Background

Glial fibrillar acidic protein (GFAP) autoimmunity is a recently identified disease, at the frontier of auto-immune encephalitis and gliopathies. Clinical features associated to this new entity are still not fully evaluated; especially the risk of relapse and the disability outcome.

Objectives

To report the clinical, biological, imaging features, and the clinical course of a French cohort of patients with GFAP autoantibodies.

Methods

We retrospectively included all patients tested positive for GFAP antibodies since 2017, from two French referral centers (auto-immune encephalitis and rare inflammatory disorders of the brain and the spinal cord). GFAP autoantibodies were detected exclusively in the CSF, by immunohistochemistry and their specificity confirmed by cell-based assay using cells expressing human GFAPα.

Results

We identified 46 patients with GFAP antibodies. Median age at onset was 43 years and men were more affected (30/46). Infectious prodromal symptoms were found in 82% of cases. Other autoimmune diseases were found in 22% of cases and coexisting neural autoantibodies in 11% of cases, including MOG-IgG and AQP4-IgG positive cases. Tumors were present in 24%, and T cell dysfunction in 23% of cases, respectively. The most frequent presentation was acute/subacute menigoencephalitis (85%) with cerebellar dysfunction in 57% of cases. Other/associated clinical presentation included: myelitis (30%), visual tract involvement (35%) and peripheral nervous system involvement (28%). CSF showed pleocytosis (98%), oligoclonal bands (77%) and low glucose level (15%). MRI findings were heterogeneous: radial enhancement was found in 26%, periventricular diffuse T2 hyperintensity in 39%, brainstem involvement in 33%, leptomeningeal enhancement in 23%, and reversible splenial lesions in 4 cases.

39/46 patients have a monophasic course, associated to a good outcome at last follow-up (Rankin Score≤2: 89% at 15,5 months), despite a frequently severe clinical presentation (intensive care unit hospitalization: 42%). Seventy patients were treated with immunotherapy. 11/22 patients showed negativation of GFAP antibodies (median time: 2 months).

Conclusions

GFAP autoimmunity was generally associated to a good outcome and a low risk of relapse. Identification of factors associated to risk of relapse or disability, to monitor immunotherapy, is needed.

Background

Treatment options for pediatric patients with relapsing forms of multiple sclerosis (RMS) are limited. Teriflunomide, approved for adults with RMS in >80 countries, was investigated in pediatric RMS in TERIKIDS (NCT02201108), a 2-year, multicenter, multinational, randomized, double-blind (DB), placebo-controlled, parallel-group phase 3 study.

Objectives

To report the interim results in pediatric patients from the open-label (OL) period of the TERIKIDS study as of 27 November 2019.

Methods

Patients who either completed 96-week DB treatment or qualified for early switch from DB treatment to OL teriflunomide could continue in the OL period until 192 weeks after initial randomization. All patients in the OL period received teriflunomide at a dose based on body weight, equivalent to 14 mg in adults.

Results

In the DB period, teriflunomide reduced risk of relapse (−34%); however, the difference was not statistically significant versus placebo (P=0.29) so TERIKIDS did not meet its primary endpoint. Teriflunomide significantly reduced risk of relapse or high MRI activity (−43%; P=0.041; prespecified sensitivity analysis), number of new/enlarging T2 lesions (−55%; P=0.0006), and number of gadolinium-enhancing lesions (−75%; P<0.0001) relative to placebo. At the cut-off date, 100 (91.7%) patients from the teriflunomide and 52 (91.2%) from the placebo group enrolled in the OL period; 34 patients discontinued, 30 completed, and 88 were ongoing. From DB randomization to week 192, risk of relapse was numerically lower with continuous teriflunomide versus placebo/teriflunomide (hazard ratio [95% CI]: 0.61 [0.38 to 0.98]; P=0.098), as was risk of disability progression sustained for 24 weeks (hazard ratio [95% CI]: 0.552 [0.245 to 1.242]). Number of new/enlarging T2 lesions per MRI scan was reduced with continuous teriflunomide versus placebo/teriflunomide (6.3 vs 13.0; P=0.0006). Incidence of adverse events during the OL period was lower with continuous teriflunomide versus placebo/teriflunomide (68.0% vs 82.7%). Adverse events led to treatment discontinuation during the OL period in 8 patients (increased alanine aminotransferase [n=5], peripheral neuropathy [n=1], pancreatitis [n=2]).

Conclusions

Interim analysis showed that continuous teriflunomide numerically lowered the risk of clinical relapses and 24-week sustained disability progression in pediatric patients compared with delayed initiation of teriflunomide after placebo. Teriflunomide was well tolerated and had a manageable safety profile.

STUDY SUPPORT: Sanofi.

Background

To predict the clinical course of myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated disease (MOGAD) is essential to guide treatment recommendations.

Objectives

We aimed to 1) compare clinical features and disease course, and 2) to evaluate the association of MOG-Ab dynamics and relapses, between children and adults with MOGAD.

Methods

Retrospective study evaluating clinical features of 98 children and 266 adults with MOGAD, between January 2014 and September 2019. To analyse relapses over the whole disease course, a Cox regression analysis for recurrent time-to-event data was performed, introducing treatment as time-dependent covariate. To evaluate dynamics, delta mean fluorescence intensity ratio signal (ΔMFIratio) of MOG-Ab was measured in patients with a minimum time elapsed between two samples of 4 months.

Results

Median age at onset of symptoms was 10.9 (interquartile range 5.4-14.3) years in children and 36.2 (27.7-47.6) in adults. Isolated optic neuritis was the most frequent clinical presentation both in children (40.8%) and adults (55.9%), p=0.013, and acute disseminated encephalomyelitis syndrome was more frequent in children (36.7% vs. 5.6%; p<0.001). Compared to adults, children displayed a better recovery (EDSS ≥3.0 at last follow-up reached only by 10 of 97 [10.3%] vs. 66/247 [26.7%], p<0.001).

In the multivariate analysis, adults were at higher risk of relapse than children (Hazard ratio 1.41, 95%Confidence interval [CI] 1.12-1.78; p=0.003). Among the 124 participants evaluated for MOG-Ab dynamics, 36.3% became seronegative, 60.5% decrease and 3.2% increase the ΔMFIratio. At two years, 64.2% (95%CI 40.9-86.5) of non-relapsing children became MOG-Ab negative compared to 14.1% (95%CI 4.7-38.3) of relapsing ones, log-rank p<0.001, with no differences observed between non-relapsing and relapsing adults, log-rank p=0.280.

Conclusions

MOGAD differs in its clinical presentation at onset, showing a progressive shift in the clinical features across age-groups. Compared to children, adults have a higher risk of relapses and a worse functional recovery. Finally, children with monophasic disease became MOG-Ab negative earlier than relapsing ones, but not in adults. Considering these differences, management and treatment guidelines should be considered independently in children and adults.