Role Of Complement Inhibition Research Articles

A systematic review of the role of eculizumab in systemic lupus erythematosus-associated thrombotic microangiopathy

BackgroundLupus nephritis (LN) is a severe consequence of systemic lupus erythematosus (SLE) that affects approximately 40% of patients. Pathogenic immune complexes that are characteristic of LN deposit in the kidney and activate immune mediated pathways including the complement system. Complete remission rates in LN are approximately 44% highlighting the need for new treatment strategies in these patients. Eculizumab is a fully humanised IgG2/IgG4 monoclonal antibody directed at C5 and thus prevents the formation of the terminal complement complex. Eculizumab is successfully used in atypical haemolytic uraemic syndrome (aHUS) and paroxysomal nocturnal haemoglobinuria (PNH) but it is not standardly used in LN. The aim of this project was to determine whether there is any role for eculizumab as adjunctive therapy in LN.MethodsUsing a predefined search strategy on Ovid MEDLINE and EMBASE the literature was reviewed systematically to identify studies in which eculizumab had been used to treat patients with SLE. All patients were included that were treated with complement inhibitors. Favourable outcome in this study was defined as resolution of symptoms that led to treatment, discharge from hospital or recovery of renal function. Patients were excluded if there was no outcome data or if complement inhibition was unrelated to their SLE.ResultsFrom 192 abstracts screened, 14 articles were identified, involving 30 patients. All SLE patients administered eculizumab were treated for thrombotic microangiopathy (TMA) secondary to LN diagnosed either histologically (66%) or as part of a diagnosis of aHUS (73%). 93% of patients had a favourable outcome in response to eculizumab treatment, of which 46% had a favourable outcome and successfully stopped treatment without relapse in symptoms during a median follow up of 7 months. Three patients (10%) reported adverse outcomes related to eculizumab therapy.ConclusionsScientific evidence supports the involvement of complement in the pathogenesis of LN however the role of complement inhibition in clinical practice is limited to those with TMA features. This systematic review showed that in cases of LN complicated with TMA, eculizumab seems to be a very efficacious therapy. Further evidence is required to determine whether patients with refractory LN may benefit from adjunctive complement inhibition.

Updates in the management of Guillain Barre Syndrome

Barré and Strohl in 1916. Although GBS has a good prognosis (5% mortality rate), about 10% of patients experience serious disability one year after the start of neurological onset. Recent research of GBS shows that the process involves a number of subtypes with different immunological mechanism and a spectrum of clinical syndrome of acute inflammatory neuropathy. Antibodies against peripheral nerve gangliosides and their own complements are recognized as an important mechanism of nerve damage in GBS. Pharmacokinetics of intravenous immunoglobulin (IVIg) therapy and other related factors that influence prognosis has been researched. In order to investigate the possible role of complement inhibition in GBS management, new studies will be conducted. The management of GBS should be provided in appropriate hospital units, with specialist teams, intensive care and rehabilitation facilities as essential parts. This article aims to provide updated management of GBS.Citation: Imelda NC, Baktir F, Fidiana, Hidayati HB, Basuki M. Updates in the management of Guillain Barre Syndrome. Anaesth Pain & Intensive Care 2018;22 Suppl 1:S54-S57

Successful Outcome of Hyperhemolysis in Sickle Cell Disease following Multiple Lines of Treatment: The Role of Complement Inhibition

Delayed hemolytic transfusion reaction (DHTR) is a life-threatening complication in patients with sickle cell disease, characterized by difficulties in diagnosis and management. Certain reports have suggested successful salvage treatment with the terminal complement inhibitor, eculizumab. We here report evidence of complement activation and successful complement inhibition with one dose of eculizumab in an adult sickle cell disease patient presenting DHTR with hyperhemolysis. A 21-year old female sickle cell disease patient [Hb S (HBB: c.20A>T)/β-thalassemia (β-thal)] presented at our Adult Thalassaemia Unit, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece, with headaches, perioral numbness and pain in both antibrachia. The patient was admitted with the diagnosis of vaso-occlussive crisis (VOC) and treated symptomatically. On her third day of admission, due to hemoglobin (Hb) value of 6.9 g/dL with increase in reticulocytes, the patient was transfused with one unit of compatible leukodepleted red blood cells (RBC). The following day, hemolytic parameters increased, although Coombs, panel antibodies and screening tests were negative. Five days later, she again received a unit of RBCs, resulting in another increase of hemolytic parameters. During the following 2 days, there was a dramatic decrease of Hb levels to 5.4 g/dL with reticulocytes at 6.0%, negative Coombs testing and negative alloantibodies. Based on these findings, we recognized the syndrome of DHTR with hyperhemolysis. Given the lack of immediate access to other treatment, we administered intravenous rituximab, immunoglobulins and corticosteroids. As there was no response, one dose of eculizumab (900 mg) was then administered with ciprofloxacin as prophylaxis. The patient remains well 6 months post treatment.

The role of complement inhibition in transplantation and Freidreich’s ataxia: clinical features, pathogenesis and management

The role of complement inhibition in transplantation and Freidreich’s ataxia: clinical features, pathogenesis and management

The role of complement inhibition in kidney transplantation.

The complement system which belongs to the innate immune system acts both as a first line of defence against various pathogens and as a guardian of host homeostasis. The role of complement has been recently highlighted in several aspects of kidney transplantation: ischaemia-reperfusion, antibody-mediated rejection and native kidney disease recurrence. Experimental data, availability of complement-blocking molecules (mainly the anti-C5 monoclonal antibody, eculizumab) and several trials in human kidney transplant recipients has led to some areas of agreement and some disappointment. So far, eculizumab has shown great efficacy in treatment and prevention of atypical haemolytic and uraemic syndrome, some efficacy in the prevention of antibody-mediated and so far no efficacy in the prevention of delayed graft function. Among the numerous potentially available drugs potentially interfering with complement, recent focus has been made on C1 blockers in the setting of antibody-mediated rejection with promising results. Complement is now recognized as a major player in transplant immunology, several targets are going to be tested to define precisely which ones may be potentially useful in clinical practice.

A Novel Approach for Treatment of Cold Agglutinin Syndrome-Related Severe Hemolysis

Intravascular hemolysis related to cold agglutinin syndrome results from the activation of the classical complement pathway by red blood cell (RBC) surface I/i antigen bound autoantibodies. Despite built-in mechanisms that limit continued downstream complement activation, some patients may develop life-threatening intravascular hemolysis due to the formation of membrane attack complexes. We present a case of severe intravascular hemolysis due to cold agglutinin syndrome that was treated successfully using proximal complement inhibition with commercial C1 esterase inhibitor. The role of complement inhibition in controlling the intravascular hemolysis and resolving the immune dysfunction that leads to the syndrome is discussed. J Hematol. 2016;5(1):30-33 doi: http://dx.doi.org/10.14740/jh242w

An Update in Guillain-Barré Syndrome

Guillain-Barré syndrome (GBS) was first described in 1916 (Guillain G, 1916) and is approaching its 100th anniversary. Our knowledge of the syndrome has hugely expanded since that time. Once originally considered to be only demyelinating in pathology we now recognise both axonal and demyelinating subtypes. Numerous triggering or antecedent events including infections are recognised and GBS is considered an immunological response to these. GBS is now considered to be a clinical syndrome of an acute inflammatory neuropathy encompassing a number of subtypes with evidence of different immunological mechanisms. Some of these are clearly understood while others remain to be fully elucidated. Complement fixing antibodies against peripheral nerve gangliosides alone and in combination are increasingly recognised as an important mechanism of nerve damage. New antibodies against other nerve antigens such as neurofascin have been recently described. Research databases have been set up to look at factors associated with prognosis and the influence of intravenous immunoglobulin (IvIg) pharmacokinetics in therapy. Exciting new studies are in progress to examine a possible role for complement inhibition in the treatment of the syndrome.

Possible role for complement inhibition in amelioration of arthritis

Possible role for complement inhibition in amelioration of arthritis

The Role of Complement Inhibition in PNH

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, debilitating, acquired disorder that most frequently presents in early adulthood and usually continues throughout the life of a patient. PNH results in the death of approximately half of affected individuals, mainly through thrombotic complications, and until recently had no specific therapy. In 2007 eculizumab, an anti-complement antibody targeting the C5 complement component was approved for PNH by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). Eculizumab is very effective in the treatment of intravascular hemolysis and all its sequelae, which include most of the symptoms and complications of PNH. Eculizumab has revolutionized our approach to hemolytic PNH and as it markedly reduces the principal complications of PNH, namely thrombosis and renal failure, should have a significant impact on survival. However, the development of eculizumab presents new challenges in PNH, such as how to avoid complications of therapy, how to overcome some of the problems associated with treatment and who to select for treatment, as only a proportion of patients with a PNH clone will benefit. This article will review the evidence behind the use of eculizumab in PNH, the effect it will have on the complications of the disease, the most appropriate selection of patients for therapy, the optimal management and the potential complications of the therapy.