Patients' and rheumatologists' perceptions on dose reduction of rituximab in rheumatoid arthritis.

OBJECTIVE: The recommended dose of a rituximab course for the treatment of Rheumatoid Arthritis (RA) consists of two infusions of 1000 mg with a 2-week interval. Evidence is growing that a lower dose could be as effective. We aimed to investigate patients' and rheumatologists' perceptions on dose reduction of rituximab. METHODS: Patients with RA treated with rituximab, and rheumatologists were invited for a qualitative study via individual semi-structured interviews. Participants were recruited based on purposive sampling to ensure diversity. Interviews were analysed according to the principles of grounded theory and the constant comparative method. RESULTS: Sixteen patients and 13 rheumatologists were interviewed. Patients and rheumatologists perceived the benefits of rituximab dose reduction for reasons of safety and societal costs. Furthermore, available evidence for the effectiveness of lower doses was mentioned as an argument in favour, in addition to the possibility to tailor the dose based on the patients' clinical manifestations. However, patients and rheumatologists had concerns about the potential loss of effectiveness and quality of life. Moreover, some rheumatologists felt uncomfortable with dose reduction due to insufficient experience with rituximab in general. Patients and rheumatologists emphasised the importance of shared decision-making, underscoring the pivotal role of physicians in this process by explaining the reasoning behind dose reduction. CONCLUSION: Although some concerns on effectiveness were perceived, both patients and rheumatologists saw potential benefits of dose reduction in terms of safety, societal costs, and application of a personalised approach. As a result, most rheumatologists and patients showed a willingness to consider dose reduction strategies.

To flare or not to flare: patients' and rheumatologists' perceptions on the on-flare retreatment strategy of rituximab in rheumatoid arthritis.

Background: Several retreatment strategies exist for rituximab in rheumatoid arthritis (RA). In some countries, reimbursement criteria require a loss of disease control for rituximab retreatment. Understanding the patients' and rheumatologists' perceptions regarding this retreatment strategy would be informative in identifying the optimal treatment administration schedule. Objectives: This study aimed to uncover patients' and rheumatologists' perceptions regarding retreatment strategies of rituximab. Design: Qualitative study - semi-structured interviews. Methods: Patients with RA, treated with rituximab, and rheumatologists were invited to participate in a qualitative study consisting of individual, in-depth, semi-structured interviews. Interviews were analysed according to the Qualitative Analysis Guide of Leuven. Results: A total of 16 patients and 13 rheumatologists were interviewed. Benefits (e.g. decreased risk of overtreatment, cost savings and long-lasting effectiveness of rituximab) and barriers (e.g. fluctuating disease activity, slow mode of action and increased glucocorticoid use) of on-flare retreatment were identified. To effectively treat on-flare, flares must first be identified timely. Both stakeholder groups acknowledged that patients are capable of recognizing flares. However, the patient's ability to discriminate between inflammatory and other types of pain was perceived as difficult. Furthermore, patients and rheumatologists stressed that patients must timely seek professional help in case of a flare, followed by a swift response from the rheumatologists. Remarkably, retreatment was approached in various ways among rheumatologists, and not always adhering strictly to the on-flare reimbursement criteria. Conclusion: This study revealed that both stakeholder groups perceived the heterogeneity in recognition of and reaction to a flare as important in influencing the effectiveness of the on-flare retreatment strategy. Moreover, this study identified the benefits and barriers of treating on-flare, which could be informative for daily practice decisions.

Patient-physician discordance impairs outcomes in early rheumatoid arthritis through less consistent treat-to-target implementation.

OBJECTIVES: We aimed to assess whether patient-physician discordance regarding disease activity affects T2T-implementation and clinical outcomes in rheumatoid arthritis (RA). METHODS: This was an analysis of the 2-year T2T-guided trial Care in early RA (CareRA). During year 1, DMARD escalations were mandated by the protocol when DAS28-CRP was >3.2. During year 2, treatment was at the rheumatologists' discretion. At each visit we assessed T2T-implementation, defined as escalating DMARDs if DAS28-CRP >3.2. Patient-physician discordance was defined by the discordance score (DS), a weighted difference between patient-reported and clinical/laboratory outcomes. Using generalised linear mixed models and multilevel mediation analysis, we studied the association between time-varying DS, T2T-implementation and the odds of remission (SDAI ≤3.3), physical functioning (HAQ-score), and radiographic progression at year 2. RESULTS: Over 2 years, 379 patients were assessed at 3129 follow-up visits. On 445 (14%) of these visits, DAS28-CRP was >3.2, and DMARDs were escalated in 217/445 (49%) of such cases. T2T-implementation declined over time and was consistently lower during the second year (year 1: 57-66%; year 2: 17-52%). Higher DS over time was negatively associated with remission and physical functioning at year 2, partly mediated by a lower proportion of T2T-adherent visits. No such association was found for radiographic progression. CONCLUSION: Even in a trial setting, T2T was applied on only around 50% of visits. T2T was less likely to be implemented with increasing patient-physician discordance regarding disease activity, which was in turn associated with less remission and worse functional outcome, but not with radiographic progression.

Viewpoint: Supporting mental health in the current management of rheumatoid arthritis: time to act!

Although clinical outcomes of RA have vastly improved in recent years, the disease's mental health impact has seemingly not decreased to the same extent. Even today, learning to live with RA is an active process involving several psychological, cognitive, behavioural and emotional pathways. Consequently, mental health disorders are more common in the context of RA than in the general population, and can be particularly detrimental both to patients' quality of life and to clinical outcomes. However, mental health is a spectrum and represents more than the absence of psychological comorbidity, and supporting patients' psychological wellbeing should thus involve a more holistic perspective than the mere exclusion or specific treatment of mental health disorders. In this viewpoint article, we build on mechanistic and historical insights regarding the relationship between RA and mental health, before proposing a practical stepwise approach to supporting patients' mental health in daily clinical practice.

Effectiveness and feasibility of a mobile health self-management intervention in rheumatoid arthritis: study protocol for a pragmatic multicentre randomised controlled trial (AEGORA).

BACKGROUND: Rheumatoid arthritis (RA) considerably impacts patients' lives. Patients' confidence in their ability to manage this impact, or self-efficacy, can be supported with self-management interventions. One approach is to use mobile health (mHealth) applications, which can additionally provide insight into disease impact by remotely monitoring patient-reported outcomes. However, user engagement with mHealth-apps is variable, and concerns exist that remote monitoring might make patients overly attentive to symptoms. METHODS: App-based Education and GOal setting in RA (AEGORA) is a multicentre, pragmatic randomised controlled trial investigating an mHealth-based self-management intervention to improve self-efficacy and remotely monitor disease impact in patients with RA. The intervention is provided via an adapted version of the application Sidekick (Sidekick Health, Reykjavik, Iceland) and consists of education, goal setting, lifestyle advice, and remote assessment of the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire. Across two centres, 120 patients will be recruited and randomised (2:1:1) to usual care or intervention group A/B (study app with weekly/monthly prompts to complete the RAID, respectively). Outcomes are assessed at baseline and after 4-6 months. The primary endpoint is a clinically important improvement (≥ 5.5/110) in the Arthritis Self-Efficacy Scale in the combined intervention group compared to usual care. Secondary endpoints are (a) non-inferiority regarding pain catastrophising, as a measure of symptom hypervigilance; (b) superiority regarding the RAID, sleep quality, and physical activity; and (c) participant engagement with the study app. Finally, the relationship between engagement, prompted frequency of RAID questionnaires, and the primary and secondary outcomes will be explored. DISCUSSION: The AEGORA trial aims to study the effectiveness of mHealth-based, multicomponent self-management support to improve self-efficacy in the context of RA, while providing potentially valuable insights into temporal disease activity dynamics and the feasibility and possible negative effects of remote symptom monitoring in this population. TRIAL REGISTRATION: Clinicaltrials.gov NCT05888181. Retrospectively registered on March 23, 2023. Study inclusion started on March 3, 2023.

Diagnostic yield of combined cranial and large vessel PET/CT, ultrasound and MRI in giant cell arteritis: A systematic review and meta-analysis.

OBJECTIVES: To estimate the diagnostic accuracy of combined cranial and large vessel imaging by PET/CT, ultrasound and MRI for giant cell arteritis (GCA). METHODS: PubMed, Embase, Cochrane and Web of Science databases were searched from inception till August 31, 2022. Studies were included if they involved patients with suspected GCA and assessed the diagnostic accuracy of combined cranial and large vessel imaging by PET/CT, ultrasound or MRI with the final clinical diagnosis as reference standard. RESULTS: Eleven (1578 patients), 3 (149 patients) and 0 studies were included for the diagnostic accuracy of ultrasound, PET/CT and MRI, respectively. Combined cranial and large vessel ultrasound had a sensitivity of 86% (76-92%) and specificity of 96% (92-98%). PET/CT of both cranial and large vessels yielded a sensitivity of 82% (61-93%) and specificity of 79% (60-90%). No studies assessed both PET/CT and ultrasound, which precluded head-to-head comparison. Addition of large vessel ultrasound to ultrasound of the temporal arteries (7 studies) significantly increased sensitivity (91% versus 80%, p < 0.001) without decrease in specificity (96% versus 95%, p = 0.57). Evaluating cranial arteries in addition to large vessels on PET/CT (3 studies) tended to increase the sensitivity (82% versus 68%, p = 0.07) without decrease in specificity (81% versus 79%, p = 0.70). CONCLUSION: Combined cranial and large vessel ultrasound and PET/CT provided excellent accuracy for the diagnosis of GCA. Either PET/CT or ultrasound may be preferred depending on setting, expertise and clinical presentation. The diagnostic accuracy of combined cranial and large vessel MRI needs to be determined in future studies.

Glucocorticoids in rheumatoid arthritis: Balancing benefits and harm by leveraging the therapeutic window of opportunity.

Glucocorticoids have been available since the early 1950s and have since become an integral part of the management of rheumatoid arthritis (RA). Due to their rapid effect, glucocorticoids have an appealing profile for treating flares or as "bridging" agents in early RA. The efficacy of glucocorticoids to treat RA has been well established, both to control disease activity and to delay the progression of joint damage. However, despite their benefits, glucocorticoids have equally well-known adverse effects. It is generally accepted that long-term use of glucocorticoids, particularly at higher doses, is not advisable, and recent guidelines for the management of RA therefore either recommend against the use of glucocorticoids or suggest using them only as bridging therapy. Perceptions on the harmful effects of glucocorticoids remain, although mainly based on observational studies. Prolonged glucocorticoid therapy at low doses is still highly prevalent in clinical practice, but recent data suggest a rather favourable risk-benefit balance for this strategy, even in senior patients. Balancing the benefits and risks of treating RA with glucocorticoids thus remains a somewhat controversial topic. This narrative review outlines the historical and current position of glucocorticoids in the management of RA, while summarising recent evidence on their beneficial and detrimental effects. Furthermore, practical strategies for the current use and tapering of glucocorticoids in RA are formulated.

Validation and predictive capacity of a Dutch version of the FLARE-RA questionnaire within the context of a TNFi-tapering trial.

Flare Assessment in Rheumatoid Arthritis (FLARE-RA) is a self-administered tool aiming to capture current or recent flares in rheumatoid arthritis (RA). We aimed to externally validate the FLARE-RA instrument and its existing cutoffs for flare detection within a bDMARD-tapering context in established RA. Data were analyzed from the Tapering Etanercept in Rheumatoid Arthritis (TapERA) trial, which studied the feasibility of tapering etanercept in patients with established RA in sustained remission. The English FLARE-RA was translated and cross-culturally adapted into Dutch, and internal consistency and test-retest reliability were evaluated with Crohnbach's alpha and intraclass correlation coefficient (ICC). Participants completed the FLARE-RA 3-monthly for 12 months. Accuracy and optimal cutoffs of FLARE-RA to detect DAS28-defined flares were assessed using area under the receiver operating characteristic curves (AUC). Association of FLARE-RA scores with current and future flares was studied using logistic generalized estimating equations (GEE). The Dutch FLARE-RA showed excellent internal consistency and test-retest reliability (Cronbach's alpha 0.96; ICC 0.96 [95% CI 0.70-1.00]). Discriminatory capacity of FLARE-RA to detect flares was acceptable (AUC 0.77, 0.80, and 0.72 for global, arthritis, and general symptoms subscales, respectively), with an optimal global score cutoff of 4/10. In GEE-models, higher FLARE-RA scores were associated with increased odds of both current and future flares. We successfully translated and cross-culturally adapted the FLARE-RA into a Dutch version and validated its capacity to detect flares in a bDMARD-tapering context in established RA. Finally, higher FLARE-RA scores might indicate an increased risk of future flares.Trial registration: EU Clinical Trials Register, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-004631-22/BE , EudraCT number 2012-004,631-22. Key Points • Translation and cross-cultural adaptation of the FLARE-RA resulted in a Dutch version with excellent internal consistency and test-retest reliability. • The FLARE-RA is a valid instrument to detect current OMERACT-defined flares within a bDMARD tapering setting, with an optimal global score cutoff of 4/10. • Higher scores on the FLARE-RA are associated with increased risk of future flares, which could be particularly relevant when considering DMARD tapering.

Psychosocial Burden Predicts Sustained Remission in Early Rheumatoid Arthritis: Unraveling the Complex Interplay of Well-Being and Disease Activity.

OBJECTIVE: This study investigated how psychosocial aspects of disease affect the probability of achieving sustained remission in early rheumatoid arthritis (RA) and explored the directionality of this relationship. METHODS: Data were analyzed from the randomized controlled Care in Early RA trial. Sustained remission was defined as a continued Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) of <2.6 from weeks 16 to 104. Patients completed the Short Form 36 (SF-36) health survey, Revised Illness Perception Questionnaire (IPQ-R), and the Utrecht Coping List. These psychosocial variables were studied at baseline and at week 16 as predictors of sustained remission with logistic regression. Next, subgroups of patients in remission at week 16 were identified by Latent Profile Analysis based on these psychosocial indicators. Time to first loss of remission was then compared between groups by Cox proportional hazards regression. Finally, directionality of associations between psychosocial indicators and DAS28-CRP was explored with cross-lagged panel models (CLPMs). RESULTS: Sustained DAS28-CRP remission was associated with higher SF-36 scores and less passive coping at baseline and with higher SF-36 scores and more positive IPQ-R outcomes at week 16. Among patients in DAS28-CRP remission at week 16 (n = 287), 2 subgroups were identified: a low psychosocial burden group (n = 231 of 287) and a high psychosocial burden group (n = 56 of 287). The low psychosocial burden group retained remission longer (hazard ratio 0.51 [0.35-0.73]). In the CLPM, temporal relationships between psychosocial well-being and DAS28-CRP were complex, bidirectional, and disease-phase dependent. CONCLUSION: Suboptimal psychosocial well-being and negative illness perceptions predicted lower probability of sustained remission in an early RA cohort. Illness perceptions appeared to become more clinically relevant with time. Finally, 1 in 5 patients showed worse psychosocial outcomes despite early remission, and these patients tended to lose remission earlier.

Engagement and attrition with eHealth tools for remote monitoring in chronic arthritis: a systematic review and meta-analysis.

OBJECTIVES: Although eHealth tools are potentially useful for remote disease monitoring, barriers include concerns of low engagement and high attrition. We aimed to summarise evidence on patients' engagement and attrition with eHealth tools for remotely monitoring disease activity/impact in chronic arthritis. METHODS: A systematic literature search was conducted for original articles and abstracts published before September 2022. Eligible studies reported quantitative measures of patients' engagement with eHealth instruments used for remote monitoring in chronic arthritis. Engagement rates were pooled using random effects meta-analysis. RESULTS: Of 8246 references, 45 studies were included: 23 using smartphone applications, 13 evaluating wearable activity trackers, 7 using personal digital assistants, 6 including web-based platforms and 2 using short message service. Wearable-based studies mostly reported engagement as the proportion of days the tracker was worn (70% pooled across 6 studies). For other eHealth tools, engagement was mostly reported as completion rates for remote patient-reported outcomes (PROs). The pooled completion rate was 80%, although between-study heterogeneity was high (I2 93%) with significant differences between eHealth tools and frequency of PRO-collection. Engagement significantly decreased with longer study duration, but attrition varied across studies (0%-89%). Several predictors of higher engagement were reported. Data on the influence of PRO-reporting frequency were conflicting. CONCLUSION: Generally high patient engagement was reported with eHealth tools for remote monitoring in chronic arthritis. However, we found considerable between-study heterogeneity and a relative lack of real-world data. Future studies should use standardised measures of engagement, preferably assessed in a daily practice setting. TRIAL REGISTERATION NUMBER: The protocol was registered on PROSPERO (CRD42021267936).

Longitudinal trajectories of fatigue in early RA: the role of inflammation, perceived disease impact and early treatment response.

OBJECTIVE: Fatigue is common in rheumatoid arthritis (RA). We aimed to explore its longitudinal course, predictors and association with disease activity in early RA. METHODS: Data came from the 2-year treat-to-target trial CareRA (Care in early RA) and its 3-year extension. Fatigue was measured on Visual Analogue Scale, Multidimensional Fatigue Inventory and Short Form-36 (SF-36) vitality. Longitudinal fatigue trajectories were identified with multivariate growth mixture modelling. Early predictors of fatigue and the association of fatigue and its trajectories with disease activity and clinical/psychosocial outcomes were studied with linear mixed models and multilevel mediation. RESULTS: We included 356 and 244 patients in the 2-year and 5-year analyses, respectively. Four fatigue trajectories were identified: rapid, gradual, transient improvement and early deterioration, including 10%, 14%, 56% and 20% of patients. Worse pain, mental health and emotional functioning were seen in the early deterioration group. Higher pain, patient global assessment (PGA) and disability (Health Assessment Questionnaire), lower SF-36 mental components, and fewer swollen joints at baseline predicted higher fatigue over 5 years, while early disease remission strongly improved 5-year fatigue. The association between Simple Disease Activity Index and fatigue was mediated by PGA, pain, mental health and sleep quality. CONCLUSIONS: Although fatigue evolves dynamically over time in early RA, most patients do not achieve sustained fatigue improvement despite intensive disease-modifying antirheumatic drug therapy. Higher 5-year fatigue levels were seen in patients with more perceived disease impact and fewer swollen joints at baseline. Conversely, early inflammatory disease control strongly improved long-term fatigue, pointing towards an early window of opportunity to prevent persistent fatigue.

New indicator for discordance between patient-reported and traditional disease activity outcomes in patients with early rheumatoid arthritis.

OBJECTIVE: To unravel disease impact in early RA by separately quantifying patient-reported (PRF), clinical (CF) and laboratory (LF) factors. We propose a new indicator, the discordance score (DS), for early identification and prediction of patient's unmet needs and of future achievement of sustained remission (SR) and RA-related quality of life (QoL). METHODS: Factor-scores obtained by factor analysis in the CareRA trial, allowed to compute DS, reflecting the difference between PRF and the mean of CF and LF. Improvement from baseline to week 104 (%) and area-under-the-curve (AUC) across time points per factor-score were calculated and compared between patients achieving/not achieving sustained (week 16-104) remission (DAS28CRP < 2.6) with ANOVA. Logistic and linear regressions were used to predict SR based on previous factor and discordance scores, and QoL at year 1 and 2 based on DS at week 16. RESULTS: PRF, CF and LF scores improved rapidly within 8 weeks. PRF improved 57%, CF 90% and LF 27%, in those achieving SR, compared with 32% (PRF: P = 0.13), 77% (CF: P < 0.001) and 9% (LF: P = 0.36) in patients not achieving SR. Patients achieving SR had an AUC of 15.7, 3.4 and 4.8 for PRF, CF and LF, respectively, compared with 33.2, 10.1 and 7.2 in participants not achieving SR (P < 0.001 for all). Early discordance was associated with later factor scores, QoL and self-efficacy. CONCLUSIONS: All factor scores improved rapidly, especially in patients achieving sustained remission. Patient-reported burden improved less. Discordance scores could help predicting the need for additional non-pharmacological interventions to achieve sustained remission and decrease disease impact.

Psychological stress in rheumatoid arthritis: a systematic scoping review.

BACKGROUND: Rheumatoid arthritis (RA) considerably impacts patients' mental health. However, it is largely unclear how people suffering from RA experience psychological stress beyond depression or anxiety, and what drives stress in these patients. OBJECTIVE: To examine the impact of RA on psychological stress, as follows: 1) How is stress defined and described in studies on RA? 2) Do patients with RA experience more stress than the general population or people suffering from other chronic conditions? 3) What are risk factors for developing stress in this context? METHODS: We systematically searched EMBASE, PubMed, Web of Science Core Collection and Cochrane Library for English language peer-reviewed reports published up to 19 April 2020. Eligible studies included any measure or definition of psychological stress as an outcome in patients with RA. Data were extracted on patient and study characteristics, instruments used to measure stress and predictors of stress, and were summarized descriptively. Study quality was assessed with the MINORS or AXIS-tool for longitudinal and cross-sectional studies, respectively. RESULTS: Among 11.115 potentially relevant studies, 16 studies were included. Remarkably, 13 different instruments to measure stress were reported in these studies. Different types of stress experienced by patients with RA included role stress, social stress, and work stress. Work stress and social stress, particularly resulting from interpersonal stressors, were reported as more prevalent in patients with RA compared to healthy controls. Stress at disease onset appeared more pronounced in patients with RA compared to people suffering from osteoarthritis, while psychological stress was reported as higher in patients with chronic pain syndromes compared to patients with RA. More disability, more pain, less social support, lower income, younger age and personality traits like excessive worrying, pessimism, and sensitivity to anxiety, seemed to increase the risk for higher stress levels. CONCLUSIONS: This scoping review is, to our knowledge, the first to address the important heterogeneity of the measurement tools and definitions of psychological stress in RA research. This review could provide a basis to standardize the concept of stress in people suffering from RA, with a view to proposing tailored stress-reducing interventions.

Pericarditis as a manifestation of IgG4-related disease.

IgG4-related disease (IgG4-RD) is a systemic, immune-mediated fibro-inflammatory disease that can affect virtually every organ system. It is usually insidious in onset and often mimics malignant or other inflammatory disorders. Diagnosis frequently requires a combination of clinical, serological, radiographic, and histopathological features, including increased serum-IgG4 levels and tissue infiltration of IgG4-positive plasma cells with associated fibrosis. Unlike more frequently affected sites, including the hepatobiliary system, salivary glands and retroperitoneum, pericardial involvement of IgG4-RD has only rarely been described. We report the case of a 76-year-old woman presenting with refractory pericarditis and imminent cardiac tamponade, successfully treated with therapeutic pericardiectomy. A diagnosis of IgG4-RD was made based on elevated serum-IgG4 levels and the presence of typical pericardial histopathological findings, meeting all 3 of the 2011 comprehensive diagnostic criteria for IgG4-RD. Following pericardiectomy, the patient remained in remission without a need for glucocorticoids or additional immunosuppressive therapy. Adding to this case, we reviewed the literature for previously described cases of IgG4-RD presenting with pericarditis and described their characteristics and the available treatment options. Our case-based literature review provides a clear overview of the diagnostic process for IgG4-RD and the need to apply classification criteria with the necessary caution, particularly in the case of rare disease manifestations, including pericarditis.

The perception of stakeholders on the applicability of nurse-led clinics in the management of rheumatoid arthritis.

OBJECTIVES: RA should be treated to target in a process of shared decision-making with patients. Person-centred care is essential to meeting specific patient needs. Nurse-led clinics, where a nurse is responsible for care, have demonstrated added value in some countries but are still not implemented widely. This study aimed to explore stakeholders' perceptions of advantages, disadvantages and conditions for the implementation of nurse-led clinics for RA in Belgium. METHODS: We performed a cross-sectional qualitative study consisting of five semi-structured focus group interviews. Rheumatology nurses, patients with RA and rheumatologists were interviewed as stakeholders. The analysis was carried out by three researchers according to the Qualitative Analysis Guide of Leuven (QUAGOL), formulating a conceptual framework of overarching themes and deconstructing this into perceived advantages, disadvantages and conditions. RESULTS: Two focus groups with nurses (total n = 16), two with patients (n = 17) and one with rheumatologists (n = 9) were conducted. The interview synthesis resulted in five overarching themes across stakeholders: efficiency of care, disease management, legal and organizational requirements, the conventional role of the nurse and the extended role of the nurse. All stakeholders perceived additional education for nurses as essential, but rheumatologists debated nurses' abilities to lead a rheumatology clinic. Furthermore, patients preferred care protocols to guide nurses, and care providers approached this reluctantly. Generally, patients with a well-controlled disease were perceived as the ideal candidates for nurse-led care. CONCLUSION: Nurse-led clinics could provide many benefits but require additional nurse education and a legal and organizational framework before being implemented widely and successfully.