Eculizumab (Soliris)

Number: 0807

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses eculizumab (Soliris) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of eculizumab (Soliris) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of eculizumab, call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Site of Care Utilization Management Policy applies. 

For information on site of service for Soliris infusions, see Utilization Management Policy on Site of Care for Specialty Drug Infusions. 

1. Criteria for Initial Approval

   Aetna considers eculizumab (Soliris) medically necessary for any of the following indications when criteria are met: 
   

   1. Atypical hemolytic uremic syndrome

      For treatment of atypical hemolytic uremic syndrome not caused by Shiga toxin when all of the following criteria are met:

      1. ADAMTS 13 activity level above 5%; and
      2. Absence of Shiga toxin; or

   2. Paroxysmal nocturnal hemoglobinuria (PNH)

      For treatment of PNH when all of the following are met:

      1. The diagnosis of PNH was confirmed by detecting a deficiency of glycosylphosphatidylinositol-anchored proteins (GPI-APs) as demonstrated by either of the following:

         1. At least 5% PNH cells; or
         2. At least 51% of GPI-anchored protein deficient poly-morphonuclear cells; and
            

      2. Flow cytometry is used to demonstrate GPI-anchored proteins deficiency; or

   3. Generalized myasthenia gravis (gMG)

      For treatment of gMG when all of the following criteria are met:

      1. Anti-acetylcholine receptor (AchR) antibody positive; and
      2. Myasthenia Gravis Foundation of America (MGFA) clinical classification II to IV; and
      3. MG activities of daily living (MG-ADL) total score greater than or equal to 6; and
      4. Meets both of the following:
         
         

         1. Member has had an inadequate response to at least two immunosuppressive therapies listed below:

            1. azathioprine
            2. cyclosporine
            3. mycophenolate mofetil
            4. tacrolimus
            5. methotrexate
            6. cyclophosphamide
            7. rituximab; and
               

         2. Member has inadequate response to chronic IVIG; or

   4. Neuromyelitis Optica Spectrum Disorder (NMOSD)

      For treatment of NMOSD when all of the following criteria are met:

      1. Anti-aquaporin-4 (AQP4) antibody positive; and
      2. Member exhibits one of the following core clinical characteristics of NMOSD:
         
         
         1. Optic neuritis; or
         2. Acute myelitis; or
         3. Area postrema syndrome (episode of otherwise unexplained hiccups or nausea and vomiting); or
         4. Acute brainstem syndrome; or
         5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions; or
         6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions; and
            

      3. The member will not receive the requested drug concomitantly with other biologics for the treatment of NMOSD.

      Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections). 

2. Continuation of Therapy

   Aetna considers the continuation of eculizumab (Soliris) therapy medically necessary for the following indications when criteria met:
   

   1. Atypical hemolytic uremic syndrome (aHUS)

      For members requesting reauthorization and there is no evidence of unacceptable toxicity or disease progression while on the current regimen and member demonstrates a positive response to therapy (e.g., normalization of lactate dehydrogenase (LDH) levels, platelet counts);

   2. Paroxysmal nocturnal hemoglobinuria (PNH)

      For members requesting reathorization and there is no evidence of unacceptable toxicity or disease progression while on the current regimen and member demonstrates a positive response to therapy (e.g., improvement in hemoglobin levels, normalization of LDH levels);

   3. Generalized myasthenia gravis (gMG)

      For members requesting reauthorization and there is no evidence of unacceptable toxicity or disease progression while on the current regimen and member demonstrates a positive response to therapy (e.g., improvement in MG-ADL score, changes compared to baseline in Quantitative Myasthenia Gravis (QMG) total score);

   4. Neuromyelitis optica spectrum disorder (NMOSD)

      For members requesting reauthorization when all of the following criteria are met: 

      1. There is no evidence of unacceptable toxicity or disease progression while on the current regimen; and
      2. The member demonstrates a positive response to therapy (e.g., reduction in number of relapses); and
      3. The member will not receive the requested drug concomitantly with other biologics for the treatment of NMOSD.

Related Policies

• CPB 0634 - Non-myeloablative Hematopoietic Cell Transplantation (Mini-Allograft / Reduced Intensity Conditioning Transplant)

Dosage and Administration

Note: Approvals may be subject to dosing limits in accordance with FDA-approved labeling, accepted compendia, and/or evidence-based practice guidelines. Below includes dosing recommendations as per the FDA-approved prescribing information. 

Eculizumab is available as Soliris in 300 mg single‐use vials for intravenous (IV) infusion. Each vial contains 30 mL of 10 mg/mL sterile, preservative‐free solution.

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Recommended dosage of eculizumab for PNH in members 18 years of age and older:

• 600 mg IV every weekly for the first 4 weeks, followed by
• 900 mg IV for the fifth dose 1 week later, then
• 900 mg IV every 2 weeks thereafter.

Atypical Hemolytic Uremic Syndrome (aHUS)

Recommended dosage of eculizumab for aHUS in members 18 years of age or older:

• 900 mg every weekly for the first 4 weeks, followed by
• 1200 mg for the fifth dose 1 week later, then
• 1200 mg every 2 weeks thereafter.

Recommended dosage of eculizumab for members less than 18 years of age with aHUS is based upon body weight according to Table 1 below.

Table 1: Dosing recommendations for aHUS in members less than 18 years of age

Body Weight	Induction	Maintenance
40 kg and over	900 mg weekly x 4 doses	1200 mg at week 5; then 1200 mg every 2 weeks
30 kg to less than 40 kg	600 mg weekly x 2 doses	900 mg at week 3; then 900 mg every 2 weeks
20 kg to less than 30 kg	600 mg weekly x 2 doses	600 mg at week 3; then 600 mg every 2 weeks
10 kg to less than 20 kg	600 mg weekly x 1 dose	300 mg at week 2; then 300 mg every 2 weeks
5 kg to less than 10 kg	300 mg weekly x 1 dose	300 mg at week 2; then 300 mg every 3 weeks

Generalized Myasthenia Gravis (gMG) or Neuromyelitis Optica Spectrum Disorder (NMOSD)

Recommended dosage of eculizumab for gMG or NMOSD

• 900 mg weekly for the first 4 weeks, followed by
• 1200 mg for the fifth dose 1 week later, then
• 1200 mg every 2 weeks thereafter.

Administer Soliris at the recommended dosage regimen time points, or within two days of these time points.

Source: Alexion Pharmaceuticals, 2020.

Experimental and Investigational

Aetna considers eculizumab experimental and investigational when criteria are not met and for all other indications including the following (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Age-related macular degeneration
• Antibody-mediated rejection
• Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis
• Anti-phospholipid antibody syndrome
• Autoimmune hemolytic anemia
• Bevacizumab-associated thrombotic microangiopathy (TMA)
• Cold agglutinin disease secondary to coronavirus disease 2019 (COVID-19)
• C3 glomerulopathy/glomerulonephritis/nephropathy
• Coronavirus disease 2019 (COVID-19) 
• Dense deposit disease
• Gemcitabine-induced thrombotic microangiopathy (TMA)
• Guillain-Barre syndrome
• Hemolytic cold agglutinin disease
• Hyperhemolysis syndrome
• IgA nephropathy
• Immune complex-mediated membranoproliferative glomerulonephritis
• Inflammatory myositis (e.g., dermatomyositis and polymyositis)
• Ischemia-reperfusion injury in kidney transplantation
• Lupus nephritis
• Malignant atrophic papulosis
• Multi-focal motor neuropathy
• Non-exudative (dry) macular degeneration
• Preeclampsia with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome
• Prevention of graft loss in kidney transplant recipients
• Prevention of intravascular hemolysis due to red blood cell alloantibodies
• Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS)
• Stem cell transplant-associated thrombotic microangiopathy
• Systemic lupus erythematosus
• Thrombotic thrombocytopenic purpura (TTP)
• Transverse myelitis.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
88184	Flow cytometry, cell surface, cytoplasmic, or nuclear marker, technical component only; first marker
+88185	each additional marker (List separately in addition to code for first marker)
88187	Flow cytometry, interpretation; 2 to 8 markers
88188	9 to 15 markers
88189	16 or more markers
96413 - 96417	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J1300	Injection, eculizumab, 10 mg
Other HCPCS codes related to the CPB:
J9311	Injection, rituximab 10 mg and hyaluronidase
J9312	Injection, rituximab, 10 mg
Q5115	Injection, rituximab-abbs, biosimilar, (Truxima), 10 mg
Q5119	Injection, rituximab-pvvr, biosimilar, (ruxience), 10 mg
Q5123	Injection, rituximab-arrx, biosimilar, (riabni), 10 mg
ICD-10 codes covered if selection criteria are met:
D59.30 - D59.39	Hemolytic-uremic syndrome [covered for persons with atypical hemolytic uremic syndrome without serious unresolved Neisseria meningitis infection] [not covered for Shiga toxin E. coli-related hemolytic uremic syndrome(STEC-HUS)]
D59.5	Paroxysmal nocturnal hemoglobinuria [Marchiafava-Micheli]
G36.0	Neuromyelitis optica
G70.00 - G70.01	Myasthenia gravis
ICD-10 codes not covered for indications listed in the CPB (not an all inclusive list):
D59.1	Other autoimmune hemolytic anemias [hyperhemolysis syndrome and for the prevention of intravascular hemolysis due to red blood cell alloantibodies]
D59.12	Cold autoimmune hemolytic anemia [Cold agglutinin disease]
D68.312	Antiphospholipid antibody with hemorrhagic disorder
D68.61	Antiphospholipid syndrome [anti-phospholipid antibody syndrome]
G37.3	Acute transverse myelitis in demyelinating disease of central nervous system
G61.0	Guillain-Barre syndrome
G62.81	Critical illness polyneuropathy [multi-focal motor neuropathy]
H35.30	Unspecified macular degeneration [senile]
H35.3110 - H35.3293	Age-related macular degeneration
H35.351 - H35.359	Cystoid macular degeneration
H50.811 - H50.812	Duane's syndrome
J12.82	Pneumonia due to coronavirus disease 2019
M31.10 - M31.19	Thrombotic microangiopathy [Thrombotic thrombocytopenic purpura]
M31.30 - M31.31	Wegener's granulomatosis
M31.7	Microscopic polyangiitis
M32.0 - M32.9	Systemic lupus erythematosus
M33.00 - M33.19 M33.90 - M33.99	Dermatopolymyositis
M60.80 - M60.89	Other myositis [inflammatory myositis]
N00.5 - N00.6	Acute nephritic syndrome [membranoproliferative glomerulonephritis]
N01.5 - N01.6	Rapidly progressive nephritic syndrome [membranoproliferative glomerulonephritis]
N03.5 - N03.6	Chronic nephritic syndrome [membranoproliferative glomerulonephritis]
N04.5 - N04.6	Nephrotic syndrome [membranoproliferative glomerulonephritis]
N05.0 - N05.9	Unspecified nephritic syndrome [deposit disease/C3 glomerulonephritis] [IgA nephropathy]
N06.5 - N06.6	Isolated proteinuria [membranoproliferative glomerulonephritis]
N07.5 - N07.6	Hereditary nephropathy [membranoproliferative glomerulonephritis]
N08	Glomerular disorders in diseases classified elsewhere [deposit disease/C3 glomerulonephritis]
O14.20 - O14.25	HELLP syndrome
T86.00 - T86.99	Complication of transplanted organ and tissue [antibody-mediated rejection]
U07.1	COVID-19
Z94.0	Kidney transplant status [prevention of graft loss]

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis
• Atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy
• Generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AchR) antibody positive
• Neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive

Limitations of Use: Soliris is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).

Eculizumab is available as Soliris (Alexion Pharmaceuticals, Inc.), which is a recombinant humanized monoclonal antibody (IgG2/4k) that binds specifically to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b‐9. Eculizumab inhibits terminal complement mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).

Soliris carries a labeled black box warning for life-threatening and fatal meningococcal infections. The Prescribing Information for Soliris recommends that patients and healthcare providers comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies. In addition, patients should be immunized with meningococcal vaccines at least 2 weeks prior to administering the first dose of Soliris, unless the risks of delaying Soliris therapy outweigh the risks of developing a meningococcal infection. Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Thus, monitoring patients for early signs of meningococcal infections is recommended,  and evaluate immediately if infection is suspected.

Soliris is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the Soliris REMS, prescribers must enroll in the program (Alexion Pharmaceuticals, 2020).

Soliris is contraindicated in patients with unresolved serious Neisseria meningitidis infection, and patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying Soliris treatment outweigh the risks of developing a meningococcal infection.

The most frequently reported adverse reactions in the PNH randomized trial (10% or more overall and greater than placebo) include headache, nasopharyngitis, back pain, and nausea. The most frequently reported adverse reactions in aHUS single arm prospective trials (20% or more) include headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, pyrexia. The most frequently reported adverse reaction in the gMG placebo-controlled clinical trial (10% or more) is musculoskeletal pain. The most frequently reported adverse reactions in the NMOSD placebo-controlled trial (10% or more) include upper respiratory infection, nasopharyngitis, diarrhea, back pain, dizziness, influenza, arthralgia, pharyngitis, and contusion (Alexion Pharmaceuticals, 2020).

Atypical Hemolytic Uremic Syndrome (aHUS)

Hemolytic uremic syndrome is defined by the triad of mechanical hemolytic anemia, thrombocytopenia and renal impairment.  Atypical HUS (aHUS) defines non Shiga-toxin-HUS and even if some authors include secondary aHUS due to Streptococcus pneumoniae or other causes, aHUS designates a primary disease due to a disorder in complement alternative pathway regulation.  Atypical HUS represents 5  to 10 % of HUS in children, but the majority of HUS in adults.  The incidence of complement-aHUS is not known precisely.  However, more than 1,000 aHUS patients investigated for complement abnormalities have been reported.  Onset is from the neonatal period to the adult age.  Most patients present with hemolytic anemia, thrombocytopenia and renal failure and 20 % have extra renal manifestations.  Two to 10 % die and 1/3 progress to end-stage renal failure at first episode.  Half of patients have relapses.  Mutations in the genes encoding complement regulatory proteins factor H, membrane cofactor protein (MCP), factor I or thrombomodulin have been demonstrated in 20 to 30 %, 5 to 15 %, 4 to 10 % and 3 to 5 % of patients respectively, and mutations in the genes of C3 convertase proteins, C3 and factor B, in 2 to 10 % and 1 to 4 %.  In addition, 6 to 10 % of patients have anti-factor H antibodies.  Diagnosis of aHUS relies on

1. no associated disease,
2. no criteria for Stx-HUS (stool culture and polymerase chain reaction for Stx; serology for anti-lipopolysaccharides antibodies), and
3. no criteria for thrombotic thrombocytopenic purpura (serum ADAMTS 13 activity greater than 10 %). 

Investigation of the complement system is required (C3, C4, factor H and factor I plasma concentration, MCP expression on leukocytes and anti-factor H antibodies; genetic screening to identify risk factors).  The disease is familial in approximately 20 % of pedigrees, with an autosomal recessive or dominant mode of transmission.  As penetrance of the disease is 50 %, genetic counseling is difficult.  Plasma therapy (plasma exchange or fresh frozen plasma infusion) has been first line treatment.  Patients with aHUS who have reached end-stage renal failure are theoretically candidates to renal transplantation.  However, the overall risk of aHUS recurrence after renal transplantation is 50 % and the risk of graft loss 80 to 90 % in patients with recurrence.  Case reports and 2 phase II trials suggested that the complement C5 blocker eculizumab will be the next standard of care (Loirat and Fremeaux-Bacchi, 2011).

Scheiring and associates (2010) stated that hemolytic uremic syndrome (HUS) entails the triad of hemolytic anemia, thrombocytopenia, and acute renal failure.  The classical form [D(+) HUS] is caused by infectious agents, and it is a common cause of acute renal failure in children.  The entero-hemorrhagic Escherichia coli-producing Shiga toxin (Stx) is the most common infectious agent causing HUS.  Other infectious agents are Shigella and Streptococcus pneumoniae.  Infections by Streptococcus pneumoniae can be severe and has a higher acute mortality and a higher long-term morbidity compared to HUS by Stx.  Atypical HUS [D(-)Stx(-)HUS] are often used by pediatricians to indicate a presentation of HUS without preceding diarrhea.  Almost all patients with D(-)Stx(-)HUS have a defect in the alternative pathway (e.g., mutations in the genes for complement factor H, factor I, and membrane co-factor protein).  Mutations in the factor H gene are described more often.  The majority of children with D(+) HUS develop some degree of renal insufficiency, and about 2/3 of children with HUS will require dialysis, while about 1/3 will have milder renal involvement without the need for dialysis.  Standard treatment of acute renal failure includes appropriate fluid and electrolyte management, anti-hypertensive therapy, and the initiation of renal replacement therapy when appropriate.  Specific management issues in HUS include treatment of the hematological complications of HUS, monitoring for extra-renal involvement, avoiding anti-diarrheal drugs, and possibly avoiding of antibiotic therapy.  In addition to the obligatory supportive treatment and tight control of hypertension, there is anecdotal evidence that plasma therapy may induce remission and, in some cases, maintain it.  Fresh frozen plasma contains factor H at physiological concentrations.  A new therapy for D(-)Stx(-)HUS is eculizumab, which prevents the generation of the inflammatory peptide C5a and the cytotoxic membrane-attack complex C5b-9. These investigators noted that they have the first positive results. Furthermore, in a review on atypical HUS, Kavanagh and Goodship (2010) noted that although early reports of the effectiveness of eculizumab are promising, the outcome of a recent clinical trial is awaited. Waters and Licht (2011) stated that clinical trials are now underway to evaluate the effectiveness of eculizumab in the management of both plasma-sensitive and plasma-resistant atypical HUS.

Tschumi et al (2011) stated that the prognosis for patients with aHUS is poor, and plasma exchange represents the first-line therapy. These investigators reported the case of a 9-year old girl with frequent relapsing aHUS due to heterozygous factor H mutation who was initially treated with plasma exchange 3 times per week with 150 % plasma exchange volume. This treatment frequently caused allergic reactions and school absences. Because any reduction in the frequency of plasma exchange immediately induced relapses of the aHUS, treatment with eculizumab, 600 mg every 2 weeks, was started and plasma exchange completely stopped. On this drug regimen the patient showed no evidence of disease activity during a period of more than 24 months. Renal function improved, proteinuria disappeared, the number of anti-hypertensive medications could be decreased, and the quality of life increased substantially. The inhibition of the terminal complement pathway by eculizumab was also confirmed by renal biopsy, which showed the absence of thrombotic microangiopathy 2 months after the initiation of eculizumab therapy. This case illustrated the long-term favorable outcome of aHUS with eculizumab treatment.

Lapeyraque et al (2011) stated that the use of early-onset plasma therapy for aHUS is recommended, but optimal long-term treatment regimen is not well-defined. Eculizumab has shown success in patients with aHUS. These researchers reported a 7-year old girl with aHUS associated with factor H mutations successfully treated with eculizumab. Weekly plasma infusion (PI) of 25 to 30 ml/kg with short-term intensified PI during aHUS exacerbations was effective for 4.3 years. Progressive mild renal failure (stage 2) was attributed to chronic glomerular lesions. Subsequently, the patient exhibited aHUS exacerbation unresponsive to intensified PI. Eculizumab was initiated at 600 mg, resulting in immediate and complete inhibition of terminal complement activation. During the week following treatment, these investigators observed a complete reversal of aHUS activity. She has been receiving 600 mg eculizumab every 2 weeks for the last 12 months. She had no aHUS exacerbation, and serum creatinine level returned to normal.  In this patient, eculizumab led to control of PI-resistant aHUS exacerbation and chronic microangiopathic hemolytic activity.  Clinical trials are ongoing to assess the safety and effectiveness of this drug in the management of aHUS.

On September 23, 2011, the FDA approved eculizumab to treat patients with aHUS.  The safety and effectiveness of eculizumab for the treatment of aHUS were established in two single-arm trials in 37 adults and adolescent patients with aHUS and one retrospective study in 19 pediatric patients and 11 adult patients with aHUS.  Patients treated with eculizumab in these studies experienced a favorable improvement in renal function, including elimination of the requirement for dialysis in several patients with aHUS that did not respond to plasma therapy.  Patients treated with eculizumab also exhibited improvement in platelet counts and other blood parameters that correlate with aHUS disease activity.  The most common side effects observed in patients treated with eculizumab for aHUS included anemia, diarrhea, headache, hypertension, leukopenia, nausea, vomiting, as well as upper respiratory and urinary tract infections.  This new indication for eculizumab is being approved with an extension of the existing Risk Evaluation and Mitigation Strategy (REMS), to inform health care professionals and patients about the known risk of life-threatening meningococcal infections.  Eculizumab is contraindicated in patients with unresolved serious Neisseria meningitidis infection.

Myasthenia Gravis

The FDA approved eculizumab as a treatment for adult patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AchR) antibody-positive.

Howard, et al. (2017) reported on a phase III, randomized, double-blind, placebo-controlled multicenter study (REGAIN) of eculizumab in patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. Eligible patients were 18 years of age or older, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomization, or rituximab within 6 months before screening, were excluded. The investigators randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomization was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. Between April 30, 2014, and Feb 19, 2016, investigators randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). Although the primary efficacy endpoint was not met, several secondary endpoints showed a potential benefit for eculizumab. The improvement appeared during the first 4 weeks of treatment and lasted for the 6 months of the study.No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group).  Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy.  The investigators concluded that the change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis.  The investigators noted that eculizumab was well tolerated. The investigators stated that use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result. The investigators stated that further research into the role of complement is needed.

The administration of eculizumab does not require concurrent vitamin B12 administration in persons without concurrent vitamin B12 deficiency. The Product Insert of Soliris (eculizumab) does not mention the use of vitamin B12 supplementation. 

Neuromyelitis Optica Spectrum Disorder (NMOSD)

In an open-label, pilot study, Pittock and associates (2013) examined the use of eculizumab in the treatment of NMO spectrum disorders.  Between October 20, 2009, and November 3, 2010, these researchers recruited patients from 2 U.S. centers into an open-label trial.  Patients were AQP4-IgG-seropositive, aged at least 18 years, had a NMO spectrum disorder, and had at least 2 attacks in the preceding 6 months or 3 in the previous 12 months.  Patients received meningococcal vaccine at a screening visit and 2 weeks later began eculizumab treatment.  They received 600-mg intravenous eculizumab weekly for 4 weeks, 900-mg in the 5th week, and then 900-mg every 2 weeks for 48 weeks.  The co-primary end-points were efficacy (measured by number of attacks [new worsening of neurological function lasting for more than 24 hours and not attributable to an identifiable cause]) and safety.  Secondary end-points were disability (measured by expanded disability status scale), ambulation (Hauser score), and visual acuity.  At follow-up visits (after 6 weeks and 3, 6, 9, and 12 months of treatment; and 3 and 12 months after discontinuation), complete neurological examination was undertaken and an adverse event questionnaire completed.  These investigators enrolled 14 patients, all of whom were women.  After 12 months of eculizumab treatment, 12 patients were relapse-free; 2 had had possible attacks.  The median number of attacks per year fell from 3 before treatment (range 2 to 4) to 0 (0 to 1) during treatment (p < 0.0001).  No patient had worsened disability by any outcome measure.  Median score on the expanded disability status scale improved from 4.3 (range 1.0 to 8.0) before treatment to 3.5 (0 to 8.0) during treatment (p = 0.0078).  Two patients improved by 2 points and 3 improved by 1 point on the Hauser score; no change was recorded for the other patients.  Visual acuity had improved in at least 1 eye by 1 point in 4 patients, and by 2 points in 1 patient; no change was recorded for other patients.  One patient had meningococcal sepsis and sterile meningitis about 2 months after the first eculizumab infusion, but resumed treatment after full recovery.  No other drug-related serious adverse events occurred.  Eight attacks in five patients were reported within 12 months of eculizumab withdrawal.  The authors concluded that eculizumab seems to be well-tolerated, significantly reduce attack frequency, and stabilize or improve neurological disability measures in patients with aggressive NMO spectrum disorders.  Moreover, they stated that the apparent effects of eculizumab deserve further investigation in larger, RCTs.

Fujihara (2012) stated that neuromyelitis optica (NMO) or Devic's disease is an inflammatory neurologic disease characterized by severe optic neuritis and transverse myelitis.  Other features of NMO include female preponderance, higher onset age, severe functional disability, longitudinally extensive spinal cord lesions (longer than 3 vertebral segments), and oligoclonal IgG bands negativity.  Brain lesions are not uncommon in NMO.  The relation between NMO and multiple sclerosis (MS) has long been a matter of controversy, but since the discovery of anti-aquaporin 4 (AQP4) antibody (NMO-IgG), an NMO-specific autoantibody, the clinical, MRI, and laboratory features that distinguish NMO from MS have been clarified.  Anti-AQP4 antibody binds to the extracellular domain of AQP4, which is highly expressed in end-feet of astrocytes.  Recent neuropathological studies, analysis of cerebrospinal fluid-glial fibrillary acidic protein (CSF-GFAP) levels during relapse and experimental studies strongly suggested that NMO is an anti-AQP4 antibody-mediated astrocytopathic disease and that T cell-mediated central nervous system (CNS) inflammation is necessary to develop NMO.  Also, interleukin-6 (IL-6) is remarkably elevated in the CSF and appears to regulate plasmablasts to produce anti-AQP4 antibody.  Therefore, from the therapeutic point of view, depletion of anti-AQP4 antibody, suppression of T cell response to trigger relapse and anti-IL-6 therapy seemed to be pivotal.  High-dose intravenous methylprednisolone is the first-line therapy for acute exacerbations of NMO.  But plasma exchange should be started soon if corticosteroid is not effective.  If untreated, AQP4 antibody-positive patients are highly likely to experience relapses within a year.  Therefore, immunosuppressive therapy (corticosteroids, immunosuppressants, rituximab) should be initiated without delay.  Preliminary results suggested that eculizumab can also prevent relapse in NMO.  Meanwhile, interferon-beta, a first-line disease modifying drug of MS, is ineffective in NMO.  Moreover, symptomatic therapy for pain, paresthesia, spasticity, dysuria and constipation that commonly occur in the chronic stage of NMO is also important to improve patients' quality of life.

On June 27, 2019, the FDA announced the approval of Soliris (eculizumab; Alexion Pharmaceuticals) injection for intravenous use for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. NMOSD is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord.  

FDA approval was based on a randomized, double-blind, time-to-event trial in which 143 adults with NMOSD who had antibodies against AQP4 were randomly assigned in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or matched placebo. Participants were eligible if were 18 years of age or older, had diagnosis of NMO or NMOSD, AQP4 antibody seropositive, had at least 2 relapses in the last 12 months or 3 relapses in the last 24 months with at least 1 relapse in the 12 months prior to the screening, and had an Expanded Disability Status Score (EDSS) less than or equal to 7. If a participant entered the study receiving immunosuppressive therapy (IST) for relapse prevention, the participant must have been on a stable maintenance dose of IST(s) prior to screening and must have remained on that dose for the duration of the study, unless the participant experienced a relapse. The use of concurrent corticosteroids was limited to 20 mg per day or less. Exclusion criteria prior to screening included use of rituximab within 3 months, mitoxantrone within 3 months, and intravenous immunoglobulin within 3 weeks. The primary end point was the first adjudicated relapse. Secondary outcomes included the adjudicated annualized relapse rate, quality-of-life measures, and the score on the Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death). Pittock and colleagues (2019) state that adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group (p<0.001). The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (p<0.001). The mean change in the EDSS score was -0.18 in the eculizumab group and 0.12 in the placebo group. The investigators concluded that among patients with AQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. Compared to treatment with placebo, the study showed that treatment with eculizumab reduced the number of NMOSD relapses by 94 percent over the 48-week course of the trial, as well as, reduced the need for hospitalizations and the need for treatment of acute attacks with corticosteroids and plasma exchange (Alexion Pharmaceuticals, 2019b; Pittock et al, 2019; FDA, 2019).

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria (PNH), a rare form of hemolytic anemia, is an acquired genetic blood disorder characterized by red blood cells (RBC) that develop abnormally and are destroyed by the body’s own complement system. A genetic mutation in PNH patients leads to the generation of populations of abnormal of RBC (known as PNH cells) that are deficient in the terminal complement inhibitors, rendering PNH RBC’s sensitive to persistent terminal complement‐mediated destruction. PNH is caused by a somatic mutation of the X-linked phosphatidylinositol glycan class A (PIGA) gene, which results in the absence of the glycosylphosphatidylinositol-linked proteins necessary to protect cells from complement-mediated lysis. The destruction and loss of these PNH cells (intravascular hemolysis) results in low RBC counts that causes the symptoms of PNH, and can lead to disability and premature death.

The symptoms of PNH can include thrombosis, pulmonary hypertension, and damage to organs such as the brain, liver, gastro‐intestinal system, and kidneys. Patients may also experience a variety of symptoms that can interfere with quality of life including: abdominal pain, difficulty swallowing, poor physical function, shortness of breath, erectile dysfunction, and debilitating fatigue. About one person out of a million people will be diagnosed with PNH. An estimated 8,000 to 10,000 people in North America and Europe are affected by PNH.

Prior to 1990, diagnosis of PNH was made by means of complement-based tests.  In the past 10 years, flow cytometry has become the gold standard test as it has increased sensitivity to detect small clones, ability to measure clonal size, and is not affected by blood transfusions (Preis et al, 2014).  Uncontrolled complement activity in PNH leads to systemic complications, principally through intravascular hemolysis and platelet activation (Hill et al, 2013).  The primary clinical manifestations of PNH entail intra-vascular hemolytic anemia, thrombosis in vessels, and bone marrow failure.  Inactivating mutations appear only in a proportion of cells (PNH cells) and this proportion can vary among patients.  Treatment of PNH has largely been supportive care measures including anti-coagulation, folic acid supplementation, hydration, and red blood cell (RBC) transfusion until the development of eculizumab (Zareba, 2007; Madkaikar et al, 2009). 

Schrezenmeier, et al. (2014) reported on the characteristics of the first 1610 patients enrolled in the International PNH Registry. Median disease duration was 4.6 years. Median granulocyte paroxysmal nocturnal hemoglobinuria clone size was 68.1% (range 0.01-100%). Overall, 16% of patients had a history of thrombotic events and 14% a history of impaired renal function. Therapies included anticoagulation (31%), immunosuppression (19%), and eculizumab (25%). Frequently reported symptoms included fatigue (80%), dyspnea (64%), hemoglobinuria (62%), abdominal pain (44%), and chest pain (33%). Patients suffered from poor quality of life; 23% of patients had been hospitalized due to paroxysmal nocturnal hemoglobinuria-related complications and 17% stated that paroxysmal nocturnal hemoglobinuria was the reason they were not working or were working less.

Pivotal clinical studies of eculizumab in PNH were performed in persons with PNH who were transfusion-dependent, representing a subgroup of patients in the most severe end of the disease spectrum.  The European Medicines Agency has stated that "there is only experience in the treatment of patients with previous history of transfusions."  Although estimates of the proportion of persons with PNH with disease severity similar to study subjects have varied (15 % to 40 %) (Kar, 2007; Connock et al, 2008; Scottish Medicines Consortium, 2007; London New Drugs Group, 2008), this subgroup represents a minority of persons with PNH.  In a submission by the manufacturer of eculizumab to the National Health Service, the manufacturer anticipated that eculizumab would be reserved for use in the most severely affected patients (estimated to be 15 % of PHN patients) (Alexion Pharma, 2008). 

A phase II pilot study examined the effect of eculizumab on transfusion requirements and hemolysis.  Adult patients with a history of PNH for at least 6 months who had received at least 4 red cell transfusions in the preceding 12 months were eligible.  Eleven transfusion-dependent patients with PNH received transfusions of eculizumab (600 mg) every week for 4 weeks, followed 1 week later by a 900-mg does and then by 900-mg every other week through week 12.  The primary endpoint of this study was hemolysis as measured by LDH.  The mean transfusion rate decreased from 2.1 units per patient per month to 0.6 units per patient per month.  Mean lactate dehyhdrogenase (LDH) levels (a measure of hemolysis) decreased from 3,111 IU/L before treatment to 594 IU/L during treatment (p = 0.002).

In the pivotal randomized controlled clinical study (Transfusion Reduction Efficacy and Safety Using Eculizumab in Paroxysmal Nocturnal Hemoglobinuria [TRIUMPH]), Hillmen and colleagues (2006) enrolled 87 PNH patients who had received at least 4 transfusions in the prior 12 months, had a flow cytometric confirmation of at least 10 % PNH cells, and platelet counts of at least 100,000/microliter.  All subjects received meningococcal vaccination prior to treatment, and were randomized to receive either eculizumab (n = 43) or placebo (n = 44).  Prior to randomization, all patients underwent an initial observation period to confirm the need for transfusion of RBCs and to identify the hemoglobin (Hb) concentration (the "set-point"), which would define each patient’s Hb stabilization and transfusion outcomes.  Patients who did not need a red cell transfusion during the 3-month observation were not eligible for randomization.  The Hb set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms.  Endpoints related to hemolysis included the numbers of patients achieving Hb stabilization, the number of RBC units transfused, fatigue, and health-related quality of life.  To achieve a designation of Hb stabilization, a patient had to maintain a Hb concentration above the Hb set-point and avoid any transfusion of RBCs for the entire 26-week period.  Hemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of PNH RBCs was monitored by flow cytometry.  Patients receiving anti-coagulants and systemic corticosteroids at baseline continued these medications.

The 2 primary endpoints of the study were hemoglobin stabilization and the number of units of packed red blood cells transfused.  Patients treated with eculizumab had significantly reduced hemolysis (p < 0.001) resulting in improvements in anemia as indicated by increased Hb stabilization and reduced need for RBC transfusions compared to placebo-treated patients.  These effects were seen among patients within each of the 3 pre-study RBC transfusion strata (4 to 14 units; 15 to 25 units; greater than 25 units).  Eculizumab increased the baseline score for fatigue by 6.4 points on the FACIT-Fatigue instrument (score range 0 to 52), where a change of 3 or more points is the minimal change that is considered clinically significant.  Patients also reported improvements in health-related quality of life.  No thrombotic episodes were seen in the eculizumab group (21 of 43 patients in this group were on anti-coagulant drugs), whereas one thrombotic episode was reported in the placebo group (11 of 44 in this group were on anti-coagulant drugs).  Because changes in medications were not permitted, the impact of eculizumab on supportive therapy is not known.

In a 3rd, open-label study (Safety in Hemolytic PNH Patients Treated with Eculizumab: A Multi-centre Open-label Research Design Study [SHEPHERD]), Brodsky et al (2008) examined the safety and effectiveness of eculizumab in 97 subjects who had received at least 1 transfusion in the prior 24 months and with at least 30,000 platelets/microliter. A PNH type III RBC proportion of 10% or more as assessed by flow cytometry and LDH levels of 1.5 times or more the upper limit of the normal range were also required. All subjects received meningococcal vaccination prior to receiving an open-label, non-placebo-controlled, 52-week.  Concomitant medications included anti-thrombotic agents in 63 % of the patients and systemic corticosteroids in 40 % of the patients.  Overall, 96 of the 97 enrolled patients completed the study (1 patient died following a thrombotic event).  Efficacy outcomes for SHEPHERD were similar to those reported in both the phase II pilot study and TRIUMPH with transfusion-dependent stabilization of hemoglobin concentration, reduction in red-cell transfusion requirement, reduction in intravascular hemolysis (on the basis of a reduction in serum LDH concentration) and improvement in quality of life, particularly fatigue.  A reduction in intra-vascular hemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in a reduced need for RBCs transfusion and less fatigue.  Two patients with a history of thrombosis had a thrombotic event during the study.

All patients who participated in the 3 clinical trials described above were eligible for the extension study in which patients contined to receive eculizumab. Of 195 eligible patients, 187 enrolled in this long-term extension study which lasted 104 weeks. All patients sustained a reduction in intravascular hemolysis over a total eculizumab exposure time ranging from 10 to 54 months. There were fewer thrombotic events with eculizumab treatment than during the same period of time prior to treatment. However, the majority of patients received concomitant anticoagulants; the effects of anti-coagulant withdrawal during eculizumab therapy was not studied.

Despite differences in patient selection criteria in the TRIUMPH study and the SHEPHERD study, subjects in each study were similar in representing a subgroup of subjects at the most severe end of the spectrum of PNH disease.  In a recent review of eculizumab for PNH published in the Lancet, Parker (2009) observed that although entry criteria for the open-label SHEPHERD study were different fom those of the pivotal randomized controlled TRIUMPH study, no detailed statistical comparison between the demographic and baseline characteristics of the population of the 2 studies was presented in these publications.  Therefore, the extent of the difference could not be discerned from the data presented in these publications.  Parker noted, however, that data in a subsequent report showed considerable overlap in the 2 populations, including platelet count (162,000 per microliter for SHEPHERD versus 136,000 per microliter for SHEPHERD), size of PNH granulocyte clone (95 % for TRIUMPH versus 96 % for SHEPHERD), median proportion of type III red blood cell clones at baseline (greater than 30 % in TRIUMPH and SHEPHERD), and median LDH at baseline (2,200 U/L in TRIUMPH and 2,051 U/L for SHEPHERD).

Paroxysmal nocturnal hemoglobinuria is associated with a marked increase in venous thrombosis in the hepatic, other intra-abdominal, and peripheral veins.  While this propensity to thrombosis is not well understood, it is thought to be due to activation of complement on the platelet surface, which stimulates removal of complement complexes by vesiculation; the resulting circulating microparticles are rich in phosphatidylserine and are highly thrombogenic (Rosse, 2007; Rosse, 2010).  The risk of thrombosis appears to be significantly related to the size of the PNH clone.  In 2 series, almost all patients developing thrombosis had more than 50 % or more than 61 % PNH granulocytes (Nishimura et al, 2004; Moyo et al, 2004; and Rosse, 2010).

There is a lack of reliable evidence of the effect of eculizumab on survival or on the incidence of thromboembolic events (CADTH, 2010).  No evidence on the effect of eculizumab on thromboembolism was submitted to regulatory authorities.  Studies that have used "suboptimal" experimental design suggest that eculizumab might ameliorate the thrombophilia of PNH (Parker et al, 2007; Parker, 2009).  Although these studies suggest a role for eculizumab in the management of thromboembolic complications of PNH, "this issue would be best addressed by a prospective, randomized study" (Parker et al, 2007).

To assess the rate of thromboembolic events prior to and following initiation of eculizumab, Hillman et al (2007) compared retrospectively collected data to observational data in patients patients from the original pilot trial, TRIUMPH, SHEPHERD and the Phase IIIb extension study. Thromboembolism events were assessed in the major adverse vascular event (MAVE) criteria (see Appendix).  The principal investigators were responsible for the description, location, method of diagnosis, date of diagnosis, and date of resolution of each MAVE.  Events that antedated treatment with eculizumab were identified retrospectively from the period starting from the earlier of either the date of diagnosis of PNH or the date of the first thrombotic event to the time of the first eculizumab treament. The study found a relative reduction of 85% in thromboembolism event rate during eculizumab treatment.  In a critique of the study by Hillman et al, Parker noted that, with this method of comparing retrospective data with observational data, Hillman et al noted a substantial reduction in thromboembolic events in patients treated with eculizumab.  For example, the rate of thromboembolism was 7.37 events per 100 patient years before eculizumab treatment compared with 1.07 events per 100 patient years during treatment (p < 0.001), and thromboembolic events were reduced from 39 before treatment to 3 during eculizumab treatment (p < 0.001).  No data were provided to determine whether the magnitude of reduction in thromboembolic events observed during eculizumab treatment is the same or different across different types of thromboembolic events.  There are also no direct survival data available for eculizumab.

Parker observed that, in the only part of the study that was randomized and included a placebo group (TRIUMPH), one thromboembolic event occurred in the placebo group (11 of 44 patients were on anticoagulant drugs) and no thromboembolic events occurred in the eculizumab-treated group (21 of 43 patients were anticoagulated).  Parker observed that a large difference in the pretreatment thromboembolic rate was also seen among the treatment groups.  For example, in the placebo group of TRIUMPH, the thromboembolic event rate was 2.34 per 100 patient years, versus a thromboembolic event rate of 12.67 per 100 patient years for SHEPHERD.  Parker noted that these differences do not seem to be due to differences in baseline characteristics of the patients because the PNH clone sizes were equivalent.  A high rate of pre-treatment thromboembolic events (10.31 per 100 patient years) was reported in patients treated with anti-thrombotic drugs in the Hillman study, whereas complete protection against thromboembolism in patients with PNH treated with warfarin was previously reported in an earlier study coauthored by Hillmen (Hall et al, 2003), where data were also collected retrospectively.

A review by the Canadian Agency for Drugs and Technologies in Health (2010) concurred that although this study suggests a significant reduction in thrombotic event rates, "limitations associated with retrospective data collection and non-randomized studies limit the scientific validity of these data."

An assessment by the All Wales Medicines Strategy Group (2009) noted that the rates of baseline thrombosis in the eculizumab trials was substantially higher than the rate in patients at presentation in one of the natural history studies presented to the group by the manufacturer of eculizumab.  The group noted that although a significant proportion of subjects in these clinical studies received anticoagulants, it is not clear what proportion of patients who received anti-coagulants achieved adequate anticoagulation (e.g., INR levels within therapeutic range) either prior to initiation or eculizumab or during eculizumab treatment. Thus, it is not known whether improvements in thromboembolic event rates following eculizumab treatment may have been due to improved use of anti-coagulation.

In a post-hoc analysis of the extension study, eculizumab treatment was associated with a significant increase in the likelihood of improvement and prevention of worsening of kidney function (Hillmen et al, 2010).  This is an analysis of data from studies that were not designed to assess the impact of eculizumab on renal function; thus, this analysis has limitations similar to the previously described post-hoc analysis of the association of eculizumab with thrombosis.

Hill, et al. (2010) investigated the effect of eculizumab on NO depletion, dyspnea and measures of pulmonary hypertension. This study was carried out with patients from the TRIUMPH trial only. Treatment with eculizumab significantly reduced NO depletion, dyspnea and decreased the proportion of patients with elevated pro-brain naturetic peptide (proBNP).

Most of the published literature regarding the use of eculizumab in patients with PNH has been derived from studies of 187 patients that were enrolled in the clinical trials that lead to FDA approval.  To date, few studies have evaluated eculizumab outside the context of a clinical trial (Varela and Brodsky, 2013).

Kelly et al (2010) evaluated 79 consecutive patients treated with eculizumab in the UK between May 2002 and July 2010.  Of the 79 patients, 34 were enrolled in one of the original clinical trials.  Mean LDH at the initiation of treatment was 2872 U/L, mean PNH RBC clone size was 34 %, mean PNH granulocyte clone size was 96.4 %, and the mean number of units of PRBCs transfused within the 12 months prior to the study was 19.9.  The authors reported that the survival of patients treated with eculizumab was not different from age- and sex-matched normal controls (p = 0.46) but was significantly better than 30 similar patients managed before eculizumab (p = 0.030). 

Dezen et al (2013) reported on a retrospective, single center study that evaluated the response of 30 patients with PNH to treatment with eculizumab.  Of 73 patients diagnosed with a PNH clone at Johns Hopkins University, 30 were treated with eclizumab and were the subjects of this study.  Of note, out of these 30 patients, 5 were enrolled on the TRIUMPH or SHEPHERD trial.  Mean LDH at the initiation of treatment was 1,489 IU/L, mean PNH RBC clone size was 37.5 %, mean PNH granulocyte clone size was 86.5 %, and mean Hgb was 8.6 g/dL.  Over 863 patient-months of eculizumab treatment, 4 patients had a complete response, 16 had a partial response, and 10 had a suboptimal response.

A number of authorities have concluded that treatment with eculizumab is not appropriate for all patients with PNH (Willacy, 2009; Parker, 2009; Parker, 2011).  Parker (2009) has stated that, due to the heterogenous nature of PNH, "treatment with eculizumab is not appropriate for all patients with PNH."  Parker explained that the extent to which the abnormal PNH clone expands varies widely among patients.  Patients with a small number of PNH clonal cells have few symptoms and do not need PNH-specific treatment.  In addition, patients with hypoplastic PNH, characterized by moderate to severe cytopenias and hypoplastic bone marrow, are less likely to respond to eculizumab, because bone marrow suppression, rather than complement-mediated hemolysis is the major mechanism of anemia; these patients are likely to respond to immunosuppressive therapy. 

The European Medicines Agency concluded that "[e]vidence of clinical benefit of Soliris in patients with PNH is limited to patients with history of transfusions."

Brodsky (2010) commented that the only effective therapies for paroxysmal nocturnal hemoglobinuria are allogeneic bone marrow transplantation and inhibition of terminal complement with eculizumab. However, eculizumab does not improve bone marrow function and is not very effective for aplastic anemia/PNH. The author noted, moreover, that eculizumab is expensive, does not eradicate the PNH clone, and must be given lifelong; thus, it is best reserved for patients with classical paroxysmal nocturnal hemoglobinuria.

Brodsky (2009) stated that patients with classic PNH have signs and symptoms of intravascular hemolysis. These patients tend to have a normocellular to hypercellular bone marrow with erythroid hyperplasia, an elevated reticulocyte count, a large population of PNH cells (usually > 60% PNH granulocytes) and a lactic dehydrogenase (LDH) that is 2 to 10 times the upper limit of normal. Hemoglobinuria, smooth muscle dystonias (eg, esophageal spasm and erectile dysfunction), severe fatigue, and thrombosis are common in patients with classic PNH. Patients with small PNH clones in the setting of bone marrow failure probably represent bone marrow failure that is immune mediated, and immunosuppressive therapy is probably the most effective therapy in these patients.

An open-label, prospective 12-week phase II study (AEGIS) evaluated the effectiveness of eculizumab in reducing hemolysis (primary endpoint) in 29 Japanese patients with PNH, with enrollment criteria similar to previously published pivotal studies (Kanakura et al, 2011).  Adults and adolescents were enrolled in the study if they had been diagnosed with PNH for at least 6 months and had a PNH RBC clone size of at least 10%, lactate dehydrogenase (LDH) levels >1.5 times the upper limit of normal (240 U/L), a platelet count >30 x 109/L, and a neutrophil count of greater than 500/µL. Patients were to have received or could have benefited from at least one RBC transfusion over the past 2 years. The mean PNH RBC clone size at initiation of the study was 43.6%, the mean LDH was 1827.6 U/L, the mean granulocyte clone size was 91.7%, the mean hemoglobin was 8 g/dL, and the median number of PRBCs transfused within the previous 12 months was 14. The investigators reported an 87% reduction in hemolysis and subsequent improvement in anemia with eculizumab. The long-term efficacy and safety of eculizumab was assessed in a 2-year extension to the AEGIS study (Kanakura et al., 2013). The investigators reported that eculizumab treatment led to an immediate and sustained reduction in intravascular hemolysis and red blood cell transfusions compared with baseline levels. There were no reports of thromboembolism during eculizumab treatment.

Hillmen et al (2013) reported on the long-term safety and efficacy of eculizumab in patients with hemolytic PNH who had participated in one of the three prospective parent trials: the Phase II pilot study and its extensions, the Phase III TRIUMPH or the Phase III SHEPHERD study. At the end of these initial studies, 187 of the 195 patients enrolled in an open-label extension study. All patients had a minimum of 10% PNH red blood cells at enrollment in the parent trials. Mean baseline hemoglobin in subjects was 9.37 g/dL, and mean LDH was 22293 U/L.  All three parent trials employed the same dosing regimen: 600-mg infusions of eculizumab every week for 4 weeks, followed 1 week later by a single 900-mg dose, and then a maintenance dose of 900 mg every 14 (±2) days until the end of the study. In the extension study patients continued to receive the maintenance dose of eculizumab.The entire period of eculizumab administration across the parent and extension trials was 66 months, although a 36-month cut-off was used for safety and efficacy assessments to ensure that there were a sufficient number of patients for robust statistical analysis. The median eculizumab treatment duration was 30·3 months, with a maximum duration of 66 months. All patients showed a rapid decrease from baseline in serum LDH. This decrease was maintained with sustained eculizumab treatment; the median LDH value at 36 months was 279 U/L (range: 88–1417 U/Ll), a relative reduction from baseline of 86·9%. The percentage of patients achieving transfusion independence was 82·1% (64 of 78) by the last 6 months of treatment, compared with only 8·2% (16 of 195) in the 6 months prior to the start of treatment, a relative increase of 90.0%. Fourteen of 78 patients (17·9%) continued to require transfusions between months 30 and 36. The number of units of PRBCs transfused over the course of the study significantly decreased from a mean of 11·2 units in the 6 months prior to starting eculizumab to 3·5 units between months 30 and 36 (P = 0·0001). The percentage of patients free from TEs increased from 67·7% before treatment to 96·4% during treatment. Eighty-four patients in this study received concomitant anticoagulant therapy..The percentage of patients showing improvement, worsening or no change in chronic kidney disease was 44·8%, 6·9% and 48·3% respectively, at 36 months. Four patient deaths were reported, all unrelated to treatment, resulting in a 3-year survival estimate of 97·6%. Although nearly all patients reported at least one adverse event, discontinuation from treatment due to a nonfatal adverse event was seen in only five patients over the entire period of study.

Overall benefits of eculizumab in PNH have been estimated; using a Markov model, Coyle, et al. (2014) estimated that treatment of PNH with eculizumab is associated with 1.13 greater life years and 2.45 more quality adjusted life years (QALYs) per person than current standard of care.

A systematic review of evidence for eculizumab by the Institute for Clinical Effectiveness and Health Policy (Pichon Riviere et al, 2011) concluded that "the available evidence shows that eculizumab is effective in reducing complement-mediated hemolysis", but that "the evidence is not very strong since there is no CRCT [controlled randomized clinical trials] conducted on prevention of thrombotic events."  The assessment stated that "it has not been determined if eculizumab therapy increases survival of PNH patients yet."  The assessment noted that, "although some private insurance companies in the United States give coverage to certain patients, most health systems in different countries do not cover it due to its high costs and because it provides marginal benefits when compared with standard care for PNH."

Varela and Brodsky (2013) stated that the severity of symptoms is variable among patients diagnosed with PNH and not all patients require treatment. The authors state there are no clear guidelines for the use of eculizumab, but that it should not be routinely administered to patients who are minimally symptomatic or whose PNH clone size is very small. Given that eculizumab is expensive, does not eradicate the PNH clone, and must be given lifelong, it is best reserved for patients with prominent signs and symptoms of classical PNH. The author noted that, besides the original trials that led to the approval of eculizumab for treatment of PNH, not many other studies have been conducted to evaluate the long-term effects of eculizumab. The authors stated that more experience with administration of eculizumab should provide more evidence for clearer treatment parameters such as when to initiate treatment.

In a Lancet review of eculizumab for PNH, Parker (2009) explained the eculizumab does not increase the risk of catastrophic hemolytic crisis if the drug is discontinued.  He noted that, of 195 patients in clinical trials, 16 had discontinued treatment with no catastrophic hemolysis reported.  During treatment with eculizumab, the percentage of PNH erythrocytes in peripheral blood increases because eculizumab enhances survival of the abnormal cells by protecting them against complement-mediated lysis.  The fact that treatment with eculizumab increases the proportion of these cells initially raised concerns that discontinuation of the drug might result in a hemolytic crisis.  Parker (2009) reported, however, that 16 patients have discontinued treatment with eculizumab without having exacerbation of hemolysis.  A more recent report by the Canadian Agency for Technology Assessment in Health (CADTH, 2010) also noted that, despite the theoretical possibility of a rebound effect upon discontinuation of eculizumab, no cases have been identified to date.

A Cochrane review (Marti-Carvajal et al, 2014) assessed the clinical benefits and harms of eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria (PNH). The authors conducted a comprehensive search strategy. They included randomized controlled trials (RCTs) comparing eculizumab with placebo or best available therapy for patients with a confirmed diagnosis of PNH. The primary outcome was overall survival. The authors identified one multicenter (34 sites) phase III RCT involving 87 participants. The trial compared eculizumab versus placebo, and was conducted in the US, Canada, Europe, and Australia with 26 weeks of follow-up. This small trial had high risk of bias in many domains (attrition and selective reporting). It was sponsored by a pharmaceutical company. No patients died during the study. By using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (scores can range from 0 to 100, with higher scores on the global health status and functioning scales indicating improvement), the trial showed improvement in health-related quality of life in patients treated with eculizumab (mean difference (MD) 19.4, 95% confidence interval [CI]: 8.25 to 30.55; P = 0.0007; low quality of evidence). By using the Functional Assessment of Chronic Illness Therapy Fatigue instrument (scores can range from 0 to 52, with higher scores indicating improvement in fatigue), the trial showed a reduction in fatigue (MD 10.4, 95% CI 9.97 to 10.83; P = 0.00001; moderate quality of evidence) in the eculizumab group compared with placebo. Eculizumab compared with placebo showed a greater proportion of patients with transfusion independence: 51% (22/43) versus 0% (0/44); risk ratio (RR) 46.02, 95% CI 2.88 to 735.53; P = 0.007; moderate quality of evidence; and withdrawal for any reason: 4.7% (2/43) versus 22.72% (10/44); RR 0.20, 95% CI 0.05 to 0.88; P = 0.03; moderate quality of evidence. Due to the low rate of events observed, the included trial did not show any difference between eculizumab and placebo in terms of serious adverse events: 9.3% (4/43) versus 20.4% (9/44); RR 0.15, 95% CI 0.15 to 1.37; P = 0.16; low quality of evidence. The authors did not observe any difference between intervention and placebo for the most frequent adverse events. One participant receiving placebo showed an episode of thrombosis. The trial did not assess overall survival, transformation to myelodysplastic syndrome and acute myelogenous leukemia, or development or recurrence of aplastic anemia on treatment. The authors concluded that this review has detected an absence of evidence for eculizumab compared with placebo for treating paroxysmal nocturnal hemoglobinuria (PNH), in terms of overall survival, nonfatal thrombotic events, transformation to myelodysplastic syndrome and acute myelogenous leukemia, and development and recurrence of aplastic anemia on treatment. Current evidence indicates that compared with placebo, eculizumab increases health-related quality of life and increases transfusion independence. During the execution of the included trial, no patients died. Furthermore, the intervention seems to reduce fatigue and withdrawals for any reason. The safety profile of eculizumab is unclear. These conclusions are based on one small trial with risk of attrition and selective reporting bias.The authors concluded, therefore, that the prescription of eculizumab for treating patients with PNH can neither be supported nor rejected, unless new evidence from a large high quality trial alters this conclusion. Therefore, the authors urged the reader to interpret the trial results with much caution. Future trials on this issue should be conducted according to the SPIRIT statement and reported according to the CONSORT statement by independent investigators, and using the Foundation of Patient-Centered Outcomes Research recommendations.

Kelly et al (2015) designed a questionnaire to solicit data on pregnancies in women with PNH and sent it to the members of the International PNH Interest Group and to the physicians participating in the International PNH Registry. The investigators assessed the safety and efficacy of eculizumab in pregnant patients with PNH by examining the birth and developmental records of the children born and adverse events in the mothers. Of the 94 questionnaires that were sent out, 75 were returned, representing a response rate of 80%. Data on 75 pregnancies in 61 women with PNH were evaluated. There were no maternal deaths and three fetal deaths (4%). Six miscarriages (8%) occurred during the first trimester. Requirements for transfusion of red cells increased during pregnancy, from a mean of 0.14 units per month in the 6 months before pregnancy to 0.92 units per month during pregnancy. Platelet transfusions were given in 16 pregnancies. In 54% of pregnancies that progressed past the first trimester, the dose or the frequency of use of eculizumab had to be increased. Low-molecular-weight heparin was used in 88% of the pregnancies. Ten hemorrhagic events and 2 thrombotic events were documented; both thrombotic events occurred during the postpartum period. A total of 22 births (29%) were premature. Twenty cord-blood samples were examined for the presence of eculizumab; the drug was detected in 7 of the samples. A total of 25 babies were breast-fed, and in 10 of these cases, breast milk was examined for the presence of eculizumab; the drug was not detected in any of the 10 breast-milk samples. The authors concluded that eculizumab provided benefit for women with PNH during pregnancy, as evidenced by a high rate of fetal survival and a low rate of maternal complications.

Dezern and Borowitz (2018) discuss the ICCS/ESCCA consensus guidelines regarding the clinical utility of detecting glycosyl phosphatidylinositol (GPI)-deficient cells in PNH and other bone marrow failure disorders. The authors state that flow cytometry is used to detect the deficiency in PNH. Their guidelines provide guidance to clinicians on patient selection and test interpretation (including PNH clone testing). The authors note that when PNH flow cytometry testing is interpreted correctly, the results ("including presence and size of the clonal populations and the cell types involved") will allow the clinician "to classify the disease appropriately; evaluate the risk of disease progression; and subsequently monitor response to therapy". The authors emphasize the positive contribution of flow cytometry testing in the diagnosis, classification, and monitoring of patients.

Other Indications

Eculizumab is also being examined in the treatment of various disorders/syndromes including antibody-mediated rejection, Guillain-Barre syndrome, and systemic lupus erythematosus.  However, there is currently insufficient evidence to support the use of eculizumab for these conditions.

Stegall and Gloor (2010) described recent studies regarding the mechanisms of antibody-mediated rejection (AMR) and new clinical protocols aimed at prevention and/or treatment of this difficult clinical entity.  These investigators noted that the natural history of acute AMR after positive cross-match kidney transplantation involves an acute rise in donor-specific alloantibody in the first few weeks following transplantation.  Whereas the exact cellular mechanisms responsible for AMR are not known, it seems likely that both pre-existing plasma cells and the conversion of memory B cells to new plasma cells play a role in the increased donor-specific alloantibody production.  One recent study suggested that combination therapy with plasmapheresis, high-dose IVIG and rituximab was more effective treatment for AMR than high-dose IVIG alone, but the role of anti-CD20 antibody is still unclear.  Two new promising approaches to AMR focus on depletion of plasma cells with bortezomib as well as the inhibition of terminal complement activation with eculizumab.  The authors concluded that the pathogenesis of AMR in several different clinical settings is becoming clearer and more effective treatments are being developed.  Whether the prevention or successful treatment of AMR will decrease the prevalence of chronic injury and improved long-term graft survival will require longer-term studies.  Moreover, in a review on advances in diagnosing and managing AMR, Jordan et al (2010) stated that newer approaches in treating AMR include bortezomib and eculizumab.

McCaughan and associates (2012) stated that dense deposit disease is a rare glomerulonephritis caused by uncontrolled stimulation of the alternative complement pathway.  Allograft survival after kidney transplantation is significantly reduced by the high rate of disease recurrence.  No therapeutic interventions have consistently improved outcomes for patients with primary or recurrent disease.  This was the first reported case of recurrent dense deposit disease being managed with eculizumab.  Within 4 weeks of renal transplantation, deteriorating graft function and increasing proteinuria were evident.  A transplant biopsy confirmed the diagnosis of recurrent dense deposit disease.  Eculizumab was considered after the failure of corticosteroid, rituximab and plasmapheresis to attenuate the rate of decline in allograft function.  There was a marked clinical and biochemical response following the administration of eculizumab.  This case provided the first evidence that eculizumab may have a place in the management of crescentic dense deposit disease.  The authors noted that more information is needed to clarify the effectiveness and role of eculizumab in dense deposit disease but the response in this patient was encouraging.  The results of clinical trials of eculizumab in this condition are eagerly awaited.

In an open-label, proof of concept efficacy and safety study, Bomback et al (2012) examined the effects of eculizumab for dense deposit disease and C3 glomerulonephritis.  A total of 6 subjects with dense deposit disease or C3 glomerulonephritis were treated with eculizumab every other week for 1 year.  All had proteinuria greater than 1 g/day and/or acute kidney injury (AKI) at enrollment.  Subjects underwent biopsy before enrollment and repeat biopsy at the 1-year mark.  The subjects included 3 patients with dense deposit disease (including 1 patient with recurrent dense deposit disease in allograft) and 3 patients with C3 glomerulonephritis (including 2 patients with recurrent C3 glomerulonephritis in allograft).  Genetic and complement function testing revealed a mutation in CFH and MCP in 1 subject each, C3 nephritic factor in 3 subjects, and elevated levels of serum membrane attack complex in 3 subjects.  After 12 months, 2 subjects showed significantly reduced serum creatinine, 1 subject achieved marked reduction in proteinuria, and 1 subject had stable laboratory parameters but histopathologic improvements.  Elevated serum membrane attack complex levels normalized on therapy and paralleled improvements in creatinine and proteinuria.  The authors concluded that clinical and histopathologic data suggest a response to eculizumab in some but not all subjects with dense deposit disease and C3 glomerulonephritis.  Elevation of serum membrane attack complex before treatment may predict response.  They stated that additional research is needed to define the subgroup of dense deposit disease/C3 glomerulonephritis patients in whom eculizumab therapy can be considered.

In a Cochrane review, Gordon and colleagues (2012) evaluated the effects of immunosuppressants and immunomodulatory treatments for dermatomyositis and polymyositis.  These investigators searched the Cochrane Neuromuscular Disease Group Specialized Register (August 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3 2011), MEDLINE (January 1966 to August 2011), EMBASE (January 1980 to August 2011) and clinicaltrials.gov (August 2011). They checked the bibliographies of identified trials and wrote to disease experts. These researchers included all randomized controlled trials (RCTs) or quasi-RCTs involving participants with probable or definite dermatomyositis and polymyositis as defined by the criteria of Bohan and Peter, or definite, probable or mild/early by the criteria of Dalakas. In participants without a classical rash of dermatomyositis, inclusion body myositis should have been excluded by muscle biopsy. These investigators considered any immunosuppressant or immunomodulatory treatment. The 2 primary outcomes were the change in a function or disability scale measured as the proportion of participants improving 1 grade, 2 grades etc, pre-defined based on the scales used in the studies after at least 6 months, and a 15 % or greater improvement in muscle strength compared with baseline after at least 6 months. Other outcomes were: the International Myositis Assessment and Clinical Studies Group (IMACS) definition of improvement, number of relapses and time to relapse, remission and time-to-remission, cumulative corticosteroid dose and serious adverse effects. Two authors independently selected papers, extracted data and assessed risk of bias in included studies. They collected adverse event data from the included studies. The review authors identified 14 relevant RCTs; they excluded 4 trials. The 10 included studies, 4 of which have been added in this update, included a total of 258 participants. Six studies compared an immunosuppressant or immunomodulator with placebo control, and 4 studies compared 2 immunosuppressant regimes with each other. Most of the studies were small (the largest had 62 participants) and many of the reports contained insufficient information to assess risk of bias. Amongst the 6 studies comparing immunosuppressant with placebo, 1 study, investigating IVIG, showed statistically significant improvement in scores of muscle strength in the IVIG group over 3 months. Another study investigating etanercept showed some evidence of a steroid-sparing effect, a secondary outcome in this review, but no improvement in other assessed outcomes. The other 4 randomized placebo-controlled trials assessed either plasma exchange and leukapheresis, eculizumab, infliximab or azathioprine against placebo and all produced negative results. Three of the 4 studies comparing 2 immunosuppressant regimes (azathioprine with methotrexate, ciclosporin with methotrexate, and intra-muscular methotrexate with oral methotrexate plus azathioprine) showed no statistically significant difference in efficacy between the treatment regimes. The 4th study comparing pulsed oral dexamethasone with daily oral prednisolone and found that the dexamethasone regime had a shorter median time to relapse but fewer side effects. Immunosuppressants were associated with significant side effects. The authors concluded that this systematic review high-lighted the lack of high quality RCTs that evaluate the effectiveness and toxicity of immunosuppressants in inflammatory myositis.

Diaz-Manera et al (2012) noted that new treatments for immune mediated diseases have increased notably in the past decade.  Monoclonal antibodies directed against different components of the immune system have appeared, along with new drugs from the hematology field. In the case of myasthenia gravis (MG), many of these new treatments have been used in experimental animal models and also in patients.  These investigators reviewed the progress in the field of MG treatment achieved in the last 5 years.  Firstly, the authors' current treatment protocol was introduced. Secondly, new data from recent randomized trials and case series of patients treated with methotrexate, cyclophosphamide, rituximab or improved systems of apheresis was reported.  Finally, all future treatments were discussed that are currently under evaluation in pre-clinical animal models of experimental autoimmune MG. Evidence supporting the use of methotrexate and rituximab in MG has been published recently, in addition to conflicting randomized trials that were not successful, evaluating the use of tacrolimus as a steroid sparing agent.  New promising treatments are currently under evaluation in clinical trials, such as belimumab and eculizumab.

An UpToDate review on “Investigational immunosuppressive drugs and approaches in clinical kidney transplantation” (Vella, 2013) states that “Agents currently under development include eculizumab, alefacept, voclosporine, sotrastaurin, tasocitinib, and bortezomib.  The roles for bortezomib and eculizumab in the management of antibody mediated rejection remain to be defined.  All of the other agents discussed in this topic review either have had their development discontinued or remain in early phase clinical trials”.

Canaud et al (2013) stated that thrombotic microangiopathy (TMA) is one of the hallmark vascular lesions of anti-phospholipid syndrome nephropathy (APSN).  These lesions are at high risk of recurrence after kidney transplantation.  The complement pathway is thought to be active in this process.  These researchers used eculizumab to treat 3 consecutive kidney transplant recipients with post-transplant TMA due to APSN recurrence that was resistant to plasmapheresis and explored the complement deposition and apoptotic and vascular cell markers on the sequential transplant biopsies.  Treatment with eculizumab resulted in a rapid and dramatic improvement of the graft function in all 3 patients and in improvement of the TMA lesions within the graft.  None of these patients had TMA flares after eculizumab was withdrawn.  At the time of TMA diagnosis, immunofluorescence studies revealed intense C5b-9 and C4d depositions at the endothelial cell surface of the injured vessels.  Moreover, C5b-9 co-localized with vessels exhibiting a high rate of apoptotic cells.  Examination of sequential biopsies during eculizumab therapy showed that TMA lesions, C4d and apoptotic markers were rapidly cleared, but the C5b-9 deposits persisted for several months as a footprint of the TMA.  Finally, these investigators noticed that complement inhibition did not prevent the development of the chronic vascular changes associated with APSN.  They stated that eculizumab seems to be an efficient method for treating severe forms of post-transplant TMA due to APSN recurrence.  Moreover, terminal complement inhibition does not prevent the development of chronic APSN.

Nobile-Orazio and Gallia (2013) stated that multi-focal motor neuropathy (MMN) is a purely motor mononeuritis multiplex characterized by the presence of conduction block on motor but not on sensory nerves and by the presence of high titers of anti-GM1 antibodies.  Several studies pointed to a pathogenetic role of the immune system in this neuropathy, although this has not yet been proved.  Several uncontrolled studies and RCTs have demonstrated the efficacy of therapy with high-dose IVIG in MMN.  However, this therapy has a short-lasting effect that needs to be maintained with periodic infusions.  This can be partly overcome by the use of subcutaneous immunoglobulin (SCIG) at the same dose.  The high cost and need for repeated infusions have led to the search for other immune therapies, the efficacy of which had not yet been confirmed in RCTs.  In addition, some therapies, including corticosteroids and plasma exchange, are not only ineffective, but have been associated with clinical worsening.  More recently, a number of novel therapies have been investigated in MMN, including interferon-β1a, rituximab, and eculizumab.  Preliminary data from open-label uncontrolled studies showed that some patients improve after these therapies; however, RCTs are needed to confirm effectiveness.

Burwick and Feinberg (2013) noted that severe preeclampsia with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome is a leading cause of maternal and neonatal morbidity and mortality worldwide.  Occurrence at an extremely premature gestational age is most challenging as there are dichotomous imperatives: delivery as definitive therapy for maternal health versus prolongation of pregnancy to avoid prematurity and associated morbidities.  These researchers described a patient presenting with severe preeclampsia/HELLP syndrome at 26 weeks gestation that was treated with eculizumab, which resulted in marked clinical improvement and complete normalization of laboratory parameters.  Pregnancy was prolonged 17 days, likely resulting in a reduction of neonatal morbidity with its associated short- and long-term health care costs.  The authors concluded that successful use of eculizumab in this case suggested that complement inhibition may be an effective treatment strategy for severe preeclampsia/HELLP syndrome.  The finding of this single-case study needs to be validated by well-designed studies.

Leung and Landa (2013) stated that ARMD is the leading cause of irreversible blindness in developed countries.  There are currently no cures, but there are promising potential therapies that target the underlying disease mechanisms of dry ARMD.  Stem cells, ciliary neurotrophic factor, rheopheresis, ozonated auto-hemotherapy, as well as prostaglandins show promise in stabilizing or improving visual acuity; and AREDS vitamins may reduce progression to severe ARMD.  Adjuvant therapy like low-vision rehabilitation and implantable miniature telescopes may help patients adjust to the sequelae of their disease, and herbal supplementation with saffron, zinc monocysteine and phototrop may be helpful.  Therapies that are currently in clinical trials include brimonidine, doxycycline, anti-amyloid antibodies, complement inhibitors, hydroxychloroquine, intra-vitreal fluocinolone acetate and vasodilators (e.g., sildenafil and moxaverine).  Therapies that have not been shown to be effective include POT-4, eculizumab, tandospirone, anecortave acetate, the antioxidant OT-551, sirolimus and vitamin E.

Orandi and colleagues (2014) stated that incompatible live donor kidney transplantation is associated with an increased rate of AMR and subsequent transplant glomerulopathy.  For patients with severe, oliguric AMR, graft loss is inevitable without timely intervention.  These investigators reviewed their experience rescuing kidney allografts with this severe AMR phenotype by using splenectomy alone (n = 14), eculizumab alone (n = 5), or splenectomy plus eculizumab (n = 5), in addition to plasmapheresis.  The study population was 267 consecutive patients with donor-specific antibody undergoing desensitization.  In the first 3 weeks after transplantation (median = 6 days), 24 patients developed sudden onset oliguria and rapidly rising serum creatinine with marked rebound of donor-specific antibody, and a biopsy that showed features of AMR.  At a median follow-up of 533 days, 4 of 14 splenectomy-alone patients experienced graft loss (median = 320 days), compared to 4 of 5 eculizumab-alone patients with graft failure (median = 95 days).  No patients treated with splenectomy plus eculizumab experienced graft loss.  There was more chronic glomerulopathy in the splenectomy-alone and eculizumab-alone groups at 1 year, whereas splenectomy plus eculizumab patients had almost no transplant glomerulopathy.  The authors concluded that these data suggested that for patients manifesting early severe AMR, splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function.  These preliminary findings need to be validated by well-designed studies.

In a prospective, double-masked, randomized clinical trial, Yehoshua et al (2014) evaluated the effect of eculizumab on the growth of geographic atrophy (GA) in patients with ARMD.  Patients with GA measuring from 1.25 to 18 mm(2) based on spectral-domain optical coherence tomography (OCT) imaging were included in this study.  Patients were randomized 2:1 to receive I.V. eculizumab or placebo over 6 months.  In the eculizumab treatment-arm, the first 10 patients received a low-dose regimen of 600 mg weekly for 4 weeks followed by 900 mg every 2 weeks until week 24, and the next 10 patients received a high-dose regimen of 900 mg weekly for 4 weeks followed by 1,200 mg every 2 weeks until week 24.  The placebo group was infused with saline.  Patients were observed off treatment for an additional 26 weeks.  Both normal-luminance and low-luminance visual acuities were measured throughout the study, and the low-luminance deficits were calculated as the difference between the letter scores.  Main outcome measure was change in area of GA at 26 weeks.  A total of 30 eyes of 30 patients were enrolled; 18 fellow eyes also met inclusion criteria and were analyzed as a secondary end-point.  For the 30 study eyes, mean square root of GA area measurements ± standard deviation at baseline were 2.55 ± 0.94 and 2.02 ± 0.74 mm in the eculizumab and placebo groups, respectively (p = 0.13).  At 26 weeks, GA enlarged by a mean of 0.19 ± 0.12 and 0.18 ± 0.15 mm in the eculizumab and placebo groups, respectively (p = 0.96).  At 52 weeks of follow-up, GA enlarged by a mean of 0.37 ± 0.22 mm in the eculizumab-treated eyes and by a mean of 0.37 ± 0.21 mm in the placebo group (p = 0.93, 2 sample t-test).  None of the eyes converted to wet ARMD; no drug-related adverse events were identified.  The authors concluded that systemic complement inhibition with eculizumab was well-tolerated through 6 months; but did not decrease the growth rate of GA significantly.

Tobin et al (2014) noted that longitudinally extensive transverse myelitis (LETM) is a frequently devastating clinical syndrome which has come into focus for its association with NMO.  Recent advances in the diagnosis of NMO have led to very sensitive and specific tests and advances in therapy for this disorder.  Longitudinally extensive transverse myelitis is not pathognomonic of NMO, therefore it is important to investigate for other causes of myelopathy in these patients.  These researchers discussed recent advances in NMO diagnosis and treatment and the differential diagnosis in patients presenting with LETM.  Fluorescence-activated cell sorting and cell binding assays for NMO-IgG are the most sensitive for detecting NMO spectrum disorders.  Patients who have a clinical presentation of NMO, who have been tested with older ELISA or immunofluorescence assay and been found to be negative, should be re-tested with a fluorescence-activated cell sorting assay when available, particularly in the presence of recurrent LETM.  The authors stated that novel therapeutic strategies for LETM in the context of NMO include eculizumab, which could be considered in patients with active disease who have failed azathioprine and rituximab.  Moreover, they noted that thorough investigation of patients with LETM who are negative for NMO-IgG may lead to an alternate cause for myelopathy.

Rosenblad et al (2014) noted that immunoglobulin A (IgA) nephropathy is a chronic glomerulonephritis with excessive glomerular deposition of IgA1, C3 and C5b-9, which may lead to renal failure.  These researchers described the clinical course of an adolescent with rapidly progressive disease leading to renal failure in spite of immunosuppressive treatment.  Due to refractory disease the patient was treated with eculizumab (anti-C5) for 3 months in an attempt to rescue renal function.  Treatment led to clinical improvement with stabilization of the glomerular filtration rate (GFR) and reduced proteinuria.  Discontinuation of treatment led to a rapid deterioration of renal function.  This was followed by a single dose of eculizumab, which again reduced creatinine levels temporarily.  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.  These preliminary findings need to be validated by well-designed studies.

Bevacizumab-Associated Thrombotic Microangiopathy

Hilburg and colleagues (2021) stated that bevacizumab is used in the management of various solid malignancies.  The adverse effect profiles of angiogenesis inhibitors, such as bevacizumab, have become increasingly well characterized and include renal manifestations such as hypertension, proteinuria, and TMA.  Eculizumab inhibits terminal-complement activation and is used in the treatment of aHUS.  There has been growing usage of eculizumab in the treatment of bevacizumab-associated TMA.  These researchers carried out a systematic review of the literature to identify full-text articles that described the use of eculizumab for bevacizumab-associated TMA.  The systematic review identified 522 unique articles of which 5 were included in the final review; 9 cases, including 2 new cases presented in this review, were identified in which eculizumab was used in the management of bevacizumab-associated TMA.  Hematologic parameters and kidney function stabilized or improved in all cases, and the 2 patients who needed renal replacement therapy were able to discontinue dialysis.  The authors concluded that given the findings of this systematic review, the use of eculizumab in the treatment of bevacizumab-associated TMA warrants further study, especially in severe cases.

Valerio and associates (2021) noted that TMA is a syndrome triggered by a wide spectrum of situations, some of which are specific to the oncology setting.  It is characterized by a Coombs-negative microangiopathic hemolytic anemia, thrombocytopenia and organ injury, with characteristic pathological features, resulting from platelet microvascular occlusion.  TMA is rare and its cancer-related subset even more so.  TMA triggered by drugs is the most common within this group, including classic chemotherapy and the latest targeted therapies.  The neoplastic disease itself and HSCT could also be potential triggers.  Evidence-based medical guidance in the management of cancer-related TMA is scarce and the previous knowledge regarding primary TMA is valuable to understand the disease mechanisms and the potential treatments.  These researchers stated that while eculizumab has emerged as one of the most promising treatments for other TMAs, such as aHUS, its efficacy in HSCT-TMA is arguably modest.  Retrospective studies that showed superior results when compared to plasmapheresis were based on small samples.  Worse outcomes were described in patients with higher sC5b-9, with a lower likelihood to respond to treatment.  The moderate therapeutic success achieved with eculizumab has led to investigation of other targeted therapies that act on various stages of the complement system.  Some studies, still on phase II/III, already show encouraging results.  The authors concluded that there is currently no solid evidence supporting any particular therapeutic approaches; RCTs would be the only way to make it possible to recommend a specific therapy.

Sterner and Rose (2022) stated that TMA are a rare group of life-threatening hematological conditions characterized by thrombocytopenia and microangiopathic hemolytic anemia.  Although the understanding of the pathophysiology and the availability of diagnostic testing has improved for primary TMAs, such as TTP, the pathophysiology underlying secondary TMAs, including drug-induced TMAs (DITMAs), remains less clear.  In a single-case study, these investigators reported the unique case of a patient with a history of multiple myeloma (MM) that presented 4 months following the initiation of bortezomib therapy with a bortezomib-associated TMA that responded to TPE with plasma replacement and eculizumab therapy.   The authors concluded that this case demonstrated the possible use of TPE with plasma replacement and eculizumab therapy in DITMA patients who failed to respond after discontinuation of the suspected medication.

C3 Glomerulopathy

Vivarelli and Emma (2014) stated that C3 glomerulopathy (C3G) is a newly defined clinical entity comprising glomerular lesions with predominant C3 staining.  Under this definition are now included membrano-proliferative glomerulonephritis type II (dense deposit disease) and C3 glomerulonephritis.  This group of glomerular diseases with a heterogeneous histological aspect shares a common pathogenesis (i.e., a dysregulation of the alternative pathway of complement in the fluid phase leading to C3 deposition in the kidney).  Recent advances have expanded the understanding of the underlying mechanisms, leading to the hypothesis that blocking the alternative complement pathway may be an effective treatment for C3Gs, as has been shown in other renal diseases driven by alternative pathway dysregulation, such as aHUS.  Results of 11 published cases of patients with different forms of C3G treated with eculizumab are encouraging.  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.  Moreover, they stated that clinical trials assessing effectiveness of different complement blockers on the background of the individual complement profile are needed.

Lebreton and colleagues (2017) reported on 4 pediatric cases of C3 glomerulopathy treated with eculizumab.  Patients 1, 2 and 3 were diagnosed with nephritic syndrome with alternative complement pathway activation (low C3, C3Nef-positive) and C3G at the age of 9, 13 and 12 years, respectively.  Treatment with eculizumab normalized proteinuria within 1, 2 and 7 months, respectively.  Proteinuria relapsed when eculizumab was withdrawn, but the re-introduction of eculizumab normalized proteinuria.  Patient 4 was diagnosed with C3G at 9 years of age, with progression to end-stage renal disease (ESRD) within 2 years, followed by a first renal transplantation (R-Tx) with early disease recurrence and graft loss within 39 months.  After a second R-Tx, the patient rapidly presented with biological and histological recurrence: therapy with eculizumab was started, with no effect on proteinuria after 5 months, in a complex clinical setting (i.e., association of C3G recurrence, humoral rejection and BK nephritis).  Eculizumab was withdrawn due to multiple viral re-activations, but the re-introduction of the drug a few months later enabled a moderate decrease in proteinuria.  The authors concluded that the findings of these cases showed the effectiveness of eculizumab, at least on native kidneys, in pediatric C3G; however, they stated that larger international studies are needed to confirm the safety and benefit of eculizumab therapy.

Gonzalez Suarez and colleagues (2020) noted that C3G is associated with a high rate of recurrence and graft loss following kidney transplantation (KTx).  In a systematic review, these researchers examined the efficacy of different treatments for C3G recurrence following KTx.  Databases (Medline, Embase, and Cochrane Database) were searched from inception through May 3, 2019.  Studies were included that reported outcomes of adult KTx recipients with C3G.  Effect estimates from individual studies were combined using the random-effects, generic inverse variance method of DerSimonian and Laird.  A total of 12 studies (7 cohort studies and 5 case series) consisting of 122 KTx patients with C3G (73 C3 glomerulonephritis (C3GN) and 49 dense deposit disease (DDD)) were included.  The pooled estimated rates of allograft loss among KTx patients with C3G were 33 % (95 % CI: 12 % to 57 %) after eculizumab, 42 % (95 % CI: 2% to 89 %) after therapeutic plasma exchange (TPE), and 81 % (95 % CI: 50 % to 100 %) after rituximab.  Subgroup analysis based on type of C3G was carried out.  Pooled estimated rates of allograft loss in C3GN KTx patients were 22 % (95 % CI: 5 % to 46 %) after eculizumab, 56 % (95 % CI: 6% to 100 %) after TPE, and 70 % (95 % CI: 24 % to 100 %) after rituximab.  Pooled estimated rates of allograft loss in DDD KTx patients were 53 % (95 % CI: 0 % to 100 %) after eculizumab.  Data on allograft loss in DDD after TPE (1 case series, 0/2 (0 %) allograft loss at 6 months) and rituximab (1 cohort, 3/3 (100 %) allograft loss) were limited.  Among 66 patients (38 C3GN, 28 DDD) who received no treatment (due to stable allograft function at presentation and/or clinical judgment of physicians), pooled estimated rates of allograft loss were 32 % (95 % CI: 7 % to 64 %) and 53 % (95 % CI: 28 % to 77 %) for C3GN and DDD, respectively.  Among treated C3G patients, data on soluble membrane attack complex of complement (sMAC) were limited to patients treated with eculizumab (n = 7); 80 % of patients with elevated soluble membrane attack complex of complement (sMAC) before eculizumab responded to treatment.  Furthermore, all patients who responded to eculizumab had normal sMAC levels after post-eculizumab.  The authors concluded that the findings of this study suggested that the lowest incidence of allograft loss (33 %) among KTX patients with C3G were those treated with eculizumab.  Among those who received no treatment for C3G due to stable allograft function, there was a high incidence of allograft loss of 32 % in C3GN and 53 % in DDD; and sMAC level may help to select good responders to eculizumab. 

The authors stated that this study had several drawbacks.  First, all included studies were observational or case series in design, making them susceptible to selection bias.  Second, there was no standard treatment for C3G to allow comparison of interventions; therefore, data from patients who did not receive treatment other than supportive therapy was provided as a reference.  Third, the rates of remissions or relapses were not reported in most of the included studies.  Only the rate of graft loss was available for pooled analysis.  The audience should be aware of these drawbacks when interpreting these findings.  Although the findings of the meta-analysis suggested that eculizumab might be considered as an additional therapy for C3G in KTx patients, the pooled sample size remained small, and further controlled trials describing the efficacy of eculizumab, TPE, or rituximab are needed.  Lastly, there are currently ongoing clinical trials of complement inhibitors for the treatment of C3G among non-KTx patients.  These researchers stated that future studies are needed to evaluate and compare the safety and efficacy of these various complement inhibitors for the treatment of C3G among KTx recipients.

Coronavirus Disease 2019 (COVID-19) / Cold Agglutinin Disease Secondary to COVID-19

In an open label, multi-center, Expanded Access Program (EAP), Burwick et al (2022) examined the safety and effectiveness of eculizumab for the treatment of severe coronavirus disease 2019 (COVID-19) in pregnant and post-partum individuals.  Subjects enrolled at the authors’ center from August 2020 to February 2021.  Hospitalized patients were eligible if they had severe COVID-19 with bilateral pulmonary infiltrates and oxygen requirement.  Eculizumab was administered on day 1 (1,200 mg IV) with additional doses if still hospitalized (1,200 mg IV on days 4 and 8; 900 mg IV on days 15 and 22; optional doses on days 12 and 18).  The primary outcome was survival at day 15.  Secondary outcomes included survival at day 29, need for mechanical ventilation, and duration of hospital stay.  These investigators examined pharmacokinetic and pharmacodynamic data, safety, and adverse outcomes.  A total of 8 subjects were enrolled at the Cedars-Sinai Medical Center, 6 during pregnancy (mean of 30 ± 4.0 weeks) and 2 in the post-partum period.  Baseline oxygen requirement ranged from 2 L/min nasal cannula to 12 L/min by non-rebreather mask.  The median number of doses of eculizumab was 2 (range of 1 to 3); the median time to hospital discharge was 5.5 days (range of 3 to 12).  All subjects met the primary outcome of survival at day 15, and all were alive and free of mechanical ventilation at day 29.  In 3 subjects, these researchers demonstrated that free C5 and soluble C5b-9 levels decreased following treatment.  There were no serious maternal or neonatal AEs attributed to eculizumab at 3 months.  The authors described the use of eculizumab in the treatment of severe COVID-19 in a small series of pregnant and post-partum adults; these researchers stated that a larger study comparing eculizumab to the standard of care (SOC) is recommended to determine the safety and effectiveness of eculizumab for the treatment of COVID-19 in pregnant and breast-feeding individuals.

The authors stated that this study was limited by a small sample size (n = 8) and lack of a comparator arm.  While this EAP protocol was open to pregnant and breast-feeding adults at other sites including 6 other centers in the U.S. and 5 hospitals in France, the authors’ center was the only site that enrolled pregnant as well as post-partum individuals, limiting the total number of subjects in this subgroup.  Data were not collected for pregnant and breast-feeding women with COVID-19 who did not receive eculizumab; thus, these researchers could not determine if eculizumab was superior to SOC alone, including the use of remdesivir and dexamethasone.  The COVID-19 landscape has changed considerably since the initial study design and COVID-19 vaccines are now widely available.  Criteria for disease severity has changed over time and these results may not apply to pregnant individuals infected with more recent viral strains (e.g., Omicron variant).  However, the criteria used in this trial to define severe illness were similar to the current criteria outlined by the National Institute of Health (NIH).

Dawudi et al (2022) noted that impaired immune response with uncontrolled inflammation and various immunological disorders have been reported during SARS-CoV-2 infection.  These investigators reported a case of cold agglutinin disease (CAD) occurring during severe COVID-19 in an intensive care unit (ICU) in France.  A patient was presented with acute respiratory distress syndrome (ARDS), acute renal failure and hemolytic anemia.  Direct antiglobulin test was positive with a cold agglutinin titer of 1/512.  No other cause than COVID-19 explained the occurrence of CAD; however, causality could not be formally established.  Persistent anemia despite transfusion therapy and the short-term life-threatening situation, prompted the infusion of eculizumab, which quasi-fully resolved hemolysis within a few days; however, the patient died from his severe COVID-19 infection.  The authors concluded that data regarding the specific treatment of CAD during COVID-19 are rare.  Moreover, these researchers stated that although additional studies are needed, eculizumab may be considered in critical situations.  These researchers stated that specific treatment strategies for CAD, such as eculizumab, should be examined in larger studies and more research is still needed to fully understand the underlying mechanisms of action.

Gemcitabine-Induced Thrombotic Microangiopathy

In a retrospective, observational, multi-center study, Grall and colleagues (2021) examined the efficacy of eculizumab in patients with gemcitabine-induced TMA (G-TMA).  This trial was carried out in 5 French centers between 2011 and 2016.  A total of 12 patients with a G-TMA treated by eculizumab were included.  The main characteristics were acute renal failure (100 %), including stage-3 AKI (58 %) and renal replacement therapy (17 %), hypertension (92 %) and diffused edema (83 %).  Eculizumab was started after a median of 15 days (range of 4 to 44) following TMA diagnosis.  A median of 4 injections of eculizumab was carried out (range of 2 to 22).  Complete hematological remission was attained in 10 patients (83 %) and blood transfusion significantly decreased after only 1 injection of eculizumab (median of 3 packed RBCs (range of  0 to 10) before treatment versus 0 (range of 0 to 1) after 1 injection, p < 0.001); renal function recovered completely in 2 patients (17 %), and 8 achieved a partial remission (67 %).  Compared to a control group of G-TMA without use of eculizumab, renal outcome was more favorable.  At the end of the follow-up, median estimated glomerular filtration rate (eGFR) was 45 versus 33 ml/min/1.73m2, respectively in the eculizumab group and in the control group.  The authors concluded that these findings suggested that eculizumab was efficient on hemolysis and reduced transfusion requirement in G-TMA.  Moreover, they stated that eculizumab may improve renal function recovery. 

The authors stated that these findings had the usual drawbacks of those of a retrospective study, in particular concerning the probable presence of confounding factors; moreover, the number of patients was small (n = 12).  Thus, further larger controlled studies are needed to definitely confirm these findings, which will be very difficult given the rarity of the disease.  These studies should also address whether gemcitabine should be considered contraindicated after resolution of G-TMA.  Only 1 patient had a genetic evaluation of the alternative complement pathway.  Nevertheless, in France, a quantitative analysis of the complement is sometimes performed in this context of TMAs secondary to gemcitabine.  If this is abnormal, it is completed by the genetic evaluation.  The authors now know that there is no pathogenic variant found in secondary TMAs in the vast majority of patients.  On the other hand, this study rather suggested a transient activation of the alternate pathway of complement.  Finally, there were analyzable kidney biopsies in just 3 patients, so it was difficult to draw broad conclusions regarding the findings in G-TMA.

Guillain-Barre Syndrome

van Doorn (2009) noted that epidemiological studies have shown that the incidence of Guillain-Barre syndrome (GBS) remains stable at about 2/100,000 per year; but that there have been changes in hospitalization use, likely due to the widespread availability of intravenous immunoglobulin (IVIG).  Research into mechanisms has shown the importance of single amino acids in Campylobacter jejuni and the importance of ganglioside conformation.  In a murine model of anti-ganglioside antibody-mediated neuropathy, eculizumab was effective in reversing clinical disease and preventing pathology.  This suggests trials of eculizumab in GBS should be considered.  However, there are no new randomized controlled trials in GBS to report.

In a randomized, multi-center, double-blind, phase-II clinical trial, Misawa and colleagues (2018) examined the safety and efficacy of eculizumab in patients with severe GBS.  This study was a 24-week, placebo-controlled study carried out in 13 hospitals in Japan.  Eligible patients with GBS were aged 18 years or older and could not walk independently (GBS functional grade 3 to 5).  Patients were randomly assigned (2:1) to receive 4 weeks of IVIG plus either eculizumab (900 mg) or placebo; randomization was done via a computer-generated process and web response system with minimization for functional grade and age.  The study had a parallel non-comparative single-arm outcome measure.  The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade less than or equal to 2] at week 4) in the eculizumab group and safety in the full analysis set.  For the efficacy end-point, these researchers pre-defined a response rate threshold of the lower 90 % CI boundary exceeding 50 %.  Between August 10, 2015, and April 21, 2016, a total of 34 patients were assigned to receive either eculizumab (n = 23) or placebo (n = 11).  At week 4, the proportion of the patients able to walk independently (functional grade less than or equal to 2) was 61 % (90 % CI: 42 to 78; n = 14) in the eculizumab group, and 45 % (20 to 73; n = 5) in the placebo group.  Adverse events (AEs) occurred in all 34 patients; 3 patients had serious AEs: 2 in the eculizumab group (anaphylaxis in 1 patient and intra-cranial hemorrhage and abscess in another patient) and 1 in the placebo group (depression).  The possibility that anaphylaxis and intra-cranial abscess were related to eculizumab could not be excluded.  No deaths or meningococcal infections occurred.  The authors concluded that the primary outcome measure did not reach the pre-defined response rate.  However, because this was a small study (n = 23 for the eculizumab-treated group) without statistical comparison with the placebo group, the safety and efficacy of eculizumab needs to be investigated in larger RCTs.

In a Cochrane review, Doets and colleagues (2020) examined the effects of pharmacological agents other than plasma exchange (PE), IVIG and corticosteroids for the treatment of GBS.  On 28 October 2019, these investigators searched the Cochrane Neuromuscular Specialized Register, CENTRAL, Medline, and Embase for treatments for GBS.  They also searched clinical trials registries.  They included all RCTs or quasi-RCTs of acute GBS (within 4 weeks from onset) of all types and degrees of severity, and in individuals of all ages.  These researchers discarded trials that examined only corticosteroids, IVIG or PE.  They included other pharmacotherapies or combinations of treatments compared with no treatment, placebo or another treatment.

These researchers found 6 trials of 5 different interventions eligible for inclusion in this review.  The trials were conducted in hospitals in Canada, China, Germany, Japan and the U.K., and included a total of 151 subjects.  All trials randomized subjects aged 16 years and older (mean or median age in the trials ranged from 36 to 57 years in the intervention groups and 34 to 60 years in the control groups) with severe GBS, defined by the inability to walk un-aided.  One trial also randomized patients with mild GBS who were still able to walk un-aided.  These investigators identified 2 new trials at this update.  The primary outcome measure for this review was improvement in disability grade 4 weeks after randomization; 4 of 6 trials had a high risk of bias in at least one respect.  These investigators also examined all evidence for the outcome mean improvement in disability grade as very low certainty, which meant that they were unable to draw any conclusions from the data.  One RCT with 19 subjects compared interferon beta-1a (IFNb-1a) and placebo.  It was uncertain whether IFNb-1a improved disability after 4 weeks (MD -0.1; 95 % CI: -1.58 to 1.38; very low-certainty evidence).  A trial with 10 subjects compared brain-derived neurotrophic factor (BNDF) and placebo.  It was unclear if BDNF improved disability after 4 weeks (MD 0.75; 95 % CI: -1.14 to 2.64; very low-certainty evidence).  A trial with 37 subjects compared cerebrospinal fluid (CSF) filtration and PE.  It was unclear if CSF filtration improved disability after 4 weeks (MD 0.02; 95 % C:I -0.62 to 0.66; very low-certainty evidence).  One trial that compared the Chinese herbal medicine tripterygium polyglycoside with corticosteroids with 43 participants did not report the RR for an improvement by 1 or more disability grade after 4 weeks; but did report improvement after 8 weeks.  It was unclear if tripterygium polyglycoside improved disability after 8 weeks (RR 1.47; 95 % CI: 1.02 to 2.11; very low-certainty evidence).  These researchers carried out a meta-analysis of 2 trials comparing eculizumab and placebo with 41 subjects.  It was unclear if eculizumab improved disability after 4 weeks (MD -0.23; 95 % CI: -1.79 to 1.34; very low-certainty evidence).  Serious AEs were uncommon in each of the trials and evidence was graded as either low or very low.  It was unclear if serious AEs were more common with IFNb-1a versus placebo (RR 0.92, 95 % CI: 0.23 to 3.72; 19 subjects), BNDF versus placebo (RR 1.00, 95 % CI: 0.28 to 3.54; 10 subjects) or CSF filtration versus PE (RR 0.13, 95 % CI: 0.01 to 2.25; 37 subjects).  The trial of tripterygium polyglycoside did not report serious AEs.  There may be no clear difference in the number of serious AEs after eculizumab compared to placebo (RR 1.90, 95 % CI: 0.34 to 10.50; 41 subjects).  These investigators found no clinically important differences in any of the outcome measures selected for this review in any of the 6 trials; however, sample sizes were small; thus, clinically important benefit or harm could not be excluded.  The authors concluded that all 6 RCTs were too small to exclude clinically important benefit or harm from the assessed interventions.  The certainty of the evidence was low or very low for all interventions and outcomes.

Hemolytic Uremic Syndrome caused by Shiga Toxin-Producing E. Coli (STEC-HUS)

In a multi-center, retrospective study, Pecheron and associates (2018) studied 33 children from 15 centers treated with eculizumab for severe hemolytic uremic syndrome caused by Shiga toxin-producing E. coli (STEC-HUS).  Indication for eculizumab was neurologic involvement in 20 patients, cardiac and neurologic involvement in 8, cardiac involvement in 2, and digestive involvement in 3.  Based on medical status at last follow-up, patients were divided into 2 groups: favorable (n = 15) and unfavorable outcomes (n = 18).  Among patients with favorable outcome, 11/14 patients (79 %) displayed persistent blockade of complement activity before each eculizumab re-injection.  Conversely, in patients with unfavorable outcome, only 9/15 (53 %) had persistent blockade (p = non-significant).  Among 28 patients presenting neurological symptoms, 19 had favorable neurological outcome including 17 with prompt recovery following first eculizumab injection.  Only 2 adverse effects potentially related to eculizumab treatment were reported.  The authors concluded that these findings may support the use of eculizumab in severe STEC-HUS patients, especially those presenting severe neurological symptoms.  However, these researchers stated that this study was limited by absence of a control group and use of multiple therapeutic interventions in treatment groups; thus, prospective, controlled trials are needed.

Loos and colleagues (2018) stated that STEC-HUS is often associated with a severe morbidity including neurological involvement and a mortality of 1 to 5 %.  Although STEC-HUS is often self-limited, improvement of treatment strategies is needed for cases with complications and, among others, PE/plasmapheresis and use of antibiotics have been advocated.  With the availability of eculizumab, now a standard treatment of atypical HUS, several series have addressed its use in STEC-HUS, with variable response; RCTs are lacking.  The authors noted that Pecheron et al (2018) presented a cohort of 33 pediatric patients with severe HUS treated with eculizumab.  Neurological involvement was observed in 85 % of the patients and 94 % required dialysis.  Most patients (55 %) did not benefit from eculizumab and renal dysfunction as well as neurological sequelae did not resolve.  In a subgroup of patients, however, rapid neurological improvement was described.  In the post-hoc-defined group of patients with favorable outcome, there was a trend towards more sustained complement inhibition, although this finding was not significant compared to patients with an unfavorable outcome.  The authors concluded that because multiple interventions were used and the study did not include any control group, future controlled studies are needed to resolve the debate as to whether eculizumab can be an effective treatment for both prevention and treatment of complications in STEC-HUS.

Walsh and Johnson (2019) noted that HUS remains a leading cause of pediatric AKI.  In approximately 90 % of cases, HUS is a consequence of infection with STEC, most commonly serotype O157:H7.  Acute mortality from STEC-HUS is now less than 5 %; however, there is significant long-term renal morbidity in 1/3 of survivors.  Currently, no specific treatment exists for STEC-HUS.  There is growing interest in the role of complement in the pathogenesis of STEC-HUS due to the discovery of inherited and acquired dysregulation of the alternative complement system in the closely related disorder, aHUS.  The authors concluded that the treatment of aHUS has been revolutionized by the introduction of eculizumab; however, the role of complement and anti-complement therapy in STEC-HUS remains unclear.

Hyperhemolysis Syndrome/Prevention of Intravascular Hemolysis due to Red Blood Cell Alloantibodies

Gupta and colleagues (2015) stated that hyperhemolysis is a serious transfusion reaction, most often described in patients with hemoglobinopathies. Hyperhemolysis is characterized by the destruction of host red blood cells (RBCs), in addition to donor RBCs, via an unknown mechanism. These researchers presented the case of a 58-year old woman with treated human immunodeficiency virus and a normal Hb electrophoresis; she developed hyperhemolysis in the setting of a delayed hemolytic transfusion reaction (DHTR). The patient was ABO group B and had a previously identified anti-Fy(b) alloantibody. After transfusion of Fy(b)-RBCs, she developed a DHTR and was found to have anti-E, anti-C(w), anti-s, and an additional antibody to an unrecognized high-frequency RBC alloantigen. Subsequent transfusion of ABO-compatible RBCs that were negative for Fy(b), E, C(w), and s antigens resulted in immediate intravascular hemolysis. In the absence of bleeding, her hematocrit (Hct) decreased to 10.2 %. An extensive serologic evaluation failed to identify the specificity of the high-frequency antibody. Severe hemolytic reactions also occurred despite pre-transfusion conditioning with eculizumab. The Hct and clinical symptoms slowly improved after the cessation of transfusions and treatment with erythropoietin and steroids. This case demonstrated several noteworthy features including hyperhemolysis in a patient without a Hb disorder, the development of an antibody to an unknown RBC antigen, and the failure of eculizumab to prevent intravascular hemolysis after transfusion. The authors concluded that hyperhemolysis is not restricted to patients with hemoglobinopathies. Whether eculizumab offers any benefit in the hyperhemolysis syndrome or in the prevention of intravascular hemolysis due to RBC alloantibodies remains uncertain.

Immune Complex-Mediated Membranoproliferative Glomerulonephritis

Chanchlani and colleagues (2017) stated that there had been recent developments in the understanding of the pathogenesis of membrano-proliferative glomerulo-nephritis (MPGN) supporting a prominent role for the complement alternative pathway (AP).  MPGN due to AP dysregulation has been further classified into dense-deposit disease (DDD) and C3 glomerulonephritis (C3GN), and grouped together as C3 glomerulopathy (C3G).  This entity includes all glomerular lesions that are characterized by predominant C3 accumulation with minimum or scant Ig deposition and highlights the pathogenetic contribution of complement.  On the other hand, MPGN secondary to autoimmune diseases or infections is labeled as immune complex-mediated MPGN.  C3G is associated with a poor prognosis, as 30 % to 50 % of patients progress to ESRD within 10 years of diagnosis, and about 50 % have recurrence after transplantation.  Complement targeting therapy (e.g., eculizumab) has recently emerged as a novel therapeutic option for patients with C3G.  There had been few case reports to describe the effectiveness of eculizumab in patients with C3G, but the literature is scarce in the pediatric population.  Moreover, there is very little insight into the long-term safety and efficacy regarding the use of eculizumab in immune complex-mediated MPGN.  These investigators presented the case of a child with refractory immune complex-mediated MPGN who was successfully treated with eculizumab for a period of 4 years.  The authors concluded that eculizumab appeared to be a safe and effective therapeutic option in pediatric patients with immune complex-mediated MPGN.  Moreover, they stated that further prospective studies in a larger patient cohort are needed to better understand the long-term clinical implications of eculizumab treatment in pediatric patients with immune complex-mediated MPGN, with a special emphasis on determining the optimal duration of treatment.

The authors stated that this study had several drawbacks.  It was a single-case study.  Also, a repeat renal biopsy after eculizumab therapy to document changes in the histopathology after therapy was not available.  Nevertheless, this report demonstrated that a few patients with histopathological features of immune complex-mediated MPGN who were resistant to conventional treatment may have abnormalities in the alternate complement pathway and may benefit from the use of complement targeting therapy.  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.

Ischemia-Reperfusion Injury in Kidney Transplantation

Kaabak and colleagues (2018) stated that ischemia-reperfusion injury (IRI) has multiple effects on a transplanted allograft, including delayed or impaired graft function, compromised long-term survival, and an association with an increased incidence of rejection.  Eculizumab has been postulated to be an effective agent in the prevention or amelioration of IRI.  These researchers performed a prospective, single-center RCT involving 57 pediatric kidney transplant recipients between 2012 and 2016.  The immunosuppressive protocol included 2o doses of alemtuzumab; half of the patients were randomized to receive a single dose of eculizumab prior to transplantation.  Maintenance immunosuppression was based on a combination of low-dose tacrolimus and mycophenolate, without steroids.  Eculizumab-treated patients had a significantly better early graft function, less arteriolar hyalinosis and chronic glomerulopathy on a protocol biopsies taken on day 30, 1 year, and 3 years after transplantation.  In the eculizumab group, 4 non-vaccinated children lost their grafts during the course of a flu-like infection.  The authors concluded that eculizumab was associated with better early graft function and improved graft morphology; however, there was an unacceptably high number of early graft losses among the eculizumab-treated children.  They stated that while the use of eculizumab is a promising strategy, the best approach to complement inhibition remains to be established.

Lupus Nephritis

Wright and colleagues (2020) noted that lupus nephritis (LN) is a severe consequence of 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 therapeutic approaches in these patients.  Eculizumab is a fully humanized IgG2/IgG4 monoclonal antibody directed at C5; thus, preventing the formation of the terminal complement complex.  It is successfully used in patients with aHUS and PNH; however, it is not standardly used in LN.  These researchers examined if there is any role for eculizumab as adjunctive therapy in LN.  Using a pre-defined search strategy on Ovid Medline and Embase the literature was reviewed systematically to identify studies in which eculizumab had been used in the treatment of patients with SLE. All patients who were treated with complement inhibitors were included.  Favorable 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.  From 192 abstracts screened, 14 articles were identified, involving 30 patients.  All SLE patients administered eculizumab were treated for TMA secondary to LN diagnosed either histologically (66 %) or as part of a diagnosis of aHUS (73 %).  A total of 93 % of patients had a favorable outcome in response to eculizumab treatment, of which 46 % had a favorable outcome and successfully stopped treatment without relapse in symptoms during a median follow-up of 7 months; 3 patients (10 %) reported adverse outcomes related to eculizumab therapy.  The authors concluded that available scientific 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 appeared to be an effective therapy.  Moreover, these researchers stated that further evidence is needed to examine if patients with refractory LN may benefit from adjunctive complement inhibition.

The authors stated that one drawback of this study was that data related to the serological or non-renal parameters of disease was only available for 4 of the 30 patients included.  These data may provide increased evidence on the risks or benefits of using eculizumab for LN-associated TMA in SLE patients.

Malignant Atrophic Papulosis

Malignant atrophic papulosis (MAP), also known as Degos disease, is an extremely rare disease that is characterized by its unique skin presentation (namely, central, porcelain-white atrophic lesions with a telangiectatic rim) (Huang, et al., 2018).  MAP has the following 2 variants: cutaneous MAP is manifested in the skin alone, whereas systemic MAP affects the gastro-intestinal (GI) tract, CNS, lungs, and other internal organs.  Some patients who present with only cutaneous symptoms at first may develop systemic symptoms several years later.  Although the exact pathologic mechanisms are unclear, it was suggested in a that MAP is a vascular injury syndrome that involves complement component C5b-9 complex deposition and high expression of interferon-alpha.  The prognosis of systemic MAP is poor and typically fatal within a few years.  Nonetheless, because the C5b-9 complex is detected in MAP, some researchers have suggested combined treatment with eculizumab and treprostinil.

Huang and colleagues (2018) reported on a girl with systemic MAP who had severe CNS involvement and responded to eculizumab.  Before the introduction of eculizumab and treprostinil, no studies had reported an effective treatment of neurologic involvement in MAP, and surgical drainage had not been found to be effective for sub-dural effusion.  However, the combination treatment may entail a considerable economic burden on the patient and family.  The authors stated that although their patient died after 18 months of eculizumab treatment, her initial response was impressive, and neurologic function showed gradual improvement.  They stated that this case showed that eculizumab could improve patients’ CNS manifestations, although its long-term effectiveness and combined use with treprostinil require additional clinical examination.

Prevention of Graft Loss in Kidney Transplant Recipients

Plasse and colleagues (2021) stated that among kidney transplant recipients (KTRs) with ESRD due to aHUS, recurrence is associated with poor allograft outcomes.  In a retrospective, cohort study, these researchers compared graft and patient survival of aHUS KTRs with and without prophylactic/early use of eculizumab at the time of transplantation.  This trial was carried out using the U.S. Renal Data System (USRDS).  Out of 123,624 ESRD patients transplanted between January 1, 2008, and June 1, 2016, these investigators identified 348 (0.28 %) patients who had "hemolytic uremic syndrome" as the primary cause of ESRD.  These researchers then linked these patients to datasets containing the Healthcare Common Procedure Coding System (HCPCS) code for eculizumab infusion.  Patients who received eculizumab prior to or within 30 days of transplant represented the exposure group.  The authors calculated crude incidence rates and performed exact logistic regression, adjusted for recipient age and sex, for the study outcomes of graft loss, death-censored graft loss, and mortality.  They also estimated the average treatment effect (ATE) by propensity-score matching, to reduce the bias in the estimated treatment effect on graft loss.  The final study cohort included 335 aHUS KTRs (23 received eculizumab, 312 did not), with a mean duration of follow-up of 5.8 ± 2.7 years.  There were no significant differences in baseline demographic and clinical characteristics between the eculizumab versus non-eculizumab group.  Patients who received prophylactic/early eculizumab were less likely to experience graft loss compared with those who did not receive eculizumab (0 % versus 20 %, p = 0.02), with an adjusted odds ratio (OR) of 0.13 (p = 0.02).  In the propensity-score-matched sample, the ATE (eculizumab versus non-eculizumab) was -0.20 (95 % CI: -0.25 to -0.15, p < 0.001); thus, treatment was associated with an average of 20 % reduction in graft loss.  There was no significant difference in the risk of death between the 2 groups.  The authors concluded that although there was no significant difference in the risk of death, prophylactic/early use of eculizumab was significantly associated with improved graft survival among aHUS KTRs.  They stated that these findings should be considered hypothesis-generating and serve to instruct potential prophylactic strategies to prevent graft loss in future RCTS.  

The authors stated that this study had several drawbacks.  First, the USRDS is largely an administrative database and does not provide detailed clinical information.  Although the majority of the study cohort likely had aHUS as the primary cause of ESRD, it was possible that a smaller subset of these patients had typical HUS (STEC).  Furthermore, the clinical phenotype and genotype of the study cohort that could inform the risk of recurrence following transplantation were unknown, the underlying etiology of graft loss was unknown, and data on therapeutic PE were unavailable.  Second, the eculizumab group may have included patients who were treated for aHUS recurrence many months before transplantation (while on dialysis) as well as those who may have been treated for aHUS recurrence in the early post-transplant period.  Third, given the possibility of confounding by indication to the extent that the decision to use eculizumab may be dependent on the patients’ baseline clinical characteristics, these investigators carried out propensity-score modeling to reduce the bias in the estimated treatment effect.  Fourth, these researchers could not conclude about causality given the retrospective nature of this study.  Last, the sample size was relatively small, reflecting the rarity of aHUS.

Stem Cell Transplant-Associated Thrombotic Microangiopathy

Kim and colleagues (2015) noted that transplant-associated thrombotic micro-angiopathy (TA-TMA) is a multi-factorial disorder, which occurs as a result of treatment-related endothelial injury and underlying disease process after hematopoietic stem cell transplantation (HSCT). The reported incidence of TA-TMA after HSCT is 0 % to 74 % and has shown to be associated with mortality rate of up to 100 %. Transplant-associated TMA is often diagnosed late in the disease progression, and therapeutic plasma exchange (TPE) has not been shown to produce a high response rate. These investigators reviewed pharmacologic treatment options for TA-TMA. All English-language articles describing pharmacologic treatments for TA-TMA were identified using Ovid in the Medline database (1966 to May 2014). Search was limited to the HSCT population. Approximately 50 % to 63 % of patients with TA-TMA responded to withdrawal of the offending agent (calcineurin inhibitors) and TPE, and many will require additional treatment to better control the disease. Unfortunately, there is no established treatment strategy for TA-TMA. A number of pharmacologic agents that have been explored for the treatment of TA-TMA include rituximab, vincristine, defibrotide, pravastatin, and eculizumab. The overall response rates of these agents were similar (69 % to 80 %); however, the differences in the treatment costs vary significantly between these agents. Defibrotide is an investigational agent in the United States; therefore, it is not readily available for use. The authors concluded that larger studies are needed to validate the role of these pharmacologic agents in TA-TMA as upfront therapy and in TPE-refractory patients.

de Fontbrune et al (2015) stated that TMA occurring after allogeneic HSCT has a devastating prognosis. Response rates to current therapies (mainly PE) are unsatisfactory. Thrombotic micro-angiopathy after allogeneic HSCT shares similarities with aHUS in the underlying pathomechanisms. Eculizumab has been associated with impressive results in aHUS. These investigators retrospectively analyzed 12 patients who received eculizumab between 2010 and 2013 for severe post-HSCT TMA. All 12 patients had severe TMA with neurological and/or renal involvement; 58 % were refractory to first-line PE. At the time of TMA diagnosis, infections were present in 50 % of the patients and acute graft-versus-host disease (GVHD) in 33 %. Patients were treated with eculizumab according to the aHUS therapeutic scheme. With a median follow-up of 14 months, hematological response and overall survival (OS) were 50 % and 33 %, respectively. Active acute GVHD at TMA diagnosis was the only factor associated with worse OS (p = 0.009). The authors concluded that response rate and OS after eculizumab in this cohort compared favorably with previously published data in TMA after allogeneic HSCT. Moreover, they stated that prospective trials are needed to confirm these results.

Jodele et al (2015) stated that hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is now a well-recognized and potentially severe complication of HSCT that carries a high risk of death.  In those who survive, TA-TMA may be associated with long-term morbidity and chronic organ injury.  Recently, there have been new insights into the incidence, pathophysiology, and management of TA-TMA.  Specifically, TA-TMA can manifest as a multi-system disease occurring after various triggers of small vessel endothelial injury, leading to subsequent tissue damage in different organs.  While the kidney is most commonly affected, TA-TMA involving organs such as the lung, bowel, heart, and brain is now known to have specific clinical presentations.  These investigators  reviewed the most up-to-date research on TA-TMA, focusing on the pathogenesis of endothelial injury, the diagnosis of TA-TMA affecting the kidney and other organs, and new clinical approaches to the management of this complication after HSCT.

These researchers stated that the most promising targeted therapy to date for HSCT-associated TMA is complement blockade with eculizumab, but eculizumab therapy itself poses certain challenges such as the reported difficulty of achieving therapeutic levels in critically ill HSCT patients, limited availability in certain countries, and significant cost associated with this therapy.  In a pilot study of 6 children treated with eculizumab for multi-visceral TA-TMA, these investigator observed that patients after HSCT required higher doses or more frequent eculizumab infusions than currently recommended to achieve therapeutic drug levels and a clinical response in children with aHUS.  The authors’ extended experience in 18 patients (unpublished) treated with eculizumab supports their initial observations for eculizumab dosing and monitoring requirements in the HSCT population; 12 of 18 patients (67 %) with high risk disease had resolution of TA-TMA using the intensified dosing regimen guided by pharmacodynamic monitoring by measuring CH50 and adjusting eculizumab dosing schedule to maintain an adequately suppressed CH50 level.  The main 2 assays used for measuring CH50 are enzyme immunoassay and hemolysis assay.  To achieve and to sustain therapeutic eculizumab level greater than 99 µg/ml, CH50 should be less than 10 % of the lower limit of normal, corresponding to 0 to 3 CAE if using a standard enzyme immunoassay or 0 to 15 CH50 units if the Diamedix hemolytic assay is used.  Patients with C4d deposition in the renal arterioles and without documented complement gene abnormalities or detectable CFH autoantibodies also have a favorable response to eculizumab.  It is important to note that treatment time to control TA-TMA in the HSCT population is longer from what it is typically seen in aHUS and at least 4 to 6 weeks of induction therapy with therapeutic eculizumab levels should be continued before considering a patient a non-responder.  Larger, multi-institutional, controlled studies are certainly needed to better evaluate the use of eculizumab in HSCT recipients, but the authors’ pilot data support that patients with TA-TMA and high risk features, who historically have very poor outcome, should at least be considered as early candidates for eculizumab, as delaying therapy may prevent patients from achieving the best response and maximizing recovery of organ function.  It is recommended to use eculizumab as a monotherapy with pharmacodynamics monitoring and dose adjustments.  Concurrent use of therapeutic plasma exchange (TPE) would remove eculizumab from the blood as well as replenish C5 available for activation, and supplemental doses would be required after each TPE session.  Concurrent use of eculizumab and rituximab may affect rituximab activity as this medication in part depends on complement activity.

The authors concluded that eculizumab has been shown to be effective even in patients with multi-visceral high risk disease if started early and dosed appropriately.  Complement blockade in HSCT patients will likely be required as only a temporary measure to resolve acute TA-TMA and will therefore not have the down side of requiring lifelong complement blockade and the associated immunosuppression required in such patients as those with PNH or aHUS.  Risk stratification can identify patients who may most benefit this therapy, but should be validated in larger, multi-center cohorts.  Other novel complement-targeting agents should be investigated as potential therapeutic options for TA-TMA to reduce or even eliminate cost-limiting factors currently relevant to eculizumab therapy.

Dhakal et al (2017) stated that TA-TMA is a rare entity with no standard of care and high mortality, despite the use of PE.  Using specific search terms, all cases having TA-TMA treated with eculizumab and indexed in Medline (English language only) by November 2014 were reviewed.  A total of 26 cases, 53 % men, had a median age of 33 years (range of 2 to 61); TA-TMA occurred after stem-cell transplant (35 %) or solid-organ transplant (65 %), frequently associated with the use of cyclosporine or tacrolimus (96 %).  A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS 13) level was always greater than 10 %.  After TA-TMA diagnosis, the following drug adjustments were made: discontinuation of cyclosporine or tacrolimus in 45 %, dose reduction in another 27 %, continuation of the drugs in 23 %, and switch from cyclosporine to tacrolimus in remaining 5 %; PE was performed in approximately 43 %.  The median interval between transplant and initiation of eculizumab was 63 days (range of 11 to 512).  A median of 5.5 doses (range of 2 to 21) of eculizumab was utilized with 92 % response occurring after a median of 2 doses (range of 1 to 18).  At a median follow-up of 52 weeks (range of 3 to 113), the survivors (92 %) were doing well.  The authors concluded that within the limits of this retrospective analysis, this study demonstrated that eculizumab use may result in high response rate and 1-year survival in patients with TA-TMA refractory to discontinuation of calcineurin inhibitor and PE.

Zhang and colleagues (2021) noted that TA-TMA is a life-threatening complication in patients undergoing HSCT.  Eculizumab has been used in the treatment of TA-TMA, and several studies have reported the benefit of eculizumab in patients with TA-TMA; however, the results remain controversial.  In a systematic review and meta-analysis, these researchers examined the safety and efficacy of eculizumab in the treatment of TA-TMA.  They searched PubMed and Embase for studies on the safety and efficacy of eculizumab in TA-TMA patients.  Efficacy outcomes consisted of overall response rate (ORR), complete response rate (CRR), and survival rate at the last follow-up (SR).  Safety outcomes were AEs, including infection, sepsis, impaired liver function, infusion reactions, and death.  A total of 116 patients from 6 studies were subjected to meta-analysis.  The pooled estimates of ORR, CRR, and SR for TA-TMA patients were 71 % (95 % CI: 58 % to 82 %), 32 % (95 % CI: 11 % to 56 %), and 52 % (95 % CI: 40 % to 65 %), respectively.  Only 1 patient presented with a severe rash, and infection was the most common AEs.  The main causes of death were infection and GVHD.  The authors concluded that available evidence suggested that eculizumab improved SR and ORR in patients with TA-TMA and that eculizumab was well-tolerated; however, the number of studies was limited, and the findings were based mainly on data from observational studies.  These researchers stated that higher quality RCTs and more extensive prospective cohort studies are needed to examine the safety and efficacy of eculizumab in the treatment of TA-TMA.

The authors stated that review/meta-analysis had several drawbacks.  First, there was a complete lack of RCTs and a limited study population size, and investigators had conducted limited studies on the efficacy of eculizumab for TA-TMA.  Second, although there was a great deal of heterogeneity among the included studies, the limited number of included studies prevented these investigators from analyzing the sources of heterogeneity.  Third, AEs were generalized in the article; thus, they did not have access to security data for AEs.

Systemic Lupus Erythematosus

Robak and Robak (2009) stated that systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell hyperactivity and defective T-cell function, with production of high titer auto-antibodies.  In the recent years, conceptual advances and the introduction of new therapies are yielding improvements in the management of this disease; clinical studies have been undertaken with selected monoclonal antibodies (mAbs) in the treatment of SLE.  The important role of B cells in the pathogenesis of autoimmune disorders has provided a strong rationale to target B cells in SLE.  Selective therapeutic depletion of B-cells became possible with the availability of the anti-CD20 antibody rituximab and anti-CD22 antibody epratuzumab.  Several clinical studies confirm high activity of rituximab in SLE patients especially with lupus nephritis and neuropsychiatric involvement.  Recently, several new mAbs reacting with CD20 have been developed.  New mAbs directed against CD20 include fully human mAb ofatumumab, which has a greater than 90 % humanized framework and GA-101, a novel third-generation fully humanized and optimized mAb.  These agents are highly cytotoxic against B-cell lymphoid cells.  Pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 play an important role in propagating the inflammatory process responsible for tissue damage.  Blocking of these cytokines by mAbs can be also a successful therapy for patients with SLE.  Finally, mAb eculizumab that specifically inhibits terminal complement activation has been recently developed and investigated in the phase I single dose study in SLE.

Sciascia and colleagues (2017) reviewed available literature on the effectiveness of eculizumab for the treatment of renal involvement in patients with SLE.  These researchers conducted a literature search developed a priori, to identify articles reporting clinical experience with the use of eculizumab in SLE patients, focusing on renal involvement.  The search strategy was applied to Ovid Medline, Embase, In-Process and Other Non-Indexed Citation, Cochrane Central Register of Controlled Trials and Scopus from 2006 to present.  Abstracts from EULAR and ACR congresses were also screened.  They included 6 publications describing the renal outcome in SLE patients receiving eculizumab; 5 out of 6 cases described the occurrence of TMA in renal biopsies of patients with known SLE; 3 cases with biopsy-proven lupus nephritis (LN) and 2 patients with SLE-related APS without histologic evidence of LN.  One study reported the outcome of a patient with severe refractory LN successfully treated with eculizumab.  All patients, regardless of the presence of concomitant LN, presented with severe hypocomplementemia and renal function impairment.  All patients showed a sustained improvement of renal function and normalization of complement parameters after treatment with eculizumab (median follow-up of 9 months [range of 1 to 17).  The authors concluded that despite the limitations of the currently available evidence, existing data are promising and provide preliminary support for the use of eculizumab in selected cases of SLE with renal involvement, especially in the presence of TMA, or in patients with refractory LN.

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Appendix

Appendix A: Major Adverse Vascular Events (MAVE)

Venous thrombosis

• Acute peripheral vascular occlusion,
• Clinically apparent distal embolization (e.g., lower extremity ulceration, tissue necrosis, gangrene, limb amputation or other end-organ damage)
• Deep vein thrombosis,
• Hepatic/portal vein thrombosis,
• Mesenteric/splenic vein thrombosis,
• Pulmonary embolus, 
• Renal vein thrombosis,
• Thrombophlebitis.

Arterial thrombosis

• Cerebrovascular accident,
• Myocardial infarction,
• Transient ischemic attack,
• Unstable angina.

Source: Hillmen 2007, 2019

Appendix B: Criteria for Diagnosis of Severe Aplastic Anemia

The diagnostic criteria for severe aplastic anemia are:

• Bone marrow cellularity less than 25 percent (or cellularity 25 to 50 percent if less than 30 percent of residual cells are hematopoietic); and
• At least two of the following are present:
  
  
  • Peripheral blood absolute reticulocyte count less than 20,000 per microL (<20 × 10⁹/L)
  • Peripheral blood platelet count less than 20,000 per microL (<20 × 10⁹/L)
  • Peripheral blood absolute neutrophil count (ANC) less than 500 per microL (<0.5 × 10⁹/L).

Source: Epocrates, 2019, Schrier, 2018

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References