Rare voice box involvement in IgG4-RD can make diagnosis difficult

IgG4-related disease (IgG4-RD) can in some cases affect the voice box, causing symptoms such as voice changes and difficulty breathing. These cases can also be difficult to diagnose and treat, a review study highlights.

Noting that this rare manifestation of IgG4-RD is likely to go unrecognized, the researchers emphasized the need for careful evaluation to help patients receive an accurate diagnosis and appropriate treatment as early as possible, ideally before permanent damage develops in the throat and airways.

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“Heightened recognition of IgG4-RD in patients with otherwise unexplained [voice box narrowing or tumor-like masses] is essential,” the researchers wrote. “Timely diagnosis and coordinated multidisciplinary management may help prevent progression to irreversible … airway disease and improve long-term airway function.”

The study, “Laryngeal IgG4-Related Disease: A Systematic Review of Clinical Features and Management,” was published in The Laryngoscope.

IgG4-RD is a rare disorder in which immune cells infiltrate tissues in different organs throughout the body. This abnormal immune activity can cause inflammation, tissue scarring, and tumor-like masses or enlargements, leading to a wide range of symptoms.

In rare cases, IgG4-RD can affect the larynx, a structure in the neck that’s commonly called the voice box because it houses the vocal cords. This is known as laryngeal IgG4-RD.

“Involvement of the larynx … appears rare, and likely underrecognized,” the researchers wrote, adding that diagnosis of laryngeal IgG4-RD is “challenging” and “therapeutic data are limited.”

Here, a team of scientists reviewed the scientific literature to assess what is currently known about laryngeal IgG4-RD. A total of 27 published studies — covering 32 people with laryngeal IgG4-RD — were included in the final analysis.

Voice changes were the most common symptom

Most studies were case reports describing a single individual. Patients’ median age was 54 years (range, 15-80 years), and slightly more than half were female.

The most common presenting symptoms of laryngeal IgG4-RD, reported in more than half of patients, were voice changes such as hoarseness. Shortness of breath was also a common symptom. “Overall, presentations were dominated by progressive voice change and symptoms of airway compromise,” the researchers wrote.

Available data from airway evaluation with endoscopes (flexible tubes equipped with cameras and other tools) and imaging scans showed airway narrowing, mass-like lesions, and swelling among the most frequently reported findings.

To diagnose IgG4-RD, clinicians usually rely on biopsies, in which a sample of affected tissue is removed and examined for characteristic immune-cell infiltration and other disease-related tissue changes. More than one-third of the 31 biopsy-confirmed cases required a repeat biopsy, most often because initial superficial samples did not provide a definitive result.

A definitive diagnosis often required deeper tissue samples from the larynx, obtained using an endoscope or through surgery.

People with IgG4-RD often have higher-than-normal blood levels of a specific type of antibody called immunoglobulin G4 (IgG4), which is where the disease gets its name. However, in about 60% of biopsy-proven cases of laryngeal IgG4-RD, blood IgG4 levels were within the normal range, which may further complicate diagnosis, the team noted.

“Diagnosis is often delayed owing to … frequent nondiagnostic initial biopsies and the limited reliability of [blood] IgG4 levels,” the researchers wrote. They said these findings highlight the need to take biopsy samples from deeper tissue in the larynx when IgG4-RD is suspected.

Treatment included medicines and airway procedures

Treatment data, available for 31 of the cases, showed that 90% of patients were treated with glucocorticoids, which are anti-inflammatory medications commonly used to manage IgG4-RD. Some patients also underwent procedures to relieve airway obstruction, including endoscopic procedures and surgery, either alone or along with medications.

Over a median follow-up period of 16 months (nearly 1.5 years), glucocorticoid treatment was often initially effective, though patients often experienced disease recurrence when doses were reduced, necessitating additional treatments. Endoscopic airway procedures used alone were associated with high relapse rates.

The researchers stressed that the small number of patients reported in the literature makes it impossible to draw definitive conclusions about how best to treat laryngeal IgG4-RD. Still, the available evidence supports the rationale combining medications with mechanical airway interventions when needed.

“Management typically requires a multimodal approach that addresses both immune-mediated inflammation and mechanical airway obstruction,” the scientists wrote.

Overall, the researchers said that clinicians should consider IgG4-RD in people with unexplained narrowing of the larynx, airway masses, or recurring inflammation of the larynx.

“These data provide the most comprehensive characterization to date of laryngeal IgG4-RD,” the researchers wrote. “IgG4-RD involving the larynx and upper airway is an uncommon and likely underrecognized manifestation of [IgG4-RD].”