Tight Control Strategies Research Articles

P653 Tight control and Treat to target increase the rates of Transmural remission and Transmural response in Crohn’s disease

Abstract Background increasing evidence support the use of Transmural remission as a treatment target in Crohn’s disease (CD) but few patients can reach it with currently available therapies. Treat-To-Target (T2T) and Tight-Control (TC) strategies may potentially improve these results. Methods Methods: single-center retrospective study including 123 CD patients with active colonoscopy (CN) and magnetic resonance enterography (MRE) at baseline and with available follow-up CN and MRE for reassessment of remission. We evaluated the effects of T2T and TC strategies on the rates of Transmural remission and Transmural response. Patient submitted to bowel surgery between examinations were excluded. Definitions CN activity: ulcers in non-operated patients or Rutgeerts score> i1 in operated patients; MRE activity: bowel thickness >3 mm and enhancement on T1/T2 sequences. Transmural remission: inactive CN and MRE at reassessment; Transmural response: improvement from baseline in either examination. T2T: treatment decisions resulting in both clinical remission (Harvey-Bradshaw <5) and fecal calprotectin remission (Fc <250 ug/g) at reassessment. TC: treatment decisions resulting in persistent Fc remission (≥ 2 consecutive results, including reassessment). Results 48.0% and 42.3% of patients followed a T2T and TC strategy, respectively. Transmural remission and Transmural response were reached by 33.3% and 69.1% of patients, respectively. T2T resulted in higher rates of Transmural remission (55.9% vs 12.5%, P<0.001) and Transmural response (91.5% vs 48.4%, P<0.001). TC was also associated with higher rates of Transmural remission (51.9% vs 19.7%, P<0.001) and Transmural response (90.4% vs 53.5%, P<0.001). In multivariate regression, T2T (OR 9.30 95%CI 2.85-30.30, P<0.001), TC (OR 3.85 95%CI 1.18-12.54, P=0.025) and starting biologic treatment (OR 3.63 95%CI 1.36-9.70, P=0.010) were independent predictors of reaching Transmural response. T2T was the only independent predictor of reaching Transmural remission (OR 6.540 95%CI 2.41-17.74, P<0.001). Conclusion Patients following a T2T and TC strategy presented higher rates of Transmural remission and Transmural response.

Cost-Effectiveness of Tight Control for Crohn's Disease With Adalimumab-Based Treatment: Economic Evaluation of the CALM Trial From a Canadian Perspective.

Crohn’s disease (CD) is associated with reduced quality of life, increased absenteeism and high direct medical costs resulting from frequent hospitalizations and surgeries. Tumor necrosis factor–alpha inhibitors (TNFi’s) have transformed the therapeutic landscape and enabled a shift from a symptom control to a treat-to-target strategy. The Effect of Tight Control Management on Crohn’s Disease (CALM) trial demonstrated tight control (TC), with TNFi dose changes informed by biochemical markers of inflammation, achieved higher mucosal healing rates compared with conventional management (CM) based on symptoms. A Markov model compared TC and CM strategies from the perspective of the Canadian public payer using patient-observation data from the CALM trial. A regression model estimated weekly CD Activity Index–based transition matrices over a 5-year horizon and included covariates to improve extrapolation of outcomes beyond the 48-week trial assessment period. Costs of CD-related hospitalizations, biomarker tests and adalimumab injections were sourced from public data. Other direct medical costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. Absenteeism was monetized and included in a sensitivity analysis. Over the 5-year time horizon, TC reduced hospitalization costs by 64% compared with CM. Other direct medical costs were reduced by 22%; adalimumab costs increased by 38%, generating an ICER of $35,168 per QALY gained. Absenteeism costs were reduced by 54%, and, when that was included in the model, TC became dominant compared with CM. Management of CD with TC is cost-effective compared with CM in Canada and is dominant if indirect costs associated with absenteeism are included. Trial registration number: NCT01235689.

Nickel, an essential virulence determinant of Helicobacter pylori: Transport and trafficking pathways and their targeting by bismuth.

Metal acquisition and intracellular trafficking are crucial for all cells and metal ions have been recognized as virulence determinants in bacterial pathogens. Nickel is required for the pathogenicity of H. pylori. This bacterial pathogen colonizes the stomach of about half of the human population worldwide and is associated with gastric cancer that is responsible for 800,000 deaths per year. H. pylori possesses two nickel-enzymes that are essential for in vivo colonization, a [NiFe] hydrogenase and an abundant urease responsible for resistance to gastric acidity. Because of these two enzymes, survival of H. pylori relies on an important supply of nickel, implying tight control strategies to avoid its toxic accumulation or deprivation. H. pylori possesses original mechanisms for nickel uptake, distribution, storage and trafficking that will be discussed in this review. During evolution, acquisition of nickel transporters and specific nickel-binding proteins has been a decisive event to allow Helicobacter species to become able to colonize the stomach. Accordingly, many of the factors involved in these mechanisms are required for mouse colonization by H. pylori. These mechanisms are controlled at different levels including protein interaction networks, transcriptional, post-transcriptional and post-translational regulation. Bismuth is another metal used in combination with antibiotics to efficiently treat H. pylori infections. Although the precise mode of action of bismuth is unknown, many targets have been identified in H. pylori and there is growing evidence that bismuth interferes with the essential nickel pathways. Understanding the metal pathways will help improve treatments against H. pylori and other pathogens.

An Update on Imaging in Rheumatoid Arthritis

Modern imaging modalities allow accurate detection of both inflammation and damage in rheumatoid arthritis (RA) joints. This narrative review aims to summarize the recent literature relating to magnetic resonance imaging (MRI), musculoskeletal ultrasound (MSUS) and high-resolution peripheral quantitative computerized tomography (HR-pQCT). Imaging has aided understanding of the pathogenesis of RA: HR-pQCT studies suggest that cortical micro-channels may facilitate erosive changes in the setting of synovitis. Both MRI and MSUS studies have aimed to quantify the degree of changes seen in asymptomatic people where age-related changes are common, highlighting the importance of understanding the thresholds of ‘normality’. Whilst synovitis has been considered the characteristic feature of RA, there is growing evidence that imaging-detected tenosynovitis may be of importance in predicting the development of RA, diagnosing RA and predicting flare in stable RA. Much focus has been placed on recent MRI and MSUS studies demonstrating that systematic repeated imaging of RA treated with tight control strategies does not improve outcomes at the group level; however these studies did not explore pre-test probability issues at the individual patient level. The literature is somewhat mixed on whether MRI and MSUS may provide useful guidance on which patients in remission can safely have therapy de-escalated. Recent work has also continued to validate and refine pathology definitions and semi-quantitative scoring for these tools as outcome measures in clinical trials. A review of recently published literature allowed the identification of several themes: understanding pathogenesis, attempts to define ‘normal’ joints on imaging, the utility of imaging in the diagnosis of RA, predicting the development of RA in at risk populations and the relevance to Ra clinical practice and trials.

Treatment strategies are more important than drugs in the management of rheumatoid arthritis.

The treatment of inflammatory arthritides has been changed dramatically in the past two decades with the introduction of the biological (b) disease-modifying anti-rheumatic drugs (DMARDs) as well as the targeting synthetic (ts) DMARDs that can be used as monotherapy or in combination with conventional synthetic (cs) DMARDs. The concept of treat to target (T2T) and tight control monitoring of disease activity represents a therapeutic paradigm of modern rheumatology. In rheumatoid arthritis (RA), this treatment approach has proven to be effective in many clinical trials and is now a well-established approach. The most common treatment strategies rely on the combination of csDMARDs (mainly methotrexate, sulfasalazine and hydroxychloroquine). This comes from different studies which compare the outcomes of combination therapies versus csDMARD monotherapy or versus methotrexate plus biologics in early RA patients. Here, we review the literature of the most important T2T studies for RA patients. The results showed that a tight control strategy appears to be more important than a specific drug to control RA. T2T approach aiming for remission or low disease activity can be achieved in early RA patients using less expensive drugs in comparison to newer drugs and this may need to be recognised in the future recommendations for the management of RA. KEY POINTS: • Tight-control and treat-to-target (T2T) strategies are the cornerstone in achieving remission or low disease activity in rheumatoid arthritis (RA) • A plethora of clinical trials has confirmed the efficacy of csDMARDs when the tight-control and T2T strategies are applied • T2T and tight-control strategies are a less expensive option in comparison to newer drugs and may be recognised in the future recommendations for the management of RA. • Treatment decisions and strategies are more important than just the drugs.

Novel Therapeutic Approaches in Rheumatoid Arthritis: Role of Janus Kinases Inhibitors.

Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone destruction and several systemic features. Cardiovascular, pulmonary, psychological, and muscle involvement are the main comorbidities of RA and are responsible for the severity of the disease and long-term prognosis. Pharmacological treatment of rheumatic diseases has evolved remarkably over the past years. In addition, the widespread adoption of treat to target and tight control strategies has led to a substantial improvement of outcomes, so that drug-free remission is nowadays a realistic goal in the treatment of RA. However, despite the availability of multiple therapeutic options, up to 40% of patients do not respond to current treatments, including biologics. Small-molecule therapies offer an alternative to biological therapies for the treatment of inflammatory diseases. In the past 5 years, a number of small-molecule compounds targeting Janus Kinases (JAKs) have been developed. Since JAKs are essential for cell signaling in immune cells, in particular controlling the response to many cytokines, their inhibitors quickly became a promising class of oral therapeutics that proved effective in the treatment of RA. Tofacitinib is the first Janus Kinase (JAK) inhibitor approved for the treatment of RA, followed more recently by baricitinib. Several other JAK inhibitors, are currently being tested in phase II and III trials for the treatment of a different autoimmune diseases. Most of these compounds exhibit an overall acceptable safety profile similar to that of biologic agents, with infections being the most frequent adverse event. Apart from tofacitinib, safety data on other JAK inhibitors are still limited. Long-term follow-up and further research are needed to evaluate the general safety profile and the global risk of malignancy of these small molecules, although no clear association with malignancy has been reported to date. Here, we will review the main characteristics of JAK inhibitors, including details on their molecular targets and on the clinical evidences obtained so far in the treatment of RA.

Effect of treat-to-target strategies on bone erosion progression in early rheumatoid arthritis: An HR-pQCT study.

To investigate the efficacy of two tight-control treatment strategies aimed at simplified disease activity score [SDAI] remission (SDAI ≤ 3.3) compared to DAS28 remission (DAS28 < 2.6) on progression of bone erosions in early rheumatoid arthritis (ERA) patients using high-resolution peripheral quantitative computed tomography (HR-pQCT). This was an open-label study in which 80 early RA patients were randomized to receive 1-year of tight-control treatment. Group 1 (n = 37) aimed at SDAI ≤ 3.3 and group 2 (n = 43) aimed at DAS28-CRP < 2.6. The number and size of bone erosions, as well as the bone mineral density (BMD) surrounding bone erosion at the second metacarpophalangeal joint (MCP2), were measured at baseline and 12 months. After 12 months, images were analyzed in 63 patients. Changes in clinical parameters, number and size of bone erosions as well as the BMD surrounding bone erosion between the two treatment groups were similar. Therefore, a post-hoc analysis including all 63 patients was performed to elucidate the independent predictors of erosion progression and repair. Multivariate analysis revealed that not achieving sustained SDAI remission at month 6, 9 and 12 (p = 0.034) and rheumatoid factor >16U (p = 0.021) were independent predictors associated with an increase in erosion volume. Logistic regression analysis showed that achieving sustained SDAI remission (p = 0.043) was associated with partial erosion repair. Although more stringent treatment target did not notably affect clinical treatment outcome and erosion progression at 1 year, achieving sustained SDAI remission was found to be associated with partial erosion repair.

Controversies in rheumatoid arthritis glucocorticoid therapy

Despite therapeutic innovations in the past 20 years, glucocorticoids (GC) are still widely used for the symptomatic treatment of rheumatoid arthritis (RA). Studies have demonstrated the clinical and structural efficacy of moderate doses (i.e. 30–60 mg/d) GC in addition to disease modifying anti-rheumatic drug (DMARD) initiation in early RA. A combination of a low dose of GC (i.e. 7.5–10 mg/d) and DMARDs increases remission rates and decreases the risk of medium-term structural progression in early RA. Intravenous and intramuscular administration of GC associated with DMARD initiation or intra-articular GC injections in symptomatic joints in tight control strategies increase remission rates in early RA. However, due to the risk of adverse events such as infections, cardiovascular events, or increased mortality induced by long-term use of GC, even at low-doses (e.g. 5 mg/d), GC should be prescribed at a minimal dose, for the shortest possible duration, and in association with DMARD initiation in early RA or DMARD change in active established RA.

Controverses sur la corticothérapie dans la polyarthrite rhumatoïde

Despite therapeutic innovations of the last 20 years, glucocorticoids (GC) are widely used as symptomatic treatment in rheumatoid arthritis (RA). Studies have demonstrated the clinical and structural efficacy of medium-dose (30–60 mg/d) GC in addition to disease modifying antirheumatic drugs (DMARDs) initiation in early RA. Combination of low-dose GC (7.5–10 mg/d) and DMARDs improve the remission rates and decrease medium-term structural progression risk in early RA. Intravenous and intramuscular GC associated with DMARDs initiation or GC intra-articular injections in symptomatic joints in tight control strategies increase remission rates in early RA. However, because of adverse event risk, such as infectious, cardiovascular events or mortality, induced by long-term use of GC, even with low-dose GC (5 mg/d), GC should be prescribed at minimal dose, for the shortest duration and in association with DMARDs initiation in early RA or DMARDs change in active established RA.

Low disease activity (DAS28≤3.2) reduces the risk of first cardiovascular event in rheumatoid arthritis: a time-dependent Cox regression analysis in a large cohort study

ObjectiveSystemic inflammation appears to contribute to the excess risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA). The objective of this study was to investigate the effect of different levels...

Psoriatic arthritis in 2015: Advancement continues in imaging, tight control and new drugs.

In 2015, a EULAR task force released evidence-based recommendations on the use of imaging in the clinical management of spondyloarthritis, including psoriatic arthritis. These recommendations, together with articles dealing with tight control strategies and use of the IL-17A inhibitor secukinumab, have consolidated progress in the management of psoriatic arthritis.

Using observational data to emulate a randomized trial of dynamic treatment-switching strategies: an application to antiretroviral therapy.

When a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individual's time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy). We review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting. Of 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95% confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death. Although our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses.

Quality in rheumatoid arthritis care.

While most rheumatology practices are characterized by strong commitment to quality of care and continuous improvement to limit disability and optimize quality of life for patients and their families, the actual step toward improvement is often difficult. This is because there are still barriers to be addressed and facilitators to be captured before a satisfying and cost-effective practice management is installed. Therefore, this review aims to assist practicing rheumatologists with quality improvement of their daily practice, focusing on care for rheumatoid arthritis (RA) patients. First we define quality of care as "the degree to which health services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge". Often quality is determined by the interplay between structure, processes, and outcomes of care, which is also reflected in the corresponding indicators to measure quality of care. Next, a brief overview is given of the current treatment strategies used in RA, focusing on the tight control strategy, since this strategy forms the basis of international treatment guidelines. Adherence to tight control strategies leads, also in daily practice, to better outcomes in patients with regard to disease control, functional status, and work productivity. Despite evidence in favor of tight control strategies, adherence in daily practice is often challenging. Therefore, the next part of the review focuses on possible barriers and facilitators of adherence, and potential interventions to improve quality of care. Many different barriers and facilitators are known and targeting these can be effective in changing care, but these effects are rather small to moderate. With regard to RA, few studies have tried to improve care, such as a study aiming to increase the number of disease activity measures done by a combination of education and feedback. Two out of the three studies showed markedly positive effects of their interventions, suggesting that change is possible. Finally, a simple step-by-step plan is described, which could be used by rheumatologists in daily practice wanting to improve their RA patient care.

Management of juvenile idiopathic arthritis: hitting the target.

The treatment of juvenile idiopathic arthritis (JIA) is evolving. The growing number of effective drugs has led to successful treatment and prevention of long-term sequelae in most patients. Although patients with JIA frequently achieve lasting clinical remission, sustained remission off medication is still elusive for most. Treatment approaches vary substantially among paediatric rheumatologists owing to the inherent heterogeneity of JIA and, until recently, to the lack of accepted and well-evidenced guidelines. Furthermore, many pertinent questions related to patient management remain unanswered, in particular regarding treatment targets, and selection, intensity and sequence of initiation or withdrawal of therapy. Existing JIA guidelines and recommendations do not specify treat-to-target or tight control strategies, in contrast to adult rheumatology in which these approaches have been successful. The concepts of window of opportunity (early treatment to improve long-term outcomes) and immunological remission (abrogation of subclinical disease activity) are also fundamental when defining treatment methodologies. This Review explores the application of these concepts to JIA and their possible contribution to the development of future clinical guidelines or consensus treatment protocols. The article also discusses how diverse forms of standardized, guideline-led care and personalized treatment can be combined into a targeted, patient-centred approach to optimize management strategies for patients with JIA.

Biomarkers predicting a need for intensive treatment in patients with early arthritis.

The heterogeneous nature of rheumatoid arthritis (RA) complicates early recognition and treatment. In recent years, a growing body of evidence has demonstrated that intervention during the window of opportunity can improve the response to treatment and slow—or even stop—irreversible structural changes. Advances in therapy, such as biologic agents, and changing approaches to the disease, such as the treat to target and tight control strategies, have led to better outcomes resulting from personalized treatment to patients with different prognostic markers. The various biomarkers identified either facilitate early diagnosis or make it possible to adjust management to disease activity or poor outcomes. However, no single biomarker can bridge the gap between disease onset and prescription of the first DMARD, and traditional biomarkers do not identify all patients requiring early aggressive treatment. Furthermore, the outcomes of early arthritis cohorts are largely biased by the treatment prescribed to patients; therefore, new challenges arise in the search for prognostic biomarkers. Herein, we discuss the value of traditional and new biomarkers and suggest the need for intensive treatment as a new surrogate marker of poor prognosis that can guide therapeutic decisions in the early stages of RA.

THU0234 Short-Term Clinical Outcome and Ultrasonographic-Synovitis Dynamics in Rheumatoid Arthritis Patients in Dmards-Induced SDAI Remission under Drug-Free Conditions

BackgroundThe introduction of DAS-driven intensive treatment strategies in early rheumatoid arthritis (RA) has allowed the achievement of drug-induced clinical remission in a significant percentage of cases. Previous studies have also...

How low to aim in rheumatoid arthritis? Learning from other disciplines

Treat-to-target strategies have been widely adopted as the standard of care for the management of patients with rheumatoid arthritis. The concept of ‘tight control’ is prevalent in other disciplines, particularly...

SAT0060 Tight Control Schedules Could be a Burden to Patients with Early RA, but they do not Negatively Impact the Improved Quality of Life Via Decreased Disease Activity - Results from the Camera Trials

BackgroundTight control with treat-to-target as treatment strategy is widely used to prevent a severe outcome of rheumatoid arthritis (RA). Our CAMERA (Computer Assisted Management of Early Rheumatoid Arthritis)1 study demonstrated...

AB0454 EULAR-DAS28 versus RAPID3 for treatment monitoring in patients with rheumatoid arthritis receiving tnf inhibitors

Backgroundtreat-to-target and tight control strategies are actually the two main paradigms in the treatment of rheumatoid arthritis (RA), aiming to improve patients outcome by achieving either remission or minimal disease...

THU0102 EULAR-DAS28 versus RAPID3 for treatment monitoring in patients with rheumatoid arthritis treated with rituximab

Backgroundtreat-to-target and tight control strategies are actually the two main paradigms in the treatment of rheumatoid arthritis (RA), aiming to improve patients outcome by achieving either remission or minimal disease...