RANKL-RANK-OPG Pathway in Charcot Diabetic Foot: Pathophysiology and Clinical-Therapeutic Implications

Charcot Foot (CF), part of a broader condition known as Charcot Neuro-Osteoarthropathy (CNO), is characterized by neuropathic arthropathy with a progressive alteration of the foot. CNO is one of the most devastating complications in patients with diabetes mellitus and peripheral neuropathy but can also be caused by neurological or infectious diseases. The pathogenesis is multifactorial; many studies have demonstrated the central role of inflammation and the Receptor Activator of NF-kappa B ligand (RANKL)-Receptor Activator of NF-kappa B (RANK)-Osteoprotegerin (OPG) pathway in the acute phase of the disease, resulting in the serum overexpression of RANKL. This overexpression and activation of this signal lead to increased osteoclast activity and osteolysis, which is a prelude to bone destruction. The aim of this narrative review is to analyze this signaling pathway in bone remodeling, and in CF in particular, to highlight its clinical aspects and possible therapeutic implications of targeting drugs at different levels of the pathway. Drugs that act at different levels in this pathway are anti-RANKL monoclonal antibodies (Denosumab), bisphosphonates (BP), and calcitonin. The literature review showed encouraging data on treatment with Denosumab, although in a few studies and in small sample sizes. In contrast, BPs have been re-evaluated in recent years in relation to the high possibility of side effects, while calcitonin has shown little efficacy on CNO

RANKL-RANK-OPG Pathway in Charcot Diabetic Foot: Pathophysiology and Clinical-Therapeutic Implications

Charcot Foot (CF), part of a broader condition known as Charcot Neuro-Osteoarthropathy (CNO), is characterized by neuropathic arthropathy with a progressive alteration of the foot. CNO is one of the most devastating complications in patients with diabetes mellitus and peripheral neuropathy but can also be caused by neurological or infectious diseases. The pathogenesis is multifactorial; many studies have demonstrated the central role of inflammation and the Receptor Activator of NF-κB ligand (RANKL)-Receptor Activator of NF-κB (RANK)-Osteoprotegerin (OPG) pathway in the acute phase of the disease, resulting in the serum overexpression of RANKL. This overexpression and activation of this signal lead to increased osteoclast activity and osteolysis, which is a prelude to bone destruction. The aim of this narrative review is to analyze this signaling pathway in bone remodeling, and in CF in particular, to highlight its clinical aspects and possible therapeutic implications of targeting drugs at different levels of the pathway. Drugs that act at different levels in this pathway are anti-RANKL monoclonal antibodies (Denosumab), bisphosphonates (BP), and calcitonin. The literature review showed encouraging data on treatment with Denosumab, although in a few studies and in small sample sizes. In contrast, BPs have been re-evaluated in recent years in relation to the high possibility of side effects, while calcitonin has shown little efficacy on CNO

Overview of Ankle Arthropathy in Hereditary Hemochromatosis

Hereditary hemochromatosis (HH) is an autosomal recessive bleeding disorder characterized by tissue overload of iron. Clinical systemic manifestations in HH include liver disease, cardiomyopathy, skin pigmentation, diabetes mellitus, erectile dysfunction, hypothyroidism, and arthropathy. Arthropathy with joint pain is frequently reported at diagnosis and mainly involves the metacarpophalangeal and ankle joints, and more rarely, the hip and knee. Symptoms in ankle joints are in most cases non-specific, and they can range from pain and swelling of the ankle to deformities and joint destruction. Furthermore, the main radiological signs do not differ from those of primary osteoarthritis (OA). Limited data are available in the literature regarding treatment; surgery seems to be the gold standard for ankle arthropathy in HH. Pharmacological treatments used to maintain iron homeostasis can also be undertaken to prevent the arthropathy, but conclusive data are not yet available. This review aimed to assess the ankle arthropathy in the context of HH, including all its aspects: epidemiology, physiopathology, clinical and imaging presentation, and all the treatments available to the current state of knowledge

Tibiotalar and Tibiotalocalcaneal Arthrodesis with Paragon28 Silverback^TM Plating System in Patients with Severe Ankle and Hindfoot Deformity

Background and Objectives: The treatment of end-stage ankle osteoarthritis (OA) and associated hindfoot deformities remains a major challenge for orthopedic surgeons. Numerous techniques and surgical approaches have been proposed for tibiotalar (TT) and tibiotalocalcaneal (TTC) arthrodesis, from arthroscopic to open, as well as numerous devices proposed for internal fixation (retrograde intramedullary nails, cannulated screws, and plating systems). The aim of this study was to retrospectively analyze the results, with at least 18 months of follow-up, with SilverbackTM TT/TTC Plating System Paragon28 in a group of 20 patients with severe OA and hindfoot deformities (mainly secondary post-traumatic OA). Materials and Methods: The demographic characteristics and past medical history of the patients were collected and analyzed to identify the cause of the pathology. The degree of OA and deformity were quantified based on foot and ankle weight-bearing radiography and CT examination. Pre- and post-operative clinical and functional scores (ROM, VAS, AOFAS, FFI, and SF-36) and radiographic parameters (anterior distal tibial angle, tibiotalar angle, coronal tibiotalar angle, and hindfoot alignment angle) were evaluated. Results: All of the patients showed clinical and radiographic fusion at an average of 14 weeks (range 12–48), with improvement in pain and functional scores, without major surgical complications and/or infections. Conclusions: Despite the limitations of our study, the results with this new plating system showed good results in terms of bone consolidation, post-operative complications, and improvement of pain and quality of life in patients with severe OA and deformities of the ankle and hindfoot

Diagnostic Yield of 2 Strategies for Adult Celiac Disease Identification in Primary Care

Goals: To compare the diagnostic yield and cost-consequences of 2 strategies, screening regardless of symptoms versus case finding (CF), using a point-of-care test (POCT), for the detection of celiac disease (CD) in primary care, to bridge the diagnostic gap of CD in adults. Materials and Methods: All subjects under 75 years of age who consecutively went to their general practitioners' offices were offered POCT for anti-transglutaminase immunoglobulin A antibodies. The POCT was performed on all subjects who agreed, and then a systematic search for symptoms or conditions associated with higher risk for CD was performed, immediately after the test but before knowing the test results. The 2 resulting groups were: (a) POCT positive and (b) symptomatic subject at CF. Subjects were defined as symptomatic at CF in the presence of 1 or more symptoms. All POCT-positive or symptomatic subjects at CF were referred to the CD Centers for confirmation of CD. Data on resource consumption were gathered from patients' charts. Cost of examinations, and diagnostic and laboratory tests were estimated with regional outpatient tariffs (Sicily), and a price of €2.5 was used for each POCT. Results: Of a total of 2197 subjects who agreed to participate in the study, 36 (1.6%) and 671 (30.5%) were POCT positive and symptomatic at CF, respectively. The yield from the screening and CF was 5 new celiac patients. The total cost and mean cost for each new CD case were €7497.35 and €1499.47 for the POCT screening strategy, and €9855.14 and €1971.03 for the CF strategy, respectively. Assuming consecutive use of both strategies, performing POCT only in symptomatic subjects at CF, the calculated yield would be 4 new diagnoses with a total cost of €2345.84 and a mean cost of €586.46 for each newly diagnosed patient. Only 1 patient was celiac despite a negative POCT. Conclusions: Testing symptomatic subjects at CF only by POCT seems the most cost-effective strategy to bridge the diagnostic gap of adult CD in primary care. © 2017 Wolters Kluwer Health, Inc. All rights reserved

Diagnostic Yield of 2 Strategies for Adult Celiac Disease Identification in Primary Care

Goals: To compare the diagnostic yield and cost-consequences of 2 strategies, screening regardless of symptoms versus case finding (CF), using a point-of-care test (POCT), for the detection of celiac disease (CD) in primary care, to bridge the diagnostic gap of CD in adults. Materials and Methods: All subjects under 75 years of age who consecutively went to their general practitioners' offices were offered POCT for anti-transglutaminase immunoglobulin A antibodies. The POCT was performed on all subjects who agreed, and then a systematic search for symptoms or conditions associated with higher risk for CD was performed, immediately after the test but before knowing the test results. The 2 resulting groups were: (a) POCT positive and (b) symptomatic subject at CF. Subjects were defined as symptomatic at CF in the presence of 1 or more symptoms. All POCT-positive or symptomatic subjects at CF were referred to the CD Centers for confirmation of CD. Data on resource consumption were gathered from patients' charts. Cost of examinations, and diagnostic and laboratory tests were estimated with regional outpatient tariffs (Sicily), and a price of \u20ac2.5 was used for each POCT. Results: Of a total of 2197 subjects who agreed to participate in the study, 36 (1.6%) and 671 (30.5%) were POCT positive and symptomatic at CF, respectively. The yield from the screening and CF was 5 new celiac patients. The total cost and mean cost for each new CD case were \u20ac7497.35 and \u20ac1499.47 for the POCT screening strategy, and \u20ac9855.14 and \u20ac1971.03 for the CF strategy, respectively. Assuming consecutive use of both strategies, performing POCT only in symptomatic subjects at CF, the calculated yield would be 4 new diagnoses with a total cost of \u20ac2345.84 and a mean cost of \u20ac586.46 for each newly diagnosed patient. Only 1 patient was celiac despite a negative POCT. Conclusions: Testing symptomatic subjects at CF only by POCT seems the most cost-effective strategy to bridge the diagnostic gap of adult CD in primary care. \ua9 2017 Wolters Kluwer Health, Inc. All rights reserved