Background: Angioedema secondary to acquired C1 inhibitor deficiency (AAE) is a rare disease. It usually is associ- ated 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 presentation: A 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 prevent - ing 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. Conclusion: This 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. Keywords: Acquired angioedema, Antiphospholipid antibody syndrome, C1 inhibitor deficiency, C2 deficiency, Lymphoma, Rituximab, Heterozygous C4 deficiency family history of angioedema . The prevalence of AAE Background has been estimated to be around 1: 600,000 . The asso - Angioedema secondary to acquired C1 inhibitor defi - ciation of AAE with APS has been reported rarely [3–6], ciency (AAE) presents with recurrent episodes of skin though its association preceding or following MGUS and mucosal swelling clinically indistinguishable from (monoclonal gammopathy of undetermined significance) the hereditary form. Clinically the two are differentiated and lymphomas is a common one . Low serum C2 by the later onset of symptoms in AAE and the lack of and C4 levels have been frequently found in AAE since the disease was first reported in the literature [ 8]. A *Correspondence: firstname.lastname@example.org low CH50 may be detected in any disease that involves Department of Internal Medicine, Wright State University Boonshoft activation of the classical complement pathway, but an School of Medicine, Allergy and Asthma Centre of Dayton, 8039 Washington Village Drive, Suite #100, Centerville, Dayton, OH 45458, USA Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Bonnin et al. Allergy Asthma Clin Immunol (2018) 14:24 Page 2 of 7 undetectable CH50 suggests that a complement com- than 40%. The clinical and laboratory data suggested a ponent is markedly depleted, functionally deficient or diagnosis of AAE. Further complement studies revealed absent . an undetectable level of C2 (Table 1). A C1q binding We report a case of AAE in a patient with APS with assay was positive although a C3d binding immune com- undetectable levels of complement C2, C4, and an unde- plex assay was negative. An initial C1q level was below tectable CH50 who initially was found in a 24-h urine the level of detection but a hemolytic C1q functional collection for immunofixation to have a free monoclonal assay was normal, suggesting C1q consumption. C2 level kappa light chain. She was first diagnosed with monoclo - and function were low, C3 level and function were nor- nal gammopathy of undetermined significance (MGUS), mal, and C4 level was undetectable and function was zero and eventually with NHL 3 years after her first episode of (Table 2). Free and bound IgG anti-C1 esterase inhibi- angioedema. We present in this report the serial evolu- tor measured by enzyme-linked immunosorbent assay tion of those complement parameters with danazol and (ELISA) was negative. An assay for IgG anti-C1q anti- rituximab therapies and afterwards when she was in clin- body was negative. Assays for IgA or IgM anti-C1 inhibi- ical remission. To our knowledge our patient is the first tor or anti-C1q antibodies were not available (Table 3). case reported to demonstrate the combination of these An ANA, anti-SSA/SSB and dsDNA antibodies were neg- three diseases, with absence of not only C4, but also C2, ative. IgG, IgM and IgA anti-cardiolipin antibodies were coexisting in the same patient and all three conditions to positive. The titer for IgM anti-phosphatidyl serine anti - be responsive to rituximab therapy. body was 163.1 (normal < 22 MPS), and an IgA anti-beta 2 glycoprotein antibody level was 103.8 (normal < 20 AU). Case presentation No lupus anticoagulant was detected. APS was diagnosed A 64 y/o Caucasian female developed pain in her left on March 2009. leg in December 2008. A venous ultrasound identified Serum protein electrophoresis (SPE) with immuno- a thrombus. Her use of supplemental estrogen was felt fixation was negative. Urine electrophoresis with immu - to be a contributing factor. She was placed initially on nofixation was positive for free monoclonal kappa light enoxaparin followed by warfarin for 6 months. Thereafter chains. Chest, abdominal and pelvic CT scans did not she received aspirin 81 mg daily. show adenopathy or organomegaly. She was referred to In January 2009, she developed mild facial and lip hematology/oncology. A bone marrow biopsy was nor- swelling initially attributed to facial trauma from a cat mal on pathological analysis and flow cytometry. A posi - scratch. She went to the emergency department (ED) tron emission tomography (PET) scan was negative. All where she was treated with antihistamines and steroids these findings led to a diagnosis of MGUS. and released. However, later that night she experienced The patient had five more episodes of facial and oro - oropharyngeal swelling and she returned to the emer- pharyngeal edema through July 2011, each requiring hos- gency department. She was admitted to the intensive care pital admission. Acute treatment with 1000 units purified unit for observation and treatment with antihistamines pdf-C1INH (Cinryze, Shire) was effective at curtailing and systemic steroids. Evaluation by otorhinolaryngol- episodes although on two occasions, a second dose was ogy during her admission revealed oropharyngeal edema, needed (Fig. 1). Patient weighted around 81 kg during the however, the remainder of her evaluation was unremark- times she received purified pdf-C1INH. After the fifth able. She was discharged home 3 days later. hospitalization the potential risks and benefits of prophy - During the admission, an undetectable C4 level was lactic treatment were discussed with the patient. Because identified. She was then referred to allergy/immunology of her APS and recent history of DVT, it was mutually for evaluation of angioedema and an undetectable C4 decided to initiate danazol therapy. Doses of 100 mg level. The family history for angioedema was negative. A twice daily prevented further episodes. The dose was review of her medication list to identify medications clas- then decreased to the lowest effective dose of 100 mg in sically associated with an increased risk of angioedema the morning and 50 mg at bedtime. On demand icatibant revealed that she was taking aspirin 81 mg once daily was prescribed in August 2011 when it received FDA but had not been on an angiotensin converting enzyme approval but was not been administered due to success of inhibitor. She was no longer on estrogen therapy. She other therapeutic interventions. Danazol was continued had no history of diseases associated with C4 deficiency until March 2013. including Systemic Lupus Erythematous (SLE) and mac- In January 2012, she began to experience night ular degeneration. sweats and fatigue. Her physical examination revealed Further laboratory workup after the undetectable C4 the presence of splenomegaly. Her CBC revealed ane- level had been confirmed, revealed low quantitative levels mia, leukopenia, and thrombocytopenia. Her LDH and of C1 inhibitor and C1q. C1 inhibitor function was less beta-2-microglobulin were elevated. Serum protein Bonnin et al. Allergy Asthma Clin Immunol (2018) 14:24 Page 3 of 7 Table 1 Baseline biological parameters of the patient and its changes with treatment C1 INH C1 INH C3D IC Protein Protein Cardiolipin Cardiolipin Cardiolipin C1Q Binding Assay C1INH Fxn C1QC2C3C4 CH50 Assay Esterace Esterace IGG IGM IGA *** ** 0–8 Abnormal < 11–26 21–39 < 23GPL < 11 MPL < 22 APL Reference ValuePosive > 10.8 5–8.6 mg/dl1.6–3.5 mg/dl 90–180 mg/dl16–47 mg/dl 31–66 μ/ml Negave 40 mg/dl mg/dl μ/ml μ/ml μ/ml OCT 09' 39.2303 < 2 FEB 09' <3.6 undetected 120 25.4 221.8 25.4 MAR 09' < 9 <106.9 267.8 27.3 26.3* 5.3* 131* <1.7* 0* * MAR 09' (83-125 UG/ML) (22.2-39.8 UG/ML) (66-162 mg/dL) (11-39 mg/dL) (176-382u/ml) MAR 10' < 9 < 10 Lab after Danazol introduced on July 2010 OCT 10' 96.3 < 1.32 < 10 APR 11' 6.9 (≤ or=25.1) < 99 5.9104 < 2 JUL 11'8 84 < 2 < 10 JAN 12'5 undetected < 2 < 10 Lab after Rituximab was introduced supplementary to Danazol on May 2012 JUL 12'87115.3 < 1.3812 12 5.868.132.1 SEP 12'91125.5 < 1.32 16 8.8239.114.5 OCT 12'> 100186.6 < 1.32 26 4.556.49.7 NOV 12'100 5.3< 1.3110 3 28 188.8.131.52 DEC 12'855.6 < 1.32 24 5.426.611.1 FEB 13'99276.4 < 1.3111 3 32 184.108.40.206 MAR 13'> 100345.6 < 1.3113 4 44 9.321.87.8 Lab after Danazol discontinued + Rituximab treatment continued on Mar 2013 APR 13'91215.5 <1.3 1094 41 220.127.116.11 JUN 13'91217.9 <1.3117 7 Lab after Rituximab discontinued on Nov 2013 DEC13' 87 26 82 12611 60 <1414< 11 JUN14' 93 26 6.11.8 11914 60 5.76.8 8.1 JAN15' 90 27 5.81.7 11212 16 6.634.89.2 * Naonal Jewish Health ** SLI- Quest Diagnoscs, Nichols Valencia *** EZ- Quest Diagnoscs, Nichols SJC Table 2 Complement Function and Level of the Patient on March 2009 Complement function Reference range (units/mL) Complement level Reference range C1Q 2949 2515–9414 26.3 83–125 UG/mL C2 104 15,354–46,242 5.3 22.2–39.8 UG/mL C3 16,725 11,249–42,887 131 66–162 mg/dL C4 0 400,000–43,000,000 < 1.7 11–39 mg/dL CH50 0 176–382 Labs performed at National Jewish Health, Denver, Colorado Table 3 Complement and C1 EST IHN autoantibody profile CD5—CD10+ CD20+ and BCL6+ cells, consistent with follicular lymphoma. A PET scan was done and revealed Antibodies Result Reference range strong spleen uptake. The patient was diagnosed with C1Q autoantibody 3 [< 4.2]% of STD low-grade B cell non-Hodgkin’s lymphoma, stage IV-B C1 EST IHN—autoantibody free IgG 25.4 [0.89–39.1]% of STD in April 2012. Treatment options were discussed with C1 EST IHN—autoantibody bound IgG 3 [0.3–46.3]% of STD the patient. It was elected to treat her with a single agent, Labs performed at National Jewish Health, Denver, Colorado rituximab. Treatment was initiated in May 2012 with four doses of rituximab at 375 mg/m , as initial induc- tion therapy. By the end of the induction phase she was not experiencing night sweats or fatigue and her anemia, electrophoresis revealed an elevation of alpha 2 globulin leukopenia and thrombocytopenia had resolved. A post fraction, with an M- band present in the gamma region. treatment PET scan was negative. The patient declined Immunofixation revealed a monoclonal IgM-Kappa another bone marrow biopsy. Following successful induc- gammopathy. A bone marrow biopsy was performed tion therapy, a maintenance schedule with rituximab at for the second time. It showed infiltration by monoclo - 375 mg/m was given. nal lymphocytes. Immunoperoxidase stains identified Danazol pdh - C1INHC Rituximab Bonnin et al. Allergy Asthma Clin Immunol (2018) 14:24 Page 4 of 7 Fig. 1 Swelling of patient before and after 24 h of treatment Immunologic re-evaluation after initiation of rituxi- entertained the possibility that the pathogenesis of her mab therapy, found that her anti-cardiolipin antibodies angioedema was due to an autoimmune process like her levels decreased. The C4 quantitation remained below APS. The undetectable levels of C2, C4 and an undetecta - normal levels, although the C1 inhibitor functional assay ble CH50 suggested either a primary C2 or C4 deficiency, normalized. Because of persistently decreased C4 levels, or less likely, a secondary deficiency due to autoantibody C4-genetic analysis was done. The C4 protein concen - production and marked complement consumption . tration by radio immunodiffusion assay was 13.4 mg/dL. Additional data revealing a low C1q level and positive Immunofixation of EDTA plasma detected C4A3 and C1q binding activity suggested an acquired C1 inhibitor C4B1 protein allotypes. Quantitative real-time polymer- deficiency due to anti-C1 inhibitor autoantibodies. Using ase reactions for complement C4 gene copy numbers an IgG- specific detection assay, anti-C1 inhibitor was performed in three independent experiments revealed: not detected. The failure to detect an IgG anti-C1 inhibi - Total C4 = 3, C4A = 1, C4B = 2. These results are com - tor is not surprising since 30% of patients with acquired patible with heterozygous C4A deficiency, suggesting a C1 inhibitor deficiency have undetectable anti-C1 inhibi - genetic component for the low levels of C4 observed in tor antibodies . A limitation of our case presentation this patient. A follow-up interview with the patient in is that we were not able to check for IgA or IgM anti-C1 July 2016 found that she remained lymphoma free and inhibitor antibodies, which can be present in AAE . without recurrence of angioedema or any thrombotic In an ongoing effort to evaluate for a lymphoprolifera - events. tive process, a 24-h urine collection for immunoelectro- phoresis and immunofixation was done. It was positive Discussion and conclusions for a free kappa light chain. Further workup for a lym- AAE association with lymphoproliferative disorders phoproliferative disorder was negative. Interestingly, or autoantibodies is well established [10, 11]. AAE is serum immunofixation was repeated 3 years later and uncommon. However, recently series have reported the was found to be positive for a monoclonal IgM kappa presentation, associations and responses to treatment in component, suggesting that the acquired C1 inhibitor large cohorts of patients with AAE [2, 7, 12]. This patient, deficiency in this patient was related to a lymphoprolifer - in addition to having AAE, met the Sapporo Criteria for ative process and its M component. Previous studies have the diagnosis of Antiphospholipid Syndrome . APS shown that the M component may have anti-C1-INH has rarely been reported to be associated with acquired autoantibody neutralizing activity . C1 inhibitor deficiency [3–6]. Her NHL immunophenotype was consistent with fol- The presentation of angioedema at 64 years of age in licular lymphoma. The most common lymphoma asso - the presence of a low C4, suggested she had AAE. The ciated with cases of AAE, is splenic marginal zone detection of a quantitatively decreased C1 inhibitor in lymphoma [7, 12]. However, the most frequent type of combination with decreased C1 inhibitor function was lymphomas associated with C1 inhibitor deficiency, diagnostic of a C1 inhibitor deficiency. A combination of symptomatic or not, in a case series of patients with lym- low C4 and low C1 inhibitor function has 98% specific - phoma was diffuse large B cell lymphoma . ity for C1 inhibitor deficiency and a 96% negative predic - Once the diagnosis of AAE was established, human pd- tive value . With the discovery that the patient had C1INHc (Cinryze-Shire) was made available for imme- a normal SPE and a normal serum immunofixation, we diate administration upon this patient’s presentation Bonnin et al. Allergy Asthma Clin Immunol (2018) 14:24 Page 5 of 7 in the ED. Although a dose of 1000 units was generally multifactorial. Studies of patients with antiphospholipid effective at stopping the progression of her angioedema, antibodies have shown that these patients uniformly a second dose with 1000 units was administered within have significantly elevated complement activation prod - 24 h on her fourth and sixth admissions due to the per- ucts . This, in combination with complement activa - sistence of lower lip swelling. Due to the recurrent nature tion due to the intrinsic complement binding capacity of her angioedema episodes, we elected to try danazol. of the monoclonal IgM protein or its potential role as an Tranexamic acid is considered to be more effective than autoantibody, as evidenced by the acquired C1 inhibitor danazol [2, 7]. Despite studies showing patients receiving deficiency, lead to the uncontrolled, marked consump - danazol for > 2 years had increased coagulation , the tion of early complement components. The heterozygous known increased risk of thrombosis in patients receiving C4 deficiency resulted in the expected decrease in C4 antifibrinolytics , influenced the decision to start the level that increased but never normalized after rituximab danazol trial. Danazol has been used extensively in both therapy. Prior to therapy, baseline, ‘normally’ decreased hereditary angioedema and AAE [18, 19] due to its abil- C4 levels were rapidly consumed by a monoclonal IgM ity to efficiently increase C1 inhibitor production. In our kappa-associated lymphoproliferative disease causing C1 patient, danazol was well tolerated and it did prevent fur- inhibitor depletion and ongoing complement consump- ther episodes of AAE as long as the total dose was not tion resulting in undetectable levels. lower than 150 mg/day. In addition to observe clinical This case is unique for multiple reasons. To the best of benefits, the complement profile did change, similar to our knowledge this is the first reported case of an unde - previous reports . Later rituximab, a B cell depleting tectable C2 in a patient presenting with AAE. Also, this chimeric anti-CD20 monoclonal antibody , was used is the first report of AAE, APS and NHL co-existing in as monotherapy to treat her NHL. Although initially used the same patient. Furthermore, simultaneous serological in the treatment of lymphomas, it has also been used in improvement induced by rituximab monotherapy in all a multitude of autoimmune diseases. Its use in APS has three diseases has not being previously reported. Clini- seldom been reported . Furthermore, its administra- cally her AAE and NHL improved with administration of tion has been reported only in individual cases of AAE rituximab, but it is not clear if there was clinical benefit in patients [7, 22–25]. Its efficacy on the three coexisting the patient’s APS from rituximab as previously reported conditions of our patient probably depends in that all her . She did not show any evidence of thrombotic diseases were consequence of a monoclonal IgM kappa recurrence from 2009 to 2012 in spite of no anticoagu- producing B cell lymphoproliferation. lant therapy. Interestingly, there was clinical improve- A quantitatively undetectable C2 and essentially absent ment in the frequency of angioedema episodes with the C2 function posed an interesting interpretative prob- administration of an attenuated androgen, danazol. This lem. While it is known that C2 levels are decreased in improvement was associated with a partial correction of patients with C1 inhibitor deficiency , the finding of some of the complement abnormalities, most notably an an undetectable C2 is not. This data strongly suggested a increase in C1 INH level, although never attaining a ‘nor- potential C2 deficiency, although she did not have history mal’ level. Near complete resolution of serological and of recurrent pyogenic infections, SLE, or atherosclerosis clinical findings required the correction of the monoclo - commonly associated with homozygous C2 deficiency nal proliferative process by rituximab. This lymphopro - . Normalization of C2 levels after treatment with liferative process, either alone, or concomitantly with rituximab ruled out a C2 deficiency and suggested a anti-cardiolipin antibodies, drove marked complement consumptive process for its markedly low level. Interest- consumption resulting in the markedly abnormal com- ingly her C4, also undetectable initially, never normal- plement findings described herein. ized, suggesting a heterozygous C4 deficiency. This was confirmed by C4 genotyping studies showing that the Abbreviations patient had a single C4A gene and two C4B genes. Com- AAE: angioedema secondary to acquired C1 inhibitor deficiency; APS: plement deficiencies have been associated with SLE and antiphospholipid syndrome; ED: emergency department; SLE: systemic lupus erythematous; PET: positron emission tomography; MGUS: monoclonal gam- other autoimmune disorders, but are rarely reported to mopathy of undetermined significance; SPE: serum protein electrophoresis; be associated to APS . pdh-C1INH: plasma-derived human C1-INH concentrates; NHL: non-Hodgkin In conclusion, this patient presented with a compli- lymphoproliferative disorder. cated clinical course culminating in the detection of a Authors’ contributions monoclonal IgM producing lymphoproliferative dis- AB has done all the analysis of the data, writing the paper, organization of ease. The pathological B cell proliferation likely was the tables, and distributing the work to be done by the co-authors. He also has found and read the majority of references used in this paper. CD and TM ultimately responsible for her C1 INH deficiency and has participating giving their suggestions and editing the paper from the APS. The complement abnormalities detected are likely beginning to the end. WR helped editing the paper from the beginning to the Bonnin et al. Allergy Asthma Clin Immunol (2018) 14:24 Page 6 of 7 end, helped finding and analyzing some references, analyzing data, and his 5. Szeplaki G, Varga L, Szepvolgyi A, Simon K, Blasko B, Nagy E. Karadi, Fust G, thoughts were essential for this paper. All authors read and approved the final Farkas H: acquire angioedema associated with primary antiphospholipid manuscript. syndrome in a patient with antithrombin III deficiency. Int Arch Allergy Immunol. 2008;146:164–8. Author details 6. 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He teaches 2016;95:33. medical students and family and internal medicine residents. He has 8. Caldwell JR, Ruddy S, Schur PH, Austen KF. Acquire C1 deficiency in published a case report in complement deficiency (Factor I), and also on lymphosarcoma. Clin Immunol Immunopathol. 1972;1:39–52. hereditary angioedema type II. Dr. DeBrosse published while in training in 9. Wen L, Atkinson JP, Giclas PC. Clinical and laboratory evaluation of com- eosinophilic esophagitis and Dr. Moncrief in epidemiology. Dr. Richmond was plement deficiency. J Allergy Clin Immunol. 2004;113:585–93. in academic medicine for about 20 years. Director of the Allergy and Immunol- 10. Schreiber AD, Zweiman B, Atkins P, Goldwein F, Pietra G, Atkinson B, ogy division at Rush Medical Center. He has published in immunodeficiency. Abdou NI. Acquired angioedema with lymphoproliferative disorder: asso- ciation of C1 inhibitor with cellular abnormality. Blood. 1976;48:567–80. Acknowledgements 11. 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