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.

Population-based incidence rates of 15 neuromuscular disorders: a nationwide capture-recapture study in the Netherlands.

Most neuromuscular disorders are rare, but as a group they are not. Nevertheless, epidemiological data of specific neuromuscular disorders are scarce, especially on the incidence. We applied a capture-recapture approach to a nationwide hospital-based dataset and a patients association-based dataset to estimate the annual incidence rates for fifteen neuromuscular disorders in the Netherlands. The annual incidence rates per 100,000 population varied from 0.03/100,000 (95% CI 0.00 ‒ 0.06) for glycogenosis type 5 to 0.9/100,000 (95% confidence interval 0.7 ‒ 1.0) for myotonic dystrophy type 1. The summed annual incidence rate of these disorders was 4.1 per 100,000 per population. Nine of the provided incidence rates were previously unavailable, three rates were similar to the rates in the literature, and three rates were generally higher compared to previous findings but with overlapping confidence intervals. This study provides nationwide incidence rates for fifteen neuromuscular disorders predominantly diagnosed in adult life, nine which were previously unavailable. The capture-recapture approach provided estimates of the total number of individuals with neuromuscular disorders. To complete the gaps in the knowledge of disease frequencies, there is a need for estimates from an automated, obligatory data collection system of diagnosed and newly diagnosed patients with neuromuscular disorders.

A protocol for scoping reviews on the role of whole-body and dedicated body-part magnetic resonance imaging for assessment of adult and juvenile idiopathic inflammatory myopathies.

Currently, standardized magnetic resonance imaging (MRI) scoring systems and protocols for assessment of idiopathic inflammatory myopathies (IIMs) in children and adults are lacking. Therefore, we will perform a scoping review of the literature to collate and evaluate the existing semi-quantitative and quantitative MRI scoring systems and protocols for the assessment and monitoring of skeletal muscle involvement in patients with IIMs. The aim is to compile evidence-based information that will facilitate the future development of a universal standardized MRI scoring system for both research and clinical applications in IIM. A systematic search of electronic databases (PubMed, EMBASE, and Cochrane) will be undertaken to identify relevant articles published between January 2000 and October 2023. Data will be synthesized narratively. This scoping review seeks to comprehensively summarize and evaluate the evidence on the scanning protocols and scoring systems used in the assessment of diagnosis, disease activity, and damage using skeletal muscle MRI in IIMs. The results will allow the development of consensus recommendations for clinical practice and enable the standardization of research methods for the MRI assessment of skeletal muscle changes in patients with IIMs.

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.

Mobile element insertions in rare diseases: a comparative benchmark and reanalysis of 60,000 exome samples.

Mobile element insertions (MEIs) are a known cause of genetic disease but have been underexplored due to technical limitations of genetic testing methods. Various bioinformatic tools have been developed to identify MEIs in Next Generation Sequencing data. However, most tools have been developed specifically for genome sequencing (GS) data rather than exome sequencing (ES) data, which remains more widely used for routine diagnostic testing. In this study, we benchmarked six MEI detection tools (ERVcaller, MELT, Mobster, SCRAMble, TEMP2 and xTea) on ES data and on GS data from publicly available genomic samples (HG002, NA12878). For all the tools we evaluated sensitivity and precision of different filtering strategies. Results show that there were substantial differences in tool performance between ES and GS data. MELT performed best with ES data and its combination with SCRAMble increased substantially the detection rate of MEIs. By applying both tools to 10,890 ES samples from Solve-RD and 52,624 samples from Radboudumc we were able to diagnose 10 patients who had remained undiagnosed by conventional ES analysis until now. Our study shows that MELT and SCRAMble can be used reliably to identify clinically relevant MEIs in ES data. This may lead to an additional diagnosis for 1 in 3000 to 4000 patients in routine clinical ES.

Successful treatment of respiratory failure in Hirayama disease.

Hirayama disease is a self-limiting cervical motor neuron disease, usually affecting the spinal cord at level C7-T1. We share an unusual case of Hirayama disease in a young man affecting roots C4-C6. He presented in coma due to diaphragm weakness and hypercapnic respiratory failure. Diagnosis was achieved via clinical presentation, neurophysiological examination, ultrasonography of the diaphragm and dynamic MR-imaging. Conservative treatment with a cervical collar resulted in remarkable improvement in respiratory and motor function.

Treatment with add-on IVIg in Myositis Early In the diSease course May be sUperior to Steroids alone for reaching CLinical improvEment (TIME IS MUSCLE): study protocol of a phase-2 double-blind placebo-controlled randomised trial.

INTRODUCTION: For idiopathic inflammatory myopathies (IIM) ('myositis') standard initial treatment is high-dosed glucocorticoids, which results in relatively slow improvement of muscle strength. Early immunosuppression or modulation by intensive treatment ('hit-early, hit-hard') may induce faster reduction of disease activity and prevent chronic disability due to disease-induced structural muscle damage. Intravenous immunoglobulin (IVIg) in addition to standard glucocorticoid treatment may be promising in this regard as was shown in various studies: add-on IVIg improved symptoms and muscle strength in refractory myositis patients and monotherapy IVIg improved outcomes after 9 weeks, in about half of treatment-naive patients. HYPOTHESIS: We hypothesise that early add-on IVIg leads to a greater clinical response after 12 weeks in patients with newly diagnosed myositis, in comparison to prednisone monotherapy. Second, we expect that early treatment with add-on IVIg leads to a faster time to improvement and sustained positive effects on multiple secondary outcomes. METHODS: The Time Is Muscle trial is a phase-2 double-blind placebo-controlled randomised trial. Forty-eight patients with IIM will be treated with IVIg or placebo at baseline (within 1 week after diagnosis) and after 4 and 8 weeks, in addition to standard therapy with prednisone. The primary outcome is the Total Improvement Score (TIS) of the myositis response criteria at 12 weeks. At baseline, and after 4, 8, 12, 26 and 52 weeks, relevant secondary outcomes will be assessed, including time to moderate improvement (TIS≥40), mean daily prednisone dosage, physical activity, health-related quality of life, fatigue and MRI muscle imaging parameters. ETHICS AND DISSEMINATION: Ethical approval was obtained from the medical ethics committee of the Academic Medical Centre, University of Amsterdam, the Netherlands (2020_180; including a first amendment approval at the 12 April 2023; A2020_180_0001). The results will be distributed through conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: EU Clinical trials register (2020-001710-37).

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.

Outcomes after robotic thymectomy in nonthymomatous versus thymomatous patients with acetylcholine-receptor-antibody-associated myasthenia gravis.

The aim of this study was to investigate the surgical and long-term neurological outcomes of patients with acetylcholine-receptor-antibody-associated myasthenia gravis (AChR-MG) who underwent robotic thymectomy (RATS). We retrospectively analyzed the clinical-pathological data of all patients with AChR-MG who underwent RATS using the DaVinci® Robotic System at the MUMC+ between April 2004 and December 2018. Follow-up data were collected from 60 referring Dutch hospitals. In total, 230 myasthenic patients including 76 patients with a thymoma (33.0%) were enrolled in this study. Mean follow-up time, procedure time and hospitalization were, respectively 65.7 ± 43.1 months, 111±52.5 min and 3.3 ± 2.2 days. Thymomatous patients had significantly more frequently and more severe complications than nonthymomatous patients (18.4% vs. 3.9%, p<0.001). Follow up data was available in 71.7% of the included patients. The Myasthenia Gravis Foundation of America postintervention score showed any kind of improvement of MG-symptoms after RATS in 82.4% of the patients. Complete stable remission (CSR) or pharmacological remission (PR) of MG was observed in 8.4% and 39.4% of the patients, respectively. Mean time till CSR/PR remission after thymectomy was 26.2 ± 29.2 months. No statistical difference was found in remission or improvement in MGFA scale between thymomatous and nonthymomatous patients. RATS is safe and feasible in patients with MG. The majority of the patients (82.4%) improved after thymectomy. CSR and PR were observed in 8.4% and 39.4% of the patients, respectively, with a mean of 26.2 months after thymectomy. Thymomatous patients had more frequently and more severe complications compared to nonthymomatous patients.

Anoctamin-5 related muscle disease: clinical and genetic findings in a large European cohort.

Anoctamin-5 related muscle disease is caused by biallelic pathogenic variants in the anoctamin-5 gene (ANO5) and shows variable clinical phenotypes: limb-girdle muscular dystrophy type 12 (LGMD-R12), distal muscular dystrophy type 3 (MMD3), pseudometabolic myopathy or asymptomatic hyperCKaemia. In this retrospective, observational, multicentre study we gathered a large European cohort of patients with ANO5-related muscle disease to study the clinical and genetic spectrum and genotype-phenotype correlations. We included 234 patients from 212 different families, contributed by 15 centres from 11 European countries. The largest subgroup was LGMD-R12 (52.6%), followed by pseudometabolic myopathy (20.5%), asymptomatic hyperCKaemia (13.7%) and MMD3 (13.2%). In all subgroups, there was a male predominance, except for pseudometabolic myopathy. Median age at symptom onset of all patients was 33 years (range 23-45 years). The most frequent symptoms at onset were myalgia (35.3%) and exercise intolerance (34.1%), while at last clinical evaluation most frequent symptoms and signs were proximal lower limb weakness (56.9%) and atrophy (38.1%), myalgia (45.1%) and atrophy of the medial gastrocnemius muscle (38.4%). Most patients remained ambulatory (79.4%). At last evaluation, 45.9% of patients with LGMD-R12 additionally had distal weakness in the lower limbs and 48.4% of patients with MMD3 also showed proximal lower limb weakness. Age at symptom onset did not differ significantly between males and females. However, males had a higher risk of using walking aids earlier (P = 0.035). No significant association was identified between sportive versus non-sportive lifestyle before symptom onset and age at symptom onset nor any of the motor outcomes. Cardiac and respiratory involvement that would require treatment occurred very rarely. Ninety-nine different pathogenic variants were identified in ANO5 of which 25 were novel. The most frequent variants were c.191dupA (p.Asn64Lysfs*15) (57.7%) and c.2272C>T (p.Arg758Cys) (11.1%). Patients with two loss-of function variants used walking aids at a significantly earlier age (P = 0.037). Patients homozygous for the c.2272C>T variant showed a later use of walking aids compared to patients with other variants (P = 0.043). We conclude that there was no correlation of the clinical phenotype with the specific genetic variants, and that LGMD-R12 and MMD3 predominantly affect males who have a significantly worse motor outcome. Our study provides useful information for clinical follow up of the patients and for the design of clinical trials with novel therapeutic agents.

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.

Multimodality Screening For (Peri)Myocarditis In Newly Diagnosed Idiopathic Inflammatory Myopathies: A Cross-Sectional Study.

BACKGROUND: Cardiac involvement in idiopathic inflammatory myopathy (IIM or "myositis") is associated with an approximate 4% mortality, but standardised screening strategies are lacking. OBJECTIVE: We explored a multimodality screening on potentially reversible cardiac involvement -i.e. active (peri)myocarditis -in newly diagnosed IIM. METHODS: We included adult IIM patients from 2017 to 2020. At time of diagnosis, patients underwent cardiac evaluation including laboratory biomarkers, electrocardiography, echocardiography, and cardiac magnetic resonance imaging (CMR). Based on 2019 consensus criteria for myocarditis, an adjudication committee made diagnoses of definite, probable, possible or no (peri)myocarditis. We explored diagnostic values of sequentially added diagnostic modalities by Constructing Classification and Regression Tree (CART) analysis in patients with definite/probable versus no (peri)myocarditis. RESULTS: We included 34 IIM patients, in whom diagnoses of definite (six, 18%), probable (two, 6%), possible (11, 32%), or no (peri)myocarditis (15, 44%) were adjudicated. CART-analysis showed high-sensitivity cardiac troponin T (cut-off value < 2.3 times the upper limit of normal (xULN)) ruled out (peri)myocarditis with a sensitivity of 88%, while high-sensitivity troponin I (cut-off value > 2.9 xULN for females and > 1.8 xULN for males) ruled in (peri)myocarditis with a specificity of 100%. Applying high-sensitivity cardiac troponins with these cut-off values in a diagnostic algorithm without and with a CMR to the total population of 34 patients demonstrated a diagnostic accuracy for a clear diagnosis of probable/definite or no (peri)myocarditis of 59% and 68%, respectively. CONCLUSIONS: A diagnostic algorithm for detection of (peri)myocarditis in adult IIM may consist of sequential testing with high-sensitivity cardiac troponins and CMR.

B-cell receptor profiling before and after IVIG monotherapy in newly diagnosed idiopathic inflammatory myopathies.

OBJECTIVE: To unravel B-cell receptor (BcR) characteristics in muscle tissues and peripheral blood and gain more insight into BcR repertoire changes in peripheral blood in idiopathic inflammatory myopathies (IIMs), and study how this correlates to the clinical response to IVIG. METHODS: Nineteen treatment-naive patients with newly diagnosed IIM were prospectively treated with IVIG monotherapy. RNA-based BcR repertoire sequencing was performed in muscle biopsies collected before, and in peripheral blood (PB) collected before and nine weeks after IVIG treatment. Results were correlated to patients' clinical improvement based on the total improvement score (TIS). RESULTS: Prior to IVIG treatment, BcR clones found in muscle tissue could be retrieved in peripheral blood. Nine weeks after IVIG treatment, new patient-specific dominant BcR clones appeared in peripheral blood while pre-treatment dominant BcR clones disappeared. The cumulative frequency of all dominant BcR clones before treatment was significantly higher in individuals who responded to IVIG compared with those who did not respond to IVIG, and correlated with a higher CK. During follow-up, a decrease in the cumulative frequency of all dominant clones correlated with a higher TIS. CONCLUSION: In treatment-naive patients with newly diagnosed IIM, muscle tissue and peripheral blood share expanded BcR clones. In our study a higher cumulative frequency of dominant BcR clones in blood before treatment was associated with a higher CK and better treatment response, suggesting that response to IVIG may depend on the composition of the pre-treatment BcR repertoire.

TCRß clones in muscle tissue share structural features in patients with idiopathic inflammatory myopathy and are associated with disease activity.

Objectives: To characterize the T cell receptor (TCRß) repertoire in peripheral blood and muscle tissues of treatment naïve patients with newly diagnosed idiopathic inflammatory myopathies (IIMs). Methods: High throughput RNA sequencing of the TCRß chain was performed in peripheral blood and muscle tissue in twenty newly-diagnosed treatment-naïve IIM patients (9 DM, 5 NM/OM, 5 IMNM and 1 ASyS) and healthy controls. Results thereof were correlated with markers of disease activity. Results: Muscle tissue of IIM patients shows more expansion of TCRß clones and decreased diversity when compared to peripheral blood of IIM as well as healthy controls (both p=0.0001). Several expanded TCRß clones in muscle are tissue restricted and cannot be retrieved in peripheral blood. These clones have significantly longer CDR3 regions when compared to clones (also) found in circulation (p=0.0002), while their CDR3 region is more hydrophobic (p<0.01). Network analysis shows that clonal TCRß signatures are shared between patients. Increased clonal expansion in muscle tissue is significantly correlated with increased CK levels (p=0.03), while it tends to correlate with decreased muscle strength (p=0.08). Conclusion: Network analysis of clones in muscle of IIM patients shows shared clusters of sequences across patients. Muscle-restricted CDR3 TCRß clones show specific structural features in their T cell receptor. Our results indicate that clonal TCRß expansion in muscle tissue might be associated with disease activity. Collectively, these findings support a role for specific clonal T cell responses in muscle tissue in the pathogenesis of the IIM subtypes studied.

Comprehensive overview of autoantibody isotype and subclass distribution.

The presence of autoreactive antibodies is a hallmark of many autoimmune diseases. The effector functions of (auto)antibodies are determined by their constant domain, which defines the antibody isotype and subclass. The most prevalent isotype in serum is IgG, which is often the only isotype used in diagnostic testing. Nevertheless, autoantibody responses can have their own unique isotype/subclass profile. Because comparing autoantibody isotype profiles may yield new insights into disease pathophysiology, here we summarize the isotype/subclass profiles of the most prominent autoantibodies. Despite substantial variation between (and within) autoantibody responses, this unprecedented comparison shows that autoantibodies share distinctive isotype patterns across different diseases. Although most autoantibody responses are dominated by IgG (and mainly IgG1), several specific diseases are characterized by a predominance of IgG4. In other diseases, IgE plays a key role. Importantly, shared features of autoantibody isotype/subclass profiles are seen in clinically unrelated diseases, suggesting potentially common trajectories in response evolution, disease pathogenesis, and treatment response. Isotypes beyond IgG are scarcely investigated in many autoantibody responses, leaving substantial gaps in our understanding of the pathophysiology of autoimmune diseases. Future research should address isotype/subclass profiling in more detail and incorporate autoantibody measurements beyond total IgG in disease models and clinical studies.