Dr. Linker has received consultant fees, speaking fees, and/or honoraria (less than $10,000 each) from Celgene, Pharmion, and PDL BioPharma.
Stem cell transplant for myelodysplastic syndrome–associated histiocytoid sweet's syndrome in a patient with arthritis and myalgias
Article first published online: 26 NOV 2008
Copyright © 2008 by the American College of Rheumatology
Arthritis Care & Research
Volume 59, Issue 12, pages 1832–1834, 15 December 2008
How to Cite
Kaiser, R., Connolly, K., Linker, C., Maldonado, J. and Fye, K. (2008), Stem cell transplant for myelodysplastic syndrome–associated histiocytoid sweet's syndrome in a patient with arthritis and myalgias. Arthritis & Rheumatism, 59: 1832–1834. doi: 10.1002/art.24061
- Issue published online: 26 NOV 2008
- Article first published online: 26 NOV 2008
- Manuscript Accepted: 17 JUL 2008
- Manuscript Received: 5 MAY 2008
- Arthritis Foundation Post-Doctoral Fellowship Award
Sweet's syndrome is an acute febrile neutrophilic dermatosis first described by Robert Sweet in 1964 (1). It can occur as an idiopathic entity but can also be drug induced or associated with a number of malignancies (2). Eighty-five percent of associated malignancies are hematologic, most commonly acute myelogenous leukemia (AML) (3). The diagnosis is based upon the presence of the single major criterion and 2 of 4 minor criteria. The major criterion is histologic demonstration of a neutrophilic dermatosis without evidence of vasculitis (2). The minor criteria include 1) a fever >38°C, 2) association with malignancy or connective tissue disease, 3) an excellent response to corticosteroid or potassium iodide therapy, and 4) an elevated erythrocyte sedimentation rate or leukocytosis.
Sweet's syndrome is also seen in patients with myelodysplastic syndromes (MDS). MDS is a group of stem cell disorders caused by disturbances in progenitor cell growth and maturation that are characterized by progressive and refractory cytopenias (4). The disorders frequently progress to AML. The decreased survival in these patients is generally due to infections related to the severe cytopenias. When Sweet's syndrome is present, it portends a poor prognosis in patients with MDS (4). The association of MDS and Sweet's syndrome with cryofibrinogenemia has been reported once previously (5).
We report a case of MDS-associated Sweet's syndrome with concomitant cryofibrinogenemia in a 57-year-old man. He proved refractory to traditional therapies (including corticosteroids, cytotoxic agents, and plasmaphoresis) and was treated with stem cell transplantation.
A 57-year-old man presented with an 18-month history of severe arthritis, myalgias, and morning stiffness lasting 30–60 minutes. He reported numbness and paresthesias of his 4th and 5th fingers bilaterally and of the bottoms of both feet. Medical history was significant only for hypertension and a remote 20 pack-year smoking history. He denied fever, sicca symptoms, gastrointestinal symptoms, or Raynaud's phenomenon. Seronegative rheumatoid arthritis was diagnosed, but despite a therapeutic regimen that included nonsteroidal antiinflammatory drugs, systemic corticosteroids, and methotrexate (up to 25 mg subcutaneously per week), he continued to experience severe arthralgias and myalgias.
Several months later, the patient developed multiple tender, raised, annular erythematous lesions on his trunk and ankles. A skin biopsy demonstrated a perivascular and interstitial infiltrate of lymphocytes, granulocytes, and histiocytes. Immunoperoxidase staining revealed a prominent population of cells of monomyelocyte lineage. The biopsy specimen was thought to be consistent with a diagnosis of histiocytoid Sweet's syndrome (6, 7). A malignancy workup, including chest radiograph, bone scan, computed tomography of the abdomen, colonoscopy, and serum protein electrophoresis and immunofixation, was negative.
The patient was then referred to the rheumatology clinic at the University of California, San Francisco. Physical examination revealed Cushingoid features with synovial proliferation of both wrists, an effusion of the left knee, and Achilles tendon tenderness bilaterally. His skin examination revealed multiple tender, erythematous, annular lesions of the trunk, neck, and upper arms (Figures 1A and B), and purpura of his elbows, knees, and toes bilaterally (Figure 1C). Rheumatoid factor, HLA–B27, antinuclear antibody, anti–cyclic citrullinated peptide antibody, double-stranded DNA antibody, complement, Russell's viper venom test, anticardiolipin antibody, anti-SSA and anti-SSB antibody, and antineutrophil cytoplasmic antibody assays were all negative or normal. Radiographs of the sacroiliac joints, hands, and feet were normal.
A bone marrow biopsy sample, obtained in January 2007 because of a persistent macrocytic anemia, demonstrated morphologic abnormalities diagnostic of myelodysplasia. Blasts were not increased, cytogenetics were normal, and myelodysplasia was classified as refractory anemia. At that time, the hematocrit was 28.9%, the erythrocyte sedimentation rate was 68 mm/hour, the C-reactive protein level was elevated at 178 mg/liter, the lactate dehydrogenase was elevated at 227 IU/liter, and the patient was found to have a cryofibrinogenemia with a cryocrit of 3%.
To control his arthralgias, myalgias, and rash, the patient required dosages of prednisone of up to 60 mg/day throughout courses of treatment with other agents. Treatments with colchicine, dapsone (175 mg daily for more than 1 year in addition to weekly subcutaneous methotrexate 25 mg), and plasmaphoresis (3 days during the first week then twice weekly for 3 weeks) followed by 1 gm of intravenous cyclophosphamide failed to control the disease enough to allow the prednisone to be tapered below 20 mg/day, even though the cryofibrinogen was successfully eliminated. Mycophenolate mofetil at a dosage of 500 mg twice daily was then added as a steroid-sparing agent but was discontinued after a few months when the patient developed pneumonia. Therefore, the patient was referred to the hematologic malignancy service at the University of California, San Francisco. Thalidomide was thought to be inadequate to treat this patient's MDS and associated symptoms; therefore, his MDS was treated with 4 monthly cycles of 5-azacytidine between July and October 2007 with complete resolution of his skin symptoms but with no improvement in his blood counts, and with a continued need for red blood cell transfusions. In addition, his rheumatic symptoms persisted without change.
In November 2007, a bone marrow sample showed 15% blasts and his myelodysplasia had progressed to refractory anemia with excess blasts (RAEB-2). His skin findings were returning on 5 mg of daily prednisone. The patient was then treated with intensive chemotherapy including idarubicin, cytarabine, and etoposide, and he achieved a complete remission of his myelodysplasia. While in remission, he received an allogeneic stem cell transplant from his sibling in February 2008. He is currently doing well overall, has not had recurrence of the skin findings or arthralgias, but is being treated for acute graft-versus-host disease.
With the characteristic rash, histology, underlying MDS, and laboratory abnormalities, our patient met the criteria required for a diagnosis of Sweet's syndrome. The presence of myalgias and purpuric patches at distal sites is not a common feature of Sweet's syndrome and prompted the evaluation for cryoglobulins and cryofibrinogen. In a retrospective study of 607 patients with cryoglobulins, Trejo et al found only 1 case of associated MDS (8). Our patient is the second with the triad of MDS, Sweet's syndrome, and cryofibrinogenemia. Watanabe et al postulated that cryofibrins, cryoproteins found in chilled serum, may be a cause of the vascular damage seen in Sweet's syndrome (5). In their own case report of a patient with neutrophilic dermatosis, cryofibrinogenemia, and MDS, Watanabe et al were able to detect cryofibrinogen deposition on blood vessel walls and their surrounding area, indicating that cryofibrinogens may contribute to vascular injury (in the absence of vasculitis).
Treatments for cryofibrinogenemia include stanozolol, streptokinase (intravenous), steroids, prednisone in combination with azathioprine, and prednisone with chlorambucil. Cyclophosphamide is usually not effective alone and plasmaphoresis may be helpful. Our patient's cryofibrinogenemia was treated effectively with cyclophosphamide, mycophenolate mofetil, and plasmaphoresis; however, many of his other symptoms persisted.
Although arthralgias occur in 33–62% of cases of Sweet's syndrome, arthritis occurs in only 10–15% of cases (9). Arthritis usually involves large joints and is asymmetric, which was the case with our patient's knee and bilateral wrist involvement. Although arthritis can occur before (as with our patient) or after the skin lesions appear, skin and joints tend to flare simultaneously (10). Radiographs are normal except for soft tissue swelling and synovial fluid is mildly inflammatory and predominantly neutrophilic (10). The etiology of arthritis in Sweet's syndrome is currently unknown.
Our patient was initially offered the option of stem cell transplant as the only known cure for MDS. The literature contains many case reports of MDS associated with Sweet's syndrome (3–5, 11–31). Standard therapies include systemic corticosteroids, colchicine, and potassium iodide, while therapies used in refractory patients include thalidomide, cyclosporine, and cyclophosphamide. Only 2 of these case reports were treated with stem cell transplantation (15, 22), and both of these transplants were performed in the setting of acute leukemic transformation. When our patient's MDS progressed to RAEB-2, he underwent induction therapy and received a stem cell transplant.
Dr. Kaiser had full access to all of the data in the study and takes responsibility for the integrity of the data.
Study design. Kaiser, Fye.
Acquisition of data. Kaiser.
Analysis and interpretation of data. Kaiser.
Manuscript preparation. Kaiser, Connolly, Linker, Maldonado, Fye.