When Lupus Masks the Lab: Why a Single Complement Test Can Mislead Angioedema Diagnosis

For decades, immunologists have leaned on a seemingly simple biochemical shortcut: if a patient with recurrent swelling shows profoundly low levels of the complement protein C1q, the cause is almost certainly acquired angioedema due to C1-inhibitor deficiency rather than the inherited form of the disease. A new case report from Saitama Medical University, published in the Journal of Cutaneous Immunology and Allergy, dismantles that assumption with unusual force. The researchers describe a Japanese family in which hereditary C1-inhibitor deficiency and systemic lupus erythematosus overlap in a single patient, producing C1q values so low that they convincingly mimicked an acquired disease — until family testing revealed the truth.

The proband, a woman in her late forties, had endured recurrent episodes of non-pitting edema affecting her face, extremities, and abdomen since her mid-teens. The attacks, estimated at fifteen to twenty per year, each lasted two to four days, occurred without the hives that characterize allergic swelling, and stubbornly resisted antihistamines, glucocorticoids, and even epinephrine. She had never taken the medications most often implicated in drug-induced angioedema, including angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, dipeptidyl peptidase-4 inhibitors, or exogenous estrogens. Crucially, she also carried a diagnosis of systemic lupus erythematosus made in adolescence, though the disease had remained clinically quiescent on stable low-dose prednisolone, with no recent flares, significant proteinuria, serositis, or active mucocutaneous disease.

Laboratory testing performed in both 2020 and 2022 painted a picture that seemed, at first glance, unambiguous. Her C4 levels sat persistently at 3.0 milligrams per deciliter, far below normal. Her C1-inhibitor antigen levels measured 7 and then 5 milligrams per deciliter, with functional activity of 31 percent and then less than 25 percent — a pattern classic for type 1 C1-inhibitor deficiency, in which the protein is both quantitatively reduced and functionally impaired. But then came the anomaly: C1q was undetectable at both time points, falling below the assay’s detection limit of 1.5 milligrams per deciliter on each occasion.

That finding should have pointed decisively toward acquired angioedema. In the hereditary form of the disease, C1q is typically normal, because the genetic defect impairs only the C1-inhibitor protein itself, leaving the rest of the classical complement pathway largely intact. In the acquired form, by contrast, consumption or autoimmune destruction of C1-inhibitor triggers runaway activation of the classical pathway, dragging C1q down with it. Profoundly low C1q has therefore long been regarded as one of the most reliable biochemical fingerprints separating the two conditions. Faced with an undetectable C1q in a middle-aged woman, the clinical team reasonably worried that an acquired process — potentially signaling an underlying lymphoproliferative disorder or monoclonal gammopathy — was hiding beneath the surface.

The initial workup, however, came back clean. Serum protein electrophoresis with immunofixation revealed no monoclonal protein, and computed tomography showed no lymphadenopathy. Anti-C1q antibodies, anti-C1-inhibitor antibodies, and sequencing of the SERPING1 gene — the gene whose mutations cause hereditary angioedema type 1 and type 2 — had not yet been performed at the time of publication, and the authors are careful to acknowledge that they cannot claim definitive exclusion of acquired disease. What they could do, and what ultimately proved decisive, was something far simpler and more powerful: test the family.

Five biologically related individuals spanning three generations, including members of a collateral line, underwent repeat complement testing. The results were striking in their internal consistency. The proband’s son, sister, niece, and father all showed reproducibly low C4 alongside low C1-inhibitor antigen and function — the biochemical signature of type 1 hereditary angioedema — yet none of them had lupus. And their C1q values told a completely different story from the proband’s. The son’s C1q measured 14.7 and then 13.8 milligrams per deciliter; the sister’s, 10.1 and then 11.0; the niece’s, 12.4 and then 10.7 — all comfortably within reference ranges. Only the father showed subnormal C1q at 6.9 and then 6.1 milligrams per deciliter, but his position within a multigenerational pedigree carrying the same C1-inhibitor defect still argued strongly for hereditary transmission rather than an independent acquired process.

The overall pattern, the authors conclude, was not acquired angioedema with low C1q, but familial C1-inhibitor deficiency with discordant C1q values — with the most extreme reduction confined to the one family member who also had systemic lupus erythematosus. This distinction is far from academic. Hereditary angioedema and lupus have been reported together before, and their coexistence can complicate complement interpretation in ways that clinicians may not anticipate. Low serum C1q can arise from multiple distinct mechanisms: inherited C1q deficiency, immune-complex-mediated consumption of the classical pathway as seen in active lupus, hypocomplementemic urticarial vasculitis, or cryoglobulinemic vasculitis, and acquired C1-inhibitor deficiency associated with monoclonal gammopathy, lymphoproliferative disease, or autoimmunity. In this patient, the absence of severe childhood infections, urticarial vasculitis-like lesions, cryoglobulinemic features, monoclonal protein, or lymphadenopathy made most alternatives unlikely, leaving overlapping lupus as the most plausible driver of her extreme C1q reduction.

The clinical stakes of getting this right are considerable. Labeling the proband as having acquired angioedema on the basis of C1q alone would have contradicted her adolescent onset, a clear three-generation familial pattern, and repeated concordant deficiency of C1-inhibitor antigen and function in her relatives. It would also have redirected her clinical care toward surveillance for hematologic malignancy rather than management of a lifelong genetic condition with well-established treatment pathways. Conversely, the authors emphasize, a low C1q result should never simply be ignored. It justifies structured surveillance and confirmatory testing, particularly because acquired C1-inhibitor deficiency can be associated with monoclonal gammopathy and hematologic disease that require their own monitoring and intervention.

The report also extends an earlier family description published by the same group, adding two new dimensions: serial C1q measurements across all tested relatives, and direct demonstration that profound C1q reduction can coexist with hereditary C1-inhibitor deficiency in a patient with overlapping lupus. The principal limitation remains the absence of molecular and autoantibody confirmation — SERPING1 sequencing and anti-C1-inhibitor antibody testing are still pending. Even so, the most parsimonious interpretation, the authors argue, is hereditary type 1 C1-inhibitor deficiency with lupus-associated or immune-mediated C1q reduction in the proband, rather than acquired angioedema diagnosed on the strength of a single complement value.

The broader lesson for clinicians managing recurrent angioedema is one of disciplined humility toward individual biomarkers. In patients with recurrent swelling — especially when onset is early and family clustering is evident — very low C1q should trigger a thorough confirmatory evaluation for acquired disease, but it should never be allowed to override a hereditary pattern revealed by age at onset, family history, and repeated testing of relatives. Complement biology, like the patients it serves, rarely obeys a single number.

Subject of Research: Diagnostic pitfalls of low C1q in distinguishing hereditary from acquired C1-inhibitor deficiency angioedema in a family with overlapping systemic lupus erythematosus

Article Title: Low C1q alone should not be taken as diagnostic of acquired angioedema in a kindred with familial type 1 C1-inhibitor deficiency and overlapping systemic lupus erythematosus

Article References: Takagi, A., Takamura, S., & Fukuda, T. (2026). Low C1q alone should not be taken as diagnostic of acquired angioedema in a kindred with familial type 1 C1-inhibitor deficiency and overlapping systemic lupus erythematosus. Journal of Cutaneous Immunology and Allergy, 9, Article 16999. https://doi.org/10.3389/jcia.2026.16999

Image Credits: AI Generated

DOI: 10.3389/jcia.2026.16999

Keywords: hereditary angioedema, acquired angioedema, C1-inhibitor deficiency, C1q, systemic lupus erythematosus, complement system, C4, SERPING1, family testing, monoclonal gammopathy, biomarker interpretation, immunology