Novel Use of Siltuximab in a Patient with Somatic UBA1 Mutated VEXAS Syndrome

doi:10.21203/rs.3.rs-4952720/v1

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Case Report

Novel Use of Siltuximab in a Patient with Somatic UBA1 Mutated VEXAS Syndrome

https://doi.org/10.21203/rs.3.rs-4952720/v1

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published 17 Oct, 2024

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VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an increasingly recognized disorder that occurs due to somatic mutations of a ubiquitin-activating enzyme encoded by ubiquitin-like modifier activating enzyme 1 gene, UBA1. Clinical findings associated with VEXAS syndrome include recurrent fevers, polychondritis, periorbital edema, pleural effusions, myocarditis and/or pericarditis, hepatosplenomegaly, myelodysplastic syndrome, cytopenias, inflammatory arthritis, neutrophilic dermatosis, and deep venous thrombosis. Novel renal manifestations like interstitial nephritis are infrequent, and to our knowledge, acute renal failure due to C3 glomerulonephritis (C3GN) has not yet been reported. Overwhelming systemic inflammation can result in morbid end-organ damage and death. While there is no formal guideline or established protocol for its management, treatment of VEXAS syndrome with tocilizumab, an interleukin-6 (IL-6)-directed therapy, has been described in the literature. Here, we report a case of a 71-year-old male patient presenting with C3GN as an initial manifestation of VEXAS syndrome and explore the rationale for our approach to treatment with IL-6 blockade. Our patient was initially treated with two inpatient doses of tocilizumab with successful transition to siltuximab in the outpatient setting. He continues to benefit from ongoing siltuximab treatment for more than one year to date without any safety issues or relapse of VEXAS syndrome.

VEXAS

Siltuximab

UBA1

IL-6

systemic inflammation

C3 glomerulonephritis

case report

VEXAS syndrome is a phenotypically heterogenous autoinflammatory condition named for five of its characteristic pathologic features (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) [1, 2]. In contrast to typical case-control-type studies that rely on clinical similarities, Beck and colleagues used a genotype-driven (phenotype-neutral) approach to establish the genetic basis of VEXAS syndrome as a somatic mutation in UBA1, the gene encoding the major ubiquitin-activating enzyme (E1) that is responsible for ubiquitylation-dependent intracellular signaling and protein degradation [1]. This inactivating X-linked gene mutation is limited to myeloid cells in the blood and results in a shortened and catalytically impaired isoform of UBA (UBA1c), with subsequent depletion of cytoplasmic UBA1 [1, 3, 4]. Loss of ubiquitination has been shown to lead to accumulation of unfolded or ubiquitinated protein, triggering the unfolded protein response and ultimately systemic inflammation [3, 5]. Other autoinflammatory syndromes in humans have also been associated with impaired ubiquitination [5–7].

The clinical presentation of VEXAS syndrome is highly variable, with symptoms mimicking those of other inflammatory syndromes [1–3, 8]. Additionally, patients with VEXAS syndrome often fulfill diagnostic criteria for other hematologic disorders and/or rheumatologic disorders (e.g., relapsing polychondritis) [2, 4, 9, 10]. Diagnosis of unexplained hematologic inflammatory syndromes can be challenging, and recent clinical and translational advances have led to clinical division of such conditions into three broad categories: monogenic inflammatory disorders, cytokine storm disorders, and disorders associated with monoclonal or polyclonal hypergammoglobulinemia [9]. While this division may aid in the clinical diagnosis of these rare and often overlooked diseases, overlap among the categories still exists. For example, the clinical features and laboratory abnormalities associated with the monogenic inflammatory disorder VEXAS syndrome have also been observed in cytokine storm syndromes, like the IL-6-driven lymphoproliferative disorder idiopathic multicentric Castleman Disease (iMCD) [9]. With VEXAS syndrome, systemic inflammation can affect a variety of organs and tissues, including the skin, lungs, blood vessels, and cartilage [10]. Hematologic manifestations include myelosuppression, thromboembolic disease, and progressive bone marrow failure and myeloid malignancy [10, 11]. Clinical findings may include recurrent fevers, polychondritis, periorbital edema, pleural effusions, myocarditis and/or pericarditis, hepatosplenomegaly, myelodysplastic syndrome, inflammatory arthritis, neutrophilic dermatosis, and deep venous thrombosis, with laboratory findings reflecting elevated levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) [1–4, 6, 12–15]. To date, renal manifestations of VEXAS syndrome have been relatively infrequent [6, 15–17].

Like many inflammatory hematologic disorders, VEXAS syndrome is associated with substantial morbidity and mortality and affected patients are often refractory to pharmacotherapy including frontline corticosteroids [2, 3, 9]. While a variety of treatments have been proposed based on its pathophysiology, there is no formal guideline or established protocol for its management. Treatments such as corticosteroids, disease-modifying antirheumatic drugs, and targeted biologics have generally been focused on managing the symptoms of VEXAS syndrome, but corticosteroid dependence, other toxicities, and/or minimal effectiveness limit the available treatment options [2, 3, 8, 18].

Here we present the case of a patient with a unique renal manifestation of VEXAS syndrome who remains stable at 1-year postdiagnosis on outpatient maintenance therapy with the interleukin-6 (IL-6) inhibitor siltuximab.

A 71-year-old male with obesity, obstructive sleep apnea, type 2 diabetes mellitus, and longstanding stage 3 chronic kidney disease presented to our academic medical center for evaluation of progressive dyspnea. A loculated left pleural effusion of unclear etiology was identified on chest computed tomography (CT) scan and the patient was subsequently admitted for its characterization and management. During that hospitalization, the patient was also found to have normocytic hypoproliferative anemia (hemoglobin 8.4 g/dL, mean corpuscular volume 80 fL, reticulocyte percent 2.4%), elevated inflammatory markers (ESR 121 mm/h, CRP 270 mg/L, ferritin 455 ng/mL), and worsening of chronic renal insufficiency (baseline serum creatinine of 2 mg/dL one year earlier and 2.94 mg/L on admission). A CT scan of the abdomen and pelvis revealed enlargement of both kidneys, with loss of corticomedullary differentiation and perirenal inflammation with perirenal space fluid and nodules. A kidney biopsy revealed acute tubular injury, mild diabetic glomerulosclerosis, mild tubular atrophy and interstitial fibrosis. The patient received intermittent doses of intravenous (IV) furosemide with some improvement in volume overload and was discharged to an acute inpatient rehabilitation facility for functional recovery.

One month later, the patient required readmission due to generalized weakness, fevers, bilateral leg edema, diffuse pain, resting tremors, and altered mental status. He had further progression of acute renal failure, initially identified during the preceding hospitalization, and worsening, symptomatic hypercalcemia refractory to medical management requiring intermittent hemodialysis. Given persistent fevers, he was started on empiric broad spectrum antimicrobial therapy, although no sources of infection were identified. The results of initial diagnostic tests are summarized in Table 1 and depicted in Fig. 1. Notable results include a moderate macrocytic hypoproliferative anemia, monocytosis, immunoglobulin A (IgA) kappa monoclonal gammopathy, mild hypofibrinogenemia, hypercalcemia, elevated inflammatory markers (e.g., ESR, CRP), and elevated serum creatinine. He also developed multiple erythematous indurations in the skin of his upper and lower extremities (Fig. 2). A repeat abdominopelvic CT revealed progression of the abnormal appearance of the kidneys. A fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan showed bilateral renal enlargement and the presence of an FDG-avid renal and perirenal mass, suggestive of an infiltrative process (Fig. 3). A repeat kidney biopsy showed a polyclonal population of lymphoid cells, histiocytes, and plasma cells, without evidence of a lymphoproliferative neoplasm. Further staining for IgG4 and Epstein-Barr virus (EBV) were negative (Fig. 4).

Table 1

Results of initial laboratory, imaging, and pathology tests
Parameter	Result
Coagulation tests	• PT and aPTT WNL • Fibrinogen < 200 mg/dL
Myeloma workup	• Individual immunoglobulins WNL
Rheumatologic tests	• Cytokine panel showing elevated IL-10, IL-6, and IL-2 • Elevated ESR, CRP and ferritin • Negative ANCA, MPO antibodies, PR3 antibodies, RF, and smooth muscle antibody • Normal NK cell assay • IgG4 level WNL • Elevated C3 and C4 • Negative VEGF
Cerebrospinal fluid	• Normal cellularity and chemistry • Negative bacterial cultures • Negative cryptococcal antigen
Pleural fluid	• Normal cellularity and chemistry • Negative bacterial and fungal cultures
Bone marrow workup	• Hypercellular (50%), with trilineage hematopoiesis showing mild morphologic dyspoiesis and no increase in blasts • No morphologic or overt immunophenotypic evidence of plasma cell neoplasm • Congo red stain negative for amyloid deposition
Renal and perirenal mass biopsy (Fig. 3)	• H&E-stained sections of the perinephric mass show fibroadipose tissue with a mixed inflammatory infiltrate comprised of plasma cells, lymphocytes, histiocytes, eosinophils and neutrophils. • Staining for CD138 and Kappa/Lambda ISH do not reveal evidence of a plasma cell neoplasm. • CD3 and CD20 highlight a mix of T- and B-lymphocytes and show no evidence of lymphoma. • Pancytokeratin is negative for carcinoma.
Infectious workup	• Negative blood, urine, pleural fluid, and CSF cultures • Negative HHV6 and HHV8, HIV, viral hepatitis panel, cryptococcal antigen, RPR, adenovirus, and EBV
Toxicology	• Negative drug screen • Negative heavy metal screen
Imaging	• Chest CT showed a large loculated right pleural effusion with passive atelectasis in the right lung • PET scan showed bilateral enlarged kidneys with diffuse stranding, mild hypermetabolic activity, and surrounding small soft tissue density nodules with mild hypermetabolic activity concerning for a diffuse parenchymal disease of the kidney (e.g., lymphoma) • Brain MRI WNL
Pertinent genetic tests	• Possibly mosaic for the p.(M41L) pathogenic variant in UBA1 • p.(Met41Leu) (ATG > CTG): c.121 A > C in exon 3 of UBA1 (NM_003334.3)
ANCA, antineutrophilic cytoplasmic antibody; aPTT, activated partial thromboplastin time; C3 and C4, complements 3 and 4, respectively; CRP, C-reactive protein; CT, computed tomography (scan); EBV, Ebstein Barr virus; ESR, erythrocyte sedimentation rate; H&E, hematoxylin and eosin; HHV, human herpesvirus; HIV, human immunodeficiency virus; IgG4, immunoglobulin G 4; IL, interleukin; ISH, in situ hybridization; MPO, myeloperoxidase (antibodies); MRI, magnetic resonance imaging (scan); NK cells, natural killer cells; PET, positron emission tomography (scan); PR3, proteinase 3 (antibodies); PT, prothrombin time; RF, rheumatoid factor; RPR, rapid plasma reagin; UBA1, ubiquitin-like modifier activating enzyme 1; VEGF, vascular endothelial growth factor; WNL, within normal limits.

At this point, most of the autoinflammatory syndromes that were tested for, including iMCD, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes) syndrome, and IgG4 disease, had been excluded based on laboratory and pathological data. His myeloid mutation panel was positive for a mutation in ASXL1, which has been implicated in about 40% of patients with chronic myelomonocytic leukemia (CMML) [19]. The patient met criteria for CMML based on his persistently elevated monocyte count; however, this diagnosis did not explain his multisystem inflammation, warranting further investigation. Without a clear etiology for his progressive decline, empiric high-dose IV methylprednisolone was initiated. Although his ESR decreased from 3 times the upper level of normal to within normal limits, the patient developed significant hyperglycemia requiring initiation of subcutaneous basal and bolus insulin. About four days after steroid initiation, his mental status continued to decline, with frequent episodes of delirium, paranoia and refusal to eat or comply with medical treatment. The results of the cytokine panel ordered earlier in the admission showed elevated levels of IL-6. The patient was started on tocilizumab (8 mg/kg IV), which led to marked and sustained responses in ESR, CRP, and serum creatinine (Fig. 1). Four days after the first dose of tocilizumab, the patient was tapered off methylprednisolone (dose decreased by 25% every 3 days) and later transitioned to oral prednisone. A second dose of tocilizumab was administered, just over 2 weeks after the first. Mosaic Targeted Variant Testing for the UBA1 gene (GeneDx), prompted by the suspicion for VEXAS syndrome revealed a pathogenic variant in UBA1, corresponding to mutation c.121A > G. Taken in sum, the patient was diagnosed with VEXAS syndrome, with his perirenal inflammatory infiltrate representing a previously unreported autoinflammatory renal manifestation of the disease.

On discharge, the patient continued IL-6 blockade as an outpatient with a switch from tocilizumab to siltuximab (11 mg/kg every 3 weeks IV for 4 doses, then every 6 weeks IV thereafter). While there is no consensus on the definition of a complete response (CR) versus a partial response (PR) in VEXAS syndrome, subsequent FDG-PET scans at Months 1, 4, and 6 after initiation of IL-6 blockade revealed reduction in the perinephric soft tissue stranding of both kidneys, decreasing hydronephrosis, and decreasing FDG uptake which was deemed a PR. At the time of this submission, over one year after his initial presentation, the patient’s overall condition remains stable and his renal function has returned to baseline levels. The patient continues to receive maintenance prednisone (range: 5–40 mg daily) and siltuximab every 6 weeks, which he has tolerated well.

VEXAS syndrome should be considered as part of the differential in patients with unexplained manifestations of autoimmunity and concomitant hematologic disease [10]. Although there is no consensus on the treatment of this disorder, the use of anti-inflammatory medications and immunosuppression has been employed with limited efficacy in some patients [2, 3, 8]. A retrospective case series by Bourbon, et. al describes the outcomes of 11 patients (measured in median time to next treatment [TTNT]; defined as time to addition of new steroid-sparing agent) with VEXAS syndrome treated with different anti-inflammatory and immunosuppressive modalities [4]. Most patients (n = 10) were initially treated with and responded to corticosteroids, but relapse and corticosteroid dependence limited their utility as monotherapy (median TTNT, 3.9 months). As such, all patients required more than one agent in addition to corticosteroids, with a median of 3 therapeutic lines. The steroid-sparing agents (median TTNT) used included Janus kinase (JAK) inhibitors (ruxolitinib [n = 2] and tofacitinib [n = 1], TTNT not reached during median follow-up of 25.1 months), the hypomethylating agent azacytidine (n = 4; 21.9 months), the calcineurin inhibitor cyclosporine (n = 3; 12.7 months), the anti-IL-6 receptor tocilizumab (n = 4; 8 months), methotrexate (n = 3; 7.4 months), and the anti-tumor necrosis factor α agent adalimumab (n = 3; 3.4 months). A more recent prospective cohort study of 44 patients with VEXAS syndrome described the outcomes of patients treated with various steroid-sparing agents, most commonly IL-6 inhibitors (n = 9) and JAK inhibitors (n = 6), as well as erythropoietin stimulating agents, canakinumab, adalimumab, methotrexate, azacytidine, azathioprine, colchicine, dapsone, ustekinumab, and multiple myeloma (MM)-directed therapies [12]. This study showed a benefit (as assessed by disease control) in about one-third of patients who received therapies targeting IL-6, IL-1, and JAK and hypomethylating agents, however, none of these therapies appeared to confer steroid-sparing benefits.

Interleukin-6 is a cytokine that mediates acute phase response to infection or tissue injury as well as differentiation of B and T (CD4 + and T helper 17) cells, and its dysregulation contributes to inflammation in immune-mediated diseases [20]. Two FDA-approved anti-IL-6 therapies that have been explored for the treatment of VEXAS syndrome include tocilizumab and siltuximab. Although both drugs target IL-6 signaling they do so via different mechanisms [21]. Tocilizumab targets both soluble and membrane-bound IL-6 receptors [22], whereas siltuximab targets IL-6 directly, preventing IL-6 from binding to its receptor [23]. Tocilizumab is indicated for the treatment of a variety of conditions (e.g., rheumatoid arthritis [RA], giant cell arteritis [GCA], systemic sclerosis-associated interstitial lung disease [SSc-ILD], polyarticular juvenile idiopathic arthritis [PJIA], systemic juvenile idiopathic arteritis [SJIA], cytokine release syndrome [CRS], coronavirus disease 2019 [COVID-19]), and dosage varies by indication [22]. Conversely, siltuximab is indicated for the treatment of human herpesvirus-8 (HHV8)-negative and human immunodeficiency virus (HIV)-negative multicentric Castleman’s disease (MCD) and is administered by IV infusion every 3 weeks [23]. Both drugs require regular monitoring (e.g., platelet count, absolute neutrophil count) [22, 23], and tocilizumab has a boxed warning related to the risk of serious infections [22].

Successful treatment of VEXAS syndrome with IL-6 blockade has been previously described in a case report by Goyal et. al, in which corticosteroid therapy was slowly tapered and ultimately discontinued following continued treatment with tocilizumab in a previously steroid-dependent patient [18]. Another report highlighted the successful use of siltuximab in combination with low-dose prednisolone in the complete resolution of inflammatory manifestations in a patient with VEXAS syndrome complicated by complement-mediated vasculopathy, though follow-up was limited to 2 months [24]. A narrative systematic review evaluated the effectiveness (measured as treatment response) and safety of treatment strategies for VEXAS syndrome on a total of 116 patients [8]. A CR was defined as resolution of clinical symptoms and normalization of inflammatory and hematologic parameters, whereas PR was defined as the improvement, but not complete resolution, of such symptoms and laboratory parameters. In contrast, no response (NR) was defined as a worsening or lack of improvement in clinical symptoms and laboratory parameters. Among those treated with tocilizumab (n = 15) for a median duration of follow-up of 9 months (range: 2–13 months), 12 patients received tocilizumab as monotherapy. A CR was observed in 3 patients (20%), a PR was observed in 6 patients (40%), and NR was observed in 2 patients (13.3%); one patient had discontinued treatment prior to response evaluation. Dose reduction of corticosteroid therapy was reported in 66% (6/9) of patients receiving tocilizumab. Adverse events (reported for 10 patients) included severe pancytopenia (n = 1), neutropenia (n = 1), herpes zoster (n = 2), Pneumocystis jirovecii pneumonia (n = 1), thrombosis (n = 1), Nocardia infection (n = 1), and death due to jejunum perforation (n = 1).

VEXAS syndrome is still a relatively newly defined diagnosis, and this case highlights a unique renal manifestation of VEXAS syndrome in the form of C3 glomerulonephritis, an inflammatory perirenal infiltrate, and worsened renal function in a patient with existing stage 3 chronic kidney disease. To our knowledge, this is the first report of such a case. Our patient was initially managed with high doses of methylprednisolone, and although there was some decrease in the ESR, insulin-dependent hyperglycemia necessitated steroid discontinuation. Because our patient experienced bone marrow suppression, the use of JAK inhibitors was precluded. A cytokine panel showing elevated levels of IL-6, in addition to the progressive deterioration of the clinical status, provided a potential therapeutic target for treatment with tocilizumab. The availability of tocilizumab in the inpatient setting also contributed to our decision to implement its use. Upon discharge, the patient transitioned to off-label treatment with siltuximab (administered every 6 weeks) given that it is more readily available in the outpatient setting. While response criteria are not clearly defined, we followed a similar approach for reporting outcomes that has been used previously and considered our patient to have achieved a PR to therapy, defined as improved but not fully resolved clinical symptoms and laboratory abnormalities, based on PET scan results and improvement in renal and bone marrow function [8]. A well tolerated and lasting response to siltuximab therapy has been observed. At the time of submission of this report, our patient remains stable on siltuximab for over a year thus far. This exceeds the TTNT of 8 months (n = 11) and median duration of follow-up of 9 months (n = 6) in previous reports of patients with VEXAS syndrome who were treated with tocilizumab [4, 8].

While our patient demonstrated benefit from IL-6 blockade, we recognize the considerable heterogeneity in the cases of VEXAS syndrome that have been described in the literature. We aim to expand the knowledge and awareness of this rare condition and provide rationale for our treatment approach in this unique case. In the absence of randomized controlled trials evaluating the efficacy and safety of siltuximab in the treatment of VEXAS syndrome, our experience suggests a potential role for siltuximab use in the management of VEXAS syndrome, particularly for continuation in the outpatient setting for those with elevated levels of IL-6.

Data availability

This manuscript does not report data generation or analysis.

Competing Interests:

Financial interests: The authors declare they have no financial interests.

Funding statement

Writing support was funded by Recordati Rare Diseases Inc.

Ethical approval

The Office of Human Research Ethics at the University of North Carolina Chapel Hill has issued a determination that the research presented here does not constitute human subjects research as defined under federal regulations and does not require institutional review board (IRB) approval.

Consent to publish The participant has consented to the submission of the case report to the journal.

Author contributions

BCN- Prepared the original draft, interpreted the data, clinically involved in patient care, wrote the manuscript

JR- clinically involved in patient care, interpreted the data, contributed to writing the manuscript, figure design

MS- clinically involved in patient care, interpreted the data, reviewed the manuscript

SM- involved in patient care, reported the pathology data

SMR- clinically directed care, interpreted the data, conceptualization

All authors have read and agreed to the published version of the manuscript, gave final approval of the version to be submitted and read, corrected, and approved the manuscript

Acknowledgments

The authors thank Lisa Kohoutek, PharmD, BCPS, Joana Carvalho, PhD, and Tiago Barros Silva, PharmD, PhD, of Med Communications, Inc., for medical writing and editorial assistance, which was funded by Recordati Rare Diseases Inc.

Conflicts of interest:

Manish K. Saha: Honoraria from Calliditas, Travere, ChemoCentryx, and Elsevier

Samuel M. Rubinstein: Ad-hoc consulting with EUSA pharma, Janssen, BMS, Sanofi, Lava Therapeutics

Joshua Rivenbark: Research support from Agios

Beck DB, Ferrada MA, Sikora KA et al (2020) Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med 383:2628–2638. https://doi.org/10.1056/NEJMoa2026834
Saad AJ, Patil MK, Cruz N, Lam CS, O’Brien C, Nambudiri VE (2024) VEXAS syndrome: a review of cutaneous findings and treatments in an emerging autoinflammatory disease. Exp Dermatol 33:e15050. https://doi.org/10.1111/exd.15050
Kobak S (2023) VEXAS syndrome: Current clinical, diagnostic and treatment approaches. Intractable Rare Dis Res 12:170–179. https://doi.org/10.5582/irdr.2023.01020
Bourbon E, Heiblig M, Gerfaud Valentin M et al (2021) Therapeutic options in VEXAS syndrome: insights from a retrospective series. Blood 137:3682–3684. https://doi.org/10.1182/blood.2020010177
Tao P, Wang S, Ozen S et al (2021) Deubiquitination of proteasome subunits by OTULIN regulates type I IFN production. Sci Adv 7:eabi6794. https://doi.org/10.1126/sciadv.abi6794
van der Made CI, Potjewijd J, Hoogstins A et al (2022) Adult-onset autoinflammation caused by somatic mutations in UBA1: a Dutch case series of patients with VEXAS. J Allergy Clin Immunol 149:432–439e4. https://doi.org/10.1016/j.jaci.2021.05.014
Damgaard RB, Walker JA, Marco-Casanova P et al (2016) The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity. Cell 166:1215–1230e20. https://doi.org/10.1016/j.cell.2016.07.019
Boyadzhieva Z, Ruffer N, Kötter I, Krusche M (2023) How to treat VEXAS syndrome: a systematic review on effectiveness and safety of current treatment strategies. Rheumatology (Oxford) 62:3518–3525. https://doi.org/10.1093/rheumatology/kead240
Henrie R, Cherniawsky H, Marcon K et al (2022) Inflammatory diseases in hematology: a review. Am J Physiol Cell Physiol 323:C1121–C1136. https://doi.org/10.1152/ajpcell.00356.2021
Grayson PC, Patel BA, Young NS (2021) VEXAS syndrome. Blood 137:3591–3594. https://doi.org/10.1182/blood.2021011455
Obiorah IE, Patel BA, Groarke EM et al (2021) Benign and malignant hematologic manifestations in patients with VEXAS syndrome due to somatic mutations in UBA1. Blood Adv 5:3203–3215. https://doi.org/10.1182/bloodadvances.2021004976
Patel BA, Ferrada M, Quinn K et al (2023) Clinical manifestations are evolving and progressive in patients with VEXAS syndrome. Blood 142:703. https://doi.org/10.1182/blood-2023-187454
Beck DB, Ferrada MA, Sikora KA et al (2020) Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. Supplementary appendix. N Engl J Med 383:2628–2638. https://doi.org/10.1056/NEJMoa2026834
Khitri MY, Guedon AF, Georgin-Lavialle S et al (2022) Comparison between idiopathic and VEXAS-relapsing polychondritis: analysis of a French case series of 95 patients. RMD Open 8:e002255. https://doi.org/10.1136/rmdopen-2022-002255
Georgin-Lavialle S, Terrier B, Guedon AF et al (2022) Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients. Br J Dermatol 186:564–574. https://doi.org/10.1111/bjd.20805
Koster MJ, Lasho TL, Oltneau H et al (2024) VEXAS syndrome: Clinical, hematologic features and a practical approach to diagnosis and management. Am J Hematol 99:284–299. https://doi.org/10.1002/ajh.27156
Poulter JA, Collins JC, Cargo C et al (2021) Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. Blood 137:3676–3681. https://doi.org/10.1182/blood.2020010286
Goyal A, Narayanan D, Wong W et al (2022) Tocilizumab for treatment of cutaneous and systemic manifestations of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome without myelodysplastic syndrome. JAAD Case Rep 23:15–19. https://doi.org/10.1016/j.jdcr.2022.02.022
Patnaik MM, Tefferi A (2022) Chronic myelomonocytic leukemia: 2022 update on diagnosis, risk stratification, and management. Am J Hematol 97:352–372. https://doi.org/10.1002.ajh.26455
Tanaka T, Nazaraki M, Kishimoto T (2018) IL-6 immunotherapy. Cold Spring Harb Perspect Biol 10:a028456. https://doi.org/10.1101/cshperspect.a028456
Potere N, Batticciotto A, Vecchié A et al (2021) The role of IL-6 and IL-6 blockade in COVID-19. Expert Rev Clin Immunol 17:601–618. https://doi.org/10.1080/1744666X.2021.1919086
Actemra. Prescribing information. Genentech; December 2022. Accessed May 7 (2024) https://www.gene.com/download/pdf/actemra_prescribing.pdf
Sylvant (2024) Prescribing information. EUSA Pharma; December 2019. Accessed May 7, https://sylvant.com/wp-content/themes/sylvant_dtc/assets/docs/sylvant-prescribing-info.pdf
Staels F, Betrains A, Woei-A-Jin FJSH et al (2021) Case report: VEXAS syndrome: from mild symptoms to life-threatening macrophage activation syndrome. Front Immunol 12:678927. https://doi.org/10.3389/fimmu.2021.678927

Competing interest reported. Joshua Rivenbark: Research support from Agios; Manish K. Saha: Honoraria from Calliditas, Travere, ChemoCentryx, and Elsevier; Samuel M. Rubinstein: Ad-hoc consulting with EUSA pharma, Janssen, BMS, Sanofi, Lava Therapeutics; Beatriz Cáceres-Nazario and Stephanie Mathews have no competing interests.

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Novel Use of Siltuximab in a Patient with Somatic UBA1 Mutated VEXAS Syndrome

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