followed, with Expanded Disability Status Scale (EDSS) available for 10 years post-onset in 145/176 (82%) patients and 15 years post-onset EDSS in 83 patients (mean follow-up entire group 12.7 years post-onset). RW accounted for a large amount of worsening seen in the first 15 years of RMS. RW was less frequent over time, but accounted for most EDSS changes in the first decade of MS (167/267, 63% of EDSS changes), and remained important even in years 11-15 (17/50, 34% of EDSS changes). Median change in disability due to RW vs PW was similar over the entire 15 years. CONCLUSIONS: Worsening of treated MS was associated with relapses in many RMS patients throughout the first 15 years after onset, suggesting an opportunity for long-term benefit through relapse reduction.

Long-term outcomes of peginterferon beta-1a in multiple sclerosis: results from the ADVANCE extension study, ATTAIN.

BACKGROUND: ADVANCE was a phase III trial of the efficacy and safety of subcutaneous peginterferon beta-1a 125 µg every 2 or 4 weeks in patients with relapsing-remitting multiple sclerosis (RRMS). ATTAIN was a 2-year extension study of ADVANCE. The aim was to evaluate the long-term safety, tolerability, and efficacy of peginterferon beta-1a 125 µg every 2 or 4 weeks in ATTAIN. METHODS: ADVANCE dosing schedules were maintained in ATTAIN, except that every-4-weeks dosing patients were switched to every-2-weeks dosing after conversion of the study to an open-label protocol. ATTAIN was considered complete when the last patient completed the 96-week extension study. Primary endpoints included adverse event (AE) and serious AE (SAE) incidence. Secondary endpoints included relapse, magnetic resonance imaging, and disability outcomes. RESULTS: Of the 1512 patients randomized in ADVANCE, 1076 (71%) continued treatment in ATTAIN; of these, 842 (78%) completed the open-label extension study. During ATTAIN, 478 patients (87%) in the every-2-weeks group and 471 patients (89%) in the every-4-weeks group experienced an AE; SAEs were reported in 90 patients (16%) in the every-2-weeks group and 113 patients (21%) in the every-4-weeks group. The most frequent AEs reported were injection site reactions and flu-like symptoms, both of which numerically decreased over time. Peginterferon beta-1a every 2 weeks versus every 4 weeks significantly reduced the adjusted annualized relapse rate over 6 years (0.188 versus 0.263, p = 0.0052) and the risk of relapse over 5 years (36% versus 49%, p = 0.0018). Fewer new T1, new/newly enlarging T2, and gadolinium-enhancing magnetic resonance imaging lesions were observed with every-2-weeks dosing than every-4-weeks dosing over 4 years. CONCLUSIONS: Results from the ADVANCE extension study, ATTAIN, confirm the favorable long-term safety and tolerability profile of peginterferon beta-1a in patients with RRMS and provide additional evidence for the clinical and radiological benefits associated with this therapy.

Understanding the impact of relapses in the overall course of MS; refinement of the 2 stage natural history model.

Recent studies suggest a need for refinement of the traditional two phase model of relapse onset multiple sclerosis (RMS) to include dynamically changing subgroups within the broad category of secondary progressive MS (SPMS). These studies challenge the traditional notion that relapses play a minor role in comparison to a secondary progressive (perhaps degenerative) process. Patients fulfilling the broad definition for SPMS may take several courses, including variable rates and patterns of overall worsening. New paradigms or models for mapping the trajectory of disability in RMS and SPMS (clinical phenotyping), including periods of remission, may impact our understanding of the underlying pathology, and will be important in assessing treatments.

Treatment of Neuropathic Pain and Functional Limitations Associated With Multiple Sclerosis Using an MRI-Compatible Spinal Cord Stimulator: A Case Report With Two Year Follow-Up and Literature Review.

OBJECTIVE: To report a case with two years follow-up of neuropathic pain and functional limitations associated with multiple sclerosis (MS) effectively treated with an MRI conditional spinal cord stimulator (SCS) system that allowed for spinal imaging. To present a comprehensive literature review of spinal cord stimulator utilization in the treatment of multiple sclerosis. DESIGN: Case report and literature review. INTERVENTION: Treatment was a spinal cord stimulation implant after successful trial. Pain scores, medication utilization, and functional outcomes were reviewed. Pre- and post-SCS implant MRI spine images were obtained. RESULTS: At 24 months follow-up, the patient has had a 77% reduction in pain and a 99% reduction in opioid use. Furthermore, he had improvement in reported tactile sensation, spasticity levels, and ambulation. Post-SCS implant, MRI images at 18 months follow-up provided the ability to review the spinal cord with minimal artifact. No new MS documented plaques occurred during this time period. A literature review demonstrated 33 published reports including a total of 496 trialed and 744 implanted patients. Only 3 of the reports occurred after the year 2000. CONCLUSIONS: We report the successful treatment of MS-associated pain and functional limitations with an MRI conditional spinal cord stimulator system. The ability to obtain post-implant MRI imaging of not only the brain but also the spinal cord in MS patients allows for the continued need to document and follow disease progression, especially with the advancements in pharmacological therapy.

Specific clinical phenotypes in relapsing multiple sclerosis: The impact of relapses on long-term outcomes.

OBJECTIVE: The impact of relapses on the disease course of relapsing MS remains to be determined. This study aims to identify and characterize clinical phenotypes of relapse onset MS in a longitudinally studied cohort. METHODS: We recorded the clinical course of MS during the first decade of disease, using five-year epochs. Patients were stratified as: no worsening due to relapse or secondary progression (type A), relapse with worsening seen without secondary progression (type B), secondary progression with no worsening due to relapse (type C), worsening due to relapses mixed with secondary progression (type D). RESULTS: Of 176 patients followed from diagnosis for 12.62 ± 4.18 years, 93.2% (164/176) had increased disability in their first 5-year epoch of MS and 52.2% (72/138) in the next. The phenotypes significantly differed by EDSS change during each epoch (p<0.001), final confirmed MSSS (p ≤ 0.002) and relapse rate (p<0.001). Type D fared worse than others by change in EDSS and MSSS. CONCLUSION: We identified multiple specific phenotypes of MS and temporal shifts between phenotypes according to relapse type and progression.

Improvement in relapse recovery with peginterferon beta-1a in patients with multiple sclerosis.

BACKGROUND: Subcutaneous peginterferon beta-1a every 2 weeks significantly affects clinical outcomes in patients with relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: To explore relationships between relapses and worsening of disability in patients with RRMS, and assess the treatment effect of peginterferon beta-1a on relapse recovery. METHODS: Post-hoc analysis of the 2-year, randomized, double-blind, parallel-group, Phase 3 ADVANCE study. The severity of relapses, proportion of patients with relapses associated with residual disability (onset of 24-week confirmed disability progression (CDP) within 90 days following a relapse), and persistence of changes in Functional Systems Scores, were compared between treatment groups. RESULTS: Subcutaneous peginterferon beta-1a every 2 weeks significantly reduced the proportion of patients experiencing relapse associated with CDP over 2 years (6.6%, compared with 15.1% of patients who received placebo in Year 1; p = 0.02). Reduction in relapses associated with residual disability was greater than the treatment effect on overall relapse rate, and occurred despite similar relapse severity across treatment groups. CONCLUSIONS: The beneficial effect of peginterferon beta-1a on risk of CDP may be attributable to the combination of an overall reduction in the risk of relapses and improvement in recovery from relapses, thus limiting further disability progression. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00906399.