Kermani, Tanaz A.

Abstract Background VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is due to a somatically acquired mutation of the E1-ubiquitin ligase UBA1, leading to the expression of a catalytically impaired isoform in myeloid cells. VEXAS syndrome combines severe auto-inflammatory manifestations and is frequently associated with myeloid neoplasia (MN). The outcome of VEXAS is poor, and most patients require high dose corticosteroids to reduce inflammation (Bourbon et al. Blood 2021). Therapeutic options besides steroids are currently limited in those patients. In this multicenter retrospective study, we report some clinical efficacy of JAK inhibitors (JAKi) in VEXAS patients. Patients We analyzed retrospectively 24 UBA1 mutated patients (Met41 or previously reported alternative splicing site) treated with JAKi (11 with ruxolitinib (RUXO), 11 with tofacitinib (TOFA), 1 with baricitinib, 1 with upadicitinib) in 7 French, 1 Portugese and 2 US centers. Complete clinical (CCR) and complete biological response (CBR) were defined as complete resolution of clinical symptoms and normalization of inflammation markers (C reactive protein, CRP) respectively. Partial clinical (PCR) and biological (PBR) response were defined by reduction of at least 50% of clinical or inflammation markers, respectively. Results All 24 patients were males with a median age at VEXAS diagnosis of 72 years [range 54-89]. Thirteen had documented myeloid neoplasia (MN) (1 CMML-0, 1 other MDS/MPN, 10 MDS). Clinical manifestations at VEXAS diagnosis include skin involvement (87.5%), arthritis or arthralgia (83.3%), vasculitis (37.5%), fever (75%), ocular manifestations (29.2%) and pulmonary infiltrates (41.6%). IPSS-R was very low/low/intermediate in 8/3/2 cases respectively. Median time between first VEXAS related clinical manifestations and JAKi onset was 2.45 years [0.15-5.45]. Prior to JAKi onset, patients had received a median of 2.5 immunosuppressive/immunomodulatory treatments [range 0-9]. After 1 month, 12/24 (50%) patients had achieved clinical and/or biological response. CCR and CBR was achieved in 7/11 (64%) and 6/11 (54%) patients treated with RUXO, and in 3/13 (23%) and 2/13 (15%) patients treated with other JAKi (figure A). After 3 months, CCR and CBR was 100% and 80% (10 evaluable patients) in the RUXO group as compared to 25% and 25 % in patients treated with other JAKi (8 evaluable patients) (p=0.0036 et 0.0055 respectively, figure B). RUXO efficacy was similar in patients with (n=9) or without (n=2) associated MN. In RUXO treated patients, median CRP and steroid dose reduction was 72.5% [range 21.5- 99.5] and 66.25% [range 0-75] respectively at 3 months. With a median follow-up of 4 months [range 1.4-12], only 1 RUXO treated patient had lost response, whereas median time to next of treatment was 3.4 months with other JAKi (figure C). Of the 13 patients with MN, 7 were RBC transfusion dependent at JAKi onset (6 with RUXO, 1 with other JAKi). Four of 6 patients treated with RUXO achieved RBC transfusion independence at 3 months, but not the patient treated with other JAKi. Regarding safety, severe adverse events were reported in 6 patients: 3 deep vein thrombosis, (2 with TOFA/1 with RUXO), 1 pneumonia (RUXO), 1 enterohemorrhagic E. Coli infection (RUXO), and 1 lethal legionellosis (TOFA)). Conclusion Ruxolitinib (and less often other JAK inhibitors used in this study) provides rapid response in most VEXAS patients, allowing in two third of the cases corticosteroid dose reduction/withdrawal and RBC transfusion independence in 4/6 patients with MN who were initially transfusion dependent. Those retrospective preliminary results, with limited follow up, must be interpreted with caution and will be updated at the meeting. The effect of RUXO on VEXAS patients with concomitant MN will soon be studied prospectively in a Groupe Francophone des Myélodysplasies (GFM) clinical study. Figure 1 Figure 1. Disclosures Galicier: Novartis Pharma Sas, Sanofi Aventis France: Consultancy; Lilly France, Baxalta France, Sanofi Aventis France Sas: Other: Payments as Speaker for Educational Program; Shire France SA, Janssen-Cilag, Pfizer Sas: Other: Invitation to Congress. Hirsch: Novartis Pharma: Consultancy; Daiichi Sankyo Oncology: Consultancy. Warrington: Eli Lilly: Research Funding; Kiniksa: Research Funding. Fenaux: Novartis: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria.

Abstract Objective To study the prevalence, risk and clinical associations of hypothyroidism among several forms of vasculitis. Methods Patients with GCA, Takayasu’s arteritis (TAK), PAN and the three forms of ANCA-associated vasculitis [AAV; granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA)] enrolled in a prospective, multicentre, longitudinal study were included. Results The study included data on 2085 patients [63% female, 90% White] with a mean age of 54.6 years (s.d. 17.2). Diagnoses were GCA (20%), TAK (11%), PAN (5%), GPA (42%), microscopic polyangiitis (8%) and EGPA (14%). Hypothyroidism was present in 217 patients (10%) (83% female), with a mean age 59.8 years (s.d. 14.5). Age- and sex-adjusted risk of hypothyroidism was GCA, odds ratio (OR) 0.61 (95% CI 0.41, 0.90); TAK, OR 0.57 (95% CI 0.31, 1.03); PAN, OR 0.59 (95% CI 0.25, 1.38); GPA, OR 1.51 (95% CI 1.12, 2.05); microscopic polyangiitis, OR 1.81 (95% CI 1.18, 2.80) and EGPA, OR 0.82 (95% CI 0.52, 1.30). Among patients with AAV, age- and sex-adjusted risk of hypothyroidism was higher with positive MPO-ANCA [OR 1.89 (95% CI 1.39, 2.76)]. The clinical manifestations of vasculitis were similar in patients with and without hypothyroidism, except transient ischaemic attacks, which were more frequently observed in patients with GCA and hypothyroidism (12% vs 2%; P = 0.001). Conclusions Differences in the risk of hypothyroidism among vasculitides may be due to genetic susceptibilities or immune responses. This study confirms an association of hypothyroidism with MPO-ANCA.

Objectives To define the elementary ultrasound (US) lesions in giant cell arteritis (GCA) and to evaluate the reliability of the assessment of US lesions according to these definitions in a web-based reliability exercise. Methods Potential definitions of normal and abnormal US findings of temporal and extracranial large arteries were retrieved by a systematic literature review. As a subsequent step, a structured Delphi exercise was conducted involving an expert panel of the Outcome Measures in Rheumatology (OMERACT) US Large Vessel Vasculitis Group to agree definitions of normal US appearance and key elementary US lesions of vasculitis of temporal and extracranial large arteries. The reliability of these definitions on normal and abnormal blood vessels was tested on 150 still images and videos in a web-based reliability exercise. Results Twenty-four experts participated in both Delphi rounds. From originally 25 statements, nine definitions were obtained for normal appearance, vasculitis and arteriosclerosis of cranial and extracranial vessels. The ‘halo’ and ‘compression’ signs were the key US lesions in GCA. The reliability of the definitions for normal temporal and axillary arteries, the ‘halo’ sign and the ‘compression’ sign was excellent with inter-rater agreements of 91–99% and mean kappa values of 0.83–0.98 for both inter-rater and intra-rater reliabilities of all 25 experts. Conclusions The ‘halo’ and the ‘compression’ signs are regarded as the most important US abnormalities for GCA. The inter-rater and intra-rater agreement of the new OMERACT definitions for US lesions in GCA was excellent.

ObjectiveTo compare patients with large‐vessel giant cell arteritis (LV‐GCA) characterized by wall thickening, stenosis, and/or occlusion of subclavian arteries to those with subclavian dilatation.MethodsFor the purposes of the present retrospective study, 2 different subsets of LV‐GCA were identified and compared from an established cohort of patients with radiographic evidence of subclavian artery vasculitis secondary to GCA: LV‐GCA with wall thickening, stenosis, and/or occlusion of subclavian arteries (Group 1), and LV‐GCA with dilatation of subclavian arteries without wall thickening or stenotic changes (Group 2).ResultsThe study included 109 patients in Group 1 and 11 in Group 2. Large‐vessel involvement secondary to GCA was diagnosed significantly later in patients from Group 2 compared to those from Group 1 (median 15.3 versus 0.0 months; P = 0.010). Compared to patients from Group 1, those from Group 2 were more frequently male (17% versus 45%; P = 0.027), ever smokers (42% versus 73%; P = 0.048), and more frequently had a history of coronary artery disease (11% versus 36%; P = 0.018). At LV‐GCA diagnosis, 10 of the 11 patients (91%) from Group 2 had aortic dilatation compared to 13 of 109 patients (12%) from Group 1 (P < 0.001). During the followup period, the prevalence of aortic aneurysm was significantly higher in patients from Group 2 compared with those from Group 1 (64% versus 7% at 5 years; P < 0.001).ConclusionTwo different subsets of LV‐GCA were identified. Given the strong association between subclavian artery dilatation and aortic aneurysm, such patients should be evaluated and monitored carefully for aortic dilatation.