Structural Progression in Patients with Definite and Non-Definite Arrhythmogenic Right Ventricular Cardiomyopathy and Risk of Major Adverse Cardiac Events.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited disease characterised by early arrhythmias and structural changes. Still, there are limited echocardiography data on its structural progression. We studied structural progression and its impact on the occurrence of major adverse cardiovascular events (MACE). In this single-centre observational cohort study, structural progression was defined as the development of new major or minor imaging 2010 Task Force Criteria during follow-up. Of 101 patients, a definite diagnosis of ARVC was made in 51 patients, while non-definite 'early' disease was diagnosed in 50 patients. During 4 years of follow-up (IQR: 2-6), 23 (45%) patients with a definite diagnosis developed structural progression while only 1 patient in the non-definite (early) group gained minor imaging Task Force Criteria. Male gender was strongly associated with structural progression (62% of males progressed structurally, while 88% of females remained stable). Patients with structural progression were at higher risk of MACE (64% of patients with MACE had structural progression). Therefore, the rate of structural progression is an essential factor to be considered in ARVC studies.

Structural disease modification in axial spondyloarthritis.

"Disease modification" in axial spondyloarthritis (axSpA) seeks to not only alleviate clinical symptoms but also alter the disease's natural course by impeding new bone formation. Recent years have witnessed the effectiveness of treatments, including biologics and nonsteroidal anti-inflammatory drugs, in managing axSpA symptoms. Emerging evidence points toward their potential impact on slowing structural disease progression. This comprehensive review centers on the pivotal role of inhibiting new bone formation in axSpA disease modification. It delves into the significance of imaging techniques for assessing disease progression and explores the disease-modifying properties of available axSpA treatments, encompassing NSAIDs, TNF inhibitors, IL-17 inhibitors, and JAK inhibitors. This article offers valuable insights into the evolving landscape of disease modification strategies in axial spondyloarthritis, highlighting the multifaceted approaches used to attain these objectives.

Novel insights into the anatomy and histopathology of the sacroiliac joint and correlations with imaging signs of sacroiliitis in case of axial spondyloarthritis.

For a better understanding of the pathophysiology of spondyloarthropathy (SpA), a detailed anatomical description of the sacroiliac joint is required because sacroiliitis is the earliest and most common sign of SpA and an essential feature for the diagnosis of ankylosing spondylitis. Beyond the anatomy, the histopathology of sacroiliac entheses and immunological mechanisms involved in sacroiliitis are crucial for a better understanding of disease causation. In this narrative review, we discuss the core anatomical, histological, and immunohistological observations involved in the development of sacroiliitis, focusing particularly on imaging-based information associated with sacroiliitis. Finally, we try to answer the question of whether at the sacroiliac joint, enthesitis precedes synovitis and subchondral bone changes in SpA.

Ultrasonographic Involvement of the anterior chest wall in Spondyloarthritis: Factors associated with 5-years structural progression. A prospective study in 58 patients.

INTRODUCTION: To evaluate, factors associated with new ultrasonographic lesions of the anterior chest wall in spondyloarthritis (SpA) after a follow up of 5 years. METHODS: SpA Patients included in 2013 in a first study were evaluated five years later. Ultrasound B mode and power Doppler examination of the two sternoclavicular joints and the manubrio-sternal joint were performed by the same two examinators at baseline and five years later. The presence of erosion, synovitis, ankylosis, power Doppler signal, joint effusion and joint space narrowing were assessed blind of the first evaluation. RESULTS: Among the 131 patients at baseline, 58 patients were evaluated 5 years later. The mean age was 48.2±11.9 years old, with 86% of male and mainly an axial disease (78%). Patient characteristics are comparable to the original cohort. The most frequent lesions were ankylosis of the manubriosternal joint (38%) and erosions of the sternoclavicular joint (29%). 31 patients (53%) developed a new lesion of the ACW. There is a statistically significant association between new lesions of the ACW and higher ASDAS CRP (1,86±1,07 VS 3,0±2,17 P<0,01) and with CRP (5,34±7,85 VS 16,2±35, P=0,035) in the moment of the examination. There was no baseline factor associated with the structural progression. CONCLUSION: The occurrence of new lesions of the anterior chest wall is associated with a higher disease activity and a higher CRP at 5 years.

High penetrance and similar disease progression in probands and in family members with arrhythmogenic cardiomyopathy.

AIMS: We aimed to assess structural progression in arrhythmogenic cardiomyopathy (AC) patients and mutation-positive family members and its impact on arrhythmic outcome in a longitudinal cohort study. METHODS AND RESULTS: Structural progression was defined as the development of new Task Force imaging criteria from inclusion to follow-up and progression rates as annual changes in imaging parameters. We included 144 AC patients and family members (48% female, 47% probands, 40 ± 16 years old). At genetic diagnosis and inclusion, 58% of family members had penetrant AC disease. During 7.0 [inter-quartile range (IQR) 4.5-9.4] years of follow-up, 47% of family members without AC at inclusion developed AC criteria, resulting in a yearly new AC penetrance of 8%. Probands and family members had a similar progression rate of right ventricular outflow tract diameter (0.5 mm/year vs. 0.6 mm/year, P = 0.28) by mixed model analysis of 598 echocardiographic examinations. Right ventricular fractional area change progression rate was even higher in family members (-0.6%/year vs. -0.8%/year, P < 0.01). Among 86 patients without overt structural disease or arrhythmic history at inclusion, a first severe ventricular arrhythmic event occurred in 8 (9%), of which 7 (88%) had concomitant structural progression. Structural progression was associated with higher incidence of severe ventricular arrhythmic events adjusted for age, sex, and proband status (HR 21.24, 95% CI 2.47-182.81, P < 0.01). CONCLUSION: More than half of family members had AC criteria at genetic diagnosis and yearly AC penetrance was 8%. Structural progression was similar in probands and family members and was associated with higher incidence of severe ventricular arrhythmic events.

Structural progression in axial spondyloarthritis.

Functional disability in axial spondyloarthritis is related to the structural progression caused by the disease, thus largely contributing to its global burden and still representing a major challenge in management. Diagnosis at an early inflammatory stage of the disease is the hallmark for a better disease control and management. The natural history of axial spondyloarthritis is now better understood with imaging studies and long-term follow-up data, with some predictive factors for structural progression being identified. Non-steroidal anti-inflammatory drugs are still considered as the first line treatment for axial spondyloarthritis, however, their impact on structural progression is conflicting. Recent data on biologic disease-modifying anti-rheumatic drugs, such as tumor necrosis factor inhibitors have shown significant retardation of radiographic damage after several years of treatment, while first data with interleukin-17 inhibitors were also positive. Novel emerging drugs are being evaluated with promising results on halting disease progression. This review summarizes the predictors of radiographic progression in patients with axial spondyloarthritis as well as the current evidence on the effect of available treatments on structural progression.

Early clinical response and long-term radiographic progression in recent-onset rheumatoid arthritis: Clinical remission within six months remains the treatment target.

OBJECTIVES: The primary objective was to evaluate the correlation between 5-year radiographic structural disease progression and early clinical remission in recent-onset rheumatoid arthritis (RA). The secondary objective was to assess the correlation between erosion development in joints free of damage at baseline and early clinical remission. METHODS: A single-center retrospective study was performed in 133 patients meeting ACR criteria for RA of recent onset. Two radiologists independently quantified radiographic structural lesions at the hands and forefeet using the Sharp van der Heijde (SVdH) Score at the diagnosis then 5 years later. The patients were divided into two groups based on whether the lesions were stable (SVdH Score increase ≤ 10 points, Xray-STAB group) or had worsened (SVdH Score increase > 10 points, Xray-PROG group). The clinical response was assessed after 3, 6, and 12 months. Clinical remission was defined based on the DAS28-CRP, SDAI, CDAI, and ACR/EULAR Boolean remission criteria. RESULTS: Of the 133 patients, 90 were in the Xray-STAB group (mean SVdH score increase, 2.4 ± 2.9) and 43 in the Xray-PROG group (22.9 ± 13.4). The 6-month disease activity indices were higher in the Xray-PROG group (P < 0.05). Achieving a 6-month clinical remission had 58.6%, 39.1%, 40.0%, and 32.2% sensitivity for predicting 5-year radiographic stability when the DAS28-CRP, SDAI, CDAI, and Boolean definition were used, respectively; corresponding values for specificity were 73.8%, 85.7%, 83.7%, and 90.5%. CONCLUSION: Achieving a clinical remission within 6 months is key to preventing radiographic structural progression in patients with recent-onset RA.

Radiographic Progression According to Baseline C-reactive Protein Levels and Other Risk Factors in Psoriatic Arthritis Treated with Tofacitinib or Adalimumab.

OBJECTIVE: To evaluate the effect of baseline risk factors on radiographic progression in patients with active psoriatic arthritis (PsA) who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) and were treated with tofacitinib or adalimumab (ADA). METHODS: Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. OPAL Broaden was a 12-month, double-blind phase III trial. Patients received tofacitinib 5 mg twice daily (BID; n = 107), tofacitinib 10 mg BID (n = 104), or ADA 40 mg once every 2 weeks (n = 106), all with 1 background csDMARD. Radiographs (baseline and Month 12) were scored using the van der Heijde-modified total Sharp score (mTSS) for PsA. Radiographic nonprogression was defined as an increase from baseline in mTSS ≤ 0.5, ≤ 0, or ≤ 0.66. Changes from baseline in mTSS and nonprogression (≤ 0.5 increase from baseline in mTSS) were analyzed by baseline C-reactive protein (CRP) > 2.87 or ≤ 2.87 mg/l. Baseline predictors of radiographic progression were analyzed. RESULTS: At Month 12, > 90% of patients receiving tofacitinib or ADA met all radiographic nonprogression criteria. Mean changes from baseline through Month 12 in mTSS, erosion, and joint space narrowing scores were close to 0. Changes in radiographic outcomes were minimal, irrespective of baseline CRP levels > 2.87 or ≤ 2.87 mg/l, with a small numerical difference observed for tofacitinib 5 mg BID. A significant relationship was observed between baseline CRP level and increases from baseline in mTSS > 0.5 at Month 12. CONCLUSION: Elevated CRP levels at baseline were associated with greater structural progression. Changes in radiographic outcomes were minimal regardless of CRP levels. [Clinical trial registration number (www.ClinicalTrials.gov): NCT01877668].

Structural damage progression in patients with early rheumatoid arthritis treated with methotrexate, baricitinib, or baricitinib plus methotrexate based on clinical response in the phase 3 RA-BEGIN study.

The objective of this study was to evaluate structural damage progression based on clinical response in rheumatoid arthritis patients with no or limited prior disease-modifying anti-rheumatic drug treatment receiving the Janus kinase (JAK)1/JAK2 inhibitor baricitinib 4 mg, methotrexate (MTX), or the combination. Data from the phase 3 RA-BEGIN study were analysed post hoc. Proportions of patients with structural damage progression (change from baseline greater than the smallest detectable change in modified total Sharp score) at week 52 were evaluated based on sustained Disease Activity Score for 28-joint count with serum high-sensitivity C-reactive protein (DAS28-hsCRP) ≤ 3.2 or Simplified Disease Activity Index (SDAI) score ≤ 11; no formal statistical comparisons between treatments were performed to test these proportions. Baseline factors associated with risk of structural damage progression, including Clinical Disease Activity Index (CDAI) score, were identified using multivariate analysis. Patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to experience structural damage progression at week 52. In patients achieving these responses, structural damage progression was less likely with baricitinib monotherapy or plus MTX than with MTX monotherapy. In patients not achieving these sustained clinical thresholds, structural damage progression was less likely with baricitinib plus MTX than with either monotherapy. Independent of treatment, baseline factors significantly associated with increased risk of structural damage progression included higher hsCRP and CDAI score, smoking, female sex, and lower body mass index. In conclusion, patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to show structural damage progression, irrespective of treatment.

Optic Disc Image Subtraction as an Aid to Detect Glaucoma Progression.

PURPOSE: To present a digital image subtraction technique to alert clinicians to signs of glaucomatous optic disc progression. METHODS: Ninety-two glaucomatous eyes (65 patients) were included. Thirty-three eyes were identified as progressive and 59 as stable based on comparison of baseline and follow-up stereoscopic disc photographs by three masked glaucoma specialists. The disc images were aligned and converted to gray scale and underwent histogram matching to enhance contrast and account for illumination differences. The difference in image intensity between baseline and follow-up images was shown as a colormap superimposed on the grayscale follow-up image. A graded scale (1, no progression, to 5, definitive progression) was used by three masked glaucoma experts to score progression probability on the colormap images. Sensitivity, specificity, and accuracy of the classification were computed. Weighted κ statistics summarized agreement of categorical gradings. RESULTS: Median time interval between two visits was 4.4 years (range: 1.0-16.8). Clinicians detected glaucoma deterioration in 25 to 27 of the progressive group and 8 to 10 of stable eyes based on subtraction maps. Sensitivities/specificities of the clinicians were 0.76 to 0.82 and 0.86 to 0.89, respectively. Classification accuracy ranged from 81.5% to 84.8%. Agreement among clinicians was good (weighted κ = 0.68; 95% confidence interval [CI]: 0.60-0.77) for progression grades (1-5 scales) and was substantial (weighted κ = 0.81; 95% CI: 0.74-0.85) for binary scores. CONCLUSIONS: The proposed software provides a single static image that clinicians can use with other structural/functional tests to detect glaucoma progression. TRANSLATIONAL RELEVANCE: Provision of a subtraction colormap in the setting of electronic medical records can improve monitoring of glaucoma by alerting clinicians to possible signs of progression.

Disease-modifying anti-rheumatic drug effect of denosumab on radiographic progression in rheumatoid arthritis: a systematic review of the literature.

The aim of this study was to evaluate the structural effect of denosumab on patients with rheumatoid arthritis (RA). We performed a systematic review of the literature in the following databases: PubMed, Cochrane, Web of Science, ClinicalTrials.gov , and the WHO International Clinical Trials Registry Platform. All studies evaluating the structural effect of denosumab on RA and meeting predefined criteria were included. Data regarding disease activity, progression of joint damage, joint space narrowing, and safety were recorded. Among 168 studies identified, only 4 were finally included in this review, involving a total of 687 patients. These 4 studies showed that denosumab is effective on joint damage at 6 and 12 months as compared to placebo, alendronate, and biological disease-modifying anti-rheumatic drugs (bDMARDs) alone. No effect was observed in terms of joint space narrowing, and DAS28 and HAQ scores remained unchanged. No case of osteonecrosis of the jaw or atypical fracture was recorded, and safety was similar in both denosumab and control groups. Denosumab appears to be effective on joint erosion at 6 and 12 months in patients with RA meeting the ACR criteria, treated or not by a biologic, with excellent safety.

Examining the validity of the rheumatoid arthritis magnetic resonance imaging score according to the OMERACT filter-a systematic literature review.

Objective: To examine whether the RA MRI score (RAMRIS) for RA of the wrist/hand meets the OMERACT filter criteria-truth (validity), discrimination and feasibility. Methods: We conducted a systematic literature review in PubMed and Scopus, from 1970 through June 2014, focused on MRI measures of synovitis, osteitis/bone marrow oedema, erosions and/or joint space narrowing in RA randomized controlled trials and observational studies with cohort size ⩾10. Strength of evidence was assessed using the Cochrane Handbook criteria. Results: Of 634 MRI titles/abstracts, 202 met the review criteria, with 92 providing at least 1 type of validity. Four articles provided criterion validity, and 26 articles utilized RAMRIS to assess 1.5 T MRI images. Histopathology data showed inflammation corresponding to MRI of synovitis and osteitis. MRI erosions corresponded to those identified with CT. Content and construct validity for RAMRIS synovitis, osteitis and erosions were documented by correlations with clinical, laboratory and/or radiographic data. Each measure was sensitive to change and responsive to therapy. RAMRIS synovitis and osteitis were able to discriminate between the efficacy of treatments vs placebo in 12-week studies, whereas RAMRIS erosions required studies of ⩾24 weeks. Conclusion: RAMRIS synovitis, osteitis and erosions imaged with 1.5 T MRI are valid and useful for evaluating joint inflammation and damage for RA of the wrist/hand, according to the OMERACT filter.

Location-independent analysis of structural progression of osteoarthritis-Taking it all apart, and putting the puzzle back together makes the difference.

OBJECTIVE: The metric accepted by regulatory bodies for determining structural progression in clinical trials of knee osteoarthritis (OA) remains change in radiographic joint space width in the medial femorotibial compartment. However, magnetic resonance imaging has revealed that cartilage loss is spatially heterogeneous, and that it is enigmatic which knee will lose cartilage at which location. Whereas previous reviews have focused on imaging in general, the purpose of this particular perspective is to highlight availability and applications of location-independent analysis methodology in measuring structural progression in epidemiological and interventional clinical trials, and to highlight its specific advantages over existing methodologies. METHODS: Narrative review/perspective based on a Pubmed search of original articles from 2009 to current. RESULTS: Ordering longitudinal change in subregion cartilage thickness by magnitude and direction, and averaging such ordered values or sums of negative and positive changes across knees is shown to be superior in detecting risk factors and interventional effects on structural progression of knee OA. Further, the methodology permits exploration of cartilage loss and gain simultaneously, phenomena that are missed when measurements are confined to cartilage volume or thickness loss in plates or compartments. CONCLUSIONS: Given spatial heterogeneity of cartilage loss in knee OA, location-independent analysis by MRI may provide opportunity for a paradigm shift. The authors recommend use of a location-independent metrices as the structural endpoints in epidemiological and intervention trials, particularly when examining anabolic and catabolic drug effects. Location-independent methods may be translated to analysis of cartilage composition and other articular tissues.

Log-gamma linear-mixed effects models for multiple outcomes with application to a longitudinal glaucoma study.

Glaucoma is a progressive disease due to damage in the optic nerve with associated functional losses. Although the relationship between structural and functional progression in glaucoma is well established, there is disagreement on how this association evolves over time. In addressing this issue, we propose a new class of non-Gaussian linear-mixed models to estimate the correlations among subject-specific effects in multivariate longitudinal studies with a skewed distribution of random effects, to be used in a study of glaucoma. This class provides an efficient estimation of subject-specific effects by modeling the skewed random effects through the log-gamma distribution. It also provides more reliable estimates of the correlations between the random effects. To validate the log-gamma assumption against the usual normality assumption of the random effects, we propose a lack-of-fit test using the profile likelihood function of the shape parameter. We apply this method to data from a prospective observation study, the Diagnostic Innovations in Glaucoma Study, to present a statistically significant association between structural and functional change rates that leads to a better understanding of the progression of glaucoma over time.

A novel optic nerve photograph alignment and subtraction technique for the detection of structural progression in glaucoma.

PURPOSE: To highlight changing features over time within a single static image through the auto-alignment and subtraction of serial optic nerve photographs. METHODS: Subtraction maps were generated from auto-aligned (EyeIC, Narbeth, PA) baseline and follow-up images using Adobe Photoshop software. They demonstrated progressive retinal nerve fibre layer (RNFL) defects, optic disc haemorrhage (DH), neuroretinal rim loss (RL) and peripapillary atrophy (PPA). A masked glaucoma specialist identified features of progression on subtraction map first, then assessed feature strength by comparison with original images using alternation flicker. Control images with no progression and parallax-only images (as determined by flicker) were included. RESULTS: Eighty eyes of 67 patients were used to generate subtraction maps that detected glaucoma progression in 87% of DH (n = 28, sensitivity (Se) 82%, specificity (Sp) 98%) and 84% of PPA (n = 30, Se 80%, Sp 98%) cases. The lowest rate of detection was seen with RL at 67% (n = 31, Se 65%, Sp 100%). The subtraction technique was most sensitive for detecting parallax (n = 39, Se 98%, Sp 94%). Features of glaucoma progression appeared equally strong in flicker and subtraction images, but parallax was often enhanced on subtraction maps. Among control images selected for absence of features of glaucomatous change (n = 9) in original flicker images, no features were detected on subtraction maps. CONCLUSIONS: Auto-alignment and subtraction of serial optic nerve photographs reliably detects features of glaucoma progression with a single static image. Parallax identification may also be facilitated. Auto-alignment and subtraction of serial optic nerve photographs may prove especially useful in education and printed publications when dynamic imaging is not feasible.