Expert Perspective: Hematologic Malignancies and Vasculitis.

CLINICAL CHALLENGE

The patient, a 69‐year‐old man, presents to the emergency department with four days of left pleuritic chest and mid‐epigastric abdominal pain associated with low‐grade fever and night sweats. He has no cranial or polymyalgia rheumatica symptoms. Computed tomography (CT) of the abdomen and pelvis raises concern for aortitis (Figure 1A ). 18 F‐labeled fluorodeoxyglucose (FDG) positron emission tomography (PET) CT demonstrates increased FDG uptake in the abdominal aorta with surrounding fat stranding and diffuse bone marrow uptake (Figure 1B ). Laboratory evaluation finds elevated markers of inflammation, normocytic anemia, monocytosis (2,700 monocytes/μL, 33%), and otherwise unrevealing serologic and infectious studies (Supplemental Table 1 ). Fifty milligrams of oral prednisone daily is initiated for idiopathic aortitis, with complete resolution of symptoms over weeks and normalization of computed tomography angiogram after the end of the steroid taper five months later. However, after discontinuation of steroid treatment, low‐grade fevers and chest pain return with a negative ischemia evaluation. Repeat PET CT demonstrates resolution of prior abdominal FDG uptake but a new focus of uptake in the lower thoracic aorta with associated fat stranding. Laboratory evaluation again reveals monocytosis (2,800 monocytes/μL, 37.8%) and anemia with new thrombocytopenia (Supplemental Table 1 ). Sixty milligrams of prednisone and interleukin‐6 receptor inhibition (IL‐6Ri) with 8 mg/kg of intravenous monthly tocilizumab (TCZ) are initiated for large vessel vasculitis (LVV), with symptom resolution.

The patient is referred to a hematology oncologist for bicytopenia and persistent monocytosis. A bone marrow biopsy is performed. Core biopsy and aspirate findings demonstrate markedly hypercellular marrow with left‐shifted maturation, erythroid and megakaryocytic dysplasia, and no increase in blasts (<5%) (Figure 1C and D ). A next‐generation sequencing (NGS) panel for hematologic malignancy identifies two TET2 mutations in trans as well as PHF6 and ASXL1 mutations. Cytogenetics shows normal male karyotype without fusions or rearrangements detected. In the setting of persistently elevated monocyte levels >500 × 10 9 /L greater than three months, a diagnosis of chronic myelomonocytic leukemia (CMML) is made, with a plan to monitor given mild cytopenia and no bleeding. 1 , 2

BACKGROUND

Systemic vasculitis describes a collection of rare diseases each caused by inflammation of blood vessel walls that can cause severe systemic complications. 3 , 4 The pattern of vascular inflammation and resultant damage is frequently variable and may be mimicked or directly triggered by infection or malignancy. Myeloid and lymphoid hematologic malignancy have long been recognized in association with vasculitis and were recognized by the 2012 Consensus Conference on the Nomenclature of Systemic Vasculitis as vasculitis associated with probable etiology (cancer‐associated). 4 We will refer to this as vasculitis with concomitant hematologic malignancy (VCHM). This is a rapidly evolving field with a limited but growing evidence base. Because of increased use of molecular diagnostics in hematologic clinical practice, rheumatologists should be aware of the diagnostic and treatment complexity in rare patients with VCHM, who often have refractory disease and are at risk of comorbidity from both hematologic and inflammatory disease and their treatments.

Here, we discuss our collaborative approach to diagnosis and management of VCHM shared between rheumatology and hematology/oncology in the context of relatively limited literature. We focus on myeloid neoplasia as a clinically relevant model of the emerging recognition of overlap between our fields, with more limited discussion of associations with lymphoid forms of VCHM, such as cryoglobulinemic vasculitis, which have been previously discussed in the literature. 5

APPROACH

Rheumatology approach to hematologic diagnostic testing in patients with new or suspected vasculitis

When to consider hematologic malignancy

We consider hematologic malignancy as part of the broader differential diagnosis in all patients with new imaging or pathologic findings suggestive of vasculitis as a concurrent and potentially underlying diagnosis or a diagnostic mimic, especially when unusual clinical features are present (Table 1 ). Vasculitis can occur as a “hematoinflammatory” feature across a wide variety of hematologic malignancy and often co‐occurs with indolent and lower‐risk disease stages monitored in clinic with or without specific disease‐modifying treatment. 6 For example, giant cell arteritis (GCA) and Beçhet disease can be associated with myeloid neoplasms such as myelodysplastic syndrome (MDS) or CMML. Furthermore, leukocytoclastic vasculitis (LCV) with chronic monoclonal antibody–producing lymphoid malignancies can be associated with chronic lymphocytic leukemia and/or Waldenström macroglobulinemia. Additionally, polyarteritis nodosa (PAN) and LCV can occur in both myeloid and lymphoid malignancies, with an enrichment of PAN in hairy cell leukemia 7 , 8 , 9 , 10 (Supplemental Figure 1 ).

Patients with hematologic malignancy, especially myeloid neoplasia, can also have other significant inflammatory features. For example, 10% to 45% of individuals with MDS and CMML have concurrent inflammation, with common categories including vasculitis, neutrophilic dermatosis, inflammatory arthritis, and connective tissue disease; nonspecific inflammation, fever, chondritis, crystalline arthritis, inflammatory eye diseases, autoimmune cytopenia, and acquired bleeding diatheses, among others, have also been described. 11 , 12 , 13 , 14 , 15 , 16 Suggesting bidirectional interactions and/or shared risk, antecedent autoimmune disease was likewise found more frequently in patients with MDS (odds ratio [OR] 1.5 and 2.1, respectively) and acute myeloid leukemia (AML) (OR 1.29 and 1.7, respectively) in two large case‐control studies using registry data from the United States and Sweden; systemic vasculitis had particularly high effect sizes (OR 6.23–23.8). 17 , 18

The pathogenesis of VCHM and other inflammatory features of hematologic malignancy remains an active area of research. Recent genomic mutational analyses have identified some hematopoietic somatic mutations that may determine collective biologic pathways. 6 For example, novel somatic mutations in UBA1 have been identified as a shared robust monogenic driver of the adult‐onset systemic inflammatory syndrome VEXAS which is an acronym for the defining features of the disorder, namely v acuoles, E 1 enzyme, X ‐linked, a utoinflammatory, s omatic syndrome. Organ manifestations of VEXAS include vasculitis as well as hematologic malignancies such as MDS or plasma cell dyscrasias. 19 , 20 , 21 Additionally, somatic mutations in hematologic malignancy driver genes have recently been identified and associated with forms of vasculitis and worse clinical trajectories, including cryoglobulinemic vasculitis and GCA. 22 , 23 , 24 , 25 , 26 For the purposes of this review, we will discuss VEXAS separately from MDS, with the recognition that there is a lack of distinction between VEXAS and other hematologic malignancies in the pre‐2021 literature.

Approach to diagnostic testing when considering VCHM

Laboratory testing. Because most patients with vasculitis do not have hematologic malignancy, we do not exhaustively test all patients with a new diagnosis of vasculitis with a bone marrow biopsy and flow cytometry, for example. However, we always consider the presteroid complete blood cell count (CBC) with differential and, if available, the historic CBC with differential trend as a vital piece of diagnostic information to integrate with other diagnostic testing that, from our hematologic evaluation minimally, includes erythrocyte sedimentation rate, C‐reactive protein, lactate dehydrogenase (LDH), serum protein electrophoresis (SPEP), serum‐free light chains (SFLC), cryoglobulins, C3, and C4 (Figure 2 ).

Some laboratory abnormalities in patients with vasculitis significantly raise our suspicion for underlying hematologic malignancy and lead us to initiate hematology consultation or referral (Figure 2 ). Inflammatory diseases such as vasculitis often cause anemia, neutrophil‐dominant leukocytosis, and thrombocytosis. In contrast, erythrocytosis, neutropenia, persistent monocytosis or lymphocytosis, thrombocytopenia, and especially bicytopenia or pancytopenia are uncommon and merit further evaluation. 23 Eosinophilia is commonly recognized by rheumatologists and has its own broad differential diagnosis, including eosinophilic granulomatosis with polyangiitis, IgG4‐related disease, and hematologic mimics (Table 1 ), as has previously been described. 27 In the absence of lymphocytosis, elevated SPEP and SFLC are more likely to reveal monoclonal gammopathy of uncertain significance (MGUS) than plasma cell dyscrasia. Both these diagnoses increase in prevalence with age and can be followed annually in clinic in the absence of clinical features of hypercalcemia, bone pain, and renal dysfunction. However, together with elevated LDH and cryoglobulin levels and hypocomplementemia, especially of C4 or consistent clinical phenotype (Table 1 ), these may also support consideration of MGUS‐ or lymphoid malignancy–associated cryoglobulinemia or amyloidosis (Figure 2 ). In patients developing vasculitis or perivascular inflammation during treatment of solid tumors, especially with neutrophilia and possibly circulating blasts on CBC, we look for antecedent granulocyte colony stimulating factor (G‐CSF) exposure.

Imaging. We approach vasculitis imaging somewhat differently in individuals with known hematologic malignancy or suspicious hematologic laboratory abnormalities. In individuals who have known or suspected LVV or fever of unknown origin phenotype, our diagnostic test of choice is PET CT. PET can be useful to diagnose large and medium vessel vasculitis as well as some forms of hematologic malignancy, particularly lymphomas, and can identify lymphadenopathy or tissue level uptake to guide biopsy. 28 , 29 Prominent bone marrow uptake is often seen in hematologic malignancy, but this is also a common and nonspecific finding in nonmalignant inflammatory disease and must be considered together with other clinical and laboratory features. 29 In patients with periaortic FDG‐avid sheathing that may be reminiscent of IgG4‐related disease, imaging features such as “hairy kidneys,” bony uptake, or splenomegaly should raise concern for the histiocytic disease Erdheim–Chester disease, caused by somatic mutations in the BRAF/MAPK pathway in myeloid progenitor cells; we have rarely also observed this phenotype in individuals with CMML. Tissue biopsy and hematologic evaluation, including molecular genetic testing, is required to reach diagnosis (Table 1 ). Based on our experience (as described in our index patient above), we additionally consider hematologic malignancy phenotypically in individuals with LVV and atypical patterns of vessel involvement such as older adults with abdominal aortitis, waxing and waning perivascular and patchy vascular uptake, or prominent lower extremity disease. In all patients undergoing PET for question of LVV, atherosclerosis is an important LVV mimic; expert radiology review is key. 30 Although we do not initiate hematology referral in the absence of hematologic abnormalities by vascular pattern, we do monitor the CBC with differential with more scrutiny.

Histopathology. We preferentially obtain tissue diagnoses, even if an imaging or clinical diagnosis would have otherwise been accepted in a provider's practice, if evaluation is suggestive of hematologic malignancy or the pattern of disease includes a mimic (Table 1 ). We consider additional diagnostic testing such as flow cytometry from peripheral blood or lymph node biopsy if lymphadenopathy is prominent, especially if steroid exposure is necessary to treat vasculitis and may obscure a concurrent lymphoid malignancy diagnosis. Of note, the negative predictive value of flow cytometry in the diagnosis of diffuse large B cell lymphoma from peripheral blood is highly limited. 31 For patients who do not respond to therapy as expected and hematologic malignancy was not originally considered, we reconsider a broader differential diagnosis that includes malignancy and often requires a tissue biopsy to pursue definitive diagnosis (Table 1 ).

When to consider and how to test for VEXAS

Initially described in late 2020, the literature surrounding VEXAS has rapidly evolved and has been extensively reviewed. 6 , 32 Briefly, VEXAS is caused by somatic hematopoietic mutations in X‐linked UBA1 , encoding the primary ubiquitin‐activating enzyme upstream of most cellular ubiquitin conjugation. 19 , 33 Mutations are enriched at an M41 hotspot and lead to highly penetrant syndromic but variable autoinflammatory and hematologic disease. 19 , 20 , 34 , 35 More recent extension of whole‐gene sequencing has demonstrated several mutations across the gene, including recurrent non‐M41 mutations in patients with MDS and autoinflammatory phenotype. 33 , 36 , 37 , 38 Typically affecting men, VEXAS can rarely impact women who have congenital or somatic monosomy X.

The most common forms of vasculitis in VEXAS are PAN and LCV, though other forms of vasculitis have been described in a small retrospective cases series and review of the literature. 21 Other common inflammatory features of disease include fever, chondritis, rash (especially neutrophilic dermatoses), ocular inflammation, pulmonary infiltrates, renal dysfunction, and inflammatory arthritis. 19 , 34 , 35 These systemic features are responsive to high‐dose steroids but often nonresponsive to most disease‐modifying antirheumatic drugs (DMARDs) and biologic therapies. 19 , 34 , 35 Common hematologic manifestations include macrocytic anemia, thrombosis, thrombocytopenia, lymphopenia, monocytopenia, vacuoles in erythroid and myeloid progenitors, and incident MDS (~30%–50%) or plasma cell dyscrasia (~25%), including MGUS and, less frequently, myeloma. 19 , 20 , 39 In a large population‐based cohort study of individuals with MDS, 1% had UBA1 variants (n = 26 of 2,027), of which 44% were known or likely pathogenic and the remaining were of uncertain significance. 38 In comparison, pathogenic UBA1 variants were detected in 8% of individuals in a cohort with relapsing polychondritis (n = 7 of 92) and in 0% of men with GCA (n = 0 of 612).

Collectively, we consider VEXAS in patients with robust adult‐onset multisystem inflammation with or without vasculitis, especially, though not universally, if cytopenia or macrocytosis is present and the patient is male, with a broader differential diagnosis including myeloid neoplasia with inflammatory features. LVV appears to be an uncommon phenotype. Testing should ideally include whole‐gene UBA1 sequencing, not limited amplicon testing at M41, and is commercially available from companies such as the Genomic Testing Cooperative and Blueprint Genetics. This can currently be performed by rheumatology or hematology/oncology, but in the future, it is most likely to be incorporated into hematologic clinical NGS mutation panels for hematologic malignancy.

Hematology approach to diagnosis and management of suspected VCHM

Hematology consultation should be pursued in patients with vasculitis and cytopenia if counts are severe or trending down despite treatment (Figure 2 ) or associated with symptoms such as difficult‐to‐treat or chronic infections, presence of bleeding or bruising, worsening fatigue, and/or B symptoms. Persistent overproduction of cells such as lymphocytosis, erythrocytosis, or, as in this case, monocytosis should also lead to hematology consultation, especially when cytopenia coexists. Hematologists will consider a wide differential diagnosis that includes various hematologic malignancies and a multitude of alternative and potentially reversible diagnoses (Figure 2 ). For example, monocytosis is most commonly reactive to acute or chronic infection. If no reversible cause is identified or if cytopenia or cytoses persists despite their treatment, further tests are needed, including bone marrow aspirate and biopsy and various context‐dependent functional and molecular clonal analyses that may include flow cytometry, NGS, cytogenetics, T cell receptor clonality, and fluorescence in situ hybridization. In our practices, these tests are typically ordered and interpreted by the hematologist or oncologist, given their expertise.

Various forms of myeloid neoplasia can display persistent monocytosis, which may phenotypically overlap histopathology, and are differentiated by molecular diagnostics and, in this case, yield a diagnosis of CMML. 40 NGS has been particularly transformational in diagnosis, risk stratification, and etiologic understanding of hematologic malignancy. Prognostic scoring systems use clinically obtained variables such as NGS mutations, blast percentage, blood cell counts, and transfusion dependency to predict risk of progression of disease to AML and overall survival to help guide clinical interventions. 41 , 42 Importantly, as our understanding of mutations evolves, clinically obtained NGS panels are often not comprehensive. Thus, it is essential to review what was tested when considering “negative” test results. For example, no panel genetic testing before 2021 included UBA1 testing. Although not obtained in this case, flow cytometry of peripheral blood from patients with CMML also often demonstrates an immunophenotypic skew toward CD14 ++ CD16 + classical monocytes reaching a threshold of ≥94%, highly suggestive against reactive monocytosis. 2 , 43 , 44

Curative treatment for CMML requires hematopoietic stem cell transplantation (HSCT), which carries its own significant risks of morbidity and mortality. 40 This patient has intermediate‐risk CMML by multiple scoring systems. Therapy for lower‐risk disease generally includes supportive measures such as transfusions and medications that improve cytopenias, whereas individuals with high symptom burden are increasingly managed with off‐label Janus kinase inhibitors (JAKi), especially ruxolitinib (RUX). For higher‐risk and/or progressive disease, DNA methyltransferase inhibitors (DNMTi) and HSCT can also be used (Supplemental Table 2 ). 40 Notably, the clinical presence of autoimmune or inflammatory diseases is not included in risk stratification, and whether autoimmune features of MDS or CMML impacts prognosis is controversial. 14 , 40 , 45 Because manifestations are variable, these do not have a standardized treatment approach and are often treated according to type and severity of disease in collaboration with rheumatology.

Our patient

Fevers and chest pain resolve with immunosuppression. At the third infusion of TCZ, cytopenias are noted to worsen, with a white blood cell count of 6,600/μL, a hemoglobin level of 7.8 g/dL, and a platelet count of 80,000/μL, leading to TCZ discontinuation. Prednisone is tapered off over the next several months. Erythroid‐stimulating agent therapy is prescribed for persistent macrocytic anemia after a repeat bone marrow aspirate and biopsy confirms no increase in blasts concerning for progression, the erythropoietin level is noted to be 17 mU/mL, and other nutritional test results are normal (Supplemental Table 2 ).

Use of immunomodulators and chemotherapy in the treatment of VCHM

What data exist to support the use of immunosuppression or chemotherapy in VCHM ?

The data driving the treatment of patients with inflammatory features of heterogenous hematologic malignancy, including VCHM, are highly limited. Response, as well as lack of response, of vasculitis to either leukemic‐focused therapies or immunosuppressive therapies has been described. Furthermore, patients with noncutaneous active or recent prior malignancies were deliberately excluded from transformational vasculitis clinical trials. 46 , 47 , 48 , 49 From retrospective case series focused on VCHM, observational data suggest that patients with underlying hematologic malignancy may have more prolonged refractory treatment courses than individuals without known or established hematologic malignancy, especially in patients with small vessel vasculitis. 9 , 10

Some therapies, such as cyclophosphamide or B cell depletion with rituximab (RTX), may have shared use in the management of vasculitis and underlying hematologic malignancy, particularly in B cell lymphoproliferative diseases. Standard practice is to treat underlying symptomatic cryoglobulinemia with or without vasculitis by treating the underlying cause, such as hematologic malignancy or any underlying infection (such as hepatitis C virus), as has been described. 5 , 50 In a single‐center retrospective study of 64 patients with cryoglobulinemic vasculitis treated with RTX, 50% of all patients had underlying B cell lymphoproliferative disease. Interestingly, CD20 depletion with both RTX and obinutuzumab has been recognized to trigger vasculitis flares, and 12 of 14 patients with a flare in this study also had underlying malignancy. However, none of these events were of sufficient severity to lead to therapy discontinuation, though additional steroid therapy or chemotherapy was added in some cases. 51

In myeloid neoplasia, innate immune dysregulation has long been recognized, and some pathways have been targeted for this primary indication. For example, proinflammatory cytokines, including tumor necrosis factor (TNF), IL‐1b, and IL‐6, are increased in the serum of patients with MDS, AML, and chronic myeloid leukemia and may have prognostic significance because higher TNF levels are associated with inferior prognosis, and lower IL‐1b levels are associated with longer survival in MDS. 52 , 53 , 54 Initial small open‐label studies (n =2–15) in the early 2000s studying short‐term TNF inhibition in MDS had mixed clinical results, with improvements of cytopenia in some patients and worsening in others. 55 , 56 , 57 However, three months of TNF inhibition was overall well tolerated, with the notable finding of high levels of clinically significant infections in neutropenic patients. More recently, identification of recurrently up‐regulated inflammatory pathways in high‐resolution analyses of patient samples has reinvigorated interest in immunomodulation in myeloid neoplasias and its genetically defined clonal precursors 14 (Supplemental Figure 1 ), though these immunomodulatory agents are not used therapeutically outside of clinical trials. Exceptions are that some forms of myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis, carry US Food and Drug Administration–labeled indications for use of RUX. Therapeutic use has also been described in early‐phase trials for symptomatic CMML and VEXAS observational data. 58 , 59 , 60 , 61 Similarly, short‐term use of IL‐6Ri has a labeled indication in cytokine release syndrome (CRS) in the setting of chimeric antigen receptor T cell use and is used off‐label for CRS in haploidentical HSCT, with observational data described in VEXAS.

Data describing the use of biologic therapies or chemotherapy to specifically treat myeloid neoplasia–associated VCHM are sparse, with most data from retrospective case series and case‐control series from France. In a retrospective MDS/CMML VCHM cohort (n = 70), patients were most often treated with steroids, followed by DMARDs, biologics, and the DNMTi azacytidine (5AC). Relapse of vasculitis was high, near 60%, and was higher for those treated with DMARDs only, though the small number of patients per group limits analyses. 62 Other retrospective data suggest 5AC may have benefit in treating inflammatory features of MDS/CMML and VEXAS, recently reproduced in a prospective phase 2 trial in which 41% of patients were found post hoc to have VEXAS. 63 However, only a small portion of these patients had vasculitis; seven of eight patients in the retrospective study and two of three patients in the prospective study showed at least a partial response. Of note, molecular clearance of the UBA1 ‐mutated clone has been described with 5AC but not RUX in limited patients with VEXAS. 60 , 64

Worsening of cytopenia, infection, and thrombosis are all significant concerns with immunosuppressive treatment, especially with underlying hematologic malignancy. As in allcomers treated with RUX and IL‐6Ri, cytopenia, especially thrombocytopenia and neutropenia, is an expected toxicity but can be managed with close monitoring. Myelosuppression is likewise an expected toxicity with the use of DNMTi (Supplemental Table 2 ). For example, 57% to 91% of patients with MDS treated with 5AC in the AZA‐001 study experienced myelosuppression. 65 5AC and RUX have the most real‐world retrospective data in myeloid neoplasia, and both have been associated with clinically significant but manageable infections. 66 , 67 The comparative effect size of specific medications on infection is difficult to discern given immense heterogeneity. In a more homogenous but smaller population of patients diagnosed with VEXAS in a retrospective multicenter registry from France (n = 74), patients with serious infections had a higher rate of RUX use compared to those using biologics and 5AC. Finally, thrombosis is increased in many patients with VCHM, especially in VEXAS and MPN, such as ET/PV. From the same retrospective French VEXAS registry, thrombosis did occur in patients treated with both JAKi (n = 5 of 78) and IL‐6Ri (n = 12 of 51) more often than in patients treated with other biologics (n = 3 of 65). Notably, patients continued therapy significantly longer with IL‐6Ri, and especially JAKi, than with other drugs owing to perceived clinical efficacy. 61 Interestingly, in a phase 2 trial evaluating RUX in MPN, RUX treatment surprisingly had no increased risk of the most common thrombotic complication, splanchnic thrombosis. 68 Similarly, in meta‐analyses of patients with MPN treated with RUX, there were no increased or decreased rates of thrombosis. 69 , 70 Mouse models of JAK2 ‐mutated MPN have similarly found reduced NETosis and thrombosis in JAK2 V617F mice treated with RUX. 71 Because most patients with VCHM have MDS or CMML rather than other MPN, the relationship between thrombosis and RUX or other immunosuppressive therapies in these conditions, as well as VEXAS, and optimal prophylaxis remains unclear and requires further investigation.

What is our clinical practice?

Clinical practice requires collaborative care and shared decision‐making between rheumatology and hematology/oncology providers and the patient based on factors such as vasculitis and malignant risks, comorbid diseases, fitness for therapy, and personal preferences. For patients in the community, we recommend referral to tertiary care to facilitate coordinated care. There is considerable evidence that VCHMs are interconnected and may mutually drive worsening disease states. The challenge for clinicians is to determine which disease to “treat first,” with the hope that control of one may mitigate the other with lowest toxicity. It is essential to determine and discuss prognosis of each diagnosis with patients and their loved ones to help them make decisions that impact both clinical outcome and quality of life.

We treat patients with VCHM proportionately to severity of organ manifestations, clarity of diagnosis, and effective therapies available for the type of vasculitis and malignant diagnosis. We aggressively pursue and exonerate infection in patients who may have previously been immunosuppressed from treatment or immune dysfunction related to malignancy, often with support from infectious disease colleagues with expertise in immunocompromised hosts. We do not consider atypical patterns of vascular inflammation to be definitive of infection without evidence thereof.

If vasculitis treatment is required, we use steroids as a backbone of induction therapy and attempt to taper to the lowest tolerated dose (Figure 3 ). In some individuals with VCHM and current treatment of VEXAS, some maintenance doses of steroids may be required. Although the data are limited, we use pneumocystis prophylaxis in all patients with VCHM taking steroids greater than 20 mg for more than one month. We immunize patients with influenza, COVID‐19, pneumococcal, and recombinant zoster vaccines, ideally before treatment. In patients for whom recombinant zoster vaccine has not been given before steroids, we strongly consider valacyclovir prophylaxis, especially if they have had prior episodes of varicella‐zoster virus. Given expected neutropenic states with use of JAKi or chemotherapy, we recommend valacyclovir or acyclovir prophylaxis, though data are limited. We screen all patients for tuberculosis and hepatitis B and C serologic tests and initiate appropriate treatment or prophylaxis for positive results.

For patients with B cell malignancies and especially those with cryoglobulinemic vasculitis, we strongly favor using therapies that could treat both malignancy and vasculitis, such as RTX. However, we consider the addition of other immunomodulatory treatments if RTX is ineffective in treating vasculitis despite effective treatment of malignancy, commensurate with degree and phenotype of disease involvement. If neither malignancy nor vasculitis is treated, we favor enhanced malignancy‐directed therapy (Figure 3 ).

Due to significant risks of myelosuppression, infection and negative impact on quality of life from an infusion schedule of DNMTi, steroids or other rheumatic steroid‐sparing agents are strongly considered for the treatment of VCHM with concurrent diagnosis of myeloid neoplasia. Importantly, therapeutic decisions in this context will depend on malignancy type and risk of progression (Figure 3 ). Depending on clinical phenotype, we prefer steroid‐sparing agents that have some evidence of safety and mutual benefit in myeloid neoplasia as well as vasculitis, while recognizing comparative data regarding progression of each condition, and adverse events are highly limited. We and others disfavor the use of conventional DMARDs given limited evidence of efficacy and risk of myelotoxicity. 45 The presence of AML or high‐risk disease typically drives the imminent addition of chemotherapy, and VCHM may be bridged with steroid monotherapy, if needed. However, many individuals with VCHM have lower‐risk disease and will not meet hematologic criteria for treatment.

In rheumatic treatments, we have the most experience with effective IL‐6Ri use in LVV across a host of underlying myeloid neoplasia. We often see progression of thrombocytopenia and neutropenia with IL‐6Ri but not typically to a severe range. Rheumatology is reluctant to initiate immunosuppressive medications when the platelet count is approximately <75,000 or absolute neutrophil count (ANC) is approximately <1,000 given the risk of bleeding or infection, though the exclusion criteria for a phase 2 trial of RUX in CMML 59 were a platelet count <35,000 and ANC <250. Hematologists monitor CBC with differential more frequently, such as weekly or bimonthly, in these cases. We may collaboratively tolerate some thrombocytopenia or neutropenia depending on degree of cytopenia, transfusion needs, response of vasculitis (if there are flares with vascular damage during periods of treatment discontinuation), and availability of alternate treatment options. Reminiscent of the approach to manage other paraneoplastic syndromes with treatment of the underlying disorder, we consider treatment of MDS, CMML, and VEXAS with DNMTi therapy in patients with severe or significant refractory and/or progressive inflammatory manifestations, even in lower‐risk patients in whom its use is off‐label (Figure 3 ).

Our patient: continued treatment and testing

Fevers and chest pain return one month after discontinuing steroids. In anticipation of starting 5AC for new transfusion‐dependent anemia and relapsing CMML‐associated LVV refractory to steroid taper, repeat marrow and NGS mutation panel testing are performed, without substantial changes in atypia, blast count, or new mutations compared to before. He begins intravenous 5AC infusions (Supplemental Table 2 ). Initial leukopenia (white blood cell count between 2,000 and 3,000 per μL) is tolerated, and at the end of 10 cycles, he achieves steroid and transfusion independence. A PET CT at one year shows no evidence of LVV, and he has no further vasculitis symptoms. Preferring to avoid upfront HSCT, he eventually transitions to oral decitabine/cedazuridine for the next 2.5 years. Ultimately, his cytopenia progresses, though blasts remain <5%, and he proceeds to curative HSCT.

Longitudinal management in patients with VCHM

Multidisciplinary care for patients with VCHM

Longitudinal care for patients with VCHM is often complex and poses unique clinical challenges. Patients may develop multiple autoimmune and/or inflammatory features as well as toxicity from disease and/or treatment. Additionally, patients with VCHM tend to be older, and individuals with MDS or CMML additionally have higher population risks for common diseases of aging, including cardiovascular, pulmonary, and metabolic diseases. 72 For patients with new symptoms, we consider a broad differential diagnosis that includes common age‐related diseases, as well as uncommon infections, inflammation, and progression of malignancy, and we attempt to obtain objective evidence to differentiate these in a timely matter. For example, patients with CMML have hypersensitivity to granulocyte–macrophage colony‐stimulating factor (GM‐CSF) and may exhibit leukemoid reactions with infection that can mimic disease progression. Similarly, they may experience robust response to vaccinations, with often self‐limited significant arm swelling, erythema, and pain, which can be associated with increased risk for thrombosis. Collaborative care teams beyond rheumatology and hematology/oncology from other disciplines with clinical interest and expertise in sicker patients with unusual manifestations of disease are helpful and may include infectious disease, vascular medicine, neurology, dermatology, pulmonology, nephrology, and radiology, among others. Depending on severity, these may require inpatient admission for expedited multidisciplinary evaluation. Given the complexity of care for patients with VCHM, evaluation in tertiary referral centers to provide multidisciplinary care is recommended.

Rheumatologic role in monitoring and longitudinal management of VCHM

We guide diagnostics to monitor known vasculitis and help evaluate possible multisystem inflammatory disease, which rheumatology is well experienced to diagnose as a specialty focused on systemic disease. We typically observe patients through allogeneic HSCT at clinical visits approximately every one to two months early in the diagnosis, every three months once the disease has stabilized, and at least annually in periods of prolonged remission. For patients with LVV, we favor PET CT to monitor response to therapy and to test for symptomatic flare. Laboratory testing and frequency depends on the pattern of vasculitis and organ system involved but should minimally include CBC with differential, a complete metabolic panel, and monitoring of affected or symptomatic organ systems. We obtain yearly Ig levels, which, when low, have been associated with increased risk of infection in both myeloid neoplasia and some forms of vasculitis, especially when treated with RTX. 73 , 74 , 75 We anticipate, test, and manage bone mineral density in patients with steroid use.

Hematology/oncology pearls for a rheumatologist in monitoring and longitudinal management of VCHM

The natural history of myeloid neoplasia is eventual progression of disease without treatment. Notably, VEXAS behaves differently from forms of MDS without UBA1 mutation and rarely progresses to AML. 38 When used, DNMTi are given monthly in repeated cycles, continuing until progression of disease or toxicities prevent continuation (Supplemental Table 2 ). The benefit of treatment is that about 40% to 50% of patients will have some hematologic response, including ~17% complete remission when the disease is controlled for some time, but progression will eventually occur unless HSCT is feasible. DNMTi treatment requires CBC monitoring, with the expectation that blood cell counts will reach nadir around day 14 after the first day of treatment and will improve around days 21 to 28 just before the subsequent cycle. With this count recovery, some of the symptoms from the VCHM or other inflammatory condition can flare, and it is important to consider steroid‐based therapy to manage the symptoms at this cyclical time point until disease control is optimized, typically after cycles three to four. 63 We recommended patients stay on monthly treatment cycles irrespective of count recovery because phase 3 studies have repeatedly shown better response rates with demonstrated adherence to the schedule. 76 For HSCT‐eligible patients with inflammatory complications, such as VCHM and VEXAS, the hope is that transplantation can control both disease processes, although specific data around this question are currently limited, with a prospective clinical trial underway in VEXAS. 77

Implications of the bidirectional relationship in VCHM and future directions

We hope that as research progresses, we will have more data‐driven options to safely, effectively, and perhaps mutually treat VCHM. For example, clinical trials investigating anti‐GM‐CSF in CMML are ongoing, and a phase 2 trial has also suggested therapeutic effect in GCA. 78 In myeloid neoplasia, it is not clear whether malignancy‐directed or vasculitis‐directed therapy is superior, especially given the paucity of available agents. Further refinement of the genotype–phenotype patterns of these entities may also guide optimal upfront therapies for patients and likewise generate genetic models to dissect development of vasculitis as well as hematologic malignancy. For example, beyond UBA1 , the mutations of TET2 and IDH1/2 have emerged in association with various inflammatory diseases across the spectrum of precursor clonal genetic lesions to myeloid neoplasia. 12 , 14 , 23 , 79 , 80 , 81 With the increasing development of well‐tolerated oral targeted therapies for specific mutations, such as IDH inhibitors, these novel agents may be effective in mutually managing disease, though this currently represents a small portion of patients. Furthermore, there is emerging interest in prevention therapies whereby therapies can be delivered to hematologic precursor lesions, which may be more amenable to immunomodulation or other molecular targeted approaches (Supplemental Figure 1 ).

Here, we have focused primarily on VCHM, but we know there are other clinical presentations that extend the paradigm that inflammatory disease can overlap, with hematologic malignancies as common presentations of uncommon disease. 14 Accurate identification of the primary malignancy is essential, especially as multiple distinct clones, including in different lineages, are increasingly identified in patients via high‐resolution analyses available in clinic (Supplemental Figure 1 ). For example, patients with rheumatoid arthritis and Felty syndrome can have either a concurrent overlapping diagnosis of MDS, large granular lymphocytic (LGL) leukemia, or MGUS. In this case, determining which clone may be driving disease and symptomatology may change choice of therapy, from DNMTi for MDS to methotrexate or cyclophosphamide for LGL. As new immunomodulatory agents are introduced in solid and hematologic malignancies and cellular therapies likewise transition into clinical trial for rheumatic disease, we anticipate the dual possibility of new inflammatory toxicities and, hopefully, also transformative treatments. Further prospective research is needed to investigate these known and yet unrecognized relationships between NGS mutations, clinical response, toxicity, and inflammatory phenomena in this new era of increasing recognition of interconnection between our fields.

CONCLUSIONS

Hematologic malignancy and systemic vasculitis are uncommon diseases, of which rare subtypes have strong associations. Hematologic malignancy should always be considered in the differential diagnosis of systemic vasculitis as a mimic, concomitant diagnosis, or possible adverse outcome. CBC with differential, PET scan, tissue biopsy, and clonal analyses, especially with NGS, are helpful to discriminate diagnoses and delineate risks. Some somatic mutations, such as UBA1 mutated in VEXAS, are shared drivers of vasculitis and hematologic malignancy. Data regarding treatment of VCHM are limited. Vasculitis‐directed therapy and neoplasia‐directed therapies may each be effective, and risk of infection is high with both approaches. Care of overlap syndromes benefits from proactive collaboration across multiple disciplines. The underlying etiology of how these disorders are connected remains an area of active research, with the goal to inform best therapies and practices for management. Prospective research focused on the integration of NGS testing into the diagnostic workup of vasculitis and other adult‐onset inflammatory diseases will likely lead to advances in the field. Further study may generate mechanistic insights into vasculitis pathogenesis and refine treatment paradigms.

AUTHOR CONTRIBUTIONS

All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr. Carraway confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.

Supporting information

Disclosure form .

Appendix S1: Supplementary Information

ACKNOWLEDGMENTS

The authors would like to thank Drs. Ayaz Aghayev and Keith Spinali from Brigham and Women's Hospital Radiology Department and Dr. Megan Nakashima from Cleveland Clinic Hematopathology for assistance with images, and Dr. Zachary Wallace from Massachusetts General Hospital Rheumatology Unit and Dr. Paul Monach from VA Boston Healthcare System Rheumatology Department for critical comments. Figures were generated in BioRender.

REFERENCES

1 Arber DA , Orazi A , Hasserjian RP , et al. International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data . Blood 2022 ; 140 ( 11 ): 1200 – 1228 . 35767897 10.1182/blood.2022015850 PMC9479031

2 Khoury JD , Solary E , Abla O , et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms . Leukemia 2022 ; 36 ( 7 ): 1703 – 1719 . 35732831 10.1038/s41375-022-01613-1 PMC9252913

3 Zeek PM . Periarteritis nodosa and other forms of necrotizing angiitis . N Engl J Med 1953 ; 248 ( 18 ): 764 – 772 . 13046612 10.1056/NEJM195304302481805

4 Jennette JC , Falk RJ , Bacon PA , et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides . Arthritis Rheum 2013 ; 65 ( 1 ): 1 – 11 . 23045170 10.1002/art.37715

5 Muchtar E , Magen H , Gertz MA . How I treat cryoglobulinemia . Blood 2017 ; 129 ( 3 ): 289 – 298 . 27799164 10.1182/blood-2016-09-719773

6 Grayson PC , Beck DB , Ferrada MA , et al. VEXAS syndrome and disease taxonomy in rheumatology . Arthritis Rheumatol 2022 ; 74 ( 11 ): 1733 – 1736 . 35696333 10.1002/art.42258 PMC9617773

7 Vitale C , Montalbano MC , Salvetti C , et al. Autoimmune complications in chronic lymphocytic leukemia in the era of targeted drugs . Cancers (Basel) 2020 ; 12 ( 2 ): 282 . 31979293 10.3390/cancers12020282 PMC7072470

8 Wooten MD , Jasin HE . Vasculitis and lymphoproliferative diseases . Semin Arthritis Rheum 1996 ; 26 ( 2 ): 564 – 574 . 8916300 10.1016/s0049-0172(96)80044-8

9 Fain O , Hamidou M , Cacoub P , et al. Vasculitides associated with malignancies: analysis of sixty patients . Arthritis Rheum 2007 ; 57 ( 8 ): 1473 – 1480 . 18050165 10.1002/art.23085

10 Greer JM , Longley S , Edwards NL , et al. Vasculitis associated with malignancy. Experience with 13 patients and literature review . Medicine (Baltimore) 1988 ; 67 ( 4 ): 220 – 230 . 3292873 10.1097/00005792-198807000-00003

11 Mekinian A , Grignano E , Braun T , et al. Systemic inflammatory and autoimmune manifestations associated with myelodysplastic syndromes and chronic myelomonocytic leukaemia: a French multicentre retrospective study . Rheumatology (Oxford) 2016 ; 55 ( 2 ): 291 – 300 . 26350487 10.1093/rheumatology/kev294

12 Hong LE , Wechalekar MD , Kutyna M , et al. IDH‐mutant myeloid neoplasms are associated with seronegative rheumatoid arthritis and innate immune activation . Blood 2024 ; 143 ( 18 ): 1873 – 1877 . 38457663 10.1182/blood.2023023593 PMC11076852

13 Watad A , Kacar M , Bragazzi NL , et al. Somatic mutations and the risk of undifferentiated autoinflammatory disease in MDS: an under‐recognized but prognostically important complication . Front Immunol 2021 ; 12 : 610019 . 33679746 10.3389/fimmu.2021.610019 PMC7933213

14 Belizaire R , Wong WJ , Robinette ML , et al. Clonal haematopoiesis and dysregulation of the immune system . Nat Rev Immunol 2023 ; 23 ( 9 ): 595 – 610 . 36941354 10.1038/s41577-023-00843-3 PMC11140722

15 Zahid MF , Barraco D , Lasho TL , et al. Spectrum of autoimmune diseases and systemic inflammatory syndromes in patients with chronic myelomonocytic leukemia . Leuk Lymphoma 2017 ; 58 ( 6 ): 1488 – 1493 . 27739921 10.1080/10428194.2016.1243681

16 Peker D , Padron E , Bennett JM , et al. A close association of autoimmune‐mediated processes and autoimmune disorders with chronic myelomonocytic leukemia: observation from a single institution . Acta Haematol 2015 ; 133 ( 2 ): 249 – 256 . 25413011 10.1159/000365877

17 Kristinsson SY , Björkholm M , Hultcrantz M , et al. Chronic immune stimulation might act as a trigger for the development of acute myeloid leukemia or myelodysplastic syndromes . J Clin Oncol 2011 ; 29 ( 21 ): 2897 – 2903 . 21690473 10.1200/JCO.2011.34.8540 PMC3138717

18 Anderson LA , Pfeiffer RM , Landgren O , et al. Risks of myeloid malignancies in patients with autoimmune conditions . Br J Cancer 2009 ; 100 ( 5 ): 822 – 828 . 19259097 10.1038/sj.bjc.6604935 PMC2653768

19 Beck DB , Ferrada MA , Sikora KA , et al. Somatic mutations in UBA1 and severe adult‐onset autoinflammatory disease . N Engl J Med 2020 ; 383 ( 27 ): 2628 – 2638 . 33108101 10.1056/NEJMoa2026834 PMC7847551

20 Patel N , Dulau‐Florea A , Calvo KR . Characteristic bone marrow findings in patients with UBA1 somatic mutations and VEXAS syndrome . Semin Hematol 2021 ; 58 ( 4 ): 204 – 211 . 34802541 10.1053/j.seminhematol.2021.10.007

21 Watanabe R , Kiji M , Hashimoto M . Vasculitis associated with VEXAS syndrome: a literature review . Front Med (Lausanne) 2022 ; 9 : 983939 . 36045928 10.3389/fmed.2022.983939 PMC9420898

22 Singh M , Jackson KJL , Wang JJ , et al. Lymphoma driver mutations in the pathogenic evolution of an iconic human autoantibody . Cell 2020 ; 180 ( 5 ): 878 – 894.e19 . 32059783 10.1016/j.cell.2020.01.029

23 Robinette ML , Weeks LD , Kramer RJ , et al; Association of somatic TET2 mutations with giant cell arteritis. Association of somatic TET2 mutations with giant cell arteritis . Arthritis Rheumatol 2024 ; 76 ( 3 ): 438 – 443 . 37909388 10.1002/art.42738 PMC10922498

24 Gutierrez‐Rodrigues F , Wells KV , Jones AI , et al. Clonal haematopoiesis across the age spectrum of vasculitis patients with Takayasu's arteritis, ANCA‐associated vasculitis and giant cell arteritis . Ann Rheum Dis 2024 ; 83 ( 4 ): 508 – 517 . 38049983 10.1136/ard-2023-224933 PMC10939924

25 Arends CM , Weiss M , Christen F , et al. Clonal hematopoiesis in patients with anti‐neutrophil cytoplasmic antibody‐associated vasculitis . Haematologica 2020 ; 105 ( 6 ): e264 – e267 . 31582546 10.3324/haematol.2019.223305 PMC7271609

26 Guedon AF , Ouafdi A , Belfeki N , et al. Higher risk profile among patients with TET2‐mutated giant cell arteritis: a cluster analysis . RMD Open 2024 ; 10 ( 4 ): e004694 . 39658053 10.1136/rmdopen-2024-004694 PMC11647381

27 Klion AD . Approach to the patient with suspected hypereosinophilic syndrome . Hematology Am Soc Hematol Educ Program 2022 ; 2022 ( 1 ): 47 – 54 . 36485140 10.1182/hematology.2022000367 PMC9821533

28 Dejaco C , Ramiro S , Duftner C , et al. EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice . Ann Rheum Dis 2018 ; 77 ( 5 ): 636 – 643 . 29358285 10.1136/annrheumdis-2017-212649

29 Kouijzer IJE , Mulders‐Manders CM , Bleeker‐Rovers CP , et al. Fever of unknown origin: the value of FDG‐PET/CT . Semin Nucl Med 2018 ; 48 ( 2 ): 100 – 107 . 29452615 10.1053/j.semnuclmed.2017.11.004

30 Robinette ML , Rao DA , Monach PA . The immunopathology of giant cell arteritis across disease spectra . Front Immunol 2021 ; 12 : 623716 . 33717128 10.3389/fimmu.2021.623716 PMC7946968

31 Bertram HC , Check IJ , Milano MA . Immunophenotyping large B‐cell lymphomas. Flow cytometric pitfalls and pathologic correlation . Am J Clin Pathol 2001 ; 116 ( 2 ): 191 – 203 . 11488065 10.1309/BA3U-RMTU-D7UJ-M8DR

32 Beck DB , Werner A , Kastner DL , et al. Disorders of ubiquitylation: unchained inflammation . Nat Rev Rheumatol 2022 ; 18 ( 8 ): 435 – 447 . 35523963 10.1038/s41584-022-00778-4 PMC9075716

33 Collins JC , Magaziner SJ , English M , et al. Shared and distinct mechanisms of UBA1 inactivation across different diseases . EMBO J 2024 ; 43 ( 10 ): 1919 – 1946 . 38360993 10.1038/s44318-024-00046-z PMC11099125

34 Georgin‐Lavialle S , Terrier B , Guedon AF , et al; French VEXAS group ; GFEV ; GFM ; CEREMAIA ; MINHEMON . 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 2022 ; 186 ( 3 ): 564 – 574 . 34632574 10.1111/bjd.20805

35 Ferrada MA , Savic S , Cardona DO , et al. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis . Blood 2022 ; 140 ( 13 ): 1496 – 1506 . 35793467 10.1182/blood.2022016985 PMC9523373

36 Sakuma M , Blombery P , Meggendorfer M , et al. Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies . Leukemia 2023 ; 37 ( 5 ): 1080 – 1091 . 36823397 10.1038/s41375-023-01857-5 PMC10169658

37 Faurel A , Heiblig M , Kosmider O , et al. Recurrent mutations of the active adenylation domain of UBA1 in atypical form of VEXAS syndrome . HemaSphere 2023 ; 7 ( 4 ): e868 . 36999004 10.1097/HS9.0000000000000868 PMC10043588

38 Sirenko M , Bernard E , Creignou M , et al. Molecular and clinical presentation of UBA1‐mutated myelodysplastic syndromes . Blood 2024 ; 144 ( 11 ): 1221 – 1229 . 38687605 10.1182/blood.2023023723 PMC12060156

39 Olteanu H , Patnaik M , Koster MJ , et al. Comprehensive morphologic characterization of bone marrow biopsy findings in a large cohort of patients with VEXAS syndrome: a single‐institution longitudinal study of 111 bone marrow samples from 52 patients . Am J Clin Pathol 2024 ; 161 ( 6 ): 609 – 624 . 38413044 10.1093/ajcp/aqad186

40 Patnaik MM , Tefferi A . Chronic myelomonocytic leukemia: 2024 update on diagnosis, risk stratification and management . Am J Hematol 2024 ; 99 ( 6 ): 1142 – 1165 . 38450850 10.1002/ajh.27271 PMC11096042

41 Elena C , Gallì A , Such E , et al. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia . Blood 2016 ; 128 ( 10 ): 1408 – 1417 . 27385790 10.1182/blood-2016-05-714030 PMC5036538

42 Wassie EA , Itzykson R , Lasho TL , et al. Molecular and prognostic correlates of cytogenetic abnormalities in chronic myelomonocytic leukemia: a Mayo Clinic‐French Consortium Study . Am J Hematol 2014 ; 89 ( 12 ): 1111 – 1115 . 25195656 10.1002/ajh.23846

43 Tarfi S , Harrivel V , Dumezy F , et al; Groupe Francophone des Myélodysplasies (GFM). Multicenter validation of the flow measurement of classical monocyte fraction for chronic myelomonocytic leukemia diagnosis . Blood Cancer J 2018 ; 8 ( 11 ): 114 . 30429467 10.1038/s41408-018-0146-8 PMC6235983

44 Jestin M , Tarfi S , Duchmann M , et al; Groupe Francophone des Myélodysplasies (GFM). Prognostic value of monocyte subset distribution in chronic myelomonocytic leukemia: results of a multicenter study . Leukemia 2021 ; 35 ( 3 ): 893 – 896 . 32684630 10.1038/s41375-020-0955-1

45 Zhao LP , Sébert M , Mékinian A , et al. What role for somatic mutations in systemic inflammatory and autoimmune diseases associated with myelodysplastic neoplasms and chronic myelomonocytic leukemias? Leukemia 2023 ; 37 ( 6 ): 1186 – 1190 . 37024519 10.1038/s41375-023-01890-4

46 Stone JH , Tuckwell K , Dimonaco S , et al. Trial of tocilizumab in giant‐cell arteritis . N Engl J Med 2017 ; 377 ( 4 ): 317 – 328 . 28745999 10.1056/NEJMoa1613849

47 Stone JH , Merkel PA , Spiera R , et al; RAVE‐ITN Research Group . Rituximab versus cyclophosphamide for ANCA‐associated vasculitis . N Engl J Med 2010 ; 363 ( 3 ): 221 – 232 . 20647199 10.1056/NEJMoa0909905 PMC3137658

48 Jones RB , Tervaert JW , Hauser T , et al; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA‐associated renal vasculitis . N Engl J Med 2010 ; 363 ( 3 ): 211 – 220 . 20647198 10.1056/NEJMoa0909169

49 Wechsler ME , Akuthota P , Jayne D , et al; EGPA Mepolizumab Study Team. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis . N Engl J Med 2017 ; 376 ( 20 ): 1921 – 1932 . 28514601 10.1056/NEJMoa1702079 PMC5548295

50 Dammacco F , Lauletta G , Vacca A . The wide spectrum of cryoglobulinemic vasculitis and an overview of therapeutic advancements . Clin Exp Med 2023 ; 23 ( 2 ): 255 – 272 . 35348938 10.1007/s10238-022-00808-1 PMC8960698

51 Martin de Fremont G , Chiron A , Krzysiek R , et al. Flare of a mixed cryoglobulinaemic vasculitis after obinutuzumab infusion . Clin Exp Rheumatol 2021 ; 39 ( 2 suppl 129 ): 52 – 55 . 10.55563/clinexprheumatol/rit83o 33506759

52 Kitagawa M , Saito I , Kuwata T , et al. Overexpression of tumor necrosis factor (TNF)‐α and interferon (IFN)‐γ by bone marrow cells from patients with myelodysplastic syndromes . Leukemia 1997 ; 11 ( 12 ): 2049 – 2054 . 9447819 10.1038/sj.leu.2400844

53 Wetzler M , Kurzrock R , Estrov Z , et al. Altered levels of interleukin‐1 beta and interleukin‐1 receptor antagonist in chronic myelogenous leukemia: clinical and prognostic correlates . Blood 1994 ; 84 ( 9 ): 3142 – 3147 . 7949186

54 Nievergall E , Reynolds J , Kok CH , et al. TGF‐α and IL‐6 plasma levels selectively identify CML patients who fail to achieve an early molecular response or progress in the first year of therapy . Leukemia 2016 ; 30 ( 6 ): 1263 – 1272 . 26898188 10.1038/leu.2016.34

55 Maciejewski JP , Risitano AM , Sloand EM , et al. A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)‐Fc fusion protein in patients with myelodysplastic syndrome . Br J Haematol 2002 ; 117 ( 1 ): 119 – 126 . 11918541 10.1046/j.1365-2141.2002.03381.x

56 Deeg HJ , Gotlib J , Beckham C , et al. Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: a pilot study . Leukemia 2002 ; 16 ( 2 ): 162 – 164 . 11840280 10.1038/sj.leu.2402356

57 Stasi R , Amadori S . Infliximab chimaeric anti‐tumour necrosis factor alpha monoclonal antibody treatment for patients with myelodysplastic syndromes . Br J Haematol 2002 ; 116 ( 2 ): 334 – 337 . 11841434

58 Padron E , Dezern A , Andrade‐Campos M , et al; Myelodysplastic Syndrome Clinical Research Consortium. A multi‐institution phase I trial of ruxolitinib in patients with chronic myelomonocytic leukemia (CMML) . Clin Cancer Res 2016 ; 22 ( 15 ): 3746 – 3754 . 26858309 10.1158/1078-0432.CCR-15-2781 PMC5278764

59 Hunter AM , Newman H , Dezern AE , et al. Integrated human and murine clinical study establishes clinical efficacy of ruxolitinib in chronic myelomonocytic leukemia . Clin Cancer Res 2021 ; 27 ( 22 ): 6095 – 6105 . 34253584 10.1158/1078-0432.CCR-21-0935 PMC8595542

60 Heiblig M , Ferrada MA , Koster MJ , et al. Ruxolitinib is more effective than other JAK inhibitors to treat VEXAS syndrome: a retrospective multicenter study . Blood 2022 ; 140 ( 8 ): 927 – 931 . 35609174 10.1182/blood.2022016642 PMC9412002

61 Hadjadj J , Nguyen Y , Mouloudj D , et al; FRENVEX . Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX . Ann Rheum Dis 2024 ; 83 ( 10 ): 1358 – 1367 . 38777378 10.1136/ard-2024-225640

62 Roupie AL , Guedon A , Terrier B , et al; On behalf MINHEMON (French Network of dysimmune disorders associated with hemopathies) and SNFMI. Vasculitis associated with myelodysplastic syndrome and chronic myelomonocytic leukemia: French multicenter case‐control study . Semin Arthritis Rheum 2020 ; 50 ( 5 ): 879 – 884 . 32896704 10.1016/j.semarthrit.2020.07.002

63 Mekinian A , Zhao LP , Chevret S , et al. A phase II prospective trial of azacitidine in steroid‐dependent or refractory systemic autoimmune/inflammatory disorders and VEXAS syndrome associated with MDS and CMML . Leukemia 2022 ; 36 ( 11 ): 2739 – 2742 . 36104395 10.1038/s41375-022-01698-8

64 Sockel K , Götze K , Ganster C , et al. VEXAS syndrome: complete molecular remission after hypomethylating therapy . Ann Hematol 2024 ; 103 ( 3 ): 993 – 997 . 38214707 10.1007/s00277-023-05611-w PMC10866742

65 Fenaux P , Mufti GJ , Hellstrom‐Lindberg E , et al; International Vidaza High‐Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher‐risk myelodysplastic syndromes: a randomised, open‐label, phase III study . Lancet Oncol 2009 ; 10 ( 3 ): 223 – 232 . 19230772 10.1016/S1470-2045(09)70003-8 PMC4086808

66 Mądry K , Lis K , Biecek P , et al. Predictive model for infection risk in myelodysplastic syndromes, acute myeloid leukemia, and chronic myelomonocytic leukemia patients treated with azacitidine; azacitidine infection risk model: the Polish Adult Leukemia Group Study . Clin Lymphoma Myeloma Leuk 2019 ; 19 ( 5 ): 264 – 274.e4 . 30898482 10.1016/j.clml.2019.01.002

67 Sadjadian P , Wille K , Griesshammer M . Ruxolitinib‐associated infections in polycythemia vera: review of the literature, clinical significance, and recommendations . Cancers (Basel) 2020 ; 12 ( 11 ): 3132 . 33114733 10.3390/cancers12113132 PMC7693745

68 Pieri L , Paoli C , Arena U , et al. Safety and efficacy of ruxolitinib in splanchnic vein thrombosis associated with myeloproliferative neoplasms . Am J Hematol 2017 ; 92 ( 2 ): 187 – 195 . 27880982 10.1002/ajh.24614

69 Samuelson BT , Vesely SK , Chai‐Adisaksopha C , et al. The impact of ruxolitinib on thrombosis in patients with polycythemia vera and myelofibrosis: a meta‐analysis . Blood Coagul Fibrinolysis 2016 ; 27 ( 6 ): 648 – 652 . 26569516 10.1097/MBC.0000000000000446

70 Masciulli A , Ferrari A , Carobbio A , et al. Ruxolitinib for the prevention of thrombosis in polycythemia vera: a systematic review and meta‐analysis . Blood Adv 2020 ; 4 ( 2 ): 380 – 386 . 31985808 10.1182/bloodadvances.2019001158 PMC6988397

71 Wolach O , Sellar RS , Martinod K , et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms . Sci Transl Med 2018 ; 10(436):eaan8292 . 10.1126/scitranslmed.aan8292 PMC6442466 29643232

72 Weeks LD , Marinac CR , Redd R , et al. Age‐related diseases of inflammation in myelodysplastic syndrome and chronic myelomonocytic leukemia . Blood 2022 ; 139 ( 8 ): 1246 – 1250 . 34875037 10.1182/blood.2021014418 PMC8874362

73 Toma A , Fenaux P , Dreyfus F , et al. Infections in myelodysplastic syndromes . Haematologica 2012 ; 97 ( 10 ): 1459 – 1470 . 22733024 10.3324/haematol.2012.063420 PMC3487546

74 Liberatore J , Nguyen Y , Hadjadj J , et al. Risk factors for hypogammaglobulinemia and association with relapse and severe infections in ANCA‐associated vasculitis: a cohort study . J Autoimmun 2024 ; 142 : 103130 . 37956529 10.1016/j.jaut.2023.103130

75 Barmettler S , Ong MS , Farmer JR , et al. Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia . JAMA Netw Open 2018 ; 1 ( 7 ): e184169 . 30646343 10.1001/jamanetworkopen.2018.4169 PMC6324375

76 Adès L , Girshova L , Doronin VA , et al. Pevonedistat plus azacitidine vs azacitidine alone in higher‐risk MDS/chronic myelomonocytic leukemia or low‐blast‐percentage AML . Blood Adv 2022 ; 6 ( 17 ): 5132 – 5145 . 35728048 10.1182/bloodadvances.2022007334 PMC9631625

77 Mohty R , Reljic T , Abdel‐Razeq N , et al. Assessing the efficacy of allogeneic hematopoietic cell transplantation in VEXAS syndrome: results of a systematic review and meta‐analysis . Bone Marrow Transplant 2024 ; 59 ( 10 ): 1423 – 1427 . 39060513 10.1038/s41409-024-02375-3

78 Cid MC , Unizony SH , Blockmans D , et al; KPL‐301‐C001 Investigators. Efficacy and safety of mavrilimumab in giant cell arteritis: a phase 2, randomised, double‐blind, placebo‐controlled trial . Ann Rheum Dis 2022 ; 81 ( 5 ): 653 – 661 . 35264321 10.1136/annrheumdis-2021-221865 PMC8995812

79 Zhao LP , Boy M , Azoulay C , et al. Genomic landscape of MDS/CMML associated with systemic inflammatory and autoimmune disease . Leukemia 2021 ; 35 ( 9 ): 2720 – 2724 . 33623140 10.1038/s41375-021-01152-1

80 Agrawal M , Niroula A , Cunin P , et al. TET2‐mutant clonal hematopoiesis and risk of gout . Blood 2022 ; 140 ( 10 ): 1094 – 1103 . 35714308 10.1182/blood.2022015384 PMC9461470

81 Jaiswal S , Natarajan P , Silver AJ , et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease . N Engl J Med 2017 ; 377 ( 2 ): 111 – 121 . 28636844 10.1056/NEJMoa1701719 PMC6717509