Clinical and humoral response after SARS-CoV-2 breakthrough infection in patients receiving immunosuppressant therapy.

BACKGROUND: Despite impaired humoral response in patients treated with immunosuppressants (ISPs), recent studies found similar severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection compared to controls. One potential explanation is the rapid generation of humoral response on infection, but evidence is lacking. OBJECTIVES: We investigated the longitudinal dynamics of the SARS-CoV-2 antibody repertoire after SARS-CoV-2 delta and omicron breakthrough infection in patients with immune-mediated inflammatory diseases (IMIDs) receiving ISP therapy and controls. METHODS: As a prospective substudy of the national Target-to-B! (T2B!) consortium, we included IMID patients receiving ISPs therapy and controls who reported SARS-CoV-2 breakthrough infection between July 1, 2021, and April 1, 2022. To get an impression of the dynamics of the antibody repertoire, 3 antibody titers of wild-type RBD, wild-type S, and omicron RBD were measured at 4 time points after SARS-CoV-2 breakthrough infection. RESULTS: We included 302 IMID patients receiving ISPs and 178 controls. Antibody titers increased up to 28 days after breakthrough infection in both groups. However, in IMID patients receiving therapy with anti-CD20 and sphingosine-1 phosphate receptor modulators, antibody titers were considerably lower compared to controls. In the anti-TNF group, we observed slightly lower antibody titers in the early stages and a faster decline of antibodies after infection compared to controls. Breakthrough infections were mostly mild, and hospitalization was required in less than 1% of cases. CONCLUSIONS: Most ISPs do not influence the dynamics of the SARS-CoV-2 antibody repertoire and exhibit a rapid recall response with cross-reactive antibody clones toward new virus variants. However, in patients treated with anti-CD20 therapy or sphingosine-1 phosphate receptor modulators, the dynamics were greatly impaired, and to a lesser extent in those who received anti-TNF. Nevertheless, only a few severe breakthrough cases were reported.

IgM anti-GM2 antibodies in patients with multifocal motor neuropathy target Schwann cells and are associated with early onset.

BACKGROUND: Multifocal motor neuropathy (MMN) is a rare, chronic immune-mediated polyneuropathy characterized by asymmetric distal limb weakness. An important feature of MMN is the presence of IgM antibodies against gangliosides, in particular GM1 and less often GM2. Antibodies against GM1 bind to motor neurons (MNs) and cause damage through complement activation. The involvement of Schwann cells (SCs), expressing GM1 and GM2, in the pathogenesis of MMN is unknown. METHODS: Combining the data of our 2007 and 2015 combined cross-sectional and follow-up studies in Dutch patients with MMN, we evaluated the presence of IgM antibodies against GM1 and GM2 in serum from 124 patients with MMN and investigated their binding to SCs and complement-activating properties. We also assessed the relation of IgM binding and complement deposition with clinical characteristics. RESULTS: Thirteen out of 124 patients (10%) had a positive ELISA titer for IgM anti-GM2. Age at onset of symptoms was significantly lower in MMN patients with anti-GM2 IgM. IgM binding to SCs correlated with IgM anti-GM2 titers. We found no correlation between IgM anti-GM2 titers and MN binding or with IgM anti-GM1 titers. IgM binding to SCs decreased upon pre-incubation of serum with soluble GM2, but not with soluble GM1. IgM anti-GM2 binding to SCs correlated with complement activation, as reflected by increased C3 fixation on SCs and C5a formation in the supernatant. CONCLUSION: Circulating IgM anti-GM2 antibodies define a subgroup of patients with MMN that has an earlier onset of disease. These antibodies probably target SCs specifically and activate complement, similarly as IgM anti-GM1 on MNs. Our data indicate that complement activation by IgM antibodies bound to SCs and MNs underlies MMN pathology.

Patient-reported daily functioning after SARS-CoV-2 vaccinations in autoimmune neuromuscular diseases.

BACKGROUND AND PURPOSE: There are concerns for safety regarding SARS-CoV-2 vaccines for patients with autoimmune neuromuscular disease. We compared daily functioning using disease-specific patient-reported outcome measures (PROMs) before and after SARS-CoV-2 vaccinations. METHODS: In this substudy of a prospective observational cohort study (Target-to-B!), patients with myasthenia gravis (MG), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and idiopathic inflammatory myopathy (IIM) vaccinated against SARS-CoV-2 were included. Surveys of daily functioning (Myasthenia Gravis Activities of Daily Living, Inflammatory Rasch-Built Overall Disability Scale, Multifocal Motor Neuropathy Rasch-Built Overall Disability Scale, and Health Assessment Questionnaire-Disability Index) were sent before first vaccination and every 60 days thereafter for up to 12 months. Regression models were constructed to assess differences in PROM scores related to vaccination, compared to scores unrelated to vaccination. We also assessed the proportion of patients with deterioration of at least the minimal clinically important difference (MCID) between before first vaccination and 60 days thereafter. RESULTS: We included 325 patients (median age = 59 years, interquartile range = 47-67, 156 [48%] female sex), of whom 137 (42%) had MG, 79 (24%) had CIDP, 43 (13%) had MMN, and 66 (20%) had IIM. PROM scores related to vaccination did not differ from scores unrelated to vaccination. In paired PROMs, MCID for deterioration was observed in three of 49 (6%) MG patients, of whom none reported a treatment change. In CIDP, MCID for deterioration was observed in eight of 29 patients (28%), of whom two of eight (25%) reported a treatment change. CONCLUSIONS: SARS-CoV-2 vaccination had no effect on daily functioning in patients with autoimmune neuromuscular diseases, confirming its safety in these patients.

A 21-bp deletion in the complement regulator CD55 promotor region is associated with multifocal motor neuropathy and its disease course.

BACKGROUND AND AIMS: To further substantiate the role of antibody-mediated complement activation in multifocal motor neuropathy (MMN) immunopathology, we investigated the distribution of promotor polymorphisms of genes encoding the membrane-bound complement regulators CD46, CD55, and CD59 in patients with MMN and controls, and evaluated their association with disease course. METHODS: We used Sanger sequencing to genotype five common polymorphisms in the promotor regions of CD46, CD55, and CD59 in 133 patients with MMN and 380 controls. We correlated each polymorphism to clinical parameters. RESULTS: The genotype frequencies of rs28371582, a 21-bp deletion in the CD55 promotor region, were altered in patients with MMN as compared to controls (p .009; Del/Del genotype 16.8% vs. 7.7%, p .005, odds ratio: 2.43 [1.27-4.58]), and patients carrying this deletion had a more favorable disease course (mean difference 0.26 Medical Research Council [MRC] points/year; 95% confidence interval [CI]: 0.040-0.490, p .019). The presence of CD59 rs141385724 was associated with less severe pre-diagnostic disease course (mean difference 0.940 MRC point/year; 95% CI: 0.083-1.80, p .032). INTERPRETATION: MMN susceptibility is associated with a 21-bp deletion in the CD55 promotor region (rs2871582), which is associated with lower CD55 expression. Patients carrying this deletion may have a more favorable long-term disease outcome. Taken together, these results point out the relevance of the pre-C5 level of the complement cascade in the inflammatory processes underlying MMN.

Disease activity in patients with immune-mediated inflammatory diseases after SARS-CoV-2 vaccinations.

For patients with immune-mediated inflammatory diseases (IMIDs), concerns exist about increased disease activity after vaccination. We aimed to assess changes in disease activity after SARS-CoV-2 vaccination in patients with IMIDs, and determine risk factors for increased disease activity. In this substudy of a prospective observational cohort study (Target-to-B!), we included patients with IMIDs who received a SARS-CoV-2 vaccine. Patients reported changes in disease activity on a five-point Likert scale every 60 days for up to twelve months after first vaccination. In case of self-reported increased activity, hospital records were screened whether the treating physician reported increased activity, and for potential intensification of immunosuppressive (ISP) treatment. Mixed models were used to study determinants for self-reported increased disease activity. In total, 2111 patients were included for analysis after primary immunization (mean age 49.7 years [SD 13.7], 1329/2111 (63.0%) female), from which 1266 patients for analysis after first additional vaccination. Increased disease activity at 60 days after start of primary immunization was reported by 223/2111 (10.6%). In 96/223 (43.0%) the increase was confirmed by the treating physician and in 36/223 (16.1%) ISP treatment was intensified. Increased disease activity at seven to 60 days after additional vaccination, was reported by 139/1266 (11.0%). Vaccinations were not temporally associated with self-reported increased disease activity. Conversely, increased disease activity before first vaccination, neuromuscular disease, and multiple sclerosis were associated. Altogether, self-reported increased disease activity after vaccination against SARS-CoV-2 was recorded in a minority of patients and was generally mild. Moreover, multivariate analyses suggest that disease related factors, but not vaccinations are the major determinants for self-reported increased disease activity.

The RESISTANT study (Respiratory Muscle Training in Patients with Spinal Muscular Atrophy): study protocol for a randomized controlled trial.

BACKGROUND: Spinal Muscular Atrophy (SMA) is characterized by progressive and predominantly proximal and axial muscle atrophy and weakness. Respiratory muscle weakness results in impaired cough with recurrent respiratory tract infections, nocturnal hypoventilation, and may ultimately lead to fatal respiratory failure in the most severely affected patients. Treatment strategies to either slow down the decline or improve respiratory muscle function are wanting. OBJECTIVE: The aim of this study is to assess the feasibility and efficacy of respiratory muscle training (RMT) in patients with SMA and respiratory muscle weakness. METHODS: The effect of RMT in patients with SMA, aged ≥ 8 years with respiratory muscle weakness (maximum inspiratory mouth pressure [PImax] ≤ 80 Centimeters of Water Column [cmH2O]), will be investigated with a single blinded randomized sham-controlled trial consisting of a 4-month training period followed by an 8-month open label extension phase. INTERVENTION: The RMT program will consist of a home-based, individualized training program involving 30-breathing cycles through an inspiratory and expiratory muscle training device. Patients will be instructed to perform 10 training sessions over 5-7 days per week. In the active training group, the inspiratory and expiratory threshold will be adjusted to perceived exertion (measured on a Borg scale). The sham-control group will initially receive RMT at the same frequency but against a constant, non-therapeutic resistance. After four months the sham-control group will undergo the same intervention as the active training group (i.e., delayed intervention). Individual adherence to the RMT protocol will be reviewed every two weeks by telephone/video call with a physiotherapist. MAIN STUDY PARAMETERS/ENDPOINTS: We hypothesize that the RMT program will be feasible (good adherence and good acceptability) and improve inspiratory muscle strength (primary outcome measure) and expiratory muscle strength (key secondary outcome measure) as well as lung function, patient reported breathing difficulties, respiratory infections, and health related quality of life (additional secondary outcome measures, respectively) in patients with SMA. DISCUSSION: RMT is expected to have positive effects on respiratory muscle strength in patients with SMA. Integrating RMT with recently introduced genetic therapies for SMA may improve respiratory muscle strength in this patient population. TRIAL REGISTRATION: Retrospectively registered at clinicaltrial.gov: NCT05632666.

Longitudinal prospective cohort study to assess peripheral motor function with extensive electrophysiological techniques in patients with Spinal Muscular Atrophy (SMA): the SMA Motor Map protocol.

BACKGROUND: Hereditary spinal muscular atrophy (SMA) is a motor neuron disorder with a wide range in severity in children and adults. Two therapies that alter splicing of the Survival Motor Neuron 2 (SMN2) gene, i.e. nusinersen and risdiplam, improve motor function in SMA, but treatment effects vary. Experimental studies indicate that motor unit dysfunction encompasses multiple features, including abnormal function of the motor neuron, axon, neuromuscular junction and muscle fibres. The relative contributions of dysfunction of different parts of the motor unit to the clinical phenotype are unknown. Predictive biomarkers for clinical efficacy are currently lacking. The goals of this project are to study the association of electrophysiological abnormalities of the peripheral motor system in relation to 1) SMA clinical phenotypes and 2) treatment response in patients treated with SMN2-splicing modifiers (nusinersen or risdiplam). METHODS: We designed an investigator-initiated, monocentre, longitudinal cohort study using electrophysiological techniques ('the SMA Motor Map') in Dutch children (≥ 12 years) and adults with SMA types 1-4. The protocol includes the compound muscle action potential scan, nerve excitability testing and repetitive nerve stimulation test, executed unilaterally at the median nerve. Part one cross-sectionally assesses the association of electrophysiological abnormalities in relation to SMA clinical phenotypes in treatment-naïve patients. Part two investigates the predictive value of electrophysiological changes at two-months treatment for a positive clinical motor response after one-year treatment with SMN2-splicing modifiers. We will include 100 patients in each part of the study. DISCUSSION: This study will provide important information on the pathophysiology of the peripheral motor system of treatment-naïve patients with SMA through electrophysiological techniques. More importantly, the longitudinal analysis in patients on SMN2-splicing modifying therapies (i.e. nusinersen and risdiplam) intents to develop non-invasive electrophysiological biomarkers for treatment response in order to improve (individualized) treatment decisions. TRIAL REGISTRATION: NL72562.041.20 (registered at https://www.toetsingonline.nl . 26-03-2020).

Primary SARS-CoV-2 infection in patients with immune-mediated inflammatory diseases: long-term humoral immune responses and effects on disease activity.

BACKGROUND: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV-2 infection. We aimed to investigate long-term humoral immune responses against SARS-CoV-2 and increased disease activity after a primary SARS-CoV-2 infection in unvaccinated IMID patients on ISPs. METHODS: IMID patients on active treatment with ISPs and controls (i.e. IMID patients not on ISP and healthy controls) with a confirmed SARS-CoV-2 infection before first vaccination were included from an ongoing prospective cohort study (T2B! study). Clinical data on infections and increased disease activity were registered using electronic surveys and health records. A serum sample was collected before first vaccination to measure SARS-CoV-2 anti-receptor-binding domain (RBD) antibodies. RESULTS: In total, 193 IMID patients on ISP and 113 controls were included. Serum samples from 185 participants were available, with a median time of 173 days between infection and sample collection. The rate of seropositive IMID patients on ISPs was 78% compared to 100% in controls (p < 0.001). Seropositivity rates were lowest in patients on anti-CD20 (40.0%) and anti-tumor necrosis factor (TNF) agents (60.5%), as compared to other ISPs (p < 0.001 and p < 0.001, respectively). Increased disease activity after infection was reported by 68 of 260 patients (26.2%; 95% CI 21.2-31.8%), leading to ISP intensification in 6 out of these 68 patients (8.8%). CONCLUSION: IMID patients using ISPs showed reduced long-term humoral immune responses after primary SARS-CoV-2 infection, which was mainly attributed to treatment with anti-CD20 and anti-TNF agents. Increased disease activity after SARS-CoV-2 infection was reported commonly, but was mostly mild. TRIAL REGISTRATION: NL74974.018.20, Trial ID: NL8900. Registered on 9 September 2020.

Magnetic resonance reveals mitochondrial dysfunction and muscle remodelling in spinal muscular atrophy.

Genetic therapy has changed the prognosis of hereditary proximal spinal muscular atrophy, although treatment efficacy has been variable. There is a clear need for deeper understanding of underlying causes of muscle weakness and exercise intolerance in patients with this disease to further optimize treatment strategies. Animal models suggest that in addition to motor neuron and associated musculature degeneration, intrinsic abnormalities of muscle itself including mitochondrial dysfunction contribute to the disease aetiology. To test this hypothesis in patients, we conducted the first in vivo clinical investigation of muscle bioenergetics. We recruited 15 patients and 15 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. MRI and 31P magnetic resonance spectroscopy, the modality of choice to interrogate muscle energetics and phenotypic fibre-type makeup, was performed of the proximal arm musculature in combination with fatiguing arm-cycling exercise and blood lactate testing. We derived bioenergetic parameter estimates including: blood lactate, intramuscular pH and inorganic phosphate accumulation during exercise, and muscle dynamic recovery constants. A linear correlation was used to test for associations between muscle morphological and bioenergetic parameters and clinico-functional measures of muscle weakness. MRI showed significant atrophy of triceps but not biceps muscles in patients. Maximal voluntary contraction force normalized to muscle cross-sectional area for both arm muscles was 1.4-fold lower in patients than in controls, indicating altered intrinsic muscle properties other than atrophy contributed to muscle weakness in this cohort. In vivo31P magnetic resonance spectroscopy identified white-to-red remodelling of residual proximal arm musculature in patients on the basis of altered intramuscular inorganic phosphate accumulation during arm-cycling in red versus white and intermediate myofibres. Blood lactate rise during arm-cycling was blunted in patients and correlated with muscle weakness and phenotypic muscle makeup. Post-exercise metabolic recovery was slower in residual intramuscular white myofibres in patients demonstrating mitochondrial ATP synthetic dysfunction in this particular fibre type. This study provides the first in vivo evidence in patients that degeneration of motor neurons and associated musculature causing atrophy and muscle weakness in 5q spinal muscular atrophy type 3 and 4 is aggravated by disproportionate depletion of myofibres that contract fastest and strongest. Our finding of decreased mitochondrial ATP synthetic function selectively in residual white myofibres provides both a possible clue to understanding the apparent vulnerability of this particular fibre type in 5q spinal muscular atrophy types 3 and 4 as well as a new biomarker and target for therapy.

Risk factors associated with short-term adverse events after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory diseases.

BACKGROUND: Studies have suggested incremental short-term adverse events (AE) after repeated vaccination. In this report, we assessed occurrence and risk factors for short-term AEs following repeated SARS-CoV-2 vaccination in patients with various immune-mediated inflammatory diseases (IMIDs). METHODS: Self-reported daily questionnaires on AEs during the first 7 days after vaccination were obtained of 2259 individuals (2081 patients and 178 controls) participating in an ongoing prospective multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B-COVID). Relative risks were calculated for potential risk factors associated with clinically relevant AE (rAE), defined as AE lasting longer than 2 days or impacting daily life. RESULTS: In total, 5454 vaccinations were recorded (1737 first, 1992 second and 1478 third vaccinations). Multiple sclerosis, Crohn's disease and rheumatoid arthritis were the largest disease groups. rAEs were reported by 57.3% (95% CI 54.8-59.8) of patients after the first vaccination, 61.5% (95% CI 59.2-63.7) after the second vaccination and 58% (95% CI 55.3-60.6) after the third vaccination. At day 7 after the first, second and third vaccination, respectively, 7.6% (95% CI 6.3-9.1), 7.4% (95% CI 6.2-8.7) and 6.8% (95% CI 5.4-8.3) of patients still reported AEs impacting daily life. Hospital admissions and allergic reactions were uncommon (<0.7%). Female sex (aRR 1.43, 95% CI 1.32-1.56), age below 50 (aRR 1.14, 95% CI 1.06-1.23), a preceding SARS-CoV-2 infection (aRR 1.14, 95% CI 1.01-1.29) and having an IMID (aRR 1.16, 95% CI 1.01-1.34) were associated with increased risk of rAEs following a vaccination. Compared to the second vaccination, the first vaccination was associated with a lower risk of rAEs (aRR 0.92, 95% CI 0.84-0.99) while a third vaccination was not associated with increased risk on rAEs (aRR 0.93, 95% CI 0.84-1.02). BNT162b2 vaccines were associated with lower risk on rAEs compared to CX-024414 (aRR 0.86, 95% CI 0.80-0.93). CONCLUSIONS: A third SARS-CoV-2 vaccination was not associated with increased risk of rAEs in IMID patients compared to the second vaccination. Patients with an IMID have a modestly increased risk of rAEs after vaccination when compared to controls. Most AEs are resolved within 7 days; hospital admissions and allergic reactions were uncommon. TRIAL REGISTRATION: NL74974.018.20 , Trial ID: NL8900. Registered on 9 September 2020.

Breakthrough infections with the SARS-CoV-2 omicron (B.1.1.529) variant in patients with immune-mediated inflammatory diseases.

OBJECTIVES: To compare the cumulative incidence and disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with immune-mediated inflammatory diseases (IMID) on immunosuppressants and controls, and to investigate determinants for breakthrough infections. METHODS: Data were used from an ongoing national prospective multicentre cohort study on SARS-CoV-2 vaccination responses in patients with IMID in the Netherlands (Target-to-B! (T2B!) study). Patients wih IMID on immunosuppressants and controls (patients with IMID not on immunosuppressants and healthy controls) who completed primary immunisation were included. The observation period was between 1 January 2022 and 1 April 2022, during which the SARS-CoV-2 omicron (BA.1 and BA.2 subvariant) was dominant. A SARS-CoV-2 breakthrough infection was defined as a reported positive PCR and/or antigen test at least 14 days after primary immunisation. A multivariate logistic regression model was used to investigate determinants. RESULTS: 1593 patients with IMID on immunosuppressants and 579 controls were included. The cumulative incidence of breakthrough infections was 472/1593 (29.6%; 95% CI 27% to 32%) in patients with IMID on immunosuppressants and 181/579 (31.3%; 95% CI 28% to 35%) in controls (p=0.42). Three (0.5%) participants had severe disease. Seroconversion after primary immunisation (relative risk, RR 0.71; 95% CI 0.52 to 0.96), additional vaccinations (RR 0.61; 95% CI 0.49 to 0.76) and a prior SARS-CoV-2 infection (RR 0.60; 95% CI 0.48 to 0.75) were associated with decreased risk of breakthrough infection. CONCLUSIONS: The cumulative incidence of reported SARS-CoV-2 omicron breakthrough infections was high, but similar between patients with IMID on immunosuppressants and controls, and disease severity was mostly mild. Additional vaccinations and prior SARS-CoV-2 infections may reduce the incidence of breakthrough infections.

Multi-parametric quantitative magnetic resonance imaging of the upper arm muscles of patients with spinal muscular atrophy.

Quantitative magnetic resonance imaging (qMRI) is frequently used to map the disease state and disease progression in the lower extremity muscles of patients with spinal muscular atrophy (SMA). This is in stark contrast to the almost complete lack of data on the upper extremity muscles, which are essential for carrying out daily activities. The aim of this study was therefore to assess the disease state in the upper arm muscles of patients with SMA in comparison with healthy controls by quantitative assessment of fat fraction, diffusion indices, and water T2 relaxation times, and to relate these measures to muscle force. We evaluated 13 patients with SMA and 15 healthy controls with a 3-T MRI protocol consisting of DIXON, diffusion tensor imaging, and T2 sequences. qMRI measures were compared between groups and related to muscle force measured with quantitative myometry. Fat fraction was significantly increased in all upper arm muscles of the patients with SMA compared with healthy controls and correlated negatively with muscle force. Additionally, fat fraction was heterogeneously distributed within the triceps brachii (TB) and brachialis muscle, but not in the biceps brachii muscle. Diffusion indices and water T2 relaxation times were similar between patients with SMA and healthy controls, but we did find a slightly reduced mean diffusivity (MD), λ1, and λ3 in the TB of patients with SMA. Furthermore, MD was positively correlated with muscle force in the TB of patients with SMA. The variation in fat fraction further substantiates the selective vulnerability of muscles. The reduced diffusion tensor imaging indices, along with the positive correlation of MD with muscle force, point to myofiber atrophy. Our results show the feasibility of qMRI to map the disease state in the upper arm muscles of patients with SMA. Longitudinal data in a larger cohort are needed to further explore qMRI to map disease progression and to capture the possible effects of therapeutic interventions.

Genetic, biochemical, and clinical spectrum of patients with mitochondrial trifunctional protein deficiency identified after the introduction of newborn screening in the Netherlands.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is included in many newborn screening (NBS) programs. Acylcarnitine-based NBS for LCHADD not only identifies LCHADD, but also the other deficiencies of the mitochondrial trifunctional protein (MTP), a multi-enzyme complex involved in long-chain fatty acid ß-oxidation. Besides LCHAD, MTP harbors two additional enzyme activities: long-chain enoyl-CoA hydratase (LCEH) and long-chain ketoacyl-CoA thiolase (LCKAT). Deficiency of one or more MTP activities causes generalized MTP deficiency (MTPD), LCHADD, LCEH deficiency (not yet reported), or LCKAT deficiency (LCKATD). To gain insight in the outcomes of MTP-deficient patients diagnosed after the introduction of NBS for LCHADD in the Netherlands, a retrospective evaluation of genetic, biochemical, and clinical characteristics of MTP-deficient patients, identified since 2007, was carried out. Thirteen patients were identified: seven with LCHADD, five with MTPD, and one with LCKATD. All LCHADD patients (one missed by NBS, clinical diagnosis) and one MTPD patient (clinical diagnosis) were alive. Four MTPD patients and one LCKATD patient developed cardiomyopathy and died within 1 month and 13 months of life, respectively. Surviving patients did not develop symptomatic hypoglycemia, but experienced reversible cardiomyopathy and rhabdomyolysis. Five LCHADD patients developed subclinical neuropathy and/or retinopathy. In conclusion, patient outcomes were highly variable, stressing the need for accurate classification of and discrimination between the MTP deficiencies to improve insight in the yield of NBS for LCHADD. NBS allowed the prevention of symptomatic hypoglycemia, but current treatment options failed to treat cardiomyopathy and prevent long-term complications. Moreover, milder patients, who might benefit from NBS, were missed due to normal acylcarnitine profiles.

The reimbursement for expensive medicines: stakeholder perspectives on the SMA medicine nusinersen and the Dutch Coverage Lock policy.

BACKGROUND: The reimbursement for expensive medicines poses a growing challenge to healthcare worldwide. In order to increase its control over the costs of medicines, the Dutch government introduced the Coverage Lock (CL) policy in 2015. The CL postpones decisions regarding reimbursement of expensive medicines until detailed advice on i.e., cost-effectiveness has been given. The CL has been in place for six years, has raised many questions and concerns, but currently, no evaluation is known to the authors. A better understanding of the effects of the CL on all stakeholders involved may contribute to reflections on the CL process and help find ways to improve it. An evaluation of Dutch policy will also be relevant for other countries that aim to optimize reimbursement procedures for expensive treatments. To perform this evaluation, we focused on the CL procedure for the medicine nusinersen. Nusinersen is the first treatment for spinal muscular atrophy (SMA). Following EMA approval in May 2017, it was placed in the CL. The analysis of cost-effectiveness and added therapeutic value resulted in an advice for reimbursement limited to children younger than 9.5 years at the start of treatment; this was implemented from August 2018 onwards. METHODS: Qualitative stakeholder perspective analysis of the CL procedure focusing on nusinersen with 15 stakeholders. RESULTS: Stakeholders raised key issues of the CL based on their experience with nusinersen: emotional impact of the CL, duration of the CL procedure, appropriateness of the CL procedure for different types of medicines, transparency of the CL, a wish for patient-centred decision-making and the lack of uniformity of access to expensive treatments. DISCUSSION: Stakeholders supported measures to control healthcare expenses and to ensure reasonable pricing. They considered the delay in access to therapies and lack of procedural transparency to be the main challenges to the CL. Stakeholders also agreed that the interests of patients deserve more attention in the practical implementation of the reimbursement decision. Stakeholders suggested a number of adjustments to improve the CL, such as a faster start with conditional reimbursement programs to ensure access and intensify European collaboration to speed up the assessment of the medicine.

'This battle, between your gut feeling and your mind. Try to find the right balance': Parental experiences of children with spinal muscular atrophy during COVID-19 pandemic.

AIMS: Parents of children with spinal muscular atrophy (SMA) often struggle with the all-consuming nature of the demands of caring for a child with substantial physical needs. Our aim was to explore experiences, challenges and needs of parents of a child with SMA in a COVID-19 pandemic situation. METHOD: Nineteen parents of 21 children (15 months to 13 years of age) with SMA types 1-3 participated in semi-structured interviews in June to July 2020. The interviews were analysed using inductive thematic analysis. RESULTS: Parents mentioned the protection of the health and well-being of the child as the central perspective and driving force during the COVID-19 pandemic. Three subthemes were identified: (1) responsibility, (2) balancing vulnerability and resilience and (3) (in)security. Some parents focused on the positive aspects during the lockdown, such as continuation of nusinersen treatment and family life. Some parents described helpful and positive cognitions to cope with the situation. In general, parents described a need for information with regard to COVID-19 and their child with SMA and a need for discussing their dilemmas and insecurities with a healthcare professional. INTERPRETATION: Parents put the health and well-being of their children first during the pandemic. From this study, we learned that parents of children with SMA need information and value direct contact with a healthcare professional to share their dilemmas and insecurities. The dialogue can help to empower parents in the conflicts and decisions they have to make during a pandemic.

Biomarker profiles of endothelial activation and dysfunction in rare systemic autoimmune diseases: implications for cardiovascular risk.

OBJECTIVES: Vasculopathy is an important hallmark of systemic chronic inflammatory connective tissue diseases (CICTD) and is associated with increased cardiovascular risk. We investigated disease-specific biomarker profiles associated with endothelial dysfunction, angiogenic homeostasis and (tissue) inflammation, and their relation to disease activity in rare CICTD. METHODS: A total of 38 serum proteins associated with endothelial (dys)function and inflammation were measured by multiplex-immunoassay in treatment-naive patients with localized scleroderma (LoS, 30), eosinophilic fasciitis (EF, 8) or (juvenile) dermatomyositis (34), 119 (follow-up) samples during treatment, and 65 controls. Data were analysed by unsupervised clustering, Spearman correlations, non-parametric t test and ANOVA. RESULTS: The systemic CICTD, EF and dermatomyositis, had distinct biomarker profiles, with 'signature' markers galectin-9 (dermatomyositis) and CCL4, CCL18, CXCL9, fetuin, fibronectin, galectin-1 and TSP-1 (EF). In LoS, CCL18, CXCL9 and CXCL10 were subtly increased. Furthermore, dermatomyositis and EF shared upregulation of markers related to interferon (CCL2, CXCL10), endothelial activation (VCAM-1), inhibition of angiogenesis (angiopoietin-2, sVEGFR-1) and inflammation/leucocyte chemo-attraction (CCL19, CXCL13, IL-18, YKL-40), as well as disturbance of the Angiopoietin-Tie receptor system and VEGF-VEGFR system. These profiles were related to disease activity, and largely normalized during treatment. However, a subgroup of CICTD patients showed continued elevation of CXCL10, CXCL13, galectin-9, IL-18, TNFR2, VCAM-1, and/or YKL-40 during clinically inactive disease, possibly indicating subclinical interferon-driven inflammation and/or endothelial dysfunction. CONCLUSION: CICTD-specific biomarker profiles revealed an anti-angiogenic, interferon-driven environment during active disease, with incomplete normalization under treatment. This warrants further investigation into monitoring of vascular biomarkers during clinical follow-up, or targeted interventions to minimize cardiovascular risk in the long term.

Quantification of disease progression in spinal muscular atrophy with muscle MRI-a pilot study.

OBJECTIVES: Quantitative MRI (qMRI) of muscles is a promising tool to measure disease progression or to assess therapeutic effects in neuromuscular diseases. Longitudinal imaging studies are needed to show sensitivity of qMRI in detecting disease progression in spinal muscular atrophy (SMA). In this pilot study we therefore studied one-year changes in quantitative MR parameters in relation to clinical scores. METHODS: We repeated quantitative 3 T MR analysis of thigh muscles and clinical testing one year after baseline in 10 treatment-naïve patients with SMA, 5 with Type 2 (21.6 ± 7.0 years) and 5 with Type 3 (33.4 ± 11.9 years). MR protocol consisted of Dixon, T2 mapping and diffusion tensor imaging (DTI). The temporal relation of parameters was examined with a mixed model. RESULTS: We detected a significant increase in fat fraction (baseline, 38.2% SE 0.6; follow-up, 39.5% SE 0.6; +1.3%, p = 0.001) in all muscles. Muscles with moderate to high fat infiltration at baseline show a larger increase over time (+1.6%, p < 0.001). We did not find any changes in DTI parameters except for low fat-infiltration muscles (m. adductor longus and m. biceps femoris (short head)). The T2 of muscles decreased from 28.2 ms to 28.0 ms (p = 0.07). Muscle strength and motor function scores were not significantly different between follow-up and baseline. CONCLUSION: Longitudinal imaging data show slow disease progression in skeletal muscle of the thigh of (young-) adult patients with SMA despite stable strength and motor function scores. Quantitative muscle imaging demonstrates potential as a biomarker for disease activity and monitoring of therapy response.

Quantitative magnetic resonance imaging of the brachial plexus shows specific changes in nerve architecture in chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and motor neuron disease.

BACKGROUND: The immunological pathophysiologies of chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) differ considerably, but neither has been elucidated completely. Quantitative magnetic resonance imaging (MRI) techniques such as diffusion tensor imaging, T2 mapping, and fat fraction analysis may indicate in vivo pathophysiological changes in nerve architecture. Our study aimed to systematically study nerve architecture of the brachial plexus in patients with CIDP, MMN, motor neuron disease (MND) and healthy controls using these quantitative MRI techniques. METHODS: We enrolled patients with CIDP (n = 47), MMN (n = 29), MND (n = 40) and healthy controls (n = 10). All patients underwent MRI of the brachial plexus and we obtained diffusion parameters, T2 relaxation times and fat fraction using an automated processing pipeline. We compared these parameters between groups using a univariate general linear model. RESULTS: Fractional anisotropy was lower in patients with CIDP compared to healthy controls (p < 0.001), patients with MND (p = 0.010) and MMN (p < 0.001). Radial diffusivity was higher in patients with CIDP compared to healthy controls (p = 0.015) and patients with MND (p = 0.001) and MMN (p < 0.001). T2 relaxation time was elevated in patients with CIDP compared to patients with MND (p = 0.023). Fat fraction was lower in patients with CIDP and MMN compared to patients with MND (both p < 0.001). CONCLUSION: Our results show that quantitative MRI parameters differ between CIDP, MMN and MND, which may reflect differences in underlying pathophysiological mechanisms.

Parents' perspectives on nusinersen treatment for children with spinal muscular atrophy.

AIM: To gain insight into parents' perspectives about their decision-making process concerning nusinersen treatment for their child, including perceived needs and concerns, and to explore factors that influence this process. METHOD: This was an exploratory qualitative interview study among parents of children with spinal muscular atrophy types 1 to 3. Data were analysed using inductive thematic analysis. RESULTS: Nineteen parents of 16 children representing 13 families participated. A wide variety of perspectives was reported ranging from a biomedical approach, which focused on battling the disease, to a holistic approach, which aimed for a good quality of life for their child. The most important factors that helped parents to decide were honest and neutral communication with their physician and access to available information. INTERPRETATION: It is important physicians understand that there are different perspectives influencing the decision-making process. Physicians should create an environment that allows parents to accept or reject treatment by communicating honestly and openly with them and by discussing both options extensively. Clear information about pros and cons, recent developments in research, and the experiences of other parents should be made available to enable parents to make an informed decision. What this paper adds Parents perceived different needs and concerns about nusinersen treatment, which emphasized individual differences. Parents' perspectives varied from battling the disease to preserving quality of life. Life expectancy, stopping deterioration, and improving quality of life were the perceived benefits of nusinersen treatment. Open communication about the pros and cons of treatment with clinicians facilitated decision-making. Clear and honest information facilitated the alignment of values and goals.

T2 relaxation-time mapping in healthy and diseased skeletal muscle using extended phase graph algorithms.

PURPOSE: Multi-echo spin-echo (MSE) transverse relaxometry mapping using multi-component models is used to study disease activity in neuromuscular disease by assessing the T2 of the myocytic component (T2water ). Current extended phase graph algorithms are not optimized for fat fractions above 50% and the effects of inaccuracies in the T2fat calibration remain unexplored. Hence, we aimed to improve the performance of extended phase graph fitting methods over a large range of fat fractions, by including the slice-selection flip angle profile, a through-plane chemical-shift displacement correction, and optimized calibration of T2fat . METHODS: Simulation experiments were used to study the influence of the slice flip-angle profile with chemical-shift and T2fat estimations. Next, in vivo data from four neuromuscular disease cohorts were studied for different T2fat calibration methods and T2water estimations. RESULTS: Excluding slice flip-angle profiles or chemical-shift displacement resulted in a bias in T2water up to 10 ms. Furthermore, a wrongly calibrated T2fat caused a bias of up to 4 ms in T2water . For the in vivo data, one-component calibration led to a lower T2fat compared with a two-component method, and T2water decreased with increasing fat fractions. CONCLUSION: In vivo data showed a decline in T2water for increasing fat fractions, which has important implications for clinical studies, especially in multicenter settings. We recommend using an extended phase graph-based model for fitting T2water from MSE sequences with two-component T2fat calibration. Moreover, we recommend including the slice flip-angle profile in the model with correction for through-plane chemical-shift displacements.