Central diabetes insipidus more common in AAV patients with GPA

Antibodies against PR3 protein raise AAV relapse risk in patient group: study

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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Among people with ANCA-associated vasculitis (AAV), those with central diabetes insipidus are more frequently diagnosed with granulomatosis with polyangiitis (GPA), a type of AAV, according to a study in China.

Central diabetes insipidus, or CDI, is a rare disease characterized by excessive thirst and excessive urine.

Patients with CDI also have more ear, nose, and throat (ENT) and eye involvement, but less kidney involvement than those who do not have CDI.

Moreover, while CDI was not associated with a higher risk of relapse, the presence of antibodies against the proteinase 3 (PR3) protein — one of the most common AAV-driving antibodies — was considered a risk factor for disease relapse in this patient group.

The study, “Clinical characteristics and primary outcomes of patients with ANCA-associated vasculitis and central diabetes insipidus,” was published in the journal Frontiers in Endocrinology.

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Central diabetes insipidus affects up to 4% of AAV patients

AAV is a group of disorders characterized by inflammation and damage to small blood vessels that affect organ and tissue function. The inflammation is usually caused by ANCAs, self-reactive antibodies that target one of two proteins — PR3 and myeloperoxidase (MPO) — in neutrophils, a type of immune cell.

Central diabetes insipidus is a rare condition that “may precede or follow the diagnosis of AAV,” the researchers wrote, adding it has been reported to affect 1.3%-3.9% of AAV patients. CDI occurs due to a deficiency in the antidiuretic hormone (ADH), which helps the kidneys control the amount of water and salt in the body.

In AAV patients, CDI may be caused by inflammation of the blood vessels that supply the brain’s pituitary gland, which stores and releases ADH, or by the presence of clumps of immune cells, called granulomas, in the pituitary gland that originate from the ear, nose, and throat.

However, the long-term effect of AAV-associated CDI and related risk factors associated with disease prognosis are still unknown.

To understand the clinical characteristics and prognosis of AAV patients with CDI, researchers in China retrospectively analyzed data from 1,203 hospitalized AAV patients who were followed at their hospital from January 2012 to April 2022.

A total of 16 patients (1.3%) had AAV-associated CDI. Their average age was 49 years, and more than half (56.3%) were men. In terms of AAV types, most had GPA (87.5%), while microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis were diagnosed in one patient each (6.25%).

In 50% of the patients, symptoms of CDI first led them to seek medical care, while the remaining patients first experienced AAV symptoms.

Regarding organ involvement, the ENT were the most commonly affected (81.3% of the patients), followed by the eye (62.5%), nervous system (50%), lung (43.8%), skin (31.3%), and kidney (18.8%).

Nearly all patients (93.7%) had pituitary gland abnormalities detected by MRI, and about one-third of them had lesions with a recognizable volume.

All patients were treated with anti-inflammatory and immunosuppressive AAV treatments, mostly oral prednisone, a glucocorticoid (100% of patients); cyclophosphamide (87.5%); and into-the-vein methylprednisolone, another glucocorticoid (50%).

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50% of patients experienced partial or complete remission during follow-up

During about four years of follow-up, eight patients (50%) experienced partial or complete AAV remission. The disease recurred in six patients (37.5%) and two patients (12.5%) died due to heart failure and infection.

Desmopressin acetate tablets, a medication used to treat CDI that works as ADH, was given to 87.5% of patients, 70% of whom showed a reduction in urine and became less reliant on CDI treatment/desmopressin acetate tablets.

A follow-up MRI revealed that pituitary gland lesions had shrunk in all seven evaluated patients, and one patient fully recovered from CDI, no longer needing desmopressin treatment.

Among patients with GPA-associated CDI, 42.9% had MPO-ANCAs, 35.7% PR3-ANCAs, and 21.4% were negative for both antibody types. Those with ANCAs against PR3 had more severe disease and received the most aggressive treatment; however, they showed a significantly higher recurrence rate relative to the other two groups (80% vs. 0%-33.3%).

This is consistent with previous studies showing that AAV patients with anti-PR3 antibodies are more likely to relapse, and have harder-to-treat disease.

Further analyses found that while CDI was not associated with AAV recurrence, the presence of anti-PR3 antibodies was a significant predictor of disease relapse. No risk factors for survival outcomes were identified in AAV-associated CDI.

When compared with 80 age-, sex-, and AAV type-matched patients without CDI, those with CDI were more commonly diagnosed with GPA (87.6% vs. 33.8%), while MPA was less common (6.3% vs. 38.8%).

The CDI group also showed more ENT involvement (81.3% vs. 35%) and eye involvement (62.5% vs. 11.3%), and less kidney involvement (18.8% vs. 63.3%). They had fewer red blood cells in their urine and a higher estimated glomerular filtration rate, indicative of a better kidney function, than those who did not have CDI.

“There were no statistically significant differences in treatment or prognosis between the two groups,” the researchers wrote.

The team then compared the demographic and clinical features of 29 Asian versus 42 Western AAV patients with CDI. These included the group of patients analyzed in their study and cases previously reported in the literature.

Asian patients tended to be older men (48 vs. 40 years) and had a higher MPO-ANCA positivity (31% vs. 0%), whereas patients in Western countries were more commonly positive for PR3-ANCAs (59.5% vs. 31%).

“There was no significant difference between the two groups in terms of [whole-body] involvement,” the researchers wrote.

About half of all cases of AAV-associated CDI experienced reductions in AAV and CDI.

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Asian patients appear to have worse AAV outcomes

However, Asian patients appeared to have worse AAV outcomes than the other patients, with a higher proportion experiencing disease recurrence (20.7% vs. 11.9%) and dying (13.8% vs. 4.8%). An opposing trend was observed for CDI, with more Asian patients experiencing improvements relative to those of Western countries (27.6% vs. 14.3%).

“Further genomic studies are required to illustrate the population differences between Asian and Western countries,” the team wrote.

The inclusion of patients from a single center, and only hospitalized patients with more severe conditions, were pointed out by the researchers as study limitations.

Also, “AAV-associated CDI is a rare condition; therefore, prolonged follow-up periods and larger [groups of patients] are required to illustrate the role of PR3-ANCA positivity as a risk factor for predicting recurrence,” the researchers wrote.