Measuring treatment adverse event burden in myasthenia gravis: Single-center prospective evaluation utilizing the Adverse Event Unit (AEU).

INTRODUCTION/AIMS: We developed a patient- and physician-weighted consensus unit called the adverse event unit (AEU) that quantifies and compares adverse event (AE) burden among any group of medications in neurological patients. In this study we evaluated preliminary validity and feasibility of measuring AE burden with the AEU in myasthenia gravis (MG). METHODS: This is a single-center, prospective, 1-year, observational study of adult MG patients presenting for routine care between April 1, 2021 and March 31, 2022. The MG Activities of Daily Living (MG-ADL), the 15-item MG Quality of Life revised (MG-QOL15r), MG-Composite, and AEU scores were obtained at all visits. A priori primary feasibility metric was AEU completion rate equal to (within 3.8%, one-sided 95% confidence interval [CI]) or better than MG-ADL completion rate. Time to administer AEU and MG-ADL/MG-QOL15r, correlation between AEU total score and MG-QOL15r, and median AEU scores for each MG medication were evaluated. RESULTS: Fifty-four patients completed 67 study visits; side effects were reported at 75% of the visits. The study met the primary feasibility endpoint; AEU and MG-ADL were recorded at all visits. Times to administer the AEU (median 5 minutes) and MG-ADL/MG-QOL15r were similar. We observed a weak correlation of 0.29 (95% CI 0.03 to 0.51, P = .032) between AEU and MG-QOL15r scores. Non-statistically significant differences in median AEU scores were observed among MG medications. DISCUSSION: Our data demonstrate preliminary feasibility and validity of using the AEU to measure AE burden in MG. Future studies will compare AE burden among MG treatments and evaluate clinically meaningful AEU scores in MG.

A crisis in US drug pricing: Consequences for patients with neuromuscular diseases, physicians and society, part 1.

Drug prices in the United States have reached astounding heights, negatively impacting patients and society. The vast majority of prescription drug spending is on brand name drugs, which are protected from typical market pressures by FDA exclusivity and intellectual property patents. Drugs to treat "orphan" diseases, of particular relevance to neuromuscular clinicians, are some of the most expensive in all of medicine. The Orphan Drug Act's original intent was to incentivize the creation of drugs that would otherwise provide little economic payoff. While it has facilitated incredible, life-changing drugs for our patients, it has also become a source of abuse. Many expensive drugs approved under the Orphan Drug Act were previously available for compassionate use or for another indication at much lower prices. As patients increasingly face high drug prices, it is important for clinicians to understand a drug's risk for inducing financial toxicity, as the financial and emotional consequences of an overpriced low-value drug may outweigh its intended benefit.

A crisis in US drug pricing: Consequences for patients with neuromuscular diseases, physicians, and society, part 2.

Escalating drug costs place patients at risk for financial toxicity and demand that physicians understand and act on the ethical and economic principles related to drug pricing. This manuscript reviews these principles and provides clinicians with a framework to think about the value of the drugs prescribed for patients with neuromuscular diseases. A key component of addressing the drug pricing crisis will be establishing a value based (benefit/cost) drug pricing framework. Determining the value of a drug is difficult and requires estimating the benefit and costs to patients and society while integrating indirect and contextual variables. Other considerations in drug pricing include "externality," the value to society derived from innovation. The Institute for Clinical and Economic Review (ICER) is a leading independent research organization providing clinicians with value-based price "benchmarks." All physicians must educate themselves in drug pricing principles and be prepared to have conversations regarding individual and societal value with the patients they serve.

Cross-sectional analysis of the Myasthenia Gravis Patient Registry: Disability and treatment.

INTRODUCTION: The Myasthenia Gravis Patient Registry (MGR) is a voluntary, patient-submitted database dedicated to improve understanding of care/burden of myasthenia gravis (MG). METHODS: In this study we present analyses of baseline records through July 2017 (n = 1140) containing data on the MG-Activities of Daily Living (MG-ADL) and the MG 15-item Quality of Life (MG-QOL15) instruments, two validated scales assessing quality of life in MG patients at sign-up into the MGR. RESULTS: Most registrants reported moderate to severe impairment of health-related quality of life, with a median MG-ADL score of 6 and a median MG-QOL15 score of 21. Seventy-one percent of the patients had received pyridostigmine. Corticosteroids, mycophenolate mofetil, and azathioprine were the most common immunomodulators/immunosuppressants, with 85% of participants having ever using one of these agents. Forty-seven registrants reported receiving intravenous immunoglobulin, and 30% received plasma exchange. Twelve percent reported other treatments, and 40% were unsure whether they received less common therapies. Forty percent had undergone thymectomy. DISCUSSION: The MGR data correlate well with other MG cohorts. Many MG patients remain negatively impacted despite treatment.

Investigation of the psychometric properties of the inclusion body myositis functional rating scale with rasch analysis.

INTRODUCTION: The Inclusion Body Myositis Functional Rating Scale (IBMRFS) is a 10-item clinician-rated ordinal scale developed for people with inclusion body myositis. METHODS: Single observations of the IBMFRS were collected from 132 patients. After Rasch analysis, modifications were made to the scale to optimize fit to the Rasch model while maintaining clinical validity and utility. RESULTS: The original IBMFRS did not fit the assumptions of the Rasch model because of multidimensionality of the scale. Items assessed local dependence, disordered step thresholds, and differential item functioning. Deconstructing the scale into upper limb (IBMFRS-UL) and lower limb (IBMFRS-LL) scales improved fit to the Rasch model. A 9-item scale with the swallowing item removed (IBMFRS-9) remained multidimensional but demonstrated the ability to discriminate patients along the severity continuum. IBMFRS-UL, IBMFRS-LL, and IBMFRS-9 scores were transformed to a 0-100 scale for comparability. DISCUSSION: This analysis has led to the development of 3 optimized versions of the IBMFRS. Muscle Nerve 60: 161-168, 2019.

Long-term safety and efficacy of eculizumab in generalized myasthenia gravis.

INTRODUCTION: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy. METHODS: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients. RESULTS: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001). DISCUSSION: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019.

Thymectomy may not be associated with clinical improvement in MuSK myasthenia gravis.

INTRODUCTION: A randomized trial demonstrated benefit from thymectomy in nonthymomatous acetylcholine receptor (AChR)-antibody positive myasthenia gravis (MG). Uncontrolled observational and histologic studies suggest thymectomy may not be efficacious in anti-muscle-specific kinase (MuSK)-MG. METHODS: The therapeutic impact of thymectomy was evaluated from data collected for a multicenter, retrospective blinded review of rituximab in MuSK-MG. RESULTS: Baseline characteristics were similar between thymectomy (n = 26) and nonthymectomy (n = 29) groups, including treatment with rituximab (42% vs. 45%). At last visit, 35% of thymectomy subjects reached the primary endpoint, a Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) score of minimal manifestations (MM) or better, compared with 55% of controls (P = 0.17). After controlling for age at onset of MG, rituximab, prednisone, and intravenous immunoglobulin/plasma exchange treatment, thymectomy was not associated with greater likelihood of favorable clinical outcome (odds ratio = 0.43, 95% confidence interval 0.12-1.53, P = 0.19). DISCUSSION: Thymectomy was not associated with additional clinical improvement in this multicenter cohort of MuSK-MG patients. Muscle Nerve 59:404-410, 2019.

Chronic Acquired Polyneuropathy Patient Reported Index (CAPPRI) in chronic inflammatory demyelinating polyradiculoneuropathy.

To date there are only two validations on the Chronic Acquired Polyneuropathy Patient-Reported Index (CAPPRI) questionnaire, both originated from the North America. We sought to translate and validate CAPPRI for use in Serbian patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We included 109 CIDP patients. CAPPRI, short form (36) health survey (SF-36), Medical Research Council Sum Score (MRC-SS), Inflammatory Neuropathy Cause and Treatment (INCAT) sensory and disability scores, Beck Depression Inventory (BDI), and Krupp's Fatigue Severity Scale (FSS) were used. Serbian CAPPRI questionnaire was understandable and the language was appropriate and simple. Calculation demonstrated good person (0.9) and item (0.9) reliability with adequate item (4.1), and person (2.9) separation indices. There was a minor floor effect (13.8%), and no ceiling effect. All items had good fit, except items 2 (pain), 5 (sleeping), and 14 (eating) to some degree. Category responses were well ordered and organized, except item 14 (eating). The CAPPRI score did not vary regarding gender, age, or education. Patients with worse scores on MRC-SS, INCAT sensory score, INCAT disability score, FSS, and BDI had worse scores on CAPPRI (P < .01). The CAPPRI score showed strong correlation with the SF-36 score (rho = -0.76, P < .01). The Serbian version of the CAPPRI is reliable and valid patient-reported index for patients with CIDP, able to differentiate between levels of impairment and disability in this disease.

Construction and validation of the chronic acquired polyneuropathy patient-reported index (CAP-PRI): A disease-specific, health-related quality-of-life instrument.

INTRODUCTION: Generic health-related quality-of-life (HRQOL) patient-reported outcome measures have been used in patients with chronic immune-mediated polyneuropathies. We have created a disease-specific HRQOL instrument. METHODS: The chronic acquired polyneuropathy patient-reported index (CAP-PRI) was developed and validated in multiple steps. Items were initially generated through patient and specialist input. The performance of the preliminary 20 items was analyzed via a prospective, 5-center study involving chronic immune-mediated polyneuropathy patients. RESULTS: Data analysis suggested modification to a 15-item scale with 3 response categories rather than 5. The final CAP-PRI was validated in another prospective, 5-center study. The CAP-PRI appeared to be a unidimensional outcome measure that fit the Rasch model in our multicenter cohort. It correlated appropriately with outcome measures commonly used in this patient population. CONCLUSIONS: The CAP-PRI is a simple disease-specific HRQOL measure that appears to be useful for clinical care and possibly also for clinical trials. Muscle Nerve 54: 9-17, 2016.

International clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent validation of the MG-QOL15r.

INTRODUCTION: The MG-QOL15 is a validated, health-related quality of life (HRQOL) measure for myasthenia gravis (MG). Widespread use of the scale gave us the opportunity to further analyze its clinimetric properties. METHODS: We first performed Rasch analysis on >1,300 15-item Myasthenia Gravis Quality of Life scale (MG-QOL15) completed surveys. Results were discussed during a conference call with specialists and biostatisticians. We decided to revise 3 items and prospectively evaluate the revised scale (MG-QOL15r) using either 3, 4, or 5 responses. Rasch analysis was then performed on >1,300 MG-QOL15r scales. RESULTS: The MGQOL15r performed slightly better than the MG-QOL15. The 3-response option MG-QOL15r demonstrated better clinimetric properties than the 4- or 5-option scales. Relative distributions of item and person location estimates showed good coverage of disease severity. CONCLUSIONS: The MG-QOL15r is now the preferred HRQOL instrument for MG because of improved clinimetrics and ease of use. This revision does not negate previous studies or interpretations of results using the MG-QOL15. Muscle Nerve 54: 1015-1022, 2016.

Can mycophenolate mofetil be tapered safely in myasthenia gravis? A retrospective, multicenter analysis.

INTRODUCTION: Mycophenolate mofetil (MMF) is frequently used to treat myasthenia gravis, but there is little information to guide clinicians on the safety of reducing the dose in well-controlled patients. METHODS: This retrospective chart review at 3 institutions identified 92 patients who had undergone MMF taper after achieving either pharmacologic remission or minimal manifestations status. Statistical analysis was performed to assess differences in patient characteristics between patients who had successfully tapered MMF and those who relapsed. RESULTS: Of 92 patients undergoing a taper, 30 relapsed. The relapses were mild, transient, and usually responded to increased MMF dose. MG crisis did not occur. The mean dose at time of relapse was 888 mg/day. Patients with relapses were tapered more quickly (8.4 vs. 62.4 months). CONCLUSIONS: Tapering MMF appears safe after years of disease stability. Reducing the dose at a dose of only 500 mg/day every 12 months is recommended.

Myasthenia Gravis.

Myasthenia gravis is an autoimmune neuromuscular disease caused by antibodies directed against the postsynaptic muscle membrane. The clinical hallmark of the disease is fluctuating and fatigable weakness that affects the ocular muscles (resulting in diplopia and ptosis), the bulbar muscles (causing dysphagia, dysarthria, and dyspnea), and extremity muscles. The diagnosis is most often made with serological testing that identifies either acetylcholine receptor antibodies or muscle-specific tyrosine kinase antibodies. Electrodiagnostic testing has a role in supporting the diagnosis. There are many available treatments that result in improvement of function and quality of life. Treatment should be individualized after consideration of many factors, including disease distribution and severity, patient comorbidities, age, serological status, and what is known about the efficacy and safety of the various treatments.

The modified rankin scale to assess disability in myasthenia gravis: Comparing with other tools.

INTRODUCTION: We explored the modified Rankin scale (mRS) as a tool to quantitate disability in myasthenia gravis (MG). Our aim was to correlate patients' perception of their disability with that of the care provider and determine its relationship with other MG-related scores. METHODS: We evaluated 107 MG patients at 2 neurological centers. Patients were assessed over the telephone before and after clinic visits using the 15-item Myasthenia Gravis Quality-of-Life index (MG-QOL15) and mRS. At the clinic, patients were assessed using the MG-QOL15, MG Composite (MGC), and mRS. RESULTS: The MG-QOL15 correlated with the MGC, mRS, and assessors' scores of patients. Assessors' perception of disease burden was in line with that of the patients' scoring. MG-QOL15 scores obtained over the telephone were consistent with those obtained in the clinic. Scores were generally higher in patients receiving steroids at >5 mg/day and in those receiving or seeking benefits. CONCLUSION: The MG-QOL15 and mRS are useful for estimating disability in MG.

Does change in acetylcholine receptor antibody level correlate with clinical change in myasthenia gravis?

INTRODUCTION: The objective of this study is to determine if change in acetylcholine receptor antibody (AChR-ab) levels reflects change in clinical severity in patients with myasthenia gravis (MG). METHODS: We reviewed results from a prospective trial in MG and from all 85 patients in an MG Clinic who had AChR-ab determinations performed at least twice by the same commercial laboratory. RESULTS: Change in AChR-ab levels correlated only weakly with change in clinical severity. AChR-ab levels fell in 92% of patients who improved and in 63% who did not. A fall in AChR-ab level had a positive predictive value for clinical improvement of 83% and a negative predictive value of only 59%. CONCLUSIONS: AChR-ab levels fell in almost all patients who improved, but also in most patients who did not. Thus, we do not recommend commercially available AChR-ab levels as a biomarker of improvement in MG. However, antibody levels might be useful as a marker for inadequate immunotherapy.

Electrical impedance myography correlates with standard measures of ALS severity.

INTRODUCTION: Electrical impedance myography (EIM) can be used to assess amyotrophic lateral sclerosis (ALS) progression. The relationship between EIM values and standard assessment measures, however, is unknown. METHODS: EIM 50 kHz phase data from 60 subjects who participated in a longitudinal natural history study of ALS were correlated with handheld dynamometry (HHD), the ALS Functional Rating Scale-Revised (ALSFRS-R) score, and motor unit number estimation (MUNE). RESULTS: Moderate strength correlations between EIM parameters and HHD were observed for both whole-body and individual upper and lower extremity values. Similarly, moderate strength correlations were observed between EIM and ALSFRS-R upper and lower extremity subscores, but not total ALSFRS-R scores. MUNE correlated significantly with single muscle EIM data but not with whole body or upper or lower extremity values. CONCLUSIONS: These results support the concept that EIM can serve as a meaningful measure of disease severity in ALS.

Psychometrics evaluation of Charcot-Marie-Tooth Neuropathy Score (CMTNSv2) second version, using Rasch analysis.

Charcot-Marie-Tooth Neuropathy Score second version (CMTNSv2) is a validated clinical outcome measure developed for use in clinical trials to monitor disease impairment and progression in affected CMT patients. Currently, all items of CMTNSv2 have identical contribution to the total score. We used Rasch analysis to further explore psychometric properties of CMTNSv2, and in particular, category response functioning, and their weight on the overall disease progression. Weighted category responses represent a more accurate estimate of actual values measuring disease severity and therefore could potentially be used in improving the current version.