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The American Journal of Medicine (2006) 119, e3-e5 CLINICAL COMMUNICATION TO THE EDITOR
Rituximab-induced Elimination of Acquired
frequent administration of C1-inhibitor concentrate, leading Angioedema Due to C1-Inhibitor Deficiency
to very frequent attacks of severe These at-tacks may be life-threatening and obviously have a major impact on morbidity and quality of life.
Here we describe 3 patients with such a therapy-resistant Acquired deficiency of C1 inhibitor is a relatively rare severe acquired deficiency of C1 inhibitor, who show a but serious disorder, causing frequently occurring, severe normalization of C1-inhibitor plasma levels and a complete remission of angioedema attacks after treatment with anti- ciency of C1 inhibitor may be caused by the formation of auto-antibodies (type II ) but may also occur in the settingof lymphoproliferative disorders (type In the latter CASE REPORT
case, at least 2 mechanisms have been proposed to explainthe decrease of C1 inhibitor. One involves anti-C1-inhibitor Three patients with acquired angioedema had very frequent specificity of the antibody produced by the malignant B-cell (Ͼ1/10 days) angioedema attacks despite treatment with clone; the other assumes consumption of C1 inhibitor by danazol (150-300 mg/day), alone or in combination with excessive activation of C1, the first complement factor, by tranexamic acid (2-3 g daily). Severe angioedema attacks immune complexes consisting of the idiotype of the anti- (defined as an attack in the upper airway or a serious body produced by the malignant clone and anti-idiotype abdominal attack) were treated with intravenous adminis- antibodies. The ongoing consumption of C1 inhibitor in the tration of 1000 U of plasma-derived C1-inhibitor concen- latter situation will cause a deficiency of this protease in- trate (Sanquin, Amsterdam, the Netherlands). The 3 patients It is becoming increasingly clear that many of the had high requirements for C1-inhibitor concentrate admin- patients with lymphoproliferative disorders have specific istration (mean consumption 2500-9000 U/month). The di- anti-C1 inhibitor antibodies, making the distinction between agnostic criteria for acquired angioedema were based on the type I and II forms of acquired C1-inhibitor deficiency less clinical presentation with recurrent attacks of angioedema, the absence of a family history of C1-inhibitor deficiency, Patients with acquired C1-inhibitor deficiency can some- onset of the angioedema attacks at age Ͼ25 years, a low times be successfully managed by treatment of the under- level of C1-inhibitor (Ͻ0.5 U/mL) and C4 (Ͻ100 mg/L) in lying disorder, and patients in which no such underlying plasma, low levels of C1q (Ͻ80 IU/mL), the presence of disease is diagnosed or who do not require specific treat- anti-C1-inhibitor antibodies (optionally), and a diagnosis of ment for this disease are treated with androgenic steroids, a lymphoproliferative disorder (optionally).
such as danazol (which stimulates hepatic production of One of the patients (patient A, female, age 45 years) had or with lysine analogues, such as epsilon positive anti-C1-inhibitor IgG antibodies. One patient (pa- caproic acid or tranexamic acid (which act by inhibition of tient B, female, age 70 years) was recently diagnosed with plasmin formation, that is important in the pathogenesis of an indolent follicular B-cell lymphoma, stage IV, with lo- In case of severe angioedema (for example, calization in spleen, bone marrow and peripheral blood, for located in the upper airways or severe abdominal attacks) which no specific treatment was given so far, and in 1 patient (patient C, male, age 68 years) no underlying cause for the C1-inhibitor deficiency was found. Patient A and immunosuppressive agents in patients with autoimmune C1 patient C were diagnosed with acquired C1-inhibitor defi- inhibitor deficiency is successful in some but not all ciency for 12 and 7 years, respectively.
Although the majority of patients can be managed success- In an attempt to reduce the frequency and severity of the fully, some patients are resistant to treatment, even despite angioedema attacks, patient A and C were treated withprednisolone (50 mg/day) in combination with cyclophos-phamide (150 mg/day). However, these treatment regimens Requests for reprints should be addressed to Marcel Levi, MD, De- had no effect at all on the clinical course or C1-inhibitor partment of Internal Medicine, Academic Medical Centre F-4, Meiberg- levels in plasma during 3-6 months follow-up. Hereupon dreef 9, 1105 AZ Amsterdam, the Netherlands.
and after provision of informed consent by the patients, all 0002-9343/$ -see front matter 2006 Elsevier Inc. All rights reserved.
The American Journal of Medicine, Vol 119, No 8, August 2006 3 patients were treated with anti-CD20 monoclonal antibod-ies (Rituximab, Roche, the Netherlands, 375 mg/m2, onceevery week for a total of 4 doses). After 3-4 months fol-lowing this treatment, in all 3 patients the frequency ofangioedema attacks was drastically reduced, along with amarked reduction in C1-inhibitor concentrate requirement,and after 8-10 months, patients were completely free fromany angioedema attack The clinical improvementwas associated with increasing levels of C1-inhibitor inplasma to (near) normal levels at 10-12 months after treat-ment and a normalization of C4 levels in 2 of 3 patientsNo adverse effects of the treatment were noted inthe patients, except for some mild diffuse muscle and jointpain in 1 patient starting after the fourth administration ofanti-CD20 antibodies and persisting for 4-5 months.
We here show successful treatment of acquired angioedema
with administration of anti-CD20 antibodies in 3 patients.
Patients with very frequent attacks of severe angioedema
requiring high doses of C1-inhibitor concentrate became
asymptomatic 3-4 months after anti-CD20 treatment. Al-
though we realize that this type of case series with success-
ful outcome does not provide the ultimate proof of efficacy
of this treatment for patients with acquired C1-inhibitor
deficiency, we feel the results are rather compelling and
suggest that further study is warranted. It is not very likely
that spontaneous remission of acquired C1-inhibitor defi-
ciency would have occurred in the 2 patients with a very
long history of this disorder or in the untreated patient with
acquired angioedema and the indolent B-cell lymphoma.
Another limitation of this observation is that it is not yet
clear whether the effect of CD20 antibody treatment is
definitive or that relapse of the disease will occur. So far,
patients have been followed for a mean period of 12 months
without signs of recurrence of angioedema, but we realize
that a longer follow-up period may be required. Neverthe-
less, when a relapse occurs, repeat treatment with anti-
CD20 antibodies is an option to be considered.
Rituximab is a chimeric antibody directed toward human CD20, and its administration leads to a transient eliminationof CD20-positive B-cells by thus far not completely under-stood mechanisms, including antibody-dependent cellularcytotoxicity, complement activation, and induction of B-celThis CD20-directed treatment has beenshown to be highly effective in the (adjunctive) treatment oflymphoproliferative disorders, in particular B-cell lympho- Effect of the administration of anti-CD20 antibodies In addition, rituximab also has been shown to be (indicated with arrows) in 3 patients with acquired C1-inhibitor effective in therapy-resistant autoimmune such deficiency (patient A: ‘ and black bars, patient B:  and stripedbars, patient C: ● and white bars) on plasma levels of C1-inhibitor and C4, frequency of serious angioedema attacks (upper airway edema, facial edema, severe edema of extremities or genitals, and report suggested that administration of Rituximab in a pa- severe abdominal attacks) and the monthly requirement for C1- tient with diffuse B-cell lymphoma also affected the occur- rence of angioedema attacks in this In our expe-rience presented here, anti-CD20 treatment was effective inboth auto-antibody-associated C1-inhibitor deficiency and Rituximab-induced Elimination of Acquired Angioedema in the patients with C1-inhibitor deficiency in the frame- 3. Jackson J, Sim RB, Whelan A, Feighery C. An IgG autoantibody work of a lymphoproliferative disorder. It is likely that in which inactivates C1-inhibitor. Nature. 1986;323:722-724.
4. Cicardi M, Zingale LC, Pappalardo E, Folcioni A, Agostoni A. Au- both situations the point of impact of anti-CD20 antibodies toantibodies and lymphoproliferative diseases in acquired C1-inhibitor must be the antibody producing B-cell clone. Importantly, deficiencies. Medicine (Baltimore). 2003;82:274-281.
as mentioned before, the distinction between the 2 types of 5. Carugati A, Pappalardo E, Zingale LC, Cicardi M. C1-inhibitor defi- acquired angioedema is rather unclear and many overlap ciency and angioedema. Mol Immunol. 2001;38:161-173.
6. D’Incan M, Tridon A, Ponard D, et al. Acquired angioedema with C1 inhibitor deficiency: is the distinction between type I and type II still In conclusion, we here demonstrate successful treatment relevant? Dermatology. 1999;199:227-230.
of severe and conventional treatment-resistant acquired an- 7. Cicardi M, Beretta A, Colombo M, Gioffre D, Cugno M, Agostoni A.
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17. Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell- 1. Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor defi- targeted therapy with rituximab in patients with rheumatoid arthritis.
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