PMC9760706_01
Clinical manifestations and histopathology. (A) Multiple erythematous plaques and nodular lesion on the upper limbs. (B) Urticarial lesions on the back. (C) Erythematous lesions on the abdomen. (D) Infiltration of inflammatory cells from the upper dermis to the subcutaneous fat (hematoxylin-eosin stain, original magnification x 100). (E) High magnification of dermal infiltrates around the perivascular region. The inflammatory infiltrates contain neutrophils, histiocytes, lymphoid cells, and eosinophils (hematoxylin-eosin stain, original magnification x 400).
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F1
Erythematous nodules and large and small plaques were seen on the upper extremities (Figure 1A), urticarial papules and plaques on the back (Figure 1B), and diffuse erythema on the abdomen (Figure 1C). A skin biopsy revealed perivascular inflammatory infiltrates in the entire dermis and in the subcutaneous fat (Figure 1D). The infiltrates consisted of mature neutrophils admixed with MPO-positive CD163-positive myeloid cells (Figures 3C,D), lymphoid cells, and eosinophils (Figure 1E).
Overview of patient's disease course. TCZ, tocilizumab; PSL, prednisolone; NSAID, Non-Steroidal Anti-Inflammatory Drug; BMA, bone marrow aspirate; Hb, hemoglobin (normal range, 13.7-16.8 g/L); WBC, white blood cells (normal range, 3,300-8,600/muL); Tc, thrombocytes (normal range, 158,000-348,000/muL); CRP, C-reactive protein (normal < 3 mg/L).
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F2
A timeline of the clinical manifestations and treatments for more than 2 years is shown in Figure 2. As shown in Figure 2, both CRP and neutrophil counts were elevated when VEXAS syndrome was active.
Additional tests for diagnosis and treatment. (A) Bone marrow aspirate smears show cytoplasmic vacuolization in myeloblasts (x40 magnification). (B) Sanger sequencing of genomic DNA derived from whole peripheral blood. The c.122T > C mutation is detected at position p.Met41 of the UBA1 gene. (C) There are many CD163-positive cells, suggesting macrophages and histiocytes in the dermis (CD163 immunostaining, original magnification x 100). (D) The majority of infiltrates are MPO-positive (MPO immunostaining, original magnification x 100). (E) Serum d-ROM level before and after treatment. The d-ROM levels are expressed in Carratelli units (Carr. U.). The d-ROM levels decreased significantly after treatment with oral prednisone (15 mg/d) and the first intravenous injections of tocilizumab (400 mg).
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F3
Bone marrow examination showed the vacuolization of myeloid precursor cells (Figure 3A). The infiltrates consisted of mature neutrophils admixed with MPO-positive CD163-positive myeloid cells (Figures 3C,D), lymphoid cells, and eosinophils (Figure 1E). Sequencing analysis of whole peripheral blood identified the UBA1 variant c.122T > C, which results in p.Met41Thr (Figure 3B). The d-ROM level was significantly decreased after treatment with oral prednisone (15 mg/d) and the first intravenous injection of tocilizumab (400 mg) (Figure 3E).
Quantification of mosaicism. UBA1 somatic variants of granulocytes from peripheral blood, peripheral blood mononuclear cells (PBMCs), saliva, and urine. Mutation mosaicism was analyzed by using the MiSeq Sequencing System (Illumina, Inc.) after polymerase chain reaction (PCR) amplification of the target. The target is the UBA1 (NM_003334.4) missense mutation c.122T > C (p.Met41Thr) on chromosome X (47199052 T/C). Total depth and mutation mosaicism were measured by bam-readcount (ver 0.8.0). A commercial genome was used as a control.
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F4
A detailed analysis of mutation mosaicism using the MiSeq Sequencing System (Illumina, Inc.) after the PCR amplification of UBA1 showed that the variant was found in 49% of granulocytes, 21% of peripheral blood mononuclear cells (PBMCs), 46% of saliva, and 4% of urine (Figure 4).