Thrombotic microangiopathy is a complex disorder associated with thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and organ damage. The disorder can be seen in association with deficiencies of ADAMTS 13, Thrombotic Thrombotic Purpura (TTP) or due to dysregulation of the complement system, atypical Hemolytic Syndrome (aHUS).
Lupus erythematosus is a multisystem immune complex disorder often associated with renal insufficiency due to glomerulonephritis, lupus nephritis (LN). TMA with progressive, life threatening thrombocytopenia, MAHA and worsening renal function can occur in these patients, despite of high dose glucocorticoids, plasmapheresis and other immune modulatory therapy. Because the clinical and laboratory presentation is indistinguishable from aHUS, the use of complement inhibition is appropriate. We present 8 cases of LN, refractory to plasma exchange (PEX), glucocorticoids, and immune therapies, who were treated with eculizumab, a monoclonal antibody to complement C5.
Patients and Methods:
We retrospectively reviewed the cases of 8 patient with SLE and aHUS diagnosed from 2009 to 2016 hospitalized at 2 large urban hospitals. The age mean, median, and range was 34.5, 34, and 21 to 59 years, respectively. The majority of patients were women (7/8). There was evidence of renal insufficiency, hemolytic anemia (elevated LDH, low haptoglobin, fragmented red blood cells), and thrombocytopenia on admission. The mean Cr was 3.1 mg/dL (median Cr 2.5, range 1.5-5.7), mean Hgb was 8.2 g/dL (median 8.4, range 5.4-11.7), mean platelets was 65.4 (median 78, range 8-91). 5/8 patients had renal biopsies which demonstrated TMA. in all cases, ADAMTS13 activity was greater the 5%.
7/8 patients responded to the eculizumab, with reduction in lactic dehydrogenase (LDH), improvement in thrombocytopenia to greater than 100 x 109/L, improvement in renal function, and anemia. 5/8 (63%) of patients were on hemodialysis during hospitalization; of the five patients on dialysis, 1 patient expired, 2 continued dialysis, and 2 were able to discontinue dialysis on follow-up. Of the 5 dialysis patients, 1 stopped dialysis on day 1 of treatment and another patient stopped on day 60 post-eculizumab. Of the 2 patients who continued dialysis, 1 patient had a previous history of an allogeneic renal transplant which was compromised by graft loss due to aHUS; renal biopsy showed evidence of thrombotic microangiopathy and graft rejection. She was positive for a thrombomodulin mutation. 7/7 living patients were screened for genetic complement mutations. Mutations were detected in 4/7 (57%) ,including complement factor H, thrombomodulin, factor B, CFHR5 and membrane co-factor protein (MCP/CD46).
All patients were treated with eculizumab per the FDA approved schedule, given meningococcal vaccinations and penicillin prophylaxis. 1 patient died with progressive TMA within 1 day of receiving eculizumab. Autopsy showed TMA and disseminated fungal infection. There were no infectious complications associated with eculizumab. 6/7 surviving patients have continued on eculizumab. 1 patient elected to discontinue treatment after 1 year. She did not have any identified mutations.
Complement inhibition, with eculizumab, is an effective treatment of patients with progressive lupus nephritis associated TMA and represents a new paradigm in treatment for this devastating disorder.
Weitz: Alexion Pharmaceuticals: Speakers Bureau.
Asterisk with author names denotes non-ASH members.