VI. Treating C3 glomerulopathy with eculizumab
- Summarise this article in your own words.
- What are the inclusion and exclusion criteria for such treatment (you may use other sources)?
- What is the cost of treatment?
- What are the other indications eculizumb?
Summary:
-C3 glomerulopathy (C3G) is characterized by deposition of complement C3 and C3 fragments due to uncontrol activation of the alternative complement pathway.
– C3G can be subclassified as dense deposit disease (DDD) and C3 glomerulonephritis (C3GN).
-Patients present urinary protein and/or hematuria and loss of renal function leads to end-stage renal disease (ESRD).
-Eculizumab is a monoclonal humanized antibody that binds C5 and prevents assembly of the membrane attack complex (C5b-9) thereby blocking the final complement cascade.
– 7 patients with C3G (five with C3GN, two with DDD) enrolled in this study.
-It retrospective study in Germany.
-Inclusion criteria were:
1.Age > 18 years .
2. Histopathological diagnosis of C3G,
3. Treatment with eculizumab.
-ACEI or (ARB) was administered to all patients for blood pressure control
and reduction of urinary protein.
– Before eculizumab administration, all patients received meningococcal vaccinations.
-4 patients improved, and 3 patients did not respond.
– sMAC levels have been suggested as a serum marker for the activity of the
alternative complement pathway and treatment response to eculizumab.
– Early diagnosis and continuous treatment are necessary for C3G. Treatment with eculizumab may be successful in some patients.
Cost of eculizumab :
Eculizumab : 10 mg/mL= 6,742.0000 $
Eculizumab is indicated in adults and children for the treatment of:
– Paroxysmal nocturnal hemoglobinuria (PNH).
– Atypical hemolytic uremic syndrome (aHUS).
– Refractory generalized myasthenia gravis (gMG) in patients who are anti-acetylcholine receptor antibody-positive.
– Neuromyelitis optica spectrum disorder (NMOSD) in patients who are anti-aquaporin-4 (AQP4) antibody-positive with a relapsing course of the disease.
previous case reports suggest that early diagnosis and continuous treatment might be necessary to affect the outcome of C3G. Treatment with
eculizumab may be successful in some patients. Prospective long-term studies will be required to identifying parameters that predict response to therapy.
Eculizumab is used to treat atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH).[6][7][5] For people with PNH, it improves quality of life and decreases the need for blood transfusions but does not appear to affect the risk of death.[1] It does not appear to change the risk of blood clots, myelodysplastic syndrome, acute myelogenous leukemia, or aplastic anemia.[1] Eculizumab is also used to treat neuromyelitis optica spectrum disorder in adults who are anti-aquaporin-4 (AQP4) antibody positive.[2]
Eculizumab has also been explored as a treatment for CD55 deficiency, also known as CHAPLE syndrome, a rare genetic disorder of the immune system. With approval for compassionate off-label use, Kurolap and colleagues treated patients with the drug and found it to have positive clinical and laboratory outcomes over an 18-month period.[9]
Eculizumab is administered in a doctor’s office or clinic by intravenous infusion.[7]
Women should not become pregnant while taking eculizumab and pregnant women should take it only if it is clearly necessary.[7]
References:
Keating, GM (December 2013). “Eculizumab: a review of its use in atypical haemolytic uraemic syndrome”. Drugs. 73 (18): 2053–66. doi:10.1007/s40265-013-0147-7. PMID 24249647. S2CID 36682579.
^ a b c d e f g “Eculizumab label” (PDF). FDA. January 2017. For label updates, see FDA index page for BLA 125166
^ a b c d e f g h i j “Soliris – Summary of Product Characteristics”. UK Electronic Medicines Compendium. 23 March 2017. Retrieved 18 July 2017.
^ a b c d Andrew Fischer Bourgoin, Beth Nuskey (April 2015). An Outlook on Biosimilar Competition (PDF) (Report). on 13 May 2015. Retrieved 29 June 2015.
This article speaks about possible treatment of C3 glomerulopathy ,with eculizumab .
C3GN is a rare serious form of GN , that is caused by complement degradation and deposition in the glomerulus.
This is caused by continuous activation of alternative complement pathway which occurs due to genetic or acquired causes .
And because eculizumab which is anti C5 , was FDA approved in other complement mediated disease as aHUS and PNH , it is proposed that it could have a benefit in C3GNs .
This study included 7 patients , 5 with C3GN and 2 with DDD , all are treated with eculizumab
4 of which have responded to treatment and the remaining 3 didn’t responde and showed progression of KFTs .
They concluded that eculizumab could be effective only if used for life , and the long the treatment breaks the less likely to have adequat response.
Inclusion criteria include
Age above 18
Histological diagnosis of C3GN
Nephrotic range proteinuria
AKI
Prior meningococcal vaccinations
Exclusion criteria
Age below 18
Non nephrotic range proteinuria
Stable KFTs
Advanced interstitial fibrosis .
Eculizumab may cost 600,000 to 1 million dollars yearly .
Eculizumab is FDA approved in treatment of atypical HUS and PNH .
Q1: C3 glomerulopathy is caused by alternative complement pathway activation. So eculizumab as a monoclonal antibody against C5 seems to be an effective treatment. C3 glomerulopathy ( C3G) is classified as dense deposit diseases (DDD) and C3GN both with predominant C3 deposits in IF microscopy. In this study, seven patients with G3G (five with C3GN and 2 with DDD) were treated with eculizumab were enrolled and clinical characteristics and response to treatment were investigated. Mean age was 29 years and mean serum creatinine at presentation was 2 mg /dl .Mean protein/creatinine ratio was 3.6. Four patients showed significant response with improving renal function and proteinuria. One patients with recurrence of C3GN after TX showed initially good response but relapsed with stopping eculizumab with no subsequent response. Two patients showed no response. So eculizumab may be an option to treat C3G patients but needs more research.
Q2: Inclusion criteria: Disease associated with dysregulation of the alternative complement cascade such as C3G and a HUS. Exclusion criteria: 1-Immune complex mediated MPGN secondary to infections, malignancies or autoimmune disease. 2 – Patients with severe glomerular sclerosis and interstitial fibrosis. 3-old age 4 – renal impairment at presentation.
Q3: The cost of Soliris is around 6820$ for 300mg vial.
Q4: Other indications for eculizumab: 1-PNH 2-a HUS 3- AMR (under investigation) 4-Mystenia Gravis 5-Neuromyelitis optical spectrum disorder (NMOSD) 6- Degos disease (off – label) 7- Other not proven indication: dermatomyositis, MGN, prevention of MGN, shiga-toxin HUS
Treating C3 glomerulopathy with eculizumab
Summarise this article in your own words.
This article evaluated effect of treatment with eculizumab on seven patients of C3 glomerulopathy (5 with C3 glomerulonephritis and 2 with dense deposit disease). They assessed change in serum creatinine and proteinuria which was defined as positive response (decrease in serum creatinine, proteinuria, and haematuria by >30%), stable (change less than 30%) or negative response (increase in serum creatinine, proteinuria and haematuria by >30%).Effect of Eculizumab was heterogeneous (4 patients showed good response, 1 had initial positive response but relapsed on discontinuation of treatment which did not respond after re-introduction of treatment, while 2 patients had no effect. So, it is important to treat early and continuously without a long break in treatment. Eculizumab has been shown to be less effective on patients with more severe glomerular sclerosis and interstitial fibrosis.
2. What are the inclusion and exclusion criteria for such treatment (you may use other sources)?
Inclusion
· Patient with crescentic rapidly progressive disease, low chronic changes on biopsy
Exclusion
· Old age
· severe proteinuria (will increase renal excretion of eculizumab)
· renal impairment at presentation
· severe glomerular pathology – more severe glomerular sclerosis and interstitial fibrosis.
3. What is the cost of treatment?
Eculizumab costed about 6820 USD for 30 ml vial of 10 mg/ml concentration.
4. What are the other indications of eculizumab?
Eculizumab has been used in
a) Atypical HUS
b) Refractory generalized myasthenia gravis
c) Neuromyelitis Optica spectrum disorders
d) Paroxysmal Nocturnal Haemoglobinuria
Summarise this article in your own words.
C3G is a rare disease with an estimated incidence of 1–2 cases per million prognosis is poor and mostly progress to ESRD with rates of up to 50% within a decade, and recurrence rates of 45–60% in allo-grafts .
characterized by uncontrolled activation of the alternative complement pathway lead to glomerular deposition of complement C3 and C3 fragments and characteristic histo-pathological features MPGN.
Based on electron microscopy analysis, C3G can be sub-classified as dense deposit disease (DDD) and C3 glomer-ulonephritis (C3GN.
Currently, there is no established therapy althogh different types of ttt was reported such as CNIs, cyclophosphamide, MMF, Rituximab, IVIG, and plasmapheresis .
Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option
Eculizumab is a monoclonal humanized antibody that binds C5 pevent its cleavge so prevent formation of membrane attack complex (C5b-9) thereby blocking the final complement Cascade.
Methods
Seven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab. Subjects underwent biopsy before enrollment.
Outcome determined by change of kidney function, and urinary protein over time.
Treatment response varied between 2 weeks and 6 months;
Results
4 patients showed either improved or stable kidney function.
3 patients did not respond.
– These latter cases also involved patient C3GN who initially responded to eculizumab but showed disease progression in the second treatment attempt .
Conclusions:
Eculizumab may be a therapeutic option for a subset of C3G patients. The response to eculizumab is heterogeneous, and early and continuous treatment may be necessary to prevent disease progression.
What are the inclusion and exclusion criteria for such treatment (you may use other sources)?
Inclusion criteria
Age above 18 y ,histopathological evidence of C3GN or DDD and all Patient treated with eculizumab
Exclusion criteria
Patients under 18 years ,Patients with severe glomerulosclerosis and interstitial fibrosis.
What is the cost of treatment?
The cost for Soliris intravenous solution (10 mg/mL) is around $6,820 for a supply of 30 milliliters.
What are the other indications eculizumb?
Paroxysmal nocturnal hemoglobinuria
HUS
Catastrophic anti-phospholipid Ab syndrome
Neuromyelitis Optica.
Transplant TMA.
Rescue ABMR together with splenectomy.
1. Summarize this article in your own words.
C3 glomerulopathy is a rare MPGN disease DUE to uncontrolled activation of the
alternative complement pathway leading to predominantly glomerular deposition of
complement C3 and C3 fragments.
Renal prognosis is poor with very few reports of spontaneous remission and a vast
majority of progression to ESRD with rates of up to 50% within a decade, and recurrence
rates of 45–60% in allografts.
Characterize clinical and pathological features of seven patients with C3G (five with
C3GN, two with DDD), evaluate their treatment response to Eculizumab, and discuss
critical features of their individual therapeutic outcome.
Conclusions:
Suggest that early diagnosis and continuous treatment might be necessary to affect the
outcome of C3G. Treatment with Eculizumab may be successful in some patients.
Prospective long-term studies will be required to identify parameters that predict
response to therapy.
2. What are the inclusion and exclusion criteria for such treatment (you may use
other sources)?
. Inclusion criteria were age > 18 years, histopathological diagnosis of C3G, and
treatment with Eculizumab.
3. What is the cost of treatment?
Eculizumab the most expensive drug in the world, at approximately US$409,500 a year
in the United States
4. What are the other indications Eculizumab?
Paroxysmal Nocturnal Hemoglobinuria.
Hemolytic Uremic Syndrome
Myasthenia Gravis.
Neuromyelitis Optica Spectrum Disorder.
Summarise this article in your own words.
This a case series study which was conducted in one Center in Germany.
Evidence level: 4. Retrospective data collection.
C3-Glomerulopathy (C3G) is a rare disease (1-2 per Million) of poor renal outcome caused by deposition of C3 and C3 fragments within the glomeruli secondary to activation of the alternative complement pathway.
C3G presents histopathologically as MPGN, and under electron microscope it is divided into DDD (dense deposition disease) and C3GN (C3-glomeulonephritis).
C3G presents clinically with hematoproteinuria, declining GFR up to ESRD in 50% of cases within 10 years.Predictors of rapid decline in renal functions include; age>18 years, DDD, and crescentic GN.
Treatment options for C3GN include: CNIs, MMF, Rituximab, Plasma exchange and Plasma infusion.
Drugs (like Eculizumab) that inhibit complement activation could be used for treatment of C3GN.
Eculizumab is a monoclonal antibody that binds C5 and prevents assembly of MAC.
This study explains the experience and outcome of treating 7 cases with C3G, 5 of which were C3GN and 2 cases were DDD. It took place between 2013 and 2016.
Eculizumab was given according to a-HUS protocol with meningococcal vaccination beforehand, treatment duration from 3-28 months.
Results and Conclusion:
Four patients experienced improved or stable renal disease.
Improvement means >30% decrease of serum creatinine, urine proteins or hematuria after 3 months of treatment.
Stable renal disease means serum creatinine, urinary protein or hematuria +/- 30% after 3 months of treatment.
Negative response means increase of >30% of serum creatinine, urine proteins or hematuria after 3 months of treatment
One patient with recurrent C3GN had relapse after initial response.
2 patients had progression of renal function deterioration
Eculizumab can be an effective treatment option for some patients with C3G, and timing and duration of therapy are important factors for the response.
Eculizumab is not effective in severe glomerular sclerosis and interstitial fibrosis. Resuming eculizumab therapy after long break did not halt progression of the disease.
Treatment with eculizumab can be beneficial in patients with C3G.
prospective long-term studies are needed to further exploration of Eculizumab treatment.
Limitations of the study:
1- Retrospective
2- Short Duration
3- Absence of Standardized IS therapy before Eculizumab.
4- Absence of serology testing and genetic testing data.
5- Duration and course of treatment were different in the cases.
What are the inclusion and exclusion criteria for such treatment (you may use other sources)?
Inclusion criteria
1-Age above 18 y
2-histopathological evidence of C3 N or DDD without evidence of severe interstitial fibrosis and glomerulosclerosis
3-Patients accept to be vaccinated against meningococcal disease
4-failed other immunosuppressive therapy like MMF, steroids plasmapheresis in first 6 months or RPGN with crescentic lesions and requiring dialysis for first two weeks
Exclusion criteria
1-Patients under 18 years
2- Patients with severe glomerulosclerosis (>50%) and interstitial fibrosis(>25%).
What is the cost of treatment?
Half million USD/patient/Year
What are the other indications eculizumb?
PNH (FDA approved)a-HUS (FDA approved)
Refractory generalized myasthenia gravis.
Hematopoietic stem cells transplant associated TMA.
Neuromyelitis Optica.
Transplant TMA.
Rescue ABMR.
Rescue therapy in catastrophic APL.
1. This study is a case series of seven patients of C3 glomerulopathy that were treated with eculizumab. C3 glomerulopathy (C3G) is a disease characterized by uncontrolled activation of the alternative complement pathway leading to predominantly glomerular deposition of complement C3 and C3 fragments and characteristic histo-pathological features for MPGN. C3 glomerulopathy is a rare disease with very poor prognosis and the vast majority of patients progress to ESKD. So far, no effective treatment has been identified, although treatment with CNIs, cyclophosphamide, MMF, Rituximab, IVIG, and plasmapheresis was reported in small cohorts.
With the emerging role of complement in C3G, complement-modulating agents have added new therapeutic options. Eculizumab is a monoclonal humanized antibody that binds C5 and prevents assembly of the membrane attack complex (C5b-9) thereby blocking the final complement Cascade.
This study showed a heterogenous response to treatment with eculizumab.
Eculizumab is less likely to improve disease outcome in patients with more severe glomerular sclerosis and interstitial fibrosis.
Eculizumab may control hematuria with reduction in glomerular inflammation.
High range urinary protein might lead to accelerated renal elimination of eculizumab and therefore weaken treatment response to eculizumab.
Eculizumab deposition in renal tissue should be taken into consideration, although their long-term effects are not obvious.
sMAC levels are not a good parameter for monitoring of the treatment.
In conclusion, early diagnosis and continuous treatment might be necessary to affect the outcome of C3G. Eculizumab can be a successful treatment option, at least in some patients with C3 glomerulopathy.
2. Inclusion criteria were age > 18 years, histopathological diagnosis of C3G, and treatment with eculizumab.
3. Eculizumab is an expensive drug and long-term use of this drug may impose a financial burden on patients.
4. Eculizumab is used in the treatment of aHUS. In contrast to aHUS, where eculizumab represents a successful therapy, response rates in C3G patients are heterogeneous. In aHUS, complement activation occurs on endothelial surfaces, leading to endothelial damage and thrombus formation. In C3G, complement activation occurs predominantly in the fluid phase resulting in excess formation of activated C3 and cleavage products, which are deposited in the kidney and raise glomerular damage.
Summary:
This article assessed the effect of eculizumab on seven patients of C3 glomerulopathy regarding: serum creatinine and proteinuria which was defined as positive response (decrease in serum creatinine, proteinuria and hematuria by >30%) The response to eculizumab was : with 4 patients showing a positive response, 1 had initial positive response but relapsed on discontinuation of treatment while 2 patients had negative response. Eculizumab has been shown to be less effective on patients with more severe glomerulosclerosis.
The cost of Eculizumab treatment is approximately 6820 USD per vial
Other indications of eculizumb
Paroxysmal Nocturnal Hemoglobinuria
Atypical HUS
Refractory generalized myasthenia gravis
Neuromyelitis Optica spectrum disorders
1. Summarise this article in your own words
C3G is a recently described, rare disease with a poor prognosis. Characterized by uncontrolled activation of the alternative complement pathway with glomerular deposition of C3 and C3 fragments, that can occur due to inherited mutation or acquired defect . It show MPGN pattern in histopathology .New therapy with Eculizumab, is the first anti-complement therapy, which is a monoclonal antibody that blocks the final complement cascade C5. So prevents the formation of complement attack complex that attack cells causing their damage.
In the study asses eculizumab in seven patients with C3G.
study supports that eculizumab can be an effective treatment choice for some patients with C3G, and timing and duration of therapy are important factors for the response. The treatment needs to be prolonged with only short breaks, as longer breaks can cause worse results and relapse. Eculizumab is not effective in severe glomerular sclerosis and interstitial fibrosis.
The study observes an improvement in hematuria and creatinine with improvement in kidney inflammation after treatment with eculizumab..
The time to C3G recurrence in the allograft varies widely in the two reported cases (after 3 yrs and after 3 months), going with other studies. Rituximab has been treatment choice in autoantibody-positive transplant recurrent C3G, but in this study it did not affect disease progression. However, this study shows that allograft recurrent C3GN can be treated with eculizumab.
2. What are the inclusion and exclusion criteria for such treatment (you may use other sources)?
Patients more than 18 years of age
· Histopathological diagnosis of C3G
· Patient treated with eculizumab
Exclusion criteria:
Age < 18 yrs
3. What is the cost of treatment?
Very expensive cost:10 mg/ml An IV infusion vial costs $6740
4. What are the other indications eculizumb?
-Transplant thrombotic microangiopathy
-Autoimmune hemolytic anaemia
– rescue therapy for ABMR
– Paroxysmal nocturnal hemoglobinuria
1. Summarise this article in your own words.
This article evaluated effect of treatment with eculizumab on seven patients of C3 glomerulopathy (5 with C3 glomerulonephritis and 2 with dense deposit disease) with reference to change in serum creatinine and proteinuria which was defined as positive response (decrease in serum creatinine, proteinuria and hematuria by >30%), stable (change less than 30%) or negative response (increase in serum creatinine, proteinuria and hematuria by >30%). The response to eculizumab was heterogeneous with 4 patients showing a positive response, 1 had initial positive response but relapsed on discontinuation of treatment which did not respond after re-introduction of treatment, while 2 patients had negative response. So, it is important to treat early and continuously without a long break in treatment. Eculizumab has been shown to be less effective on patients with more severe glomerular sclerosis and interstitial fibrosis.
2. What are the inclusion and exclusion criteria for such treatment (you may use other sources)?
Eculizumab treatment in C3 glomerulopathy:
Inclusion:Patient with crescentic rapidly progressive disease, low chronic changes on biopsy
Exclusion: If Old age, High range proteinuria (will increase renal excretion of eculizumab), renal impairment at presentation, severe glomerular pathology – more severe glomerular sclerosis and interstitial fibrosis.
Reference:
Caravaca-Fontan F, Lucientes L, Cavero T, et al. Update on C3 glomerulopathy: A complement-mediated disease. Nephron 2020;144:272-280.
3. What is the cost of treatment?
Cost of Eculizumab treatment is approximately 6820 USD for 30 ml vial of 10 mg/ml concentration.
4. What are the other indications of eculizumb?
Eculizumab has been used in
a) Atypical HUS
b) Refractory generalized myasthenia gravis
c) Neuromyelitis Optica spectrum disorders
d) Paroxysmal Nocturnal Haemoglobinuria
Summarise this article in your own words.
This article reviewed Seven patients were given eculizumab to treat C3G (5 with C3 glomerulonephritis and 2 with DDD) . The data were retrospective. The response to treatment was assessed through reduction by more than 30% of serum creatinine urinary protein, or hematuria after 3 months of treatment. All patients received Angiotensin converting enzyme inhibitors or angiotensin receptor blockers and received meningococcal vaccinations. The eculizumab dose was 900 mg weekly for 4 weeks then 1200 mg every other week.
No serious side effects were reported. There was variation in the response to treatment.4 patients condition get better or remained stable with treatment after 2 weeks and 6 months after therapy .Only one patient got a relapse when eculizumab was stopped and did not respond after re initiation.
What are the inclusion and exclusion criteria for such treatment (you may use other sources)?
Inclusion criteria
· age > 18 years
· histopathological diagnosis of C3G
· treatment with eculizumab in the record
Exclusion criteria
· Patients with unresolved serious Neisseria meningitidis infection
· Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying Soliris treatment outweigh the risks of developing a meningococcal infection
· patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS)
What is the cost of treatment?
· Vial of Eculizumab for IV infusion (10 mg/mL) cost 6,742$
· Each patient received 8 vials
· Cost per patient is 53,936$
What are the other indications eculizumb?
· Atypical haemolytic uraemic syndrome to inhibit complement-mediated thrombotic microangiopathy
· Neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody positive.
· TMA.
· Paroxysmal nocturnal haemoglobinuria ) to reduce hemolysis
· Generalized myasthenia gravis (gMG) in patients who are anti-acetylcholine receptor (AchR) antibody positive.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125166s172lbl.pdf
1-3 years data collection of 7 patients with C3GN treated with eculizumab,900 mg weekly for 4 weeks, then 1200 mg every other week. Significant improvement or stability of renal function and proteinuria in 4 patients for 2 weeks and 6 months of treatment.
Conclusion:
Eculizumab may be a good therapeutic option in some C3GN patients with better outcome in early diagnosis and maintained treatment
2-for more favorable outcome, use of eculizumab can be implemented in subset of C3GN patients who have low chronicity ;less interstitial fibrosis and glomerulosclerosis and patients less than 18 years with more than 50 % glomerular sclerosis. Recently, eculizumab main clinical indication is in cases with crescentic rapidly progressive disease.;Caravaca-Fontan,,et al 2020,update on C3 .Glomerulopathy,Nephron,144:272-280.
3-cost of treatment: differs according to manufacturer ;annual cost is around 500000 $,otherrange of cost is monthly of 2000$.
4-Other indications :PNH ,a HUS, refractory generalized myasthenia gravis, neuromyelitis optica spectrum disorder
The study goes in harmony with other previous studies in response to treatment period between 2-6 weeks.The study had similar finding to other studies in that Eculizumab may have have a promising successful outcome in managing C3G-Patients. Break-through in the course of Eculizumab treatment is associated with relapsing C3G as showed in this study and other recent previous trials .Maintenance treatment may be essential to prevent disease progression.
Summary of the article
This is a cohort retrospective study, aimed at characterizing the clinical picture of C3G and evaluating the response to Eculizumab treatment in the study group( 7 patient with C3G, small size precluded statistical analysis ).
Treatment with Eculizumab in some patients with C3G lead to better kidney function and less urinary protein excretion with hematuria parralleled the improvement in kidney function and urinary protein. In some patients included in the study, Eculizumab showed heterogenous response as these patients didn’t respond to treatment.
The study coinciding other previous studies in treatment Response period as varied between 2-6 weeks. The study also supported other studies in that Eculizumab may have have a promising and successful outcome in managing C3G-Patients. Break-through in the course of Eculizumab treatment is associated with relapsing C3G as showed in this study and recent previous puplications. Continuous treatment may be necessary to prevent disease progression.
What are the inclusion and exclusion criteria for such treatment (you may use other sources)?
Inclusion criteria:
Exclusion criteria:
Parameters for assessing the outcome:
What is the cost of treatment?
The cost of 1 vial of eculizumab 300 mg concentrate for solution for infusion is £3150.00 excluding VAT (MIMS, November 2015).
According to the summary of product characteristics, in people weighing 40 kg or more, the usual dose given by intravenous infusion is:
In people weighing less than 40 kg, the dose is adjusted according to weight.
The cost of the 5‑week initiation phase in people weighing 40 kg or more is £50,400 in aHUS and £34,650 in PNH. The cost of 4 weeks’ treatment in the maintenance phase is £25,200 in aHUS and £18,900 in PNH. This is the cost of eculizumab only (excluding VAT) and does not include any other costs incurred, such as dilution and administration.
In aHUS and PNH, the summary of product characteristics advises that treatment is continued for the patient’s lifetime, unless discontinuation of eculizumab is clinically indicated(1)
What are the other indications of eculizumb?
Eculizumab (Soliris) is indicated in adults and children for the treatment of:
Soliris is indicated in adults for the treatment of:
Referrences
C3 glomerulopathy (C3G) is a rare disease characterized by deposition of C3 and C3 fragments in glomeruli with histopathological features of membranoproliferative GN.
classified according to EM into DDD and C3GN, has poor prognosis and most patients progress to ESRD with high rate of recurrence in allografts.
It is mainly caused by dysregulation of alternative complement cascade.
No identified effective treatment is available till now but complement modulating agents may have potential benefit in treatment.
Eculizumab is a monoclonal humanized antibody prevent formation of membrane attack complex and inhibits the final complement cascade.
7 patients aged >18 years with histopathological diagnosis of C3G and treated with eculizumab were included, data was collected from medical records.
the outcome was positive treatment reponse, stable disease or negative treatment response according to change in kidney function, proteinuria and hematuria.
The study supports that eculizumab may be treatment option for some patients with C3G
Appropriate timing and frequency of eculizumab seems to increase its effectiveness
Using eculizumab in patients with severe glomerulosclerosis and interstitial fibrosis has poor outcome
the study supported that high range of proteinuria leads to rapid elimination of eculizumab decreasing its therapeutic effect.
Limitations:
Retrospective study with no standard follow up and variable therapeutic approaches were used before eculizumab
Conclusion:
Eculizumab is effective in some patients with C3G, early diagnosis and continuous treatment affect the outcome and prospective long term studies are needed.
the drug increases the risk of meningococcal infection so patients who didn’t receive the vaccine should be excluded
patients with interstitial fibrosis and advanced glomerulosclerosis should be excluded
500,000€ per patient per year, considered one of the world’s most expensive drugs
paroxysmal nocturnal hemoglobinuria
atypical hemolytic uremic syndrome
refractory generalized myasthenia gravis
hematopoietic stem cells transplant associated TMA
Wijnsma KL, Ter Heine R, Moes DJ, Langemeijer S, Schols SE, Volokhina EB, van den Heuvel LP, Wetzels JF, van de Kar NC, Brüggemann RJ. Pharmacology, pharmacokinetics and pharmacodynamics of eculizumab, and possibilities for an individualized approach to eculizumab. Clinical pharmacokinetics. 2019 Jul 1:1-6.
VI. Treating C3 glomerulopathy with eculizumab
Summarise this article in your own words.
introduction ;
C3G and aHUS share uncontrolled activation of the alternative complement pathway and patho physiological key regulators, such as mutations in complement factors or auto antibodies. However, the two diseases display fundamental differences: In aHUS, complement activation occurs on endothelial surfaces, leading to endothelial damage and thrombus formation. In C3G, complement activation occurs predominantly in the fluid phase resulting in excess formation of activated C3 and cleavage products, which are deposited in the kidney and raise glomerular damage . Despite eculizumab-driven blockage of the terminal complement cascade, upstream C3 cleavage products may cause continuing glomerular damage. Since treatment with eculizumab in C3G patients as well as in aHUS likely needs to be maintained lifelong, long-term effects such as glomerular eculizumab deposition as seen in patient C3GN5 and a previous study have to be monitored.
The study
The key parameters to determine response to eculizumab treatment were change of serum creatinine and urinary protein over time . Seven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab. Subjects underwent biopsy before enrollment. The histopathology, clinical data, and response to eculizumab treatment were analyzed. After treatment with eculizumab, four subjects showed significantly improved or stable renal function and urinary protein. A positive response occurred between 2 weeks and 6 months after therapy initiation. One subject (with allograft recurrent C3 glomerulonephritis) initially showed a positive response, but relapsed when eculizumab was discontinued, and did not respond after re-initiation of treatment. Two subjects showed impaired renal function and increasing urinary protein despite therapy with eculizumab.
study limitations ;
the major being the retrospective character and the lack of standardized follow-up, including genetic and serologic testing. Also the multitude of therapeutic approaches prior to therapy with eculizumab both in this study and published literature complicate the interpretation of the clinical course. This is mainly due to the rarity of C3 glomerulopathy, and consequently underlines the need to prospectively collect data of patients
with C3G.
Conclusions:
Eculizumab may be a therapeutic option for a subset of C3G patients. The response to eculizumab is heterogeneous, and early as well as continuous treatment may be necessary to prevent disease progression. These findings emphasize the need for studies identifying genetic and functional complement abnormalities that may help to guide eculizumab treatment and predict response.
What are the inclusion and exclusion criteria for such treatment (you may use other sources)?
Inclusion criteria were;
age > 18 years
histopathological diagnosis of C3G
treatment with eculizumab (Soliris; Alexion Pharmaceuticals, Cheshire, CT).
exclusion criteria ;
old age
patients with more severe glomerular sclerosis and interstitial fibrosis.
renal impairment at presentation
high range urinary protein might also lead to accelerated renal elimination of eculizumab and therefore weaken treatment response to eculizumab since therapeutic drug levels might not be maintained.
What is the cost of treatment?
Eculizumab 10 mg/mL- Vial for IV infusion 6,742$
Ecluzimab 300mg/30 ml vial with dosage 900 mg weekly for 4 weeks, then 1,200 mg in at week 5, then 1,200 mg every 2 weeks thereafter.
The annual cost per Year is more than 1 is 700,000$.
What are the other indications eculizumb?
Atypical haemolytic uraemic syndrome .
Transplant TMA.
Rescue ABMR
Paroxysmal nocturnal haemoglobinuria .
Refractory generalized myasthenia gravis
Neuro myelitis optica specrum disorder .
C3 glomerulopathy is a rare disease with poor prognosis cause by dysregulation of alternative complement pathway leading to C3 deposition in the glomeruli, divided according to EM into DDD and C3GN
It could be due to an inherited or acquired mutation
Methodology
This study assessed Ecluzimab as a therapeutic option for 7 patients including 5 cases of C3GN and the other 2 with DDD within 3 successive years
Evaluating serum creat. , proteinuria and hematuria 3 months post treatment
Meningococcal vaccine was given before treatment and ACEI or ARBs was given as antiproteinuric.
Results and discussion
The included patients were either having denovo C3 golomeruolpathy or relapsing after immunosuppressive therapy with atypical history, 4 cases showed either improved or stable creat., and the other 3 did not respond with varying response.
Although being a small study it indicated that ecluzimab can be a successful treatment option for those patients if given in the suitable time and for a suitable duration.
In agreement with other studies that showed that treatment breaks can result in relapse and worsening of the glomerular sclerosis and interstitial fibrosis.
Accumulation of C3 cleavage products after ecluzimab treatment can increase glomerular damage justifying the variable response to ecluzimab between C3 nephropathy and a HUS.
The study draw backs include being retrospective on small number of cases due to disease rarity as well as variability of therapy protocols given to the cases before ecluzimab was given leading to lack of standarisation also follow up for longer periods will be needed with genetic and serological testing.
Conclusion
Ecluzimab can be a treatment option along withearly diagnosis and intervention for C3 glomeruoloapthy.
Inclusion criteria
Exclusion criteria
Ecluzimab 300mg/30 ml vial with dosage 900 mg weekly for 4 weeks, then 1,200 mg in at week 5, then 1,200 mg every 2 weeks thereafter sonannual cost inYear 1 is 728,136$andYear 2 is 701,168$
in adults and children for the treatment of:
– Paroxysmal nocturnal haemoglobinuria (PNH).
– Atypical haemolytic uremic syndrome (aHUS)
in adults for the treatment of:
– Refractory generalized myasthenia gravis (gMG)
– Neuromyelitis optica spectrum disorder (NMOSD)
Reference
Gerald B. Appel, ClinicalTrials.gov Identifier,2019
C3 glomerulopathy is IF and EM based description of a disease caused by uncontrolled activation of the alternative complement pathway leading to deposition of complement C3 and C3 fragments in the glomerulus.
C3G can be subclassified as dense deposit disease (DDD) and C3 glomerulonephritis (C3GN).
The disease is extremely rare with incidence of 1–2 cases per million, Renal prognosis is poor. Dysregulation of the alternative complement cascade plays a primary role in the pathogenesis of C3G.
Uncontrolled activation of the alternative complement pathway is driven by inherited mutations in complement proteins and cofactors , or by acquired defects So far, no generally effective treatment has been identified.
Inclusion criteria were age > 18 years, histopathological diagnosis of C3G, and treatment with eculizumab.
Exclusion criteria: Patients with severe glomerulosclerosis and interstitial fibrosis(> 50% glomerular sclerosis and > 25% IF/TA)
Seven patients (five with C3GN, two with DDD) treated with eculizumab between 2013 and 2016 for C3G were enrolled in the study.
*Positive treatment response was defined as >30% decrease of serum creatinine, urinary protein, or hematuria after 3 months of treatment.
*Stable disease was defined as serum creatinine, urinary protein, or hematuria between ±30% after 3 months of treatment.
*Negative treatment response was defined as increase >30% of serum creatinine, urinary protein, or hematuria after 3 months of treatment.
-All patients received meningococcal vaccinations before eculizumab administration.
-Eculizumab was given according to aHUS standard treatment protocol.
-Eculizumab was administered weekly at a dose of 900 mg (week 1–4), followed by eculizumab every other week at a dose of 1200 mg (from week 5).
Results
The report includes five patients with C3GN and two patients with DDD.
4 out of 7 patients had improvement or stabilization of kidney function and proteinuria+ hematuria. The response happened between 2 weeks and 6 months of treatment.
One patient with recurrent C3GN had relapse after initial response.
2 patients had progression of renal function deterioration
In conclusion, Treatment with eculizumab may be successful in some patients.
Cost of the drug
Eculizumab 10 mg/mL- Vial for IV infusion 6,742$
900 mg weekly for first 4 weeks, followed by 1,200 mg for fifth dose 1 week later, then 1,200 mg every 2 weeks thereafter. SO THE COST FOR ONE COURSE IS EXTREMLY HIGH WITHOUT EVIDENCE BASED BENEFIT.
What are the other indications eculizumb
PNH, aHUS, ABMR refractory to conventional treatment,
Rescue therapy in catastrophic APL
summary:
On eculizumab treated seven C3G patients (5 glomerulonephrites, 2 dense deposit diseases). Before enrolling, subjects had biopsies. Histopathology, clinical data, and eculizumab response were studied. The result was determined by changes in serum creatinine and urine protein.
Four patients had an improved or steady renal function and urine protein after receiving eculizumab. A favourable response occurred 2 weeks to 6 months after starting treatment. One patient (with allograft recurrent C3 glomerulonephritis) responded initially but relapsed after eculizumab was stopped, and did not react when re-started. Eculizumab did not help two patients’ renal function or urine protein levels.
Eculizumab may be useful for a fraction of C3G patients. Because eculizumab has a variable response, early and ongoing therapy may be required to slow disease progression. In order to guide eculizumab therapy and predict response, researchers must detect genetic and functional complement abnormalities.
inclusion: Patients over 18 years of age with histopathological diagnosis of C3G treated with eculizumab.
Exceptions:
<18 years
cost:10 mg/ml An IV infusion vial costs $6740
Indication:
1-transplant thrombotic microangiopathy
2- atypical hemolytic uremic
3-Autoimmune hemolytic anaemia
4- rescue therapy for ABMR
5- Paroxysmal nocturnal hemoglobinuria
Summary:
Case series from single center in Germany, level 4 of evidence
C3 nephropathy rare type of glomerulonephritis, both DDD and C3 nephritis results from abnormal regulation in alternative complement pathway, diagnosis of c3 nephritis by isolated c3 deposits in IF, c3 nephritis carry poor prognosis and can progress to ESRD with high rate of relapse post transplantation.
In this case series described the patient’s characteristic by retrospective data collection including all adults > 18 years with pathological diagnosis of C3 nephritis with variables complement activity of 5 cases with C3 nephropathy and two cases of DDD , , this study aim to determine treatment outcome upon follow up with the eculizumab humanized monoclonal AB which have been used as second line in all reported cases after failed other different immunosuppressive medications like MMF , tacrolimus plasmapheresis , cyclosporine , cyclophosphamide , the eculizumab treatment was given according to AHUS protocol with the first 4 doses as induction of 900mg /week for 4-5 weeks followed by 1200mg every two weeks with meningococcal vaccination cover with in two weeks prior to treatment and assessing the response by monitoring the change in RFT and proteinuria reduction, in 3 months and upon last follow up .
Definition of treatment response or failure by using the cutoff of 30% change in creatinine and proteinuria
Eculizumab Treatment duration variables from 3-28 months
This study confirms the variable response to eculizumab therapy, 4 cases responded with stable RFT while the poor response and relapse more in cases with heavy proteinuria and more chronicity index in the biopsy 50% glomerular sclerosis and moderate IFTA 25-30% .the timing and duration of treatmnet can determine the effectivness of this drug.
C3 nephritis treatment with eculizumab based on Low quality of evidence from case reports or series , no RCT as its rare disease and eculuzimab very costly ,even the diagnosis is challenged and masked with other Complement – mediated or immune complex mediated nephritis, monoclonal immunoglobulin nephropathy that’s why we should screen all adults with c3 Nephropathy by serum – electrophoresis, this report has some adults with no records about the monoclonal screening like second DDD case at the age of 50s ?
eculizumab considered as second line therapy if no response to the MMF , steroid after 6 months with persistent or worsening proteinuria of more than 1.5gm with progressive kidney dysfunction as rescue therapy and total duration of treatment still uncertain some used for 3 months and stop if no response but in case of response with stable renal function and improved proteinuria the total duration still uncertain may continue up to 2 year and stop if relapse will restart the therapy .prolong break in therapy can lead to porgressive irrevirsible damage.
limitation of this study:
-retrospective design
-short follow up to decide about the long-term effect
-no standardization of immunosuppression therapy prior to eculizumab.
-missing data of serology and genetic testing in majority of cases
-no screen for monoclonal gammopathy case ddd2 in her 50s.
-uncertain duration of treatment with eculizumab, and treatment interrupted in some cases .
What are the inclusion and exclusion criteria for such treatment (you may use other sources)?
Inclusion, failed other immunosuppressive therapy like MMF, steroids plasmapheresis in first 6 months or RPGN with crescentic lesions and requiring dialysis for first two weeks
Exclusion: mild presentation with stable renal function and proteinuria < 1-1.5gm with good intital response conservative therapies with ACEi, STATIN, bp control and trails of MMF, steroids
What is the cost of treatment?
Very expensive drug and treatment duration indeterminate6.260$ per 300mg/30ml in US while in Oman the cost is different with different companies but its in the range of-1450- 2400 OMR per 900mg each vial of 300mg cost around 400 OMR. (Around 10.000$).
What are the other indications eculizumab?
FDA approved its use for PNH, aHUS
Rescue therapy in ABMR
Rescue therapy in catastrophic APL
Refractory generalized myasthenia gravis
Neuromyelitis Optica spectrum disorder
In our center eculizumab used for aHUS and PNH with one case report as rescue therapy for AMR back in 2015 , also we used for 3 cases of C3 Nephropathy , two brothers with confirmed C3 Nephropathy , one brother failed treatment and progress to ESRD and got transplanted from LURD and relapsed post Tx again recurrence despite treatment and he lost the graft after 3 years while his sister doing well on eculizumab with stable renal function as she started earlier and still on treatment every 4-6 weeks , 3rd case young male in his 20s age ,esrd on PD for 5 years then transplanted from his brother 2019 post transplantaion we use eculizumab for first 3 months only he is doing very well since 2019 with normal graft function on tacrolimus and MMFplus steroid , off eculizumab with normal c3 and nil proteinuria , no relapse .
Dear all
Why do you think we brought this journal for discussion?
What is the main limitation in this study and all studies using Ecluzimab?
Treatment with eculizumab based on Low quality of evidence from case reports or case series no RCTs as its use limited in very rare diseases as second line or rescue therapy for uncertian duration in addition its very expensive therapy .
Dear Prof. Dr. Ali
In this case series, seems no standardization. as it is case series this is probable. for there could not be a unique evaluation for ECULIZUMAB here. even in the case of FSGS, FSGS can be a result for most of the primary nephritis syndromes. In patient c3gn4 for example we do not know the results of IF staining. even the stage at which biopsy is not stated .
I have two cases one of them is followed by my till from A-z but the other (his sister) is followed as post-transplant patient.
the sister is 7 years transplant patient with an acceptable level of proteinuria <1 gram, with normal function (no place for much detail here). she is on TAC/MMF/prednisolone
Both patients are phenotypic identical (syndromic facies)
MY patient of interest is C3GN (renal biopsy). we diagnosed him by chance during the workup of hematuria and proteinuria (the main complaint was abdominal pain and constipation, the patient was admitted by internal medicine because of hyperkalemia k:6.5) further workup revealed the diagnosis
primary treatment was with cyclophosphamide followed by MMF, steroid. the patient was maintained on dialysis within the first year for nearly 4-5 months followed by 2 years of free dialysis until last month when I put him on dialysis selectively to avoid urgency as I performed dialysis for one time 2 months ago for one time because of acidosis and deterioration after diarrhea.
In some: this rare entity is hard to evaluate with nonstandardized care
my aim of this contribution is to share this probable resembling diagnosis
before I go into details of the paper, I wished it could be a good choice, but I think this is hard to be (no proof for who to benefit) nobody can afford this money. In Turkey, we only can have special permission to use I aHUS patients.
The cost of the drug and the uncertainty about the duration of treatment are the main limiting factors for eculizumab studies.
C3 gloerulopathy is a new term used to describe uncontrolled activation of alternative complement pathway with subsequent glomerular deposition of C3 & its fragments. Histopathologically it belongs to MPGN pattern. It can be divided ( according EM finding) into C3GN & DDD.
It is rare disease with poor renal outcome, mostly progressed to ESRD with high recurrence after renal transplantation. Predictors of rapid progression to ESRD:
The uncontrolled activation of alternative complement can be caused by inherited mutation of complement proteins & cofactors or due to acquired defects. Different treatment strategies are used ( CNI, MMF, rituximab, plasma infusion or PP) with inconclusive results. Because the defect in the complement activation new drugs that inhibit complement activation is tried(eculizumab).
Study summery:
The study include 7 patients ( 5 C3GN, 2 DDD) who treated with eculizumab.
Inclusion criteria:
Aim of study is observing the change of renal function, urinary protein & hematuria after treatment with eculizumab
Positive treatment response mean reducing 30% of s.creatinine, urinary protein or hematuria after 3 months of treatment
Stable disease define as s. creatinine, urinary protein or hematuria +/- 30% after 3 months
Negative treatment response mean >30% increment in s. creatinine, urinary protein or hematuria.
Treatment with ACE-I or ARB to control blood pressure & reducing urinary protein. All patients receive meningococcal vaccine before treatment.
The dose of eculizumab in first months was 900 mg weekly then 1200 mg every other week. Statistical analysis didn’t performed due to small study population.
4 patients show either improved or stable renal function & usually the response occur after 2-6 months, while 3 patients had no response to treatment.
sMAC level used to assess alternative complement pathway activity & response to treatment, but several patients had normal level even before treatment. Hematuria improved even in patients with deteriorating renal function. In summary eculizumab is effective in some patients especially who treated early before development of chronic changes, also treatment with eculizumab may need long term because disease recurrence & disease progression occur after discontinuation of eculizumab.
Indications of eculizumab:
Cost of eculizumab 10mg (30ml) 6.820$
Treating C3 glomerulopathy with eculizumab
Summary:
C3G is a recently described, rare disease with a poor prognosis. Characterized by uncontrolled activation of the alternative complement pathway with glomerular deposition of C3 and C3 fragments, that can occur due to inherited mutation or acquired defect. It shares histopathologic character of membranoproliferative glomerulonephritis (MPGN) which, caused by immune complex-mediated dysregulation of the classical complement cascade. Uncontrolled activation of the alternative
C3G is subclassified as dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) based on electron microscopy. There is not conclusive treatment for C3G yet, in contrast to MPGN, which is managed by treating underlying infections, autoimmune diseases, or cancer.
Treatment with immunosuppression drugs, plasma infusion and Plasmerepharesis have been tried with indecisive results. New therapy with Eculizumab, is the first anti-complement therapy, which is a monoclonal antibody that blocks the final complement cascade C5. So prevents the formation of complement attack complex that attack cells causing their damage.
In the present study, the authors assess response to eculizumab of seven patients with C3G.
The study population consisted of patients with atypical history (HIV, kidney graft, de novo C3G, DDD, C3GN), the study revealed heterogeneous response; improvement, stable function or no response. Treatment response varied between 2 weeks and 6 months. The study supports that eculizumab can be an effective treatment choice for some patients with C3G, and timing and duration of therapy are important factors for the response. The treatment needs to be prolonged with only short breaks, as longer breaks can cause worse results and relapse. Eculizumab is not effective in severe glomerular sclerosis and interstitial fibrosis. Resuming eculizumab therapy after long break did not halt progression of the disease.
Old age, renal impairment at presentation, and severe glomerular pathology are predictors of ESRD in patients with C3G.
Serum MAC levels have been proposed as a marker for the alternative complement pathway activity as well, to the response to eculizumab.
The study observes an improvement in hematuria and creatinine in parallel with improvement in kidney inflammation after treatment with eculizumab.
Proteinuria cause eculizumab elimination, so weaken its treatment response. In these cases, eculizumab serum concentrations monitoring to detect underdosing and serum CH50 levels might be helpful.
since C3G patient needs eculizumab therapy to be maintained lifelong, therefore its long-term effects have to be monitored and as the study period was too short; it was unlikely to give conclusive results in this regard.
The time to C3G recurrence in the allograft varies widely in the two reported cases (after 3 yrs and after 3 months), going with other studies. Rituximab has been treatment choice in autoantibody-positive transplant recurrent C3G, but in this study it did not affect disease progression. However, this study shows that allograft recurrent C3GN can be treated with eculizumab.
Limitation of the study:
· Being retrospective
· Lack of standardized follow-up, including genetic and serologic testing.
· The abundant therapy given prior to treatment with eculizumab complicate the interpretation of the clinical course.
Conclusion:
Treatment with eculizumab may be useful in some patients with C3G. prospective long-term studies will be needed to determine predictors to treatment response with eculizumab.
Inclusion criteria:
· Patients more than 18 years of age
· Histopathological diagnosis of C3G
· Patient treated with eculizumab
Exclusion criteria:
Age < 18 yrs
Cost:
10 mg/ml Vial for IV infusion costs 6,742.000 $.
Average daily drug cost is 1.994.89 $
Indications are:
1- Transplant associated thrombotic microangiopathy.
2- Atypical hemolytic uremic syndrome
3- Cold agglutinin disease
4- Neuromyelitis optica spectrum disorder
5- Paroxysmal nocturnal hemoglobinuria
6- Warm type autoimmune hemolytic anemia
7- IN treatment of sever COVID 19.
References:
1. Diurno F, Numis FG, Porta G, Cirillo F, Maddaluno S, Ragozzino A, et al. Eculizumab treatment in patients with COVID-19: preliminary results from real-life ASL Napoli 2 Nord experience. Eur Rev Med Pharmacol Sci. 2020 Apr;24(7):4040–7.
2. Patriquin CJ, Kuo KHM. Eculizumab and Beyond: The Past, Present, and Future of Complement Therapeutics. Transfus Med Rev [Internet]. 2019;33(4):256–65. Available from: https://www.sciencedirect.com/science/article/pii/S0887796319301324
3. Pharmacoeconomic Report: Eculizumab (Soliris): Alexion Pharma Canada Corp. Indication: Neuromyelitis optica spectrum disorder [Internet] Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2020 Oct. Appendix 1, Cost Comparison Table. Available from: https://www.ncbi.nlm.nih.gov/books/NBK567499/
Summarise this article in your own words
C3 glomerulopathy is rare, sever disease with poor prognosis. the pathogenesis involve inherited as well as acquired dysregulation of the alternative complement pathway. treatment with eculizumab is a therapeutic option.
Methods:
settings: data collected from medical records of Freiburg medical center, Germany from 2013- 2016.
patients: seven patients( 5 with C3GN, 2 with DDD) treated with eculizumab from 2013- 2016. data collected from time of initiation of treatment till last follow up.
Inclusion criteria:
Exclusion criteria:
any patient who do not meet the inclusion criteria.
Ethical approval:
The Ethics Committee of the University Medical Center, Freiburg, Germany.
Intervention:
Eculizumab administered weekly at dose of 900 mg from week 1-4, then every other week at a dose of 1200 mg from week 5.
Positive treatment response was defined as > 30% decrease of serum creatinine, urine protein, or hematuria after 3 months of treatment.
stable disease defined as serum creatinine , urine protein, hematuria of 30% or lower after 3 months of treatment.
Negative treatment response defined as an increase >30% of serum creatinine, urine protein, hematuria.
Outcome: the change in renal function and urinary protein overtime.
Results:
Conclusion:
Eculizumab may be a therapeutic option for a subset of C3GN patients. the response to treatment is heterogeneous, early and continuous treatment may be necessary to prevent disease progression.
What is the cost of treatment?
The cost for IV solution 10 mg/ml is around $ 6,820, and 34,985$ per prescription, annually around 500,000$. The cost differ according to the manficture company.
What are the other indications eculizumb?
Summarise this article in your own words.
According to immunofluorescence, three types of MPGN are identified
C3 glomerulopathy is a rare disease occurring in 1-2 cases per million
Caused by dysregulation of the alternative pathway of complement system due to either mutation or acquired defect in complement protein leading to uncontrolled activation with subsequent deposition of C3 in glomeruli, thus it shares the same pathogenesis of aHUS but aHUS occur in solid phase (complement on the cell surface) while C3 glomerulopathy occur at fluid phase
Aggressive disease with most of the patient develop ESRD, risk factors for the development of ESRD include age> 16 years, renal impairment at presentation, DDD type, and crescentic GN
Recurrent disease with around 50 % recur after transplantation
No effective treatment till now
In this study, eculizumab is given to 7 patients with biopsy-proven C3 glomerulopathy, 2 of them have DDD (aggressive subtype) and 3 of them have recurrent C3 glomerulopathy post-transplantation.
All patients are followed regarding proteinuria, hematuria, and serum creatinine
Dosage: 900 mg weekly for 1 month then 1200 mg is given in the 5th week then start maintenance dose 1200 mg/2 weeks
Successful treatment was defined as the occurrence of > 30% reduction of creatinine, proteinuria, and hematuria after 3 months
ACEI or ARBS were administered in all patients
Meningococcal vaccination was given to all patients
Outcome
Conclusion
What are the inclusion and exclusion criteria for such treatment (you may use other sources)?
Inclusion criteria
Exclusion criteria
What is the cost of treatment?
What are the other indications eculizumab?
1- FDA approved in the treatment of PNH
2- FDA approved in the treatment of complement medicated TMA (a HUS)
3- Promising result in the treatment of C3 glomerulopathy treatment
4- Promising result in the treatment of recurrent C3 glomerulopathy and complement medicated TMA following transplantation
5- Refractory generalized myasthenia gravis who are antiacetylcholine receptor antibody positive.
6- Neuromyelitis optica spectrum disorder who are aquaporin-4-antibody positive.
Summarise this article in your own words.
Data of five patients with C3GN and two patients with DDD treated with eculizumab were analysed.
Four patients showed either improved or stable kidney function, and three patients did not respond. Treatment response varied between 2 weeks and 6 months. Timing and duration of treatment seem to be important factors for the effectiveness. Short treatment breaks may result in reversible loss of kidney function and urinary protein, while longer breaks can result in disease progression, deterioration of kidney function, and treatment resistance. Eculizumab is less likely to improve disease outcome in patients with more severe glomerular sclerosis and interstitial fibrosis. Old age, renal impairment at presentation, and severe glomerular pathology were identified as predictors of ESRD in patients with C3G. In aHUS, complement activation occurs on endothelial surfaces, leading to endothelial damage and thrombus formation. In C3G, complement activation occurs predominantly in the fluid phase resulting in excess formation of activated C3 and cleavage products, which are deposited in the kidney and raise glomerular damage. Despite eculizumab-driven blockage of the terminal complement cascade, upstream C3 cleavage products may cause continuing glomerular damage. This provides reasons for diverging response rates to eculizumab in. Long-term effects such as glomerular eculizumab deposition needs to be evaluated. The time to allograft recurrence in transplant patients varies widely.
Conclusion – Early diagnosis and continuous treatment might be necessary to affect the outcome of C3G. Treatment with eculizumab may be successful in some patients.
What are the inclusion and exclusion criteria for such treatment (you may use other sources)?
Inclusion –
age > 18 years,
histopathological diagnosis of C3G, ABMR
Exclusion-
with unresolved serious Neisseria meningitidis infection.
who are not currently vaccinated against Neisseria meningitidis.
What is the cost of treatment?
1200 mg dose costs 6500 USD.
What are the other indications eculizumb?
Paroxysmal Nocturnal Hemoglobinuria
ABMR
cTMA
Myasthenia Gravis
Neuromyelitis Optica Spectrum Disorder