Can myelodysplastic syndrome (MDS) and VEXAS syndrome contribute to elevated C-reactive protein (CRP) levels and anemia?

VEXAS Syndrome and MDS Both Cause Elevated CRP and Anemia

Yes, both myelodysplastic syndrome (MDS) and VEXAS syndrome independently contribute to elevated C-reactive protein (CRP) levels and anemia, though through distinct mechanisms—MDS primarily through ineffective hematopoiesis causing cytopenias, and VEXAS through combined autoinflammation and clonal hematopoiesis.

Myelodysplastic Syndrome and Anemia

MDS is fundamentally characterized by anemia as its most common manifestation:

• Over 90% of MDS patients present with anemia at diagnosis, and 60% will experience severe anemia during their disease course 1
• The WHO classification defines multiple MDS subtypes, all of which include anemia or cytopenias as core features, including refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), and refractory cytopenias with multilineage dysplasia (RCMD) 1
• Anemia in MDS results from ineffective erythropoiesis with dysplastic changes in bone marrow precursors 1

However, MDS itself does not typically cause elevated CRP. The provided guidelines focus extensively on cytopenias but do not describe systemic inflammation or elevated inflammatory markers as primary features of MDS 1. If a patient with MDS has elevated CRP, consider secondary causes such as infection (particularly in neutropenic patients), iron overload complications, or a coexisting inflammatory condition like VEXAS syndrome.

VEXAS Syndrome: Dual Pathology of Inflammation and Hematologic Abnormality

VEXAS syndrome causes both elevated inflammatory markers and anemia through its unique pathophysiology:

Inflammatory Component and Elevated CRP

• VEXAS is a systemic autoinflammatory disorder caused by somatic UBA1 gene mutations, presenting with persistent systemic inflammation that would manifest as elevated CRP 2, 3
• Patients experience therapy-resistant autoinflammatory symptoms requiring high-dose corticosteroids for control 4, 5
• The inflammatory manifestations include musculoskeletal involvement in 71% of cases, with pain and stiffness as major complaints 6, 5

Hematologic Component and Anemia

• 72% of VEXAS patients present with anemia, typically macrocytic and hyperchromic 6, 3, 4
• Nearly half of VEXAS patients develop myelodysplastic syndromes, creating overlapping hematologic pathology 2
• The anemia results from both the inflammatory process and associated clonal hematopoiesis affecting erythroid precursors 2, 3
• Bone marrow examination reveals characteristic cytoplasmic vacuoles in myeloid and erythroid precursors in the vast majority of cases 3, 4

Clinical Implications When Both Conditions Coexist

The combination of VEXAS and MDS represents a particularly challenging clinical scenario:

• When MDS patients develop persistent systemic inflammation with elevated inflammatory markers despite appropriate MDS management, screen for UBA1 mutations to identify VEXAS syndrome 4
• The emergence of macrocytic anemia with therapy-resistant inflammatory symptoms persisting over 18 months should prompt early UBA1 mutation testing 4
• Most VEXAS-associated MDS cases are lower-risk by IPSS criteria, but the combined inflammatory and hematologic burden significantly impacts morbidity 6

Treatment Considerations

• Corticosteroids provide initial response in most VEXAS patients but require high doses and cause recurrence with tapering 6, 5
• JAK inhibitors (such as ruxolitinib) and hypomethylating agents (azacitidine) have achieved complete responses in selected cases 6, 2, 5
• Allogeneic hematopoietic stem cell transplantation may offer curative potential for selected patients with combined VEXAS and MDS 6, 2

Diagnostic Algorithm

When encountering a patient with both elevated CRP and anemia:

1. If MDS is already diagnosed and new inflammatory symptoms with elevated CRP develop: Consider VEXAS syndrome and order UBA1 mutation testing, particularly if symptoms are steroid-dependent 4

2. If presenting with both findings simultaneously: Perform bone marrow examination looking for both MDS features (dysplasia, blast percentage) and VEXAS features (cytoplasmic vacuoles in myeloid/erythroid precursors) 3, 4

3. If inflammatory symptoms persist >18 months despite immunosuppressive therapy with concurrent cytopenias: Strongly consider UBA1 mutation screening 4

Common pitfall: Attributing elevated CRP in an MDS patient solely to infection or other secondary causes without considering VEXAS syndrome, leading to delayed diagnosis and prolonged ineffective treatment 3, 4.