Pulmonary hypertension (PH) is a rare but potentially lethal complication of plasma cell dyscrasia (PCD), with polyneuropathy (P), organomegaly (O), endocrinopathy (E), M-protein (M) and skin changes (S) known as POEMS syndrome. Cyclic AMP response element binding protein (CREB) levels are decreased in smooth muscle cells (SMCs) in remodeled pulmonary arteries from animals with pulmonary hypertension and atherogenic systemic arteries and cardiomyocytes from hypertensive individuals. It is thought that direct phosphorylation, proteolysis and intracellular localization are key mechanisms regulating CREB content and activity in SMCs. Cell culture experiments showed that proteosome inhibitors can restore cellular CREB content.1 Moreover, Bortezomib, a proteosome inhibitor, is an active and approved therapy for PCD.2.
A 64 year old white male with past medical history of coronary artery disease post CABG was in his usual state of health until three months prior to presentation when he developed significant shortness of breath on minimal exertion with ascites and lower extremity edema. He went from being an active working individual to almost completely bedbound. He had poor appetite and lost 20 pounds despite his volume overload. He denied any chest pain or symptoms suggestive of cardiac ischemia. Upon medical evaluation he was found to have WHO Class III CHF symptoms. Echocardiogram was done that showed normal left ventricular ejection fraction of 60% and pulmonary hypertension with PA systolic pressure of 65mmHg. Subsequently, left and right heart catheterizations with vasodilator challenge were performed that confirmed his pulmonary hypertension. Lab work-up revealed elevated transaminases, ESR, BNP, and proteinurea with M-spike on serum protein electrophoresis. After extensive diagnostic work-up which included liver, bone marrow, right heart and kidney biopsies, he was found to have PCD (15% plasma cells, IgG lambda) with POEMS like syndrome in addition to pulmonary hypertension, secondary right heart failure, and membranoproliferative glomerulonephritis. He was started on Ambrisetan, endothelin receptor antagonist, for his PH and Bortezomib, proteosome inhibitor, for his PCD. Patient’s dyspnea got significantly better after cycle#1 despite experiencing side-effects from his PH medications which had to be held for a while and subsequently improved back to his baseline by cycle#4. By cycle#2, he was found to be in near complete remission with complete normalization of his bone marrow and serum electrophoresis by the end of therapy. By cycle#3 his Raynaud’s syndrome was significantly better with less dysesthesia which completely resolved by cycle#6. His edema almost complete resolved by the end of the therapy. His PCD has been controlled for almost 16 months so far. He is currently on minimal dose of Lasix with minimal dyspnea on exertion and back to his active life.
Although the improvement in PH symptoms can be due to PH and PCD directed therapies, the fact that PH medications were on hold when early symptom improvement was reported attributes such effect to Bortezomib. Moreover, the early and brisk response in PH symptoms agrues for an additional faster pathway than the mere PCD cytoreduction and ensuing secondary cytokine changes.
This case not only demonstrates for the first time the potential therapeutic activity of proteosome inhibitors in POEMS associated PH, but also serves as an in vivo experiment that supports an underlying etiologic role for proteosomal degradation of CREB in SMCs. Further exploration of the role of proteosome inhibition in such disease, is warranted.
Shantanu Saraswat, No Financial Disclosure Information; No Product/Research Disclosure Information