Practitioner Forum The Most Expensive Drug in the World: To Continue or Discontinue, That Is the Question Rola Khedraki, MD; Zorawar Noor, MD; and James Rick, MD, PhD Tailoring treatment based on genetics and medical history may be preferable for patients with atypical hemolytic uremic syndrome who face lifelong therapy on an expensive medication and increased risk of infection. 59-year-old man with a During his hospitalization, he 1.55 mg/dL. His hemogram showed 20-year history (1994) of developed pronounced expressive normochromic normocytic ane- HIV well controlled on aphasia and lethargy but was able to mia (hemoglobin [Hb] level A highly active antiretroviral follow simple commands. A com- 10.2 g/dL) with schistocytes. Serum therapy (HAART) therapy (base- puted tomography (CT) scan of the samples were initially unreportable line viral load undetectable, CD4+ head revealed a left lacunar infarc- by the laboratory due to severe he- cell count 781), presented to a com- tion, and he was transferred to the molysis, but his haptoglobin level was munity hospital (May 7, 2014) with VA Long Beach Healthcare System in found to be low and, conversely, LDH abdominal pain. The patient’s girl- California for further care of a pos- remarkably high. Fifteen days after friend reported unusual behavior for sible stroke. admission, his CD4+ cell count was 1 week before admission, including Shortly after arrival, he devel- 141. An abdominal CT scan showed decreased appetite, binge drinking, oped a fever of 100.9º F. His pulse right lower quadrant abdominal free and nonadherence to HAART therapy. was 100 bpm and regular, blood fluid and thickening of the termi- There was no history of fever, il- pressure was 164/92 mm Hg, and nal ileum with surrounding strand- legal medication use, or diarrhea. respiratory rate was 14 breaths per ing, suggestive of terminal ileitis, and In addition to HIV, his past history minute. A physical examination he was started on piperacillin- was remarkable for hepatitis B, hy- was remarkable for somnolence, tazobactam. A lumbar puncture was pertension, and left lower extremity disorientation, and aphasia. He was unremarkable, and HAART medica- amputation secondary to a motor ve- grimacing to light palpation in all tions were resumed. The patient re- hicle accident. He had a remote his- 4 quadrants of the abdomen and had quired intubation and a ventilator for tory of cocaine, PCP (phencyclidine), diffuse purpura on skin examination. acute respiratory failure. LSD (lysergic acid diethylamide), Laboratory results showed worsen- Empiric treatment for presumed marijuana, and alcohol misuse and a ing thrombocytopenia, acute kidney thrombotic thrombocytopenic pur- 50 pack-year smoking history. His injury with proteinuria and hemoglo- pura (TTP) with plasmapheresis and family history was remarkable for a binuria, and hemolysis (schistocytes, methylprednisolone was ineffective, mother who died of pancreatic cancer. low haptoglobin level, and elevated and the patient required mechanical lactate dehydrogenase [LDH]). ventilation and hemodialysis. Dr. Khedraki is a resident physician and Dr. Noor The patient’s changes in base- In refractory cases of TTP- is chief resident physician, both in internal medi- line laboratory results were platelet hemolytic uremic syndrome, ritux- cine at the University of California, Irvine. Dr. Rick 3 3 is a staff physician at the Long Beach Healthcare count 206,000 mm to 64,000 mm , imab, a monoclonal antibody di- System in California. serum creatinine level 0.98 mg/dL to rected at CD20 present on B 22 • FEDERAL PRACTITIONER • JULY 2016 www.fedprac.com lymphocytes, is added empirically Thrombotic Thrombocytopenic is usually seen in young children as effective salvage therapy and was Purpura secondary to Shiga toxin-producing therefore tried in this case.1 Thrombocytopenic purpura oc- Escherichia coli (STEC).6 Hemolytic However, the addition of ritux- curs in about 3 cases per 1,000,000 uremic syndrome, also referred to as imab failed to improve the patient’s adults per year.3 It occurs when STEC-HUS or typical HUS, is a rare condition, and he developed fur- the metalloproteinase enzyme disease affecting 10 to 20 people per ther seizure activity and evidence ADAMTS13 activity is impaired, million annually. About 10% of these of new lacunar infarctions as seen interrupting its function to cleave patients are classified as having aHUS on magnetic resonance imaging of large sticky von Willebrand fac- because STEC is not implicated in the brain. His hospital course was tor (vWF) multimers, resulting in their disease. It is of interest that, un- complicated by recurrent hemopty- coagulation in microvasculature by like aHUS, STEC-HUS is usually a sis and respiratory failure, requiring increased platelet aggregation, hemo- self-limited disease of children, the assisted ventilation and eventually lysis from shearing of red blood cells, majority of whom recover without tracheostomy. and compromised circulation to the relapse, and evidence that eculi- A normal ADAMTS13 level (72%) highly vascularized kidney and other zumab improves prognosis in STEC- and negative Shiga toxin test changed vital organs.4 The hallmark of TTP HUS is not compelling.5 the diagnosis to atypical hemolytic is a severely decreased ADAMTS13 uremic syndrome (aHUS). Mean activity (< 5% of normal) second- Atypical Hemolytic Uremic complement C3 (74 mg/dL) and ary to coexisting conditions, such as Syndrome C4 (9 mg/dL) levels were low. Plas- cancer, pregnancy, HIV infection, ad- Atypical HUS is a complement- mapheresis was discontinued, and verse effects (AEs), or antibodies to mediated disease. The usual func- treatment with eculizumab (Soliris, ADAMTS13.5 tion of complement proteins is to Alexion Pharmaceuticals) was initi- The TTP pentad of thrombocy- destroy foreign cells and activate im- ated. Meningococcal vaccine was ad- topenia, hemolytic anemia, neuro- mune cells. However, in aHUS this ministered post-eculizumab, aimed at logic symptoms, renal failure, and protective defense system goes awry reducing but not eliminating the risk fever were present in our patient. resulting in a pathologic thrombotic of meningococcemia.2 Two weeks The patient had a known HIV in- milieu. Specifically, aHUS is a contin- later, the patient’s platelet count nor- fection but no exposure to medica- uous complement mediated attack malized, renal function improved, tions associated with TTP (such as on vascular endothelial beds due to hemolysis resolved, and the patient acyclovir, quinine, oxymorphone, the failure of protein regulators to regained full mental status. Eight platelet aggregation inhibitors, or terminate the complement cascade. weeks after initiating eculizumab, he immunosuppressants). Prior to ob- Unlike typical HUS, which is usu- no longer required dialysis. taining ADAMTS13 level, the patient ally associated with a Shiga-toxin was treated empirically for TTP with producing gastrointestinal infection, DISCUSSION early and daily plasma exchange to the trigger in aHUS is unknown and Generalized thrombosis of smaller remove the inhibitor of ADAMTS13 thought to be associated with a ge- blood vessels (thrombotic micro- and replace it with fresh frozen netic predisposition. angiopathy [TMA]) occurs in 3 un- plasma. Rituximab also was used to Atypical HUS distinguishes itself common syndromes—TTP, HUS, inhibit production of antibodies to from TTP and HUS in that it does not and aHUS—all with similar clinical ADAMTS13 from CD20 B lympho- respond to plasma exchange, corti- presentations but distinct pathologic cytes. These empiric clinical mea- costeroids, rituximab, or other im- etiologies and treatment. These syn- sures were not effective in stopping munosupressants. This is due to the dromes share a clinical picture of his decline in renal and neurologic distinct underlying pathophysiology thrombocytopenia, hemolytic ane- functions. of aHUS in which the problem is the mia, and renal failure. Hemolysis in unbridled activation of the alternate these conditions is manifested by Hemolytic Uremic Syndrome arm of the complement system. schistocytes, elevated lactate dehy- Like TTP, HUS is also a consequence The complement system is part drogenase from damaged cells, de- of thrombotic microangiopathy. of the innate immune system, which creased haptoglobin, anemia, and However, in contrast to TTP, which is acts with or without the adaptive im- hemoglobinuria. more commonly seen in adults,3 HUS mune system it “complements” by www.fedprac.com JULY 2016 • FEDERAL PRACTITIONER • 23 ATYPICAL HEMOLYTIC UREMIC SYNDROME amplifying a cascade of responses to The patient achieved full recovery of erning generic drugs, and informed eliminate the trigger pathogen. There neurologic, renal, and hematologic consent from patients participating in are 3 complement pathways—clas- impairments after treatment with ec- clinical trials. sical, lectin, and alternate. The al- ulizumab, the recombinant human- An unintended consequence was ternate complement pathway, whose ized monoclonal antibody that binds that the development of medications activation generates C5a complement to the complement protein C5 brake for uncommon diseases became fis- (anaphylotoxin), was most pertinent and inhibits its enzymatic cleavage, cally unattractive to the pharma- to this case. This precipitates a num- thereby interfering with the produc- ceutical industry, ie, “orphaned.” ber of downstream protein cleaving tion of the MAC and cell lysis. The Orphan Drug Act was enacted events that