Low-dose methotrexate and severe neutropenia in patients undergoing renal dialysis.
код для вставкиСкачать1060 LETTERS Low-dose methotrexate and severe neutropenia in patients undergoing renal dialysis To the Editor: We administered a single dose of 2.5 mg of methotrexate (MTX) to 2 patients undergoing renal dialysis, 1 with severe rheumatoid arthritis ( R A ) and the other with polymyositis (PM) and scleroderma, in an effort to treat severe and life-threatening complications of their inflammatory diseases. Even though the dose of MTX was smaller than that usually administered, both patients developed severe neutropenia. and 1 patient developed thrombocytopenia. One of the patients died of complications of infection after bone marrow recovery. Patient I . a 52-year-old woman, was receiving continuous ambulatory peritoneal dialysis (CAPD) for renal failure secondary to hypertension. Hemodialysis was initiated in 1983 and was switched to CAPD when all hemodialysis access sites were exhausted. RA had been present since 1970, with severe involvement of her hands and knees. She was homebound and required full-time care. Because increasing wrist and hand synovial thickening hindered independent performance of the mechanics of CAPD, prednisone therapy (20 mglday) was begun. Disease-modifying agents were also recommended. MTX was selected, and 2.5 mg of this agent was administered on March 2. 1989 (Table I ) . Her blood urea nitrogen (BUN) level was 44 mgldl, creatinine level 10.7 mgldl, albumin level 2.5 gm/dl. and the results of liver enzyme tests were normal. On March 3 and 4. pharyngitis and oral ulcerations developed. On March 6, a rash appeared, and the patient sought medical care and was hospitalized for parenteral hydration, mouth care, and analgesia. Laboratory findings at admission included a normal white blood cell (WBC) count and normal differential and platelet counts, but on March 8 the WBC count had decreased to 2,000/rnrn3. Lcucovorin and appropriate antibiotics were prescribed. and isolation techniques were started when bacteremia was discovered. Charcoal hemoperfusion also was begun. The bone marrow recovered 15 days postadmission, but the patient had persistent fever, and her condition slowly deteriorated. She died of cardiac arrest 3 weeks after bone marrow recovery. At autopsy, a large subdiaphragmatic abscess was discovered. Patient 2 was a 47-year-old woman with systemic sclerosis. PM and renovascular hypertension developed in December 1988. approximately 4 years after the onset of Raynaud's phenomenon and tight skin. Dialysis was started because of increasing renal failure in spite of antihypertensive treatment. On February 9, 1989. she was transferred to our hospital, where dialysis was continued. Laboratory data on admission included a BUN level of 44 mgldl. a creatinine level of 6.9 mg/dl, an albumin level of 3.2 mgldl, and normal findings on liver enzyme tests. Her hospital stay was complicated by persistent fever, which returned to normal when azathioprine, used for the treatment of PM. was discontinued. Because of the continued muscle weakness, elevated creatine phosphokinase (CPK) values ( - 5 0 0 normalized units/ dl), and the patient's unwillingness to take additional prednisone, a single dose of MTX. at 2.5 mg. was administered on Arthritis and Rheumatism, Vol. 33, No. 7 (July 1990) February 27, 1989. The patient was then released for outpatient hernodialysis at another facility. On discharge, her hemoglobin level was 9.4 gm. her WBC count was 4,900/mm3 with 70% segmented neutrophils, and her platelet count was 172,000/mm3. Her medications upon discharge included labetalol (300 mg twice a day), enalapril (20 mg 3 times a day). clonidine (0.2 mglday as a weekly patch). nifedipine (30 mg 3 times a day), and prednisone (I0 mg/day). At home while receiving outpatient dialysis. the patient developed fever. A chest radiograph revealed pneumonitis. and antibiotics were administered. A complete blood cell count on March 8 revealed a hemoglobin level of 8.0 mgldl, a WBC count of 1,900/mm3 with 42% segmented neutrophils, and a platelet count of 271.~00/mm~. The WBC count ranged from 1,500/mm3 to 2,600/mm3 until March 15. when it increased to 5.200/mm3. The lowest percent of polymorphonuclear leukocytes found was 33%. l h e hemoglobin level also increased, to 9.4 gm. MTX levels were not determined, and leucovorin was not administered. We are aware of the potential adverse effects of MTX in patients with renal disease; however, our patients' need for prompt amelioration of their inflammatory diseases necessitated treatment with a disease-modifying drug, and unusually low doses of MTX were used. The patient with RA had clinically active disease and was receiving 20 mg of prednisone daily. which allowed her to use her hands to perform peritoneal dialysis exchanges. Azathioprine therapy was discussed, but the longer time for therapeutic results to be realized with this agent prompted selection of MTX. The second patient had renal failure secondary to renovascular hypertension due to scleroderma and PM, which limited her ability to ambulate. Her muscle weakness slowly improved with azathioprine and prednisone therapy until the onset of daily fever. which was thought to be a side effect of the arathioprine, necessitated the cessation of that drug. MTX was administered only when the patient refused additional prednisone medication and when CPK levels and muscle weakness increased. Potential side effects and merits of alternative therapy were discussed with both patients. In 1988. Janknegt et a1 ( I ) described the pharrnacokinetics of MTX in a CAPD-treated patient with severe psonasis. Flfteen milligrams of M l X was administered intravenously, with "very good" clinical response. Nonrenal clearance of MTX appeared to be important in their patient; enterohepatic excretion of MTX has been described previously ( 2 4 ) . In spite of temporary neutropenia and thrombocytopenia. it was suggested that lower doses of MTX might provide adequate therapeutic response with greater safety in patients undergoing renal dialysis. We used leucovorin in the first patient, administering as much as 75 mglday orally, although it was not started until 6 days after the MTX administration. Its effectiveness in reducing the bone marrow depression was uncertain (Table 1). We had considered interrupting enterohepatic circulation in this patient with orally administered charcoal or cholestyramine. but decided against this treatment because of the presence of oral mucositis. In retrospect, nasogastric instillation of cholestyramine might have been valuable. Cholestyramine binds MTX in vitro. and has been used therapeutically in 2 patients receiving high-dose MTX (3). Nurnberg et a1 have recently demonstrated biliary clearance of MTX at I5 ml/minute in an RA patient with a biliary fistula (4). The second patient recovered without the use of LETTERS 1061 Table 1. Laboratory findings in patient I . who was receiving continuous ambulatory peritoneal dialysis, after treatment with a single dose of oral methotrexate followed by leucovorin rescue. Date Drug 3/2/89 3/6/89t 3/8/89 3/9/89$ 31 I0/89+ 311 4/89 3/16/89 3120189 2.5 mg MTX 75 mg leucovorin 75 mg leucovorin 75 mg leucovorin 75 mg leucovorin - - Serum MTX level. pmolesniter 0.12 0.09 0.13 0.10 0.02 ND co.01 WBC, Hgb. gm/dl x 10’/mm’ Platelets. (% segments) x IO’lmm’ 10.7 11.0 ND 10.0 7.0 6. I 9.0 9.2 (81) 2.0 (SO) 1.8 (61) 0.8 (15) 0.5 (24) 3.1 (30) 10.0 (27) 323 270 ND I50 99 35 71 * Serum methotrexate (MTX) levels were determined by fluorescence polarization on a TDX, using Abbott reagents (Abbott Laboratories. North Chicago. IL). Hgb = hemoglobin; WBC = white blood cells; ND = not determined. t Date of hospital admission. $ Charcoal hemoperfusion was performed. leucovorin or hemoperfusion. She was continued on her regimen of hemodialysis 3 times a week, with antibiotic use and standard isolation techniques. Her PM improved and CPK levels normalized without additional treatment and have remained constant for more than 5 months post-MTX administration. The final decision to use MTX in the 2 patients described was made only after a lengthy discussion with colleagues and a review of the report by Janknegt et al(1). It was our impression that, under extenuating circumstances. other rheumatologists are using or might consider using MTX in patients similar to the 2 described here. However. this report documents the catastrophic events we encountered. Oral administration of MTX in renal dialysis patients seems equivalent to continuous infusion of the drug, since there are few effective means for removing MTX from body fluids without adequate renal function. MTX is poorly cleared with hernodialysis and cleared even less with peritoneal dialysis (5). Cholestyramine administration was not used in our patients but may be of some value in providing nonrenal clearance of MTX (3,4). Measurements of MTX levels and earlier leucovorin administration might have helped our first patient, but our overall experience with both patients has convinced us that MTX cannot be used safely in renal dialysis patients. Michael H. Ellman. MD Susan Hou, MD Michael Reese Hospital and Medical Center Chicago, IL David Ginsberg. MD Highland Park Hospital Highland Park, IL I . Janknegt R , Nube MI. van den Hoogenband HM. Oldenhof HGJ. Steenhoek A. Vree TB: Pharmacokinetics of methotrexate in continuous ambulatory peritoneal dialysis. Pharm Weekbl [Sci] 10:8689, 1988 2. Steinberg SE, Campbell CL, Bleyer WA. Hillman RS: Enterohepatic circulation of methotrexate in rats in vitro. Cancer Res 42:127%1282, 1982 3. Erttmann R, Landbeck G : Effect of oral cholestyramine on the elimination of high-dose methotrexate. J Cancer Res Clin Oncol I10:48-50, 1985 4. Nurnberg B. Jacobi A. Faulkner R, Koehnke R. Hoffman I. Furst D: Biliary elimination of low dose methotrexate in man (abstract). Arthritis Rheum 31 (suppl 4):S116. 1988 5 . Thierry FX. Vernier I . Dueymes JM.Roche H, Canal P. Meeus F. Pourrat JP, Conte JJ: Acute renal failure after high-dose methotrexate therapy (letter). Nephron 51:416417, 1989 Nonsteroidal antiinflammatory drugs and the lupus anticoagulant To the Editor: The lupus anticoagulant (LAC), found in patients with systemic lupus erythematosus (SLE) and diverse other conditions, has recently been the focus of much attention ( 1-3). LAC is a phospholipid-specific immunoglobulin that interferes in vitro with the activation of prothrombin (4). Paradoxically, the anticoagulant has been associated not with bleeding, but with arterial and venous thromboses and fetal loss. Multiple mechanisms may underlie its pathogenicity. and questions concerning therapy remain unresolved. We report a case of SLE in which the nonsteroidal antiinflammatory drug (NSAID) ibuprofen may have protected against LAC-related complications. The patient, a SO-year-old man, was admitted to the hospital in April 1985 with headache and visual disturbance. He had a history of pericarditis and Raynaud’s phenomenon, and, for many years, was treated for arthralgias with ibuprofen alone. A few weeks previously. the patient had stopped taking the drug because he believed it to be ineffective. Noteworthy findings on physical examination included visual field defects, adenopathy. and splenomegaly. Laboratory findings included anemia and thrombocytopenia, antinuclear and anti-native DNA antibodies, and a markedly prolonged partial thromboplastin time, which was not corrected by the addition of normal plasma. Computed tomography (CT) revealed a left occipital infarction. With the resumption of ibuprofen (600 mg 4 times a day) and the institution of prednisone at an initial dosage of 80 mglday, the patient did well. In March 1986, the ibuprofen was discontinued be-
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