Brain. 2021 Nov 23:awab327. doi: 10.1093/brain/awab327. Online ahead of print.

ABSTRACT

Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear correlations between variant type and clinical features have not been observed so far. Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom. In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches.

PMID:35190816 | DOI:10.1093/brain/awab327

Front Immunol. 2022 Feb 4;13:785231. doi: 10.3389/fimmu.2022.785231. eCollection 2022.

ABSTRACT

Uveal melanoma (UM) is an orphan disease with a mortality of 80% within one year upon the development of metastatic disease. UM does hardly respond to chemotherapy and kinase inhibitors and is largely resistant to checkpoint inhibition. Hence, further therapy approaches are urgently needed. To improve clinical outcome, we designed a trial employing the 3rd generation personalized IKKβ-matured RNA-transfected dendritic cell (DC) vaccine which primes T cells and in addition activates NK cells. This ongoing phase I trial [NCT04335890 (www.clinicaltrials.gov), Eudract: 2018-004390-28 (www.clinicaltrialsregister.eu)] investigates patients with treatment-naive metastatic UM. Monocytes are isolated by leukapheresis, differentiated to immature DCs, matured with a cytokine cocktail, and activated via the NF-κB pathway by electroporation with RNA encoding a constitutively active mutant of IKKβ. Three types of antigen-RNA are co-electroporated: i) amplified mRNA of the tumor representing the whole transcriptome, ii) RNA encoding driver mutations identified by exome sequencing, and iii) overexpressed non-mutated tumor antigens detected by transcriptome sequencing. This highly personalized DC vaccine is applied by 9 intravenous infusions in a staggered schedule over one year. Parallel to the vaccination, standard therapy, usually an immune checkpoint blockade (ICB) as mono (anti-PD-1) or combined (anti-CTLA4 and anti-PD-1) regimen is initiated. The coordinated vaccine-induced immune response encompassing tumor-specific T cells and innate NK cells should synergize with ICB, perhaps resulting in measurable clinical responses in this resistant tumor entity. Primary outcome measures of this trial are safety, tolerability and toxicity; secondary outcome measures comprise overall survival and induction of antigen-specific T cells.

PMID:35185883 | PMC:PMC8854646 | DOI:10.3389/fimmu.2022.785231

Lancet Neurol. 2022 Mar;21(3):203. doi: 10.1016/S1474-4422(22)00046-1.

NO ABSTRACT

PMID:35182497 | DOI:10.1016/S1474-4422(22)00046-1

Orphanet J Rare Dis. 2022 Feb 16;17(1):54. doi: 10.1186/s13023-022-02216-w.

ABSTRACT

INTRODUCTION: This study implemented MendelScan, a primary care rare disease case-finding tool, into a UK National Health Service population. Rare disease diagnosis is challenging due to disease complexity and low physician awareness. The 2021 UK Rare Diseases Framework highlights as a key priority the need for faster diagnosis to improve clinical outcomes.

METHODS AND RESULTS: A UK primary care locality with 68,705 patients was examined. MendelScan encodes diagnostic/screening criteria for multiple rare diseases, mapping clinical terms to appropriate SNOMED CT codes (UK primary care standardised clinical terminology) to create digital algorithms. These algorithms were applied to a pseudo-anonymised structured data extract of the electronic health records (EHR) in this locality to "flag" at-risk patients who may require further evaluation. All flagged patients then underwent internal clinical review (a doctor reviewing each EHR flagged by the algorithm, removing all cases with a clear diagnosis/diagnoses that explains the clinical features that led to the patient being flagged); for those that passed this review, a report was returned to their GP. 55 of 76 disease criteria flagged at least one patient. 227 (0.33%) of the total 68,705 of EHR were flagged; 18 EHR were already diagnosed with the disease (the highlighted EHR had a diagnostic code for the same RD it was screened for, e.g. Behcet's disease algorithm identifying an EHR with a SNOMED CT code Behcet's disease). 75/227 (33%) EHR passed our internal review. Thirty-six reports were returned to the GP. Feedback was available for 28/36 of the reports sent. GP categorised nine reports as "Reasonable possible diagnosis" (advance for investigation), six reports as "diagnosis has already been excluded", ten reports as "patient has a clear alternative aetiology", and three reports as "Other" (patient left study locality, unable to re-identify accurately). All the 9 cases considered as "reasonable possible diagnosis" had further evaluation.

CONCLUSIONS: This pilot demonstrates that implementing such a tool is feasible at a population level. The case-finding tool identified credible cases which were subsequently referred for further investigation. Future work includes performance-based validation studies of diagnostic algorithms and the scalability of the tool.

PMID:35172857 | PMC:PMC8848904 | DOI:10.1186/s13023-022-02216-w

Pediatr Pulmonol. 2022 Feb 15. doi: 10.1002/ppul.25859. Online ahead of print.

ABSTRACT

BACKGROUND: While the advent of CFTR modulator use has improved daily life and long term prognosis of CF for many with approved CFTR mutations, approximately 10% of people with CF (pwCF) have only symptomatic treatments available.

METHODS: Between June 10-July 1, 2021, Emily's Entourage distributed a 38-question anonymous survey targeted at pwCF not benefitting from approved modulators via social media and email to pwCF and CF advocacy groups in and outside the U.S. regarding health status, impact of CF, unmet needs and clinical research interest.

RESULTS: There were 431 survey respondents representing pwCF on five continents. The majority of pwCF had moderate lung disease (50.3%). Ineligibility based on CFTR mutation (64.1%) was the most frequently reported reason pwCF were not on modulators. PwCF reported the most impacted aspects of life were mental (66.7%) and physical (40.7%) health. Financial concerns and feelings of isolation were commonly reported. Witnessing improvements for peers with access to modulators was both uplifting and disheartening. The majority of pwCF would be interested in participating in future clinical research (77.6%), although some living outside of the US cited lack of opportunity to participate in clinical trials as a barrier.

CONCLUSIONS: PwCF who are ineligible, intolerant or lack access to modulators have a high burden of disease impacting their physical and mental health. Although most are happy for those who are benefiting from modulators, they are eager for the opportunity to experience similar improvements for themselves, and willing to participate in clinical trials of new therapies. This article is protected by copyright. All rights reserved.

PMID:35170259 | DOI:10.1002/ppul.25859

Orphanet J Rare Dis. 2022 Feb 14;17(1):47. doi: 10.1186/s13023-022-02176-1.

ABSTRACT

BACKGROUND: In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process.

STUDY DESIGN: This multi-center, prospective controlled study has a two-phase cohort design.

METHODS: Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD's outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2).

OUTCOMES: Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients' quality of life and evaluation of care; and f) physicians' satisfaction with the innovative care approach.

CONCLUSIONS: This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease. Trial registration ClinicalTrials.gov; Identifier: NCT03563677; First posted: June 20, 2018, https://clinicaltrials.gov/ct2/show/NCT03563677 .

PMID:35164804 | PMC:PMC8842899 | DOI:10.1186/s13023-022-02176-1

West Afr J Med. 2022 Jan 31;39(1):52-58.

ABSTRACT

BACKGROUND: Bronchiectasis is often considered an orphan disease in developed societies. This may not be the case with low-income countries. Currently there is a paucity of data on the pattern and presentation of this condition in Nigeria.

OBJECTIVE: This study was undertaken to determine the frequency and pattern of presentation of bronchiectasis in a tertiary healthcare facility in Uyo, South-South, Nigeria.

METHODS: We carried out a three-year prospective study of adult patients aged between 15-85 years diagnosed with bronchiectasis in the University of Uyo Teaching Hospital in Uyo, Nigeria between 2016 and 2019.

RESULTS: Eighty-two patients were identified from the clinic register. Out of these, 76 were recruited into the study; made up of 44(57.9%) males and 32 (42.1%) females. The average age of the patients was 49.7 ± 14.1 years. Sixteen (21.1%) of the patients were HIV positive. Forty-four (57.9%) patients had previously been treated for pulmonary tuberculosis. Majority of the patients; 72 (94.7%) had chronic productive cough. Sixty-four (84.2%) had at least one episode of exacerbation within the last 12 months while 36(47.4%) had a severe exacerbation requiring hospitalisation. Hospitalisation was associated with several factors with the strongest contributor being the presence of respiratory distress on physical examination (OR 15.4 p= 0.002).

CONCLUSION: Bronchiectasis is not an uncommon disease amongst our patients. A previous history of pulmonary tuberculosis is the commonest associated predisposing medical condition. There is a high rate of exacerbation among these patients with respiratory distress as the strongest predictor of hospitalisation.

PMID:35166095

Cells. 2022 Feb 4;11(3):546. doi: 10.3390/cells11030546.

ABSTRACT

BACKGROUND: Mucolipidosis IV (MLIV) is an autosomal recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by a loss of function of the lysosomal channel transient receptor potential mucolipin-1 and is associated with an early pro-inflammatory brain phenotype, including increased cytokine expression. The goal of the current study was to determine whether blood cytokines are linked to motor dysfunction in patients with MLIV and reflect brain inflammatory changes observed in an MLIV mouse model.

METHODS: To determine the relationship between blood cytokines and motor function, we collected plasma from MLIV patients and parental controls concomitantly with assessment of motor function using the Brief Assessment of Motor Function and Modified Ashworth scales. We then compared these profiles with cytokine profiles in brain and plasma samples collected from the Mcoln1-/- mouse model of MLIV.

RESULTS: We found that MLIV patients had prominently increased cytokine levels compared to familial controls and identified profiles of cytokines correlated with motor dysfunction, including IFN-γ, IFN-α2, and IP-10. We found that IP-10 was a key differentiating factor separating MLIV cases from controls based on data from human plasma, mouse plasma, and mouse brain.

CONCLUSIONS: Our data indicate that MLIV is characterized by increased blood cytokines, which are strongly related to underlying neurological and functional deficits in MLIV patients. Moreover, our data identify the interferon pro-inflammatory axis in both human and mouse signatures, suggesting that interferon signaling is an important aspect of MLIV pathology.

PMID:35159355 | DOI:10.3390/cells11030546

Epilepsy Behav. 2022 Mar;128:108586. doi: 10.1016/j.yebeh.2022.108586. Epub 2022 Feb 11.

ABSTRACT

OBJECTIVE: Developmental and epileptic encephalopathies (DEE) entail moderate to profound communication and other impairments that are poorly measured by typical clinical outcomes assessments (COA). We examined the potential of alternative approaches, specifically, the use of raw scores and COAs outside of their intended age ranges.

METHODS: In a cross-sectional survey, 120 parents of children with Dravet Syndrome, Lennox-Gastaut syndrome, KCNQ2-DEE, KCNB1-DEE, and SCN2A-DEE (ages 1-35 years) completed the Adaptive Behavior Assessment System-3 for ages 0-5 years, modified checklist for autism (mCHAT), communication and social behavior scales (CSBS), communication matrix (CM), and several parent-reported classifiers of communication. Adaptive Behavior Assessment System communication and social raw scores were the primary and adjunctive outcomes. Floor and ceiling effects, dispersion and convergence with related measures were assessed with appropriate parametric and nonparametric statistical techniques.

RESULTS: Median chronological age (CA) was 8.7 years (Interquartile range (IQR): 5.3-13.5). Adaptive Behavior Assessment Systemcommunication and social age equivalents were 12.5 months (IQR 7.5-28) and 16.5 months (IQR 9-31). Most raw scores corresponded to standardized scores indicating performance <3 standard deviations below the general population mean. Adaptive Behavior Assessment System raw scores demonstrated minimal floor and ceiling effects (<1-2.5%). In linear regression models, scores correlated with age under 6 years (communication, p = 0.001; social, p = 0.003) but significantly flattened out thereafter. Scores varied substantially by DEE group (both p < 0.001) and decreased with higher convulsive seizure frequency (communication, p = 0.01, social, p = 0.02). There was good convergence with mCHAT, CSBS, and CM scores (all r > 0.8).

SIGNIFICANCE: Raw scores and out-of-range COAs may provide measures that are sensitive at the very limited levels of functioning typical of profoundly impaired, older patients with DEEs. To ensure that targeted trial outcomes are responsive to meaningful change, development of these approaches will be essential to clinical trial readiness for novel therapies for rare DEEs.

PMID:35158285 | DOI:10.1016/j.yebeh.2022.108586

Probl Sotsialnoi Gig Zdravookhranenniiai Istor Med. 2022 Jan;30(1):134-137. doi: 10.32687/0869-866X-2022-30-1-134-137.

ABSTRACT

The article presents the results of analysis of specialized medical care of children with life threatening and chronic progressive rare (orphan) diseases resulting in life span shortening or disability. The possibility of medication support of children with rare diseases. The development of patient routing system considering characteristics of particular disease and possibilities of the subjects of the Russian Federation is one of most important directions of enhancement of needed medical care support.

PMID:35157394 | DOI:10.32687/0869-866X-2022-30-1-134-137

MMW Fortschr Med. 2022 Feb;164(Suppl 4):24-26. doi: 10.1007/s15006-021-0588-y.

NO ABSTRACT

PMID:35146713 | DOI:10.1007/s15006-021-0588-y

MMW Fortschr Med. 2022 Feb;164(Suppl 4):3. doi: 10.1007/s15006-021-0659-0.

NO ABSTRACT

PMID:35146706 | DOI:10.1007/s15006-021-0659-0

Orphanet J Rare Dis. 2022 Feb 10;17(1):43. doi: 10.1186/s13023-022-02194-z.

ABSTRACT

Rare diseases (RD) are conditions that affect a small number of people and hence do not get the focus on government health priorities in a resource-constrained setting such as India. Therefore, it is essential to focus on strengthening and utilizing the existing public health framework for the optimal usage of healthcare resources. In this regard, National Health Mission (NHM) is one of the crucial programs initiated by the government of India to address the health needs of the under-served. As Phase 1 of the NHM moves towards completion, we explored the Reproductive, Maternal, Newborn, Child, and Adolescent Health (RMNCH + A) program under NHM to assess their potential and limitations to aid RD care. We found that some of the disease-prevention initiatives of NHM address certain RDs and can easily be expanded to manage many such preventable RDs. In addition, NHM programs can provide a unique epidemiological data repository to strengthen the National Rare Disease Registry. These programs can also play important role in providing a continuum of care for many RDs that need lifelong management. However, existing programs have a limited scope to provide specialized RD-related treatments, which is better served in a more focused system. Thus, considering RDs in the design of the existing programs may help RD management better through prevention, data collection, and providing a continuum of care.

PMID:35144652 | PMC:PMC8832777 | DOI:10.1186/s13023-022-02194-z

Orphanet J Rare Dis. 2022 Feb 10;17(1):44. doi: 10.1186/s13023-022-02196-x.

ABSTRACT

INTRODUCTION: The neurofibromatoses (NF) are a group of rare, genetic diseases sharing a predisposition to develop multiple benign nervous system tumors. Given the wide range of NF symptoms and medical specialties involved in NF care, we sought to evaluate the level of awareness of, and agreement with, published NF clinical guidelines among NF specialists in the United States.

METHODS: An anonymous, cross-sectional, online survey was distributed to U.S.-based NF clinicians. Respondents self-reported demographics, practice characteristics, awareness of seven NF guideline publications, and level of agreement with up to 40 individual recommendations using a 5-point Likert scale. We calculated the proportion of recommendations that each clinician rated "strongly agree", and assessed for differences in guideline awareness and agreement by respondent characteristics.

RESULTS: Sixty-three clinicians (49% female; 80% academic practice) across > 8 medical specialties completed the survey. Awareness of each guideline publication ranged from 53%-79% of respondents; specialists had higher awareness of publications endorsed by their medical professional organization (p < 0.05). The proportion of respondents who "strongly agree" with individual recommendations ranged from 17%-83%; for 16 guidelines, less than 50% of respondents "strongly agree". There were no significant differences in overall agreement with recommendations based on clinicians' gender, race, specialty, years in practice, practice type (academic/private practice/other), practice location (urban/suburban/rural), or involvement in NF research (p > 0.05 for all).

CONCLUSIONS: We identified wide variability in both awareness of, and agreement with, published NF care guidelines among NF experts. Future quality improvement efforts should focus on evidence-based, consensus-driven methods to update and disseminate guidelines across this multi-specialty group of providers. Patients and caregivers should also be consulted to proactively anticipate barriers to accessing and implementing guideline-driven care. These recommendations for improving guideline knowledge and adoption may also be useful for other rare diseases requiring multi-specialty care coordination.

PMID:35144646 | PMC:PMC8832755 | DOI:10.1186/s13023-022-02196-x

BMC Pregnancy Childbirth. 2022 Feb 10;22(1):110. doi: 10.1186/s12884-022-04453-0.

ABSTRACT

BACKGROUND: Bilateral simultaneous fallopian tubal pregnancy is one of the rarest forms of ectopic pregnancy. Due to the lack of unique features and clinical presentation to distinguish bilateral from unilateral ectopic pregnancy, challenges the diagnosis.

CASE REPORT: A 27-year-old Asian woman presented with pelvic pain and vaginal bleeding. Pelvic transvaginal ultrasound showed fluid in Douglas Pouch and posterior fornix puncture revealed unclotted blood. Laparoscopic examination unveiled bilateral ectopic pregnancy with two corpus luteum visible in the right ovary, suggesting a double spontaneous unilateral ovulation. Bilateral fallopian tube fenestration and embryo extraction were performed to preserve fertility.

CONCLUSION: Diagnosis of bilateral tubal pregnancy is difficult during preoperative ultrasound examination and careful examination during laparoscopic inspection of the whole pelvic cavity to avoid missed diagnosis.

PMID:35144595 | PMC:PMC8832656 | DOI:10.1186/s12884-022-04453-0

Rev Prat. 2021 Nov;71(9):1025-1028.

NO ABSTRACT

PMID:35147326

Z Evid Fortbild Qual Gesundhwes. 2022 Feb 7:S1865-9217(21)00216-6. doi: 10.1016/j.zefq.2021.11.003. Online ahead of print.

ABSTRACT

BACKGROUND: Vascular anomalies are orphan diseases that occur in all age groups and range from purely aesthetic to potentially life-threatening conditions. This thesis paper outlines the typical conferring problems in patient management and possible structural solutions for a better patient treatment in the future.

METHODS: A multi-perspective author panel consisting of key stakeholders from the German Interdisciplinary Society of Vascular Anomalies and the German Society for Surgery defined problem areas and possible solutions including quality indicators as criteria for certified interdisciplinary Vascular Anomalies Centers (VAC).

RESULTS: According to the literature available, clearly defined nomenclature and nosological entities often remain unused in this field, and consented diagnostic and therapeutic evidence is rare. Expert opinions dominate and in some cases lead to disparate recommendations. Typical patient problems arise from this situation, exemplified in patient vignettes. Centralized and standardized patient treatment in interdisciplinary VAC may be a solution to this problem. These centers should agree on a set of general principles and quality indicators with an additional minimum set of structural and procedural criteria.

DISCUSSION: The present position paper outlines perspectives for implementing certified interdisciplinary VAC. There is a need for a comprehensive nomenclature, access to interdisciplinary treatment centers, more scientific evidence, and further education in this rare group of diseases.

CONCLUSION: Use of scientifically sound and patient-relevant criteria for certifying the interdisciplinary quality of VAC is expected to improve health care in Germany.

PMID:35144912 | DOI:10.1016/j.zefq.2021.11.003

S Afr Med J. 2022 Feb 2;112(1):13522.

NO ABSTRACT

PMID:35139996

BMC Med Inform Decis Mak. 2022 Feb 5;22(1):33. doi: 10.1186/s12911-022-01770-4.

ABSTRACT

BACKGROUND: Semantic similarity is a valuable tool for analysis in biomedicine. When applied to phenotype profiles derived from clinical text, they have the capacity to enable and enhance 'patient-like me' analyses, automated coding, differential diagnosis, and outcome prediction. While a large body of work exists exploring the use of semantic similarity for multiple tasks, including protein interaction prediction, and rare disease differential diagnosis, there is less work exploring comparison of patient phenotype profiles for clinical tasks. Moreover, there are no experimental explorations of optimal parameters or better methods in the area.

METHODS: We develop a platform for reproducible benchmarking and comparison of experimental conditions for patient phentoype similarity. Using the platform, we evaluate the task of ranking shared primary diagnosis from uncurated phenotype profiles derived from all text narrative associated with admissions in the medical information mart for intensive care (MIMIC-III).

RESULTS: 300 semantic similarity configurations were evaluated, as well as one embedding-based approach. On average, measures that did not make use of an external information content measure performed slightly better, however the best-performing configurations when measured by area under receiver operating characteristic curve and Top Ten Accuracy used term-specificity and annotation-frequency measures.

CONCLUSION: We identified and interpreted the performance of a large number of semantic similarity configurations for the task of classifying diagnosis from text-derived phenotype profiles in one setting. We also provided a basis for further research on other settings and related tasks in the area.

PMID:35123470 | PMC:PMC8818208 | DOI:10.1186/s12911-022-01770-4

Orphanet J Rare Dis. 2022 Feb 5;17(1):36. doi: 10.1186/s13023-022-02182-3.

ABSTRACT

BACKGROUND: The extent to which different US private insurers require their enrollees to meet the same coverage criteria before gaining access to treatment is unclear. Our objective was to scrutinize the patient access criteria imposed by US private insurers for a set of rare neuromuscular disease (NMD) disease-modifying therapies (DMTs).

METHODS: We examined coverage policies issued by 17 large US private insurers for the following NMD treatments: nusinersen and onasemnogene abeparvovec for spinal muscular atrophy, edaravone for amyotrophic lateral sclerosis, and eteplirsen for Duchenne muscular dystrophy. We reviewed the plans' coverage policies and identified the patient access criteria, including clinical prerequisites, step therapy protocols, and prescriber requirements. We compared the plans' patient access criteria with the therapies' US Food and Drug Administration (FDA)-labeled indications.

RESULTS: The included insurers issued 65 coverage policies for the included therapies. Plans imposed coverage restrictions beyond the FDA-approved indications in 60 coverage policies; plans did not cover eteplirsen in five policies. No therapy was covered the same way by all insurers. Plans applied clinical criteria beyond the FDA label indication in 56 policies and step therapy protocols in three policies. Plans required that a neurologist prescribe the therapy in 37 policies, 22 of which required the neurologist to have expertise in the particular disease. Plans often required patients to suffer from symptoms of particular severity; e.g. for eteplirsen, plans differed in their 6-min walk test requirements; for edaravone, some plans required that patients had normal respiratory function, while others required only that patients did not require ventilation; for nusinersen and onasemnogene abeparvovec, plans differed in the number of SMN2 gene copies they required patients to have (SMN2 copy number is correlated with disease severity).

CONCLUSIONS: The evaluated large US private insurers tended to impose coverage restrictions beyond the FDA label indication for the included set of rare NMD DMTs. Plans rarely applied the same patient access criteria in their coverage policies for the same products. Inconsistent coverage criteria mean that patients with different insurers have variable access to the same therapies across insurers.

PMID:35123543 | PMC:PMC8817582 | DOI:10.1186/s13023-022-02182-3