Double Jeopardy: Autoimmune Myelofibrosis with Pyoderma Gangrenosum
A 33-year-old African American woman with no significant past medical history presented to an outside hospital with 3 months of oropharyngeal ulcers and odynophagia. She was also noted to be pancytopenic (hemoglobin 7.4 g/dL, mean corpuscular volume 81 fL, platelets 100,000/mm3, white blood cells 3000/mm3, absolute neutrophil count 600/mm3) with blood smear findings of teardrop cells and anisopoikilocytosis. She did not have splenomegaly. A bone marrow biopsy revealed marked fibrosis with residual trilineage hematopoiesis and without atypical megakaryocytes, dysplasia, or increase in blasts (Figure 1). Testing for JAK2 V617F and MPL mutations was negative.
She was diagnosed at the outside hospital as having acute myelofibrosis and given a poor prognosis with an estimated survival of 8-10 months. She was treated with oral lenalidomide and weekly granulocyte-colony stimulating factor. After a month on lenalidomide and granulocyte-colony stimulating factor she had no response in her cytopenias and developed worsening of her oral ulcers with new right inframammary and inguinal ulcerated skin plaques. She was then referred to our facility (Johns Hopkins Bayview Medical Center) for further work-up of her hematological and skin disease.
She was afebrile with a heart rate of 108 beats per minute and normal blood pressure, respiratory rate, and oxygen saturation. Cutaneous findings were remarkable for an impressive 13 cm × 7 cm inframammary ulcerated plaque with violaceous, undermined borders and eschar formation. There was a similarly appearing, right inguinal ulcerated plaque measuring 10 cm × 6 cm extending into her right labia majora, with multiple satellite lesions measuring 2 cm in diameter (Figure 2). Her buccal mucosa showed multiple aphthous ulcers measuring <1 cm. Additionally, she had about 10 quarter-sized, crusted plaques on her scalp. All wounds were purulent and exquisitely tender to touch. Cardiac, pulmonary, abdominal, and neurologic examinations were unremarkable; there was no palpable lymphadenopathy or hepatosplenomegaly.
Computed tomography of the chest, abdomen, and pelvis was notable for mild diffuse patchy sclerosis of the sternum, thoracolumbar spine, and ribs with a normal 10.8-cm-sized spleen. Punch biopsy of the inguinal lesion demonstrated a mixed inflammatory infiltrate, granulation tissue and necrosis, with no evidence of vasculitis. Tissue stains and cultures were negative for bacteria, acid-fast bacilli, and fungi.
Based on the clinical and histologic findings, we diagnosed this as pyoderma gangrenosum, a neutrophilic skin disorder characterized by sterile pustules that rapidly enlarge, necrotize, and ulcerate into painful characteristic wounds with violaceous, undermined borders. Pyoderma gangrenosum is often associated with autoimmune disorders such as inflammatory bowel disease and arthritides, and has a predilection for young and middle-aged women.1, 2 We were careful to assess for both infection and vasculitis, as pyoderma gangrenosum is a diagnosis of exclusion. While pyoderma gangrenosum most commonly affects the lower extremities, it can involve any part of the body, including the breasts,3, 4 oral mucosa,5, 6, 7 and genitals.5, 7, 8 The patient was started on prednisone 60 mg by mouth daily, which improved her oral ulcers and odynophagia.
On steroids we also noticed improvement of her blood counts and evidence of recovering bone marrow function based on a reticulocyte index of 5% (absolute reticulocyte count of 185 k/mm3). An extensive laboratory work-up ruled out infection with syphilis, chlamydia, human immunodeficiency virus, hepatitis B, hepatitis C, and parvovirus B19. She was found to be mildly antinuclear antibody positive (titer 1:80), but negative for rheumatoid factor, anti-double stranded DNA, anti-Sjögren’s-syndrome-related antigen A and B (SSA/B), anti-saccharomyces cerevisiae antibodies (ASCA), cytoplasmic-anti neutrophil cytoplasmic antibodies (c-ANCA), perinuclear-anti neutrophil cytoplasmic antibodies (p-ANCA), lupus anticoagulant, and anticardiolipin antibodies. C3 and C4 levels were also normal.
We then considered the diagnosis of autoimmune myelofibrosis, a rare condition with very good prognosis when recognized and treated appropriately.9 Although autoimmune myelofibrosis is often associated with systemic erythematous lupus,10 it also occurs in the absence of any well-defined autoimmune syndromes.9 Like our patient, autoimmune myelofibrosis patients respond extremely well to steroids, and more than half demonstrate reduced marrow fibrosis on follow-up biopsy.11 In contrast to primary myelofibrosis, which typically affects patients >60 years old, autoimmune myelofibrosis is more likely to affect patients in their 30s.10 Furthermore, this diagnosis is consistent with our patient’s lack of splenomegaly and other findings typical of myeloproliferative neoplasms such as positivity for the JAK2 V617F mutation, atypical megakaryocytes, and dysplasia on the marrow.11 Our patient had findings of osteosclerosis, which has been reported in autoimmune myelofibrosis as well.12 While other forms of myeloproliferative neoplasms have been associated with pyoderma gangrenosum,13 this is the first published account, of which we are aware, of autoimmune myelofibrosis and pyoderma gangrenosum occurring together.
The pathogenesis of pyoderma gangrenosum is still largely unclear. Current theories indicate that neutrophil dysfunction, immune system dysregulation, and inflammatory cytokines are key contributing factors.14 In our patient, both syndromes presented synchronously with multisystem involvement driven by autoimmunity.
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-Cole Sterling, BS, Genevieve M. Crane, MD, PhD, Jihad Al-hariri, MD, Satish Shanbhag, MBBS, MPH
This article originally appeared in the January 2017 issue of The American Journal of Medicine.