Diagnosing and Managing Infection in Total Ankle Replacement.

Infections after total ankle replacement (TAR) within the first 4 weeks after implantation can be managed successfully with 1 or several debridements, irrigation, and a change of polyethylene inlay. Late infections require implant removal. Low-grade infections might be an underestimated problem so far. Although single-surgery revisions are reported in the literature, the authors' experience with 2-stage revisions using an antibiotics-loaded bone cement spacer is better. Additional antibiotics are used to support the surgical treatment. After antibiotic therapy of 12 weeks, the final treatment includes ankle or tibio-talo-calcaneal fusion and, with limitations, revision TAR.

Loose Bodies Found in the Human Intra-Articular Space Showed Characteristics Similar to Endochondral Bone Formation.

OBJECTIVE: Loose bodies are free-floating tissues of cartilage and bone that can cause pain, swelling, the inability to straighten the knee, or intermittent locking of the knee. Loose bodies can arise from degenerative joint disease, flake fractures, osteochondritis dissecans, or chondromatosis. We hypothesized that loose bodies can be classified in stages with tissue characteristics similar to endochondral ossification. DESIGN: Loose bodies were harvested from patients undergoing joint replacement. Samples were processed for histology, gene expression analysis, and micro-computed tomography (µCT). Cartilage- and bone-related genes and proteins were selected for immunofluorescence stainings (collagen type I, II, and X, SOX9 [SRY-box transcription factor 9], and MMP13 [matrix metalloproteinase 13]) and gene expression analysis (FN [fibronectin], COL1A1, COL2A1, COL10A1, SOX9, MMP13, and aggrecan [ACAN]). RESULTS: Loose bodies were grouped in 4 stages: fibrous, (mineralized) cartilaginous, cartilage and bone, and bone. Hyaline-like cartilage tissue with Benninghoff arcades was present in stages 2 and 3. A transition from cartilaginous to mineralized tissue and bone trabecula was defined by an increase in COL1A1 and COL10A1 (stage 3 vs. 4: p = 0.047) positive area. Stage 4 showed typical trabecular bone tissue. The relative volume of calcified tissue (mineralized cartilage and bone tissue) decreased with stages (stages 1-2 vs. 3: p = 0.002; stage 1-2 vs. 4: p = 0.012). COL2A1 expression and stained area decreased from stages 1-2 to 4 (p = 0.010 and p = 0.004). ACAN expression decreased from stage 1-2 to stage 3 (p = 0.049) and stage 4 (p = 0.002). CONCLUSION: Loose bodies show tissue characteristics similar to endochondral ossification. They are probably a relevant substrate for regenerative therapeutic interventions in joint disease.

[Gout (ICD 10: M10): a retrospective analysis of the data from the histopathological arthritis register of the DGORh]. / Gicht (ICD-10: M10): Eine retrospektive Analyse der Daten des histopathologischen Arthritisregisters der DGORh.

BACKGROUND: Gout is considered to be the most common inflammatory arthritis worldwide. The histopathological arthritis register of the German Society for Orthopedic Rheumatology (DGORh) was founded in 2018. The aim of this register is a systematic collection of histopathological data on joint pathologies. As part of a master's thesis in medicine at the Sigmund Freud Private University (Vienna, Austria) the data on gout cases were retrospectively analyzed. OBJECTIVE: The objective of this analysis was to determine the prevalence of gout, the localizations of gout in the musculoskeletal system and the sensitivity of clinical gout diagnostics. MATERIAL AND METHODS: In cooperation with the Medical Treatment Center for Histology, Cytology and Molecular Diagnostics in Trier, Germany (MVZ-HZMD-Trier GmbH; Germany), tissue samples from 190 different orthopedic clinics and practices were analyzed and 7595 datasets were collected and stored in an arthritis register created by the DGORh. All gout cases stored between 1 January 2018 and 20 January 2020 were eligible for retrospective analysis (N = 102). RESULTS: The prevalence of gout was calculated at 1.34%. Of 108 histopathologically confirmed urate crystal depositions and gout granulomas, 76 were found in the lower extremities (70.37%), 30 in the upper extremities (27.78%) and 2 in the spinal joints (1.85%). The sensitivity of clinical gout diagnostics could be determined at 73.53%. CONCLUSION: Gout affects different anatomical regions with the first metatarsophalangeal joint being the main localization site. The sensitivity of clinical gout diagnostics was determined at 73.53%. These results emphasize the importance of histopathology in gout diagnostics.

[Particle disease and its effects on periarticular tissue]. / Abrieberkrankungen und deren Effekte auf das umliegende Gewebe.

Particle disease is the condition caused by wear debris on surrounding tissues and influences the well-being of arthroplasty patients. This condition is multifactorial due to the type of bearing couple, head size and implant position. Subsequent periprosthetic osteolysis and soft tissue reactions, can lead to revision THA surgery. The periprosthetic synovial membrane (synovial-like interface membrane, SLIM) is used in diagnostics when the cause of implant failure is uncertain. Detailed analysis of synovial fluid and bone marrow could improve the diagnostic procedure and strengthen the cases for revision surgery and the underlying biology. A large number of research approaches on this topic have evolved and continue to be utilized in the clinic.

[Does inflammatory activity of Charcot foot affect successful corrective arthrodesis?] / Beeinflusst die Entzündungsaktivität des Charcot-Fußes eine erfolgreiche Korrekturarthrodese?

BACKGROUND: Neuro-osteoarthropathy of the foot (CN) is divided into an active and inactive stage, with impact on the further treatment. The histopathological Charcot score (HCS) can be used, to grade the inflammatory activity in tissue samples. RESEARCH QUESTION: This study aims to clarify whether successful bony healing after arthrodesis is related to inflammatory activity of the disease. MATERIAL AND METHOD: N = 80 patients underwent corrective arthrodesis of the midfoot (group 1) or hindfoot/ankle (group 2). A distinction was made between patients with/without diabetes mellitus and with/without pain perception. Intraoperative samples were taken to determine HCS. The osseous healing of the arthrodesis was determined by computed tomography 12 weeks postoperatively. RESULTS: There was an indirect correlation between bony consolidation and HCS. In group 2, there was a significantly worse bony healing in patients without pain sensation. There seems to be a tendency for HCS to be increased in patients without diabetes/no pain sensation. DISCUSSION: The present study confirms the assumption that corrective arthrodesis should be performed in the inactive stage of CN only. High activity levels obviously impede bony healing. HCS represents a relevant prognostic tool for surgical treatment.

The histopathological synovitis score is influenced by biopsy location in patients with knee osteoarthritis.

INTRODUCTION: Osteoarthritis (OA) and rheumatoid arthritis (RA) represent the most common forms of arthritis, which are mainly caused by mechanical and inflammatory components, respectively. Determination of synovial inflammation in synovial biopsies via the histopathological Krenn score may be crucial for correct diagnosis and treatment. Specifically, it remains unclear whether synovitis scores differ among multiple biopsy locations within a single joint. MATERIALS AND METHODS: Eighty synovial samples were taken from four standardized regions of the knee in 20 patients (ten primary OA, ten secondary OA) undergoing total knee arthroplasty (TKA) or total synovectomy. The Krenn synovitis score (grade 0-9) was determined in a blinded manner by two expert pathologists in all biopsies. Next to the inter-rater reliability, we evaluated the agreement of the determined scores among the four biopsy locations within each knee. RESULTS: The inter-rater reliability between the two pathologists was very high (Cohen's kappa = 0.712; r = 0.946; ICC = 0.972). The mean synovitis score was significantly higher in knees with secondary than in primary OA (p = 0.026). Importantly, we found clear differences between the scores of the four different biopsy locations within the individual knee joints, with an average deviation of 10.6%. These deviations were comparable in knees with primary and secondary OA (p = 0.64). CONCLUSIONS: While we confirmed the synovitis score as a reliable and reproducible parameter to assess the histopathological synovitis grade in the knee, the considerable variability within the joint indicates that multiple synovial biopsies from different regions should be obtained to enable reliable results of the synovitis score.

Arthrofibrosis following primary total hip arthroplasty: a distinct clinical entity.

INTRODUCTION: Arthrofibrosis is a relatively frequent complication after total knee arthroplasty. Although stiffness after total hip arthroplasty (THA), because of formation of heterotopic ossification or other causes, is not uncommon, to the authors' best knowledge, arthrofibrosis after THA has not been described. The aim of this study is to describe the arthrofibrosis of the hip after primary THA using an established clinical and histological classification of arthrofibrosis. MATERIALS AND METHODS: We retrospectively examined all patients who were histologically confirmed to have arthrofibrosis after primary THA during revision surgery by examination of tissue samples in our clinic. Arthrofibrosis was diagnosed according to the histopathological SLIM-consensus classification, which defines seven different SLIM types of the periimplant synovial membrane. The SLIM type V determines the diagnosis of endoprosthesis-associated arthrofibrosis. RESULTS: The study population consists of 66 patients who were revised due to arthrofibrosis after primary THA. All patients had a limitation in range of motion prior to revision with a mean flexion of 90° (range from 40 to 125), mean internal rotation of 10° (range from 0 to 40) and mean external rotation of 20° (range from 0 to 50). All patients had histological SLIM type V arthrofibrosis, corresponding to endoprosthesis-associated arthrofibrosis. Histological examination revealed that seven patients (10.6%) had particle-induced and 59 patients (89.4%) had non-particle-induced arthrofibrosis. CONCLUSION: This is the first description of endoprosthetic-associated arthrofibrosis after primary THA on the basis of a well-established histological classification. Our study results could enable new therapeutic and diagnostic opportunities in patients with such an arthrofibrosis. Surgeons should keep arthrofibrosis as a possible cause for stiffness and pain after primary THA in mind. LEVEL OF EVIDENCE: Diagnostic study, Level of Evidence IV.

[Typing and particle analysis of squeaking hip endoprostheses : First histopathological analysis to examine the squeaking pathogenesis of ceramic-on-ceramic bearings]. / Typisierung und Partikelanalyse von Squeaking-Hüftendoprothesen : Erste histopathologische Analyse zur Untersuchung der Squeaking-Pathogenese von Keramik-Keramik-Gleitpaarungen.

BACKGROUND: Since the use of ceramic-on-ceramic (CoC) hip endoprostheses complications in the form of squeaking noises have occasionally occurred. OBJECTIVES: This is the first histopathological analysis of the synovia-like interface membrane (SLIM) of ceramic squeaking hip endoprostheses with the aim to gain new insights into the squeaking pathogenesis. MATERIALS AND METHODS: Seven CoC hip endoprostheses with squeaking pathogenesis are analyzed by SLIM consensus classification, particle algorithm, CD3 quantification, semiquantitative CD68 macrophages, Oil-Red positive macrophages, hemosiderin evaluation and in two cases by energy dispersive X­ray spectroscopy (EDX). RESULTS: In 1733 hip joint prosthesis pathology cases, a squeaking revision incidence of 0.40% was determined. In addition to SLIM type I (1/7), only SLIM type IV (6/7) was detected. 4/7 CoC cases showed combinations of micro, macro and, for the first time, supramacro (166.5 µm) ceramic wear particles. The EDX analysis confirmed the ceramic and an additional metallic abrasion. Increased focal concentrated low inflammatory markers (CD3/CD68) with hemosiderin (5/7) and lipid depositions (Oil-Red positive macrophages) (6/7) occurred. CONCLUSIONS: A pathogenetic connection between SLIM type I/IV and squeaking can be assumed. SLIM types showed a partly light microscopic ceramic particle-dependent, partly independent predominantly low-grade inflammation. Hemosiderin and Oil-Red positive macrophages are signs of synovial tissue damage and indicate biomechanical misload (impingement) and dysfunction as cause of the squeaking pathogenesis.

The contribution of the histopathological examination to the diagnosis of adverse local tissue reactions in arthroplasty.

The histopathological examination of the periprosthetic soft tissue and bone has contributed to the identification and description of the morphological features of adverse local tissue reactions (ALTR)/adverse reactions to metallic debris (ARMD). The need of a uniform vocabulary for all disciplines involved in the diagnosis and management of ALTR/ARMD and of clarification of the parameters used in the semi-quantitative scoring systems for their classification has been considered a pre-requisite for a meaningful interdisciplinary evaluation.This review of key terms used for ALTR/ARMD has resulted in the following outcomes: (a) pseudotumor is a descriptive term for ALTR/ARMD, classifiable in two main types according to its cellular composition defining its clinical course; (b) the substitution of the term metallosis with presence of metallic wear debris, since it cannot be used as a category of implant failure or histological diagnosis; (c) the term aseptic lymphocytic-dominated vasculitis- associated lesion (ALVAL) should be replaced due to the absence of a vasculitis with ALLTR/ALRMD for lymphocytic-predominant and AMLTR/AMRMD for macrophage-predominant reaction.This review of the histopathological classifications of ALTR/ARMD has resulted in the following outcomes: (a) distinction between cell death and tissue necrosis; (b) the association of corrosion metallic debris with adverse local lymphocytic reaction and tissue necrosis; (c) the importance of cell and particle debris for the viscosity and density of the lubricating synovial fluid; (d) a consensus classification of lymphocytic infiltrate in soft tissue and bone marrow; (e) evaluation of the macrophage infiltrate in soft tissues and bone marrow; (f) classification of macrophage induced osteolysis/aseptic loosening as a delayed type of ALTR/ARMD; (g) macrophage motility and migration as possible driving factor for osteolysis; (h) usefulness of the histopathological examination for the natural history of the adverse reactions, radiological correlation, post-marketing surveillance, and implant registries.The review of key terms used for the description and histopathological classification of ALTR/ARMD has resulted in a comprehensive, new standard for all disciplines involved in their diagnosis, clinical management, and long-term clinical follow-up. Cite this article: EFORT Open Rev 2021;6:399-419. DOI: 10.1302/2058-5241.6.210013.

Degeneration of the articular disc in the human triangular fibrocartilage complex.

INTRODUCTION: Traumatic injuries of the triangular fibrocartilage complex (TFCC) are frequent reasons for ulnar wrist pain. The assessment of the extent of articular disc (AD) degeneration is important for the differentiation of acute injuries versus chronic lesions. MATERIALS AND METHODS: The AD of the TFCC of eleven human cadaver wrists was dissected. Degeneration was analyzed according to the grading of Krenn et al. Hematoxylin-eosin was used to determine the tissue morphology. Degeneration was evaluated using the staining intensity of alcian blue, the immunohistochemistry of the proteoglycan versican and the immunoreactivity of NITEGE, an aggrecan fragment. RESULTS: The staining homogeneity of HE decreased with higher degeneration of the AD and basophilic tissue areas were more frequently seen. Two specimens were characterized as degeneration grade 1, five specimens as grade 2, and four specimens as grade 3, respectively. Staining intensity of alcian blue increased with higher degeneration grade of the specimens. Immunoreactivity for NITEGE was detected around tissue fissures and perforations as well as matrix splits. Immunoreactivity for versican was found concentrated in the tissue around matrix fissures and lesions as well as loose connective tissue at the ulnar border of the AD. Specimens with degeneration grade 2 had the strongest immunoreactivity of NITEGE and versican. Cell clusters were observed in specimens with degeneration grade 2 and 3, which were stained by alcian blue and immunoreactive for NITEGE and versican. Increasing age of the cadaver wrists correlated with a higher degree of degeneration (p < 0.0001, r = 0.68). CONCLUSIONS: The fibrocartilage of degenerated ADs contains NITEGE and versican. The amount of the immunoreactivity of these markers allows the differentiation of degenerative changes into three grades. The degeneration of the AD increases with age and emphasizes its important mechanical function.

Aggregated neutrophil extracellular traps occlude Meibomian glands during ocular surface inflammation.

PURPOSE: Obstructive Meibomian gland dysfunction (MGD) is one of the leading causes of evaporative dry eye disease. Meibomian glands at the eyelid secrete lipids that prevent evaporation of the aqueous tear film. The pathogenesis of obstructive MGD is incompletely understood to date. Herein, we aim to investigate the pathogenesis of obstructive MGD using murine and human samples with various forms of ocular surface inflammation. METHOD: The presence of Neutrophil extracellular Traps (NETs) was detected with immunofluorescence analysis of ocular surface discharge and biopsy samples from patients with blepharitis. Tear fluid from patients with MGD and blepharitis were evaluated for the presence of inflammatory mediators using bead based immunoassay. Murine model of allergic eye disease (AED) was performed to investigate the role of NETs in MG occlusion. RESULTS: we show that the ocular discharge from patients with blepharitis contains aggregated neutrophil extracellular traps (aggNETs). Furthermore, the ducts of human Meibomian glands affected by blepharitis were largely congested by aggNETs. Tear fluid from patients with MGD showed elevated neutrophil chemoattractants (C5a, IL6, IL8 and IL18). C5a and IL8 correlated with the degree of deficiency of tear fluid. In the murine model of allergic eye disease (AED), aggNETs accumulated in the MG leading to occlusion of their ducts and the retrograde pent-up of the fluid followed by acinar atrophy. Constraining aggNET formation by genetic or pharmacological inhibition of peptidyl arginine deiminase type 4 (PADI4) effectively reduced MG damage. CONCLUSION: We conclude that aggNETs occlude MG causing MGD after ocular surface inflammation.

[ARMD reaction patterns in knee arthroplasty : A novel hypothetical mechanism: hingiosis]. / ARMD-Reaktionsmuster bei Kniegelenkendoprothesen : Ein neuer hypothetischer Mechanismus: Hingiose.

BACKGROUND: There are case descriptions of pronounced peri-implant inflammatory reactions and necrosis in non-infectious knee joint replacements with metal-polyethylene pairing. OBJECTIVES: Due to the histopathological similarities to the dysfunctional metal-on-metal (MoM) hip joint replacement, MoM-like reactions in knee joint arthroplasty ("ARMD-KEP") are proposed and a histopathological comparison is made. MATERIALS AND METHODS: This analysis evaluates five cases of "ARMD-KEP" using: (1) the SLIM consensus classification, (2) the particle algorithm, (3) the CD3 focus score and (4) the AVAL score. The comparison groups consist of 11 adverse cases of MoM hip and 20 cases of knee joint arthroplasty without adverse reaction. RESULTS: The ARMD-KEP cases were identified as SLIM type VI. Their median ALVAL score was 10. The CD3 focus score confirmed an adverse reaction. Particle corrosion was found in two of five cases. CONCLUSIONS: This data indicates that, in rare cases, an adverse MoM-like reaction may be present in knee replacements, with inflammatory and immunological expression similar to that of the adverse MoM reaction in the hip. The pathomechanisms can be discussed as follows: (1) secondary metal-metal contact, (2) dysfunctional loading of the coupling mechanism and (3) corrosion of the metal components. Much like trunnionosis in the hip, the term "hingiosis" is proposed for corrosion phenomena in dysfunctional conditions of coupled knee endoprosthetic systems.

[Very rare cases of periprosthetic malignant neoplasms : Data from 4000 cases of endoprosthetic joint replacements from the histopathologic implant register]. / Nachweis hoch seltener periprothetischer maligner Neoplasien : Ergebnisse von 4000 Gelenkendoprothesen aus dem histopathologischen Implantatregister.

BACKGROUND: In 2016, the AG 11 (work group for implant-material-intolerance) of the German society for Orthopaedics and Orthopaedic Surgery (DGOOC) created a histopathologic implant register (HIR). The goal was to conduct a retrospective data analysis based on the revised SLIM-consensus-classification, which defines eight different failure mechanisms. QUESTIONS: The analysis of 4000 cases of endoprosthetic joint replacements addressed the following questions: 1. What is the frequency distribution of different SLIM-types? 2. How does durability of endoprosthetic joint replacements differ among SLIM-types? 3. What kind of periprosthetic malignant neoplasia can be detected and how often? RESULTS: SLIM-type I was diagnosed in 1577 cases (n = 1577, 39.4%), SLIM-type II in 577 cases (n = 577; 14.4%), SLIM-type III in 146 cases (n = 146; 3,7%), SLIM-type IV in 1151 cases (n = 1151; 28.8%), SLIM-type V in 361 cases (n = 361; 9.0%), SLIM-type VI in 143 cases (n = 143; 3.6%), SLIM-type VII in 42 cases (n = 42; 1.0%), and SLIM-type VIII in 3 cases (n = 3; 0.075%). There was statistical significance in implant durability between the different SLIM types. Among the different reasons for endoprosthetic joint replacement failure, non-infectious causes have the biggest share at 81%, with SLIM-type I (39.5%), and SLIM-type IV (29.4%) being the predominant SLIM types. Three cases of periprosthetic malignant neoplasia (SLIM-type VIII) were detected: one case of small B lymphocytic lymphoma/BCLL (C85.9; ICD-O: 9670/3), one case of diffuse large B­cell lymphoma/DLBCL (C83.3; ICD­O 9680/3), and one case of anaplastic large cell lymphoma (C84.7; ICD-O: 9714/3), with the latter ones being the causes for joint replacement , which indicates that malignant neoplasia is a very rare cause of endoprosthetic joint replacement (n = 2; 0.05%). DISCUSSION: These data are complete new, especially as concerns arthrofibrosis (SLIM-type V), adverse inflammatory reactions (SLIM-type VI), and the very rare cases of periprosthetic malignant neoplasia, SLIM-type VIII, as a reason for revision. Since neither the annual review (2017) of the EPRD, nor the national evaluation report (2017) of the IQTIG provide sufficient data, this indicates the relevance of the HIR of the AG 11 of the DGOOC.

Lipoma arborescens - Uncommon Diagnosis for Joint Swelling: Case Report and Review of the Literature. / Lipoma arborescens ­ Differenzialdiagnose bei Gelenkschwellung: Falldarstellung und Literaturübersicht.

INTRODUCTION: Soft tissue swelling of the knee joint can be caused by many diseases. Lipomas are one of the most reasonable differential diagnoses we have to consider. Therefore, we now present the uncommon case of a Lipoma arborescens (LA) and differentiate it from a quite similar manifesting spindle cell lipoma as follows. CASE REPORT: A 49-years old patient reports about progressive knee pain for four years and observes an increasing joint swelling. This swelling is a soft tissue, shiftable tumour, not painful. The magnetic resonance imaging (MRI) with contrast agent brings the diagnosis of an advanced osteoarthritis of the knee joint and classifies the tumour as LA. Subsequently, we treat the osteoarthritis by implanting a total knee arthroplasty with simultaneous intraoperative tumour resection performed as total synovectomy. The histopathological processing confirms the clinically and radiologically made diagnosis of LA. SUMMARY: Lipoma arborescens presents an uncommon subgroup of Lipomas, which is characterized by a slowly progressive increasing soft tissue swelling, especially around bigger human joints. Due to its intraarticular location, the LA might become clinically relevant when it reaches a certain tumour size. Looking at the diagnostics, sonography, MRI and especially the histopathological processing give the crucial results. Final proof can only be made by histopathological examination. Additionally, we have some differential diagnoses to exclude. Under these we predominantly find the spindle cell lipoma, synovial haemagioma, vascular synovial malformations and tenosynovial giant-cell tumour. Furthermore, an atypical lipomatous tumour should be excluded by FISH-analysis via determining the MDM2-Genamplification.

Neutrophil Extracellular Traps Initiate Gallstone Formation.

The presence of gallstones (cholelithiasis) is a highly prevalent and severe disease and one of the leading causes of hospital admissions worldwide. Due to its substantial health impact, we investigated the biological mechanisms that lead to the formation and growth of gallstones. We show that gallstone assembly essentially requires neutrophil extracellular traps (NETs). We found consistent evidence for the presence of NETs in human and murine gallstones and describe an immune-mediated process requiring activation of the innate immune system for the formation and growth of gallstones. Targeting NET formation via inhibition of peptidyl arginine deiminase type 4 or abrogation of reactive oxygen species (ROS) production, as well as damping of neutrophils by metoprolol, effectively inhibit gallstone formation in vivo. Our results show that after the physicochemical process of crystal formation, NETs foster their assembly into larger aggregates and finally gallstones. These insights provide a feasible therapeutic concept to prevent cholelithiasis in patients at risk.

[Histopathological Charcot score on intraoperative tissue samples from the foot : A prospective investigation]. / Histopathologischer Charcot-Score an intraoperativen Gewebeproben vom Fuß : Prospektive Untersuchung.

BACKGROUND: Charcot neuropathy is a severe complication in patients with neuropathy. Without treatment, CN can lead to a destruction and collapse of the foot, with subsequent ulceration and infection. Finding an early diagnosis is essential and is based on clinical and radiological parameters (X-ray and MRI) because there is still no specific and reliable test. GOAL: Defining and validation of a Charcot score with defined histopathologic criteria. METHOD: Tissue samples from 37 surgeries (Charcot-group n = 20, control-group n = 17) from tarsal bones were taken prospectively. A semiquantitative histopathological score based on four defined criteria of fibrous-osteo-cartilage tissues (maximum 21 points) was defined, the scoring modalities were orientated towards the evaluated HOES score (histopathological osteomyelitis evaluation score) for osteomyelitis. A comparison of the Charcot-group with diabetes mellitus and verified CN as well as neuropathy with the control group with signs of CN or neuropathy was performed. RESULTS: Significant differences could be shown between the Charcot group and the control group in the score (10.5 vs 3.5 pts, p-value <0.001). There was a high significant correlation between the established tools for diagnostics of CN and the score (p-value <0,001). CONCLUSION: The histopathological Charcot score can detect a CN with high significance and correlates with high significance to established diagnostic tools for CN. It could represent a simple and cost-effective additive tool to verify CN in uncertain cases.

General synovitis score and immunologic synovitis score reflect clinical disease activity in patients with advanced stage rheumatoid arthritis.

The purpose of this study was to investigate the relationship between clinical disease activity in patients with advanced stage rheumatoid arthritis (RA) on treatment with Disease Modifying Antirheumatic Drugs (DMARDs) and histopathological scores of synovial inflammation. To this end, synovial biopsies of 62 RA patients who underwent surgery for either synovectomy or total joint arthroplasty were assessed by a general synovitis score (GSS) and an immunologic synovitis score (IMSYC). The clinical disease activity index (CDAI) was significantly correlated with both the GSS and the IMSYC (r = 0.65, p = <0.001, r = 0.68, p = <0.001). Compared to patients with moderate and high disease activity, there was a significantly lower expression of T cell (CD3), B cell (CD20) and neutrophil (CD15) markers in synovial tissue of patients with low activity, but similar expression of the macrophage marker CD68. Subgroup analyses revealed no differences between small and large joints, seropositive and seronegative RA and patients with or without prednisolone treatment. However, we found a significantly stronger correlation of CDAI with IMSYC in patients undergoing arthroplasty (r = 0.82) than in patients undergoing synovectomy (r = 0.55). In addition, there was a stronger correlation of CDAI with GSS in patients treated with methotrexate (r = 0.86) than in patients with TNFα blockade (r = 0.55). In summary, the present study demonstrates that the histopathological scores GSS and IMSYC in general reflect clinical disease activity in patients with advanced stage rheumatoid arthritis, but that there is some heterogeneity between subgroups of patients within the cohort. In the future, molecular characterization of synovial inflammatory cell populations, including plasma cell infiltrates, will help to further defined clinically important subtypes of RA and treatment response.

Frontline Science: Aggregated neutrophil extracellular traps prevent inflammation on the neutrophil-rich ocular surface.

Eye rheum is a physiological discharge, which accumulates at the medial angle of the healthy eye soon after opening in the morning. Microscopic evaluation of eye rheum revealed the presence of viable neutrophils, bacteria, epithelial cells, and particles, aggregated by neutrophil extracellular traps. We observed that in the evening, during eye closure, high C5a recruited neutrophils to the tear film and activated them. In this hypoxic area rich in CO2 , neutrophils fight microbial aggressors by degranulation. Immediately after eye opening, the microenvironment of the ocular surface changes, the milieu gets normoxic, and loss of CO2 induces subtle alkalinization of tear film. These conditions favored the formation of neutrophil extracellular traps (NETs) that initially covers the ocular surface and tend to aggregate by eyelid blinking. These aggregated neutrophil extracellular traps (aggNETs) are known as eye rheum and contain several viable neutrophils, epithelial cells, dust particles, and crystals packed together by NETs. Similar to aggNETs induced by monosodium urate crystals, the eye rheum shows a robust proteolytic activity that degraded inflammatory mediators before clinically overt inflammation occur. Finally, the eye rheum passively floats with the tear flow to the medial angle of the eye for disposal. We conclude that the aggNETs-based eye rheum promotes cleaning of the ocular surface and ameliorates the inflammation on the neutrophil-rich ocular surfaces.

IMSYC immunologic synovitis score: A new score for synovial membrane characterization in inflammatory and non-inflammatory arthritis.

OBJECTIVES: Krenn synovitis Score has been developed by Krenn et al. in order to assess synovitis severity and is used in synovial research. Cell signature of synovial tissue can be studied using immunohistochemistry and is of interest as a biomarker for both prognosis and prediction of response to treatment. However, no synovitis score including immunohistochemistry exists yet. In order to answer this unmet need, we propose a new Immunologic Synovitis score (IMSYC) adding 5 components to the Krenn score: CD68, CD3, CD20, CD31 and Ki67 immunostaining. In this study, we aimed to validate this new IMSYC by studying its diagnostic performances in a well-defined collection of synovial samples. METHODS: Synovial samples from patients were obtained during surgical procedures. CD68, CD3, CD20, CD31 and KI67 immunohistochemistry were performed. RESULTS: In total, 77 patients were included. In total, 45 were females, mean age was 63.1 years. Forty had inflammatory arthritis, mainly rheumatoid arthritis (31/40). Non inflammatory arthritis group included 35 patients with mainly osteoarthritis. Mean Krenn score and IMSYC were significantly higher in the inflammatory group (P<0.001). ROC analysis of diagnostic performances determined the score of 13.5 out of 24 as the cut-off that gave the best ratio for discrimination between inflammatory and non-inflammatory arthritis with a sensitivity of 71.8% and specificity of 98%. CONCLUSION: We propose a new synovitis score including immunohistochemistry. This score has a better sensitivity and specificity than the Krenn score and represents a more functional synovitis evaluation. IMSYC could be further used in better categorizing synovial tissue phenotype and give a basis for tissue driven therapy.