The costs of care from a US claims database in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease of the central nervous system that often leads to severe disability. Patients with highly active NMOSD have approximately a 10-times higher hospital inpatient admission rate compared with patients without NMOSD. Accurate assessments of the impact of NMOSD treatments on the burdens of illness require quantitative metrics of these burdens, including costs of care. METHODS: This study evaluated claims data from the IBM MarketScan Commercial and Medicare Supplemental Databases between 2014 and 2018. Patients were included based on inpatient or outpatient claims meeting criteria defined for NMOSD. Non-NMOSD controls were matched 5:1 to patients with NMOSD. Total costs of healthcare services in consumer price index-adjusted 2019 US dollars during the 1-year postindex follow-up period were calculated for patients and controls. RESULTS: Patients with NMOSD required more healthcare services and incurred significantly greater costs for inpatient hospitalizations (annual mean [SD] cost: $29,054 [$144,872] vs controls $1521 [$10,759]), outpatient services ($24,881 [$35,463] vs $4761 [$26,447]), and emergency department (ED) visits ($2400 [$7771] vs $408 [$2579]). Almost 12% of patients with NMOSD were further burdened with plasma exchange or intravenous immunoglobulin G treatments, costing an annual median (interquartile range) of $1684 ($566-$3817) and $24,353 ($5425-$42,975), respectively. CONCLUSIONS: Compared with controls, patients with NMOSD had significantly higher costs associated with hospitalizations, ED visits, and prescriptions. These results highlight the considerable economic burden of NMOSD, which may be favorably impacted by disease-modifying therapies that are regulatory-approved to be safe and effective.

Burden and cost of comorbidities in patients with neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is associated with various comorbidities, including non-autoimmune and autoimmune conditions. The burden and cost of illness for NMOSD are unclear, particularly in the context of comorbidities. METHODS: Claims data from IBM MarketScan Commercial and Medicare Supplemental Databases between 2014 and 2018 were analyzed. Patients with NMOSD were specified as having inpatient or outpatient claims for NMOSD diagnosis or specific NMOSD symptoms claims and no subsequent claims for multiple sclerosis (MS) or use of MS disease-modifying therapy (DMT). Continuous enrollment ≥ 6 months before and ≥ 1 year after the first claim (index date) was required for study inclusion. Total costs stratified by comorbidities within 12 months post-index date were calculated per patient and compared 1:5 with matched non-NMOSD controls. RESULTS: A total of 162 patients with NMOSD and 810 non-NMOSD controls were evaluated. A significantly higher proportion of NMOSD patients had comorbidities than non-NMOSD controls (66.7% vs 41.5%; P < 0.001). Concomitant autoimmune disease occurred in 19.1% vs 4.9% (P < 0.001) of patients with NMOSD vs non-NMOSD controls. NMOSD patients incurred significantly higher total median (interquartile range) healthcare costs per patient ($68,386.48 [$23,373.54-$160,862.70]) than matched non-NMOSD controls with autoimmune disease ($17,215.13 [$6715.48-$31,441.93]; P < 0.001) or patients with NMOSD without autoimmune comorbidity ($23,905.42 [$8632.82-$67,251.54]; P = 0.022). Similarly, patients with NMOSD and non-autoimmune comorbidities incurred higher median healthcare costs than matched controls. CONCLUSIONS: Patients with NMOSD experience significant disease burden and cost that are amplified by comorbidities. Effective therapies are needed, particularly for patients with concomitant autoimmune disease.

Identification and temporal trends of patients with neuromyelitis optica spectrum disorder in a US insurance claims database.

BACKGROUND: This US claims-based study aimed to identify and characterize temporal trends in diagnostic pathways for patients likely to have neuromyelitis optica spectrum disorder (NMOSD). METHODS: Patients were identified from IBM MarketScan Commercial Databases if, within 1 year, they had two NMOSD claims separated by ≥ 60 days; two transverse myelitis (TM) or optic neuritis (ON) claims separated by ≥ 60 days, and one additional symptom (TM, ON, or area postrema syndrome); or one NMOSD claim and one additional symptom. The first NMOSD or TM/ON claim was the index date, and the second claim was the diagnosis date. Similar methodology was used in temporal trend and incidence and prevalence analyses. RESULTS: Among 1,901 patients with NMOSD, 34.2% were identified by two NMO claims, 53.2% by ON or TM +1 symptom, and 12.6% by one NMOSD claim +1 symptom. Anti-aquaporin-4 immunoglobin G (AQP4-IgG) autoantibody tests and magnetic resonance imaging was used for 23.0% and 71.9% of cases, respectively. Across cohorts, 21.4-49.1% had multiple sclerosis (MS) diagnosis claims prior to index date, and 37.3-60.6% had an MS diagnosis, 14.9-31.0% had MS disease-modifying therapy (DMT) claims and 6.3-44.8% had immunosuppressive therapy (IST) claims <1 year after diagnosis. Over time, there were slight changes in MS diagnosis claims, AQP4-IgG autoantibody testing, and DMT and IST use before and after NMOSD diagnosis. LIMITATIONS: This study is limited by the information available in US claims databases, which included the potential for misclassification of NMOSD based solely on claims codes and lack of reimbursement for AQP4-IgG testing by insurance companies. CONCLUSIONS: Among patients likely to have NMOSD, low AQP4-IgG testing rates, IST use, frequent MS diagnosis claims, and DMT use highlight the need for a diagnostic algorithm and timely treatment of NMOSD.

Clinical outcomes of patients with giant cell arteritis treated with tocilizumab in real-world clinical practice: decreased incidence of new visual manifestations.

BACKGROUND: Placebo-controlled clinical trials have demonstrated the efficacy of tocilizumab (TCZ) for remission maintenance and glucocorticoid sparing in patients with giant cell arteritis (GCA). However, limited data exist on the effectiveness and safety of TCZ for GCA in real-world clinical practice. METHODS: This was a retrospective, single-center analysis of patients with GCA treated with intravenous or subcutaneous TCZ (2010-2018). Outcomes evaluated before and after TCZ initiation included occurrence of flare, time to flare, annualized flare rate, flare characteristics (i.e., polymyalgia rheumatica [PMR] symptoms, cranial manifestations), prednisone use, and safety. Flare was defined as the recurrence of unequivocal GCA manifestations requiring treatment intensification. Subgroup analyses of patients with PMR or visual manifestations at GCA diagnosis were performed. RESULTS: Sixty patients with GCA were included. The median (IQR) disease duration before and after the start of TCZ was 0.6 (0.2-1.6) and 0.5 (0.3-1.4) years, respectively. At least 1 flare was observed in 43 patients (71.7%) before and in 18 (30.0%) after TCZ initiation. Median (IQR) time to flare was 0.5 (0.3-0.7) years before TCZ treatment and 2.1 (0.6-2.6) years after TCZ initiation (HR 0.22; 95% CI 0.10-0.50; p = 0.0003). The annualized flare rate significantly decreased following TCZ use (before TCZ 1.4 [95% CI 1.0-2.1]; after TCZ 0.6 [95% CI 0.3-1.0] events/year; p < 0.001). Similar improvements were observed in patients with visual manifestations or PMR symptoms at GCA diagnosis. TCZ reduced the incidence of new visual manifestations, and no flares associated with permanent vision loss occurred while patients were receiving TCZ. Mean (SD) prednisone dose at TCZ onset and at the end of follow-up was 30 (18.3) and 5 (6.9) mg/day, respectively (p < 0.0001). After TCZ initiation, 46.6% of patients successfully discontinued prednisone. The incidence of adverse events, primarily attributed to glucocorticoids, was similar before and after TCZ initiation. CONCLUSIONS: In this real-world setting, TCZ improved GCA clinical outcomes significantly and demonstrated effectiveness in the subgroups of patients with PMR symptoms and GCA-related visual manifestations at GCA diagnosis. No new cases of blindness occurred after TCZ initiation. Adverse events, many attributable to glucocorticoids, were comparable before and after TCZ treatment.

Effect of disease duration and other characteristics on efficacy outcomes in clinical trials of tocilizumab for rheumatoid arthritis.

OBJECTIVE: To determine the extent to which disease duration, alone or in combination with other baseline clinical and non-clinical factors, explains variations in outcome of tocilizumab initiated in biologic-naïve patients with established RA. METHODS: In this pooled analysis of phase 3 and 4 clinical trials conducted by the sponsor, predictors of response, including demographics, disease characteristics at baseline (start of tocilizumab dosing) and study characteristics (e.g. patient inclusion criteria, tocilizumab dosing regimen) were evaluated. Response was measured as change from baseline to week 24 in Clinical Disease Activity Index (CDAI) and HAQ-Disability Index (HAQ-DI) scores and as the proportions of patients who experienced ≥50% improvement based on ACR criteria (ACR50) and CDAI remission (≤2.8) rates at week 24. RESULTS: Improvements in all outcomes investigated were observed in patients receiving tocilizumab. Although disease duration was statistically significant in the models, it accounted for <2% of variation in CDAI and HAQ-DI score changes from baseline to week 24; baseline CDAI and HAQ-DI values accounted for 32% and 15% of variations, respectively. Doubling of disease duration reduced the odds of achieving an ACR50 response by only 9%, and each additional 5-year period of disease duration decreased the odds of achieving CDAI remission by only 15%. CONCLUSION: RA duration, alone or in combination with other baseline characteristics, had a statistically significant but clinically small effect on the outcomes of tocilizumab initiated in biologic-naïve patients with established RA.

Long-term safety and effectiveness of tocilizumab in patients with rheumatoid arthritis and inadequate responses to csDMARDs and/or TNF inhibitors: an open-label study close to clinical practice.

OBJECTIVE: To assess the long-term safety, tolerability, and effectiveness of tocilizumab (TCZ) as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in clinical practice in patients with moderate to severe rheumatoid arthritis (RA). METHODS: Patients in the 24-week, open-label ACT-SURE study who had at least a moderate EULAR response by week 24 and were from a participating country were eligible for this long-term extension (LTE); the patients continued to receive TCZ 8 mg/kg intravenously every 4 weeks as monotherapy or in combination with ≥ 1 csDMARD for up to an additional 108 weeks. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs). Effectiveness endpoints included Disease Activity Score in 28 joints (DAS28) responses, American College of Rheumatology (ACR) responses, and patient-reported outcomes (PROs). RESULTS: Of the 1102 patients who completed the core 24-week study, 934 participated in the LTE; the median exposure to TCZ was 64.3 weeks. From baseline to the end of the LTE, AEs and SAEs occurred in 90% and 9% of patients, respectively. The overall event rates (95% CI) of AEs and SAEs were 406.5 per 100 patient-years (PY) (395.5, 417.8) and 8.8 per 100 PY (7.3, 10.6), respectively. Mean (SD) improvement in DAS28 was 4.12 (1.18), P < 0.0001. The DAS28 remission rates, ACR response rates, and PRO scores were maintained during the LTE study. CONCLUSION: In clinical practice, TCZ as monotherapy or in combination with csDMARDs was safe, well tolerated, and efficacious in patients with moderate to severe RA.

Schwann cells, but not Oligodendrocytes, Depend Strictly on Dynamin 2 Function.

Myelination requires extensive plasma membrane rearrangements, implying that molecules controlling membrane dynamics play prominent roles. The large GTPase dynamin 2 (DNM2) is a well-known regulator of membrane remodeling, membrane fission, and vesicular trafficking. Here, we genetically ablated Dnm2 in Schwann cells (SCs) and in oligodendrocytes of mice. Dnm2 deletion in developing SCs resulted in severely impaired axonal sorting and myelination onset. Induced Dnm2 deletion in adult SCs caused a rapidly-developing peripheral neuropathy with abundant demyelination. In both experimental settings, mutant SCs underwent prominent cell death, at least partially due to cytokinesis failure. Strikingly, when Dnm2 was deleted in adult SCs, non-recombined SCs still expressing DNM2 were able to remyelinate fast and efficiently, accompanied by neuropathy remission. These findings reveal a remarkable self-healing capability of peripheral nerves that are affected by SC loss. In the central nervous system, however, we found no major defects upon Dnm2 deletion in oligodendrocytes.

Median time to low disease activity is shorter in tocilizumab combination therapy with csDMARDs as compared to tocilizumab monotherapy in patients with active rheumatoid arthritis and inadequate responses to csDMARDs and/or TNF inhibitors: sub-analysis of the Swiss and Austrian patients from the ACT-SURE study.

To analyse efficacy and safety of tocilizumab in patients with rheumatoid arthritis (RA) and an inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and/or tumour necrosis factor (TNF) inhibitors of the Swiss and Austrian patients from the ACT-SURE study. This is a sub-analysis of RA patients from Switzerland and Austria, who participated in the international phase 3b, open-label, ACT-SURE study. Patients with an inadequate response to csDMARDs or TNF antagonists receiving 8 mg/kg of IV tocilizumab every 4 weeks during a 24-week time period were included into the study. Therapy with one or more csDMARDs could be continued as combination therapy with tocilizumab (Combo) or stopped, resulting in tocilizumab monotherapy (Mono), at the treating physician's discretion. These two patient groups were analysed in separate and compared. Overall, 107 (22 on Mono vs. 85 on Combo) patients were treated with tocilizumab. The percentage of patients with at least one adverse event was significantly lower in the tocilizumab combination (58.8%) as compared to the monotherapy group (81.8%, p = 0.0458). No differences in ACR20/50/70/90 response rates were observed between both treatment groups at week 24 (Mono 63.6, 40.9, 22.7, and 18.2% vs. Combo 61.2, 43.5, 25.9, and 10.6%). The median time to low disease activity (LDA) was significantly shorter in patients treated with tocilizumab combination therapy (Mono 9.1, Combo 7.9 weeks, log rank p = 0.038). In this post hoc regional sub-analysis of the ACT-SURE study, no differences for disease activity were found comparing the two patient groups at week 24. However, median time to LDA was statistically shorter in patients treated with tocilizumab combination therapy as compared to tocilizumab monotherapy. Consequently, adding tocilizumab to csDMARD therapy rather than changing to tocilizumab monotherapy may be, in our opinion, the safest strategy to reach maximum effect in RA patients with active disease despite treatment with csDMARD. csDMARDs can be withdrawn either immediately due to adverse events or after at least low disease activity has been reached.

HDAC1/2-Dependent P0 Expression Maintains Paranodal and Nodal Integrity Independently of Myelin Stability through Interactions with Neurofascins.

The pathogenesis of peripheral neuropathies in adults is linked to maintenance mechanisms that are not well understood. Here, we elucidate a novel critical maintenance mechanism for Schwann cell (SC)-axon interaction. Using mouse genetics, ablation of the transcriptional regulators histone deacetylases 1 and 2 (HDAC1/2) in adult SCs severely affected paranodal and nodal integrity and led to demyelination/remyelination. Expression levels of the HDAC1/2 target gene myelin protein zero (P0) were reduced by half, accompanied by altered localization and stability of neurofascin (NFasc)155, NFasc186, and loss of Caspr and septate-like junctions. We identify P0 as a novel binding partner of NFasc155 and NFasc186, both in vivo and by in vitro adhesion assay. Furthermore, we demonstrate that HDAC1/2-dependent P0 expression is crucial for the maintenance of paranodal/nodal integrity and axonal function through interaction of P0 with neurofascins. In addition, we show that the latter mechanism is impaired by some P0 mutations that lead to late onset Charcot-Marie-Tooth disease.

Myelin is dependent on the Charcot-Marie-Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells.

Studying the function and malfunction of genes and proteins associated with inherited forms of peripheral neuropathies has provided multiple clues to our understanding of myelinated nerves in health and disease. Here, we have generated a mouse model for the peripheral neuropathy Charcot-Marie-Tooth disease type 4H by constitutively disrupting the mouse orthologue of the suspected culprit gene FGD4 that encodes the small RhoGTPase Cdc42-guanine nucleotide exchange factor Frabin. Lack of Frabin/Fgd4 causes dysmyelination in mice in early peripheral nerve development, followed by profound myelin abnormalities and demyelination at later stages. At the age of 60 weeks, this was accompanied by electrophysiological deficits. By crossing mice carrying alleles of Frabin/Fgd4 flanked by loxP sequences with animals expressing Cre recombinase in a cell type-specific manner, we show that Schwann cell-autonomous Frabin/Fgd4 function is essential for proper myelination without detectable primary contributions from neurons. Deletion of Frabin/Fgd4 in Schwann cells of fully myelinated nerve fibres revealed that this protein is not only required for correct nerve development but also for accurate myelin maintenance. Moreover, we established that correct activation of Cdc42 is dependent on Frabin/Fgd4 function in healthy peripheral nerves. Genetic disruption of Cdc42 in Schwann cells of adult myelinated nerves resulted in myelin alterations similar to those observed in Frabin/Fgd4-deficient mice, indicating that Cdc42 and the Frabin/Fgd4-Cdc42 axis are critical for myelin homeostasis. In line with known regulatory roles of Cdc42, we found that Frabin/Fgd4 regulates Schwann cell endocytosis, a process that is increasingly recognized as a relevant mechanism in peripheral nerve pathophysiology. Taken together, our results indicate that regulation of Cdc42 by Frabin/Fgd4 in Schwann cells is critical for the structure and function of the peripheral nervous system. In particular, this regulatory link is continuously required in adult fully myelinated nerve fibres. Thus, mechanisms regulated by Frabin/Fgd4-Cdc42 are promising targets that can help to identify additional regulators of myelin development and homeostasis, which may crucially contribute also to malfunctions in different types of peripheral neuropathies.

Dynamin 2 mutations in Charcot-Marie-Tooth neuropathy highlight the importance of clathrin-mediated endocytosis in myelination.

Mutations in dynamin 2 (DNM2) lead to dominant intermediate Charcot-Marie-Tooth neuropathy type B, while a different set of DNM2 mutations cause autosomal dominant centronuclear myopathy. In this study, we aimed to elucidate the disease mechanisms in dominant intermediate Charcot-Marie-Tooth neuropathy type B and to find explanations for the tissue-specific defects that are associated with different DNM2 mutations in dominant intermediate Charcot-Marie-Tooth neuropathy type B versus autosomal dominant centronuclear myopathy. We used tissue derived from Dnm2-deficient mice to establish an appropriate peripheral nerve model and found that dominant intermediate Charcot-Marie-Tooth neuropathy type B-associated dynamin 2 mutants, but not autosomal dominant centronuclear myopathy mutants, impaired myelination. In contrast to autosomal dominant centronuclear myopathy mutants, Schwann cells and neurons from the peripheral nervous system expressing dominant intermediate Charcot-Marie-Tooth neuropathy mutants showed defects in clathrin-mediated endocytosis. We demonstrate that, as a consequence, protein surface levels are altered in Schwann cells. Furthermore, we discovered that myelination is strictly dependent on Dnm2 and clathrin-mediated endocytosis function. Thus, we propose that altered endocytosis is a major contributing factor to the disease mechanisms in dominant intermediate Charcot-Marie-Tooth neuropathy type B.

SH3TC2, a protein mutant in Charcot-Marie-Tooth neuropathy, links peripheral nerve myelination to endosomal recycling.

Patients with Charcot-Marie-Tooth neuropathy and gene targeting in mice revealed an essential role for the SH3TC2 gene in peripheral nerve myelination. SH3TC2 expression is restricted to Schwann cells in the peripheral nervous system, and the gene product, SH3TC2, localizes to the perinuclear recycling compartment. Here, we show that SH3TC2 interacts with the small guanosine triphosphatase Rab11, which is known to regulate the recycling of internalized membranes and receptors back to the cell surface. Results of protein binding studies and transferrin receptor trafficking are in line with a role of SH3TC2 as a Rab11 effector molecule. Consistent with a function of Rab11 in Schwann cell myelination, SH3TC2 mutations that cause neuropathy disrupt the SH3TC2/Rab11 interaction, and forced expression of dominant negative Rab11 strongly impairs myelin formation in vitro. Our data indicate that the SH3TC2/Rab11 interaction is relevant for peripheral nerve pathophysiology and place endosomal recycling on the list of cellular mechanisms involved in Schwann cell myelination.