Search

Purpose Allergy against implant materials is discussed controversially and still not fully understood. Despite these controversies, a relevant number of patients receive hypoallergenic knee implants. The aim of this study was to compare a new coating system with the standard implant in total knee arthroplasty (TKA). Additionally, the influence of proinflammatory cytokines on patient-reported outcome measures (PROMs) was investigated. Methods 120 patients without known metal allergy and without previous metal implants were included. The patients were randomized to receive a coated or standard TKA of the same knee system. 105 patients completed the 5 year follow-up. Patient-reported outcome measures (PROMs) including knee function (Oxford Knee Score, OKS), quality of life (SF36) and UCLA activity scale were assessed. Additionally, several cytokines with a possible role in implant allergy were measured in patient`s serum (IL-1beta, IL-5, IL-6, IL-8, IL-10, IP-10, IFN γ, TNF α). Group comparison was performed using Mann–Whitney U test for continuous values and chi-square test for categorical values. Results There were no differences in PROMs between both groups at any follow-up. The majority of patients demonstrated no elevation of the measured blood cytokines. The blood cytokine pattern after 5 years demonstrated no differences between study groups. There was a significant association between elevated IL-8 values and worse results in the overall OKS (p = 0.041), the OKS function component (p = 0.004), the UCLA activity scale (p = 0.007) and the physical component of SF36 (p = 0.001). Conclusion There were no problems with the new coating during mid-term follow-up and no differences in PROMs between coated and standard TKA. Patients with an increased inflammatory response demonstrated worse functional results, regardless of the implant. Level of evidence I. Clinical trial registration The study protocol was registered in the US National Institutes of Health’s database (http://www.clinicaltrials.gov) registry under NCT00862511.

Skin reactions to the glucose monitoring systems Dexcom G5 and G6 have been rare. In 2019, the components of the adhesive were exchanged for better skin fixation. Since then, more and more patients experienced severe skin reactions. A few months ago, 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monoacrylate (MBPA) was identified as a new component in the adhesive of the G6 model. Furthermore, it was suspected that isobornyl acrylate (IBOA) was also a component of the exchanged adhesive.Our objective was to investigate if MBPA plays a major role in the increasing skin problems of patients without a history of IBOA-sensitization. Furthermore, our aim was to examine whether IBOA is contained in the newer model adhesive and may also contribute to allergic contact dermatitis (ACD).Five patients with a newly occurred ACD caused by the glucose monitoring system Dexcom G6 were investigated. Patch testing including MBPA in three different concentrations, as well as IBOA, were performed. Gas chromatography-mass spectrometry of the newer system Dexcom G6 was carried out.All patients were shown to be sensitized to MBPA, while MBPA 0,5% showed the strongest reaction. On the other hand, IBOA was tested negative.In our study group, MBPA was observed to be the triggering allergen of the recently changed adhesive.

Introduction Periprosthetic fibroblast-like cells (PPFs) play an important role in aseptic loosening of arthroplasties. Various studies have examined PPF behavior in monolayer culture systems. However, the periprosthetic tissue is a three-dimensional (3D) mesh, which allows the cells to interact in a multidirectional way. The expression of bone remodeling markers of fibroblast-like cells in a multilayer environment changes significantly versus monolayer cultures without the addition of particles or cytokine stimulation. Gene expression of bone remodeling markers was therefore compared in fibroblast-like cells from different origins and dermal fibroblasts under transwell culture conditions versus monolayer cultures. Methods PPFs from periprosthetic tissues (n = 12), osteoarthritic (OA) synovial fibroblast-like cells (SFs) (n = 6), and dermal fibroblasts (DFs) were cultured in monolayer (density 5.5 × 103/cm2) or multilayer cultures (density 8.5 × 105/cm2) for 10 or 21 days. Cultures were examined via histology, TRAP staining, immunohistochemistry (anti-S100a4), and quantitative real-time PCR. Results Fibroblast-like cells (PPFs/SFs) and dermal fibroblasts significantly increased the expression of RANKL and significantly decreased the expression of ALP, COL1A1, and OPG in multilayer cultures. PPFs and SFs in multilayer cultures further showed a higher expression of cathepsin K, MMP-13, and TNF-α. In multilayer PPF cultures, the mRNA level of TRAP was also found to be significantly increased. Conclusion The multilayer cultures are able to induce significant expression changes in fibroblast-like cells depending on the nature of cellular origin without the addition of any further stimulus. This system might be a useful tool to get more in vivo like results regarding fibroblast-like cell cultures.

Purpose The effect of Actovegin® was investigated on PMA- and LPS-induced human peripheral blood mononuclear cells (PBMCs). Methods PBMCs (1 × 106 cells/ml) from five blood donors (2 f, 3 m; 45–55 years) were grown in medium and exposed to Actovegin® in the presence or absence of PMA or LPS. Supernatants were collected to assess the concentration of cytokines (TNF-α, IL-1beta, IL-6 and IL-10). The reactive oxygen species (ROS) were assessed by a ROS-GloTM H2O2 assay. Results Stimulation of cells by PMA or LPS (without Actovegin®) significantly increased the secretion of IL-1beta, IL-6, IL-10 and TNF-α from PBMCs, compared to controls. Pre-treatment of cells with Actovegin® (1, 5, 25, 125 µg/ml) plus PMA significantly decreased the secretion of IL-1beta from PBMCs, compared to controls (PMA without Actovegin®). In contrast, addition of Actovegin® (1, 5, 25, 125 and 250 µg/ml) plus LPS did not alter the IL-1beta production, compared to controls (LPS without Actovegin®). TNF-α, IL-6 and IL-10 do not contribute to the reduction of inflammatory reactions with Actovegin®. Conclusions Actovegin® can reduce the PMA-induced IL-1beta release and the ROS production from PBMCs. These findings may help to explain the clinically known positive effects of Actovegin® on athletic injuries with inflammatory responses (e.g., muscle injuries, tendinopathies).

Little is known about sensitization to iron (Fe) in private, occupational, and medical settings, particulary implantology.To investigate sensitization to metals, particularly to Fe, both in pre-implant individuals with presumed metal allergy and in patients with suspected metal implant allergy. To further characterize Fe-sensitized individuals.Analysis of patch test reactions to an Fe (II) sulfate-containing metal series in 183 consecutive patients (41 pre-implant, 142 metal implant bearers). Test readings were on day (D)2, D3, and D6. Evaluation of questionnaire-aided history of metal reactivity patterns and demographics of Fe reactors.Metal reactivity in pre-implant/implant/total group was: to nickel 39%/30%/32%; to cobalt 17%/15%/15%; and to chromium 7%/13%/11%. Co-sensitizations cobalt/nickel (19/58) and cobalt/chromium (11/21) were significant at P .001; co-sensitizations Fe/nickel (4/10) and chromium/knee arthroplasty (11/73) at P = .03. Ten of 183 (5.5%) reacted to Fe (2 of 41 pre-implant patients, 8 of 142 implant bearers), with 10 reacting only on D6. Fe reactivity was highest in complicated knee arthroplasty (7/73). Further peculiarities of Fe reactors included frequent isolated Fe reactivity (6/10), occupational metal exposure (7/10), previous (par)enteral Fe substitution (6/10).The 5.5% prevalence of Fe reactions suggests a potentially underestimated role of this metal allergen in general and in implant bearers. The latter also shows a distinct metal sensitization pattern.

After decades of rising prevalence of atopic and airway-related diseases, studies showed stagnating prevalence in western industrialised countries. Objective of this study is to analyse the time trend of prevalence of atopic diseases and airway-related symptoms among Bavarian children before starting primary school.Five cross-sectional studies from 2004/2005, 2006/2007, 2012/2013, 2014/2015 and 2016/2017 took place in urban and rural regions in Bavaria, Germany. Using standardized parent questionnaires children's atopic diseases and airway-related symptoms were surveyed. Logistic regression analysis (Bonferroni correction: adjusted significance level 0.005) was performed to analyse prevalence of symptoms and diseases from 2004 to 2017 for time trends.The surveys included 27384 Bavarian children aged 5-6 years (52.6% male). In all children the calculated 12-month prevalence of symptoms '≥four episodes of wheeze' (p-value = .0880) and 'rhinoconjunctivitis' (p-value = .3994) reported by parents stagnated, whereas 'wheeze' (p-value.0001; OR = 0.97; CI = [0.96-0.98]) and 'rhinitis' (p-value = .0007; OR = 0.98; CI = [0.97-0.99]) decreased. In all children the calculated lifetime prevalence of physician-diagnosed 'asthma' (p-value = .5337), and 'hay fever' (p-value = .8206) stagnated, whereas of 'bronchitis' (p-value.0001; OR = 0.98; CI = [0.98-0.99]) decreased over time. The calculated lifetime prevalence of physician-diagnosed 'atopic eczema' (p-value = .0002; OR = 0.98; CI = [0.97-0.99]) decreased in all children, whereas the calculated 12-month prevalence of the symptom 'itchy rash' increased (p-value = .0033; OR = 1.07; CI = [1.05-1.08]) over time.Several calculated prevalence of children's atopic diseases and airway-related symptoms reported by parents stagnated in a subgroup of Bavarian children before starting primary school between 2004 and 2017. The time trend of prevalence in 'wheeze', 'rhinitis' and 'bronchitis' decreased. Prevalence of 'atopic eczema' decreased over time, whereas 'itchy rash' increased.

Objective The objective of the present study was to examine the clinical and immunological parameters in samples collected from the peri-implant crevicular fluid (PICF) of machined titanium (M) abutments compared to titanium abutments with a laser-microtextured surface (LMS) on dental implants. Material and methods A total of 40 patients with one titanium implant, half of them (n=20) provided with a M abutment (control group) and the other half (n=20) with LMS abutments (test group), were included in the study. Clinical parameters pocket probing depth (PD), full-mouth plaque score (FMPS), radiographic bone loss (RBL), clinical attachment level (CAL), mucosal recession (MR), bleeding on probing (BOP), and width of keratinized mucosa (KM) were evaluated. The peri-implant sulcus fluid was analyzed for cytokines IL-1α, IL-1β, IL-6, IL-8, and IL-10 via flow cytometry. Results Clinical evaluation demonstrated no significant difference of PD (mean LMS = 3.50 mm/SD 0.95 mm vs mean M = 3.45 mm/SD 0.76 mm (p=0.855)), MR (mean LMS = 0.30 mm/SD 0.57 mm vs mean M = 0.35 mm/SD 0.67 mm (p=0.801)), CAL (mean LMS = 3.60 mm/SD 1.14 mm vs mean M = 3.55 mm/SD 0.89 mm (p=0.878)), and KM (mean LMS = 2.03 mm/SD 1.08 mm vs mean M = 2.13 mm/SD 0.92 mm (p=0.754)) between LMS and M abutments. LMS abutments showed less BOP than M abutments (26.7% vs 30.8%), but statistically not significant (p = 0.2235). Radiographic bone loss (mean LMS = 0.22 mm/SD 0.44 mm vs mean M = 0.59 mm/SD 0.49 mm) was reduced in the test group in comparison with the control group (p=0.016). In the collected PICF, the levels of pro-inflammatory cytokines IL-1α (median LMS = 180.8 pg/ml vs M = 200.9 pg/ml (p=0.968)) and IL-1β (median LMS = 60.43 pg/ml vs M = 83.11 pg/ml (p=0.4777)) were lower, and the levels of IL-6 (median LMS = 180.8 pg/ml vs M = 200.9 pg/ml (p.7 pg/ml vs M = 178.7 pg/ml (p=0.3306)) were higher in the test group, though not significantly. The levels of anti-inflammatory IL-10 were significantly increased in the test group (LMS median = 0.555 pg/ml vs M median = 0.465 pg/ml (p=0.0365)). IL-1β showed a significant correlation to radiologic bone loss (p=0.0024). The other variables IL-1α, IL-6, IL-8, and IL-10 had no significant correlation to radiological bone loss. Conclusion Within the limitations of this study, titanium implants provided with laser-microtextured surface abutments seem to demonstrate less pro-inflammatory and more anti-inflammatory activity and to show reduced radiographic bone loss compared to machined titanium abutments. Clinical relevance The use of laser-microtextured surface abutments might have the potential to support peri-implant tissue health.

Background Antibiotic-loaded (particularly gentamicin) bone cement (BC) is widely used in total joint arthroplasty (TJA) to prevent periprosthetic infections (PPIs), but may itself cause implant failure. In light of a complete lack in literature, the objective was to assess the clinical relevance of gentamicin allergy for failure of cemented total knee arthroplasties in 25 out of 250 patients with positive patch test reactions to gentamicin and otherwise unexplained symptoms by evaluating benefits from revision with change to gentamicin-free cement. Methods 15 of these 25 patients and their treating orthopaedic surgeons agreed to a re-assessment. They were surveyed regarding interim course of therapy and symptoms, including re-assessment of the Knee Injury and Osteoarthritis Outcome Score (KOOS), and underwent follow-up clinical and radiographic investigations. The initial use of gentamicin-loaded BC was reaffirmed by review of the primary implantation operative reports and respective implant passports. Primary and follow-up KOOS scores were analyzed regarding benefits from revision surgery by comparing nine patients with revision to six without revision. Results Mean follow-up time was 38 months. The entirety of patients experienced an improvement of self-reported symptoms, with revision surgery (i.e. switching to gentamicin-free BC or uncemented total knee arthroplasty) yielding significantly greater improvement (p=0.031): the nine revised patients reported a significant symptom relief (p=0.028), contrary to the six unrevised patients (p=0.14). Interestingly, the decision to proceed with revision surgery was significantly correlated with higher symptom severity (p=0.05). Conclusion In symptomatic total knee arthroplasty with gentamicin allergy, uncemented revision arthroplasty or change to gentamicin-free BC provides significant symptom relief.

Background: Antibiotic-loaded (particularly gentamicin) bone cement (BC) is widely used in total joint arthroplasty (TJA) to prevent periprosthetic infections (PPIs), but may itself cause implant failure. In light of a complete lack in literature, the objective was to assess the clinical relevance of gentamicin allergy for failure of cemented total knee arthroplasties in 25 out of 250 patients with positive patch test reactions to gentamicin and otherwise unexplained symptoms by evaluating benefits from revision with change to gentamicin-free cement.Methods: 15 of these 25 patients and their treating orthopaedic surgeons agreed to a re-assessment. They were surveyed regarding interim course of therapy and symptoms, including re-assessment of the Knee Injury and Osteoarthritis Outcome Score (KOOS), and underwent follow-up clinical and radiographic investigations. The initial use of gentamicin-loaded BC was reaffirmed by review of the primary implantation operative reports and respective implant passports. Primary and follow-up KOOS scores were analyzed regarding benefits from revision surgery by comparing nine patients with revision to six without revision.Results: Mean follow-up time was 38 months. The entirety of patients experienced an improvement of self-reported symptoms, with revision surgery (i.e. switching to gentamicin-free BC or uncemented total knee arthroplasty) yielding significantly greater improvement (p=0.031): the nine revised patients reported a significant symptom relief (p=0.028), contrary to the six unrevised patients (p=0.14). Interestingly, the decision to proceed with revision surgery was significantly correlated with higher symptom severity (p=0.05).Conclusion: In symptomatic total knee arthroplasty with gentamicin allergy, uncemented revision arthroplasty or change to gentamicin-free BC provides significant symptom relief.

Background and purpose — Metal sensitivity might provoke complications after arthroplasty. Correspondingly, coated “hypoallergenic” implants are of interest but long-term follow-up data are missing. Thus, we assessed immunological and clinical parameters in such patients. Patients and methods — 5 years’ follow-up data were obtained from 3 centers, which used either a standard total knee replacement (TKR) or the identical implant with multilayer surface zirconium nitride based coating. Of the 196 patients (mean age 68 years (44–84), 110 females) 97 had arthroplasty with a coated surface, and 99 were treated by a standard TKR of the same type. Investigations were Knee Society Score (KSS), Knee injury and Osteoarthritis Outcome Score (KOOS), radiographic analysis, and cytokine measurement in peripheral blood. Pro- and anti-inflammatory cytokines were evaluated by cytometric beads assay and RT-PCR. Results — Survival rate (Kaplan–Meier) was 98% for coated and 97% for uncoated implants after 5 years. Mechanical axis and KSS pain score (42 vs. 41 (0–50)) were comparable. Most serum cytokine levels were comparable, but mean interleukin-8 and interleukin-10 levels were higher in the group with an uncoated implant. IL-8: 37 (SD 7.5) pg/mL vs. 1.1 (SD 4.3) (p < 0.001); IL-10: 3.6 (SD 2.5) vs. 0.3 (SD 1.8) pg/mL (p < 0.001). Interpretation — There was similar clinical outcome 5 years after standard and surface-coated TKR. In peripheral blood there was an increased pro-inflammatory status, i.e., significant elevation of IL-8 and the anti-inflammatory IL-10, after standard uncoated prosthesis. Any long-term effects of these cytokine changes are unknown.

Generalized pustular psoriasis (GPP) is the most severe psoriasis variant. Mutations in the IL-36 antagonist IL36RN, in CARD14 or AP1S3 provide genetic evidence for autoinflammatory etiology but cannot explain its pathogenesis completely. Here we demonstrate that unopposed IL-36 signaling promotes antigen-driven and likely pathogenic T-helper type 17 (Th17) responses in GPP. We observed that CD4+ T cells in blood and skin lesions of GPP patients were characterized by intense hyperproliferation, production of the GPP key mediator, IL-17A, and highly restricted TCR repertoires with identical T-cell clones in blood and skin lesions, indicating antigen-driven T-cell expansions. The clonally expanded CD4+ T cells were major producers of IL-17A. IL-36 signaling substantially enhanced TCR-mediated proliferation of CD4+ T cells. Moreover, GPP patients showed preferences for HLA-DRB1∗14, HLA-DQB1∗05, and HLA-DQB1∗03. We conclude that in GPP unopposed IL-36 signaling and certain HLA-class II alleles may cooperate in promoting antigen-driven Th17 responses, which in the obvious absence of exogenous triggers may reflect autoimmune reactions. This study reveals a pathogenic pathway where innate immune dysregulation promotes T-cell−mediated inflammation in GPP.

The effect of Actovegin® was investigated on PMA- and LPS-induced human peripheral blood mononuclear cells (PBMCs).PBMCs (1 × 10Stimulation of cells by PMA or LPS (without Actovegin®) significantly increased the secretion of IL-1beta, IL-6, IL-10 and TNF-α from PBMCs, compared to controls. Pre-treatment of cells with Actovegin® (1, 5, 25, 125 µg/ml) plus PMA significantly decreased the secretion of IL-1beta from PBMCs, compared to controls (PMA without Actovegin®). In contrast, addition of Actovegin® (1, 5, 25, 125 and 250 µg/ml) plus LPS did not alter the IL-1beta production, compared to controls (LPS without Actovegin®). TNF-α, IL-6 and IL-10 do not contribute to the reduction of inflammatory reactions with Actovegin®.Actovegin® can reduce the PMA-induced IL-1beta release and the ROS production from PBMCs. These findings may help to explain the clinically known positive effects of Actovegin® on athletic injuries with inflammatory responses (e.g., muscle injuries, tendinopathies).

Co-culture studies investigating the role of periprosthetic fibroblasts (PPFs) in inflammatory osteoclastogenesis reveal contrary results, partly showing an osteoprotective function of fibroblasts and high OPG expression in monolayer. These data disagree with molecular analyses of original periosteolytic tissues. In order to find a more reliable model, PPFs were co-cultivated with peripheral blood mononuclear cells (PBMCs) in a transwell system and compared to conventional monolayer cultures. The gene expression of key regulators of osteoclastogenesis (macrophage colony-stimulating factor (MCSF), receptor activator of NF-&kappa, B ligand (RANK-L), osteoprotegerin (OPG), and tumor necrosis factor alpha (TNF&alpha, )) as well as the ability of bone resorption were analyzed. In monolayer co-cultures, PPFs executed an osteoprotective function with high OPG-expression, low RANK-L/OPG ratios, and a resulting inhibition of osteolysis even in the presence of MCSF and RANK-L. For transwell co-cultures, profound changes in gene expression, with a more than hundredfold decrease of OPG and a significant upregulation of TNF&alpha, were observed. In conclusion, we were able to show that a change of culture conditions towards a transwell system resulted in a considerably more osteoclastogenic gene expression profile, being closer to findings in original periosteolytic tissues. This study therefore presents an interesting approach for a more reliable in vitro model to examine the role of fibroblasts in periprosthetic osteoclastogenesis in the future.

The focus of this review are allergic complications following insertion of metallic orthopedic implants. Such potential allergic reactions encompass eczema, impaired wound and fracture healing, infection-mimicking reactions, effusions, pain and loosening. Nickel, cobalt and chromium seem to be the predominant eliciting allergens. Allergy might be considered prior to planned orthopaedic surgery or in patients with complications following arthroplasty We recommend, that differential diagnoses - in particular infection -should always be excluded in cooperation with surgery collegues. The clinical work up of a patient suspected of suffering from metal implant allergy should include a combined evaluation of medical history, clinical findings, patch testing and histology In vitro testing, namely the lymphocyte transformation test (LTT), can indicate metal sensitization, but needs careful interpretation.

This study was undertaken to screen periprosthetic tissues (PPTs) under specified conditions for a series of molecular components and describe them in bone remodeling processes within aseptic loosening. PPT samples were obtained from patients undergoing revision surgery of endoprostheses (n = 24) and synovial tissues from patients with OA (control) (n = 18), patients with any form of inflammatory arthritides were excluded. Tissue samples were examined via microbiology, histology (H&E, TRAP), immunohistochemistry (CD68/anti-S100a4), quantitative real-time PCR (ALP, COL1A1, cathepsin K, M-CSF, MMP13, OPG, RANK, RANKL, TNF-α, and TRAP) and an endotoxin-assay. PPT samples contained a variety of cellular components and stained positive for TRAP (56%), CD68 (100%), and S100a4 (100%). Wear debris were found in cells staining positive for CD68 and S100a4. In PPTs significantly higher ALP, COL1A1, MMP-13, RANK, RANKL, and TRAP expression were found along with a significantly higher RANKL/OPG ratio and a significantly lower OPG expression. No significant difference was observed for M-CSF, TNF-α, cathepsin K, and endotoxin levels. In conclusion we found osteogenic proteins (ALP, COL1A1), a proteolytic enzyme (MMP-13), markers for osteoclast differentiation (RANK, RANKL), and osteoclast activity (TRAP) to be increased in PPT, whereas OPG expression decreased significantly in comparison to control. We present data about a large series of molecular components in PPT and describe novel and key findings about their expression levels in regards to aseptic implant loosening. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:248-257, 2017.

Der Lymphozytentransformationstest (LTT) dient dem Nachweis einer T‑zellularen Sensibilisierung. Sein Nutzen wurde in der Vergangenheit kontrovers diskutiert. Welche Rolle kann der LTT beim Nachweis einer Metallsensibilisierung spielen? Der Stand des Wissens zum Thema LTT wird anhand der aktuellen Literatur und auch eigener Arbeiten dargestellt. In einigen Studien konnte nachgewiesen werden, dass der LTT – gerade was Metalle betrifft – eine ausreichende Spezifitat bzw. Sensitivitat besitzt. Dabei wurden in der Vergangenheit auch verschiedene modifizierte Testprotokolle entwickelt. Er stellt einen wissenschaftlichen Ansatz dar, der jeweils von den durchfuhrenden Laboren entsprechend evaluiert werden muss. Zum Nachweis einer Metallsensibilisierung kann der LTT ein sinnvolles Hilfsmittel darstellen, v. a. bei Situationen, bei denen die Exposition nicht uber die Haut, sondern im Inneren des Korpers stattfindet (z. B. Metallimplantate).

Immobilization of proteins has been examined to improve implant surfaces. In this study, titanium surfaces were modified with nanofunctionalized denosumab (cDMAB), a human monoclonal anti-RANKL IgG. Noncoding DNA oligonucleotides (ODN) served as linker molecules between titanium and DMAB. Binding and release experiments demonstrated a high binding capacity of cDMAB and continuous release. Human peripheral mononuclear blood cells (PBMCs) were cultured in the presence of RANKL/MCSF for 28 days and differentiated into osteoclasts. Adding soluble DMAB to the medium inhibited osteoclast differentiation. On nanofunctionalized titanium specimens, the osteoclast-specific TRAP5b protein was monitored and showed a significantly decreased amount on cDMAB-titanium in PBMCs + RANKL/MCSF. PBMCs on cDMAB-titanium also changed SEM cell morphology. In conclusion, the results indicate that cDMAB reduces osteoclast formation and has the potential to reduce osteoclastogenesis on titanium surfaces.

Total knee arthroplasty is a well established treatment for degenerative joint disease, which is also performed as a treatment in younger and middle-aged patients who have a significant physical activity and high life expectancy. However, complications may occur due to biological responses to wear particles, as well as local and systemic hypersensitivity reactions triggered by metal ions and particles such as cobalt, chromium and molybdenum. The purpose of the study was to perform a highly demanding activities (HDA) knee wear simulation in order to compare the wear characteristics and metal ion release barrier function of a zirconium nitride (ZrN) coated knee implant, designed for patients with suspected metal ion hypersensitivity, against an uncoated knee implant made out of CoCrMo. The load profiles were applied for 5 million HDA cycles, which represent 15–30 years of in vivo service depending on the activity level of the patient. Results showed a significant wear rate reduction for the coated group (1.01 ± 0.29 mg/million cycles) in comparison with the uncoated group (2.89 ± 1.04 mg/million cycles). The zirconium nitride coating showed no sign of scratches nor delamination during the wear simulation, whereas the uncoated femurs showed characteristic wear scratches in the articulation areas. Furthermore, the metal ion release from the coated implants was reduced up to three orders of magnitude in comparison with the uncoated implants. These results demonstrate the efficiency of zirconium nitride coated knee implants to reduce wear as well as to substantially reduce metal ion release in the knee joint.

In patients with metal implant failure, all clinical and etiological factors need to be considered, and common causes like infection, malpositioning, or mechanical elicitors should be ruled out. Implant allergy often is a diagnosis of exclusion, supported by evaluation with allergy diagnostics. In view of the lack of consensus, this chapter reports on the different diagnostic approaches suggested by expert groups. Ideally, there should be combined evaluation including patch testing (PT), histology, and lymphocyte transformation testing (LTT). There are several suggestions/limitations. PT: pre-implant testing should be only done in patients with self-reported history of “adverse reaction” to metals—but not as a general prophetic “biocompatibility” test. While an additional late reading (day 6 or 7) increases the yield of positive test reactions, there exist no evaluated test preparations for many implant metals. Testing with metal discs is not recommended. Histology: peri-implant lymphocytic infiltration is suggestive of, but not definitive for, implant allergy. LTT: this rather scientific assay demonstrates sensitization and needs to be evaluated and interpreted with care. Accordingly, each patient should be individually evaluated.

Background Psoriasis is a systemic immune-mediated chronic inflammatory disease. In the skin, the antimicrobial proteins koebnerisin (S100A15) and psoriasin (S100A7) are overexpressed in the epidermis of psoriatic lesions and mediate inflammation as chemoattractants for immune cells. Their role for systemic inflammation in circulating leukocytes is unknown. Objective The aim of the study was to identify circulating leukocyte populations as a source of koebnerisin and psoriasin. Further, immune-stimulatory effects of these S100A proteins on circulating leukocytes were evaluated and their role as therapeutic response markers in patients with psoriasis was analyzed upon UVB treatment. Methods The expression and production of koebnerisin and psoriasin by leukocytes were assessed by quantitative real-time PCR (qRT-PCR) and immunoblotting. The S100A protein mediated regulation of proinflammatory cytokines by peripheral blood mononuclear cells (PBMCs) was measured with qRT-PCR and cytometric bead assay. Results We identified circulating leukocytes as novel sources of koebnerisin (S100A15) and psoriasin (S100A7). Circulating leukocytes (PBMCs) of patients with psoriasis produced increased levels of koebnerisin and psoriasin compared to healthy individuals. Both S100A proteins further acted as ‘alarmins’ on PBMC to induce proinflammatory cytokines implicated in the pathogenesis of psoriasis, such as IL-1β, TNF-α, IL-6 and IL-8. Koebnerisin levels were suppressed in PBMC of psoriatic patients when effectively treated with narrow-band UVB. Conclusions Data suggest that koebnerisin and psoriasin are systemic pro-inflammatory mediators and koebnerisin acts as a therapeutic response marker in psoriasis.

Summary Background Arthroplasty patients with complications may be sensitized to implant components. Objectives To quantify patch test reactions to implant materials in aseptic cemented arthroplasty patients with complications, and to evaluate the benefit of late patch test reading at D6. Methods Analyses of patch test reactions to baseline series and bone cement components and of the questionnaire-aided histories of 250 consecutive patients with suspected implant allergy were performed. Patch tests were read at D2, D3, and D6. Results There were 187 positive reactions to the 29 allergens of the baseline series, and 52 to the seven allergens of the bone cement series. Forty-nine of 250 patients reacted to the bone cement series. In contrast to ‘early allergens’ such as fragrance mix, late reading at D6 increased the number of positive reactions by 11/32 for nickel, 1/5 for cobalt, and 2/4 for chromium. With bone cement components, most reactions were to gentamicin (25 of 250 patients), and 17 of 25 appeared only at D6. Conclusion Late reading is useful for patch tests with metals and bone cement components. With only D2/D3 readings, 32 reactions to nickel, cobalt, chromium and bone cement components would have been missed. This underlines the utility of late reading in general and in complicated cemented arthroplasty patients, given the unexpectedly high number of gentamicin reactions.

Cutaneous allergic reactions to implanted metal devices, for example, orthopedic, are well reported in the literature. Also, extracutaneous complications resulting from peri-implant inflammation have been observed in association with metal allergy. Nickel, cobalt, and chromium are the three most common triggers of both cutaneous and extracutaneous allergy-related complications. However, the diagnosis of metal implant allergy remains a challenge, that is, the synopsis of excluding differential diagnoses and the combination of different allergy diagnostic tools is needed. Thus, the management of metal implant allergy is also hampered by clinical uncertainty and unresolved scientific questions.

Generalized pustular psoriasis (GPP) is the most severe psoriasis variant. Mutations in the IL-36 antagonist IL36RN, in CARD14 or AP1S3 provide genetic evidence for autoinflammatory etiology but cannot explain its pathogenesis completely. Here we demonstrate that unopposed IL-36 signaling promotes antigen-driven and likely pathogenic T-helper type 17 (Th17) responses in GPP. We observed that CD4

BACKGROUND Patch test (PT) is the gold standard to reveal nickel (Ni) allergy. In vitro tests are under discussion. We aimed to establish a cytokine based in vitro assay to detect Ni sensitization. METHODS From 15 patients with positive (13f, 42-78 years) and 15 with negative PT to Ni (controls, 3f, 31-82 years) within a consecutive patient series, peripheral blood mononuclear cells (PBMC) were obtained. Six-day stimulation with three concentrations of NiSO4 was performed. Proliferative response (uptake of tritiated thymidine) and production of the cytokines IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17A, TNF-α, IFN-γ (cytometric bead array) were assessed. RESULTS Twelve of fifteen Ni PT-positive patients also had positive LTT, and all control patients were PT and LTT negative. The mean SI differed between Ni allergics and controls (P

Immunological sensitization to metals is a potential elicitor of arthroplasty failure. Since nickel (Ni) allergy is the most frequent contact allergen for cutaneous contact allergic reactions, we assessed the relation between patch test reactivity and LTT reactivity to Ni in 2 groups of patients: eczema patients without implants (30 without and 38 with cutaneous metal intolerance, CMI, e.g., eczema to jewelry, jeans button) and arthroplasty patients (100 without and 200 with complications). After establishing the appropriate in vitro Ni test concentrations, a good correlation between patch test and LTT reaction was seen in the first patient group. It was also found that "self-reported Ni allergy," e.g., CMI was only in one-third of the patients verified to be Ni allergy. In arthroplasty patients with complications, higher patch test reactivity and LTT reactivity was found—but to some extent was also found in symptom-free arthroplasty patients. Thus identification of further characteristics is needed to reveal metal implant allergy.

Anamnese und Befund: Wir berichten uber einen 60jahrigen Mann mit Erythem und Schwellung an der Haut epifokal nach Implantation eines Cardioverter/Defibrillators (ICD). Untersuchungen: Laborchemische und mikrobielle Parameter ergaben keinen Anhalt fur das Vorliegen einer Wundinfektion. Histologisch zeigte sich das Bild einer lymphozytaren Entzundungsreaktion unter Beteiligung eosinophiler Granulozyten. Eine durchgefuhrte Epikutantestung war unauffallig. Im Lymphozytentransformationst ergaben sich Hinweise fur eine Nickelsensibilisierung. Im Schrittmacher-Eluat konnte Nickel nachgewiesen werden. Therapie und Verlauf: In Zusammenschau von zwar negativer Epikutantestung, aber histologischem Bild einer Uberempfindlichkeitsreaktion und dazu passender In-vitro-Diagnostik, interpretieren wir die aseptische „Schrittmacher-Dermatitis“ des Patienten als Kontaktallergie auf im Schrittmacher enthaltenes Nickel. Nach Schrittmacher-Explantation kam es zur vollstandigen Restitution des Hautbefundes. Folgerung: Ungewohnliche Hautreaktionen bei Tragern von Herzschrittmachern werden meist als „Schrittmacher-Dermatitis“ bezeichnet. Differentialdiagnostisch ist zunachst eine Infektion auszuschliesen. Auch eine Schrittmacher-induzierte Druckschadigung oder das klinisch meist symptomlose „Schrittmacher-Erythem mit Teleangiektasien“ (Postimplantationserythem) sollten erwogen werden. Bei Verdacht auf eine Implantatunvertraglichkeit ist eine allergologische Diagnostik indiziert. Oft ist die Schrittmacherentfernung unvermeidlich.

Hintergrund Die Implantatallergiedatenlage ist luckenhaft. Deshalb verglichen wir Allergieanamnese, Epikutantest (ECT) und Lymphozytentransformationstest (LTT) einer Patientenserie der Munchner Implantatallergiesprechstunde mit beschwerdefreien Endoprothesentragern.

Die Frage nach der Allergiediagnostik kann sich vor einer Implantation oder bei komplikationsbehafteten Implantaten ergeben. Vor Implantation wird nur bei anamnestischen Hinweisen eine mogliche Metallallergie oder Allergie auf potenzielle Knochenzementkomponenten im Epikutantest (ECT) abgeklart. Eine „prophylaktisch-prophetische“ Vertraglichkeitstestung macht keinen Sinn. Bei komplikationsbehafteten Implantaten empfehlen sich nach Ausschluss haufiger Beschwerdenursachen (speziell der Low-grade-Infekt) als Basisallergiediagnostik der ECT mit der (Ni-, Co-, Cr-Praparationen enthaltenden) Standardreihe und Knochenzementkomponenten sowie als weiterer Schritt die histologische Untersuchung von periimplantarem Gewebe. Diese kann eine lymphozytar betonte periimplantare Entzundung zeigen. Erganzende Information liefern als wissenschaftliche Methoden der Lymphozytentransformationstest (LTT) zur Metallsensibilisierung und die periimplantare molekulare Zytokinanalyse zum Entzundungsmuster.

Hypersensitivity reactions to titanium (Ti) are very rare. Thus, we assessed the proinflammatory response and also potential tolerance favoringin vitroreactivity of human blood lymphocytes and monocytes (PBMC) to Ti in healthy individuals (14 without, 6 with complication-free dental Ti implants). The proliferation index (SI) in lymphocyte transformation test (LTT) and production of cytokines linked to innate immune response (IL-1β, IL-6, and TNFα) or immune regulation (IL-10) were assessed in response to TiO2particles or Ti discs. In both groups, the Ti-LTT reactivity was not enhanced (e.g.,SI<3). The control antigen tetanus toxoid (TT) gave adequate reactivity (median SI individuals without/with implant:20.6±5.97/19.58±2.99). Individuals without implant showed higher cytokine response to Ti materials than individuals with symptom-free implants; for example, TiO2rutile particle induced increase of IL-1β70.27-fold/8.49-fold versus control medium culture. PBMC of 5 of the 6 individuals with complication-free Ti implants showed anex vivoongoing production of IL-10 (mean4.18±2.98 pg/mL)-but none of the 14 controls showed such IL-10 production. Thusin vitroIL-1β-, IL-6-, and TNF-αproduction reflects “normal” unspecific immune response to Ti. This might be reduced by production of tolerogenic IL-10 in individuals with symptom-free Ti dental implants.

In knee arthroplasty patients with complications not explained by classical mechanisms, like infection or malalignment/malposition, the role of hypersensitivity to implant materials may be questioned. In 10 such patients with and 5 without metal sensitization, a combined evaluation of periimplant histology and cytokine expression, and microbiological analysis was done. In the 10 metal allergics, outcome after revision with alternative "hypoallergenic" materials (9×titanium-based, 1×oxinium-based) was evaluated. In the metal-allergic patients, scattered, partly dense T-lymphocytes were seen in periimplant tissue and there were no signs of infection. Predominant IFN-γ expression and the improvement in the postoperative WOMAC scores (mean preoperative score, 40.4; postoperative score, 55.58) supported hypersensitivity as the symptoms elicitor.

BACKGROUND: Key factors for successful porous polyethylene (PPE) implantation are rapid vascularization and low inflammatory response. Dermal fibroblasts produce a variety of pro-angiogenic and immunmodulatory factors. OBJECTIVE: The aim of this tissue engineering study was to investigate whether coating PPE implants with dermal fibroblasts in vitro is sustainable in vivo and whether the kinetics of blood vessel ingrowth and immunological responses are hereby affected. METHODS: PPE implants were cultured with syngeneic GFP-transfected dermal fibroblasts. Cells on the biomaterial were quantified before implantation into dorsal skinfold chamber preparations of C57Bl/6 mice. Uncoated implants served as controls. Angiogenic activity and leukocyte-endothelial cell interactions were repeatedly analyzed. After 10 days, mechanical integration was measured and surviving fluorescently labeled fibroblasts were quantified. Expression of inflammatory cytokines was assessed by quantitative real time-reverse transcription PCR. RESULTS: PPE implants were successfully coated with dermal fibroblasts in vitro and 69% of the cells were still detectable at the end of observation. Angiogenic parameters increased during the observation period in both groups. IL-2, IL17A and IL-10 tended to be increased in coated implants, but did not affect leukocyte-endothelial cell interactions. CONCLUSIONS: Dermal fibroblast-coating of porous polyethylene implants is feasible and sustainable in vivo. Alone it does not improve biocompatibility but may be beneficial in combination with specific growth factor supplements.

SummaryBackground The patch test is considered to be the gold standard for diagnosing nickel (Ni) allergy. The lymphocyte transformation test (LTT) can also be used to detect Ni sensitization. However, little is known about the correlation between patch test and LTT reactions to Ni. Objective To establish and validate an LTT for Ni sensitization by comparison with patch test reaction and history. Methods Fifty individuals without self-reported ‘Ni allergy’ (controls) and 50 patients with self-reported suspicion of Ni allergy were included. A questionnaire-aided history was taken, and patch tests with at least the baseline series and LTTs with various NiSO4 dilutions were performed. Results In the patch tests, 2 of 50 controls and 18 of 50 patients with self-reported suspicion of Ni allergy showed positive reactions to Ni. In the LTTs, 2 of 50 controls and 26 of 50 patients with self-reported suspicion of Ni allergy showed positive reactions to NiSO4 2.5 × 10−5 m, and 2 of 50 controls and 17 of 50 patients with self-reported suspicion of Ni allergy showed positive reactions to NiSO4 1 × 10−5 m. Sixteen of the 18 history-positive and patch test-positive patients (i.e. 88% sensitivity) were also LTT-positive, in contrast to only 2 positive LTT reactors within the 48 PT and history negative individuals (i.e. 96% specificity). [Correction added on 16 February 2017, after first online publication: The preceding sentence has been edited for language and this has been amended in this version.] Conclusion Performing the LTT with optimized stimulating conditions might be a useful additional tool for the diagnosis of Ni allergy if non-sensitized controls are included.

Nickel, chromium, and cobalt in stainless steel and Cobalt-chrome-molybdenum (CoCrMo) alloys may induce allergy. The objectives of this study were to evaluate surface coating regarding ion release, patch test reactivity, and arthroplasty performance. Materials and methods included patch test in 31 patients with metal allergy and 30 patients with no allergy to stainless steel and CoCrMo disks that are uncoated or coated by titanium nitride/zirconium nitride (TiN/ZrN). Assessment include atomic absorption spectrometry of released nickel, cobalt, and chromium from the disks after exposure to distilled water, artificial sweat and culture medium. Results showed that both coatings reduced the nickel and chromium release from stainless steel and CoCrMo disks and mostly the cobalt release from the disks (maximally 11.755 µg/cm 2 /5 d to 1.624 by Ti-N and to 0.442 by ZrN). Six of the 31 patients with metal allergy reacted to uncoated disks, but none reacted to the coated disks. The current authors report on exemplary patients with metal allergy who had symptom relief by revision with surface-coated arthroplasty. The authors concluded that the surface coating may prevent cutaneous and peri-implant allergic reactions. [ Orthopedics . 2016; 39(3):S24–S30.]

Locally destructive soft tissue pseudotumor has been reported in patients following metal-on-metal hip resurfacing arthroplasty (MoMHRA). A delayed hypersensitivity reaction type IV to nickel (Ni), chromium (Cr), or cobalt (Co) has been suggested to play a role in its aetiology. The aim of this study was to investigate the incidence and level of metal-induced systemic hypersensitivity in patients with MoMHRA, both with and without pseudotumor by measuring lymphocyte proliferation responses to metals. A total of 92 patients were investigated: (1) MoMHRA patients with pseudotumors (nine female, one male); (2) MoMHRA patients without pseudotumors (30 female, 30 male); and (3) age-matched control subjects without metal implants (9 female, 13 male). The venous blood samples were collected for serum Ni, Co, and Cr ion level measurements and lymphocyte transformation tests (LTT). A higher incidence and level of enhanced lymphocyte reactivity only to Ni was found in patients with MoMHRA compared to the patients without MoM implants, reflecting exposure and immune reactivity. However, lymphocyte reactivity to Co, Cr, and Ni did not significantly differ in patients with pseudotumors compared to those patients without pseudotumors. This suggests that systemic hypersensitivity type IV reactions, as measured by lymphocyte proliferation response to these metals, may not be the dominant biological reaction involved in the occurrence of the soft tissue pseudotumors.

In Kasuistiken wird uber Falle von Metallimplantatallergie berichtet, wahrend grosere Untersuchungen zu Haufigkeit und Auslosern fehlen. Wir betreuen seit 5 Jahren ein Metallimplantatallergieregister, in das wir Daten aus unserer Spezialsprechstunde (Munchener Implantatsprechstunde) und aus eingesandten Dokumentationsbogen eingeben. Erfasst werden Anamnese, Klinik und Allergietestergebnisse bei Patienten mit Verdacht auf Osteosynthesen-/Endoprothesenmaterialunvertraglichkeit. Unter den derzeit 239 Patienten stehen als Beschwerden Schmerzen (68,2%), Schwellung (42,1%) und Rotung (33,5%) im Vordergrund; 29,6% der Patienten weisen eine Kontaktallergie gegen Metalle auf, 24,8% gegenuber potentiellen Knochenzementkomponenten. Sonderkonstellationen wie persistierende Entzundungsreaktionen auf Metallpartikel bei Nickel-/Kobaltallergie oder Beschwerdefreiheit nach Wechsel auf Alternativmaterialien werden erkennbar. Bei Verdacht auf Implantatunvertraglichkeit sollte nach Ausschluss von Differenzialdiagnosen wie Infekt oder mechanisches Versagen auch eine allergologische Diagnostik erfolgen, zu der ein Epikutantest unter Einschluss einer Knochenzementreihe gehort.

This study was undertaken to screen periprosthetic tissues (PPTs) under specified conditions for a series of molecular components and describe them in bone remodeling processes within aseptic loosening. PPT samples were obtained from patients undergoing revision surgery of endoprostheses (n = 24) and synovial tissues from patients with OA (control) (n = 18), patients with any form of inflammatory arthritides were excluded. Tissue samples were examined via microbiology, histology (HE, TRAP), immunohistochemistry (CD68/anti-S100a4), quantitative real-time PCR (ALP, COL1A1, cathepsin K, M-CSF, MMP13, OPG, RANK, RANKL, TNF-α, and TRAP) and an endotoxin-assay. PPT samples contained a variety of cellular components and stained positive for TRAP (56%), CD68 (100%), and S100a4 (100%). Wear debris were found in cells staining positive for CD68 and S100a4. In PPTs significantly higher ALP, COL1A1, MMP-13, RANK, RANKL, and TRAP expression were found along with a significantly higher RANKL/OPG ratio and a significantly lower OPG expression. No significant difference was observed for M-CSF, TNF-α, cathepsin K, and endotoxin levels. In conclusion we found osteogenic proteins (ALP, COL1A1), a proteolytic enzyme (MMP-13), markers for osteoclast differentiation (RANK, RANKL), and osteoclast activity (TRAP) to be increased in PPT, whereas OPG expression decreased significantly in comparison to control. We present data about a large series of molecular components in PPT and describe novel and key findings about their expression levels in regards to aseptic implant loosening. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:248-257, 2017.

We report the case of a 60-year-old man with localized erythema and edema, caused by an implanted cardioverter defibrillator (ICD).An infection could be excluded by clinical examination, para clinical parameters and clinical chemistry. The histologic examination was indicative for hypersensitivity reaction. Patch test was negative but nickel sensitization was seen by lymphocyte transformation test and nickel could be measured in the pacemaker eluate.Based on the synopsis of negative patch testing, the hypersensitivity resembling histology and the corresponding in vitro analysis, the assumed cause for the dermatitis is a contact allergy to nickel as pacemaker component. After explantation, complete restitution of the skin could be observed.Unusual skin reactions in patients with cardiac pacemakers are mostly referred to as "Pacemaker dermatitis". There are various potential causes: first, an infection needs to be excluded. Then, the possibility of both "pressure damage" caused by the pacemaker and the mostly symptom free "pacemaker erythema with telangiectasia" - synonym "post implantation erythema" - needs to be considered. When suspecting an incompatibility of the implant, further allergologic testing is required. Often, the removal of the pacemaker is inevitable.

Arthroplasty patients with complications may be sensitized to implant components.To quantify patch test reactions to implant materials in aseptic cemented arthroplasty patients with complications, and to evaluate the benefit of late patch test reading at D6.Analyses of patch test reactions to baseline series and bone cement components and of the questionnaire-aided histories of 250 consecutive patients with suspected implant allergy were performed. Patch tests were read at D2, D3, and D6.There were 187 positive reactions to the 29 allergens of the baseline series, and 52 to the seven allergens of the bone cement series. Forty-nine of 250 patients reacted to the bone cement series. In contrast to 'early allergens' such as fragrance mix, late reading at D6 increased the number of positive reactions by 11/32 for nickel, 1/5 for cobalt, and 2/4 for chromium. With bone cement components, most reactions were to gentamicin (25 of 250 patients), and 17 of 25 appeared only at D6.Late reading is useful for patch tests with metals and bone cement components. With only D2/D3 readings, 32 reactions to nickel, cobalt, chromium and bone cement components would have been missed. This underlines the utility of late reading in general and in complicated cemented arthroplasty patients, given the unexpectedly high number of gentamicin reactions.