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Chronic myelomonocytic leukemia-related vasculitis mimicking giant cell arteritis

  • Sima D. Amin
    Affiliations
    Texas A&M College of Medicine, College Station, Texas
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  • Aroucha Vickers
    Affiliations
    Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas
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  • Bennett Y. Hong
    Affiliations
    Department of Ophthalmology, The University of Texas Medical Branch, Galveston, Texas
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  • Claudia M. Prospero Ponce
    Affiliations
    Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas
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  • Ibrahim F. Ibrahim
    Affiliations
    Department of Hematology and Oncology, Houston Methodist Hospital, Houston, Texas
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  • Patricia Chevez-Barrios
    Affiliations
    Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas

    Baylor College of Medicine, Houston, Texas

    Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, N.Y.

    The University of Texas MD Anderson Cancer Center, Houston, Texas
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  • Andrew G. Lee
    Correspondence
    Correspondence to: Andrew G. Lee
    Affiliations
    Texas A&M College of Medicine, College Station, Texas

    Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas

    Department of Ophthalmology, The University of Texas Medical Branch, Galveston, Texas

    Department of Ophthalmology, Neurology, and Neurosurgery Ophthalmology, Weill Cornell Medicine, New York, N.Y.

    Division of Ophthalmology, The University of Texas MD Anderson Cancer Center, Houston, Texas

    Department of Ophthalmology, The University of Iowa Hospitals and Clinics, Iowa City, Iowa

    Department of Ophthalmology, Texas A&M College of Medicine, College Station, Texas.
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Published:November 24, 2018DOI:https://doi.org/10.1016/j.jcjo.2018.08.017
      Giant cell arteritis (GCA) is a medium-to-large vessel vasculitis, commonly seen in the elderly, that can produce visual loss.
      • Borchers AT
      • Gershwin ME
      Giant cell arteritis: a review of classification, pathophysiology, geoepidemiology and treatment.
      Although the diagnosis of GCA is typically made via a temporal artery biopsy (TAB), other vasculitides have been diagnosed by TAB in patients with symptoms and signs initially suggestive of GCA. Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by persistent monocytosis, macrocytic or normocytic anemia, and thrombocytopenia.
      • Itzykson R
      • Duchmann M
      • Lucas N
      • Solary E
      CMML: clinical and molecular aspects.
      We report an unusual case of CMML-associated vasculitis mimicking GCA.
      A 69-year-old white male presented with headache, retrobulbar eye pain, and acute loss of vision in his right eye (OD) greater than the left eye (OS). His past medical history was significant for well controlled hypertension and noninsulin-dependent diabetes mellitus. He had a remote history of localized prostate cancer status postprostatectomy, but this was in remission. Family history included a father with an unknown form of leukemia.
      Visual acuity was 20/100 OD and 20/25 OS. He had a right relative afferent pupillary defect. Stimulus V Humphrey visual field (HVF) OD showed diffuse generalized depression, an inferior altitudinal field defect, a dense central scotoma, and a superior arcuate defect. A stimulus III HVF OS showed a mean deviation of –7.80 dB and an inferior arcuate defect. Fundus examination showed optic atrophy OD and grade 2 optic disc edema OS (Fig. 1, Fig. 1). Optical coherence tomography measured a global retinal nerve fiber layer thickness of 48 microns OD and 117 microns OS.
      Fig. 1.
      Fig. 1A, Left eye Stimulus III Humphrey visual field test on initial presentation. B, Right Stimulus V Humphrey visual field test on initial presentation. C, Left eye fundus photograph at initial presentation showing optic disc edema. D, Right eye fundus photograph appears normal at initial presentation.
      Fig. 1.
      Fig. 1A, Left eye Stimulus III Humphrey visual field test on initial presentation. B, Right Stimulus V Humphrey visual field test on initial presentation. C, Left eye fundus photograph at initial presentation showing optic disc edema. D, Right eye fundus photograph appears normal at initial presentation.
      Complete blood count revealed a hemoglobin of 13.4 g/dL and marked thrombocytopenia with a platelet count of 79 × 109/L (normal 150–400). White blood cell count was within normal limits at –6.1 × 109/L with monocytes 1708 /uL (28%). Erythrocyte sedimentation rate (ESR) was normal at 10 mm/hr and C-reactive protein (CRP) was also normal 1.03 mg/dL.
      A diagnosis of GCA was initially suspected, so bilateral temporal artery biopsies were performed, which revealed irregular intimal hyperplasia with focal segmental absence of the internal elastic lamina with rare CD68 positive macrophages at the level of the elastic lamina and focal disruption of elastic lamina consistent with healed or treated vasculitis (Fig. 2). Symmetry between both biopsies was noted. Myeloid cells were absent.
      Fig. 2.
      Fig. 2A, Hematoxylin and eosin stain; original magnification 20 ×. Routine section of the temporal artery that demonstrates irregular intimal hyperplasia (*) with mostly intact elastic lamina and muscularis layer (next to elastic lamina). B, Movat pentachrome stain, original magnification 20 ×. Same temporal artery stained with Movat pentachrome that demonstrates in green-yellow the intimal hyperplasia with extension under the elastic lamina (arrows) and into the muscularis layer. Elastic lamina is focally interrupted (arrows). C, Immunohistochemistry using CD68 (Ventana automated system), original magnification 20 ×. Circles show the cells in the outer margin of the elastic lamina at sites of rupture seen in the Movat stain.
      Thrombocytosis rather than thrombocytopenia is one of the hematologic manifestations of GCA, and therefore a hematology-oncology consultation was obtained in this patient. Magnetic resonance imaging (MRI) of the brain and spine with contrast was normal except for bone marrow signal abnormality in the T2, T4, and T5 vertebral bodies. Computed tomography showed mild splenomegaly of 14.7 cm. Lumbar puncture showed elevated cerebrospinal fluid protein at 90 mg/dL (normal <50 mg/dL).
      Peripheral blood smear review showed prominent acanthocytosis, moderately decreased platelets, and increased monocytes. Bone marrow aspiration of right posterior iliac crest revealed a hypercellular bone marrow for age (cellularity of 80–90%) and trilineage hematopoiesis. Flow cytometry of the bone marrow aspirate showed monocytosis (17% of total nucleated cells) with aberrant partial expression of CD56. Fluorescent in situ hybridization (FISH) identified no myelodysplastic syndrome (MDS)–associated chromosome deletions or translocations. Conventional karyotype revealed a loss of Y chromosome, an association seen in MDS but can be seen in elderly men and smokers independent of the presence of MDS. A 54-gene myeloid molecular next-generation sequencing analysis revealed a missense mutation in CBL and 2 flame-shaped mutations in TET2 and NOTCH1/PHF6 mutations. These mutations have been implicated in CMML, with TET2 a frequently identified mutation.
      • Patnaik MM
      • Zahid MF
      • Lashi TL
      • et al.
      Number and type of TET2 Mutations in chronic myelomonocytic leukemia: clinical and prognostic correlated.
      Given the aberrant, persistent monocytosis, splenomegaly, thrombocytopenia and above noted mutations, the patient was diagnosed with CMML-1. There was no evidence of transformation to acute myelogenous leukemia.
      The patient had a long treatment course. Initially the patient was hospitalized and treated with intravenous (IV) methylprednisolone 500 mg twice daily for 5 days and discharged on 40 mg prednisone taper dose. Despite treatment his vision continued to worsen. He was started on hydroxyurea 500 mg daily and IV methylprednisolone 1 gm every week for 4 weeks and then every 2 weeks. When 2 months later the patient was again hospitalized due to worsening vision, the hydroxyurea was discontinued, the IV methlypredinsone was changed to oral prednisone 30 mg, and he was started on decitabine 20 mg/m2/d (days 1–5 of 28 days). After completing 3 cycles of decitabine, the patient's vision continued to deteriorate; he was started on IL-6 antagonist, tocilizumab, for which he completed 6 doses. At 1-month follow-up his vision had stabilized bilaterally but had not improved. The decision was made to pursue treatment with a different hypomethylating agent, azacitadine, with the hope that treating the underlying CMML would positively affect his vasculitis. He received azacitdine 75 mg/m2/d (days 1–5 of 28 days) for 2 cycles. He had site reactions to azacitdine and hence, he stopped the injections. The patient has refused further treatment with either chemotherapy or toculizumab. One and a half years after initial presentation, despite high dose corticosteroids, chemotherapy, immunotherapy, and stable hematologic markers, his fundus examination showed diffuse optic atrophy OU.
      In contrast to typical GCA where the platelet count is often elevated, our patient presented with anemia, monocytosis, and thrombocytopenia.
      • Borchers AT
      • Gershwin ME
      Giant cell arteritis: a review of classification, pathophysiology, geoepidemiology and treatment.
      The presence of bone marrow infiltration on the head and spine MRI and splenomegaly are not consistent with GCA alone. The ESR and CRP in this case were both negative and a temporal artery biopsy was consistent with vasculitis. Although CMML infiltration may itself cause cranial neuropathies, this is unlikely in our case because no evidence of neural lesions was seen on the MRI. Additionally, the disease was localized with no evidence of retinitis or uveitis.
      Grignano et al. showed that vasculitis was the most commonly associated systemic autoimmune and inflammatory disease (SAIDs) in CMML.
      • Grignano E
      • Mekinian A
      • Braun T
      • et al.
      Autoimmune and inflammatory diseases associated with chronic myelomonocytic leukemia: a series of 26 cases and literature review.
      Of 26 patients examined with CMML and SAIDs, 14 had vasculitis. Twelve of these patients received first-line treatment with steroids. Although all of these patients showed complete or partial SAIDS response initially, second-line treatment was needed in 7 cases because of SAIDs relapse, steroid dependence, or steroid failure.
      • Grignano E
      • Mekinian A
      • Braun T
      • et al.
      Autoimmune and inflammatory diseases associated with chronic myelomonocytic leukemia: a series of 26 cases and literature review.
      Hamidou et al. reported on medium-sized vasculitides associated with CMML.
      • Hamidou MA
      • Boumalassa A
      • Larroche C
      • Kouri DE
      • Blétry O
      • Grolleau J
      Systemic medium-sized vessel vasculitis associated with chronic myelomonocytic leukemia.
      Of 8 cases examined, 6 showed active hematologic disease with a poor or transient response to corticosteroids and immunosuppressive drugs, also seen in our patient (Table 1).
      • Grignano E
      • Mekinian A
      • Braun T
      • et al.
      Autoimmune and inflammatory diseases associated with chronic myelomonocytic leukemia: a series of 26 cases and literature review.
      • Hamidou MA
      • Boumalassa A
      • Larroche C
      • Kouri DE
      • Blétry O
      • Grolleau J
      Systemic medium-sized vessel vasculitis associated with chronic myelomonocytic leukemia.
      • De Smit E
      • O'Sullivan E
      A diagnostic challenge: chronic myelomonocytic leukaemia and recurrent anterior ischaemic optic neuropathy.
      Table 1Types of CMML associated vasculitis, treatment, and general outcome
      StudyType of VasculitisTreatmentGeneral Outcome
      Grignano et al.
      • Grignano E
      • Mekinian A
      • Braun T
      • et al.
      Autoimmune and inflammatory diseases associated with chronic myelomonocytic leukemia: a series of 26 cases and literature review.
      Polyarteritis nodosa (n = 6)

      Giant cell arteritis (n = 3)

      Cryoglobulinemia (n = 2)

      Behçet's disease (n = 1)

      Granulomatosis with polyangeitis (n = 2)
      Steroids alone (n = 11)

      Steroids+ cyclophosphamide (n = 1)

      Anakinra for pseudo-Behçet's disease (n = 1)
      12 had complete or partial SAIDS response initially.

      7/13 needed second-line treatment (3 SAIDS relapse, 3 steroid dependence, and 1 nonresponse)
      Hamidou et al.
      • Hamidou MA
      • Boumalassa A
      • Larroche C
      • Kouri DE
      • Blétry O
      • Grolleau J
      Systemic medium-sized vessel vasculitis associated with chronic myelomonocytic leukemia.
      Polyarteritis nodosa (n = 8)Steroids alone (n = 2)

      Steroids+ cyclophosphamide, methotrexate, hydroxyurea, and/or etoposide (n = 6)
      7 deaths (2 from vasculitis complications, 3 from infections, 2 causes possibly related to vasculitis)

      1 remained alive
      De Smit and O'Sullivan
      • De Smit E
      • O'Sullivan E
      A diagnostic challenge: chronic myelomonocytic leukaemia and recurrent anterior ischaemic optic neuropathy.
      CMML-associated vasculitis unspecified (n = 1)Steroids+ hydroxycarbamide+ allopurinol (n = 1)Remained stable
      Amin et al.
      Case presented in this report.
      CMML-associated vasculitis unspecified (n = 1)Steroids, decitabine, tociluzumab, azacitdine (n = 1)Stable hematologic markers. Stable but diffuse optic atrophy OU.
      SAIDS, systemic autoimmune and/or inflammatory diseases; CMML, chronic myelomonocytic leukemia.
      low asterisk Case presented in this report.
      De Smit and O'Sullivan described a 66-year-old white male with CMML-related vasculitis who presented with sudden monocular loss of vision.
      • De Smit E
      • O'Sullivan E
      A diagnostic challenge: chronic myelomonocytic leukaemia and recurrent anterior ischaemic optic neuropathy.
      Although temporal artery biopsies were negative for GCA, an elevated ESR of 55 mm/h and CRP 2 mg/L were noted. As in our case, this patient presented with thrombocytopenia of 88 × 109/L and a monocytosis of 2.1 × 109/L. Although initial treatment with prednisone caused improvement, 5 weeks after initial presentation, this patient also reported worsening of vision. A bone marrow biopsy confirmed CMML. A skin biopsy of a rash confirmed lymphocytic vasculitis. The final diagnosis was anterior ischemic optic neuropathy caused by CMML vasculitis. He was treated with hydrocarbamide, allopurinol, and a maintenance dose of steroids and remained stable.
      • De Smit E
      • O'Sullivan E
      A diagnostic challenge: chronic myelomonocytic leukaemia and recurrent anterior ischaemic optic neuropathy.
      We believe that our patient also had visual loss due to ischemic optic neuropathy secondary to CMML vasculitis. Immunological abnormalities have been reported in myeloproliferative and myelodysplastic syndromes. Production of various cytokines in CMML may induce of immune disturbances causing vasculitis.
      • Hamidou MA
      • Boumalassa A
      • Larroche C
      • Kouri DE
      • Blétry O
      • Grolleau J
      Systemic medium-sized vessel vasculitis associated with chronic myelomonocytic leukemia.
      This case report aims to increase awareness of the possibility of CMML-related vasculitis mimicking GCA causing anterior ischemic optic neuropathy. We recommend consideration for hematologic consultation and further evaluation of possible CMML vasculitis for patients presenting with GCA-like symptoms who have thrombocytopenia (rather than thrombocytosis), monocytosis, or splenomegaly.
      Informed consent: Informed consent was obtained from the patient for publication of the material.

      Appendix. Supplementary materials

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