Journal of Autoimmune and Systemic Diseases
Editor in Chief: Kota V. Ramana
- About Journal
- Focus & Scope
- Editor in Chief
- Editorial Board
- Submit Manuscript
- Article Processing Charges
Systemic Lupus Erythematous Presenting as Acquired Angioedema: A Case Report and Review of the LiteratureJacquelynn P. Tran1, Jennifer L. McCracken2, Ahmed Morsy3, and Emilio B. Gonzalez3*
1School of Medicine, University of Texas Medical Branch, USA
2Division of Allergy and Immunology, University of Texas Medical Branch, USA
3Divison of Rheumatology, University of Texas Medical Branch, USA
*Corresponding author: Emilio B. Gonzalez, Professor and Chief, Division of Rheumatology, Department of Internal Medicine, University of Texas Medical Branch, 301 University Blvd, Rte. 0565, Galveston, TX 77555-0724, USA, Tel: 409-772-2863; Fax: 409-772-7355; E-mail: email@example.com
Received: July 26, 2017; Accepted: August 06, 2017; Published: August 13, 2017
Copyright: ©2017 Tran JP, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Citation: Tran JP, McCracken JL, Morsy A, Gonzalez EB (2017) Systemic Lupus Erythematous Presenting as Acquired Angioedema: A Case Report and Review of the Literature. J autoimmune systemic dis 1(1): 100002.
This case reports a previously healthy 30-year-old woman who developed angioedema with acquired C1 inhibitor deficiency as a rare presentation of systemic lupus erythematous. The patient had no previous family history, did not use any known inciting drugs, and had a negative work-up for lymphoproliferative disease. Her symptoms were managed with glucocorticoids and anti-histamines without significant improvement. The angioedema slowly resolved over the next several days. The subsequent episodes resolved with icatibant and she is currently receiving C1 esterase inhibitor prophylaxis. The relevant literature on acquired angioedema and systemic lupus erythematous is also reviewed.Keywords: angioedema, systemic lupus erythematous
Angioedema is a painless, non-pruritic, non-erythematous, subcutaneous swelling that often involves the face, hands, feet, gastrointestinal tract and airway. Angioedema can be classified as histaminergic or non-histaminergic, hereditary or acquired. Histamine release from cutaneous mast cell degranulation or from the blood basophil causes arteriolar vasodilation and increases endothelial permeability, leading to fluid extravasation and swelling. Angioedema related to histamine release suggest a possible atopic etiology and identifying the underlying cause is the starting point of evaluation. Histaminergic angioedema is the most common form of angioedema, is often associated with urticaria and responds to treatment with anti-histamines and corticosteroids. The absence of urticaria and lack of response to initial therapy suggests a non-histaminergic etiology, such as hereditary angioedema or kinin-mediated acquired angioedema .
Hereditary angioedema (HAE) is distinguished from acquired angioedema (AAE) by early age of onset, a positive family history and lack of medical comorbidities. The first episode of HAE typically begins in childhood or adolescence and worsens throughout the patient’s lifetime. The prevalence of HAE is estimated at 1 in 50,000 in the United States . Compared to HAE, the acquired form is considered to be much rarer, with an estimated prevalence ranging from 1 in 100,000 up to 1 in 500,000. A literature review from 2010 identified a total of 168 probable cases of AAE [3,4].
Hereditary angioedema is an autosomal dominant disease caused by a defect in the gene that controls the inhibition of C1 component of complement (C1-INH). C1 esterase inhibitor plays a critical role in regulating the activation of both the complement system and kinin system. A quantitative (type I HAE) or qualitative (type II) defect in C1-INH results in unregulated activation of both complement and kallikrein, which increases vascular permeability and fluid extravasation, and leads to subcutaneous and mucosal swelling . The first-line therapy for kinin-mediated angioedema includes the use of C1 inhibitor concentrate derived from human plasma or a synthetic bradykinin B2-receptor antagonist [6,7].
The first case of acquired angioedema documented in the literature was reported by Caldwell et al. in 1972, which occurred in the setting of lymphoma . Since the initial report, similar AAE cases have strengthen the paraneoplastic association with lymphoproliferative disorders and is now known as type I AAE. Type II AAE was subsequently described by Jackson et al. in 1986, when a patient was found to have an autoreactive immunoglobulin G against C1-INH in the absence of a lymphoproliferative disorder . The decrease in C1-INH due to destruction by autoantibodies displays similar AAE symptomatology as those with a hereditary quantitative defect of C1-INH. Although the types of AAE have a distinct pathogenesis, they are not mutually exclusive. It has been reported that these two conditions can coexist in patients .
A new category of AAE has emerged in the literature in the recent years and appears to be associated with systemic lupus erythematous (SLE) [11-14]. This paper reports a case of a young woman who presented with symptoms of angioedema that subsequently led to the diagnosis of systemic lupus erythematous.
Report of Case
A 30-year-old Hispanic woman presented to the emergency department complaining of lip swelling that started suddenly twelve hours prior to admission. Patient has no history of similar symptoms in herself or family members and does not take any medications regularly. Patient has no known drug allergies. Physical exam was remarkable for upper and lower lip swelling, and right cheek swelling without erythema, fluctuance, tenderness or warmth. There was no urticaria present. While in the ED, she was treated with famotidine, diphenhydramine, and methylprednisolone without significant improvement. The otolaryngology service performed a bedside laryngoscopy, which showed no evidence of laryngeal edema. Patient was admitted to the ICU for observation and her symptoms resolved slowly over several days despite high dose cetirizine, famotidine, and dexamethasone. The patient tested positive for antinuclear antibody (ANA) >1:1280, anti-Ro/SSA and anti-La/SSB antibodies. C1 Esterase inhibitor panel showed a low C1-INH level of 7 mg/dL (normal 21-39), with 40% functional (normal >68%). Complement component 1Q (C1q) level was low at <50 µg/mL (normal 109-242), C1q IgG was high at 35 (normal 0.0-3.9 ugE/mL), complement component 3 was low at 44 mg/dL (normal 86-184), and complement component 4 was also low at <2 mg/dL (normal 10-40). The patient had a negative workup for malignancy and monoclonal gammopathy, which included a chest CT, abdomen and pelvis CT with and without contrast, along with serum and urine protein electrophoresis.
Based on the absence of family history, age of onset, lack of known AAE inciting drugs, lack of response to treatment with anti-histamines and steroids, negative malignancy workup, and laboratory findings of low complement levels C3 and C4, low C1 esterase inhibitor and function, low c1q level and high ANA, anti-Ro/SSA and anti-La/SSB, the patient was diagnosed with acquired C1 esterase inhibitor deficiency related to autoimmunity, most likely systemic lupus erythematous. Further history reveals that patient had painful ulcers on her palate 4-5 years ago, which she attributed to drinking grapefruit juice, but denies any oral lesions since that time. She complains of occasional knee pain after prolonged standing, but denies other joint pain, swelling or erythema. She denies photosensitivity and a history of a malar rash.
Two months after the initial episode, patient presented to the ED for a one-day history of abdominal pain with five episodes of vomiting. She reports previous episodes of similar pain 3-4 times in the past 6 months. CT Abdomen/pelvis showed marked small bowel wall edema consistent with intestinal angioedema. Symptoms improved with supportive therapy and patient was discharged to follow up in clinic. Since the last hospital admission, patient had subsequent episodes of lip swelling and abdominal pain that were responsive to icatibant and has now been started on prophylactic treatment with replacement C1 esterase inhibitor.
Systemic lupus erythematous is a chronic inflammatory disease related to autoimmunity. The epidemiology of SLE is similar to AAE. There is a female predisposition and the age of onset is classically seen during childbearing age .
SLE can affect virtually every organ, and the clinical course is highly variable among patients. The range of diagnostic findings for SLE includes cutaneous disease, oral ulcers, nonerosive arthritis, serositis, renal disease, neurologic and hematologic disorders. Additional immunologic criteria include the presence of anti-nuclear antibodies, anti-double-stranded DNA antibody, antibody to Smith nuclear antigen, and low complement C3, C4 .
SLE disease activity is generally categorized into three patterns, including quiescent, relapsing and remitting to chronically active disease . Disease monitoring is required given the heterogeneity of presentation and clinical course. Clinicians must interpret the findings in the context of clinical history and physical exam, since there is no single marker of SLE disease activity. The five-year survival rate for patients with SLE is over 90%, which is partly attributed to increased detection, more sensitive diagnostic tests, and the prompt treatment of disease and complications [15,18]. Factors associated with a poor prognosis include male sex, low socioeconomic status, paediatric age or over 50 years at time of SLE onset, African-American race, presence of antiphospholipid antibodies, hypertension, renal disease, and high overall disease activity [15,19,20].
Many reported cases of acquired angioedema associated with SLE are symptomatic at the time of presentation [12,13]. This case is unusual in that the patient had no identifiable signs or symptoms of SLE at the time of admission. The patient presented with findings of low C3 and C4, low C1-INH, low C1q and high titer IgG anti-Cq1 antibody. This pattern suggested complement consumption mediated by the classical pathway due to a combination of low C1 inhibitor activity from auto-destruction, and the presence of an autoantibody presumably initiating the activation of C1q. The low level of C1q is an important distinguishing lab value between HAE and AAE. This value is normal in HAE since the defect is intrinsic to C1 esterase inhibitor.
The underlying pathophysiology of acquired angioedema and lupus has not been delineated. An early case report proposed that in the setting of SLE, the catabolism of C1-INH may be accelerated unrelated to an autoantibody against C1-INH . Siegert et al. later published a study reporting that thirty to fifty percent of all patients with SLE contained IgG autoantibodies reactive to C1q in the sera. It was noted that these IgG autoantibodies recognize collagen-like region C1q. In addition, positive correlations were found between C1q IgG titers with nephritis, dermatitis, hypocomplementemia and dsDNA antibodies .
AAE is a kinin-mediated angioedema due to a deficiency in C1 inhibitor not related to heredity. The association between AAE and SLE is rarely reported in the literature. This is one of the few cases of AAE that presented in the absence of SLE symptoms. New onset AAE should not only prompt the search for underlying lymphoproliferative disorders, it should also include investigations to look for systemic autoimmunity.
- Cicardi M, Aberer W, Banerji A, Bas M, Bernstein JA, et al. (2014) Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy 69: 602-616.
- Lumry WR (2013) Overview of epidemiology, pathophysiology, and disease progression in hereditary angioedema. Am J Manag Care 19: s103-110.
- Breitbart SI, Bielory L (2010) Acquired angioedema: Autoantibody associations and C1q utility as a diagnostic tool. Allergy Asthma Proc 31: 428-434.
- Cicardi M, Zanichelli A (2010) Acquired angioedema. Allergy Asthma Clin Immunol 6: 14.
- Pappalardo E, Zingale LC, Terlizzi A, Zanichelli A, Folcioni A, et al. (2002) Mechanisms of C1-inhibitor deficiency. Immunobiology 205: 542-551.
- Zanichelli A, Bova M, Coerezza A, Petraroli A, Triggiani M, et al. (2012) Icatibant treatment for acquired C1-inhibitor deficiency: a real-world observational study. Allergy 67: 1074-1077.
- Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, et al. (2005) C1 inhibitor deficiency: consensus document. Clin Exp Immunol 139: 379-394.
- Caldwell JR, Ruddy S, Schur PH, et al. (1972) Acquired C1 inhibitor deficiency in lymphosarcoma. Clin Immunol Immunopathol 1: 39-52.
- Jackson J, Sim RB, Whelan A, Feighery C (1986) An IgG autoantibody which inactivates C1-inhibitor. Nature 323: 722-724.
- Cicardi M, Zingale LC, Pappalardo E, Folcioni A, Agostoni A (2003) Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies. Medicine (Baltimore) 82: 274-281.
- Thong BY, Thumboo J, Howe HS, Feng PH (2001) Life-threatening angioedema in systemic lupus erythematosus. Lupus 10: 304-308.
- Habibagahi Z, Ruzbeh J, Yarmohammadi V, Kamali M, Rastegar MH (2015) Refractory Angioedema in a Patient with Systemic Lupus Erythematosus. Iran J Med Sci 40: 372-375.
- Nettis E, Colanardi MC, Loria MP, Vacca A (2005) Acquired C1-inhibitor deficiency in a patient with systemic lupus erythematosus: a case report and review of the literature. Eur J Clin Invest 35: 781-784.
- Cacoub P, Frémeaux-Bacchi V, De Lacroix I, Guillien F, Kahn MF, et al. (2001) A new type of acquired C1 inhibitor deficiency associated with systemic lupus erythematosus. Arthritis Rheum 44: 1836-1840.
- Pons-Estel GJ, Alarcón GS, Scofield L, Reinlib L, Cooper GS (2010) Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum 39: 257-268.
- Petri M (2005) Review of classification criteria for systemic lupus erythematosus. Rheum Dis Clin North Am 31: 245-254, vi.
- Vitali C, Bencivelli W, Isenberg DA, Smolen JS, Snaith ML, et al. (1992) Disease activity in systemic lupus erythematosus: report of the Consensus Study Group of the European Workshop for Rheumatology Research. II. Identification of the variables indicative of disease activity and their use in the development of an activity score. The European Consensus Study Group for Disease Activity in SLE. Clin Exp Rheumatol 10: 541-547.
- Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, et al. (2003) Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 82: 299-308.
- Kasitanon N, Magder LS, Petri M (2006) Predictors of survival in systemic lupus erythematosus. Medicine (Baltimore) 85: 147-156.
- Sutton EJ, Davidson JE, Bruce IN (2013) The systemic lupus international collaborating clinics (SLICC) damage index: a systematic literature review. Semin Arthritis Rheum 43: 352-361.
- Ochonisky S, Intrator L, Wechsler J, Revuz J, Bagot M (1993) Acquired C1 Inhibitor Deficiency Revealing Systemic Lupus erythematosus. Dermatology 186: 261-263.
- Siegert C, Daha M, Westedt ML, van der Voort E, Breedveld F (1991) IgG autoantibodies against C1q are correlated with nephritis, hypocomplementemia, and dsDNA antibodies in systemic lupus erythematosus. J Rheumatol 18: 230-234.
- Tisch R, Wang B, Atkinson MA, Serreze DV, Friedline R (2001) A glutamic acid decarboxylase 65-specific Th2 cell clone immunoregulates autoimmune diabetes in nonobese diabetic mice. J Immunol 166: 6925-6936.
- Busick RY, Aguilera C, Quinn A (2007) Dominant CTL-inducing epitopes on GAD65 are adjacent to or overlap with dominant Th-inducing epitopes. Clin Immunol 122: 298-311.
- Quinn A, McInerney MF, Sercarz EE (2001) MHC class I-restricted determinants on the glutamic acid decarboxylase 65 molecule induce spontaneous CTL activity. J Immunol 167: 1748-1757.
- Rasche S, Busick RY, Quinn A (2009) GAD65-Specific Cytotoxic T Lymphocytes Mediate Beta-Cell Death and Loss of Function. Rev Diabet Stud 6: 43-53.
- Gottlieb DI, Chang YC, Schwob JE (1986) Monoclonal antibodies to glutamic acid decarboxylase. Proc Natl Acad Sci U S A 83: 8808-8812.
- Kaufman DL, McGinnis JF, Krieger NR, Tobin AJ (1986) Brain glutamate decarboxylase cloned in lambda gt-11: fusion protein produces gamma-aminobutyric acid. Science 232: 1138-1140.
- Kaufman DL, Houser CR, Tobin AJ (1991) Two forms of the gamma-aminobutyric acid synthetic enzyme glutamate decarboxylase have distinct intraneuronal distributions and cofactor interactions. J Neurochem 56: 720-723.
- Christgau S, Schierbeck H, Aanstoot HJ, Aagaard L, Begley K, et al. (1991) Pancreatic beta cells express two autoantigenic forms of glutamic acid decarboxylase, a 65-kDa hydrophilic form and a 64-kDa amphiphilic form which can be both membrane-bound and soluble. J Biol Chem 266: 21257-21264.
- Carbone FR, Kurts C, Bennett SR, Miller JF, Heath WR (1998) Cross-presentation: a general mechanism for CTL immunity and tolerance. Immunol Today 19: 368-373.
- Ackerman AL, Giodini A, Cresswell P (2006) A role for the endoplasmic reticulum protein retrotranslocation machinery during cross-presentation by dendritic cells. Immunity 25: 607-617.
- Ackerman AL, Cresswell P (2004) Cellular mechanisms governing cross-presentation of exogenous antigens. Nat Immunol 5: 678-684.
- Harding CV, Song R (1994) Phagocytic processing of exogenous particulate antigens by macrophages for presentation by class I MHC molecules. J Immunol 153: 4925-4933.
- Shen L, Sigal LJ, Boes M, Rock KL (2004) Important role of cathepsin S in generating peptides for TAP-independent MHC class I cross-presentation in vivo. Immunity 21: 155-165.
- Quinn A, McInerney B, Reich EP, Kim O, Jensen KP, et al. (2001) Regulatory and effector CD4 T cells in nonobese diabetic mice recognize overlapping determinants on glutamic acid decarboxylase and use distinct V beta genes. J Immunol 166: 2982-2991.
- Dai YD, Jensen KP, Marrero I, Li N, Quinn A, et al. (2008) N-terminal flanking residues of a diabetes-associated GAD65 determinant are necessary for activation of antigen-specific T cells in diabetes-resistant mice. Eur J Immunol 38: 968-976.
- Krzych U, Fowler AV, Sercarz EE (1985) Repertoires of T cells directed against a large protein antigen, beta-galactosidase. II. Only certain T helper or T suppressor cells are relevant in particular regulatory interactions. J Exp Med 162: 311-323.
- Martinez NR, Augstein P, Moustakas AK, Papadopoulos GK, Gregori S, et al. (2003) Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide. J Clin Invest 111: 1365-1371.
- Sun D, Whitaker JN, Huang Z, Liu D, Coleclough C, et al. (2001) Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J Immunol 166: 7579-7587.
- Ford ML, Evavold BD (2005) Specificity, magnitude, and kinetics of MOG-specific CD8+ T cell responses during experimental autoimmune encephalomyelitis. Eur J Immunol 35: 76-85.
- Mayo S, Quinn A (2007) Altered susceptibility to EAE in congenic NOD mice: Altered processing of the encephalitogenic MOG35-55 peptide by NOR/LtJ mice. Clin Immunol 122: 91-100.
- Belizaire R, Unanue ER (2009) Targeting proteins to distinct subcellular compartments reveals unique requirements for MHC class I and II presentation. Proc Natl Acad Sci U S A 106: 17463-17468.
- Sanderson S, Shastri N (1994) LacZ inducible, antigen/MHC-specific T cell hybrids. Int Immunol 6: 369-376.
- Rammensee H, Bachmann J, Emmerich NP, Bachor OA, StevanoviÄ‡ S (1999) SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50: 213-219.
- Quesnel A, Hsu SC, Delmas A, Steward MW, Trudelle Y, et al. (1996) Efficient binding to the MHC class I K(d) molecule of synthetic peptides in which the anchoring position 2 does not fit the consensus motif. FEBS Lett 387: 42-46.
- Day PM, Esquivel F, Lukszo J, Bennink JR, Yewdell JW (1995) Effect of TAP on the generation and intracellular trafficking of peptide-receptive major histocompatibility complex class I molecules. Immunity 2: 137-147.
- Corper AL, Stratmann T, Apostolopoulos V, Scott CA, Garcia KC, et al. (2000) A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes. Science 288: 505-511.
- Sévère S, Gauvrit A, Vu AT, Bach JM (2007) CD8+ T lymphocytes specific for glutamic acid decarboxylase 90-98 epitope mediate diabetes in NOD SCID mouse. Mol Immunol 44: 2950-2960.
- Schneider SC, Ohmen J, Fosdick L, Gladstone B, Guo J, et al. (2000) Cutting edge: introduction of an endopeptidase cleavage motif into a determinant flanking region of hen egg lysozyme results in enhanced T cell determinant display. J Immunol 165: 20-23.
- Sercarz EE, Lehmann PV, Ametani A, Benichou G, Miller A, et al. (1993) Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol 11: 729-766.
- Capitani G, De Biase D, Gut H, Ahmed S, Grütter MG (2005) Structural model of human GAD65: prediction and interpretation of biochemical and immunogenic features. Proteins 59: 7-14.
- Norbury CC, Hewlett LJ, Prescott AR, Shastri N, Watts C (1995) Class I MHC presentation of exogenous soluble antigen via macropinocytosis in bone marrow macrophages. Immunity 3: 783-791.
- Norbury CC, Chambers BJ, Prescott AR, Ljunggren HG, Watts C (1997) Constitutive macropinocytosis allows TAP-dependent major histocompatibility complex class I presentation of exogenous soluble antigen by bone marrow-derived dendritic cells. Eur J Immunol 27: 280-288.
- Pozzi LA, Maciaszek JW, Rock KL (2005) Both dendritic cells and macrophages can stimulate naive CD8 T cells in vivo to proliferate, develop effector function, and differentiate into memory cells. J Immunol 175: 2071-2081.
- Hutchings P, Rosen H, O'Reilly L, Simpson E, Gordon S, et al. (1990) Transfer of diabetes in mice prevented by blockade of adhesion-promoting receptor on macrophages. Nature 348: 639-642.
- Burkart V, Kolb H (1996) Macrophages in islet destruction in autoimmune diabetes mellitus. Immunobiology 195: 601-613.
- Kurotaki T, Tamura Y, Ueda G, Oura J, Kutomi G, et al. (2007) Efficient cross-presentation by heat shock protein 90-peptide complex-loaded dendritic cells via an endosomal pathway. J Immunol 179: 1803-1813.
- Chen L, Jondal M (2009) TLR9 activation increases TAP-independent vesicular MHC class I processing in vivo. Scand J Immunol 70: 431-438.
- Delamarre L, Pack M, Chang H, Mellman I, Trombetta ES (2005) Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science 307: 1630-1634.
- Colbert JD, Matthews SP, Miller G, Watts C (2009) Diverse regulatory roles for lysosomal proteases in the immune response. Eur J Immunol 39: 2955-2965.