Magnetic Resonance Imaging Progression Research Articles

Triggers for transition from active surveillance to radical treatment of prostate cancer 2008-2020 - a case-control study.

To examine associations between objective signs of progression (triggers) and transition from active surveillance (AS) to radical treatment for prostate cancer (PC). This case-control study included men with low- or favourable intermediate-risk PC in the region of Halland, with data from The National Prostate Cancer Register (NPCR), Sweden, starting AS between 2008 and 2020. Cases were men who transitioned to radical treatment. For each case, 10 controls who remained in AS were selected without further matching. Triggers for transition to treatment were histopathological progression, magnetic resonance imaging (MRI) progression and increases in prostate-specific antigen (PSA) levels. We compared the probabilities for triggers between cases and controls, in 2008-2014 and 2015-2020, using logistic regression. Amongst 846 men, we identified 98 cases in 2008-2014 and 172 cases in 2015-2020. Histopathological progression was associated with transition, most strongly in the later period (2008-2014: odds ratios [OR] 6.88, 95% confidence interval [CI] 3.69-12.80; and 2015-2020: OR 75.29, 95% CI 39.60-143.17). MRI progression was associated with transition in 2015-2020 (OR 6.38, 95% CI 2.70-15.06), whereas an increase in PSA was weakly associated with transition in the early period. The absence of triggers was associated with no transition (2008-2014: OR 0.24, 95% CI 0.15-0.40, and 2015-2020: OR 0.09, 95% CI 0.06-0.14). The probability of no trigger was 27% in cases 2015-2020. The increase in association between histopathological trigger and transition to treatment indicates increased quality of AS. Still, amongst men treated from 2015 to 2020, 27% transitioned without any trigger.

Narrative review of magnetic resonance imaging in quantifying liver iron load.

To summarize the research progress of magnetic resonance imaging (MRI) in quantifying liver iron load. To summarize the current status and progress of MRI technology in the quantitative study of liver iron load through reviewing the relevant literature at home and abroad. Different MRI sequence examination techniques have formed a series of non-invasive methods for the examination of liver iron load. These techniques have important clinical significance in the imaging diagnosis of liver iron load. So far, the main MRI methods used to assess liver iron load are: signal intensity measurement method (signal intensity, SI) [signal intensity ratio (SIR) and difference in in-phase and out-of-phase signal intensity], T2/R2 measurement (such as FerriScan technique), ultra-short echo time (UTE) imaging technique, and susceptibility weighted imaging (including conventional susceptibility weighted imaging) (SWI), quantitative susceptibility mapping (QSM), T2*/R2* measurement, Dixon and its derivative techniques. MRI has become the first choice for the non-invasive examination of liver iron overload, and it is helpful to improve the early detection of liver injury, liver fibrosis, liver cirrhosis and liver cancer caused by liver iron overload.

Psychometric evaluation of the 5-item Medication Adherence Report Scale questionnaire in persons with multiple sclerosis.

The 5-item Medication Adherence Report Scale (MARS-5) is a reliable and valid questionnaire for evaluating adherence in patients with asthma, hypertension, and diabetes. Validity has not been determined in multiple sclerosis (MS). We aimed to establish criterion validity and reliability of the MARS-5 in persons with MS (PwMS). Our prospective study included PwMS on dimethyl fumarate (DMF). PwMS self-completed the MARS-5 on the same day before baseline and follow-up brain magnetic resonance imaging (MRI) 3 and 9 months after treatment initiation and were graded as highly and medium adherent upon the 24-cut-off score, established by receiver operator curve analysis. Health outcomes were represented by relapse occurrence from the 1st DMF dispense till follow-up brain MRI and radiological progression (new T2 MRI lesions and quantitative analysis) between baseline and follow-up MRI. Criterion validity was established by association with the Proportion of Days Covered (PDC), new T2 MRI lesions, and Beliefs in Medicines questionnaire (BMQ). The reliability evaluation included internal consistency and the test-retest method. We included 40 PwMS (age 37.6 ± 9.9 years, 75% women), 34 were treatment-naive. No relapses were seen during the follow-up period but quantitative MRI analysis showed new T2 lesions in 6 PwMS. The mean (SD) MARS-5 score was 23.1 (2.5), with 24 PwMS graded as highly adherent. The higher MARS-5 score was associated with higher PDC (b = 0.027, P<0.001, 95% CI: (0.0134-0.0403)) and lower medication concerns (b = -1.25, P<0.001, 95% CI: (-1.93-(-0,579)). Lower adherence was associated with increased number (P = 0.00148) and total volume of new T2 MRI lesions (P = 0.00149). The questionnaire showed acceptable internal consistency (Cronbach α = 0.72) and moderate test-retest reliability (r = 0.62, P < 0.0001, 95% CI: 0.33-0.79). The MARS-5 was found to be valid and reliable for estimating medication adherence and predicting medication concerns in persons with MS.

Determination of systemic inflammatory biomarkers in multiple sclerosis.

Multiple sclerosis (MS) is one of the most common demyelinating diseases of the central nervous system. We aimed to investigate serum and cerebrospinal fluid levels of different laboratory inflammatory biomarkers in patients with MS. A total of 120 subjects participated in the study, 60 of whom were diagnosed with MS, 30 with the final diagnosis of non-inflammatory diseases of the central nervous system (CNS), and 30 healthy subjects representing the control group. Regarding the progression of radiological findings after 2 years from the initial diagnosis, the MS group was divided into stationary radiological findings (n=30) and radiologically proven disease progression (n=30). In all patients, we analyzed levels of laboratory inflammatory biomarkers: C reactive protein (CRP), Neutrophil-to-lymphocyte ratio (NLR), Growth differentiation factor 15 (GDF15) in serum samples, and neurofilaments (NFs) in cerebrospinal fluid (CSF). NFs and GDF15 were analyzed initially, while CRP and NLR values were analyzed initially and after two years. We found statistically lower GDF15 values and initial CRP values in the MS group regarding the group with non-inflammatory diseases of the CNS (p<0.0001). On the other side, we determined a significant elevation of laboratory markers CRP and NLR, initially and after a two-year period, in the MS subgroup with the progression of magnetic resonance imaging (MRI) findings (p<0.0001 and p=0.050, respectively). Also, we found a positive correlation between CRP and NFs (r=0.243, p=0.04), as well as a positive correlation between CRP and GDF15 in patients with MS (r=0.769, p<0.0001). We found a significant elevation of laboratory markers of systemic inflammation, CRP, and NLR in MS patients who developed disease progression based on MRI findings. There is a need for further studies to validate current parameters to be considered as useful markers of MS activity and disability.

How accurate is MRI for diagnosing tarsal coalitions? A retrospective diagnostic accuracy study.

This study aimed to evaluate the diagnostic accuracy, inter-reader agreement, and associated pathologies on MR images of patients with confirmed TC. In this retrospective study, 168 ankle MRI exams were included, consisting of 56 patients with clinically or surgically confirmed TC and 112 controls without TC, matched for age and sex. Images were analyzed independently by three radiologists blinded to clinical information. The evaluation criteria included the presence, type, and location of TC, as well as associated pathologies. After calculating diagnostic accuracy and the odds ratio of demographic data and anatomic coalition type for associated pathologies, inter-reader agreement was assessed using kappa statistics. The majority of TCs were non-osseous (91.1%) and located at the calcaneonavicular (33.9%) or talocalcaneal joint (66.1%). Associated pathologies included adjacent and distant bone marrow edema (57.1% and 25.0%), osteochondral defect of the talar dome (OCD, 19.6%), and joint effusion (10.7%) and accessory anterolateral talar facet (17.9%). Talar OCD was associated with increased patient age (p = 0.03). MRI exhibited a cumulative sensitivity and specificity of 95.8% and 94.3% with almost perfect inter-reader agreement (κ = 0.895). MRI is a reliable method for detecting tarsal coalition and identifying commonly associated pathologies. Therefore, we recommend the routine use of MRI in the diagnostic workup of patients with foot pain and suspected tarsal coalition. MRI is an accurate and reliable modality for diagnosing tarsal coalitions and detecting associated pathologies, while improving patient safety compared to computed tomography by avoiding radiation exposure. • Despite the technological progress in magnetic resonance imaging (MRI), computed tomography (CT) is still regarded as the gold standard for diagnosing tarsal coalition (TC). • MRI had a cumulative sensitivity of 95.8% and specificity of 94.3% for detecting tarsal coalition with an almost perfect inter-reader agreement. • MRI demonstrates high accuracy and reliability in diagnosing tarsal coalitions and is useful for identifying associated pathologies, while also improving patient safety by avoiding radiation exposure.

Research progress on the correlation between MRI and impairment caused by cerebral small vessel disease: A review.

Cerebral small vessel disease (CSVD) is a chronic global brain disease mainly involving small blood vessels in the brain. The disease can be gradually aggravated with the increase of age, so it is the primary cause of brain dysfunction in the elderly. With the increasing aging of the world population and the high incidence of cerebrovascular risk factors, the incidence of CSVD is increasing day by day. CSVD is characterized by insidious onset, slow progression, diverse clinical manifestations, and difficult early diagnosis. CSVD can lead to cognitive impairment, gait impairment, affective impairment, and so on. however, it has not received enough attention from researchers in the past. In recent years, some studies have shown that CSVD patients have a high proportion of related impairment, which seriously affect patients daily life and social functions. Currently, no clear preventive measures or treatments exist to improve the condition. With the development of magnetic resonance imaging, CSVD has become more and more recognized and the detection rate has gradually improved. This paper reviews the research progress of magnetic resonance imaging and cognitive impairment, gait impairment, affective impairment, urination disorder, swallowing disorder, and other disorders to provide a useful reference for the early diagnosis and treatment of CSVD and expand new ideas.

[Exploration and expectation of magnetic resonance imaging in the evaluation of prostate cancer].

With the progress of imaging technology, magnetic resonance imaging (MRI) has become the preferred imaging method for prostate cancer due to its excellent soft tissue resolution and the capability of multiparametric and multi-planar imaging. This paper briefly describes the current application and research progress of MRI in the preoperative qualitative diagnosis, staging assessment and postoperative recurrence monitoring of prostate cancer. The purpose is to deepen the understanding of clinicians and radiologists on the value of MRI in prostate cancer, and to promote the exploration of MRI in the management of prostate cancer.

A primer on contrast agents for magnetic resonance imaging of post‐procedural and follow‐up imaging of islet cell transplant

Abstractβ‐islet cell transplantation is a promising proposed treatment for type 1 diabetes mellitus (T1DM) which can provide more physiological glucose control when compared to exogenous insulin therapy and reverse secondary consequences of diabetes. Unfortunately, β‐islet cell transplantation is not a permanent solution for patients with T1DM as 85–90% of β‐islet recipients return to exogenous insulin treatment within 5 years of the transplant. Despite its lack of success, β‐islet cell transplantation still has potential for the treatment of T1DM and significant work has been done to non‐invasively quantify β‐islet cell concentrations in transplantation to better understand the mechanism of β‐islet cell rejection. While several imaging modalities have been utilized, magnetic resonance imaging (MRI) remains at the forefront of β‐islet cell imaging due to its high resolution and lack of radiation exposure to patients. Several MRI contrast agents have been explored for the imaging of β‐islet cells including superparamagnetic iron oxide nanoparticles (SPIONs), gadolinium‐based contrast agents (GBCA), manganese (II), fluorine‐19, and theranostic agents, with SPIONs being the most extensively studied. In this review, we provide an overview of the history, recent progress, and challenges of MRI in islet transplantation with a focus on the molecular imaging agents used.

Advancements of molecular imaging and radiomics in pancreatic carcinoma.

Despite the recent progress of medical technology in the diagnosis and treatment of tumors, pancreatic carcinoma remains one of the most malignant tumors, with extremely poor prognosis partly due to the difficulty in early and accurate imaging evaluation. This paper focuses on the research progress of magnetic resonance imaging, nuclear medicine molecular imaging and radiomics in the diagnosis of pancreatic carcinoma. We also briefly described the achievements of our team in this field, to facilitate future research and explore new technologies to optimize diagnosis of pancreatic carcinoma.

Facet Joint Involvement in Early MRI Positive Axial Spondyloarthritis

Abstract Background The disease course of non-radiographic axial spondyloarthritis (nr-axSpA), usually detected by magnetic resonance imaging (MRI), is often unclear at the time of diagnosis. We investigated which MRI findings in the sacroiliac joints (SIJs) and lumbar spine including the facet joints can be observed over a two-year period in patients with newly diagnosed active inflammatory lesions in the SIJs fufilling the Assessment of SpondyloArthritis International Society criteria (ASAS) for Axial Spondyloarthritis (axSpA). Methods Patients (n=56, age&lt;45 years, 30 female and 26 male, symptom duration 3–30 months) consecutively diagnosed with unilateral or bilateral sacroiliitis through MRI during an 18-month period and meeting the ASAS criteria for axial SpA were followed up for two years. Clinical examination, laboratory tests and an MRI of the sacroiliac joints (SIJs), lumbar spine and facet joints were performed at diagnosis (t0), after one year (t1) and after two years (t2). Results At t0, 31 patients (55%) with a bone marrow edema (BME) in the SIJs already had detectable changes in the facet joints, including signs of inflammation or degenerative changes. At t2, patients with facet joint involvement in t0 not only had more significant changes in the SIJs but also significantly more changes in the vertebral bodies, including BME, fat lesions and vertebral body erosions than patients without changes in the facet joints at t0. All vertebral changes described might be potential indicators of progression to radiographic axSpA (r-axSpA). These MRI findings are seen more frequently over a short period of time than previously thought. Conclusions MRI progression in the SIJs over a two-year period is associated with increasing damage to the facet joints and vertebral bodies. Involvement of the facet joints in the early stages of the disease may indicate increasing changes in the vertebral bodies and thus a less favourable course of axSpA.

Differential Trajectory of Diffusion and Perfusion Magnetic Resonance Imaging of Rat Spinal Cord Injury.

Traumatic spinal cord injury causes rapid neuronal and vascular injury, and predictive biomarkers are needed to facilitate acute patient management. This study examined the progression of magnetic resonance imaging (MRI) biomarkers after spinal cord injury and their ability to predict long-term neurological outcomes in a rodent model, with an emphasis on diffusion-weighted imaging (DWI) markers of axonal injury and perfusion-weighted imaging of spinal cord blood flow (SCBF). Adult Sprague-Dawley rats received a cervical contusion injury of varying severity (injured = 30, sham = 9). MRI at 4 h, 48-h, and 12-weeks post-injury included T1, T2, perfusion, and DWI. Locomotor outcome was assessed up to 12 weeks post-injury. At 4 h, the deficit in SCBF was larger than the DWI lesion, and although SCBF partially recovered by 48 h, the DWI lesion expanded. At 4 h, the volume of the SCBF deficit (R2 = 0.56, padj < 0.01) was significantly correlated with 12-week locomotor outcome, whereas DWI (R2 = 0.30, padj < 0.01) was less predictive of outcome. At 48 h, SCBF (R2 = 0.41, padj < 0.01) became less associated with outcome, and DWI (R2 = 0.38, padj < 0.01) lesion volume became more closely related to outcome. Spinal cord perfusion has unique spatiotemporal dynamics compared with diffusion measures of axonal damage and highlights the importance of acute perfusion abnormalities. Perfusion and diffusion offer complementary and clinically relevant insight into physiological and structural abnormalities following spinal cord injury beyond those afforded by T1 or T2 contrasts.

Utility of Repeat MRI in Patients With Degenerative Cervical Disease.

Existing guidelines regarding indications for initial cervical spine magnetic resonance imaging (MRI) do not indicate when to perform repeat MRI in patients with previously documented degenerative disease. This study evaluates the efficacy of repeat MRI in patients with previously diagnosed degenerative cervical disease. Between 2013 and 2018, 153 patients (102 women, 51 men; mean age, 55 years; range, 19-81 years) without a history of trauma or surgery underwent cervical spine MRI 2 or more times at our institution indicated for symptoms of neck pain with or without radiculopathy. The MRI reports of repeat studies were reviewed and compared with index studies for notable changes. Notable radiographic changes were defined as any progression of the existing degenerative disease. Fifty-three of 153 (35%) patients demonstrated progression on repeat MRI. Forty-nine of the 53 patients demonstrating progression had new or worsening symptoms prior to their follow-up study (P=.03). Twenty-nine of 35 (83%) patients with new or worsening radiculopathy progressed on MRI (P<.01). Nine of 10 (90%) patients with new upper motor neuron findings demonstrated progression (P=.01). Axial neck pain alone was not statistically linked to MRI progression (P=.1). Twenty-five (16.3%) patients underwent operative management for their disease. Only 12 (48.0%) of the surgical patients presented MRI progression (P=.1). In the absence of new or worsening degenerative cervical symptoms, additional MRI studies are unlikely to reveal any radiographic progression or change clinical management from nonoperative to operative. [Orthopedics. 2023;46(2):98-102.].

Research progress in magnetic resonance imaging of primary nocturnal enuresis

原发性夜间遗尿症（PNE）是一种学龄期儿童常见的排泄障碍，指在睡眠中不能因尿意自觉醒来而出现不自主排尿的现象，严重危害儿童的身心健康。PNE的病因和发病机制仍不清楚，造成临床出现治愈率低、复发率高的现象。近些年来，磁共振成像技术在PNE的神经机制研究中得以应用，发现PNE患儿存在脑结构、脑功能和脑代谢异常，其中整个排尿控制脑网络的异常是导致遗尿发生的重要原因。本文主要对儿童PNE的磁共振成像相关研究进行综述。.

Treatment Response and Prognosis Evaluation in High‐Grade Glioma: An Imaging Review Based on MRI

In recent years, the development of advanced magnetic resonance imaging (MRI) technology and machine learning (ML) have created new tools for evaluating treatment response and prognosis of patients with high-grade gliomas (HGG); however, patient prognosis has not improved significantly. This is mainly due to the heterogeneity between and within HGG tumors, resulting in standard treatment methods not benefitting all patients. Moreover, the survival of patients with HGG is not only related to tumor cells, but also to noncancer cells in the tumor microenvironment (TME). Therefore, during preoperative diagnosis and follow-up treatment of patients with HGG, noninvasive imaging markers are needed to characterize intratumoral heterogeneity, and then to evaluate treatment response and predict prognosis, timeously adjust treatment strategies, and achieve individualized diagnosis and treatment. In this review, we summarize the research progress of conventional MRI, advanced MRI technology, and ML in evaluation of treatment response and prognosis of patients with HGG. We further discuss the significance of the TME in the prognosis of HGG patients, associate imaging features with the TME, indirectly reflecting the heterogeneity within the tumor, and shifting treatment strategies from tumor cells alone to systemic therapy of the TME, which may be a major development direction in the future. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY STAGE: 4.

Imaging of Fibrosis in Chronic Pancreatitis.

Chronic pancreatitis (CP) describes long-standing inflammation of the pancreas, which leads to irreversible and progressive inflammation of the pancreas with fibrosis. CP also leads to abdominal pain, malnutrition, and permanent impairment of exocrine/endocrine functions. However, it is difficult to assess CP pathologically, and imaging modalities therefore play an important role in the diagnosis and assessment of CP. There are four modalities typically used to assess CP. Pancreatic duct features are assessed with magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP). However, ERCP is a rather invasive diagnostic modality for CP, and can result in adverse events such as post-ERCP pancreatitis. Computed tomography (CT) is often the most appropriate initial imaging modality for patients with suspected CP, and has high diagnostic specificity. However, CT findings typically only appear in advanced stages of CP, and it is difficult to detect early CP. Endoscopic ultrasonography (EUS) provides superior spatial resolution compared with other imaging modalities such as CT and magnetic resonance imaging (MRI), and is considered the most reliable and efficient diagnostic modality for pancreatic diseases. The EUS-based Rosemont classification plays an important role in diagnosing CP in clinical practice. Evaluation of tissue stiffness can be another option to assess the diagnosis and progression of CP, and MRI and EUS can be used to assess CP not only with imaging, but also with elasticity measurement. MR and EUS elastography are expected to provide new alternative diagnostic tools for assessment of fibrosis in CP, which is difficult to evaluate pathologically.

Advanced spinal cord MRI in multiple sclerosis: Current techniques and future directions

Spinal cord magnetic resonance imaging (MRI) has a central role in multiple sclerosis (MS) clinical practice for diagnosis and disease monitoring. Advanced MRI sequences capable of visualizing and quantifying tissue macro- and microstructure and reflecting different pathological disease processes have been used in MS research; however, the spinal cord remains under-explored, partly due to technical obstacles inherent to imaging this structure. We propose that the study of the spinal cord merits equal ambition in overcoming technical challenges, and that there is much information to be exploited to make valuable contributions to our understanding of MS.We present a narrative review on the latest progress in advanced spinal cord MRI in MS, covering in the first part structural, functional, metabolic and vascular imaging methods. We focus on recent studies of MS and those making significant technical steps, noting the challenges that remain to be addressed and what stands to be gained from such advances. Throughout we also refer to other works that presend more in-depth review on specific themes. In the second part, we present several topics that, in our view, hold particular potential. The need for better imaging of gray matter is discussed. We stress the importance of developing imaging beyond the cervical spinal cord, and explore the use of ultra-high field MRI. Finally, some recommendations are given for future research, from study design to newer developments in analysis, and the need for harmonization of sequences and methods within the field.This review is aimed at researchers and clinicians with an interest in gaining an overview of the current state of advanced MRI research in this field and what is primed to be the future of spinal cord imaging in MS research.

Defining Primary Sclerosing Cholangitis: Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process

Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory disease of the bile ducts that is surrounded by much uncertainty. First of all, it is a rare disease, with reported prevalence between 0 and 31.7 per 100,000 individuals,1Boonstra K. Beuers U. Ponsioen C.Y. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review.J Hepatol. 2012; 56: 1181-1188Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar,2Barner-Rasmussen N. Pukkala E. Jussila A. et al.Epidemiology, risk of malignancy and patient survival in primary sclerosing cholangitis: a population-based study in Finland.Scand J Gastroenterol. 2020; 55: 74-81Crossref PubMed Scopus (11) Google Scholar and establishing a diagnosis can be difficult. The primary pathology is hidden deep in the liver, and there is no specific and easy noninvasive diagnostic test for PSC. Histologic features of fibrosing cholangiopathy are present in <20% of liver biopsy specimens obtained from patients with PSC and can also be seen in cases of secondary sclerosing cholangitis. Current US and European guidelines do not recommend liver biopsy for making a diagnosis of PSC except for suspected cases of small duct PSC and pediatric cases.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (247) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1230) Google Scholar In addition, biliary tract abnormalities can be found on magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiography (ERC) in a wide array of conditions (see Supplementary Table 1). Furthermore, the course of PSC can be variable. Liver transplant–free survival ranges between 14.5 and 21.3 years in large cohorts.5Weismüller T.J. Trivedi P.J. Bergquist A. et al.Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis.Gastroenterology. 2017; 152: 1975-1984Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar,6Boonstra K. Weersma R.K. van Erpecum K.J. et al.Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.Hepatology. 2013; 58: 2045-2055Crossref PubMed Scopus (348) Google Scholar An important risk factor affecting survival is the development of cholangiocarcinoma (CCA). This has a cumulative incidence of approximately 20% at 20 years after diagnosis, but one third of CCA cases become manifest within 1 year after the diagnosis of PSC.5Weismüller T.J. Trivedi P.J. Bergquist A. et al.Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis.Gastroenterology. 2017; 152: 1975-1984Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar,6Boonstra K. Weersma R.K. van Erpecum K.J. et al.Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.Hepatology. 2013; 58: 2045-2055Crossref PubMed Scopus (348) Google Scholar Last but not least, the cause of PSC is still enigmatic, and consequently, there is no therapy that has been proven to modify disease progression. In recent years, there has been an upsurge of pilot studies and phase 2 clinical trials. Phase 2 and 3 trials are hampered by the lack of established surrogate endpoints for clinical outcome, the heterogeneity of the disease course, and the lack of clear definitions for many key clinical disease characteristics.7Ponsioen C.Y. Chapman R.W. Chazouillères O. et al.Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process.Hepatology. 2016; 63: 1357-1367Crossref PubMed Scopus (95) Google Scholar While the available national and international clinical practice guidelines predominantly focus on clinical management, the International PSC Study Group (IPSCSG) has recognized that there is a vital need for clinical trials to use uniform definitions for the diagnosis of PSC and for assessing disease severity and outcomes.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (247) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1230) Google Scholar,8Chapman M.H. Thorburn D. Hirschfield G.M. et al.British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis.Gut. 2019; 68: 1356-1378Crossref PubMed Scopus (55) Google Scholar Therefore, the IPSCSG has commissioned a consensus process among its experts to issue a set of definitions to aid clinical trialists designing much needed clinical trials. To this end, an extensive consensus process was initiated, applying a hybrid between a Delphi process and a nominal group process, as was previously used by the IPSCSG and the European Crohn’s and Colitis Organization.7Ponsioen C.Y. Chapman R.W. Chazouillères O. et al.Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process.Hepatology. 2016; 63: 1357-1367Crossref PubMed Scopus (95) Google Scholar,9Dignass A. Eliakim R. Magro F. et al.Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis.J Crohns Colitis. 2012; 6: 965-990Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar Where necessary, an additional survey was conducted among all IPSCSG members (see the Supplementary Methods for details). Results are presented as a comprehensive set of consensus statements (CSs) and diagnostic criteria for PSC. Although patients with PSC are increasingly diagnosed at earlier stages of disease based on asymptomatic serum liver enzyme abnormalities, at least 45% of patients PSC present with symptoms on either a constant or intermittent basis, which significantly reduces quality of life.10Broome U. Olsson R. Lööf L. et al.Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis.Gut. 1996; 38: 610-615Crossref PubMed Google Scholar Furthermore, more than 22% of asymptomatic patients may develop symptoms within 5 years. The most common clinical symptoms associated with PSC are fatigue; pruritus; right upper quadrant (RUQ) abdominal pain; and emotional distress, which may include anxiety and depression symptoms. Pruritus and abdominal pain can fluctuate dramatically, and this may be suddenly worsened because of the development of a biliary obstruction or acute bacterial cholangitis. Therefore, clinical evaluation with laboratory testing and imaging may be necessary in the event of the sudden appearance or worsening of symptoms. Emotional distress for many patients is attributable to chronic anxiety about the uncertain etiology of the disease, the lack of effective therapy, and the risk of malignancy, among others.11Ranieri V. Kennedy E. Walmsley M. et al.The Primary Sclerosing Cholangitis (PSC) Wellbeing study: understanding psychological distress in those living with PSC and those who support them.PLoS One. 2020; 15e0234624Crossref PubMed Scopus (0) Google Scholar The incorporation of clearly defined patient-reported symptoms into the design of clinical trials is both desirable from a patient-centered perspective and highly encouraged by regulatory agencies12Ponsioen C.Y. Lindor K.D. Mehta R. et al.Design and endpoints for clinical trials in primary sclerosing cholangitis.Hepatology. 2018; 68: 1174-1188Crossref PubMed Scopus (24) Google Scholar (Box 1, CS 1.1). Recently, 2 such tools have emerged. One patient-reported outcome (PRO) dedicated to PSC showed excellent reliability and was able to discern patients with cirrhosis and those with a history of depression.13Younossi Z.M. Afendy A. Stepanova M. et al.Development and validation of a primary sclerosing cholangitis-specific patient-reported outcomes instrument: the PSC PRO.Hepatology. 2018; 68: 155-165Crossref PubMed Scopus (14) Google Scholar A more recently developed tool to assess patient-reported symptoms, the Simple Cholestatic Complaints Score, was developed through digital surveys of patients and showed good criterion and construct validity and a very high test-retest reproducibility.14Munster K.N. Dijkgraaf M.G.W. Gennep S. et al.The Simple Cholestatic Complaints Score is a valid and quick patient-reported outcome measure in primary sclerosing cholangitis.Liver Int. 2020; 40: 2758-2766Crossref PubMed Scopus (0) Google Scholar Further validation of these tools in larger and more diverse cohorts is needed.Box 1Consensus StatementsTabled 11.Clinical symptoms1.1.Assessment of symptoms in patients with PSC for clinical trial purposes should be performed through disease-specific and validated quantitative tools.1.2.Assessment of symptoms in patients with PSC should take into consideration and be distinguished from symptoms attributable to active inflammatory bowel disease and other coexistent conditions.2.Laboratory markers2.1.The presence of significant elevations of serum aminotransferase activity (>5 × ULN) and/or IgG (>2 × ULN) can be indicative of features of coexisting autoimmune hepatitis and should trigger consideration of liver biopsy for diagnostic and stratification purposes when considering enrolling a subject in a clinical trial.2.2.Serum IgG4 concentrations can be elevated in patients with PSC, in the absence of classical features of IgG4-related disease, but IgG4 elevations are not validated markers of disease diagnosis, severity, prognosis, or treatment.3.Imaging3.1.The pattern of PSC can be defined according to the appearances of cholangiography using high-quality magnetic resonance cholangiography (MRC) (at least 1.5 T):3.1.1.Small duct when a recent cholangiogram (not older than 1 year) is normal3.1.2.Intrahepatic when there are intrahepatic changes but the common ducts and first-order ducts are normal3.1.3.Extrahepatic disease when the common ducts and/or the first-order ducts are involved4.Histology4.1.Histologic findings in a liver biopsy sample from patient suspected to have PSC can be defined (classified) as follows:4.1.1.Typical of PSC: features of fibrosing cholangiopathy present (periductal fibrosis, fibro-obliterative duct lesions)4.1.2.Compatible with PSC: features of chronic biliary disease present (see text for further details) without typical bile duct lesions4.1.3.Atypical for PSC: features atypical for PSC present. Examples include•unusually prominent inflammatory activity suggesting the possibility of PSC-AIH overlap syndrome•features suggesting an alternative diagnosis, such as fatty liver disease, or IgG4-associated cholangitis.4.2.A liver biopsy specimen showing typical or compatible histologic features is required to establish a diagnosis of small duct PSC.4.3.In a person with PSC, a liver biopsy specimen showing at least moderate interface hepatitis in addition to features compatible with or diagnostic of PSC is required to establish a diagnosis of PSC with features of AIH or PSC-AIH overlap syndrome.4.4.The histologic features that indicate disease progression (staging) in PSC include fibrosis, bile duct loss, and evidence of chronic cholestasis (demonstrated by deposition of copper-associated protein in periportal hepatocytes).5.Concurrent IBD5.1.The definition and description of IBD in PSC should follow the European Crohn’s and Colitis Organization (ECCO) guidelines and Montreal classification. Any patient with established PSC should undergo a full ileocolonoscopy with histology before concurrent IBD may be excluded.5.2.When assessing the existence of backwash ileitis, it is recommended that the ECCO definition be followed. This defines backwash ileitis as continuous extension of macroscopic or histologic inflammation from the cecum into the most distal ileum.6.Staging6.1.Disease staging of PSC is defined as the histologic progression from initial disease onset to cirrhosis.6.2.A clinically significant change in disease stage is defined by a 1-point change in the Ludwig or Nakanuma system or a 2-point change in the Ishak system.6.3.Histologic cirrhosis is a clinically significant endpoint.6.4.Cirrhosis (stage 5–6 by Ishak) in PSC can be defined by an LS of >14.4 kPa measured by VCTE.6.5.Cirrhosis (stage 5–6 or greater by Ishak) in PSC can be defined by an ELF score of >9.8 or FibroTest of >7.3.7.Clinical endpoints7.1.Liver transplant:Liver transplant is an appropriate endpoint in PSC clinical trials. However, divergent indications for transplant listing (end-stage disease, dysplasia, CCA, symptoms, intractable cholangitis) and method of transplantation (deceased vs living donation) should not be grouped into a single endpoint because of the wide heterogeneity of clinical practice.7.2.Liver-related death:Liver-related death in the setting of PSC is defined as death from clinically significant portal hypertension, synthetic liver dysfunction, or specific complications from biliary disease such as hepatobiliary infections.8.Cancer development8.1.Cholangiocarcinoma:8.1.1.CCA in PSC requires pathologic confirmation and is classified according to CCA in general.8.1.2.Dysplastic changes considered precursors to CCA in PSC are defined by standard criteria.8.2.Colorectal carcinoma:8.2.1.CRC in the setting of PSC is defined according to standard criteria.9.Pediatric PSC9.1.Pediatric PSC is not a specific disease phenotype. PSC in children should be described in terms of small vs large duct involvement, whether features of overlap with AIH are present or absent, and whether IBD is present or absent, as in adult patients.9.2.Terms such as juvenile sclerosing cholangitis and autoimmune sclerosing cholangitis should be avoided.9.3.When gGT is substituted for ALP, the consensus definitions in this document are applicable to children.10.Recurrent PSC10.1.The diagnosis of rPSC is based on the presence of compatible radiologic changes (using high-quality MR) with/or without histologic findings, along with the exclusion of other causes of similar findings. Open table in a new tab Tabled 11.Clinical symptoms1.1.Assessment of symptoms in patients with PSC for clinical trial purposes should be performed through disease-specific and validated quantitative tools.1.2.Assessment of symptoms in patients with PSC should take into consideration and be distinguished from symptoms attributable to active inflammatory bowel disease and other coexistent conditions.2.Laboratory markers2.1.The presence of significant elevations of serum aminotransferase activity (>5 × ULN) and/or IgG (>2 × ULN) can be indicative of features of coexisting autoimmune hepatitis and should trigger consideration of liver biopsy for diagnostic and stratification purposes when considering enrolling a subject in a clinical trial.2.2.Serum IgG4 concentrations can be elevated in patients with PSC, in the absence of classical features of IgG4-related disease, but IgG4 elevations are not validated markers of disease diagnosis, severity, prognosis, or treatment.3.Imaging3.1.The pattern of PSC can be defined according to the appearances of cholangiography using high-quality magnetic resonance cholangiography (MRC) (at least 1.5 T):3.1.1.Small duct when a recent cholangiogram (not older than 1 year) is normal3.1.2.Intrahepatic when there are intrahepatic changes but the common ducts and first-order ducts are normal3.1.3.Extrahepatic disease when the common ducts and/or the first-order ducts are involved4.Histology4.1.Histologic findings in a liver biopsy sample from patient suspected to have PSC can be defined (classified) as follows:4.1.1.Typical of PSC: features of fibrosing cholangiopathy present (periductal fibrosis, fibro-obliterative duct lesions)4.1.2.Compatible with PSC: features of chronic biliary disease present (see text for further details) without typical bile duct lesions4.1.3.Atypical for PSC: features atypical for PSC present. Examples include•unusually prominent inflammatory activity suggesting the possibility of PSC-AIH overlap syndrome•features suggesting an alternative diagnosis, such as fatty liver disease, or IgG4-associated cholangitis.4.2.A liver biopsy specimen showing typical or compatible histologic features is required to establish a diagnosis of small duct PSC.4.3.In a person with PSC, a liver biopsy specimen showing at least moderate interface hepatitis in addition to features compatible with or diagnostic of PSC is required to establish a diagnosis of PSC with features of AIH or PSC-AIH overlap syndrome.4.4.The histologic features that indicate disease progression (staging) in PSC include fibrosis, bile duct loss, and evidence of chronic cholestasis (demonstrated by deposition of copper-associated protein in periportal hepatocytes).5.Concurrent IBD5.1.The definition and description of IBD in PSC should follow the European Crohn’s and Colitis Organization (ECCO) guidelines and Montreal classification. Any patient with established PSC should undergo a full ileocolonoscopy with histology before concurrent IBD may be excluded.5.2.When assessing the existence of backwash ileitis, it is recommended that the ECCO definition be followed. This defines backwash ileitis as continuous extension of macroscopic or histologic inflammation from the cecum into the most distal ileum.6.Staging6.1.Disease staging of PSC is defined as the histologic progression from initial disease onset to cirrhosis.6.2.A clinically significant change in disease stage is defined by a 1-point change in the Ludwig or Nakanuma system or a 2-point change in the Ishak system.6.3.Histologic cirrhosis is a clinically significant endpoint.6.4.Cirrhosis (stage 5–6 by Ishak) in PSC can be defined by an LS of >14.4 kPa measured by VCTE.6.5.Cirrhosis (stage 5–6 or greater by Ishak) in PSC can be defined by an ELF score of >9.8 or FibroTest of >7.3.7.Clinical endpoints7.1.Liver transplant:Liver transplant is an appropriate endpoint in PSC clinical trials. However, divergent indications for transplant listing (end-stage disease, dysplasia, CCA, symptoms, intractable cholangitis) and method of transplantation (deceased vs living donation) should not be grouped into a single endpoint because of the wide heterogeneity of clinical practice.7.2.Liver-related death:Liver-related death in the setting of PSC is defined as death from clinically significant portal hypertension, synthetic liver dysfunction, or specific complications from biliary disease such as hepatobiliary infections.8.Cancer development8.1.Cholangiocarcinoma:8.1.1.CCA in PSC requires pathologic confirmation and is classified according to CCA in general.8.1.2.Dysplastic changes considered precursors to CCA in PSC are defined by standard criteria.8.2.Colorectal carcinoma:8.2.1.CRC in the setting of PSC is defined according to standard criteria.9.Pediatric PSC9.1.Pediatric PSC is not a specific disease phenotype. PSC in children should be described in terms of small vs large duct involvement, whether features of overlap with AIH are present or absent, and whether IBD is present or absent, as in adult patients.9.2.Terms such as juvenile sclerosing cholangitis and autoimmune sclerosing cholangitis should be avoided.9.3.When gGT is substituted for ALP, the consensus definitions in this document are applicable to children.10.Recurrent PSC10.1.The diagnosis of rPSC is based on the presence of compatible radiologic changes (using high-quality MR) with/or without histologic findings, along with the exclusion of other causes of similar findings. Open table in a new tab A particular challenge in assessing clinical symptoms in patients with PSC is the frequent concurrence of inflammatory bowel disease (IBD), which itself can influence the clinical course of PSC and may also account for a significant proportion of symptoms, especially during periods of IBD exacerbations.15Cheung A.C. Patel H. Meza-Cardona J. et al.Factors that influence health-related quality of life in patients with primary sclerosing cholangitis.Dig Dis Sci. 2016; 61: 1692-1699Crossref PubMed Scopus (1) Google Scholar Existing tools, including the PSC PRO, do not specifically account for symptoms attributable to IBD. Although the Simple Cholestatic Complaints Score did not show a difference in PSC patient symptoms according to the presence or absence of IBD, a systematic evaluation of IBD symptoms in patients with PSC has not been performed, which can result in confounding findings. Therefore, assessment of PSC symptoms should be performed alongside specifically designed tools to detect symptoms from IBD in those with PSC-IBD or other relevant coexistent conditions (Box 1, CS 1.2) This is critically important for clinical trials that aim to use PRO measures as endpoints in PSC. Cholestatic serum liver tests are a characteristic, but nonspecific, feature of biliary disease irrespective of the nature of biliary involvement. Alkaline phosphatase (ALP) as the hallmark of cholestasis is elevated in the vast majority of patients with PSC.16Poupon R. Liver alkaline phosphatase: a missing link between choleresis and biliary inflammation.Hepatology. 2015; 61: 2080-2090Crossref PubMed Scopus (52) Google Scholar Previously, it was thought that to make a diagnosis of PSC, elevation of ALP, or gamma-glutamyl transpeptidase (gGT) in children (see the “Pediatric Primary Sclerosing Cholangitis” section) was a prerequisite. Recent studies have shown that elevated cholestatic serum parameters need not always be present. For more background, see the Supplementary Material. Aminotransferases are often moderately elevated, whereas at diagnosis, serum bilirubin and albumin levels are usually normal.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (247) Google Scholar Aminotransferase activity of more than 5 times the upper limit of normal (ULN) and a serum IgG of >2 × ULN should raise the suspicion of coexisting autoimmune hepatitis (AIH) and should trigger consideration of liver biopsy to identify histologic features that would support a diagnosis of AIH or PSC/AIH overlap, also called variant syndrome (Box 1, CS 2.1). This has management consequences, because patients with PSC/AIH commonly respond favorably to immunosuppressive medication such as corticoids and thiopurines, although not as well as patients with isolated AIH.17Boberg K.M. Chapman R.W. Hirschfield G.M. et al.Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatology. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In contrast to primary biliary cholangitis (PBC) and AIH, there is no pattern of autoantibody reactivity in patients with PSC of relevance to diagnosis or treatment. Positive titers of autoantibodies are common in PSC, including antinuclear antibody (8%–77%), smooth muscle antibody (0%–83%), and atypical perinuclear antibody (26%–94%).18Prideaux L. De Cruz P. Ng S.C. et al.Serological antibodies in inflammatory bowel disease: a systematic review.Inflamm Bowel Dis. 2012; 18: 1340-1355Crossref PubMed Scopus (121) Google Scholar,19Moiseev S. Cohen Tervaert J.W. Arimura Y. et al.2020 International consensus on ANCA testing beyond systemic vasculitis.Autoimmun Rev. 2020; 19: 102618Crossref PubMed Scopus (18) Google Scholar However, these are also frequently present in AIH, and perinuclear antineutrophil cytoplasmic antibodies can be found in ulcerative colitis (UC) in 41%–73% and in Crohn’s disease in 6%–38%.17Boberg K.M. Chapman R.W. Hirschfield G.M. et al.Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatology. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 18Prideaux L. De Cruz P. Ng S.C. et al.Serological antibodies in inflammatory bowel disease: a systematic review.Inflamm Bowel Dis. 2012; 18: 1340-1355Crossref PubMed Scopus (121) Google Scholar, 19Moiseev S. Cohen Tervaert J.W. Arimura Y. et al.2020 International consensus on ANCA testing beyond systemic vasculitis.Autoimmun Rev. 2020; 19: 102618Crossref PubMed Scopus (18) Google Scholar Serum IgG4 levels can be elevated in patients with PSC, but this has no validated bearing on diagnosis or disease severity (Box 1, CS 2.2). For distinction from IgG4-sclerosing cholangitis, see the Supplementary Material. Biliary imaging is integral to the diagnosis and classification of PSC. MRCP has been established as the noninvasive imaging of choice.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (247) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1230) Google Scholar Regarding the utility of magnetic resonance imaging (MRI) in PSC, the reader is referred to a recent publication from the IPSCSG Working Group on MRI in PSC.20Schramm C. Eaton J. Ringe K.I. et al.Recommendations on the use of magnetic resonance imaging in PSC-A position statement from the International PSC Study Group.Hepatology. 2017; 66: 1675-1688Crossref PubMed Scopus (58) Google Scholar A range of cholangiographic features are described in large duct PSC, including multifocal stricturing, focal dilatation or ectasia, ductal wall thickening within the intra- and/or extrahepatic biliary tree, obliteration of the peripheral intrahepatic ducts with pruning of the biliary tree, retraction of the ampulla, and periductal inflammation. These changes are, however, not pathognomonic of PSC, and differentiation from causes of secondary sclerosing cholangitis (especially in the absence of colitis) can be difficult. Saccular outpouchings in the extrahepatic bile ducts on cholangiography are thought to be highly specific for PSC. These diverticular outpouchings in the common hepatic and common bile duct, and—very rarely—in the cystic duct, are usually seen only in advanced disease and are reported in only 7.5% of cases in a large series of ERCs.21Ponsioen C.Y. Vrouenraets S.M.E. Prawirodirdjo W. et al.Natural history of primary sclerosing cholangitis and prognostic value of cholangiography in a Dutch population.Gut. 2002; 51: 562-566Crossref PubMed Scopus (0) Google Scholar True small duct PSC where cholangiography is normal is an infrequent finding in PSC. Two recent publications have reported on the natural history of small cohorts of small duct PSC patients followed prospectively. Progression to large duct PSC was described in 33% and 55%, respectively, after a mean of 11 years of follow-up in each study22Kozaka K. Sheedy S.P. Eaton J.E. et al.Magnetic resonance imaging features of small-duct primary sclerosing cholangitis.Abdom Radiol (NY). 2020; 45: 2388-2399Crossref PubMed Scopus (2) Google Scholar,23Ringe K.I. Bergquist A. Lenzen H. et al.Clinical features and MRI progression of small duct primary sclerosing cholangitis (PSC).Eur J Radiol. 2020; 129: 109101Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar (Box 1, CS 3.1.1). There was no correlation with any baseline MRI findings and progression to large duct PSC in either study. Strictures in the draining bile ducts are a common and clinically relevant sequela of the chronic inflammatory process that takes place in the biliary tree in PSC. From a consecutive series of 96 large duct PSC patients followed up with regular ERCs, the incidence of the development of so-called dominant strictures can be inferred to amount to approximately 10% in patients with large duct PSC.24Stiehl A. Rudolph G. Klöters-Plachky P. et al.Development of dominant bile duct stenoses in patients with primary sclerosing cholangitis treated with ursodeoxycholic acid: outcome after endoscopic treatment.J Hepatol. 2002; 36: 151-156Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar After extensive careful deliberations (outlined in the Supplementary Material), the panel delineated a number of criteria that coalesced into the working definition of a dominant stricture, as outlined in Box 2.Box 2Working Definition of Dominant StrictureTabled 1A stricture is called a possible dominant stricture when it meets the following criteria before ERC:•Imaging–High-quality MRCP or ERC with narrowing of any length in extrahepatic or first-order intrahepatic ducts, often—but not necessarily—with upstream dilatationTOGETHER WITH•Symptoms and biochemistry–Significant worsening of cholestatic symptoms within last 2 months:jaundice , biliary infection, pruritus, or RUQ pain–and–Bilirubin and/or ALP: absolute level of >1.2 × ULN and recent increase, for example, >1.2 × baseline25Gotthardt D.N. Rudolph G. Klöters-Plachky P. et al.Endoscopic dilation of dominant stenoses in primary sclerosing cholangitis: outcome after long-term treatment.Gastrointest Endosc. 2010; 71: 527-534Abstract Full Text Full Text PDF PubMed Scopus (89) Google ScholarOR•Biochemistry alone–Bilirubin and/or ALP: increase within past 6 months, for example, >1.5 × baseline, or absolute level of >2 × ULN if no previous measurement within 6 months is available26

Different Doses of Fingolimod in Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: The efficacy and safety of fingolimod for relapsing-remitting multiple sclerosis (RRMS) had been well verified in several large randomized controlled trials (RCTs) during the past decade. However, there are fewer systematic comparisons of different doses of fingolimod and whether the dose of 0.5 mg/d is the optimal one still remains to be solved. Objective: The objective of this systematic review was to evaluate the efficacy and safety of the four existing doses of fingolimod in the treatment of RRMS, especially the dose of 0.5 mg/d. Methods: MEDLINE, EMBASE, Cochrane Library, and clinicaltrials.gov were searched for RCTs which were performed to evaluate different doses of fingolimod and the corresponding control (placebo or DMTs) up to October 2020. Review Manager 5.3 software was used to assess the data. The risk ratio (RR) and mean difference (MD) was analyzed and calculated with a random effect model. Results: We pooled 7184 patients from 11 RCTs. Fingolimod 0.5 mg/d was superior to control group in all eight efficacy outcomes including annualized relapse rate (ARR) (MD −0.22, 95%CI −0.29 to −0.14, p < 0.00001) but surprisingly showed a higher risk of basal-cell carcinoma (RR 4.40, 95%CI 1.58 to 12.24, p = 0.004). Although 1.25 mg/d is more than twice the dose of 0.5 mg/d, the effect size was almost similar between them. Dose of 5 mg/d obtained an unsatisfactory efficacy while showing a greater risk of adverse events than other three doses (RR 1.17, 95%CI 1.05 to 1.30, p = 0.003). Additionally, fingolimod 0.25 mg/d not only showed a better performance in delaying the disease progress of magnetic resonance imaging (MRI), but also achieved a certain degree of patient treatment satisfaction. Conclusion: At present, 0.5 mg/d remains to be the optimal dose of fingolimod for RRMS patients but trials of a lower dose are still of great clinical significance and should be paid more attentions.

Long-term clinical and magnetic resonance imaging follow-up of dogs with osseous-associated cervical spondylomyelopathy.

BackgroundOsseous‐associated cervical spondylomyelopathy (OA‐CSM) is a complex disorder with limited long‐term survival. The longitudinal progression is currently unknown.ObjectiveTo describe changes on magnetic resonance imaging (MRI) over a 2‐year minimum period. We hypothesized that spinal lesions would progress in the majority of dogs.AnimalsEleven dogs previously diagnosed with OA‐CSM were prospectively studied. Nine dogs were treated medically, whereas 2 were treated surgically.MethodsClinical and MRI follow‐up were performed with a median time between MRI studies of 30 months (range, 24‐54). Morphologic assessment evaluated vertebral canal stenosis, spinal cord compression, foraminal stenosis, and articular processes, among other variables. Morphometric assessment included vertebral canal area, spinal cord area, area of the articular processes, and foraminal height.ResultsOn follow‐up MRI, the most affected site at the initial examination in medically treated dogs had progressed in 4 of 9 dogs, improved in 4, and was unchanged in 3. Clinically, all dogs except 2 medically treated dogs were unchanged to improve at follow‐up. Initially, 50 of 60 (83.3%) intervertebral spaces had vertebral canal stenosis, whereas in the follow‐up MRI 82.3% did. Of the sites with stenosis, 45.7% were unchanged, 18.6% improved, and 38.9% worsened. Morphometry identified significant decreases in vertebral canal and spinal cord areas at C4‐C5 through C6‐C7, and significant progression of articular process irregularities at C3‐C4 and C6‐C7.Conclusions and Clinical ImportanceThis long‐term follow‐up study of dogs with OA‐CSM did not identify clinical or MRI progression of lesions in the majority of dogs.

Progression of Central Nervous System Vasculopathy in Young Adults with Sickle Cell Anemia

Introduction Silent cerebral infarcts (SCI) and cerebral vessel stenosis are common and progressive in sickle cell anemia (SCA). Most data regarding brain lesions in SCA are cross-sectional or derive from pediatric cohorts with short follow-up not spanning the transition into adulthood. While hydroxyurea and transfusions may reduce the incidence of SCI and abnormal transcranial Doppler (TCD) in children with SCA, data on the effectiveness of these therapies in young adults are lacking. We tested the hypothesis that SCI and cerebral vessel stenosis progressed in young adults with SCA, relative to their childhood years. In addition, we explored the relationship between progression of brain vasculopathy and exposure to disease-modifying therapy. Methods We obtained brain magnetic resonance imaging (MRI) and MR angiography (MRA) in adults with SCA (HbSS or HbSβ0-thalassemia) on chronic transfusions or hydroxyurea. Participants were recruited from the IRB-approved longitudinal cohort study, Sickle Cell Clinical Research and Intervention Program (Hankins et al., PBC 2018). Participants were ages 18.0 to 32.0 at adult imaging and had at least one prior MRI/MRA between 0 and 17.9 years. Pediatric MRI/MRAs were performed for clinical indications (e.g., neurologic concern). All pediatric and adult MRI/MRAs had similar imaging protocols and were centrally reviewed by a neuroradiologist. SCIs were defined as focal T2-weighted or FLAIR hyperintensity. MRIs were considered abnormal if SCI or overt strokes were present. MRI progression was defined as new SCI or new overt strokes. Vessel stenoses were graded using a validated vasculopathy scale from 0 to 6 (Helton et al., Blood 2014). Abnormal MRA was defined as a score ≥1 and progression as any increase in the vasculopathy grading. We retrospectively ascertained childhood TCDs, treatments, overt strokes, and transient ischemic attacks (TIA, &lt;24 hours neurologic symptoms with no imaging change). The proportion of abnormal brain MRI/MRA was calculated for the participants' pediatric (0-11.9), adolescent (12.0-17.9), and young adult (18.0-32.0) years and compared using multivariate generalized linear mixed model. Multivariate logistic regression investigated the association of exposure to hydroxyurea or chronic transfusion with MRI/MRA progression from child to adulthood. Results Forty-one young adults with SCA, all African American, median age 19.0 years, (range 18.0-31.5) were included (Table 1). All received disease-modifying therapy prior to adult MRI/MRA; median duration of hydroxyurea was 10.4 years (range, 0.3 to 20.35) and chronic transfusion was 9.2 years (range, 2.5 to 14.6). Indications for chronic transfusion were: abnormal TCD (N=6), overt stroke (N=4), recurrent vaso-occlusive events (VOE) (N=1), and chronic kidney disease (N=1). Indications for hydroxyurea were: VOE (N=27), overt stroke (N=1), and abnormal TCD (N=1). The total follow-up time from pediatric to adult brain MRI/MRA was 804 person-years, during which 2 patients had new strokes and 5 had TIAs. Progression of MRI and MRA occurred in 12 (29%) and 8 (20%) young adults, respectively, in relation to their pediatric exams (p=0.04 and p=0.01), both among hydroxyurea (Figure 1a) and transfusion (Figure 1b) groups. Both MRI and MRA progression occurred more frequently among those with prior stroke or conditional or abnormal TCD velocities, p=0.015. Controlling for age at adult imaging, exposure to hydroxyurea was associated with decreased probability of MRI progression (OR=0.05, 95%CI: 0.01~0.52, p=0.01), but not MRA (OR=0.22, 95%CI: 0.02~2.34, p=0.2). When further adjusting for transfusions, exposure to hydroxyurea was still associated with decreased probability of MRI progression (OR=0.05, 95%CI: 0.4~0.64, p=0.021) but not transfusions (OR 0.94, 95%CI: 0.16~5.39, p=0.95). Conclusion Close to a quarter of young adults with SCA treated with disease-modifying therapies for approximately a decade, experienced progression of brain lesions despite treatment with disease-modifying therapies. Among patients exposed to hydroxyurea, less progression of SCIs occurred. Overt stroke or TCD elevation in childhood increased the risk of brain lesion progression. In children with SCA, the presence of SCI and vessel stenosis in childhood should prompt consideration of alternative treatments given the evidence that brain lesions progress as they emerge into adulthood. Disclosures Kang: MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Estepp:Forma Therapeutics: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Eli Lilly and Co: Research Funding; Pfizer: Research Funding; Esperion: Consultancy. Ataga:Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Modus Therapeutics: Honoraria; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. King:Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; Cell Works: Consultancy; Bioline: Consultancy; Celgene: Consultancy; Amphivena Therapeutics: Research Funding; Tioma Therapeutics (formerly Vasculox, Inc.):: Consultancy; RiverVest: Consultancy; WUGEN: Equity Ownership. Wang:Agios Pharmaceuticals: Consultancy; Novartis: Consultancy. Hankins:NHLBI: Honoraria; ASPHO: Honoraria; Novartis: Research Funding; LYNKS Foundation: Research Funding; Bluebird Bio: Consultancy; NHLBI: Research Funding; Global Blood Therapeutics: Research Funding; National Committee for Quality Assurance: Consultancy.