Definition Of Disease Activity Research Articles

P241 Gastrointestinal ultrasonography diagnostic performance and feasibility in IBD during pregnancy: a systematic review and narrative synthesis.

Abstract Background Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC) are associated to poor maternal and foetal outcomes during pregnancy, requiring a strict monitoring of the disease activity, preferably with non-invasive modalities. We aimed to evaluate the diagnostic performance and feasibility of gastrointestinal ultrasonography (GIUS) to monitor IBD activity throughout pregnancy. Methods A systematic literature review has been performed identifying studies the use of ultrasound modality in pregnant IBD women from date of inception until October 2022 using MEDLINE, Cochrane library, EMBASE and ISI Web of Science databases, with keywords including 1) ultrasound/ultrasonography2) pregnancy, and 3) IBD (CD and UC). Additional relevant studies were identified from cross-referencing and hand-searches of references of the retrieved articles. We included fully published observational studies and abstracts. Results Overall, five studies have been selected from 263 citations. All studies were highly heterogeneous in the definition of disease activity as reference standard, GIUS protocols, and outcomes. Two of them used a cut off value of fecal calprotectin (FCP) >100 [ug/g]. In one of them, clinical scores were used when FCP value was ≥100-249 [ug/g] and FCP ≥ 250 [ug/g] was considered as an active disease independently of clinical scores. Only one study used a single reference standard with a Harvey Bradshaw Index (HBI) >4. Across these 3 studies, results suggest a relatively good specificity (range 83%-98%) but low sensitivity (range 33%-84%) to detect disease’s activity. Only 1 study analysed GIUS performance in detecting remission with a sensitivity of 80% and a specificity of 92% compared to the reference standard. The size of the uterus limits the visualization of the terminal ileum and the sigmoid from the 2nd trimester and the 3rd trimester respectively. Evaluation of the rectum remains limited. Conclusion GIUS is a feasible, accessible, and accurate method to monitor disease activity in IBD pregnant women. Evidence is limited though and warrants further studies with standardized reference comparator

Reflections from the 2021 OARSI clinical trial symposium: Considerations for understanding biomarker assessments in osteoarthritis drug development - Should future studies focus on disease activity, rather than status?

ObjectiveOsteoarthritis (OA) is heterogeneous disease, for which drug development has proven to be challenging, both facilitated and hampered by changing guidelines. This is evident by the current lack of approved treatments, which improve joint function and delay joint failure. There is a need to bring together key stakeholders to discuss, align and enhance the processes for OA drug development to benefit patients. DesignTo facilitate drug development, the Osteoarthritis Research Society International (OARSI) initiated a series of annual clinical trials symposia (CTS). The aim of these symposia was to bring together academics, translational and clinical scientists, regulators, drug developers, and patient advocacy groups to share, refine and enhance the drug development process for the benefit of patients. ResultsOARSI is now considered the leading organization to facilitate open dialogue between all these stakeholders, in the intersection of understanding of the pathologies and drug development. Clearly, such a pivotal task needs an annual forum to allow stakeholders to share and discuss information, as possible solutions are joint efforts rather than a single stakeholder contribution. ConclusionsThe main topic of the 2021 CTS was how to improve clinical studies to help patients through overcoming barriers to development of new disease modifying treatments for OA. One key aspect was the focus on definitions of disease activity, status and the definitions of “illness vs disease”. There is a clear medical need to couple a given disease activity with the optimal intervention for the right patient.

Brolucizumab 12- and 16-Week Fixed Dosing Potential in Neovascular AMD: A post hoc Evaluation of Data from the HAWK and HARRIER Trials

Introduction: This post hoc analysis applies a fixed dosing stratification approach to patient-level brolucizumab data from the phase III HAWK and HARRIER trials to determine the proportion of patients who would have been assigned to fixed dosing regimens with treatment intervals of 8, 12, or 16 weeks (q8w, q12w, or q16w) based on the presence/absence of disease activity (DA) following the loading phase. The analysis also simulates central subfield thickness (CSFT) data to estimate the anatomical outcomes if the patients had been thus assigned. Of note, the limitations of this analysis include the post hoc nature of the work and the inability to directly compare HAWK and HARRIER with TENAYA and LUCERNE due to the differences in design. Design: This study was a post hoc modelling analysis of patient-level data. Methods: Using patient-level data from HAWK and HARRIER, patients (n = 730) were allocated to a fixed q16w, q12w, or q8w regimen based on assessment of DA at weeks 16 and 20. Two definitions of DA were used: DA 1, based on a phase II study of faricimab, and DA 2, a definition derived from common clinical consideration including visual acuity and anatomical changes. CSFT simulations were performed using a pharmacokinetic/pharmacodynamic model describing CSFT response to anti-VEGF treatment. Outcome measures were modelled patient allocation to fixed regimens and mean CSFT reduction. Results: Using DA definitions 1 and 2, respectively, 78% and 76% of patients in the brolucizumab arm were allocated to a greater than or equal to q12w regimen, and 56% and 52% were allocated to a q16w regimen. Mean reduction in CSFT was similar between the two study drugs with both DA definition assumptions. Conclusions: This analysis demonstrates the potential durability of action and effectiveness of brolucizumab.

P229 PillCamCrohn’sCapsule: the use of a panenteric capsule endoscopy in a Portuguese centre

Abstract Background Crohn’s disease (CD) is a complex chronic inflammatory gastrointestinal condition with variable age of onset, disease location and behaviour. PillCamCrohn’sCapsule (PCC) was recently introduced as a new system composed of a two-headed capsule which allows an extensive coverage of the gastrointestinal (GI) tract. This panenteric capsule endoscopy plays an important role in the diagnosis and monitoring of CD patients and has the potential to reduce multiple procedures in CD, consequently increasing patients’ satisfaction. However, its role in clinical practice remains undefined due to limited data. A recent study in children demonstrated its importance ina treat-to-target approach and a randomised trial is currently under-recruiting in order to evaluate the likelihood of panenteric mucosal healing in CD patients treated with Vedolizumab. The authors present an analysis of the application of this system. Methods A cross-sectional analysis of SBC from patients with suspected or established CD was performed. Data were collected retrospectively. Patients performed 2L of polyethylene glycol (PEG) prior to PCC ingestion. After PCC ingestion, patients underwent sequentially: 2 boosters of sodium phosphate (NaP). The authors assessed: indication of PCC, bowel preparation, completeness (when the capsule was naturally excreted), Lewis and CECDAI scores and complications. Diagnosis confirmation and changes in stage disease were also evaluated. Results Eighteen patients (median age 43 years, 55.6% female, established CD in 83.3%) were included in the analysis. Indications were suspected CD (16.7%), definition of disease activity and extension (27.8%) and assessment of treatment response (44.4%). All procedures were complete and had an adequate bowel cleansing (Brotzqualitative excellent n = 1, Good n = 15, fair n = 2; Brotz quantitative median 9.5). 72.2% patients presented inflammatory lesions. In established CD median Lewis was 900 and CECDAI 8.5. PCCcorroborated the diagnosis in 1 of 3 patients with suspected CD and changed the staging of the disease in known CD in 13.3% (L1 to L3 n = 1 and B1 to B2 n = 1). No complications were reported including capsule retentions. Conclusion This preliminary study showed that PCC is an effective and safe tool to use in suspected or established CD patients. In our study, this method was more frequently used for assessment of treatment response. PCC could be of great advantage in our clinical practice since it provides a complete examination of mucosal healing of the gastrointestinal tract in a single procedure, helping physicians in disease management.

Post-natalizumab disease reactivation in multiple sclerosis: systematic review and meta-analysis

Background:Natalizumab (NTZ) is sometimes discontinued in patients with multiple sclerosis, mainly due to concerns about the risk of progressive multifocal leukoencephalopathy. However, NTZ interruption may result in recrudescence of disease activity.Objective:The objective of this study was to summarize the available evidence about NTZ discontinuation and to identify which patients will experience post-NTZ disease reactivation through meta-analysis of existing literature data.Methods:PubMed was searched for articles reporting the effects of NTZ withdrawal in adult patients (⩾18 years) with relapsing–remitting multiple sclerosis (RRMS). Definition of disease activity following NTZ discontinuation, proportion of patients who experienced post-NTZ disease reactivation, and timing to NTZ discontinuation to disease reactivation were systematically reviewed. A generic inverse variance with random effect was used to calculate the weighted effect of patients’ clinical characteristics on the risk of post-NTZ disease reactivation, defined as the occurrence of at least one relapse.Results:The original search identified 205 publications. Thirty-five articles were included in the systematic review. We found a high level of heterogeneity across studies in terms of sample size (10 to 1866 patients), baseline patient characteristics, follow up (1–24 months), outcome measures (clinical and/or radiological), and definition of post-NTZ disease reactivation or rebound. Clinical relapses were observed in 9–80% of patients and peaked at 4–7 months, whereas radiological disease activity was observed in 7–87% of patients starting at 6 weeks following NTZ discontinuation. The meta-analysis of six articles, yielding a total of 1183 patients, revealed that younger age, higher number of relapses and gadolinium-enhanced lesions before treatment start, and fewer NTZ infusions were associated with increased risk for post-NTZ disease reactivation (p ⩽ 0.05).Conclusions:Results from the present review and meta-analysis can help to profile patients who are at greater risk of post-NTZ disease reactivation. However, potential reporting bias and variability in selected studies should be taken into account when interpreting our data.

Burden of Psoriatic Arthritis According to Different Definitions of Disease Activity: Comparing Minimal Disease Activity and the Disease Activity Index for Psoriatic Arthritis

ObjectiveTreat‐to‐target strategies have improved outcomes in rheumatic diseases. In psoriatic arthritis (PsA), the proposed targets are the multidimensional target minimal disease activity (MDA) and the articular target Disease Activity index for PsA (DAPSA). The aim of this study was to compare the disease burden of PsA in patients with low disease activity according to the 2 definitions, MDA and DAPSA low disease activity (DAPSA‐LDA), 1 year after diagnosis.MethodsWe obtained data on MDA, DAPSA‐LDA and disease burden 1 year after diagnosis for patients included in the Dutch southwest early PsA cohort. Disease burden was assessed in 2 domains: “Body functions,” including the Short Form 36 bodily pain (SF‐36 BP) measure, and “Activity,” including the Health Assessment Questionnaire (HAQ).ResultsAmong the 292 patients included, 48% achieved MDA and 74% achieved DAPSA‐LDA. Average scores for Body functions and Activity were better in patients who achieved MDA and those who achieved DAPSA‐LDA. The scores were significantly better in the 46% of patients who achieved both MDA and DAPSA‐LDA than in the 29% of patients who achieved only DAPSA‐LDA. The average SF‐36 BP score was higher in patients achieving both targets (73.8; 95% confidence interval [95% CI] 71.1‐76.5) than in patients achieving only DAPSA‐LDA (57.6; 95% CI 54.5‐60.8). Similarly, mean HAQ scores measuring Activity were 0.21 (95% CI 0.15‐0.26) and 0.63 (95% CI 0.53‐0.72), respectively.ConclusionAmong patients with newly diagnosed PsA, 48% achieved MDA and 74% achieved DAPSA‐LDA after 1 year of receiving usual care. The average disease burden was better in patients who achieved MDA and those who achieved DAPSA‐LDA. Also, patients who achieved only DAPSA‐LDA reported worse outcomes than those who also achieved MDA.

Defining Disease Activity and Response to Therapy in MS.

Disease activity in multiple sclerosis (MS) has classically been defined by the occurrence of new neurological symptoms and the rate of relapses. Definition of disease activity has become more refined with the use of clinical markers, evaluating ambulation, dexterity, and cognition. Magnetic resonance imaging (MRI) has become an important tool in the investigation of disease activity. Number of lesions as well as brain atrophy have been used as surrogate outcome markers in several clinical trials, for which a reduction in these measures is appreciated in most treatment studies. With the increasing availability of new medications, the overall goal is to minimize inflammation to decrease relapse rate and ultimately prevent long-term disability. The aim of this review is to give an overview on commonly used clinical and imaging markers to monitor disease activity in MS, with emphasis on their use in clinical studies, and to give a recommendation on how to utilize these measures in clinical practice for the appropriate assessment of therapeutic response.

Evidence of treatment of chronic inflammation in childhood and adolescence with biologics

Biologics, usually monoclonal antibodies or fusion proteins, are thought to specifically interfere with immunopathogenesis of chronic inflammatory diseases. In order to test these substances also in children and adolescents, financial incentives for manufacturers were created and classification of chronic inflammatory diseases and definition of disease activity, improvement, relapse and remission were established and large international research cooperation projects were founded. A selective literature search was carried out for treatment of chronic inflammatory diseases in children and adolescents with biologics including current guidelines. Only 7 out of 18 prescribed biologics have been approved for children and mostly within narrow limits. The evidence for efficacy is based on four randomized double blind placebo-controlled studies, seven withdrawal studies and seven observational studies. In spite of the limited evidence in comparison to their use in adult patients these substances are broadly used worldwide and have enlarged and substantially improved the therapeutic choices in children when conventional treatment failed or proved to be toxic. Severe adverse events including infections occasionally occur (0.01-0.03 events per patient year) but the rate of malignancies is not obviously increased; however, only two thirds of patients respond to treatment. Improvement is often incomplete, some patients deteriorate and definite termination of drug treatment is possible in only a few patients. As the prescription of biologics has become an important issue of treatment but is based on insufficient evidence data, further studies are necessary in children and adolescents with diseases, such as juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis and inherited fever syndromes. As many drugs are available these studies can be conducted against verum.

Remission in der Kinderrheumatologie

After definition of disease activity, improvement and deterioration and establishing large international research alliances, the new biologicals could be tested in patients with juvenile idiopathic arthritis (JIA) in controlled studies and the effectiveness could be shown. More frequently than ever before even children with polyarticular JIA achieved a state without residual disease activity indicating the need for a definition of remission. The Wallace criteria have attained a large circulation and define inactive disease and remission under and without antirheumatic medication. However, they are not associated with the prognosis. So far biomarkers or imaging cannot improve these clinical criteria. Although many patients achieve inactive disease few of them remain free of disease when all drugs have been stopped. Moreover, gene expression of children in remission still remains pathological. This confirms that children with JIA can be treated better and better but still cannot be cured.

Clinical laboratory markers of inflammation as determinants of chronic graft-versus-host disease activity and NIH global severity

Chronic graft versus host disease (cGVHD) remains a major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Currently there are no accepted measures of cGVHD activity to aid in clinical management and disease staging. We analyzed clinical markers of inflammation in the sera of patients with established cGVHD and correlated those with definitions of disease activity. 189 adults with cGVHD (33% moderate and 66% severe according to NIH global scoring) were consecutively enrolled onto a cross-sectional prospective cGVHD natural history study. At the time of evaluation, 80% were receiving systemic immunosuppression and failed a median of 4 prior systemic therapies (PST) for their cGVHD. Lower albumin (p<0.0001), higher CRP (C-reactive protein; p=0.043), higher platelets (p=0.030) and higher number of PST (p<0.0001) were associated with active disease defined as clinician's intention to intensify or alter systemic therapy due to the lack of response. Higher platelet count (p=0.021) and higher number of PST (p<0.0001) were associated with more severe diseased defined by NIH global score. This study identified common laboratory indicators of inflammation that can serve as markers of cGVHD activity and severity.

Does Clinical Remission Lead to Normalization of EQ-5D in Patients with Rheumatoid Arthritis and Is Selection of Remission Criteria Important?

To compare health-related quality of life (HRQOL) of patients with rheumatoid arthritis (RA) to that of the general population and to investigate the association with disease activity, focusing on different clinical remission criteria. EQ-5D data from 3156 patients with RA from 11 Danish centers were compared with Danish EQ-5D population norms (n = 16,136). The Disease Activity Score (DAS28) and the Clinical Disease Activity Index score (CDAI) were used as definitions of disease activity and clinical remission. The score difference (DeltaEQ-5D) was calculated in each patient as the difference from the age and sex-matched general population and adjusted for age, marital status, education, body mass index, smoking, exercise habits, disease duration, IgM-rheumatoid factor status, joint surgery, extraarticular features, treatment, and comorbidity in multiple linear regression models. 37% vs 22% fulfilled the DAS28 and CDAI remission criteria, respectively. The DeltaEQ-5D values for women/men in clinical remission were DAS28 0.05/0.06 vs CDAI 0.01/0.02; low disease activity: DAS28 0.12/0.13 vs CDAI 0.11/0.14; moderate disease activity: DAS28 0.18/0.20 vs CDAI 0.20/0.23; and high disease activity: DAS28 0.38/0.28 vs CDAI 0.33/0.26. Adjusting for confounders reduced the DeltaEQ-5D values between 0 and 0.04 units. Patients with RA had worse EQ-5D scores than the general population, and the difference was strongly associated with disease activity. The EQ-5D score for patients in clinical remission approached that of the general population, suggesting that strict treatment goals are critical in order to achieve near-normal HRQOL in patients with RA.

Are the pulmonary function tests and the markers of activity helpful to establish the prognosis of sarcoidosis?

The prognosis of sarcoidosis is difficult to establish. It depends mainly on the persistence of activity over time and the degree of functional impairment of the involved organs. The aim of this study was to analyze whether the pulmonary function tests and the more commonly used markers of activity, such as serum angiotensin-converting enzyme (SACE) and gallium-67 scan, are helpful to evaluate the prognosis of sarcoidosis, besides the clinical data. Over a 14-year period (1974-1987), 209 patients were diagnosed as having sarcoidosis at the Bellvitge Hospital, a 1,000-bed teaching hospital in Barcelona, Spain. Clinical, radiological, pulmonary function tests, and activity markers (SACE and gallium-67 scan) data at diagnosis were collected and classified as variables, and a definition of disease activity was established. One hundred sixteen patients were on follow-up, had all the variables available and were included in the statistical analysis. A Cox proportional-hazard regression model identified the following variables as independently influencing the persistence of activity over time: absence of erythema nodosum [risk ratio (RR) = 2.78; 95% confidence interval (CI): 1.48-5.18], age > or = 40 years (RR = 1.67; 95% CI: 1.008-1.04), SACE level > or = mean + 2 SD U/ml (RR = 1.45; CI: 0.99-1.07), hyperglobulinemia (RR = 2.47; CI: 0.98-6.24), forced vital capacity < 80% predicted (RR = 2.17; CI: 0.97-4.85), and male sex (RR = 1.8; CI: 0.95-3.45). We conclude that the pulmonary function tests and the SACE level but not the gallium scan are helpful to identify the factors predicting persistence of activity in sarcoidosis. Therefore, we recommend to add these tests to the initial clinical evaluation of patients with sarcoidosis in order to establish the prognosis and improve the therapeutic approach.

Clinical factors predicting persistence of activity in sarcoidosis: a multivariate analysis of 193 cases.

The prognosis of sarcoidosis is difficult to establish and it depends mainly on the persistence of activity over time and the degree of functional impairment of the involved organs. The aim of this study was to identify factors predicting persistence of disease activity at diagnosis. In a 14-year period (1974-1987), 209 patients were diagnosed with sarcoidosis at Bellvitge Hospital, a 1,000-bed teaching institution in Barcelona, Spain. One hundred ninety-three patients were followed up and included in the study. Clinical and radiological data were collected at diagnosis and a definition of disease activity was established. A Cox proportional-hazards regression model identified the following variables as independently influencing the persistence of activity: absence of erythema nodosum (risk ratio, RR = 2.37; 95% confidence interval, CI: 1.54-3.66), pulmonary infiltrates in chest x-ray (RR = 1.89, 95% CI: 1.28-2.8), splenomegaly (RR = 3.67, 95% CI: 1.46-9.23), age > or = 40 years (RR = 1.01, 95% CI: 1.006-1.03), and absence of lymphadenopathy in chest x-ray (RR = 2.26, 95% CI: 1.08-4.77). We suggest that the identification of factors predicting persistence of sarcoidosis activity at diagnosis may help to establish the prognosis of the disease and therefore improve the therapeutic approach.