Case report presenting the diagnostic challenges in a patient with recurrent acquired angioedema, antiphospholipid antibodies and undetectable C2 levels

Abstract

BackgroundAngioedema secondary to acquired C1 inhibitor deficiency (AAE) is a rare disease. It usually is associated with lymphoproliferative disorders. We present a case of AAE in a patient with antiphospholipid syndrome (APS), a non-Hodgkin lymphoproliferative disorder (NHL) with undetectable levels of C2, C4, and an undetectable CH50. The co-existence of AAE, APS, and NHL, with an undetectable C2 level, to the best of our knowledge, has never before reported together in the same patient.Case presentationA patient with a recent history of thrombosis presented with recurrent episodes of angioedema. The workup revealed undetectable levels of C2, C4 and undetectable CH50. Quantitative levels of C1 inhibitor and C1q were low. C1 inhibitor function was less than 40%. Anti-cardiolipin antibodies were found. The patient was initially treated on demand with intravenous plasma-derived human C1-INH concentrates, (Cinryze® Shire). Later the patient received prophylactic therapy with danazol. She was diagnosed with lymphoma 3 years after her first episode of angioedema. Single agent therapy with rituximab was not only effective in treating her lymphoma but also preventing further episodes of angioedema. Anti-cardiolipin antibody titers also declined. Additionally, marked early primary pathway complement component abnormalities and CH50 also corrected, although incomplete normalization of C4 proved to be due to a heterozygous C4 deficiency.ConclusionThis case shows the unique association of AAE, APS and NHL in a patient with undetectable levels of early complement components. Additionally, this case also shows for the first time the effectiveness of rituximab therapy in all three disease states while co-existing simultaneously in the same patient.

Long term follow-up of complement parameters to improve the management of acquired angioedema due to C1-inhibitor deficiency

“…Three of our patients received long-term angioedema prophylaxis; for the indication, concomitant diseases, underlying diseases, the side effects of medications (dislipidemia, hematological and liver malignancies, hypertension, and thrombosis) [ 6 , 19 ] and the preferences of the patient were taken into account. We could not prove objectively (regarding the number of attacks or the complement parameters) the positive effects of long-term prophylaxis (danazol, tranexamic acid) in case of our patients.…”

“…The laboratory parameters of C1–INH-AAE are characterized by reduced total hemolytic complement (CH50), C1–INH concentration and activity and C4 level, and in 75% of the cases by decreased C1q level as well. Antibodies against C1–INH (C1–INH-Ab) can be detected in a number of patients [ 4 , 6 , 7 , 8 , 9 , 10 , 13 , 16 , 19 ].…”

“…Ultimately the unregulated production of bradykinin triggers endothelial cell activation which is responsible for the increased capillary permeability and the development of angioedema. Another potential mechanism to deplete C1–INH is autoantibodies specific for C1–INH produced by malignant or dysregulated B lymphocytes [ 2 , 6 , 8 , 9 , 13 , 16 , 18 , 19 , 20 ].…”

“…Angioedema attacks can be prevented by the avoidance of trigger factors [ 1 , 4 ] and can be treated with the following: plasma-derived C1–INH (pdC1-INH), recombinant human C1–INH (rhC1-INH), bradykinin B2 antagonist (icatibant) and kallikrein inhibitor (ecallantide). For the prophylaxis of angioedema attacks, attenuated androgens and tranexamic acid can be used [ 4 , 6 , 8 , 13 , 16 , 19 , 21 , 22 ]. Recent studies have proven that rituximab (anti-CD20 antibodies) can also be effective in case of serious C1–INH-AAE.…”

Antiphospholipid Antibodies and Lipids in Hematological Malignancies

“…Currently, there are some examples of hematological malignancies in conjunction with APS, those being non-Hodgkin lymphoma (NHL) [70], extranodal NHL [71], and NHL [72]. In the last five years, multiple cases of acute and chronic leukemia with the presence of APS have also been documented [73,74] and a case of concomitant multiple myeloma with PAS [75].…”