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International audience; Relapsing polychondritis (RP) is a rare immune-mediated disease affecting cartilaginous structures. Respiratory tract manifestations are frequent and constitute a major cause of morbidity and mortality. The present review of the literature was designed to assess the efficacy of tumor necrosis factor alpha (TNF-a) inhibitors in respiratory tract involvement of RP. A MEDLINE literature search was performed from January 2000 to December 2016 to identify all studies and case reports of anti-TNF-a therapy in RP. Articles published in English or French concerning patients with respiratory tract involvement were eligible. Two authors (JB, FL) independently reviewed and extracted data concerning each patient and 2 personal cases were added. Treatment efficacy was assessed according to systemic and/or respiratory criteria. A total of 28 patients (mean age: 41.6 years; 16 females/12 males) were included in the final analysis. Anti-TNF-a therapy was associated with improved health status and respiratory symptoms in 67.8% and 60.1% of cases, respectively. These results suggest that TNF-a inhibitors could be considered for the treatment of respiratory tract involvement of RP. Abbreviations: CT = computed tomography, FDG/PET = fluorodeoxyglucose positron emission tomography, RP = relapsing polychondritis, TNF-a = tumor necrosis factor alpha.

Background Smoking is a risk factor for developing rheumatoid arthritis (RA), but the mechanism remains uncertain. We previously demonstrated that smoking lowers the T cell activation threshold by limiting programmed death protein 1 (PD-1) expression. Aim To investigate how smoking influence the levels of soluble PD-1 ligand (sPD-L1). Method Serum levels of sPD-L1 were measured in 246 RA patients and in 168 healthy subjects. The analysis was done with respect to inflammation, smoking, treatments, and autoantibody status. The effect of therapeutic TNF-inhibiting antibodies (TNFi) on sPD-L1 was studied in 16 RA patients at their first infliximab infusion. The expression of Fcγ-receptor (FcγR) subclass IIB and IIIA was analyzed with quantitative polymerase chain reaction in peripheral blood mononuclear cells (PBMCs) from 12 RA patients and 15 healthy controls, and in healthy PBMC exposed to IgG containing antibodies to cyclic citrullinated peptides (aCCP). Results The negative association between smoking and sPD-L1 in RA patients was established by multiple logistic regression (OR = 0.52, p = 0.038). Other covariates in the regression model were serum levels of IL-1β representing inflammation (OR = 1.6, p = 0.0076) and aCCP positivity (OR = 1.9, p = 0.047). First infliximab infusion repressed sPD-L1 (p = 0.023) in patients, and low levels of sPD-L1 were found in patients with early RA treated with TNFi (p = 0.018). Treatment with TNFi was associated with higher sPD-L1 in patients with long disease duration (p = 0.041) and restored levels in smokers. In vitro exposure to aCCP+ IgG suppressed sPD-L1 (p = 0.036), but aCCP+ patients with long disease duration had higher sPD-L1 (p = 0.016). High ratio of the inhibitory FcγR subclass IIB over the stimulatory IIIA resulted in low sPD-L1 release (p = 0.029). Smoking was associated with a higher FcγR IIB/IIIA ratio (p = 0.00062) and lower levels of sPD-L1 (p = 0.013). Conclusion In RA, serum sPD-L1 was related to systemic inflammation and aCCP positivity. Smoking altered the expression of FcγRs and limited sPD-L1 in RA patients, permitting inappropriate T cell responses. Differential regulation of sPD-L1 during the early and late RA may indicate transposition from acute to chronic inflammation.

Purpose To measure aggregate and particle formation in tumor necrosis factor-alpha (TNF-alpha) inhibitors etanercept, adalimumab and certolizumab pegol product samples after exposure to freezing temperature conditions similar to storage conditions previously observed in patients' homes. Methods TNF-alpha inhibitors in their original primary and secondary packaging were exposed to 32 freeze-thaw cycles (-10 degrees C for 120min/5 degrees C for 60 min) or continuous low storage temperature (-20 degrees C for 96 h) before thawing at 2-8 degrees C. Non-stressed products were used as controls. The products were analyzed by high pressure size exclusion chromatography (HP-SEC), dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), micro-flow imaging (MFI) and second derivative ultraviolet (UV) spectroscopy. Results Ten out of twenty-one stressed product samples (47.6%) showed increased particle numbers in the submicron and micron size range when compared to controls. For each product, DLS, MFI and NTA detected an increase in particle level in at least one stressed syringe (both continuous freezing and freeze-thaw), whereas HP-SEC and UV spectroscopy showed no differences between stressed and non-stressed products. Conclusion TNF-alpha inhibitors are relatively resistant to freezing temperatures similar to storage conditions previously observed in patients' homes. However, almost half of the stressed product samples showed formation of particles in the submicron and micron size range.

Reumatoidini artritis je kompleksna upalna bolest i kao takva zahtjeva kompleksan način liječenja. Napredak medicine i razvoj biološke terapije doveo je do lakšeg postizanja remisije i kontrole same bolesti. U biološkom liječenju reumatoidnog artritisa danas se upotrebaljavaju lijekovi iz skupine TNF inhibitora te IL-6 inhibitor, tocilizumab. U našem istraživanju uspoređujudi bolesnike liječene tocilizumabom i TNF inhibitorima u prvoj liniji biološkog liječenja pokazali smo da primjenom tocilizumaba brže postiže remisija, te da tijekom 18 mjeseci biološkog liječenja TNF inhibitorima češdi prekid ili mjenjanje liječenja. Ipak potrebna su i druga istraživanja koja bi mogla potvrditi ili opovrgnuti ove rezultate. Rheumatoid arthritis is complex, inflammatory disease and the main therapy has its own comlex element beacuse of that. Medical progress and development of biological therapy lead to easier way to achieve remission and compleate control of disease. Today in biological treatment of rheumatic arthritis it has been used TNF inhibtor drugs and IL-6 inhibitor, tocilizumab. Comparing patients treated with tocilizumab and TNF inhibitors as first line of biologicat therapy, in our research we have shown that application of tocilizumab has faster accomplishment of remission and within 18 months of biological treatment with TNF inhibitors there is more common abort and change of therapy. Nevertheless other research are needed to prove or deny this results.

Despite increasing numbers, ITX is still a rare form of solid organ transplantation. Due to the related immunological and surgical challenges it is only performed in specialized centres. While short-term survival has considerably improved over the last decades, long-term survival is still hampered by the high immunogenicity of the intestine, chronic rejection and the consequences of an elevated immunosuppression over time. The main focus of our studies was set on the investigation of factors that may influence long- term survival such as humoral immune responses, TNF-alpha triggered inflammatory graft injuries and eligible non-invasive rejection markers, in order to gain a better understanding on how to promote long-term graft acceptance in ITX. In two presented studies on humoral immune responses, we could show that donor-specific HLAabs have an impact on allograft rejection and may – if not treated immediately – persist in the circulating blood, causing further graft injury and possibly chronic rejection. Interestingly, we further observed, that this vascular type of rejection, may be triggered or accelerated by non-HLAabs like AT1R-Abs and ETAR-Abs. Therefore, we established a regular screening system for HLA- and non-HLA antibodies pre-and post-transplant. In addition, we introduced a consequent treatment protocol including different agents to filter antibodies or deplete antibody-secreting cells like IVIG, PP, rituximab and bortezomib to be initiated upon the first antibody detection in order to prevent their persistence and subsequent long- term graft injury. Based on an experimental rat model, we included the TNF- alpha inhibitor infliximab as an immunomodulator into our induction therapy. Infliximab was shown to attenuate IRI and to be an efficient additive to standard immunosuppression in the setting of acute rejection. Furthermore, in a clinical study infliximab was shown to sufficiently reduce the inflammatory processes observed in late allograft rejection and graft enteropathy. Whether graft enteropathy is already induced through the activated immune processes during IRI or whether it is based on similar mechanisms like NOD-2 mutations in Crohn’s disease remains to be clarified in larger prospective studies. Finally, we established a preclinical rat model for severe acute, moderate and severe chronic rejection and found that TCAIM, which has been identified as a potential marker for long-term graft acceptance in heart and kidney transplantation, may be similar beneficial in ITX. While TCAIM may potentially predict long-term graft acceptance at an early stage after transplantation, we additionally identified another non-invasive rejection marker: In the combined transplantation of a visceral graft like the intestine and a vascularized composite tissue graft like the abdominal wall we found that acute rejection manifested in the abdominal wall prior to the intestine and became visible before graft injury could spread. The underlying mechanisms of this delay have yet to be investigated in order to find out, whether remote sentinel skin grafts may become eligible also for ITX-candidates who do not require transplantation of an entire abdominal wall. In any case, this sentinel effect proved not only useful to treat rejection at an early stage, but also to make the crucial differentiation between rejection and infection. Despite several immunological challenges, ITX is no longer an experimental procedure. This is mirrored in the increasing number of transplantations and a constantly improving outcome. Nevertheless, the high immunogenicity of this organ clearly contains more immunological mechanisms and interactions than yet identified, so that translational approaches may often help to further clarify the underlying immune responses. Future studies will show whether there is still need for an overall extended immunosuppression, or whether pre-transplant risk stratifications may help to compose an individually tailored treatment regimen following the fine line between over- and under-immunosuppression., Trotz steigender Fallzahlen ist die Dünndarmtransplantation (Intestinal Transplantation - ITX) noch immer eine seltene Organtransplantation. Aufgrund der mit ihr verbundenen immunologischen und chirurgischen Herausforderungen wird sie nur in spezialisierten Zentren durchgeführt. Während sich das Kurzzeitüberleben von Patienten nach ITX in den letzten Jahrzehnten erheblich verbessert hat, ist das Langzeitüberleben aufgrund der hohen Immunogenität des Dünndarms, der möglicherweise auftretenden chronischen Rejektion und der Folgen einer kontinuierlich hohen Immunsuppression weiterhin erschwert. Um die Aussichten langfristiger Transplantatakzeptanz nach ITX zu verbessern, haben sich unsere Studien im Schwerpunkt mit Faktoren beschäftigt, die insbesondere das Langzeitüberleben beeinflussen können. Hierzu zählen humorale Immunreaktionen, TNF-alpha-induzierte entzündliche Transplantatschäden und die Identifikation geeigneter nicht-invasiver Rejektionsmarker. In zwei Studien über humorale Immunreaktionen konnten wir zeigen, dass donorspezifische HLA- Antikörper einen Einfluss auf die Rejektion des Transplantats haben und - sofern nicht sofort eine Behandlung erfolgt - im Blut überdauern, was weitere Schädigungen des Transplantats und sogar eine chronische Rejektion zur Folge haben kann. Darüber hinaus konnten wir beobachten, dass diese vaskuläre Form der Rejektion durch Non-HLA-Antikörper wie etwa AT1R-Antikörper und ETAR- Antikörper ausgelöst oder beschleunigt werden kann, sodass wir regelmäßige Screenings für HLA- und Non-HLA-Antikörper sowohl vor als auch nach der Transplantation eingeführt haben. Zusätzlich dazu haben wir ein konsequentes Therapiekonzept erstellt, welches unter anderem die Gabe verschiedener Wirkstoffe beinhaltet, um Antikörper zu filtern oder das Vorhandensein Antikörper produzierender Zellen zu verringern, wie etwa intravenöse Immunglobuline (IVIG), Plasmapherese (PP), Rituximab und Bortezomib. Um die Persistenz von Antikörpern im Blut des Patienten und damit langfristige Schädigungen des Transplantats zu verhindern, muss die Therapie umgehend nach dem ersten Nachweis von Antikörpern begonnen werden. Auf der Grundlage eines experimentellen Rattenmodells haben wir den TNF-alpha-Inhibitor Infliximab als Immunmodulator in unsere Induktionstherapie aufgenommen. Wir konnten zeigen, dass Infliximab den Ischämie-/Reperfusionsschaden im Transplantat reduziert und bei akuten Rejektionen, zusätzlich zur Standardimmunsuppression gegeben, eine effektive Therapie darstellt. Darüber hinaus konnten wir im Rahmen einer klinischen Studie zeigen, dass Infliximab auch die Entzündungsreaktionen bei der spät auftretenden Rejektion und der Transplantat-Enteropathie hinreichend reduziert. In umfangreicheren prospektiven Studien wird zu untersuchen sein, ob die Transplantat-Enteropathie bereits aufgrund der Immunaktivierung im Rahmen der Ischämie/Reperfusion hervorgerufen wird oder ob sie auf ähnlichen Mechanismen beruht, wie beispielsweise NOD-2-Mutationen bei Morbus Crohn. Wir haben außerdem ein präklinisches Rattenmodell für schwere akute, moderate und schwere chronische Rejektionen erarbeitet und dabei festgestellt, dass T-cell Activation Inhibitor Mitochon-drial (TCAIM), welches bereits bei Herz- und Nierentransplantationen als potenzieller Marker für langfristige Transplantatakzeptanz identifiziert worden ist, auch im Rahmen von ITX von Nutzen sein kann. Während also mit Hilfe von TCAIM möglicherweise bereits frühzeitig nach der Transplantation eine langfristige Akzeptanz des Transplantats vorhergesagt werden kann, haben wir darüber hinaus einen weiteren, nicht-invasiven Rejektionsmarker identifiziert: Bei der kombinierten Transplantation eines viszeralen Transplantats wie dem Dünndarm und eines vaskularisierten Gewebetransplantats (vascularised composite tissue) wie der Bauchwand stellten wir fest, dass sich eine akute Rejektion zuerst an der transplantierten Bauchwand manifestierte bevor sie am Dünndarm erkennbar wurde und so schon erkannt werden konnte, bevor sich die Rejektion im Dünndarmtransplantat ausbreitete. Die Indikatorfunktion einer gleichzeitig transplantierten Bauchwand hat sich allerdings nicht nur bei der frühzeitigen Behandlung von Rejektionen als nützlich erwiesen, sondern insbesondere auch bei der wichtigen Differenzierung zwischen Rejektion und Infektion. Die diesen Beobachtungen zugrundeliegenden Mechanismen sind noch vertieft zu untersuchen, um beurteilen zu können, ob das gleichzeitige Transplantieren vaskularisierter Vollhautlappen als Indikator einer möglichen Rejektion auch für solche ITX- Patienten in Betracht kommt, die grundsätzlich keine Transplantation der Bauchwand benötigen. Obwohl sie sich wie vor zahlreichen immunologischen Herausforderungen gegenübersieht, ist die ITX kein experimentelles Verfahren mehr. Dies spiegelt sich sowohl in der steigenden Zahl der Operationen als auch in stetig verbesserten Ergebnissen wider. Trotzdem birgt die hohe Immunogenität des Dünndarms wesentlich mehr immunologische Mechanismen und Wechselwirkungen als bisher bekannt sind, so dass translationale Ansätze möglicherweise dazu beitragen können, die zugrundeliegenden Immunreaktionen nach Transplantation weiter aufzuklären. Künftige Studien werden zeigen, ob eine umfassende Immunsuppression überhaupt noch erforderlich ist oder ob eine Risikostratifizierung bereits vor der Transplantation dabei helfen kann, für jeden Patienten ein individualisiertes Therapiekonzept zu entwickeln, das sich auf dem schmalen Grat zwischen Über- und Unterimmunsuppression bewegen kann.