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Poor Response to Eculizumab


Presentation

  • Oral Presentation Abstract #3197 Rafael Bejar, Kristen E. Stevenson, Petar Stojanov, J. Eric Zaneveld, Michal Bar-Natan, Bennett Caughey, Hui Wang, Guillermo Garcia-Manero, Hagop M.[aamds.org]
  • {[Rinsho ketsueki] The Japanese journal of clinical hematology}, year {2015}, volume {56 7}, pages { 855-60 } } Jun-ichi Nishimura Published 2015 in [Rinsho ketsueki] The Japanese journal of… DOI: 10.11406/rinketsu.56.855 This review summarizes the presentation[semanticscholar.org]
  • Abstract This review summarizes the presentation entitled "Genetic variants in C5 and poor response to eculizumab" (N Engl J Med. 2014; 370: 632-639), given at Symposium 3 entitled "Basic and clinical topics on red blood cell membrane", during the 76th[ncbi.nlm.nih.gov]
  • Disclaimer: We present factual information directly from peer reviewed medical journals. No post should be construed as medical advice and is not intended as such by the authors, editors, staff or by 2minutemedicine.com.[2minutemedicine.com]
  • They present with clinical features of unexplained hemolytic anemia like fatigue, jaundice and red colored urine.[ijcasereportsandimages.com]
Inflammation
  • In this setting, host cells become targets for repeated complement attacks, causing inflammation and cellular damage. Thus, blockage of C5 by eculizumab should be protective for host cells in aHUS.[cjasn.asnjournals.org]
  • Complement Inflamm 1991 ;8: 328 - 340 20. van den Berg CW. Purification of complement components, regulators, and receptors by classical methods. Methods Mol Biol 2000 ;150: 15 - 52 21. Zuber J, Fakhouri F, Roumenina LT, Loirat C, Fremeaux-Bacchi V.[nejm.org]
  • About Omeros Corporation Omeros is a commercial-stage biopharmaceutical company committed to discovering, developing and commercializing small-molecule and protein therapeutics for large-market as well as orphan indications targeting inflammation, complement-mediated[markets.businessinsider.com]
  • Donor-specific antibodies activate the complement in the endothelium which triggers acute rejection and facilitates the inflammation process of chronic rejection.[revistanefrologia.com]
  • The authors concluded that early initiation of eculizumab therapy in patients with progressive IgA nephropathy may have a beneficial effect by blocking complement-mediated renal inflammation.[aetna.com]
Purpura
  • Disease; ABO incompatible blood transfusions; Paroxysmal cold hemoglobinuria; Paroxysmal nocturnal hemoglobinuria; Congenital CD59 deficiency; Atypical Hemolytic Uremic Syndrome (HUS); Typical Hemolytic Uremic Syndrome (HUS); Thrombotic thrombocytopenic purpura[books.google.com]
  • George JN (2006) Thrombotic thrombocytopenic purpura. New E Journ of Med 2006; 354: 192-1935 Ruggenenti P, Noris M, Remuzzi G (2001) Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura.[omicsonline.org]
  • The ADAMTS-13 test is performed to exclude patients who have thrombotic micro-angiopathy (TMA) due to thrombocytopenic purpura (TTP).[pbs.gov.au]
  • Complications of plasma exchange in 71 consecutive patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome. Transfusion 2000; 40:896-901. 11. Parker C.[sjkdt.org]
  • Eculizumab in the treatment of refractory idiopathic thrombotic thrombocytopenic purpura. Br J Haematol, 157 (2012), pp. 772-774 [144] E. Cornec-Le Gall, Y. Delmas, L. de Parscau, L. Doucet, H. Ogier, J.F. Benoist, et al.[revistanefrologia.com]
Suggestibility
  • The in vitro binding studies suggested that the mechanism of resistance among these patients is due to a change in the C5 binding site of eculizumab.[2minutemedicine.com]
  • During the 12-week period of eculizumab treatment in the AEGIS study, two patients with PNH had markedly elevated levels of LDH that did not decrease, suggesting that eculizumab did not protect the erythrocytes in these two patients from uncontrolled[nejm.org]
  • The mechanisms of the disease remain ill-defined, but a growing body of evidence suggests that activation of the complement system may be involved.[journals.lww.com]
  • Then we proceeded with CECT scan of abdomen which was consistent with USG abdomen and was suggestive of Budd–Chiari syndrome (Figure 2A-B).[ijcasereportsandimages.com]
  • Although the transfusion requirements were not reported in the study, the authors did suggest that anemia could persist in some patients. 1 Improving QoL QoL is affected in the majority of patients with PNH with 96% complaining of fatigue and 40% having[dovepress.com]
Dark Urine
  • This prevents breakdown of red blood cells that occurs in the circulation and turns very dark urine clear almost overnight—in almost all patients.[aamds.org]
  • This can lead to low red blood cell counts (anaemia), tiredness, difficulty in functioning, pain, dark urine, kidney failure, shortness of breath and blood clots.[news-medical.net]

Workup

  • Workup for connective tissue diseases like ANA, dS-DNA and APLA were done and found to be negative. Bone marrow biopsy was done and revealed hypercellular marrow with no other abnormality.[ijcasereportsandimages.com]
  • Systematic workup also ruled out HIV infection, antiphospholipid syndrome, and occult infection. Ultrasound showed kidneys of normal size, without thrombosis of renal arteries but with global bilateral hypoperfusion.[journals.lww.com]
  • The authors concluded that given the complexity of disease pathogenesis in C3G, a patient-tailored approach including a comprehensive workup of complement abnormalities is necessary to evaluate the best treatment options.[aetna.com]

Treatment

  • In the 2 patients with a poor response, the level of hemolysis, like the LDH level, was unaffected by treatment with eculizumab, whereas in patients with a good response, hemolytic activity was completely suppressed throughout the treatment period.[nejm.org]
  • Currently, many antibody drugs are used in the world in major molecular target treatment. Eculizumab has been shown to be significantly effective except for cases in which there is a resistance mutation.[resou.osaka-u.ac.jp]
  • The levels of lactate dehydrogenase in these two patients were markedly elevated before eculizumab treatment, and were not decreased during the 12 weeks AEGIS study.[bloodjournal.org]
  • Therefore, the polymorphism in the target protein might be important to consider in patients with a poor response to the antibody-based treatments for various diseases.”[2minutemedicine.com]
  • ; an increase in serum creatinine by 25% or more compared to baseline or nadir during Soliris treatment; or, an increase in serum LDH by 25% or more over baseline or nadir during Soliris treatment.[soliris.net]

Prognosis

  • Prognosis is poor. Most patients are identified during childhood, and many do not live to adulthood. Currently, there are an estimated 140 to 200 aHUS patients in the UK.[blog.gfk.com]
  • Annual incidence of aHUS in adults and under the age of 18 are 2/1,000,000 and 3.3/1,000,000, respectively. [4], [5] Frequent relapses are seen in aHUS, and its prognosis is much worse than typical HUS. [6], [7] In 50% of children and in the majority[sjkdt.org]
  • Conversely patients with mutations in the CFH, CFI, CFB and C3 genes have a much poorer prognosis and for patients with CFH and CFI mutations, a very high chance of recurrence of disease following kidney transplant.[pbs.gov.au]
  • On admission, a high plasma creatinine level indicated a poor prognosis, and hemodialysis had to be started.[cjasn.asnjournals.org]
  • Proof of this is that it TMA worsens the prognosis and survival of the patient in all situations in which it complicates the underlying disease: post-partum, kidney transplant and HSCT, MHTN, autoimmune diseases and glomerulopathies.[revistanefrologia.com]

Etiology

  • Hetero MTHFR C677T, hetero FVL, and hetero MTHFR A1298C were the most common etiological factors being responsible for 57.1, 42.9, and 42.9% of primary BCS cases, respectively.[worldwidescience.org]
  • These investigators stated that it would be worthwhile to examine if all cases of immune complex-mediated MPGN without clear underlying etiology should undergo work-up for abnormalities in the alternate complement pathway.[aetna.com]

Epidemiology

  • Birmingham, UK: West Midlands Health Technology Assessment Collaboration, Department of Health and Epidemiology, University of Birmingham; 2008;69:1-67. Madkaikar M, Gupta M, Jijina F, Ghosh K.[aetna.com]
Sex distribution
Age distribution

Pathophysiology

  • The development of heart failure under complement inhibition and the absence of overt myocardial vascular lesions at postmortem examination suggested an independent pathophysiological process, possibly related to abnormal vasoreactivity. [4] In conclusion[journals.lww.com]
  • A recent contribution strongly underlined the possibility of recognizing a new mechanism of TA-TMA pathophysiology where the kidney seems the most common organ affected by small vessels injury [ 17 ].[omicsonline.org]
  • The pathophysiology of IgA nephropathy. J Am Soc Nephrol, 22 (2011), pp. 1795-1803 [54] J. Rojas-Rivera, G. Fernandez-Juarez, M. Praga. Rapidly progressive IgA nephropathy: a form of vasculitis or a complement-mediated disease.[revistanefrologia.com]
  • However, the abrogation of intravascular hemolysis is not the only relevant change in PNH pathophysiology associated with eculizumab treatment.[jhoonline.biomedcentral.com]
  • Recently, there have been new insights into the incidence, pathophysiology, and management of TA-TMA.[aetna.com]

Prevention

  • This mutation prevented binding andblockade by eculizumab, thereby explaining the poorresponse to the drug. However, the functional capacityof the mutant C5 to cause haemolysis was retained.[documents.tips]
  • This prevents breakdown of red blood cells that occurs in the circulation and turns very dark urine clear almost overnight—in almost all patients.[aamds.org]
  • We identified a C5 polymorphism (c.2654G A) in Japanese patients with PNH that prevents binding and blockade by eculizumab, while retaining the functional capacity of the mutant C5 to cause hemolysis.[2minutemedicine.com]
  • The increased risk of meningococcal infection seems to be due to the critical action of the terminal complement in prevention of such infections.[austinpublishinggroup.com]

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