https://orcid.org/0000-0002-0748-3784
ABSTRACT
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic) syndrome is a novel adult-onset autoinflammatory disorder caused by variants in the UBA1 gene. Here, we report a Japanese case of VEXAS syndrome in which symptoms began 1 day after the second booster dose of a coronavirus disease 2019 (COVID-19) messenger ribonucleic acid vaccine, and a UBA1 variant was subsequently confirmed. Combined with the three cases reported thus far, this suggests that the COVID-19 vaccine may be one of the triggers for development of VEXAS syndrome in Asian populations. Since COVID-19 vaccines have been reported to be associated with various autoinflammatory and autoimmune diseases, it is important to continue to pay close attention to the relationship between COVID-19 vaccines and VEXAS syndrome.
Introduction
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic) syndrome, defined in 2020, is an adult-onset autoinflammatory disorder caused by an acquired mutation in the UBA1 gene, the master ubiquitylation gene located on the X chromosome [1]. Somatic variants affecting methionine-41 (p. Met41) in the UBA1 gene can lead to a potentially fatal and treatment-refractory inflammatory syndrome. The clinical features include fever, macrocytosis, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. It is possible that some patients who were diagnosed with another inflammatory syndrome (relapsing polychondritis, Sweet syndrome, polyarteritis nodosa, or giant cell arteritis) or haematopoietic disease (myelodysplastic syndrome or multiple myeloma) harboured this genetic variant. Therefore, identification of genetic variants is already an important part of diagnosing some autoinflammatory diseases, such as VEXAS syndrome. As the association between genetic variants and rheumatic diseases becomes clearer, diagnostic approaches, disease classification, and clinical practices gradually change [2].
The coronavirus disease 2019 (COVID-19) pandemic, which began in 2019, has spread worldwide and claimed many lives quickly; however, a variety of COVID-19 vaccines have been produced [3]. The first COVID-19 vaccine was introduced in December 2020. The main types of COVID-19 vaccines are genetic vaccines that use messenger ribonucleic acid (mRNA) and novel genetic recombination technologies. Although COVID-19 mRNA vaccines have contributed safely to the control of the pandemic, infrequent yet significant adverse effects, including the onset or exacerbation of autoimmune and autoinflammatory disorders, have been reported after vaccination [4, 5]. It is suggested that mRNA vaccine shows a stronger immune response to the vaccination than the vector vaccine [6]. As the direct causal relationship between novel mRNA vaccines and autoimmune/autoinflammatory diseases remains unclear, their long-term safety requires confirmation.
To date, three cases of VEXAS syndrome following COVID-19 mRNA vaccination have been reported in the USA and France, but none have been reported in Asia [7–9]. In all cases, the characteristic symptoms of VEXAS syndrome developed within a few days of vaccination with the mRNA vaccine, and variants in the UBA1, were subsequently confirmed.
Herein, we present a Japanese case of VEXAS syndrome after COVID-19 mRNA vaccination and compare its characteristics with those of previously reported cases.
Case presentation
A 72-year-old Japanese male, who had comorbidity of hypertension and hyperuricaemia and endoscopically treated early gastric cancer, developed facial oedema and a generalised skin rash with high fever and fatigue. As shown in Figure 1, all symptoms commenced 1 day after the second booster dose and 1 month after the initial COVID-19 vaccine; both are BNT162b2 mRNA vaccines (Pfizer/BioNTech®). Glucocorticoids (GCs) or immunosuppressive drugs were not administered at the time of vaccination. After several months of persistent skin rash, the patient visited a dermatologist and was diagnosed with erythema nodosum, which spontaneously resolved. When an inactivated seasonal influenza vaccine was administered 5 months after the first symptoms, he again had a high fever and eruption with polyarthralgia, myalgia, and swelling of the left auricle. A high C-reactive protein (CRP) level, macrocytic anaemia, and pleural effusion were noted by a primary care doctor, and he was referred to our hospital for further examination.
Clinical course of this case. The bottom row represents the number of days since the first vaccination day (day 0). Ref, reference relates to the date of referral to our hospital; Adm, admission defined as the date of admission to the hospital; PSL, prednisolone; Hb, haemoglobin; MCV, mean corpuscular volume.
Sweet syndrome or relapsing polychondritis were initially considered as differential diagnoses, based on the clinical symptoms. As shown in Figure 2(a–c), the patient had generalised painful nodular erythema. Repeated skin biopsies revealed nodular dermatitis. A patchy inflammatory cell infiltrate mainly consisting of neutrophils, lymphocytes, plasma cells, and histiocytes with scattered nuclear fragments without vasculitis was observed in all layers of the dermis to the subcutaneous layer (Figure 2(d)). Ocular findings indicated bilateral scleritis, presumed to represent vasculitis of the deep episcleral vessel overlying the sclera (Figure 2(e,f)). Magnetic resonance imaging of the head revealed high-intensity signals in the bilateral auricles on T2-weighed short-tau inversion recovery and diffusion-weighted images (Figure 3(a)). Ultrasonography revealed a hypoechoic area with internal membranous septa and strong superb-microvascular imaging signals in the left elbow, suggestive of olecranon bursitis (Figure 3(b)). Olecranon bursitis is a common condition in which the bursa on the surface of the olecranon becomes inflamed. Five millilitres of serous, partially bloody, noninfectious fluid was drained through a puncture. The swelling of the olecranon bursa spontaneously decreased in about 1 month. The laboratory data on admission are presented in Table 1. Although there was an increased inflammatory response, including the serum CRP level and erythrocyte sedimentation rate, and macrocytic anaemia was observed, no autoantibodies or pathogens were detected serologically.
The findings of skin and eyes at the time of referral to our hospital. (a-c) Multiple spots and erythematous infiltrates observed on the neck, trunk, and extremities. (d) Pathological findings (haematoxylin and eosin staining, 50× magnification) from punch biopsy of erythema on the right forearm. A patchy inflammatory cell infiltrate consisting of mainly neutrophils, lymphocytes, plasma cells, and histiocytes with scattered nuclear fragments was observed from all layers of the dermis to the subcutaneous layer. (e-f) Scleritis of the palpebral conjunctiva in both eyes (e, left medial; f left lateral).
The findings of magnetic resonance images of the head and ultrasound images of the joint. (a) High-intensity signals of the bilateral auricles shown in both T2-weighed short-tau inversion recovery (left, arrows) and diffusion-weighed (right, arrows) horizontal images of magnetic resonance images. (b) The swollen olecranon bursa seen as a hypoechoic area in the greyscale (left) with dot or linear signals in the superb-microvascular imaging window (right), suggesting bursitis in the left elbow.
Laboratory data on admission.
| CBC | pt | r.v. | Biochemistry | pt | r.v. | Serology | pt | r.v. |
|---|---|---|---|---|---|---|---|---|
| WBC (/mm3) | 4240 | 4000–8000 | TP (g/dl) | 6.3 | 6.6–8.1 | CRP (mg/dl) | 3.55 | 0.00–0.14 |
| Neut. (%) | 61.8 | 40–60 | ALB (g/dl) | 3.1 | 4.1–5.1 | Ferritin (ng/ml) | 254.1 | 30–250 |
| Lymph. (%) | 24.3 | 25–45 | T-Bil (mg/dl) | 1.0 | 0.4–1.5 | CH50 (U/ml) | 42.6 | 30–45 |
| Mono. (%) | 11.6 | 3–7 | AST (U/l) | 11 | 13–30 | IgG (mg/dl) | 1651 | 861–1747 |
| Eosin. (%) | 1.6 | 1–6 | ALT (U/l) | 8 | 10–42 | IgA (mg/dl) | 476 | 93–393 |
| Baso. (%) | 0.7 | 0–1 | AMY (U/l) | 87 | 44–132 | IgM (mg/dl) | 41 | 33–183 |
| RBC (× 104/mm3) | 239 | 430–550 | ALP (U/l) | 79 | 38–113 | IgG4 | 119 | 11–121 |
| Hb (g/dl) | 8.6 | 12–16 | LD (U/l) | 181 | 124–222 | RF (IU/ml) | 4 | <18 |
| Ht (%) | 26 | 39–52 | CK (U/l) | 19 | 59–248 | anti-CCP Ab (U/ml) | 0.3 | <4.5 |
| MCV | 111 | 86–102 | LDL-cho | 96.7 | 65–163 | ANA (titre) | <40 | <40 |
| MCH | 36 | 28–34 | TG (mg/dl) | 56 | 40–234 | PR3-ANCA (U/ml) | 0.0 | <3.5 |
| MCHC | 32 | 29–35 | UA (mg/dl) | 6.1 | 3.7–7.8 | MPO-ANCA (U/ml) | 1.0 | <3.5 |
| PLT (× 104/mm3) | 19.8 | 15–35 | BUN (mg/dl) | 18.4 | 8–20 | sIL-2R (U/ml) | 606.0 | 184–486 |
| Cr (mg/dl) | 1.01 | 0.65–1.07 | ASO (IU/ml) | 42 | <166 | |||
| ESR (mm/h) | 92 | <20 | Na+ (mmol/l) | 137 | 138–145 | ACE (U/l) | 10.9 | 8.3–21.4 |
| K+ (mmol/l) | 4.1 | 3.6–4.8 | ||||||
| Coagulation | Cl− (mmol/l) | 108 | 101–108 | Pathogen tests | ||||
| PT-INR | 1.34 | Ca+ | 8.5 | 8.8–10.1 | SARS-CoV2-PCR | (-) | (-) | |
| APTT (s) | 42.4 | 24.1–31.7 | IP | 2.8 | 2.7–4.61 | β-d-glucan | < 5.0 | <20.0 |
| D-Dimer (μg/ml) | 0.45 | 0.00–0.49 | BS (mg/dl) | 98 | 73–109 | HBs Ag | 0.00 | <0.05 |
| KL-6 (U/ml) | 161 | <500 | HBs Ab | 0.00 | <10.0 | |||
| Urinalysis | NT-ProBNP (pg/ml) | 1805.5 | <126 | HCV Ab | 0.25 | <1.0 | ||
| Protein | (–) | (–) | Vit B12 (pg/ml) | 530 | 180–914 | HIV Ag/Ab | 0.05 | <1.00 |
| Occult blood | (–) | (–) | Folic acid (ng/ml) | 4.5 | >4.0 | TB-specific IFN-γ | (-) | (-) |
| Fe (μg/ml) | 43 | 40–188 | Blood culture | (-) | (-) | |||
| FOB | (–) | (–) | TIBC (μg/dl) | 211 | 253–365 | Scrub typhus IgG/M | (-) | (-) |
| CBC | pt | r.v. | Biochemistry | pt | r.v. | Serology | pt | r.v. |
|---|---|---|---|---|---|---|---|---|
| WBC (/mm3) | 4240 | 4000–8000 | TP (g/dl) | 6.3 | 6.6–8.1 | CRP (mg/dl) | 3.55 | 0.00–0.14 |
| Neut. (%) | 61.8 | 40–60 | ALB (g/dl) | 3.1 | 4.1–5.1 | Ferritin (ng/ml) | 254.1 | 30–250 |
| Lymph. (%) | 24.3 | 25–45 | T-Bil (mg/dl) | 1.0 | 0.4–1.5 | CH50 (U/ml) | 42.6 | 30–45 |
| Mono. (%) | 11.6 | 3–7 | AST (U/l) | 11 | 13–30 | IgG (mg/dl) | 1651 | 861–1747 |
| Eosin. (%) | 1.6 | 1–6 | ALT (U/l) | 8 | 10–42 | IgA (mg/dl) | 476 | 93–393 |
| Baso. (%) | 0.7 | 0–1 | AMY (U/l) | 87 | 44–132 | IgM (mg/dl) | 41 | 33–183 |
| RBC (× 104/mm3) | 239 | 430–550 | ALP (U/l) | 79 | 38–113 | IgG4 | 119 | 11–121 |
| Hb (g/dl) | 8.6 | 12–16 | LD (U/l) | 181 | 124–222 | RF (IU/ml) | 4 | <18 |
| Ht (%) | 26 | 39–52 | CK (U/l) | 19 | 59–248 | anti-CCP Ab (U/ml) | 0.3 | <4.5 |
| MCV | 111 | 86–102 | LDL-cho | 96.7 | 65–163 | ANA (titre) | <40 | <40 |
| MCH | 36 | 28–34 | TG (mg/dl) | 56 | 40–234 | PR3-ANCA (U/ml) | 0.0 | <3.5 |
| MCHC | 32 | 29–35 | UA (mg/dl) | 6.1 | 3.7–7.8 | MPO-ANCA (U/ml) | 1.0 | <3.5 |
| PLT (× 104/mm3) | 19.8 | 15–35 | BUN (mg/dl) | 18.4 | 8–20 | sIL-2R (U/ml) | 606.0 | 184–486 |
| Cr (mg/dl) | 1.01 | 0.65–1.07 | ASO (IU/ml) | 42 | <166 | |||
| ESR (mm/h) | 92 | <20 | Na+ (mmol/l) | 137 | 138–145 | ACE (U/l) | 10.9 | 8.3–21.4 |
| K+ (mmol/l) | 4.1 | 3.6–4.8 | ||||||
| Coagulation | Cl− (mmol/l) | 108 | 101–108 | Pathogen tests | ||||
| PT-INR | 1.34 | Ca+ | 8.5 | 8.8–10.1 | SARS-CoV2-PCR | (-) | (-) | |
| APTT (s) | 42.4 | 24.1–31.7 | IP | 2.8 | 2.7–4.61 | β-d-glucan | < 5.0 | <20.0 |
| D-Dimer (μg/ml) | 0.45 | 0.00–0.49 | BS (mg/dl) | 98 | 73–109 | HBs Ag | 0.00 | <0.05 |
| KL-6 (U/ml) | 161 | <500 | HBs Ab | 0.00 | <10.0 | |||
| Urinalysis | NT-ProBNP (pg/ml) | 1805.5 | <126 | HCV Ab | 0.25 | <1.0 | ||
| Protein | (–) | (–) | Vit B12 (pg/ml) | 530 | 180–914 | HIV Ag/Ab | 0.05 | <1.00 |
| Occult blood | (–) | (–) | Folic acid (ng/ml) | 4.5 | >4.0 | TB-specific IFN-γ | (-) | (-) |
| Fe (μg/ml) | 43 | 40–188 | Blood culture | (-) | (-) | |||
| FOB | (–) | (–) | TIBC (μg/dl) | 211 | 253–365 | Scrub typhus IgG/M | (-) | (-) |
Abbreviations: pt, patient; r.v., reference value; CBC, complete blood count; WBC, white blood cells; Neut., neutrophils; Lymh, lymphocytes; Mono, monocytes; Eosi., eosinocytes; Baso., basophils; RBC, red blood cells; Hb, haemoglobin; Ht, haematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin concentration; PLT, platelets; ESR, erythrocyte sedimentation rate; PT-INR, prothrombin time-international normalizsd ratio; APTT, activated partial thromboplastin time; FOB, faecal-occult-blood test; TP, total protein; ALB, albumin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; AMY, amylase; ALP, alkaline phosphatase; LD, lactose dehydrogenase; CK, creatine kinase; LDL-cho, low-density lipoprotein cholesterol; TG, triglyceride; UA, uric acid; BUN, blood urea nitrogen; Cr, creatinine; Na+, sodium ion; K+, potassium ion; Cl−, chloride ion, Ca+, calcium ion; IP, inorganic phosphorus; BS, blood sugar; KL-6, Krebs von den Lungen-6; NT-proBNP, N-terminal probrain natriuretic hormone; Vit, vitamin; TIBC, total iron binding capacity; CH50, 50% haemolytic unit of complement; Ig, immunoglobulin; RF, rheumatoid factor; anti-CCP Ab, anticyclic citrullinated peptides antibodies; ANA, antinuclear antibody; PR-3ANCA, proteinase-3 anti-neutrophil cytoplasmic antibody; MPO-ANCA, myeloperoxidase antineutrophil cytoplasmic antibody; sIL-2R, soluble interleukin-2 receptor; ASO, antistreptolysin O antibody; ACE, angiotensin converting enzyme; SARS-CoV2, severe acute respiratory syndrome coronavirus 2; PCR, polymerase chain reaction; HBs, hepatitis B virus surface; Ag, antigen; Ab, antibody; HCV, hepatitis C virus, HIV, human immunodeficiency virus; TB, tuberculosis; IFN; interferon.
Laboratory data on admission.
| CBC | pt | r.v. | Biochemistry | pt | r.v. | Serology | pt | r.v. |
|---|---|---|---|---|---|---|---|---|
| WBC (/mm3) | 4240 | 4000–8000 | TP (g/dl) | 6.3 | 6.6–8.1 | CRP (mg/dl) | 3.55 | 0.00–0.14 |
| Neut. (%) | 61.8 | 40–60 | ALB (g/dl) | 3.1 | 4.1–5.1 | Ferritin (ng/ml) | 254.1 | 30–250 |
| Lymph. (%) | 24.3 | 25–45 | T-Bil (mg/dl) | 1.0 | 0.4–1.5 | CH50 (U/ml) | 42.6 | 30–45 |
| Mono. (%) | 11.6 | 3–7 | AST (U/l) | 11 | 13–30 | IgG (mg/dl) | 1651 | 861–1747 |
| Eosin. (%) | 1.6 | 1–6 | ALT (U/l) | 8 | 10–42 | IgA (mg/dl) | 476 | 93–393 |
| Baso. (%) | 0.7 | 0–1 | AMY (U/l) | 87 | 44–132 | IgM (mg/dl) | 41 | 33–183 |
| RBC (× 104/mm3) | 239 | 430–550 | ALP (U/l) | 79 | 38–113 | IgG4 | 119 | 11–121 |
| Hb (g/dl) | 8.6 | 12–16 | LD (U/l) | 181 | 124–222 | RF (IU/ml) | 4 | <18 |
| Ht (%) | 26 | 39–52 | CK (U/l) | 19 | 59–248 | anti-CCP Ab (U/ml) | 0.3 | <4.5 |
| MCV | 111 | 86–102 | LDL-cho | 96.7 | 65–163 | ANA (titre) | <40 | <40 |
| MCH | 36 | 28–34 | TG (mg/dl) | 56 | 40–234 | PR3-ANCA (U/ml) | 0.0 | <3.5 |
| MCHC | 32 | 29–35 | UA (mg/dl) | 6.1 | 3.7–7.8 | MPO-ANCA (U/ml) | 1.0 | <3.5 |
| PLT (× 104/mm3) | 19.8 | 15–35 | BUN (mg/dl) | 18.4 | 8–20 | sIL-2R (U/ml) | 606.0 | 184–486 |
| Cr (mg/dl) | 1.01 | 0.65–1.07 | ASO (IU/ml) | 42 | <166 | |||
| ESR (mm/h) | 92 | <20 | Na+ (mmol/l) | 137 | 138–145 | ACE (U/l) | 10.9 | 8.3–21.4 |
| K+ (mmol/l) | 4.1 | 3.6–4.8 | ||||||
| Coagulation | Cl− (mmol/l) | 108 | 101–108 | Pathogen tests | ||||
| PT-INR | 1.34 | Ca+ | 8.5 | 8.8–10.1 | SARS-CoV2-PCR | (-) | (-) | |
| APTT (s) | 42.4 | 24.1–31.7 | IP | 2.8 | 2.7–4.61 | β-d-glucan | < 5.0 | <20.0 |
| D-Dimer (μg/ml) | 0.45 | 0.00–0.49 | BS (mg/dl) | 98 | 73–109 | HBs Ag | 0.00 | <0.05 |
| KL-6 (U/ml) | 161 | <500 | HBs Ab | 0.00 | <10.0 | |||
| Urinalysis | NT-ProBNP (pg/ml) | 1805.5 | <126 | HCV Ab | 0.25 | <1.0 | ||
| Protein | (–) | (–) | Vit B12 (pg/ml) | 530 | 180–914 | HIV Ag/Ab | 0.05 | <1.00 |
| Occult blood | (–) | (–) | Folic acid (ng/ml) | 4.5 | >4.0 | TB-specific IFN-γ | (-) | (-) |
| Fe (μg/ml) | 43 | 40–188 | Blood culture | (-) | (-) | |||
| FOB | (–) | (–) | TIBC (μg/dl) | 211 | 253–365 | Scrub typhus IgG/M | (-) | (-) |
| CBC | pt | r.v. | Biochemistry | pt | r.v. | Serology | pt | r.v. |
|---|---|---|---|---|---|---|---|---|
| WBC (/mm3) | 4240 | 4000–8000 | TP (g/dl) | 6.3 | 6.6–8.1 | CRP (mg/dl) | 3.55 | 0.00–0.14 |
| Neut. (%) | 61.8 | 40–60 | ALB (g/dl) | 3.1 | 4.1–5.1 | Ferritin (ng/ml) | 254.1 | 30–250 |
| Lymph. (%) | 24.3 | 25–45 | T-Bil (mg/dl) | 1.0 | 0.4–1.5 | CH50 (U/ml) | 42.6 | 30–45 |
| Mono. (%) | 11.6 | 3–7 | AST (U/l) | 11 | 13–30 | IgG (mg/dl) | 1651 | 861–1747 |
| Eosin. (%) | 1.6 | 1–6 | ALT (U/l) | 8 | 10–42 | IgA (mg/dl) | 476 | 93–393 |
| Baso. (%) | 0.7 | 0–1 | AMY (U/l) | 87 | 44–132 | IgM (mg/dl) | 41 | 33–183 |
| RBC (× 104/mm3) | 239 | 430–550 | ALP (U/l) | 79 | 38–113 | IgG4 | 119 | 11–121 |
| Hb (g/dl) | 8.6 | 12–16 | LD (U/l) | 181 | 124–222 | RF (IU/ml) | 4 | <18 |
| Ht (%) | 26 | 39–52 | CK (U/l) | 19 | 59–248 | anti-CCP Ab (U/ml) | 0.3 | <4.5 |
| MCV | 111 | 86–102 | LDL-cho | 96.7 | 65–163 | ANA (titre) | <40 | <40 |
| MCH | 36 | 28–34 | TG (mg/dl) | 56 | 40–234 | PR3-ANCA (U/ml) | 0.0 | <3.5 |
| MCHC | 32 | 29–35 | UA (mg/dl) | 6.1 | 3.7–7.8 | MPO-ANCA (U/ml) | 1.0 | <3.5 |
| PLT (× 104/mm3) | 19.8 | 15–35 | BUN (mg/dl) | 18.4 | 8–20 | sIL-2R (U/ml) | 606.0 | 184–486 |
| Cr (mg/dl) | 1.01 | 0.65–1.07 | ASO (IU/ml) | 42 | <166 | |||
| ESR (mm/h) | 92 | <20 | Na+ (mmol/l) | 137 | 138–145 | ACE (U/l) | 10.9 | 8.3–21.4 |
| K+ (mmol/l) | 4.1 | 3.6–4.8 | ||||||
| Coagulation | Cl− (mmol/l) | 108 | 101–108 | Pathogen tests | ||||
| PT-INR | 1.34 | Ca+ | 8.5 | 8.8–10.1 | SARS-CoV2-PCR | (-) | (-) | |
| APTT (s) | 42.4 | 24.1–31.7 | IP | 2.8 | 2.7–4.61 | β-d-glucan | < 5.0 | <20.0 |
| D-Dimer (μg/ml) | 0.45 | 0.00–0.49 | BS (mg/dl) | 98 | 73–109 | HBs Ag | 0.00 | <0.05 |
| KL-6 (U/ml) | 161 | <500 | HBs Ab | 0.00 | <10.0 | |||
| Urinalysis | NT-ProBNP (pg/ml) | 1805.5 | <126 | HCV Ab | 0.25 | <1.0 | ||
| Protein | (–) | (–) | Vit B12 (pg/ml) | 530 | 180–914 | HIV Ag/Ab | 0.05 | <1.00 |
| Occult blood | (–) | (–) | Folic acid (ng/ml) | 4.5 | >4.0 | TB-specific IFN-γ | (-) | (-) |
| Fe (μg/ml) | 43 | 40–188 | Blood culture | (-) | (-) | |||
| FOB | (–) | (–) | TIBC (μg/dl) | 211 | 253–365 | Scrub typhus IgG/M | (-) | (-) |
Abbreviations: pt, patient; r.v., reference value; CBC, complete blood count; WBC, white blood cells; Neut., neutrophils; Lymh, lymphocytes; Mono, monocytes; Eosi., eosinocytes; Baso., basophils; RBC, red blood cells; Hb, haemoglobin; Ht, haematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin concentration; PLT, platelets; ESR, erythrocyte sedimentation rate; PT-INR, prothrombin time-international normalizsd ratio; APTT, activated partial thromboplastin time; FOB, faecal-occult-blood test; TP, total protein; ALB, albumin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; AMY, amylase; ALP, alkaline phosphatase; LD, lactose dehydrogenase; CK, creatine kinase; LDL-cho, low-density lipoprotein cholesterol; TG, triglyceride; UA, uric acid; BUN, blood urea nitrogen; Cr, creatinine; Na+, sodium ion; K+, potassium ion; Cl−, chloride ion, Ca+, calcium ion; IP, inorganic phosphorus; BS, blood sugar; KL-6, Krebs von den Lungen-6; NT-proBNP, N-terminal probrain natriuretic hormone; Vit, vitamin; TIBC, total iron binding capacity; CH50, 50% haemolytic unit of complement; Ig, immunoglobulin; RF, rheumatoid factor; anti-CCP Ab, anticyclic citrullinated peptides antibodies; ANA, antinuclear antibody; PR-3ANCA, proteinase-3 anti-neutrophil cytoplasmic antibody; MPO-ANCA, myeloperoxidase antineutrophil cytoplasmic antibody; sIL-2R, soluble interleukin-2 receptor; ASO, antistreptolysin O antibody; ACE, angiotensin converting enzyme; SARS-CoV2, severe acute respiratory syndrome coronavirus 2; PCR, polymerase chain reaction; HBs, hepatitis B virus surface; Ag, antigen; Ab, antibody; HCV, hepatitis C virus, HIV, human immunodeficiency virus; TB, tuberculosis; IFN; interferon.
A bone marrow aspiration and biopsy did not reveal any malignancy or myelodysplasia (Figure 4(a)); however, characteristic vacuoles were observed in some myeloid (Figure 4(b)) and erythroid precursor cells (Figure 4(c)). Therefore, at the Kazusa DNA Research Institute and Yokohama City University, we performed genetic analyses of UBA1 variants, the causative genes of VEXAS syndrome. Genomic DNA was extracted from whole blood samples. The genomic gene sequence was analysed using a targeted next-generation sequencing based on the hybrid capture method; the obtained sequence was compared with the publicly available human genome reference sequence (GRCh38/h38) to detect variants. UBA1 variants (missense variant c.121A>C p. Met41Leu) were identified by DNA sequencing; the variant allele frequency was 0.861. Following the diagnosis of VEXAS syndrome, GC therapy (oral prednisolone at a dose of 30 mg/day) was initiated for systemic symptoms such as recurring fever, fatigue, and skin rashes, resulting in improved symptoms. However, during the tapering of prednisolone to 15 mg/day, the patient experienced a relapse marked by fever and shortness of breath. Computed tomography images revealed multiple fine nodules in both lungs, indicating inflammatory lesions associated with VEXAS syndrome. At that time, the cause of breath shortness could not be determined. Consequently, the patient continued receiving prednisolone treatment. He subsequently developed COVID-19 and was treated with remdesivir without serious complications; however, he developed pulmonary thromboembolism and was administered edoxaban and home oxygen therapy.
The representative findings of bone marrow specimen. (Wright–Giemsa staining, 400× magnification). Some intracellular vacuoles indicated by arrows (a) were observed, especially in myeloid (b) and erythroid (c) progenitor cells.
Discussion
Here, we report a case of VEXAS syndrome following vaccination against COVID-19. Although there are currently no diagnostic criteria for VEXAS syndrome, this case clearly showed the characteristics of the syndrome, including age, sex, clinical symptoms, vacuoles in myeloid and erythroid progenitor cells, and a UBA1 variant, which were previously defined [1]. In general, fever (60–100%), skin rash (71–100%), and arthralgia/arthritis (25–100%) are common symptoms; however, the bursitis observed in this case has rarely been reported [10]. This is the first case report of VEXAS syndrome in an Asian population after receiving the COVID-19 vaccine.
There is no clear evidence that the onset of VEXAS syndrome is associated with COVID-19 vaccination. However, the facts that symptoms of VEXAS syndrome immediately appeared after vaccination in the present case and that three other cases of VEXAS syndrome after COVID-19 vaccination have been reported in the USA and France, as summarised in Table 2, suggest a relationship between them [7–9]. Although the possibility that influenza vaccination is involved in the exacerbation cannot be ruled out, to date, no cases of VEXAS syndrome after influenza vaccination have been reported.
Comparison of post-COVID-19 mRNA vaccine VEXAS syndrome cases.
| Age (years) | Race, sex | Type of vaccine | Past history | Symptoms onset after vaccination (days) | Clinical manifestations and findings | UBA1 variant | Treatment | Outcome | Reporting country | |
|---|---|---|---|---|---|---|---|---|---|---|
| This case | 72 | Asian, M | mRNA (Pfizer/BioNTech®) | HT, HU, GERD, Gastric Ca | 1 day after second dose | Fever, eruption, auricular chondritis, scleritis, arthritis, macrocytic anaemia, and pleural effusion | p. Met 41 Leu | PSL 30 mg/day | Steroid-dependent | Japan |
| Case 17) | 56 | Hispanic, M | mRNA (Moderna®) | None | Unknown, after second and third doses | Fever, eruption, scleritis, splenomegaly, macrocytic anaemia, and thrombocytopenia | p. Met 41 Leu | Hydrocortisone → prednisone | Discharged | USA |
| Case 29) | 76 | Unkown, M | mRNA (Pfizer/BioNTech®) | HT, DM, DL | 3 days after vaccination | Fever, eruption, and scleritis | p. Met 41 Val | PSL 1 mg/kg/day | Steroid-dependent | France |
| Case 38) | 75 | Caucasian, M | mRNA (unknown) | COVID-19 (8 months prior) | 3 days after a booster dose | Fever, eruption, auricular chondritis, arthritis, periorbitis, macrocytic anaemia, and pleural effusion | p. Met 41 Thr + NOD2 mutation | Prednisone + anakinra | Prednisone tapered | USA |
| Age (years) | Race, sex | Type of vaccine | Past history | Symptoms onset after vaccination (days) | Clinical manifestations and findings | UBA1 variant | Treatment | Outcome | Reporting country | |
|---|---|---|---|---|---|---|---|---|---|---|
| This case | 72 | Asian, M | mRNA (Pfizer/BioNTech®) | HT, HU, GERD, Gastric Ca | 1 day after second dose | Fever, eruption, auricular chondritis, scleritis, arthritis, macrocytic anaemia, and pleural effusion | p. Met 41 Leu | PSL 30 mg/day | Steroid-dependent | Japan |
| Case 17) | 56 | Hispanic, M | mRNA (Moderna®) | None | Unknown, after second and third doses | Fever, eruption, scleritis, splenomegaly, macrocytic anaemia, and thrombocytopenia | p. Met 41 Leu | Hydrocortisone → prednisone | Discharged | USA |
| Case 29) | 76 | Unkown, M | mRNA (Pfizer/BioNTech®) | HT, DM, DL | 3 days after vaccination | Fever, eruption, and scleritis | p. Met 41 Val | PSL 1 mg/kg/day | Steroid-dependent | France |
| Case 38) | 75 | Caucasian, M | mRNA (unknown) | COVID-19 (8 months prior) | 3 days after a booster dose | Fever, eruption, auricular chondritis, arthritis, periorbitis, macrocytic anaemia, and pleural effusion | p. Met 41 Thr + NOD2 mutation | Prednisone + anakinra | Prednisone tapered | USA |
Abbreviations: M, male; HT, hypertension; HU, hyperuricaemia; GERD, gastro-oesophageal reflux disease; Ca, cancer; DM, diabetes mellitus; DL, dyslipidaemia; PSL, prednisolone; Met, methionine; Leu, leucine; Thr, threonine.
Comparison of post-COVID-19 mRNA vaccine VEXAS syndrome cases.
| Age (years) | Race, sex | Type of vaccine | Past history | Symptoms onset after vaccination (days) | Clinical manifestations and findings | UBA1 variant | Treatment | Outcome | Reporting country | |
|---|---|---|---|---|---|---|---|---|---|---|
| This case | 72 | Asian, M | mRNA (Pfizer/BioNTech®) | HT, HU, GERD, Gastric Ca | 1 day after second dose | Fever, eruption, auricular chondritis, scleritis, arthritis, macrocytic anaemia, and pleural effusion | p. Met 41 Leu | PSL 30 mg/day | Steroid-dependent | Japan |
| Case 17) | 56 | Hispanic, M | mRNA (Moderna®) | None | Unknown, after second and third doses | Fever, eruption, scleritis, splenomegaly, macrocytic anaemia, and thrombocytopenia | p. Met 41 Leu | Hydrocortisone → prednisone | Discharged | USA |
| Case 29) | 76 | Unkown, M | mRNA (Pfizer/BioNTech®) | HT, DM, DL | 3 days after vaccination | Fever, eruption, and scleritis | p. Met 41 Val | PSL 1 mg/kg/day | Steroid-dependent | France |
| Case 38) | 75 | Caucasian, M | mRNA (unknown) | COVID-19 (8 months prior) | 3 days after a booster dose | Fever, eruption, auricular chondritis, arthritis, periorbitis, macrocytic anaemia, and pleural effusion | p. Met 41 Thr + NOD2 mutation | Prednisone + anakinra | Prednisone tapered | USA |
| Age (years) | Race, sex | Type of vaccine | Past history | Symptoms onset after vaccination (days) | Clinical manifestations and findings | UBA1 variant | Treatment | Outcome | Reporting country | |
|---|---|---|---|---|---|---|---|---|---|---|
| This case | 72 | Asian, M | mRNA (Pfizer/BioNTech®) | HT, HU, GERD, Gastric Ca | 1 day after second dose | Fever, eruption, auricular chondritis, scleritis, arthritis, macrocytic anaemia, and pleural effusion | p. Met 41 Leu | PSL 30 mg/day | Steroid-dependent | Japan |
| Case 17) | 56 | Hispanic, M | mRNA (Moderna®) | None | Unknown, after second and third doses | Fever, eruption, scleritis, splenomegaly, macrocytic anaemia, and thrombocytopenia | p. Met 41 Leu | Hydrocortisone → prednisone | Discharged | USA |
| Case 29) | 76 | Unkown, M | mRNA (Pfizer/BioNTech®) | HT, DM, DL | 3 days after vaccination | Fever, eruption, and scleritis | p. Met 41 Val | PSL 1 mg/kg/day | Steroid-dependent | France |
| Case 38) | 75 | Caucasian, M | mRNA (unknown) | COVID-19 (8 months prior) | 3 days after a booster dose | Fever, eruption, auricular chondritis, arthritis, periorbitis, macrocytic anaemia, and pleural effusion | p. Met 41 Thr + NOD2 mutation | Prednisone + anakinra | Prednisone tapered | USA |
Abbreviations: M, male; HT, hypertension; HU, hyperuricaemia; GERD, gastro-oesophageal reflux disease; Ca, cancer; DM, diabetes mellitus; DL, dyslipidaemia; PSL, prednisolone; Met, methionine; Leu, leucine; Thr, threonine.
It is noteworthy that all post-vaccination VEXAS cases, including our case, received mRNA vaccines, regardless of the manufacturer (Table 2). Although RNA-based COVID-19 vaccines synthesise the spike protein after translation, before translation, mRNA may bind to pattern recognition receptors in the innate immune system. This binding occurs via Toll-like receptors on endosomes or melanoma differentiation-associated protein 5 and retinoic acid-inducible gene 1 in the cytoplasm, activating an inflammatory cascade that involves activation of type 1 interferon and transcription of nuclear factor-κB (NF-κB) [4]. The mRNA vaccine itself may trigger the overproduction of proinflammatory cytokines through enrichment of gene expression signatures in the NF-κB signalling pathway and activation of inflammasomes in VEXAS patients [11]. Thus, a non-mRNA vaccine may be an alternative for preventing future epidemics.
Interestingly, in Case 3, although the patient had COVID-19 without pneumonia that resolved within 10 days, the symptoms of VEXAS syndrome were observed and exacerbated immediately after the booster dose; therefore, the viral infection itself may not have influenced the onset of the disease. Our patient subsequently developed COVID-19, but with oral prednisolone and intravenous remdesivir, there was neither severe COVID-19 nor recurrence of VEXAS syndrome.
In addition to the present case and the three cases overseas, all involved middle-aged males in their 50–70s, with no racial bias. The patients had a variety of immunological diseases; however, the most common symptoms were observed within a few days after vaccination, and fever and skin rashes were present. The findings include macrocytic anaemia, elevated high inflammatory-marker levels, and pleural effusion. All patients underwent genetic testing and showed UBA1 variants, but the sequences were different in each case. All patients received GC therapy with temporal responses, and GC-sparing measures appeared to be necessary [7–9]. Several cohort studies on VEXAS have reported that patients with the UBA1 p. Met 41Leu variant are more frequently detected in a group with milder disease and better prognosis [12, 13]. However, our patient with the Leu variant had a variety of features, including recurrent fever, weight loss, scleritis, skin lesions, chondritis, and lung involvement. The difference in clinical course and prognosis between vaccine-associated VEXAS cases and vaccine-unrelated cases remains unclear. Therefore, accumulating vaccine-associated cases is important.
In conclusion, this crucial case suggests that the COVID-19 vaccine may be one of the triggers for the development of VEXAS syndrome in Asian populations. It is important to continue to pay close attention to the relationship between COVID-19 vaccines and VEXAS syndrome, and further investigations of such cases are required.
Acknowledgements
We would like to thank Dr Ryuta Nishikomori of the Ministry of Health, Labor and Welfare’s Autoinflammatory Disease Research Group and Dr Osamu Ohara of the Department of Applied Genomics, Kazusa DNA Research Institute for genetic analysis. We also thank Mr Ian P, who belongs to Editage, for providing language help and writing assistance.
Conflict of interest
None declared.
Funding
This research is supported by AMED (grant number 24ek0410107h0002).
Patient consent
The patient gave written informed consent before publication in this case report.
Ethical approval
Ethical approval statement was not required for this manuscript. This research protocol (F230200013) was approved by the Yokohama City University Life Science and Medical Research Ethics Committee, and permission was obtained from Yokohama City University Hospital (F230800043) and Tokyo Medical University (E2023-0071).
Author contributions
H.K. was responsible for the data collection and analysis. All authors critically revised the report, commented on drafts of the manuscript, and approved the final report.
References
Author notes
contributed equally to this work.
