Introduktion: Paroxysmal nokturn hemoglobinuri (PNH) är en kronisk, förvärvad, mycket sällsynt sjukdom som kännetecknas av komplementmedierad intravaskulär hemolys och är potentiellt livshotande. Sjukdomen börjar med en störning hos en hematopoetisk stamcell vilket leder till att patienter med PNH får röda blodceller som är känsliga för aktiverat komplementsystem och membranattackkomplexet (MAC). PNH kan ge symtom som exempelvis anemi, trombos och trötthet. PNH kan behandlas med komplementhämmare som förhindrar komplementaktivering och därmed komplementmedierad intravaskulär hemolys. Den först utvecklade komplementhämmaren eculizumab är en C5-hämmare som kontrollerar intravaskulär hemolys. Många patienter visar dock tecken på extravaskulär hemolys under behandling med eculizumab. Därför utvecklades det en C3-hämmare pegcetacoplan som ska även blockera extravaskulär hemolys. Syfte: Syftet med detta arbete var att studera pegcetacoplans effektivitet i komplementhämmare-naiva patienter och effektivitet i jämförelse med eculizumab vid behandling av PNH. Syftet var även att analysera skillnader i effektivitet mellan pegcetacoplan och eculizumab vid behandling av PNH. Metod: Detta examensarbete var ett litteraturarbete där sex vetenskapliga artiklar inkluderades baserat på inklusions- och exklusionskriterier. Inklusionskriterier var klinisk studie som analyserade pegcetacoplans effektivitet hos patienter med PNH. Exklusionskriterier var bland annat post hoc-analyser och fallrapporter. Artikelsökning gjordes i databasen PubMed med sökorden ”paroxysmal nocturnal hemoglobinuria pegcetacoplan”. Resultat: Pegcetacoplan-behandling ledde till och/eller bibehöll förbättringar gällande bland annat hemoglobinnivåer och LDH-nivåer hos patienter med PNH i alla sex studier. I PHAROAH och PADDOCK/PALOMINO visades en ökning av klonal distribution av typ II och typ III röda blodceller och minskning av C3 på typ II och typ III celler, vilket tolkades som att pegcetacoplan skyddar dessa celler från extravaskulär hemolys. I PRINCE var pegcetacoplan överlägsen kontrollgruppen med stödjande behandling gällande flera utfallsvariabler. I PEGASUS visade både eculizumab och pegcetacoplan effektivitet gällande bland annat LDH-nivåer men pegcetacoplan visade bättre effektivitet än eculizumab gällande hemoglobinnivåer och retikulocytantal. I uppföljningsstudien till PEGASUS och i förlängningsstudien OLE upprätthöll pegcetacoplan de tidigare uppnådda förbättringarna. Diskussion och slutsatser: Resultatet från dessa studier tyder på att pegcetacoplan är ett effektivt läkemedel med ihållande effektivitet vid behandling av PNH gällande kontroll av både intravaskulär och extravaskulär hemolys oavsett tidigare behandling med komplement-hämmare eller inte. Blockering av extravaskulär hemolys var den viktigaste skillnaden i effektivitet mellan pegcetacoplan och eculizumab. Dock skulle trovärdigheten av dessa slutsatser kunna förstärkas om det gjordes fler studier utan påverkan av Apellis Pharmaceuticals. / Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, acquired, rare disease characterized by complement-mediated intravascular hemolysis and is potentially life-threatening. The disease begins with a disorder of a hematopoietic stem cell, which results in patients with PNH having red blood cells that are sensitive to complement activation and the membrane attack complex (MAC). PNH can cause symptoms such as anemia, thrombosis and fatigue. PNH can be treated with complement inhibitors that prevent complement activation and thereby complement-mediated intravascular hemolysis. The first complement inhibitor developed, eculizumab, is a C5 inhibitor that controls intravascular hemolysis. However, many patients show signs of extravascular hemolysis during treatment with eculizumab. Therefore, a C3 inhibitor pegcetacoplan was developed that should also block extravascular hemolysis. Aim: The aim of this study was to evaluate the efficacy of pegcetacoplan in complement inhibitor-naïve patients and efficacy in comparison with eculizumab in the treatment of PNH. The aim was also to analyze differences in effectiveness between pegcetacoplan and eculizumab in the treatment of PNH. Method: This thesis was a literature review in which six scientific articles were analyzed. Inclusion criteria were clinical trial analyzing the efficacy of pegcetacoplan in patients with PNH. Exclusion criteria included post hoc analyzes and case reports. An article search was made in the PubMed database with the keywords "paroxysmal nocturnal hemoglobinuria pegcetacoplan". Results: Pegcetacoplan treatment led to and/or maintained improvements in, among other things, hemoglobin levels and LDH levels in patients with PNH in all six studies. In the PHAROAH and PADDOCK/PALOMINO studies, an increase in the clonal distribution of type II and type III red blood cells and a decrease in C3 on type II and type III cells were shown, which was interpreted as pegcetacoplan protecting these cells from extravascular hemolysis. In PRINCE, pegcetacoplan was superior to the supportive care control group on several outcome variables. In PEGASUS, both eculizumab and pegcetacoplan showed efficacy regarding, among other things, LDH levels, but pegcetacoplan showed higher efficacy than eculizumab regarding hemoglobin levels and reticulocyte count. In the follow-up study to PEGASUS and in the extension study OLE, pegcetacoplan maintained the previously achieved improvements. Discussion and conclusions: The results from these studies suggest that pegcetacoplan is an effective drug with sustained efficacy in the treatment of PNH regarding the control of both intravascular and extravascular hemolysis regardless of previous treatment with complement inhibitors or not. Blockade of extravascular hemolysis was the main difference in efficacy between pegcetacoplan and eculizumab. However, the credibility of these conclusions could be strengthened if more studies were conducted without the influence of Apellis Pharmaceuticals.

The complement system is a long and complicated event of reactions where activation leads to cleavage of different factors and ends with either inflammation or cell lysis.     Recent studies have shown that the complement system and coagulation have some elements in common. Therefore in this study it was relevant to look at the inhibition of the complement system in two different whole blood analyses of coagulation activation, thromboelastography and impedance aggregometry. Thromboelastography, or TEG®, measures the clot forming properties of whole blood and the impedance aggregometry, or Multiplate®, measures platelets’ ability to adhere and aggregate to an electrode. Four different inhibitors where used: Eculizumab, C1 inhibitor, Compstatin and OMS721, which all inhibits different parts of the complement system.     The curves from Multiplate® was presented in standard deviation and the number of reduction, while the results from TEG® was presented in before and after added inhibitor in graphs.     In conclusion, impedance aggregometry show a more specific and secure results of the inhibitors effect, which was seen by that both C1 inihibitor and Compstatin had a major influence on the area under the curve (AUC). In TEG® there were no detectable difference, which could mean TEG® is not specific enough for platelets efficiency, which is affected by the complement inhibition.

Bakgrund: Eculizumab (Solirisâ) är en monoklonal antikropp som är riktad mot C5 i komplementsystemet. Bindning av eculizumab till C5 förhindrar proteinets klyvning och därmed också aktivering. Eculizumab är godkänt för behandling av atypiskt hemolytiskt uremiskt syndrom och paroxysmal nokturn hemoglobinuri. Sedan behandlingen blivit godkänd för dessa tillstånd har även ”off-label use” vid andra tillstånd varit betydande. En tidigare studie har visat att uppemot 50 % av behandling med eculizumab är off-label use, det vill säga behandling utanför de idag godkända indikationerna. Ett av dessa tillstånd är katastrofalt antifosfolipidsyndrom (KAPS), ett mycket allvarligt tillstånd som karaktäriseras av multipla tromboser som utvecklas under kort tid i flera organ vid vilket eculizumab visat sig ha en potentiellt positiv effekt. KAPS kan uppstå om man har bakomliggande antifosfolipid syndrom (APS) och kan utlösas vid en så kallad ”second hit”, en inflammatorisk stressreaktion orsakad av exempelvis en infektion eller kirurgiskt ingrepp. Eculizumab är ett särläkemedel och är en av de dyraste läkemedelsbehandlingarna i världen. Syfte: Syftet med denna studie var att analysera fall där KAPS behandlats med eculizumab för att utvärdera om eculizumab bör vara standarbehandling vid detta tillstånd. Likheter och olikheter mellan fallen studerades för att utvärdera när det kan vara lämpligt att behandla med eculizumab. Syftet var också att utvärdera detta utifrån ett ekonomiskt perspektiv. Metod: Detta är en litteraturstudie där sökningar i PubMed gjorts efter rapporter som beskriver fall där patienter med KAPS eller som ansetts haft en risk att utveckla KAPS behandlats med eculizumab. Åtta rapporter med totalt tio fall inkluderades och analyserades. Resultat: De rapporter som analyserades visade övergripande en tydlig effekt av behandling med eculizumab. Eculizumab tolkades också i vissa fall som ett kostnadseffektivt alternativ genom bland annat förkortad intensivvård och dialysbehov. Slutsats: Eculizumab har i de fall som analyserats visat sig ha en avgörande betydelse för att reversera ett livshotande tillstånd och skulle kunna vara standardbehandling vid KAPS och förebyggande av KAPS. För att eculizumab, eller en annan komplementhämmare, ska kunna bli standardbehandling krävs ytterligare forskning på KAPS och dess relation till komplementsystemet. / Catastrophic antiphospholipidsyndrome (CAPS) is a rare but highly fatal condition characterized by thrombosis in multiple organs, often associated with a rapid progression of disease and serious complications for the patient. A rapid diagnosis and treatment is therefore a key to manage this condition. The conventional treatment, which consists of anticoagulation, steroids, plasma exchange and intravenous immunoglobulins, reduces mortality but CAPS is still associated with high mortality. To find the mechanism of how and why this condition evolves is therefore important. There has been progress to find out the pathogenesis and one clue appears to be the complement system. Therefore, a new type of treatment has been used in patients who have been diagnosed with antiphosphlipidsyndrome (APS) and have had a risk of developing CAPS, or have been diagnosed with definitive or probable CAPS. This treatment is aimed at inhibiting parts of the complement system and consists of a monoclonal antibody called eculizumab. Lately eculizumab has been used off label in patients diagnosed with CAPS and in patients that has been at risk of developing CAPS. The results of this treatment have been positive and have therefore been considered as a possible alternative for treating CAPS. The aim of this study was to evaluate if eculizumab can be an alternative to treat patients with CAPS and patients diagnosed with APS who have a risk of developing CAPS. In order to evaluate treatment with eculizumab in patients with CAPS, searches on cases were done in the database PubMed for reports of patients with CAPS or at risk of developing CAPS who have been treated with eculizumab. Eight reports with a total of ten cases were found and used in order to answer the hypothesis of this study. In the ten cases that were analyzed there was a clear connection between the treatment and the recovery. In both patients with CAPS and patients at risk of developing CAPS the treatment with eculizumab was considered of significant importance. Because of the rarity of this condition, every case makes significant impact into the understanding of this potentially fatal condition. For future new cases, the present report will stand as an important source for making decisions about treatment with eculizumab. With time and more cases with positive results eculizumab has the potential to become conventional treatment for CAPS.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22696号 / 医博第4640号 / 新制||医||1045(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 羽賀 博典, 教授 妹尾 浩, 教授 木村 剛 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

Thrombotic microangiopathies (TMA) are disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microthrombi leading to organ dysfunction. Atypical hemolytic uremic syndrome (aHUS) is a rare subtype of TMA mediated by complement dysregulation. We present a case of a 59-year-old female who presented with acute kidney injury and mild thrombocytopenia but with normal hemoglobin. We highlight the importance of prompt diagnosis of aHUS and initiating appropriate treatment with eculizumab.

Hemolytic uremic syndrome (HUS) induced by Shiga toxin-producing E. coli (STEC) is the most common causes of acute kidney injury in children. The therapy of the disease is symptomatic and the main factors leading to the development of severe course of a STEC-HUS are still unknown. In our study, we dealt with factors leading to development of a severe course of STEC-HUS in pediatric patients on both the host and pathogen side. Using retrospective analysis of the courses in children in the Czech Republic, we found that the most common cause of STEC-HUS was serotype O26 and HUS most often affected children under 3 years of age. 63,8 % required dialysis and mortality was 8.62 %. On the host side we focused on the relationship between the activation of the alternative complement pathway and the severity of the course of HUS. We found a significant difference in the level of the C3 part of complement in patients who required dialysis and patients for whom dialysis was not necessary. We also a cut-off value for the C3 part of complement and its reduction below 0.825 g / l was associated with the need for dialysis treatment and a higher incidence of extrarenal complications. Based not only on our results, it can be assumed that the therapeutic effect of complement could affect the severity of the disease....