OP0090 CLASSIFICATION OF PATIENTS WITH RELAPSING POLYCHONDRITIS BASED ON SOMATIC MUTATIONS IN UBA1
Authors: Ferrada M. , Sikora K. , Lou Y. , Wells K. , Patel B. , Ospina Cardona D. , Rose E. , Goodspeed W. , Hoffman P. , Jones A. , Wilson L. , Young N. , Savic S. , Kastner D. , Ombrello A. , Beck D. , Grayson P. 
Published: May 2021

Background:

Somatic mutations in ubiquitin activating enzyme 1 (UBA1) cause a newly defined syndrome known as VEXAS. [1] More than fifty percent of patients currently identified with VEXAS meet diagnostic criteria for relapsing polychondritis (RP).

Objectives:

To determine the prevalence VEXAS within a cohort of patients with RP, to compare their clinical, laboratory, and immunologic features and to develop a clinical algorithm to inform genetic screening for VEXAS among patients with RP.

Methods:

Exome and targeted sequencing of the UBA1 gene was performed in a prospective observational cohort of patients with RP. Clinical and immunological characteristics of patients with RP were compared based on presence or absence of UBA1 mutations. Random forest was used to derive a clinical algorithm to identify patients with UBA1 mutations. Immune populations were quantified by multipanel flow cytometry. Categorical and continuous variables were compared using the chi square or Kruskal-Wallis test. P<0.05 defined statistical significance.

Results:

Seven of 92 patients with RP (7.6%) were confirmed to have UBA1 mutations (VEXAS-RP). Six additional patients with VEXAS-RP from other cohorts were included for subsequent analyses. Patients with VEXAS-RP were all male, older at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. Patients with RP as compared with VEXAS-RP had a significantly higher prevalence of airway chondritis, costochondritis and tenosynovitis/arthralgias. (Table). Mortality was significantly greater in VEXAS-RP than RP (27% vs 2% p=0.01). Maximum ESR, CRP, and mean corpuscular volume (MCV) values were significantly greater in VEXAS-RP. Absolute monocyte, lymphocyte, and platelet counts were significantly lower in VEXAS-RP. A decision tree based on male sex, MCV>100 fl and Platelet count<200 K/ul classified between VEXAS-RP and RP with 100% sensitivity and 96% specificity.

Table 1.

Clinical Characteristics of patients with RP vs VEXAS-RP

All Patients
n=98RP
n=85VEXAS-RP
n=13p valueDemographic CharacteristicsRace, White n (%)90 (92)77 (91)13 (100)0.59Sex, Male n (%)26 (27)13 (15)13 (100)<0.0001Age, Symptom onset, years, Median (IQR)38 (30-47)37 (28-43)56 (54-64)<0.0001Clinical SymptomsFever n (%)33 (34)20 (24)13 (100)<0.0001Ear chondritis n (%)61 (62)48 (56)13 (100)0.0015Nose chondritis n (%)83 (85)71 (84)12 (92)0.68Airway chondritis n (%)37 (38)37 (44)0 (0)0.0015Tenosynovitis/arthalgias n (%)83 (85)77 (91)6 (46)0.0005Skin involvement n (%)33 (34)22 (2611 (85)<0.0001Laboratory ValuesESR, mm/hr, median (IQR)12 (6-22)11 (5-19)66.5 (42-110)<0.0001CRP, mg/L, median (IQR)2.9 (0.8-9.6)1.9 (0.6-6.3)17.7 (9.6-99.5)<0.0001Platelet count (k/uL)246(201-299)258 (227-312)145 (100-169)<0.0001MCV fL93.05 (90-98)92.2 (89-95)105 (102-115)<0.0001Absolute lymphocyte count1.6 (1.1-2.3)1.78(1.4-2.4)0.92 (0.5-1.2)<0.0001CT scan abnormalitiesPulmonary infiltrates n (%)16 (16.33)6 (7.06)10 (77)<0.0001ComplicationsDeath n (%)6 (6)3 (4)3 (23)0.029Unprovoked DVT12 (12)4 (5)8 (62)<0.0001

N number; IQR = interquartile range

Conclusion:

Mutations in UBA1 are causal for disease in a subset of patients with RP. These patients are defined by disease onset in the fifth decade of life or later, male sex, ear/nose chondritis and hematologic abnormalities. Early identification is important in VEXAS given the associated high mortality rate.

References:

[1]Beck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins JC, Pei W, Balanda N, Ross DL, Ospina Cardona D, Wu Z et al: Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med 2020, 383(27):2628-2638.

Disclosure of Interests:

None declared