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

Abstract

Acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a rare disease that can be diagnosed via complement testing. It often accompanies lymphoproliferative underlying diseases. Our study aimed to examine if there is a connection between complement parameters and the clinical symptoms of C1-INH-AAE, and, in case of a known underlying disease, its activity. The other question is how a connection, if proven, could help in the development of the therapeutic strategy of C1-INH-AAE patients. In the past 30 years, out of the 3938 patients sent to the Angioedema Center with angioedema symptoms, we have diagnosed C1-INH-AAE in 19 cases. An underlying disease was diagnosed in 15 patients. Most often lymphoma (6/19 patients) and monoclonal gammopathy of undetermined significance (6/19 patients) were found. Angioedema specific long-term prophylaxis did not result in an improvement in neither the frequency of the attacks nor in the complement parameters. A connection has been found between the presence and activity of any underlying disease, the frequency of the angioedema attacks and the decreased level of proteins of the complement system. Decreasing complement parameters warn about the appearance or the worsening of the underlying disease. The treatment of the underlying disease brings improvement in the complement parameters. Rituximab treatment reduced the number of attacks or completely made them disappear, and we experienced positive changes in complement parameters. Complement parameters supported the long-term efficacy of rituximab treatment for C1-INH-AAE. The change in complement parameters predict the relapse of the underlying disease, and it is a good indicator for the prediction of angioedematous attacks. In C1-INH-AAE, it is essential to examine the patients for underlying diseases, and to regularly follow up the patient's complement parameters.

Keywords: Acquired angioedema due to C1-inhibitor deficiency; C1-inhibitor; Classical complement pathway; Lymphoproliferative diseases; Rituximab.

Figure 1

Yearly number of angioedema attacks before and after underlying disease treatment (TR).

Figure 2

Changes of complement parameters, angioedema attacks and treatments during long term follow-up. Colour scale: green colors mean that the given parameter was in the normal range; from yellow to red, the values are further away from the normal range. Under the time axis, brown lines mean the attacks, and blue half-lines mean the treatments. Horizontal blue lines show a long-term prophylaxis, with the medication named under. Black star: diagnosis of the underlying disease. Black triangles show the type of the underlying disease and its time points. The deceased patient's timelines end without an arrow. CH50: total hemolytical complement; C1–INH cc: C1-inhibitor antigenic concentration; C1–INH act: C1-inhibitor activity; MZL: marginal zone lymphoma; MGUS: monoclonal gammopathy of undetermined significance; CLL: chronic lymphoid leukemia; MM: myeloma multiplex; VAD: chemotherapy of vincristine, doxorubicin, dexamethasone; ASCT: autologous stem cell therapy.

Figure 3

Changes of complement parameters before the treatment of the underlying disease. 0 of X axis: treatment of the underlying disease.

Figure 4

Changes of complement parameters before and after rituximab treatment.