Content validity is key when developing a new outcome measurement instrument or selecting an existing measurement instrument. Without good content validity, wrong conclusions can be drawn about an outcome that is measured. In this article, we explain that content validity refers to the relevance, comprehensiveness, and comprehensibility of the instruments' content. Content validity is not only relevant for patient-reported outcome measures but also for other outcome measurement instruments, such as clinician-reported outcome measures and performance-based tests. It is preferably assessed in qualitative studies, eg, focus group studies or Delphi studies. When developing an instrument, the focus is first on the relevance and comprehensiveness of the content of the instrument, then the content is developed, and next its comprehensibility is evaluated. Steps may be repeated. When evaluating content validity of an existing measurement instrument, the three aspects of content validity are evaluated at the same time. Content validity helps to understand whether the content of the measurement instrument is a sufficient representation of the outcome being measured (relevance and comprehensiveness), and whether the formulation used in the measurement instrument (eg, to describe instructions, items, tasks, explanations) is sufficiently understood (comprehensibility) by the people involved in the measurement.

In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. This could create new opportunities for testing in DMD animal models and/or clinical trials, possibly leading to smaller glucocorticoids dosage regimens for DMD patients.

Aims: Regeneration in skeletal muscle relies on regulated myoblast migration and differentiation, in which the transcription factor nuclear factor of activated T-cells 5 (NFAT5) participates. Impaired muscle regeneration and chronic inflammation are prevalent in myositis. Little is known about the impact of inflammation on NFAT5 localization and expression in this group of diseases. The goal of this study was to investigate NFAT5 physiology in unaffected myoblasts exposed to cytokine or hyperosmolar stress and in myositis. Methods: NFAT5 intracellular localization and expression were studied in vitro using a cell culture model of myositis. Myoblasts were exposed to DMEM solutions enriched with pro-inflammatory cytokines IFN-γ with IL-1β or hyperosmolar DMEM obtained by NaCl supplementation. NFAT5 localization was visualized using immunohistochemistry (IHC) and Western blotting (WB) in fractionated cell lysates. NFAT5 expression was assessed by WB and RT-qPCR. In vivo localization and expression of NFAT5 were studied in muscle biopsies of patients diagnosed with polymyositis (n = 6), dermatomyositis (n = 10), inclusion body myositis (n = 11) and were compared to NFAT5 localization and expression in non-myopathic controls (n = 13). Muscle biopsies were studied by means of quantitative IHC and WB of total protein extracts. Results: In unaffected myoblasts, hyperosmolar stress ensues in NFAT5 nuclear translocation and increased NFAT5 mRNA and protein expression. In contrast, pro-inflammatory cytokines did not lead to NFAT5 nuclear translocation nor increased expression. Cytokines IL-1β with IFN-γ induced colocalization of NFAT5 with histone deacetylase 6 (HDAC6), involved in cell motility. In muscle biopsies from dermatomyositis and polymyositis patients, NFAT5 colocalized with HDAC6, while in IBM, this was often absent. Conclusions: Our data suggest impaired NFAT5 localization and expression in unaffected myoblasts in response to inflammation. This disturbed myogenic NFAT5 physiology could possibly explain deleterious effects on muscle regeneration in myositis.

Background: Clinician-reported outcome measures (ClinROMs) are frequently used in clinical trials and daily practice to evaluate the disease status and evolution of skin disorders. The minimal important difference (MID) represents the smallest difference that decreases the disease impact enough to make a treatment change worthwhile for patients. As no clear guidance exists on the preferred method to calculate MIDs for ClinROMs, we evaluated how the published values for different skin disorders should be interpreted. Methods: A systematic search was performed for MIDs of ClinROMs that focus on skin disorders and/or symptoms. The results of the questions in the credibility instrument for MIDs of Devji et al., 2020 were analyzed to gain insights into the meaning of these MIDs. Results: 29 MIDs were identified. The most common skin diseases were atopic dermatitis/eczema, followed by bullous disorders and psoriasis. A minimal important difference from the patients’ perspective was determined in 31% of the cases. However, in 41.4% of the cases, it concerned a substantial rather than a minimal difference in disease severity rated by physicians. Over half (55.1%) of the studies contained an inadequate number of patients (n < 150). MID values increased substantially in patients with severe compared to mild disease. Conclusions: MIDs of ClinROMs for skin disorders should be carefully interpreted due to the substantial differences in methodology between the studies. There is an urgent need for a consensus method to report reliable MIDs. Otherwise, this lack of uniformity could not only affect the design and conclusion of clinical trials but also skew treatment decisions.