Background

Aletuzumab(ALZ) is an approved drug for the treatment of active recurrent-remitting multiple sclerosis (RRMS), with proved efficacy and safety in clinical trials. Among its most frequent adverse effects are autoinmune disorders related to secondary autoinmunity (SA) phenomena.

Objectives

We analyze and characterize secondary autoinmunity in our multiple sclerosis unit after more than five years of clinical experience.

Methods

Retrospective observational descriptive study of RRMS patients treated with ALZ in our center, characterizing SA phenomena after more than 5 years of experience

Results

n=131(77% women), with a mean age of 40,2 years (SD±9,1) and a mean time of disease of 13.8 years (SD±7,1). The mean pre-treatment EDSS was 4,5 (DS±1,6) with an prior annualized relapse rate of 1.48 (SD±0,83). SA was found in 42 patients (32%), most of them with thyroid disease (81% with 73,5% hyperthyroidism, asymptomatic majority) with aggresive treatment (surgical, radiotherapy) in 20%. Hematological SA was found in 0.01% (autoinmune thrombopenia, with monophasic course and excellent response to pharmacological treatment) and cutaneous SA in 0.05% (most of them vitiligo and well-controlled alopecia areata and one patient with chronic urticaria). Currently one patient is under study for nephropathy (0.01%). Like the available evidence, we detected an increase in SA around third year.

Conclusions

In our experience ALZ is emerging as a drug with a safety profile similar to available evidence regarding SA, although some complications have been described in other body systems, and it requires an adequate patient selection and close clinical control.

Background

Cladribine is a nucleoside analog of deoxyadenosine, recently approved for treatment of active multiple sclerosis (RMS) defined by neuroimaging or clinical features.

Objectives

We analyze our treated patients profile, efficacy and safety in real clinical practice after two years of experience.

Methods

Two-year retrospective observational study of our RMS patients treated with oral cladribine, analyzing demographic, clinical, efficacy and safety data.

Results

n=81 (78% women), mean age 37.7 years (21-65) and a previous mean EDSS of 2.67(1-6). The mean time of evolution of RMS prior to treatment was 6.7 years and the mean annualized relapse rate 1,2. 50% of patients had at least 10 lesions in T2 with a mean of ehanced lesions of 0.9 (0-4). The mean of previous treatments was 1.25 and the mean time with last treatment was 2.44. Drug tolerance was good, with less than 15% adverse effects (Aes), all mild and self-limiting. Lymphocyte counts reached a mínimum mean value of 1.03x10^3/mm³ in month 3, with subsequent recovery and only 3 patients reaching asymptomatic grade 3 (0.04%). Currently 24 patients have received second year according to protocol, haveing detected previos radiological activity in four of them (0.05%) and clinical activity in two (0.02%), being reason for discontinuation in one patient without completing complete course of treatment.

Conclusions

In our experience, and after its first two years in clinical practice, oral cladribine is emerging as a treatment with a good efficacy and safety profile in active MS, in parallel with the available evidence.

Background

Ocrelizumab is an anti-CD20 humanized monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis

Objectives

To describe baseline characteristics of patients with RRMS treated with OCR. Analyze previous disease modifying treatments(DMT), reasons to change, safety and laboratory parameters

Methods

Retrospective observational study in patients with RRMS treated with OCR from November 2016 to May 2020 at Virgen Macarena Hospital, Seville, Spain.

Demographic/disease characteristics, ARR, previous DMTs, reasons to change DMT, adverse events changes in disability, and cerebral MRI findings were collected at enrolment.

Results

38 RRMS patients were treated with OCR (65,8%females) Mean follow-up after OCR initiation:11,4 months (1-40) 47,4% have received two or more cycles of treatment.

Average age was 39.8 years (21-58) Mean time since RRMS diagnosis was 9,9 years (0,3-26,2) The patients had been treated with a mean of 1,5DMT prior to OCR. 3 of them were treatment naïve. DMT previous OCR was IFN-b 2pax, glatiramer acetate 2pax, teriflunomide 4pax, dimethyl fumarate 3pax, rituximab 1pax, fingolimod 16pax, natalizumab 3pax, alemtuzumab 3pax. The reason to DMT change were: lack of efficacy:32 pax; security:6 pax (vJC seroconversion or alemtuzumab contraindications)

After 11,4 months of OCR initiation, annualized relapse rate (ARR) decreased from 1,2 to 0, and the EDSS score remained unchanged: mean 3,8 (1,5-6,5). None of the patients had relapses after OCR initiation.

Regarding cerebral MRI parameters, Gd+ lesions diminished from 1,3 previous to 0 after OCR. T2 lesion burden showed no changes on cerebral MRI.

The more frequent adverse events were infusion reactions (26,32% of patients: 4 fatigue; 3 headache; 3 redness skin; 2 allergic reaction) All of them were mild but in two patients lead to treatment discontinuation (allergic reaction). Infections occurred in 3 patients (2 urinary tract infection, 1 zoster reactivation)

Five patients (13,2%) showed decrease in total lymphocyte count (3 grade 1; 2 grade 2) 18,9% patients showed IgM index under lower limit of the normal range. All patients showed normal levels IgG index before and after OCR. Percentage of CD19+Cells diminished in all patients: median of 14%(previous) to 1%(after OCR) No clear associations between lymphopenia/immunoglobulines and infections was detected.

Conclusions

This data shows that RRMS patients treated with OCR in a real world clinical setting show significant decreases in ARR and the majority maintain EDSS score unchanged. The most common adverse event were mild infusion reactions and mild infectious diseases. Some patients showed lymphopenia and IgM below lower limit of normal. No clear associations between lymphopenia/immunoglobulines and infections was detected.

Background

Ocrelizumab is an anti-CD20 humanized monoclonal antibody. Is the first disease modifying treatment(DMT) approved for the treatment of primary-progressive multiple sclerosis(PPMS). It has shown to reduce Confirmed Disability Progression at 12 and 24 weeks over placebo

Objectives

To describe the baseline characteristics of patients with PPMS. Analyze effectiveness, safety and laboratory parameters in PPMS patients treated with OCR

Methods

Retrospective observational study in patients with PPMS treated with OCR from January 2011 to May 2020 at Virgen Macarena Hospital, Seville, Spain.

Demographic/disease characteristics, ARR, previous DMTs, adverse events, changes in disability, and cerebral MRI findings were collected at enrolment.

Results

18 PPMS patients were treated with OCR(50%females) Mean follow-up since OCR initiation:13,8 months(1-38) 16 patients(88,89%) have received ⥸2 courses.

Average age: 47 years(37-57) Mean time since PPMS diagnosis: 5,38 years(0,5-12,3)

6 patients(33,3%) received a previous DMT(3Laquinimod, 1Rituximab, 1Fingolimod, 1Teriflunomide)

Mean EDSS changed from 5,7 to 5,8 after a mean of 13,8 months receiving OCR(1 patient worsened) None of the patients have had relapses or GD+ lesions prior or after OCR. T2 lesion burden showed no changes on cerebral MRI.

The main adverse events were infusion reactions, that appeared in 38,89% of patients (6fatigue, 1skin redness) None lead to treatment discontinuation. Infections appeared in 22,2% of patients (3urinary tract infection, 1herpes simplex reactivation) All solved with treatment.

None of the patient showed decrease in total lymphocyte count. 2 patients (11,1%) showed IgM index under lower limit of the normal range. All patients showed normal levels IgG index before and after OCR. Percentage of CD19+Cells diminished in all patients: median of 13%(previous) to 1%(after OCR) No clear assotiations between lymphopenia or low serum IgM was detected.

Conclusions

In our sample, 94,4% of PPMS patients treated with OCR show EDSS stabilization after 18 months of treatment. ARR and MRI parameters showed no changes. The main adverse events were mild infusion reactions(38,9%) and mild infections(22,2%)

The principal analytical finding was decrease of CD19+Cells and/or IgM decrease. No clear assotiations between lymphopenia or low serum IgM was detected.

Background

Neuromyelitis optica-spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system (CNS). It may be reccurent in time. It preferably affects the optic nerve and spinal cord . Several antibodies like aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibody have been involved in its pathophisiology. Currently, there is several immunomodulatory treatments that seem effective stopping disease progression. Thus, made a early diagnostic is essentially in the prognosis of the disease.

Objectives

To describe the baseline characteristics of Southwestern-european population cohort of patients diagnosed with NMOSD

Methods

Retrospective observational study in patients diagnosed with NMOSD from January 2015 to May 2020 at Virgen Macarena Hospital, Seville, Spain. Demographic/disease characteristics, previous DMTs, adverse events, changes in disability, and cerebral MRI findings were collected at enrolment.

Results

16 patients were diagnosed with NMOSD in accordance with 2015 International Panel for NMO Diagnosis criteria. All of them were womens. Average age 49 (10.6,SD). Mean time since clinical onset was 6,34 years (3.7,SD) Diagnostic delay was 3 years (3,SD). 11 patients were AQP4 antibody positive by indirect inmunofluorescence (IIF) assay (69%). 5 of patients were AQP4 and myelin oligodendrocyte glycoprotein (MOG) antibodies seronegative (31%). 3 patiens had oligoclonals bands in LCR (19%)

Mean EDSS increased from 4 to 4.1 after a mean follow-up of 3.34 years.

7 patients are treated with Rituximab (RTX)(44%), 6 patients with Azathioprine (AZT) (38%), 1 patients receive intravenous inmunoglobuline(6%) and two patients have not maintenance treatment (13%). One patient has presented one clinical relapse since current treatment administration(6%) Mean 2.98 years.

Longitudinally extensive transverse myelitis (LETM) was responsible for clinical onset in 8 patients (50%). 6 patients (37,5%) sought medical attention for first time due to Unilateral optic Neuritis, 1 patient had LETM and optic neuritis and 1 patient presented a isolated area postrema syndrome (intractable hiccups and vomiting).

Conclusions

Our sample presents similar characteristics than other populations published. The current inmunotherapy agents seem to be a safe and effective treatment for control disease progression. Thus, an acute and early diagnostic would be related with a better outcome.

Background

Rituximab (RTX) is an anti-CD20 chimeric monoclonal antibody that can eliminate B celIs. B cells may play important roles in the pathogenesis of NMOSD since it produce antibodies involved in the pathophysiology of the disease like antibodies against aquaporin-4. RTX could reducing relapsing cases and stabilising neurological functions in patients with NMOSD according to some retrospective studies with limited samples.

Objectives

To describe the baseline characteristics of patients with NMOSD treated with RTX. Analyze effectiveness and safety in NMOSD patients treated with Rituximab.

Methods

Retrospective observational study in patients with NMOSD treated with RTX from July 2015 to May 2020 at Virgen Macarena Hospital, Seville, Spain.

Demographic/disease characteristics, previous treatments, adverse events and changes in disability were collected at enrolment.

Results

10 NMOSD patients were treated with RTX (100% females) Mean follow-up since RTX initiation: 2.9±1.1 year.

Average age: 51±12.6 years Mean time since NMOSD diagnosis: 3.3±2.8 year.

Mean EDSS did not change after a mean of 2.9 year receiving RTX. 3 patients abandoned treatment due to several adverse events (itching, skin infections or throat swelling). One of the seven patients that continues with the treatmente presented a single clinical relapse.The 86% of patients that tolerate RTX shown no clinical relapse.

Conclusions

In our sample, Rituximab seem to be safe and effective in reducing clinical relapse and stabilising neurological functions. RTX was well tolerated by the 70% of patients. Mean EDSS did not change after a mean of 2.9 year receiving RTX. 86% of patients that tolerate RTX shown no clinical relapse after 2.9 year of treatment.

Background

In secondary progressive multiple sclerosis (SPMS), reduction in the rates of disability accrual after starting disease modifying therapy (DMT) has largely been limited to patients with ongoing inflammatory activity. A delayed treatment effect, termed therapeutic lag, may obscure therapeutic benefits in SPMS.

Objectives

To compare the effect of high and low efficacy DMT on disability outcomes in patients with recently active and inactive SPMS after accounting for therapeutic lag.

Methods

Using data from MSBase, a multinational MS registry, and OFSEP, the French MS registry, we identified patients with SPMS as per a previously validated objective definition. We identified patients treated with high- (natalizumab, alemtuzumab, mitoxantrone, ocrelizumab, rituximab, cladribine, fingolimod) or low-efficacy (interferons, glatiramer acetate, teriflunomide) DMT after SPMS onset. Based on our previous work, an individualised estimate of duration of therapeutic lag was calculated for each patient. Only events that occurred after the estimated therapeutic lag period were included in the analysis. Propensity score matching was used to select groups with comparable baseline characteristics. Disability and relapse outcomes were compared in paired, pairwise-censored analyses adjusted for visit density.

Results

Of 7359 patients with SPMS, 1000 patients fulfilled the criteria for study inclusion (510 active SPMS, 490 inactive SPMS). For the relapse outcomes, patients with active SPMS treated with high-efficacy DMTs experienced lower probabilities of relapses than low-efficacy DMTs (hazard ratio [HR] 0.7 [95%CI 0.5-0.9], p=0.006). Patients with inactive SPMS had similar probabilities of relapses in the high and low efficacy DMT groups (0.8 [0.6-1.2], p=0.39). No difference in the risk of 6-month sustained disability accumulation, or proportion of patients reaching EDSS>=7, was observed between groups when accounting for therapeutic lag.

Conclusions

The risk of disability accumulation in SPMS seems to be comparable in patients treated with high- and low- efficacy DMT. High efficacy DMT is superior to low efficacy therapy in reducing relapse activity in patients with active SPMS, but not those with inactive SPMS. Pre-treatment inflammatory activity, clinical or radiological, is a treatable target in SPMS which may benefit from higher-efficacy anti-inflammatory therapies.

Background

Cladribine tablets are approved for treatment of multiple sclerosis (MS) in many jurisdictions. Real-world outcomes data is very limited.

Objectives

We analysed the cladribine treatment experience in the MSBase registry. We described baseline characteristics, treatment pathways, and relapse and discontinuation outcomes in patients with ≥6 months follow-up data from cladribine initiation.

Methods

We performed a secondary data analysis using MSBase Registry data of patients with a confirmed diagnosis of MS and newly treated with cladribine tablets after regulatory approval. Descriptive statistics were used to analyze baseline patient characteristics recorded within 3 months prior to cladribine tablets initiation, including demographics, disease course and duration, prior disease modifying drugs (DMD), and Expanded Disability Status Scale (EDSS).

Results

As of the 4th June 2020, MSBase included 660 patients treated with cladribine from 9 countries, mainly from Australia and Europe. A total of 576 met all inclusion criteria. These included 496 relapsing-remitting MS (RRMS) patients. In these, median age at cladribine tablets start was 45 years and median disease duration since clinically isolated syndrome was 12.6 years. Median EDSS at cladribine tablets start was 2.5. Around 13% of all RRMS patients initiated cladribine tablets as first line therapy. Of all RRMS patients switching to cladribine tablets with a treatment gap of <6 months, the most common immediate prior DMDs were fingolimod (17%), followed by natalizumab, teriflunomide and dimethylfumarate (all appx. 10%). Total follow-up time was 340 patient-years. Annualised relapse rate (ARR) on cladribine tablets was 0.12 (95%CI 0.09-0.17), compared to a pre-cladribine ARR of 0.38. Treatment persistence was 95% after 12 months (95%CI 91-98%), and 92% after 24 months (95%CI 87-96%).

Conclusions

This study characterizes RRMS patients treated with cladribine tablets in a real-world clinic setting. First-line use was uncommon. ARR was low, consistent with clinical trial data, and early discontinuations were very rare.

Background

Ocrelizumab (OCR) is a humanised anti-CD20⁺ monoclonal antibody approved for the treatment of primary progressive multiple sclerosis (PPMS), and relapsing forms of MS, including both relapsing-remitting (RRMS) and secondary progressive MS (SPMS) with relapses.

Objectives

In a real-world setting, to describe 1) baseline characteristics of patients with MS treated with OCR, 2) treatment pathway across lines of therapy up to initiation of OCR, and 3) initial clinical experience in patients with ≥6 months follow-up data from OCR initiation.

Methods

Secondary data analysis using MSBase Registry data including patients with a confirmed diagnosis of MS and started OCR therapy within 3 months prior to or at time of MSBase eligible/initial visit. Descriptive statistics were used to analyze baseline patient characteristics' recorded within 3 months of OCR initiation, including demographics, disease course and duration, prior disease modifying therapies (DMT), and EDSS. Occurrence of relapse was analyzed in patients with ≥6 months follow-up data from OCR initiation.

Results

As of 4^th June 2020, MSBase included 2531 patients newly treated with OCR, of whom 1679 had an EDSS evaluation within 3 months of OCR start. There were 1185 patients with RRMS, 236 with SPMS, and 183 with PPMS. Median age at OCR initiation was 41.9 years, 49.5 years, to 50.1 years in RRMS, SPMS, and PPMS, respectively. Mean disease duration from symptom onset up to OCR initiation was longer in SPMS (19.7 years) than in RRMS (10.6 years) and PPMS (9.7 years). OCR was initiated as first line therapy in 17.5%, 5.5%, and 54.2% of RRMS, SPMS, and PPMS patients respectively. Most frequent previous DMT’s in RRMS were fingolimod (25.7%) and natalizumab (23.5%). 693 patients with RRMS had ≥6 months follow-up during OCR exposure. Of these, 643 remained relapse free (93%; 95% CI 86.0, 100.0) over a mean OCR exposure of 1.23 years. The annualized relapse rate (ARR) was 0.08 (95% CI 0.06-0.10), compared to an ARR of 0.85 in the 24 months pre-OCR start. In the overall cohort, treatment persistence at 12 and 24 months was 98.4% (95% CI: 97.3-9.1%) and 92.5% (95%CI 89-95%), respectively.

Conclusions

This study characterizes an international population of patients with RRMS, PPMS, and SPMS newly treated with OCR in a real-world clinical setting. First-line use was uncommon in RRMS and SPMS. During OCR treatment, ARR was below 0.1, and OCR discontinuations were very rare.

Background

Disease activity has been investigated in pregnant women with RRMS treated with low-efficacy or no therapy. How newer, more efficacious therapies affect relapse and disability progression risk after pregnancy remains understudied.

Objectives

To describe disease activity in a modern pregnancy cohort contrasted with historical cohorts. To determine the predictors of postpartum relapse and the predictors of six-month confirmed disability progression events in a contemporary pregnancy cohort.

Methods

Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 (modern cohort) were compared with those conceived between 2005-2010 and pre-2005. Annualised relapse rates (ARR) were calculated for each pregnancy trimester and 12 months either side. Predictors of time-to-relapse postpartum (1^st 3 months) and time to 6-month confirmed disability progression event were determined with clustered Cox regression analyses. Breastfeeding duration and time to DMT reinitiation were modelled as time-varying covariates.

Results

We included 1640 pregnancies from 1452 women (modern cohort). Disease-modifying therapy (DMT) used in the year before conception included interferon-beta (n=597), natalizumab (n=219) and fingolimod (n=147). Continuation of DMT up to conception increased over time (31% pre-2005 vs 54% modern cohort). Preconception ARR decreased across epochs (pre-2005: 0·58 [95% CI 0·49-0·70]; 2005-2010: 0·40 [95% CI 0·36-0·45]; modern: 0·29 [95% CI 0·27-0·32]). In all epochs, ARR decreased during pregnancy to reach similar troughs in the 3^rd trimester, and rebounded in the 1^st 3-months postpartum. Preconception use of high-efficacy DMT predicted early postpartum relapse (hazard ratio (HR) 2.1 [1.4-3.1]); although those on no DMT were also at risk of postpartum relapse, relative to women on low-efficacy DMT (HR 2.7 [1.2-5.9]). Conception EDSS ≥2, higher preconception and in-pregnancy ARR were also risk factors. DMT reinitiation, particularly of high-efficacy DMT (HR 0.17 [0.07-0.38]), was protective against postpartum relapse. Women who breastfed were less likely to relapse (HR 0.63 [0.42-0.94]). 4.5% of modern pregnancies had confirmed disability progression after delivery. This was predicted by higher pregnancy and postpartum ARR, with postpartum ARR remaining independently predictive in multivariable analysis (HR 1.5 [1.2-2.0]).

Conclusions

The early postpartum period remains a period of vulnerability for disease rebound in women with MS in the modern era. Early DMT reinitiation, particularly with high-efficacy treatment, is protective against postpartum relapse. Confirmed disability progression events after pregnnacy are uncommon in the modern era. Relapse activity is the key driver of these events.