Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study.

BACKGROUND: Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engineered them with RNA (rCAR-T)-rather than the conventional DNA approach-to target B-cell maturation antigen (BCMA) expressed on plasma cells. To test the suitability of our approach, we used rCAR-T to treat individuals with myasthenia gravis, a prototypical autoantibody disease mediated partly by pathogenic plasma cells. METHODS: MG-001 was a prospective, multicentre, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T therapy, in adults (ie, aged ≥18 years) with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher. The study was done at eight sites (ie, academic medical centres or community neurology clinics) in the USA. Lymphodepletion chemotherapy was not used. In part 1 (phase 1b), participants with Myasthenia Gravis Foundation of America (MGFA) disease class III-IV generalised myasthenia gravis received three ascending doses of Descartes-08 to determine a maximum tolerated dose. In part 2 (phase 2a), participants with generalised myasthenia gravis with MGFA disease class II-IV received six doses at the maximum tolerated dose in an outpatient setting. The primary objective was to establish safety and tolerability of Descartes-08; secondary objectives were to assess myasthenia gravis disease severity and biomarkers in participants who received Descartes-08. This trial is registered with clinicaltrials.gov, NCT04146051. FINDINGS: We recruited 16 individuals for screening between Jan 7, 2020 and Aug 3, 2022. 14 participants were enrolled (n=3 in part 1, n=11 in part 2). Ten participants were women and four were men. Two individuals did not qualify due to low baseline MG-ADL score (n=1) or lack of generalised disease (n=1). Median follow-up in part 2 was 5 months (range 3-9 months). There was no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were headache (six of 14 participants), nausea (five of 14), vomiting (three of 14), and fever (four of 14), which resolved within 24 h of infusion. Fevers were not associated with increased markers of cytokine release syndrome (IL-6, IL-2, and TNF). Mean improvements from baseline to week 12 were -6 (95% CI -9 to -3) for MG-ADL score, -7 (-11 to -3) for Quantitative Myasthenia Gravis score, -14 (-19 to -9) for Myasthenia Gravis Composite score, and -9 (-15 to -3) for Myasthenia Gravis Quality of Life 15-revised score. INTERPRETATION: In this first study of an rCAR-T therapy in individuals with an autoimmune disease, Descartes-08 appeared to be safe and was well tolerated. Descartes-08 infusions were followed by clinically meaningful decreases on myasthenia gravis severity scales at up to 9 months of follow-up. rCAR-T therapy warrants further investigation as a potential new treatment approach for individuals with myasthenia gravis and other autoimmune diseases. FUNDING: Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health.

Coexisting sporadic late onset nemaline myopathy and AL amyloid myopathy - incidental or related?

Sporadic late onset nemaline myopathy (SLONM) and amyloid myopathy are frequently unrecognized acquired and treatable myopathies, which classically present with rapidly progressive and severe proximal muscle weakness. We report a case of SLONM and amyloid myopathy associated with IgM lambda monoclonal gammopathy in a 77-year-old Caucasian man. Creatine kinase (CK) was mildly elevated. Myositis panel was negative. Electromyogram showed prominent fibrillation potentials and positive sharp waves with myopathic motor unit action potentials. Muscle biopsy revealed nemaline rods and amyloid deposits with characteristic apple-green birefringence under polarized light, and liquid chromatography tandem mass spectroscopy detected a peptide profile consistent with AL (lambda) type amyloid deposition. Genetic testing for congenital nemaline rod myopathy was negative. The patient was treated with dexamethasone and chemotherapy x3 cycles with very good partial remission. CK and lambda light chain normalized. Our case emphasizes the importance of completing a thorough histochemical and pathological evaluation by muscle biopsy analysis, to provide timely and optimal treatment of these conditions.

Unusual cases of Anti-SRP necrotizing myopathy with predominant distal leg weakness and atrophy.

Anti-SRP necrotizing myopathy is classically characterized by subacute or chronic, severe, progressive and symmetric myositis which predominantly affects proximal muscles. We report two unusual cases presenting with predominantly distal, asymmetric weakness, with selective involvement of the posterior compartment of the thighs, gastrocnemius, and soleus muscles, in addition to inflammation and edema on STIR or T2-weighted, fat-saturated MRI. In each case, creatine kinase (CK) levels were >10 times normal and myositis panels returned positive for anti-SRP. ANA, ENA, RF, and HMGCR antibody were all negative. Nerve conduction study (NCS) was normal. Electromyography (EMG) confirmed diffuse myopathy with fibrillation potentials and positive sharp waves. Additional work up, including whole exome sequencing (WES), immunohistochemical staining for different types of muscular dystrophy, and western blot for calpain 3 and dysferlin were negative. The strength and CK levels of both patients markedly improved following immunosuppression. Our cases emphasize the importance of considering anti-SRP necrotizing myopathy in patients presenting with recent onset predominant asymmetric distal leg weakness of unclear etiology, and support the usefulness of MRI of the distal legs for early recognition. Given the potential consequences of delays in treatment of this condition, the recognition of this clinical pattern is important and can allow for prompt initiation of aggressive immunotherapies.

Refractory CIDP: Clinical characteristics, antibodies and response to alternative treatment.

OBJECTIVE: To review the clinical characteristics, antibodies, and response to alternative treatments in a cohort of patients with refractory CIDP. METHODS: We reviewed the charts of all CIDP patients seen at the Oregon Health & Science University neuromuscular clinic between 2017 and 2019. We collected demographics, clinical characteristics, antibodies, and response to treatments. RESULTS: Among 45 CIDP patients studied, 34 (76%) showed improvement with first-line therapy (steroids, IVIG and/or plasmapheresis) and 11 (24%) were considered refractory to first line therapy. Of the latter, 7 of 11 patients (64%) responded to alternative treatment (cyclophosphamide or rituximab). Three were refractory to all treatment. Most patients were ambulatory without aid and a few were in remission. One patient died from complications of alcoholic liver cirrhosis. Thrombosis was seen in three patients receiving IVIG. Six patients (13%) tested positive for Neurofascin (NF) antibodies. Four tested positive for NF155 IgM antibodies only and of those, one responded to IVIG, two partially responded to IVIG and one was refractory. One patient tested positive for NF155 IgG4. Another tested positive for NF155 IgG4 and NF155 IgM. Both patients with IgG4 antibodies were refractory to IVIG, one responded to rituximab and one was refractory to all treatment. CONCLUSION: Less than a quarter of our CIDP patients did not respond to steroids, IVIG, and/or plasmapheresis. Most of the refractory patients responded to rituximab or cyclophosphamide. Patients with IgG4 NF antibodies were resistant to IVIG. The majority of refractory CIDP patients were seronegative and disease management relied on clinical judgement.

Nusinersen in adult patients with spinal muscular atrophy: Observations from a single center.

OBJECTIVE: To report our experience with adult patients with spinal muscular atrophy (SMA), some of whom were treated with nusinersen. METHODS: We reviewed charts of adult patients with SMA seen in our neuromuscular clinic between 2017 and 2019 and noted their demographics, clinical characteristics, treatment, and side effects. RESULTS: Twenty-two patients were included. Nine had type 2 and 13 type 3 SMA. Median age was 36 years (range 20-71). Most could not walk unassisted. Ten patients had significant respiratory impairment necessitating ventilation and 2 had tracheostomy. Seventeen had severe scoliosis. Ten patients were treated with nusinersen for 6-24 months (median 12 months), 3 of whom required bone laminectomy for intrathecal access. One developed bowel and bladder incontinence following the procedure. In the treated group, on average, % Medical Research Council change was 2.5% at 12 months and 3.9% at 24 months. Most untreated patients remained stable; 3 had slightly declined. Five treated patients reported subjective improvement. Treatment side effects included post lumbar puncture headache in 5 patients, 2 of whom needed blood patch, and 1 bacterial meningitis requiring inpatient treatment. Three patients stopped treatment after 12-24 months due to lack of improvement, recurrent pneumonia, or proteinuria. CONCLUSION: Side effects of nusinersen can be serious. Whereas half of treated patients reported modest improvement in function, there were no significant objective changes, which may point largely to a placebo effect. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for some adult patients with SMA, nusinersen improves subjective function and causes serious adverse effects.

Diagnosis of paraproteinemic neuropathy: Room for improvement.

OBJECTIVE: To report our institutional experience with paraproteinemic neuropathy. METHODS: We reviewed the charts of patients evaluated at our tertiary, academic neuromuscular clinic for neuropathy between 2017 and 2019 and selected those with a serum monoclonal protein. We collected patients' characteristics and reviewed their initial diagnoses and eventual outcomes. RESULTS: Fifty-four of 410 patients with neuropathy (13%) had a monoclonal protein. Of these patients, 25% had not had SPEP or IFE checked prior to referral. FLC was not checked in any of the patients prior to referral. The neuropathy was felt to be related to the monoclonal protein in 24 patients (44%). Ten patients (19%), had been misdiagnosed either because they were not screened for monoclonal protein or the monoclonal protein was considered a MGUS. AL amyloid and POEMS syndrome were the most frequently missed diagnoses. CONCLUSION: The diagnosis of paraproteinemic neuropathy was missed in nearly one in five patients in our cohort. Failure to accurately characterize a paraproteinemic neuropathy can have devastating effect on patients as some have underlying malignancies. We propose that testing serum free light chains in patients with peripheral neuropathy of unknow etiology, when SPEP/IFE are normal, may reduce the rate of misdiagnosis. Furthermore, patients with refractory CIDP should be carefully screened for POEMS syndrome.

Screening for genetic mutations in patients with neuropathy without definite etiology is useful.

OBJECTIVE: To determine the clinical usefulness of systemic genetic testing in neuropathies without definite etiology. METHODS: We systematically performed genetic testing in all patients with neuropathy who did not have a definite etiology, seen at our neuromuscular clinic between 2017 and 2020. The testing consisted of an inherited neuropathy panel (72-81 genes), which used next-generation sequencing technology. RESULTS: We screened 200 patients. Pathogenic mutations were found in 30 (15%). PMP22, TTR and GJB1, accounted for 83.3% of positive mutations. The management was altered in four patients (2%). Two patients were found to have hereditary transthyretin amyloidosis and were started on TTR gene silencers. Two patients were being treated for demyelinating autoimmune neuropathy and were diagnosed with CMT1A and CMTX. CONCLUSION: Screening for genetic mutations in patients with neuropathy without a definite etiology is useful. While only a minority of patients with unsuspected inherited neuropathy tested positive, the findings altered management in some, improving morbidity and, perhaps, mortality.

Selective serotonin reuptake inhibitors ameliorate MEGF10 myopathy.

MEGF10 myopathy is a rare inherited muscle disease that is named after the causative gene, MEGF10. The classic phenotype, early onset myopathy, areflexia, respiratory distress and dysphagia, is severe and immediately life-threatening. There are no disease-modifying therapies. We performed a small molecule screen and follow-up studies to seek a novel therapy. A primary in vitro drug screen assessed cellular proliferation patterns in Megf10-deficient myoblasts. Secondary evaluations were performed on primary screen hits using myoblasts derived from Megf10-/- mice, induced pluripotent stem cell-derived myoblasts from MEGF10 myopathy patients, mutant Drosophila that are deficient in the homologue of MEGF10 (Drpr) and megf10 mutant zebrafish. The screen yielded two promising candidates that are both selective serotonin reuptake inhibitors (SSRIs), sertraline and escitalopram. In depth follow-up analyses demonstrated that sertraline was highly effective in alleviating abnormalities across multiple models of the disease including mouse myoblast, human myoblast, Drosophila and zebrafish models. Sertraline also restored deficiencies of Notch1 in disease models. We conclude that SSRIs show promise as potential therapeutic compounds for MEGF10 myopathy, especially sertraline. The mechanism of action may involve the Notch pathway.

Bright tongue sign in patients with late-onset Pompe disease.

BACKGROUND: Late-onset Pompe disease (LOPD) is an often misdiagnosed inherited myopathy for which treatment exists. We noticed a bright tongue sign on brain MRIs of two patients who were admitted to the ICU for respiratory failure of unclear origin, and who were eventually diagnosed with LOPD. This led us to systematically review brain MRIs of patients with LOPD and various other neuromuscular disorders (NMD). MATERIALS AND METHODS: Chart and brain MRI review of patients with LOPD and other NMD. RESULTS: Abnormalities of the tongue were observed in 11/33 of the patients studied. In 10/11 patients, no comments were made with regard to the tongue abnormalities in the radiology report. Bright tongue sign was seen in 4/6 patients with LOPD and 4/28 patients with other NMD. Tongue atrophy was seen in 3/6 patients with LOPD and 6/28 patients with other NMD. CONCLUSION: Tongue abnormalities on brain MRI are common in LOPD compared to other NMD. These abnormalities are not usually reported by the radiologist. Particular attention to the tongue when reviewing brain MRIs may be an important clue for diagnosis of a patient's muscle weakness. A larger study is suggested to evaluate the sensitivity and specificity of tongue abnormalities in patients with LOPD.

Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders.

OBJECTIVE: To evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs). METHODS: We performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup. RESULTS: The overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis. CONCLUSIONS: Genome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

Late-onset Becker muscular dystrophy: Refining the clinical features and electrophysiological findings.

INTRODUCTION: The aim of this study was to characterize a unique distribution of muscle involvement in sporadic Becker muscle dystrophy (BMD). METHODS: Retrospective chart review, clinical examination, electrophysiological studies, cardiac testing, and genetic testing were performed in 5 patients. RESULTS: Predominant weakness and atrophy of biceps brachii, hip adduction, and quadriceps muscles was noted along with calf and extensor forearm hypertrophy. Finger flexor muscles were severely weak in 3 of 5 patients, a feature that could lead to a misdiagnosis of inclusion body myositis. Creatinine kinase was only mildly elevated in most patients. Electromyography was abnormal in all patients. Muscle biopsy in 1 patient demonstrated normal immunostaining for dystrophin. CONCLUSIONS: We found a unique and uniform distribution of muscle involvement in 5 sporadic cases of BMD. Recognizing these features is important for differentiating it from other myopathies that may have similar features and avoids unnecessary invasive procedures such as muscle biopsy.

Dermatomyositis as a presentation of neuromyelitis optica spectrum disorder.

IMPORTANCE: This is the first report of neuromyelitis optica spectrum disorder (NMOSD) associated with dermatomyositis (DM). REPORT: A 40year-old Caucasian female presented with 6months of worsening fatigue, rash, acute weakness worse in her lower extremities, and urinary retention. She was found to have both NMOSD and anti-melanoma differentiation-associated gene (MDA)5 positive DM with interstitial lung disease (ILD). She was treated aggressively and she regained her ability to ambulate. CONCLUSION: We recommend considering NMOSD in the differential diagnosis of patients with DM and other autoimmune disorders that also present with clinical signs of myelopathy.

Toxoplasmic encephalitis during mycophenolate mofetil immunotherapy of neuromuscular disease.

OBJECTIVE: To show that immunotherapy with medications such mycophenolate mofetil (MMF) can cause serious complications in patients with neuromuscular disorders. METHODS: Two patients with neuromuscular disorders on immunotherapy with long-term MMF who developed toxoplasmic encephalitis (TE) were included in this case series. RESULTS: One patient with myasthenia gravis and one patient with inflammatory myopathy on immunotherapy with long-term MMF developed severe TE. Diagnosis was based on clinical presentation, MRI brain imaging characteristics, and CSF PCR positivity for Toxoplasma gondii. Both patients were treated with pyrimethamine, sulfadiazine, and leucovorin for 2 months without clinical improvement, and both died. CONCLUSIONS: Immunotherapy with medications such as MMF can cause devastating TE in non-HIV patients with neuromuscular disorders. Early consideration and recognition of this complication is important to possibly prevent unfavorable outcomes. The utility of screening and prophylaxis against toxoplasmosis in individuals with neuroimmunologic disorders and other autoimmune disorders who receive immunosuppressive therapy requires future study.