Beyond pharmacotherapy: a narrative review of patient, social, and healthcare system factors influencing treatment adherence in ankylosing spondylitis.

Rett syndrome (RTT) is a rare, progressive neurodevelopmental disorder that primarily affects females and is most commonly associated with pathogenic variants in the methyl-CpG-binding protein 2 (MECP2) gene. Typical RTT is generally associated with MECP2 mutations; however, atypical RTT or RTT-like neurodevelopmental phenotypes may be associated with other genes, including CDKL5 and FOXG1 (, ). Deficiency in the MECP2 protein disrupts normal neuronal development and synaptic structure and neuron function, leading to loss of acquired purposeful hand skills and spoken language along with development of gait abnormalities, and hand stereotypies (). Compounding this, the patients also develop clinical complications and comorbidities such as seizures, and severe gastrointestinal dysfunction among others (, ). Overall, RTT and associated comorbidities contribute to substantial lifelong morbidity and higher health care resource utilization burden (, ). Historically, RTT was viewed as a pediatric condition; with symptoms emerging in early childhood (usually 6–18 months) that persist throughout a person’s life (). Although it is a debilitating and chronic condition, advances in multidisciplinary supportive care have significantly increased life expectancy among individuals with RTT; with nearly 60% individuals now surviving well into their fourth and fifth decades (). Although little has been known about the aging process of RTT, recent research has attempted to examine potential differences between younger individuals with RTT vs. adults with RTT. For example, a 15-year longitudinal natural history study of caregiver-provided historical and clinically observed RTT symptoms reported that older individuals (aged ≥30 years) reported similar severity levels of RTT as younger individuals (aged <30 years). However, the older individuals reported worsening in loss of motor features and functioning skills, but improvements in nonverbal communication compared to younger individuals (). These findings are consistent with other research which suggests that adults with RTT may face significant motor skill loss, worsening scoliosis, breathing difficulties, and severe epilepsy (). Overall, younger RTT individuals who transition into adulthood often face significant challenges in continuity of care and decline in specialized multidisciplinary support, even as the burden of chronic comorbidities such as epilepsy and scoliosis may evolve (, ). In the United States (US), real-world evidence using administrative claims data indicates that a substantial proportion of individuals may have their first observed RTT diagnosis recorded in adulthood (≥18 yrs) (). In this study, it is possible that a majority of adults may have been born before the turn of 21st century and potentially faced challenges in getting an appropriate diagnosis in childhood due to potential challenges in differentiating RTT from similar disease states. The discovery of the MECP2 gene in 1999 and the development of defined RTT diagnostic criteria in 2010 have changed the screening and diagnostic landscape of RTT to include both children and adults in diagnostic testing. Therefore, it is important for clinicians and caregivers to recognize the clinical features of RTT among adults to avoid delays in diagnosis and ensure timely initiation of treatment. Currently, trofinetide (TROF) is the first and only treatment for RTT for all individuals aged ≥2 years (). The primary clinical trial supporting the efficacy and safety of TROF in RTT was the 12-week, phase 3, placebo-controlled LAVENDER study in females with RTT aged 5–20 years (); participants who completed the study could continue treatment in LILAC and LILAC-2, 40-week and 32-month open-label extension studies of LAVENDER, respectively (, ). Additionally, the tolerability and efficacy of TROF in girls with RTT aged 2–4 years was assessed in the open-label phase 2/3 DAFFODIL study (). The only clinical trial that evaluated the efficacy and safety of TROF among adult patients (>20 years of age) with RTT aged into their forties was an early phase 2 trial (); however, the dosing in this trial was lower than that of subsequent trials. In summary, LAVENDER, LILAC, LILAC-2, and DAFFODIL included females aged 2–20 years only; thus, there is a critical need to better understand the demographic and clinical characteristics of adults >20 years of age who initiate TROF for the treatment of RTT in real-world settings. To address this need, a real-world study was conducted to examine patient demographics and clinical characteristics among adult RTT individuals who were either treated or untreated with TROF in clinical practice.