Quantification of granuloma volume and response to treatment in cutaneous sarcoidosis using 3-dimensional high-frequency ultrasound scan.
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ABSTRACT:
SUBMITTER: Rodriguez O
PROVIDER: S-EPMC5728712 | biostudies-literature | 2017 Nov
REPOSITORIES: biostudies-literature
Publications
Quantification of granuloma volume and response to treatment in cutaneous sarcoidosis using 3-dimensional high-frequency ultrasound scan.
Rodriguez Olaf O Noe Megan H MH Sehgal Chandra C Schultz Susan S Rosenbach Misha M
JAAD case reports 20171106 6
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Project description:BackgroundSarcoidosis and granuloma annulare (GA) are cutaneous granulomatous disorders that can be difficult to treat. There is evidence of underlying Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway activation in sarcoidosis, suggesting that JAK inhibition might be effective.ObjectiveTo evaluate treatment with tofacitinib, a JAK inhibitor, in patients with recalcitrant sarcoidosis and GA.MethodsA prospective evaluation of tofacitinib in 4 consecutive patients with recalcitrant cutaneous sarcoidosis (n = 3) and generalized GA (n = 1) was conducted. Immunohistochemical analysis of skin biopsy specimens from other patients with sarcoidosis (n = 21) and GA (n = 17) was performed to characterize patterns of JAK-STAT pathway activation.ResultsTofacitinib resulted in a mean improvement in the baseline Cutaneous Sarcoidosis Activity and Morphology Instrument and Granuloma Annulare Scoring Index scores of 96% (standard deviation, 2%). Histologic resolution of disease was documented in all patients (3 out of 3) who had skin biopsies while receiving therapy. Constitutive STAT1 and STAT3 activation was observed in both sarcoidosis and GA, albeit in different patterns. Signal regulatory protein α may explain the differences in JAK-STAT signaling between sarcoidosis and GA.LimitationsThe study is limited by the small number of participants.ConclusionsTofacitinib resulted in dramatic improvement in 4 patients with cutaneous sarcoidosis and GA. Larger studies are underway to better understand this effect.
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Project description:Purpose of reviewNonnecrotizing granulomas in the affected organ are the hallmark of sarcoidosis. This review summarizes most recent genetic findings in sarcoidosis with a focus on genes that might influence granuloma formation or resolution. Specific results in multiple ethnic groups and certain clinical subphenotypes, such as extra-pulmonary organ involvement, are discussed.Recent findingsAssociations of genetic variants in antigen-presenting molecules (HLA-DRB1) were shown to confer risk to sarcoidosis and certain disease phenotypes in populations of different ethnic origins. Specific DRB1 alleles, such as *0301 and *0302, appear to confer protection against chronic disease, but in an ethnic-specific manner illustrating the extensive genetic heterogeneity and complexity at this locus. Mechanistic studies of putative sarcoid antigens lend further credence to a role of HLA-DRB1 in disease pathogenesis. With relevance to granuloma formation, genes involved in apoptotic processes and immune cell activation were further confirmed (ANXA11 and BTNL2) in multiple ethnicities; others were newly identified (XAF1). Linking mechanism to clinical application, a TNF variant was shown to correlate with anti-TNF response in sarcoidosis patients.SummaryThe investigation of known and novel risk variants for sarcoidosis and specific clinical phenotypes in various ethnicities highlights the genetic complexity of the disease. Detailed subanalysis of disease phenotypes revealed the potential for prediction of extra-pulmonary organ involvement and therapy response based on the patient's genotype.
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Project description:A characteristic feature of sarcoidosis is a dysregulated immune response to persistent stimuli, often leading to the formation of non-necrotizing granulomas in various organs. Although genetic susceptibility is an essential factor in disease development, the etiology of sarcoidosis is not fully understood. Specifically, whether autoimmunity contributes to the initiation or progression of the disease is uncertain. In this study, we investigated systemic autoimmunity to vimentin in sarcoidosis. IgG antibodies to human vimentin were measured in sera from sarcoidosis patients and healthy controls. Mice immunized with recombinant murine vimentin were challenged intravenously with vimentin-coated beads to mimic pulmonary sarcoidosis. Lungs from treated mice were studied for cellular infiltration, granuloma formation, and gene expression. Immune cells in the bronchoalveolar lavage fluid were evaluated by flow cytometry. Compared to healthy controls, sarcoidosis patients had a higher frequency and levels of circulating anti-vimentin IgG. Vimentin-immunized mice developed lung granulomas following intravenous challenge with vimentin-coated beads. These sarcoidosis-like granulomas showed the presence of Langhans and foreign body multinucleated giant cells, CD4 T cells, and a heterogeneous collection of MHC II positive and arginase 1-expressing macrophages. The lungs showed upregulated pro-inflammatory gene expression, including Ifng, Il17, and Tnfa, reflecting TH1/TH17 responses typical of sarcoidosis. In addition, genes in the TH2 canonical pathway were also upregulated, congruent with increased numbers of ILC2 in the bronchoalveolar lavage. Overall, these results further validate vimentin as an autoantigen in sarcoidosis and provide evidence for an anti-vimentin immune response in disease pathogenesis. Our study also highlights the possible role of ILC2-driven TH2-like responses in the formation of lung granulomas in sarcoidosis.
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Project description:Sarcoidosis is a complex immune-mediated disease characterized by clusters of immune cells called granulomas. Despite major steps in understanding the cause of this disease, many questions remain. In this Review, we perform a mechanistic interrogation of the immune activities that contribute to granuloma formation in sarcoidosis and compare these processes with its closest mimic, tuberculosis, highlighting shared and divergent immune activities. We examine how Mycobacterium tuberculosis is sensed by the immune system; how the granuloma is initiated, formed, and perpetuated in tuberculosis compared with sarcoidosis; and the role of major innate and adaptive immune cells in shaping these processes. Finally, we draw these findings together around several recent high-resolution studies of the granuloma in situ that utilized the latest advances in single-cell technology combined with spatial methods to analyze plausible disease mechanisms. We conclude with an overall view of granuloma formation in sarcoidosis.
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Project description:BackgroundAlthough point-of-care volumetric assessments of the urinary bladder are not routinely performed in dogs, urine volume quantification can provide important clinical information including noninvasive urine output estimation.Hypothesis/objectiveUse of 3-dimensional (3D) ultrasound for determination of urinary bladder volume (UBV) in dogs will be accurate for different bladder volumes and will decrease the need for operator skill in measuring UBV compared to 2-dimensional (2D) ultrasound evaluation.AnimalsTen laboratory-bred Beagle dogs.MethodsProspective, experimental study. Urinary bladders were infused with a calculated amount of sterile saline to represent small, medium, and large volumes. Each UBV was estimated and calculated by a board-certified veterinary radiologist using 3 different 2D ultrasound formulas followed by use of a 3D ultrasound device by a novice. Measured UBVs were compared to the instilled UBV for both 2D and 3D ultrasound methods. Time from start to end of examination was recorded for both ultrasound methods in a subset of dogs.ResultsThe 3D ultrasound device underestimated UBV with a mean difference of -9.8 mL compared with 2D ultrasound that overestimated UBV with a difference of +4.2 to 20.3 mL dependent on the 2D formula used. The 3D ultrasound method took less time to measure UBV (mean of 80 seconds per measurement) compared to the 2D method (165 seconds per measurement; P = .02).Conclusions and clinical importanceThe tested 3D ultrasound device was found to be an accurate and rapid point-of-care tool for measuring UBV in dogs, providing a noninvasive method to estimate bladder volume in real time.
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Project description:Foreign body granulomas associated with polycaprolactone (PCL) filler injections are rare, yet challenging to manage. Multiple management modalities have been described. Here, we present a literature review and describe a case of histologically confirmed PCL-related granuloma, treated using ultrasound-guided injections of triamcinolone, hyaluronidase, and 5-fluorouracil combined with oral prednisolone and doxycycline.
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Project description:Quantification of peripheral nerve regeneration after injury relies upon subjective outcome measures or electrophysiology assessments requiring fully regenerated neurons. Nerve surgeons and researchers lack objective, quantifiable information on the site of surgical repair and regenerative front. To address this need, we developed a quantifiable, visual, clinically available measure of early peripheral nerve regeneration using high-frequency, three-dimensional, tomographic ultrasound (HFtUS). We conducted a prospective, longitudinal study of adult patients with ulnar and/or median nerve injury of the arm undergoing direct epineurial repair within 5 days of injury. Assessment of morphology, volumetric and 3D grey-scale quantification of cross-sectional views were made at baseline up to 15 months post-surgery. Sensory and motor clinical outcome measures and patient reported outcome measures (PROMs) were recorded. Five participants were recruited to the study. Our data demonstrated grey-scale values (an indication of axonal density) increased in distal stumps within 2-4 months after repair, returning to normal as regeneration completed (4-6 months) with concomitant reduction in intraneural volume as surgical oedema resolved. Two patients with abnormal regeneration were characterized by increased intraneural volume and minimal grey-scale change. HFtUS may quantify early peripheral nerve regeneration offering a window of opportunity for surgical intervention where early abnormal regeneration is detected.
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Project description:To report a case of panuveitis, retinal vasculitis, and optic disk granuloma due to sarcoidosis.Case report and literature review.A 26-year-old previously healthy African American male presented with four months of gradual progressive visual decline in the right eye. Clinical examination revealed severe panuveitis, retinal vasculitis, and large optic nerve mass lesion. Diffuse supraclavicular lymphadenopathy was also present. Histopathologic examination of the lymph node biopsy revealed granulomatous inflammation with some areas of caseous necrosis consistent with sarcoidosis.Sarcoidosis is a common cause of uveitis and retinal vasculitis. In rare cases, an optic disk granuloma may occur and can be treated with immunosuppressive therapy.
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Project description:The inability to effectively model sarcoidosis in the laboratory or in animals continues to hinder the discovery and translation of new, targeted treatments. The granuloma is the signature pathological hallmark of sarcoidosis, yet there are significant knowledge gaps that exist with regard to how granulomas form. Significant progress toward improved therapeutic and prognostic strategies in sarcoidosis hinges on tractable experimental models that recapitulate the process of granuloma formation in sarcoidosis and allow for mechanistic insights into the molecular events involved. Through its inherent representation of the complex genetics underpinning immune cell dysregulation in sarcoidosis, a recently developed in vitro human granuloma model holds promise in providing detailed mechanistic insight into sarcoidosis-specific disease regulating pathways at play during early stages of granuloma formation. The purpose of this review is to critically evaluate current sarcoidosis models and assess their potential to progress the field toward the goal of improved therapies in this disease. We conclude with the potential integrated use of preclinical models to accelerate progress toward identifying and testing new drugs and drug combinations that can be rapidly brought to clinical trials.
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