systemic vasculitis and myelodysplastic syndromes. a report of two cases

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ARTHRITIS L RHEUMATISM Vol. 40, No. 1, January 1997, pp 179-182 0 1997, American College of Rheumatology 179 SYSTEMIC VASCULITIS AND MYELODYSPLASTIC SYNDROMES A Report of Two Cases BRUNO PHILIPPE, LOUIS-JEAN COUDERC, DOMINIQUE DROZ, FREDERIC CHARLOTTE, GEORGES CHOUKROUN, BERNARD EPARDEAU, OLIVIER BLETRY, ISABELLE CAUBARRERE, BRUNO VARET, and OLIVIER HERMINE Two cases of systemic vasculitis associated with myelodysplastic syndromes are reported. Vasculitis may develop either before or after the diagnosis of a hema- tologic disorder, and it responds to treatment with high-dose corticosteroids. Myelodysplasticsyndromes (MDS) are character- ized by cytopenia and histologic features of hematopoi- etic dysplasia. The natural history of MDS varies widely, ranging from chronic anemia with a low propensity for leukemic conversion to disorders characterized by pro- found disturbances in blood cell production with a high risk of progression to acute leukemia or bone marrow failure. These syndromes are classified according to morphologic features and bone marrow blast cell counts (1). Some reports have suggested that MDS may be accompanied by immune disorders (2). Few cases of MDS associated with cutaneous vasculitides have been previously reported (3-6). We describe 2 patients with systemic vasculitis. One had refractory anemia with excess blasts and the other had refractory anemia, both of which are subtypes of MDS (1). CASE REPORTS Patient 1. In June 1992, a 68-year-old man developed pruritic erythematous papules on his back, shoulders, neck, Bruno Philippe, MD: Pneumologie Hapita1 Foch, Suresnes et Universite Paris-Ouest, Suresnes, and Hapita1 Necker, Paris, France; Louis-Jean Couderc, MD, Bernard Epardeau, MD, Olivier Bletry, MD, Isabelle Caubarrere, MD: HBpital Foch, Suresnes et Universite Paris-Ouest, Suresnes, France; Dorninique Droz, MD, Georges Choukroun, MD, Bruno Varet, MD, Olivier Hermine, MD: Hapita1 Necker, Paris, France; Fredtric Charlotte, MD: Hopital La PitiC Salpttritre, Paris, France. Address reprint requests to Louis-Jean Couderc, MD, Service de Pneumologie, Hapita1 Foch, 40 rue Worth, 92150 Suresnes, France. Submitted for publication February 26, 1996; accepted in revised form July 15, 1996. - and head. Skin biopsy revealed a perivascular cellular infiltrate made up of small lymphocytes and histiocytes in the dermis, with infiltration of the capillary vessel walls without leukocy- toclasia. Direct immunofluorescence showed no immunoglob- ulin or complement deposition. Laboratory tests showed mild anemia, with a hemoglo- bin level of 93 gmiliter. The white blood cell (WBC) count was 3.08 X lOY/liter, with 37% neutrophils, 56% lymphocytes, 4% monocytes, and 7% eosinophils, and the platelet count was 123 X 10’iliter. Bone marrow aspiration showed normal cellularity, with reduced segmentation and granulation of granulocytes and 5% of blasts, consistent with refractory anemia with excess blasts (1). No cytogenetic abnormality was detected. The patient received red blood cell transfusions and prednisolone, 40 mg/day, with the dosage tapered over 15 days. The cutane- ous lesions regressed within 3 days. One year later, the patient complained of an enlarged right testis and blood in his urine. No cutaneous lesion was identified. Biopsy of the epididymis showed characteristic interstitial lesions of vasculitis. Larger arteries showed fibrin- oid necrotic foci of the vessel wall and parietal thrombosis. The vessel wall was infiltrated with polymorphic inflammatory cells including polymorphonuclear neutrophils, with leukocytoclasia (Figure 1). At this time, his serum creatinine level rose to 1,045 Kmolesiliter. A transjugular renal biopsy specimen revealed exten- sive polymorphic interstitial cellular infiltration composed of lymphocytes,plasma cells, polymorphonuclear cells, and eosino- phils, as well as interstitial hemorrhage in the medulla. The arterioles and arteries were normal, the glomeruli were isch- emic, and epithelial cell necrosis was observed in the tubules. Direct immunofluorescence revealed IgA-containing intersti- tial plasma cells and C3 deposits in the vessels. No antibodies to human immunodeficiency virus, hu- man T lymphotropic virus type I, hepatitis A, B, and C viruses, cytomegalovirus, Toxoplasma, or Mycoplasma pneumoniae were detected. The results of immunologic tests for antinuclear antibodies, rheumatoid factor, cryoglobulins, immunoglobulin levels, Coombs’ test, total hemolytic complement, C3, C4, antineutrophil cytoplasmic antibodies (ANCA), and antiglo- merular basement membrane antibodies were negative or normal. No monoclonal protein was detected by serum immunoelectrophoresis.

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Page 1: Systemic vasculitis and myelodysplastic syndromes. A report of two cases

ARTHRITIS L RHEUMATISM Vol. 40, No. 1, January 1997, pp 179-182 0 1997, American College of Rheumatology 179

SYSTEMIC VASCULITIS AND MYELODYSPLASTIC SYNDROMES

A Report of Two Cases

BRUNO PHILIPPE, LOUIS-JEAN COUDERC, DOMINIQUE DROZ, FREDERIC CHARLOTTE, GEORGES CHOUKROUN, BERNARD EPARDEAU, OLIVIER BLETRY, ISABELLE CAUBARRERE,

BRUNO VARET, and OLIVIER HERMINE

Two cases of systemic vasculitis associated with myelodysplastic syndromes are reported. Vasculitis may develop either before or after the diagnosis of a hema- tologic disorder, and it responds to treatment with high-dose corticosteroids.

Myelodysplastic syndromes (MDS) are character- ized by cytopenia and histologic features of hematopoi- etic dysplasia. The natural history of MDS varies widely, ranging from chronic anemia with a low propensity for leukemic conversion to disorders characterized by pro- found disturbances in blood cell production with a high risk of progression to acute leukemia or bone marrow failure. These syndromes are classified according to morphologic features and bone marrow blast cell counts (1). Some reports have suggested that MDS may be accompanied by immune disorders (2).

Few cases of MDS associated with cutaneous vasculitides have been previously reported (3-6). We describe 2 patients with systemic vasculitis. One had refractory anemia with excess blasts and the other had refractory anemia, both of which are subtypes of MDS (1).

CASE REPORTS

Patient 1. In June 1992, a 68-year-old man developed pruritic erythematous papules on his back, shoulders, neck,

Bruno Philippe, MD: Pneumologie Hapita1 Foch, Suresnes et Universite Paris-Ouest, Suresnes, and Hapita1 Necker, Paris, France; Louis-Jean Couderc, MD, Bernard Epardeau, MD, Olivier Bletry, MD, Isabelle Caubarrere, MD: HBpital Foch, Suresnes et Universite Paris-Ouest, Suresnes, France; Dorninique Droz, MD, Georges Choukroun, MD, Bruno Varet, MD, Olivier Hermine, MD: Hapita1 Necker, Paris, France; Fredtric Charlotte, MD: Hopital La PitiC Salpttritre, Paris, France.

Address reprint requests to Louis-Jean Couderc, MD, Service de Pneumologie, Hapita1 Foch, 40 rue Worth, 92150 Suresnes, France.

Submitted for publication February 26, 1996; accepted in revised form July 15, 1996.

-

and head. Skin biopsy revealed a perivascular cellular infiltrate made up of small lymphocytes and histiocytes in the dermis, with infiltration of the capillary vessel walls without leukocy- toclasia. Direct immunofluorescence showed no immunoglob- ulin or complement deposition.

Laboratory tests showed mild anemia, with a hemoglo- bin level of 93 gmiliter. The white blood cell (WBC) count was 3.08 X lOY/liter, with 37% neutrophils, 56% lymphocytes, 4% monocytes, and 7% eosinophils, and the platelet count was 123 X 10’iliter. Bone marrow aspiration showed normal cellularity, with reduced segmentation and granulation of granulocytes and 5% of blasts, consistent with refractory anemia with excess blasts (1). No cytogenetic abnormality was detected. The patient received red blood cell transfusions and prednisolone, 40 mg/day, with the dosage tapered over 15 days. The cutane- ous lesions regressed within 3 days.

One year later, the patient complained of an enlarged right testis and blood in his urine. No cutaneous lesion was identified. Biopsy of the epididymis showed characteristic interstitial lesions of vasculitis. Larger arteries showed fibrin- oid necrotic foci of the vessel wall and parietal thrombosis. The vessel wall was infiltrated with polymorphic inflammatory cells including polymorphonuclear neutrophils, with leukocytoclasia (Figure 1). At this time, his serum creatinine level rose to 1,045 Kmolesiliter.

A transjugular renal biopsy specimen revealed exten- sive polymorphic interstitial cellular infiltration composed of lymphocytes, plasma cells, polymorphonuclear cells, and eosino- phils, as well as interstitial hemorrhage in the medulla. The arterioles and arteries were normal, the glomeruli were isch- emic, and epithelial cell necrosis was observed in the tubules. Direct immunofluorescence revealed IgA-containing intersti- tial plasma cells and C3 deposits in the vessels.

No antibodies to human immunodeficiency virus, hu- man T lymphotropic virus type I, hepatitis A, B, and C viruses, cytomegalovirus, Toxoplasma, or Mycoplasma pneumoniae were detected. The results of immunologic tests for antinuclear antibodies, rheumatoid factor, cryoglobulins, immunoglobulin levels, Coombs’ test, total hemolytic complement, C3, C4, antineutrophil cytoplasmic antibodies (ANCA), and antiglo- merular basement membrane antibodies were negative or normal. No monoclonal protein was detected by serum immunoelectrophoresis.

Page 2: Systemic vasculitis and myelodysplastic syndromes. A report of two cases

180 PHILIPPE ET AL

Figure 1. Epididymis biopsy of patient 1, showing fibrinoid necrosis and a prominent neutrophil infiltrate, with leukocytoclasia (arrows) of the arterial wall. M = media; L = lumen (hematoxylin and eosin stained, original magnification X 160). Figure 2. Lung biopsy of patient 2, showing infiltration of small vessel

walls by small lymphocytes and some polymorphonuclear leukocytes (hematoxylin and eosin stained, original magnification X 160).

The patient underwent 4 hemodialysis sessions, and he was treated with prednisone, 60 mg/day. Within 1 week, the testis appeared normal. Bone marrow cytology did not show a progression of the refractory anemia with excess blasts. The first year of followup was marked by several relapses of the cutaneous vasculitis after the prednisone dosage had been tapered to 30 mg/day for 6 months. Danazol, 600 mg/day, was begun, which made it possible to decrease the corticosteroids to 20 mg/day. The followup course was unremarkable over the next 2 years.

Patient 2. A 27-year-old man complained of dyspnea of 3 years' duration. In 1993, a chest radiograph and thoracic computed tomography scan showed diffuse bilateral interstitial infiltrates. Bronchoalveolar lavage showed a total of 144 X 103/ml alveolar cells, with 28% lymphocytes, 21% neutrophils, 1% eosinophils, and 50% alveolar macrophages (60% sid- erophages). Findings of special stains and cultures for patho- gens were negative. Open lung biopsy showed neutrophil polymorphonuclear foci and small lymphocytes, with destruc- tion of small vessel walls (Figure 2).

The patient's creatinine level and urinary sediment were normal. Results of the same immunologic and virologic tests as in patient 1 were negative or normal. His hemoglobin level was 60 gm/liter, the WBC count was 3.5 X 109/1iter, with 43% neutrophils, 40% lymphocytes, 8% eosinophils, and 6% monocytes, and the platelet count was 125 X lO'/liter. Fetal hemoglobin was increased to 8.1% (normal <2%).

Bone marrow aspirate was normocellular; granulopoi- esis was hypoplastic, with a reduction in segmentation and granulation of the granulocytes but no excess blasts. The bone marrow progenitor culture at day 10 showed virtually no granulocyte-macrophage colony-stimulating factor and 24 clusters/lO' mononuclear cells, consistent with a diagnosis of refractory anemia (1). Cytogenetic analysis gave normal results.

Fifteen days after the open lung biopsy, the patient's

dyspnea worsened. His temperature was 39"C, and a chest radiograph showed diffuse bilateral alveolar and interstitial opacities (Figure 3). Arterial blood gases obtained while the patient was breathing room air showed mild hypoxemia (Pao,

Figure 3. Chest radiograph of patient 2, showing diffuse alveolar and interstitial opacities bilaterally.

Page 3: Systemic vasculitis and myelodysplastic syndromes. A report of two cases

SYSTEMIC VASCULITIS AND MYELODYSPLASTIC SYNDROMES 181

70 mm Hg, Paco, 35 mm Hg). A blood transfusion was not done because of the patient’s religious beliefs. He was given 500 mg of methylprednisolone per day, intravenously, for 2 days, then oral prednisone 50 mg/day. His fever and dyspnea disappeared, and the Pao, increased to 97 mm Hg, within 48 hours. Simultaneously, the size of the pulmonary opacity decreased. He was discharged from the hospital on a regimen of 40 mg of prednisone daily, and was lost to followup.

DISCUSSION

Vasculitis associated with a malignancy is a well known event which occurs more often in association with hematologic diseases (particularly hairy cell leukemia) than with solid neoplasms (3,7). These vasculitides usu- ally affect the skin and joints, but rarely other organs (3-6). Vasculitis may develop either before or after the hematologic disorder is diagnosed. There have been only a few reports of suspected systemic vasculitis with lung involvement or the presence of ANCA in MDS patients (8-10).

The clinical and histologic profile of patient 1 was consistent with a diagnosis of macroscopic periarteritis nodosa, which has never been reported in MDS (8). Such a pathologic aspect has been described only in hairy cell leukemia (9). Consistent with this diagnosis, our patient did not have ANCA. The second patient presented with alveolar hemorrhage complicating the pulmonary vasculitis with no systemic involvement, and no ANCA was demonstrated. A similar vasculitis limited to the lungs has been recently reported (11).

The mechanisms underlying vasculitis remain un- known. One hypothesis would be an activation of B cells and the synthesis of organ-specific and non-organ- specific autoantibodies, which in 1 study (2), were present in 15 of 67 patients tested (22%). However, Savige et a1 (12) could not demonstrate a consistent relationship between the presence of ANCA and MDS- associated vasculitis, since only 1 of 25 patients with MDS was positive for ANCA. Another explanation has been suggested for the potential role of either autore- active T cells or autoantibodies which may sometimes occur in MDS (2). Another possibility would be that immune complexes are involved. Indeed, macrophage function is severely impaired, which results in decreased immune complex clearance (13). In addition, neutrophil chemotaxis could be accompanied by oxide anion hyper- production, which implies organ injury, such as that described in Sweet’s syndrome with lung involvement (14). Finally, another hypothesis may be that bone marrow changes play a significant role in the etiology of vasculitis (10).

Some authors have reported a worse prognosis for MDS associated with vasculitis (4). In most cases, vasculitis responded dramatically to steroids and did not usually require the addition of other immunosuppressive therapies, which may worsen MDS-related cytopenia (12,15). Consistent with these findings, and despite severe and life-threatening systemic involvement, our 2 patients responded to corticosteroid treatment. How- ever, the skin involvement in patient l recurred when the corticosteroid dosage was tapered. We therefore successfully used danazol as an immunomodulating agent (16) to prevent the recurrence of systemic involve- ment. In our 2 patients, treatment of the vasculitis had no effect on the course of the MDS.

In conclusion, our 2 patients showed clear biopsy evidence of lung and testicle involvement by vasculitis. Therefore, patients with apparently idiopathic systemic vasculitis should be evaluated for underlying MDS as well as for other well-known causes. Furthermore, in the 2 cases reported here, systemic vasculitis did not seem to be associated with a worse prognosis and responsed to high-dose corticosteroids.

ACKNOWLEDGMENT

The authors thank Ms G. Flohic for secretarial assistance.

REFERENCES

1.

2.

3.

4.

5 .

6 .

7.

8.

9.

Bennet JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralmick HR, Sulton C, French-American-British (FAB) Coop- erative Group: Proposals for the classification of the myelodys- plastic syndromes. Br J Haematol 51:189-199, 1982 Mufti GJ, Figes A, Hamblin TJ, Oscier DG, Copplestone J A Immunological abnormalities in myelodysplastic syndromes. Br J Haematol 63:143-147, 1986 Greer JM, Longley S, Edwards NL, Elfenbein GJ, Panush RS: Vasculitis associated with malignancy. Medicine (Baltimore) 67: 220-230, 1988 Castro M, Conn DL, Daniel Su WP, Garton JP: Rheumatic manifestations in myelodysplastic syndromes. J Rheumatol 18: 721-727, 1991 Green AR, Shuttleworth D, Bowen DT, Bentley D P Cutaneous vasculitis in patients with myelodysplasia. Br J Haematol 74:364- 370, 1990 Longley S, Caldwell JR, Panush RS: Paraneoplastic vasculitis: unique syndrome of cutaneous angiitis and arthritis associated with myeloproliferative disorders. Am J Med 80:1027-1030, 1986 Lacour JP, Castanet J, Perrin C, Vitteta A, Ortonne JP: Cutaneous leukocytoclastic vasculitis and renal cancer: two cases. Am J Med

Zeek PM: Periarteritis nodosa and other forms of necroziting angeiitis. N Engl J Med 248:764-772, 1953 Elkon KB, Hugues GRV, Catovsky D, Clauvel JP, Dumont J, Seligmann M, Fannenbaum H, Esdaile J: Hairy cell leukemia with polyarteritis nodosa. Lancet 2:280-282, 1979

94:104-108, 1993

Page 4: Systemic vasculitis and myelodysplastic syndromes. A report of two cases

182 PHILIPPE ET AL

10. Kuzmich PV, Ecker GA, Kdrsh J: Rheumatic manifestations in patients with myelodysplastic and myeloproliferative diseases. J Rheumatol 21:1649-1654, 1994

11. Jennings C, Tuder R, Cherniack RM, King TE, Schwarz MI: Pauciimmune pulmonary capillaritis and diffuse alveolar haemor- rhage: a vasculitic process limited to the lungs. Am J Respir Crit Care Med 151:A199, 1995

12. Savige JA, Chang L, Smith CC, Duggan JC: Myelodysplasia, vasculitis and antineutrophil cytoplasm antibodies. Leuk Lym- phoma 9:49-54, 1993

13. Komiya I, Tanoue K, Kakimura K, Kaneda M, Shimohara T,

Kuriya S, Nomura T, Saito Y: Superoxyde anion hyperproduction by neutrophils in a case of myelodysplastic syndrome. Cancer

14. Zwierznia H, Sepp N, Ringler E, Schmalzl S: Delayed maturation of skin window macrophages in myelodysplastic syndromes. Leuk Res 6:433-435, 1989

15. Warren AJ, Hedge UM, Nathwani A, Reilly IAG: Systemic vasculitis and myelodysplasia. Br J Haematol 74:627-629, 1990

16. Chabanon C, Molina L, Pegourie-Bandelier B, Bost M, Leger J, Hollard D: A review of 76 patients with myelodysplastic syndromes treated with danazol. Cancer 73:3073-3080, 1994

67:2337-2341, 1991