- Email: [email protected]
Pure red cell aplasia and lupus
Pure Red Cell Aplasia and Lupus George S. Habib, Walid R. Saliba, and Paul Froom Objective: To review the clinical and laboratory features of all reported patients with systemic lupus erythematosus (SLE) and pure red cell aplasia (PRCA). Methods: In addition to our patient, we identified cases reported during the years 1966-2000 by searching the MEDLINE literature (Winspirs). Clinical and laboratory features were compared with those reported in large series of patients with SLE but without PRCA. Results: Twenty-three additional cases were identified. In most cases, SLE was diagnosed either before or concomitantly with the diagnosis of PRCA. The clinical and laboratory features were not significantly different from those reported in large series of patients with SLE, except for less pleuritis and a trend toward less proteinuria, hallucinations, thrombopenia, and leukopenia. The natural history of PRCA and SLE was similar to that reported for PRCA alone. The disease responded to prednisone in the majority of cases, but patients frequently remained steroid dependent. Conclusions: The association between SLE and PRCA is rare. The clinical and laboratory features of SLE in such patients are similar to SLE patients without PRCA with the exception of a decreased frequency of pleuritis. Response to treatment of PRCA in those with SLE is similar to patients with PRCA but without SLE. Semin Arthritis Rheum 31:279-283. Copyright 2002, Elsevier Science (USA). All rights reserved. INDEX WORDS: Systemic lupus erythematosus; pure red cell aplasia; clinical features; laboratory findings.
P
URE RED CELL APLASIA (PRCA) is characterized by normochromic normocytic anemia and reticulocytopenia, with aplasia or severe hypoplasia of the red cell line with normal white cell and megakaryocyte lines in the bone marrow (1). PRCA may be associated with other conditions (2), but the association with systemic lupus erythematosus (SLE) is rare, and no systematic review has been published previously. Here we report a case of PRCA in a patient with SLE and summarize the previous cases reported in the English literature. METHODS
A MEDLINE search (Winspirs) was done from the years 1966 through 2000. The key words included lupus, erythroid, aplasia, hypoplasia, red cell, and anemia in various combinations. Only reports written in English were included. Cases had an established diagnosis of PRCA (1) and met the American College of Rheumatology classification
criteria for the diagnosis of SLE (3). Clinical characteristics, laboratory test results, treatment and outcome were extracted from the papers and summarized.
From the Department of Internal Medicine B, Carmel Medical Center, Haifa, Israel, and the Department of Epidemiology, Sackler Medical School, Tel Aviv University, Ramat Aviv, Israel. George S. Habib, MD: Clinical Instructor, Faculty of Medicine, Technion-Israel Institute of Technology, and Department of Internal Medicine B, Carmel Medical Center, Haifa, Israel; Walid R. Saliba, MD: Medical Resident, Department of Internal Medicine B, Carmel Medical Center, Haifa, Israel; and Paul Froom, MD: Associate Professor, Department of Epidemiology, Sackler Medical School, Tel Aviv University, Ramat Aviv, Israel. Address reprint requests to George S. Habib, MD, Department of Internal Medicine B, Carmel Medical Center, 7 Michal St, Haifa, 34362, Israel. E-mail: [email protected] Copyright 2002, Elsevier Science (USA). All rights reserved. 0049-0172/02/3104-1051$35.00/0 doi:10.1053/sarh.2002.30440
Seminars in Arthritis and Rheumatism, Vol 31, No 4 (February), 2002: pp 279-283
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Case Presentation A 31-year-old woman with a 1-month history of arthritis, skin rash, photosensitivity, and oral sores presented to the emergency room with progressive dyspnea on effort and a fever of 7 days’ duration. On physical examination she was in mild distress and looked pale. Her body temperature was 38.5°C, her pulse was 105/m, and her blood pressure was 90/50 mm Hg. There was a mild systolic cardiac murmur at the apex, and her lungs were clear. She had synovial swelling and tenderness of the proximal interphalangeal joints, wrists, and elbows and tenderness of the metacarpophalangeal joints and knees. Diffuse erythematous papules were seen on her face and upper chest, and there were a few aphthous lesions in the mouth. Laboratory results were as follows: hematocrit, 16%; hemoglobin (Hgb), 50 g/L; MCV, 81 fL; WBC, 3.3 ⫻ 109/L with 0.69 segments, 0.22 lymphocytes, and 0.06 bands; platelets, 400,000 109/L; erythrocyte sedimentation rate (Westergren) 110 mm/ hr; creatinine, 0.7 mg/dL; total bilirubin, 0.4 mg/dL; haptoglobin, 111 mg/dL (normal range, 27-139); reticulocytes, 0.2%; erythropoietin (EPO) activity, 255 mu/mL (normal ⬍19); and direct and indirect Coomb’s tests were negative. Antinuclear antibodies were positive (titer, 1:128), and antiDNA antibodies were 60 U/mL (normal ⬍30). No antibodies were found to extranuclear proteins or cardiolipins. C3 was 55 mg/dL (normal range, 80-180), and C4 was ⬍8 mg/dL (normal, 15-40). Rheumatoid factor and veneral disease research laboratory (VDRL) were negative, and hepatitis B surface antigen (HbsAg) antibodies to hepatitis C, parvovirus, and human immunodeficiency virus were not found. Thoracic computerized tomography did not reveal any masses. Bone marrow
biopsy showed normal cellularity with nearly total absence of erythroid precursors and normal megakaryocyte and myeloid lines. Iron stores were increased. The patient was transfused with 3 U red packed cells and started on 60 mg/d prednisone. Ten days after starting therapy, the reticulocyte count was 3%. The Hgb values increased gradually and were normal after 30 days of treatment. Subsequently, hydrochloroquine 200 mg twice per day was added, and corticosteroids (CS) were tapered gradually and stopped after 9 months. She remained well without anemia or symptoms associated with SLE over the next 12 months. LITERATURE REVIEW
We identified 28 cases in our literature search. Five cases were excluded, 3 cases were incomplete (4), and 2 cases did not have the needed criteria for a diagnosis of SLE (5,6). Our case and the other 23 (7-27) with adequate clinical and laboratory data are included in this summary. Clinical Features Demographic variables and Hgb levels of the patients are shown in Table 1. One patient with a Hgb level of 10 g/L at the time of PRCA diagnosis was transfusion dependent. In those cases in which SLE diagnosis preceded the diagnosis of PRCA (12 cases), the time range was between 6 weeks to 12 years, and when the diagnosis of SLE followed the diagnosis of PRCA (4 cases), the time range was between 2 months to 4 years. Pleuritis was significantly less frequent in those with PRCA compared to SLE patients in general (20% [4/20] v 44% [433/984], respectively, P ⬍ .05)(3,28-31). We excluded 4 patients in this comparison because they presented with PRCA before
Table 1: Selected Characteristics of 24 Patients With PRCA and SLE Demographic and Laboratory Variables Women (%) Median age at diagnosis of SLE (yr) (range) Median age at diagnosis of PRCA (yr) (range) Median Hgb at diagnosis of SLE (g/L) (range) Median Hgb at diagnosis of PRCA (g/L) (range) Simultaneous diagnosis of SLE and PRCA (patients) SLE diagnosed prior to PRCA (patients) PRCA preceded SLE diagnosis (patients)
No. (%) 23 (96) 33 (14-77) 35 (14-77) 102 (34-136) 50 (19-100) 8 (33) 12 (50) 4 (17)
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Table 2: Laboratory Profile of 24 Patients With SLE and PRCA
Laboratory Parameter
Positive Finding/Total Tested (%)
Patients With SLE Alone (%) (3, 28-31)* (n ⴝ 1,084)
Leukopenia Thrombocytopenia ANA Anti-DNA Decreased levels of C3 Anti SS-A Anti RNP Anti Sm Anticardiolipins False positive VDRL
8/22 (36) 1/22 (5) 23/24 (96) 7/18 (39) 7/13 (54) 5/10 (50) 3/7 (43) 0/7 (0) 3/5 (60) 3/8 (38)
46 20 97 46 51 25 19 15 35 16
Abbreviations: ANA, antinuclear antibodies; SS-A, Sjo¨gren syndrome A; RNP, ribonucleoprotein; Sm, Smith. *From 5 series in the literature.
the SLE. However, the proportions of other clinical features (arthritis/arthralgia, skin changes, hemolytic anemia, proteinuria, pericarditis, and hallucinations) were similar in both groups with a trend for less proteinuria and hallucinations. Of the 12 patients with an established diagnosis of SLE before the onset of PRCA, 9 patients had no symptoms, signs, or laboratory tests suggesting specific active organ involvement at the time of PRCA diagnosis. Concomitant diseases included single cases of the antiphospholipid syndrome, mixed connective tissue disease, and Sjo¨gren’s syndrome. There was 1 case of procainamide-induced SLE and 3 cases of thymoma (one of which was found only on autopsy). Laboratory Findings Laboratory findings (Table 2) of patients with SLE and PRCA were essentially identical to those of patients with SLE alone. Patients with SLE and PRCA tended to have less thrombopenia and leukopenia. There were also differences (not significant) in the proportion of patients with antibodies against extranuclear proteins and phospholipids; however, these tests were performed in only a few patients. One patient had end-stage renal disease. Special Studies There were special studies on the effect of patients’ serum (8,20-23,27) or T-cells (21,22,27) on erythroid colony growth (BFU-E) from their own (21,22,27) or control (8,21,23,27) progenitor cells. BFU-E growth was normal in all cases
(8,21,22,23,27). Serum was shown to suppress the growth of BFU-E in 1 of 3 cases (27) and in 3 of 4 controls (8,23,27). T-cell depletion decreased the suppressive effect of the serum in 1 of 3 cases (27). Testing for an inhibitory effect on EPO was performed in 2 patients and was found in 1 (25). Treatment and Outcome Follow-up for at least 6 months was possible with 19 patients. There were 2 spontaneous remissions: 1 in a patient with procainamide-induced SLE and PRCA after cessation of the medication and the other after a single blood transfusion. Of those treated with prednisone, 13 of 21 had a good response, which continued after cessation of the prednisone in 3 patients and required low doses in 10. There were 4 deaths (3 from pneumonia and 1 from pulmonary embolism); 2 occurred shortly after starting CS and 2 after 2- and 7-year followup. Two of 3 nonresponders to prednisone remitted after high-dose intravenous gamma globulin treatment, and 1 patient responded only after EPO treatment. DISCUSSION
The combination of SLE and PRCA is rare but probably underdiagnosed. The use of a reticulocyte count as a screening test with subsequent bone marrow examinations in those with reticulopenia likely would result in a higher frequency of this combination. It has been stated that renal and central nervous system involvement does not occur in those with
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concomitant SLE and PRCA (27). We found a trend for less proteinuria and hallucinations and a significant decrease in pleuritis in those with SLE and PRCA. Such comparisons should be interpreted with caution, however, because selection bias and length of follow-up might be responsible for the differences. In any case, the clinical presentation does not appear to be helpful in determining the likelihood of concomitant SLE and PRCA. The onset of PRCA did not correlate with symptoms of SLE. In fact, patients with SLE diagnosed previously had clinically inactive disease. Thus, these autoimmune phenomena occur independently for reasons unknown. The mechanism for PRCA appears to be multifactorial and is not due to defects in stem cells but rather to a suppressor effect of the immune system either through humeral or cellular mechanisms acting directly on stem cells or on EPO. A significant proportion of
SLE patients have positive anti-EPO antibodies in their serum, and the frequency of these antibodies is significantly higher in patients with severe anemia (32). T cells are also crucial in the pathogenesis of SLE, and most of the pathogenic autoantibodies are T-cell dependent (33). Infection with parvovirus B 19 has been associated with PRCA (34). Recently, 1 patient with SLE and PRCA was shown to have persistent infection with human parvovirus B 19 (35). The natural history of PRCA and SLE is similar to that of PRCA. The disease responds to prednisone in the majority of cases, but often the drug cannot be tapered completely. Furthermore, both early and late deaths occur. Experience with other agents is limited, but it appears reasonable to try high-dose immunoglobulin and EPO treatment for nonresponders. Spontaneous remission also may occur but is not common.
REFERENCES 1. Fisch P, Handgretinger R, Schaefer HE. Pure red cell aplasia. Br J Haematol 2000;111:1010 –22. 2. Mamiya S, Itoh T, Miura AB. Acquired pure red cell aplasia in Japan. Eur J Haematol 1997;59:199 –205. 3. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25:1271–7. 4. Jootar S, Srichaikul T, Atichartakarn V. Pure red cell aplasia in Thailand: report of twenty four cases. Southeast Asian J Trop Med Publc Health 1985;16:291–5. 5. Cavalcant J, Shadduck RK, Winkelatein A, Zeigler Z, Mendelow A. Red cell hypoplasia and increased bone marrow reticulin in systemic lupus erythematosus: reversal with corticosteroid therapy. Am J Hematol 1978;5:253– 63. 6. Oren ME, Cohen MS. Immune thrombocytopenia, red cell aplasia, lupus and hyperthyroidism. South Med J 1978;71: 1577– 8. 7. Agudelo CA, Wise CM, Lyles FM. Pure red cell aplasia in procainamide induced systemic lupus erythematosus. Report and review of the literature. J Rheumatol 1988;15:1431–2. 8. Nitche A, Taborda GD, Bouveta HM, D’antonio CC, Gronda MV. Pure red cell aplasia in a patient with systemic lupus erythematosus. J Rheumatol 1988;15:1012–3. 9. Julkunen H, Jantti J, Pettersson T. Pure red cell aplasia in mixed connective tissue disease. J Rheumatol 1989;16:1385– 6. 10. Heck LW, Alarcon GS, Ball GS, Phillips RL, Kline LB, Moreno H, et al. Pure red cell aplasia and protein-loosing enteropathy in a patient with systemic lupus erythematosus. Arthritis Rheum 1985;28:1059 – 61. 11. Franzen P, Friman C, Pettersson T, Fyhrquist F, Ruutu T. Combined pure red cell aplasia and primary autoimmune hyperparathyroidism in systemic lupus erythematosus. Arthritis Rheum 1987;30:839 – 40.
12. Francis DA. Pure red-cell aplasia: Association with systemic lupus erythematosus and primary autoimmune hypothyroidism. Br Med J Clin Res Ed 1982;284:85. 13. Nossent JC, Swaak AJG. Pure red cell aplasia in systemic lupus erythematosus. Clin Rheumatol 1988;7:527–9. 14. Yamauchi K, Arimori S. Effective methylprednisolone “pulse” therapy in myeloerythroid aplasia associated with systemic lupus erythematosus: Case report and literature review. Tokai J Exp Clin Med 1987;12:337– 41. 15. Takigawa M, Hayakawa M. Thymoma with systemic lupus erythematosus, red blood cell aplasia and herpesvirus infection. Arch Dermatol 1974;110:99 –102. 16. Mackenchnie HLN, Squires AH, Platts M, Pruzanski W. Thymoma, myasthenia gravis, erythroblastopenic anemia and systemic lupus erythematosus in one patient. CMAJ 1973;109: 733– 8. 17. Aach R, Kissane J. Lupus erythematosus with severe anemia, selective erythroid hypoplasia and multiple red blood cell antibodies (clinicopathological conference). Am J Med 1968;44:590 – 8. 18. Cassileth PA, Myers AR. Erythroid aplasia in systemic lupus erythematosus. Am J Med 1973;55:706 –10. 19. Isbister JP, Ralston M, Hayes JM, Wright R. Fulminant lupus pneumonitis with acute renal failure and red blood cell aplasia. Successful management with plasmapheresis and immunosuppression. Arch Intern Med 1981;141:1081–3. 20. Ilan Y, Naparstec Y. Pure red cell aplasia associated with systemic lupus erythematosus: Remission after a single course of intravenous immunoglobulin. Acta Haematol 1993;89:152– 4. 21. Okada H, Suzuki H, Uchida H, Kanno Y, Kitamura Y, Hisamatsu T, et al. Acquired idiopathic pure red cell aplasia in a hemodialyzed patient with systemic lupus erythematosus. Intern Med 1994;33:492–5. 22. Orbach H, Ben-Yehuda A, Ben-Yehuda D, Mano D,
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Rubinov A, Naparstec Y. Successful treatment of pure red cell aplasia in systemic lupus erythematosus with erythropoietin. J Rheumatol 1995;22:2166 –9. 23. Meyer RJ, Hoffman R, Zanjani ED. Autoimmune hemolytic anemia and periodic pure red cell aplasia in systemic lupus erythematosus. Am J Med 1978;65:342–5. 24. Duchmann R, Schwarting A, Poralla T, Meyer-zumBuschenfelde KH, Hermann E. Thymoma and pure red cell aplasia in a patient with systemic lupus erythematosus. Scand J Rheumatol 1995;24:251– 4. 25. Linardaki GD, Boki KA, Fertakis A, Tzioufas AG. Pure red cell aplasia as presentation of systemic lupus erythematosus: Antibodies to erythropoietin. Scand J Rheumatol 1999;28: 189 –91. 26. Tsai MH, Lee DT, Chen HC, Hsueh SH, Tseng CP. Systemic lupus erythematosus with pure red cell aplasia. A case report. Chin Med J 1993;52:265– 8. 27. Kiely PDW, McGukin CP, Collins D, Bevan DH, March JCW. Erythrocyte aplasia and systemic lupus erythematosus. Lupus 1995;4:407–11. 28. Fries J, Holman H. Systemic lupus erythematosus: A clinical analysis. Philadelphia. WB Saunders 1975. 29. Hochberg MC, Boyd RE, Ahearn JM, Arnett FC, Bias WB, Brovost TT, et al. Systemic lupus erythematosus: A review
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of clinico-laboratory features and immunogenetic markers in 150 patients with emphasis on demographic subsets. Medicine 1985;64:285–95. 30. Worrall JG, Snaith ML, Batchelor JR, Isenberg DA. SLE: A rheumatological view. Analysis of clinical features, serology, and immunogenetics of 100 SLE patients during long-term follow-up. Q J Med 1990;74:319 –30. 31. Pistiner M, Wallace DJ, Nessim S, Metzger AL, Klineberg JR. Lupus erythematosus in the 1980s: A survey of 570 patients. Semin Arthritis Rheum 1991;21:55– 64. 32. Tziousfas AG, Korkori SI, Petrovas CA, Moutsopoulos HM. Autoantibodies to human recombinant erythropoietin in patients with systemic lupus erythematosus. Correlation with anemia. Arthritis Rheum 1997;40:2212– 6. 33. Dayal AK, Kammer GM. The T cell enigma in lupus. Arthritis Rheum 1996;39:23–33. 34. Sabella C, Goldfarb J. Parvovirus B 19 infections. Am Fam Physician 1999;60:1455– 60. 35. Mitsunaka H, Tokuda M, Takahara J, Matoba K, Miyawaki S. A case of systemic lupus erythematosus with pure red cell aplasia possibly caused by persistent infection of human parvovirus B 19. Nihon Rinsho Meneki Gakkai Kaishi 1998; 21:220 –5.
P
URE RED CELL APLASIA (PRCA) is characterized by normochromic normocytic anemia and reticulocytopenia, with aplasia or severe hypoplasia of the red cell line with normal white cell and megakaryocyte lines in the bone marrow (1). PRCA may be associated with other conditions (2), but the association with systemic lupus erythematosus (SLE) is rare, and no systematic review has been published previously. Here we report a case of PRCA in a patient with SLE and summarize the previous cases reported in the English literature. METHODS
A MEDLINE search (Winspirs) was done from the years 1966 through 2000. The key words included lupus, erythroid, aplasia, hypoplasia, red cell, and anemia in various combinations. Only reports written in English were included. Cases had an established diagnosis of PRCA (1) and met the American College of Rheumatology classification
criteria for the diagnosis of SLE (3). Clinical characteristics, laboratory test results, treatment and outcome were extracted from the papers and summarized.
From the Department of Internal Medicine B, Carmel Medical Center, Haifa, Israel, and the Department of Epidemiology, Sackler Medical School, Tel Aviv University, Ramat Aviv, Israel. George S. Habib, MD: Clinical Instructor, Faculty of Medicine, Technion-Israel Institute of Technology, and Department of Internal Medicine B, Carmel Medical Center, Haifa, Israel; Walid R. Saliba, MD: Medical Resident, Department of Internal Medicine B, Carmel Medical Center, Haifa, Israel; and Paul Froom, MD: Associate Professor, Department of Epidemiology, Sackler Medical School, Tel Aviv University, Ramat Aviv, Israel. Address reprint requests to George S. Habib, MD, Department of Internal Medicine B, Carmel Medical Center, 7 Michal St, Haifa, 34362, Israel. E-mail: [email protected] Copyright 2002, Elsevier Science (USA). All rights reserved. 0049-0172/02/3104-1051$35.00/0 doi:10.1053/sarh.2002.30440
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Case Presentation A 31-year-old woman with a 1-month history of arthritis, skin rash, photosensitivity, and oral sores presented to the emergency room with progressive dyspnea on effort and a fever of 7 days’ duration. On physical examination she was in mild distress and looked pale. Her body temperature was 38.5°C, her pulse was 105/m, and her blood pressure was 90/50 mm Hg. There was a mild systolic cardiac murmur at the apex, and her lungs were clear. She had synovial swelling and tenderness of the proximal interphalangeal joints, wrists, and elbows and tenderness of the metacarpophalangeal joints and knees. Diffuse erythematous papules were seen on her face and upper chest, and there were a few aphthous lesions in the mouth. Laboratory results were as follows: hematocrit, 16%; hemoglobin (Hgb), 50 g/L; MCV, 81 fL; WBC, 3.3 ⫻ 109/L with 0.69 segments, 0.22 lymphocytes, and 0.06 bands; platelets, 400,000 109/L; erythrocyte sedimentation rate (Westergren) 110 mm/ hr; creatinine, 0.7 mg/dL; total bilirubin, 0.4 mg/dL; haptoglobin, 111 mg/dL (normal range, 27-139); reticulocytes, 0.2%; erythropoietin (EPO) activity, 255 mu/mL (normal ⬍19); and direct and indirect Coomb’s tests were negative. Antinuclear antibodies were positive (titer, 1:128), and antiDNA antibodies were 60 U/mL (normal ⬍30). No antibodies were found to extranuclear proteins or cardiolipins. C3 was 55 mg/dL (normal range, 80-180), and C4 was ⬍8 mg/dL (normal, 15-40). Rheumatoid factor and veneral disease research laboratory (VDRL) were negative, and hepatitis B surface antigen (HbsAg) antibodies to hepatitis C, parvovirus, and human immunodeficiency virus were not found. Thoracic computerized tomography did not reveal any masses. Bone marrow
biopsy showed normal cellularity with nearly total absence of erythroid precursors and normal megakaryocyte and myeloid lines. Iron stores were increased. The patient was transfused with 3 U red packed cells and started on 60 mg/d prednisone. Ten days after starting therapy, the reticulocyte count was 3%. The Hgb values increased gradually and were normal after 30 days of treatment. Subsequently, hydrochloroquine 200 mg twice per day was added, and corticosteroids (CS) were tapered gradually and stopped after 9 months. She remained well without anemia or symptoms associated with SLE over the next 12 months. LITERATURE REVIEW
We identified 28 cases in our literature search. Five cases were excluded, 3 cases were incomplete (4), and 2 cases did not have the needed criteria for a diagnosis of SLE (5,6). Our case and the other 23 (7-27) with adequate clinical and laboratory data are included in this summary. Clinical Features Demographic variables and Hgb levels of the patients are shown in Table 1. One patient with a Hgb level of 10 g/L at the time of PRCA diagnosis was transfusion dependent. In those cases in which SLE diagnosis preceded the diagnosis of PRCA (12 cases), the time range was between 6 weeks to 12 years, and when the diagnosis of SLE followed the diagnosis of PRCA (4 cases), the time range was between 2 months to 4 years. Pleuritis was significantly less frequent in those with PRCA compared to SLE patients in general (20% [4/20] v 44% [433/984], respectively, P ⬍ .05)(3,28-31). We excluded 4 patients in this comparison because they presented with PRCA before
Table 1: Selected Characteristics of 24 Patients With PRCA and SLE Demographic and Laboratory Variables Women (%) Median age at diagnosis of SLE (yr) (range) Median age at diagnosis of PRCA (yr) (range) Median Hgb at diagnosis of SLE (g/L) (range) Median Hgb at diagnosis of PRCA (g/L) (range) Simultaneous diagnosis of SLE and PRCA (patients) SLE diagnosed prior to PRCA (patients) PRCA preceded SLE diagnosis (patients)
No. (%) 23 (96) 33 (14-77) 35 (14-77) 102 (34-136) 50 (19-100) 8 (33) 12 (50) 4 (17)
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Table 2: Laboratory Profile of 24 Patients With SLE and PRCA
Laboratory Parameter
Positive Finding/Total Tested (%)
Patients With SLE Alone (%) (3, 28-31)* (n ⴝ 1,084)
Leukopenia Thrombocytopenia ANA Anti-DNA Decreased levels of C3 Anti SS-A Anti RNP Anti Sm Anticardiolipins False positive VDRL
8/22 (36) 1/22 (5) 23/24 (96) 7/18 (39) 7/13 (54) 5/10 (50) 3/7 (43) 0/7 (0) 3/5 (60) 3/8 (38)
46 20 97 46 51 25 19 15 35 16
Abbreviations: ANA, antinuclear antibodies; SS-A, Sjo¨gren syndrome A; RNP, ribonucleoprotein; Sm, Smith. *From 5 series in the literature.
the SLE. However, the proportions of other clinical features (arthritis/arthralgia, skin changes, hemolytic anemia, proteinuria, pericarditis, and hallucinations) were similar in both groups with a trend for less proteinuria and hallucinations. Of the 12 patients with an established diagnosis of SLE before the onset of PRCA, 9 patients had no symptoms, signs, or laboratory tests suggesting specific active organ involvement at the time of PRCA diagnosis. Concomitant diseases included single cases of the antiphospholipid syndrome, mixed connective tissue disease, and Sjo¨gren’s syndrome. There was 1 case of procainamide-induced SLE and 3 cases of thymoma (one of which was found only on autopsy). Laboratory Findings Laboratory findings (Table 2) of patients with SLE and PRCA were essentially identical to those of patients with SLE alone. Patients with SLE and PRCA tended to have less thrombopenia and leukopenia. There were also differences (not significant) in the proportion of patients with antibodies against extranuclear proteins and phospholipids; however, these tests were performed in only a few patients. One patient had end-stage renal disease. Special Studies There were special studies on the effect of patients’ serum (8,20-23,27) or T-cells (21,22,27) on erythroid colony growth (BFU-E) from their own (21,22,27) or control (8,21,23,27) progenitor cells. BFU-E growth was normal in all cases
(8,21,22,23,27). Serum was shown to suppress the growth of BFU-E in 1 of 3 cases (27) and in 3 of 4 controls (8,23,27). T-cell depletion decreased the suppressive effect of the serum in 1 of 3 cases (27). Testing for an inhibitory effect on EPO was performed in 2 patients and was found in 1 (25). Treatment and Outcome Follow-up for at least 6 months was possible with 19 patients. There were 2 spontaneous remissions: 1 in a patient with procainamide-induced SLE and PRCA after cessation of the medication and the other after a single blood transfusion. Of those treated with prednisone, 13 of 21 had a good response, which continued after cessation of the prednisone in 3 patients and required low doses in 10. There were 4 deaths (3 from pneumonia and 1 from pulmonary embolism); 2 occurred shortly after starting CS and 2 after 2- and 7-year followup. Two of 3 nonresponders to prednisone remitted after high-dose intravenous gamma globulin treatment, and 1 patient responded only after EPO treatment. DISCUSSION
The combination of SLE and PRCA is rare but probably underdiagnosed. The use of a reticulocyte count as a screening test with subsequent bone marrow examinations in those with reticulopenia likely would result in a higher frequency of this combination. It has been stated that renal and central nervous system involvement does not occur in those with
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concomitant SLE and PRCA (27). We found a trend for less proteinuria and hallucinations and a significant decrease in pleuritis in those with SLE and PRCA. Such comparisons should be interpreted with caution, however, because selection bias and length of follow-up might be responsible for the differences. In any case, the clinical presentation does not appear to be helpful in determining the likelihood of concomitant SLE and PRCA. The onset of PRCA did not correlate with symptoms of SLE. In fact, patients with SLE diagnosed previously had clinically inactive disease. Thus, these autoimmune phenomena occur independently for reasons unknown. The mechanism for PRCA appears to be multifactorial and is not due to defects in stem cells but rather to a suppressor effect of the immune system either through humeral or cellular mechanisms acting directly on stem cells or on EPO. A significant proportion of
SLE patients have positive anti-EPO antibodies in their serum, and the frequency of these antibodies is significantly higher in patients with severe anemia (32). T cells are also crucial in the pathogenesis of SLE, and most of the pathogenic autoantibodies are T-cell dependent (33). Infection with parvovirus B 19 has been associated with PRCA (34). Recently, 1 patient with SLE and PRCA was shown to have persistent infection with human parvovirus B 19 (35). The natural history of PRCA and SLE is similar to that of PRCA. The disease responds to prednisone in the majority of cases, but often the drug cannot be tapered completely. Furthermore, both early and late deaths occur. Experience with other agents is limited, but it appears reasonable to try high-dose immunoglobulin and EPO treatment for nonresponders. Spontaneous remission also may occur but is not common.
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