Successful use of eculizumab to treat atypical hemolytic uremic syndrome in patients with inflammatory bowel disease

The first patient is a 19-year-old Caucasian male who presented for the continuation of complement blockade therapy with eculizumab. He was diagnosed with CD at age 5 and started on per rectum steroid therapy with budesonide and mesalamine therapy. He did require continuous infusions of adalimumab then infliximab for control of his disease. During the initial episode of colitis/CD in 2005, he was noted to have thrombocytopenia, hemolytic anemia, schistocytes with elevations in lactate dehydrogenase. The ADAMTS13 level was not available early on in the time of his diagnosis. Though Shiga toxin was not found in stool, vitamin B12 levels was 781 nanogram (ng)/mL, red blood cell (RBC) folate levels were within normal limits 981 nanomoles/L excluding other known TMA causes at that time. Rheumatolgoic serologies like anti nuclear antibody (ANA), anti double stranded DNA (dsDNA), anti ribonucleic protein smith (RNP-smith), anti cardiolipin (anti CL), dilute russell viper venom time assay (DRVVT), and anti phospholipid antibody (anti APL Ab) studies were all negative during initial workup.

As the scientific understanding of aHUS developed, it was decided that eculizumab would be initiated on an experimental basis with institutional review board approval (in a health system in Florida). He underwent a several-month course of eculizumab with clinical response. Following discontinuation of the medication, the patient suffered a relapse a few months later. Therapy was reinitiated and was subsequently weaned off successfully. Complement testing found a high level of C5 convertase function with high soluble membrane attack complex that improved with eculizumab use.

In April 2010 the patient had a severe flare of his underlying CD despite ongoing use of adalimumab, his disease remained poorly controlled clinically. He had a concomitant serum creatinine elevation peaking at 3.13 mg/dL in 04/2010 (baseline of 0.57 mg/dL 08/2009) with a drop in hemoglobin from 12.9 g/L baseline in 08/2009 to 7.6 g/L in 03/2010. The total bilirubin concentration was not elevated but increased from a baseline of 0.1 (mg/dL) in 03/2010 to 0.8 (mg/dL) in 04/2010 during the flare. Lactate dehydrogenase (LDH) was significantly elevated at 2223 Units/L in 4/2010 and decreased after that. The platelets had decreased by ~ 50% from 366,000/uL at baseline in 02/2010 to 187,000/uL in 4/2010. ADAMTS 13 activity level was within normal limits at 44% ruling out ADAMTS13 deficiency and thrombotic thrombocytopenic purpura (TTP). Prothrombin time (PT) was 11 s with an International Normalized Ratio (INR) was 1, and activated partial thromboplastin time (aPTT) was 39 s both within normal. Fibrinogen levels were high at 471 mg/dL, and a D-dimer was high at 6.17 microgram/mL as expected in an inflammatory condition. Absolute reticulocyte count was in the upper limit of normal / slightly elevated at 2.92%.

Since the patient had an established aHUS diagnosis, eculizumab was promptly reintroduced at 900 mg (infusion dose) each week with normalization of the platelet count and LDH levels, and improvement of the serum Cr to 1 mg/dL. The patient received eculizumab (1200 mg infusions) every two weeks for 8.5 years continually after this aHUS relapse. The patient had already received appropriate meningococcal vaccinations from prior courses and was aware of the risks and benefits of pharmacological complement blockade. He has not had any issues with meningitis or other infections linked to eculizumab. Clinically, his IBD symptoms slowly improved with use of ongoing adalimumab and steroid therapy for CD/IBD along with eculizumab use for aHUS.

The effect of this regimen was the maintenance on his aHUS was the maintenance of normal hematological parameters and renal function with current serum Cr of 1 mg/dL, hemoglobin of 10–12 g/L, and LDH within normal limits. The patient has agreed to continue lifelong eculizumab in this case given his two prior relapses. No antibodies against complement factors were found, and no mutations were found. Only 60% of patients with aHUS have detectable mutations, and in some cases, the mutations can be present but are currently unknown [11]. Figure 1 details laboratory findings in patient 1 and his course during his last flare in 2010.

The second patient is a 49-year-old Caucasian female with a history of UC treated with six mercaptopurine (6MP), and steroids per rectum [budesonide]. She developed a flare of ulcerative colitis symptoms, along with increased platelet count from 322,000 platelets/uL (09/2018) to 622,000 platelets/uL (10/2018). This was a reactive thrombocytosis that occurred initially, and was clinically concomitant with a flare despite treatment with budesonide and 6MP.Her serum Cr at baseline was 0.51 mg/dL, and her hemoglobin was 13.1 g/L. She presented to the emergency department one month after the start of this flare with weakness and was found to have a decreased hemoglobin concentration of 4.3 g/L, serum Cr of 3.2 mg/dL, LDH of 1000 units/L, and schistocytes on the peripheral smear. Her platelets had droped from baseline of 322,000 platelets/ul and more recent peak of 622,000 platelets/ul to 83,000 platelets/ul; this level dropped further to 43,000 plateltes/ul at a nadir 11/17/2018. These findings and the hemolysis suggested thrombotic microangiopathy like aHUS as the likely diagnosis over 6-mercaptopurine bone marrow toxicity which was another possibility. Vitamin B12 level was normal at 769 ng/mL, serum folate level was also normal at 12.9 ng/mL. PT was 13 s with an INR of 1.3, aPTT was slightly elevated at 39 s. Fibrinogen levels were high normal range at 313 mg/dL, with an elevated D-dimer 3.28 microgram/mL. Rheumatologic serologies (ANA, anti dsDNA, anti RNP sm, anti CL, DRVVT, APL Ab) were all negative. Reticulocyte counts were obtained at 2% (normal), and one result was 3% which is slightly elevated, and not expected in bone marrow toxicity.

The finding of an ADAMTS13 level of 80.8% suggested that the cause of TMA was not TTP. The patient was transferred back to a quaternary care center, and then eculizumab was started after meningococcal vaccination. The patient agreed to the risks and benefits of complement blockade in the absence of waiting the requisite two weeks for development of meningococcal antibody titers after immunization, and antibiotic prophylaxis with penicillin-based antibiotics was provided.

The serum Cr, platelets, hemoglobin, LDH all improved quickly and normalized (Fig. 2). The patient required hemodialysis for ~ 1 week and was weaned off. Eculizumab was administered at a given dose of 900 mg weekly infusions. The patient was discharged on 1200 mg infusions of eculizumab every other week with normal lab parameters. She is currently undergoing genetic testing at the University of Iowa laboratory to look for autoantibodies and genetic mutations. The response to eculizumab and the clinical course are typical for aHUS and diagnostic.