Angioedema recurred in lupus despite normal C1-INH, case report finds

A woman in her early 20s with systemic lupus erythematosus (SLE), the most common form of the autoimmune disease lupus, developed recurrent episodes of angioedema despite having normal C1 esterase inhibitor (C1-INH) levels and function, according to a case report.

Instead, blood tests showed signs that the complement system — a network of immune proteins that helps defend the body against threats — was abnormally active, suggesting that immune processes linked to active lupus may have contributed to her recurrent swelling.

The case suggests that angioedema in people with active lupus may sometimes develop through mechanisms other than the C1-INH deficiency usually associated with acquired angioedema. The researchers stressed, however, that how complement activation might contribute to angioedema in people with lupus and normal C1-INH remains poorly understood and requires further investigation.

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The case, “From Sight to Stridor: Recurrent Angioedema in Systemic Lupus Erythematosus Associated With Complement Activation,” was published in the American Journal of Case Reports.

Angioedema is marked by sudden swelling that commonly affects the face and limbs but can also involve the digestive tract, causing abdominal pain, nausea, vomiting, and diarrhea. Swelling in the throat can make breathing difficult and can become life-threatening without prompt treatment.

Acquired angioedema (AAE) associated with C1-INH deficiency occurs when there is too little functional C1-INH, a protein that helps regulate activation of the complement system and swelling. Without enough functional C1-INH, the body produces too much bradykinin, a signaling molecule that makes blood vessels leaky and allows fluid to build up in surrounding tissues. AAE usually develops alongside another condition, such as cancer or an autoimmune disease.

Type 1 AAE occurs when C1-INH is consumed at an abnormally high rate, often in association with blood cancers or other disorders involving abnormal immune-cell growth. In Type 2 AAE, which is more commonly associated with autoimmune diseases such as lupus, autoantibodies directly bind to C1-INH and interfere with its function.

However, “emerging case reports have described patients with active SLE who develop recurrent angioedema despite preserved C1-INH levels and function,” the researchers wrote, suggesting that other complement-mediated mechanisms may be involved.

Young woman developed recurrent swelling with active SLE

Researchers described a woman in her early 20s with SLE and lupus nephritis, a complication of lupus marked by kidney inflammation and damage. She was being treated for lupus when she sought medical care for urinary symptoms, worsening kidney function, and ongoing nausea, vomiting, and diarrhea.

While waiting at an urgent care clinic, she fell asleep and awoke with worsening swelling around her left eye. A CT scan showed substantial swelling around the eye, which doctors initially thought was caused by an infection. Abdominal imaging also showed swelling in tissues around the intestines and a small amount of fluid. She was treated with antibiotics for suspected urinary and eye infections.

The next day, after she had been admitted to the hospital, the woman developed retching, excessive saliva, a sore throat, and hoarseness. A bedside laryngoscopy showed swelling in several areas of her throat, raising concern that angioedema was involving her airway.

She was treated for three days with intravenous (into-the-vein) dexamethasone, an immune-suppressing drug, along with the antihistamine diphenhydramine. Her symptoms improved over the following days.

Tests looking for the cause of the angioedema revealed an unusual pattern. Her C1-INH levels and function were normal, unlike what is typically seen in AAE associated with C1-INH deficiency. Instead, levels of the complement proteins C4 and C1q were low, a pattern that raised concern for abnormal complement activation. She also had elevated levels of antibodies against C1q and elevated C1q complement binding levels.

Together, these findings suggested that abnormal complement activation linked to active lupus may have contributed to her angioedema.

Anti-C1q antibodies may point to another swelling pathway

The researchers proposed that anti-C1q antibodies may promote excessive complement activation and possibly affect pathways involved in producing bradykinin, despite normal C1-INH levels and function. However, they emphasized that the exact mechanism remains unclear.

Over the next six months, the woman was hospitalized twice more for swelling around one eye and her lips. Her kidney function also worsened, eventually requiring dialysis, a treatment that performs some of the kidneys’ essential functions. Persistently low complement levels raised concern that her lupus remained active.

She was later started on Benlysta (belimumab), an approved SLE therapy, and no further angioedema episodes had been reported at the time of publication.

“This case highlights the diagnostic challenges surrounding complement-mediated angioedema phenotypes in autoimmune disease and underscores the importance of early recognition of airway involvement in patients with lupus,” the researchers wrote.

Further studies are needed, they added, to better understand how complement activation and antibodies against C1q may be linked to recurrent angioedema in people with SLE whose C1-INH levels and function remain normal.