Exploring the Content Validity of the Unified Wilson Disease Rating Scale: Insights from Qualitative Research.

INTRODUCTION: Wilson disease (WD) is a rare metabolic disorder of impaired copper transport manifesting in hepatic, neurological, and psychiatric symptoms. To evaluate the clinical symptoms of WD in clinical trials, a group of clinicians created the Unified Wilson Disease Rating Scale (UWDRS). Content validity of this scale has not been established. The aim of this study was to evaluate the content validity of the UWDRS Part II from the patient perspective. METHODS: This study utilized multiple qualitative research methods including concept elicitation interviews, concept/instrument mapping, and cognitive debriefing interviews. RESULTS: Concept elicitation interviews with a sample of patients with WD and one or more neurological signs/symptoms identified several signs, symptoms, and impacts related to neurological dysfunction, strengthening our understanding of the importance of the neurological aspects of the WD patient experience. Mapping neurological concepts to Part II and III items of the UWDRS showed complete coverage of all salient neurological concepts and near complete coverage of all neurological concepts reported by patients in concept elicitation interviews. Item debriefing of Part II of the UWDRS revealed that patients generally found the items clear and personally relevant to their experience with WD. CONCLUSION: Overall, the findings from this study provide evidence for the content validity of the UWDRS Part II and supportive evidence for the content validity of Part III. The UWDRS should be used in conjunction with additional clinical outcomes assessments, specifically those evaluating the hepatic and psychiatric signs/symptoms of WD, to provide a comprehensive evaluation of the WD patient experience.

The patient experience of Wilson disease: a conceptual model based on qualitative research.

BACKGROUND: Wilson disease (WD) is a rare disease wherein copper accumulates in tissues, leading to hepatic degeneration, neurological impairments, and psychiatric symptoms. This study aimed to characterize the patient experience of WD and develop a conceptual model containing key symptoms and impacts of the disease. RESULTS: A targeted literature review was conducted to develop a preliminary conceptual model of WD that was subsequently refined through one-on-one interviews with 3 WD clinicians and finalized following concept elicitation interviews with 11 patients and 1 caregiver. The literature review returned 30 articles, from which 45 concepts (35 signs/symptoms and 10 impacts) were selected for inclusion in the preliminary conceptual model. After interviews with clinicians, the model was expanded to include 45 signs/symptoms and 14 impacts. The final comprehensive conceptual model developed after interviews with patients included 54 symptoms in total (n = 22 hepatic, n = 19 neurological, n = 13 psychiatric), and 21 impacts. Across symptoms, patients reported a high level of bother, with approximately 49% of symptoms reported by patients having an average peak bother rating of ≥ 7 out of 10 (10 = most bothersome). Patient interviews identified 2 subgroups of patients: those who experience neurological, psychiatric, and hepatic symptoms and those who experience mostly hepatic and some psychiatric symptoms, but no neurological symptoms. CONCLUSIONS: This research underscores the substantial multisystemic symptoms and impacts that patients with WD describe as highly bothersome in their lives. Hepatic symptoms emerged as especially common and important to patients with WD, possibly beyond what is commonly understood in research and clinical practice. Further, the description of 2 distinct patient groups may help to inform patient management and support more targeted drug development processes.

Clinical and biochemical characteristics of adults with hypophosphatasia attending a metabolic bone clinic.

OBJECTIVES: This study sought to identify the clinical and biochemical characteristics that would help distinguish hypophosphatasia (HPP) from other metabolic bone diseases in adult patients attending a metabolic bone clinic by comparing patients who have genetically confirmed HPP with a group of patients with low bone mineral density (BMD) in the osteoporotic or osteopenic range. METHODS: Data were collected from February 2016 to October 2018 for 41 patients (n = 20 in the HPP group, n = 21 in the low-BMD group) attending the metabolic bone clinic at Sheffield, United Kingdom (UK) or who were recruited via the Rare UK Diseases Study (RUDY) platform during the same period. A study questionnaire was administered to all patients, and assessments were conducted for laboratory values, physical functions, BMD, and spine imaging. RESULTS: Patients with HPP were characterized as being younger, more likely to have metatarsal or femoral shaft fractures, and less likely to have vertebral fractures compared with patients in the low-BMD group. The HPP group had lower total and bone-specific alkaline phosphatase, higher pyridoxal 5'-phosphate (PLP), and lower, albeit sufficient, 25-hydroxyvitamin D. Low-BMD group had lower C-terminal telopeptide and tartrate-resistant acid phosphatase 5b (61.9% were on bisphosphonates at enrollment). Dual X-ray absorptiometry (DXA) analysis found that the HPP group had higher total hip and lumbar BMD T- and Z-scores compared with the low-BMD group. There were no differences found between the two groups with physical functional assessments. Results of receiver operating characteristic analysis indicated strong diagnostic accuracy of these biomarkers for HPP. Thresholds of total alkaline phosphatase (ALP) activity of 43 IU/L or less and PLP level of 120 nmol/L or more were determined to be potentially clinically useful for distinguishing HPP from other metabolic bone diseases. CONCLUSION: This study supported the use of ALP and PLP measurements as predictive of HPP diagnosis along with certain demographic and clinical characteristics (younger age, metatarsal or femoral fractures without low mean BMD T- and Z-scores on a DXA scan) that can aid in recognizing adults who should be further evaluated for HPP. The critical values identified need to be applied to an independent sample to be tested for diagnostic accuracy.

Estimation Of The Quality Of Life Benefits Associated With Treatment For Spinal Muscular Atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare, genetic, progressive neuromuscular disorder characterized by severe muscle atrophy and weakness and is a leading genetic cause of death in infants and children. Nusinersen was the first treatment targeting the underlying cause of disease approved by the FDA, EMA and other countries for patients with SMA. There are currently very limited data available on the health-related quality of life (HRQoL) burden of SMA suitable for use in a cost-effectiveness analysis. OBJECTIVE: This study was designed to estimate quality of life weights or utilities for different SMA states. METHODS: SMA case studies were developed describing Type I (infantile onset) and Type II (later-onset) patients and different outcomes from treatment. These were developed so that quality of life weights or utilities (where the value of health ranges from 1 - full health to 0 - dead) could be estimated for cost-effectiveness analysis. Clinical experts (n=5) rated each of the case studies using standardized HRQoL instruments - the EQ-5D-Y and PedsQL-NMM (baseline states only). RESULTS: The SMA Type I utilities ranged from -0.33 (requires ventilation) to 0.71 (Type I patient reclassified as Type III following treatment), with quite substantial differences between some states. Most Type I states had a utility score below zero indicating the severity of the states. The SMA Type II utilities ranged from -0.13 (worsened) to 0.72 (stands/walks unaided). In general, the results showed HRQoL improved in line with better health states. CONCLUSION: The utility scores obtained in this study highlight the very substantial burden experienced by SMA patients. Despite the limitations in the methods used, this study produced data with face validity and is a useful starting point for understanding the burden of SMA Types I and II in cost-effectiveness analysis.

Cost Effectiveness of Nusinersen in the Treatment of Patients with Infantile-Onset and Later-Onset Spinal Muscular Atrophy in Sweden.

BACKGROUND: Spinal muscular atrophy is a rare neuromuscular disorder with a spectrum of severity related to age at onset and the number of SMN2 gene copies. Infantile-onset (≤ 6 months of age) is the most severe spinal muscular atrophy and is the leading monogenetic cause of infant mortality; patients with later-onset (> 6 months of age) spinal muscular atrophy can survive into adulthood. Nusinersen is a new treatment for spinal muscular atrophy. OBJECTIVE: The objective of this study was to evaluate the cost effectiveness of nusinersen for the treatment of patients with infantile-onset spinal muscular atrophy and later-onset spinal muscular atrophy in Sweden. METHODS: One Markov cohort health-state transition model was developed for each population. The infantile-onset and later-onset models were based on the efficacy results from the ENDEAR phase III trial and the CHERISH phase III trial, respectively. The cost effectiveness of nusinersen in both models was compared with standard of care in Sweden. RESULTS: For a time horizon of 40 years in the infantile-onset model and 80 years in the later-onset model, treatment with nusinersen resulted in 3.86 and 9.54 patient incremental quality-adjusted life-years and 0.02 and 2.39 caregiver incremental quality-adjusted life-years and an incremental cost of 21.9 and 38.0 million SEK (Swedish krona), respectively. These results translated into incremental cost-effectiveness ratios (including caregiver quality-adjusted life-years) of 5.64 million SEK (€551,300) and 3.19 million SEK (€311,800) per quality-adjusted life-year gained in the infantile-onset model and later-onset model, respectively. CONCLUSIONS: Treatment with nusinersen resulted in overall survival and quality-adjusted life-year benefits but with incremental costs above 21 million SEK (€2 million) [mainly associated with maintenance treatment with nusinersen over a patient's lifespan]. Nusinersen was not cost effective when using a willingness-to-pay threshold of 2 million SEK (€195,600), which has been considered in a recent discussion by the Dental and Pharmaceutical Benefits Agency as a reasonable threshold for rare disease. Nonetheless, nusinersen gained reimbursement in Sweden in 2017 for paediatric patients (below 18 years old) with spinal muscular atrophy type I-IIIa.

Health-Related Quality of Life and Work-Related Outcomes for Patients With Mild-to-Moderate Ulcerative Colitis and Remission Status Following Short-Term and Long-Term Treatment With Multimatrix Mesalamine: A Prospective, Open-Label Study.

Background: Disease activity of patients with ulcerative colitis (UC) predicts health-related quality of life (HRQL) and work-related outcomes (eg, absenteeism, productivity). We tested whether outcomes differed among patients in complete (clinical and endoscopic) remission, partial remission, or not in remission following treatment with multimatrix mesalamine. Methods: Data were from an open-label, multicountry, prospective trial (ClinicalTrials.gov identifier: NCT01124149) of 717 adults with active mild-to-moderate UC treated with 4.8 g/day multimatrix mesalamine tablets for 8 weeks (induction period); 459 patients who achieved partial or complete remission received daily 2.4 g/day multimatrix mesalamine for 12 additional months (maintenance period). HRQL (SF-12v2 Health Survey and Short Inflammatory Bowel Disease Questionnaire) and work-related outcomes (Work Productivity and Activity Impairment questionnaire) were assessed at baseline and final visits of each treatment period. Differences in scores by remission status within each treatment period were tested using analysis of variance and analysis of covariance models, whereas mixed-effects models with repeated measures tested changes over time. Results: At their final visit of each treatment period, patients in partial remission scored significantly better on all HRQL and work-related domains than patients not in remission (all Bonferroni-adjusted P < 0.05). Scores for patients in partial remission were, almost without exception, statistically equivalent to those for patients in complete remission. Fluctuating between complete and partial remission during maintenance treatment had no impact on outcomes. Conclusions: Patients in partial remission following multimatrix mesalamine treatment had HRQL and work-related outcomes equivalent to patients in complete remission. Achievement and maintenance of partial remission may be sufficient for improvements in patients' functioning, well-being, and work performance.