Oral contraceptives and systemic lupus erythematosus

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CASE REPORT

ORAL CONTRACEPTIVES AND SYSTEMIC LUPUS ERYTHEMATOSUS MICHAEL GAROVICH, CARLOS AGUDELO, and EDWARD PISKO The relationship between oral contraceptives (OC) and systemic lupus erythematosus (SLE) is not clear. OC have been reported to induce LE cells and other serologic abnormalities ( 1-4), rheumatic complaints ( 5 ) , exacerbate SLE (6,7), and unmask SLE (8). In contrast, there have been several prospective studies of healthy women attending birth control clinics that have not shown a significant association between OC and SLE (9,lO). This case report discusses a young woman who developed SLE 4 weeks after beginning oral contraceptive therapy and who did not improve until OC were discontinued. Sixteen months after cessation of OC, the patient is completely asymptomatic, has been off therapy for over a year, completed a normal pregnancy, and is now in the second month of her second pregnancy.

CASE REPORT The patient's clinical course is summarized in Figure 1. She was an 18-year-old asymptomatic white woman who underwent a prenuptial examination on April 7, 1978 and was found to have a biological false positive serologic test for syphilis (STS). No other tests were performed. The patient was started on the oral contraceptive Demulen (ethynodiol diacetate 1.O mg, ethynil estradiol 50 pg). From the Department of Medicine, Bowman Gray School of Medicine of Wake Forest University. Michael Garovich, MD; Carlos Agudelo, MD; Edward Pisko, MD. Address reprint requests to Edward J. Pisko, MD, Assistant Professor of Medicine, Department of Medicine, Bowman Gray School of Medicine, 300 South Hawthorne Rd., Winston-Salem, NC 27103. Submitted for publication May 13, 1980; accepted in revised form August 20, 1980.

Arthritis and Rheumatism, Vol. 23, No. 12 (December 1980)

On May 10, she developed fever (temperature 105OF), cervical lymphadenopathy, and pharyngitis. Symptoms persisted, and on May 19 her complete blood cell count was normal, and a monospot test was negative. No other tests were performed. Her sore throat abated, but other symptoms continued and included generalized polyarthralgias. She was admitted to a local hospital on June 11, where she was found to have a Coombs positive hemolytic anemia with a hemoglobin of 9.6 gm and white blood count (WBC) of 3,900 cells/ mm3; sedimentation rate was 124 mm/hour and urinalysis showed proteinuria, which was not quantitated. Fluorescent antinuclear antibodies (ANA) were positive. Other significant findings included a false positive STS and a skin biopsy showing IgM and C3 deposits at the dermal-epidermal junction. A diagnosis of SLE was made, and the patient was started on 40 mg/day of prednisone and discharged from the hosptial. Because fever, polyarthralgias, and proteinuria persisted, her prednisone dosage was increased to 100 mg/day. On July 13, she was referred to our institution because of decreased cerebration, persistent fever, and proteinuria despite high dose steroid therapy. On admission, physical exam revealed a young woman disoriented to time and place and moderately distressed. Her temperature was 99.4"F, pulse was 80, respirations 16, and blood pressure 106/70. The remainder of the physical exam yielded normal findings except for a malar rash, several small white discrete lesions on the posterior tonsillar fossa, and a crusty white vaginal discharge. On admission OC were discontinued. Initial laboratory data revealed a hemoglobin of 11.1 gm%, WBC of 3,700 cells/mm3, Westergren sedimentation rate of 64 mm/hour, platelet count of 275,000/mm3, blood urea nitrogen of 15, creatinine of 1.1, and protein-

ORAL CONTRACEPTIVES AND SLE

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*4 ' dipstick for protein, not quantitated ( >I000 m g / d l Figure 1. The patient's clinical and laboratory parameters following the administrationand subsequent discontinuation of oral contraceptives. uria of 4.2 gm/24 hours with a creatinine clearance of 75 cc/minute. CH50 and C4 were normal, C3 was 36 (normal 55 to 120), ANA was positive at 1 : 100 with a homogenous pattern; RA latex, SCAT, and immune complexes (Raji cell technique) were negative. Anti-native DNA antibody was normal (less than 30%), and cerebrospinal fluid (CSF) studies revealed a protein of 136 mg with normal glucose level and no cells. The patient continued to be disoriented despite 100 mg of prednisone daily, but she became afebrile 24 hours after discontinuing OC. Electroencephalogram was abnormal with diffuse slowing and a CAT scan revealed prominent sulci suggestive of steroid therapy. As the patient's mental status deteriorated further, a trial of high dose methyl prednisolone at 30 mg/kg (1,500 mg intravenously) was begun on the fourth hospital day. On the second day of this treatment, because of lack of improvement, a repeat lumbar puncture was performed and revealed a CSF protein of 575 mg, normal glucose, 50 WBC, 82% of which were mononuclear cells and 18% polymorphonuclear leukocytes. On the third day of high dose steroids, the patient became unresponsive and had a grand ma1 seizure. Steroids were then decreased to 60 mg a day. Twenty-four hours later she became responsive and her mental status gradually improved, correlating with the tapering of steroid dosage. A renal biopsy showed diffuse proliferative glomerulonephritis

with coarse capillary and mesangial deposits Of C3 (4+), IgG (2+), and C4 (1+) by immunofluorescence. Another 24-hour urine for creatinine clearance was normal with only 275 mg of protein per 24 hours 5 days after discontinuing OC. As the patient continued to improve, steroids were tapered over the ensuing months and were discontinued on October 11, 1978. Since her last hospitalization, she remained off OC and has been asymptomatic. She subsequently had a normal pregnancy and delivery in September 1979. Antinuclear antibodies and urinalysis during pregnancy and after delivery were negative, creatinine clearances were normal with less than 100 mg protein/24 hour urine, CH50, C3 and C4 were normal. STS remains positive at 1 :2 with a negative FTA-ABS. She is currently (April 1980) 2 months into her second pregnancy, which has been uneventful.

DISCUSSION Our patient developed fever, polyarthritis, dermatitis, nephritis, and hematologic and immunologic abnormalities a few weeks after commencing oral contraceptive therapy. The persistance of her symptoms despite high dose corticosteroid therapy and the remarkable improvement and subsequent course soon after discontinuing OC suggest a strong relationship between OC therapy and her development of systemic lupus erythematosus.

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Although our patient fulfills the American Rheumatism Association criteria for SLE (1 l), it is unusual to have negative circulating immune complexes and negative anti-native DNA antibodies in the presence of active idiopathic SLE (12). This patient does fulfill Lee and Chase’s criteria for drug-induced SLE (13), although central nervous system manifestation and renal disease are unusual in drug-induced disease. However, Weinstein (14) has described complement activation and transient nephritis following hydralazine therapy. Travers and Hughes (8) discussed a patient who developed SLE 3 weeks after beginning OC therapy with ethinyl estradiol 50 pg and norethisterone acetate 1.0 mg. Both their patient and our patient did have a biological false positive STS prior to OC therapy and a false positive STS may be a marker for a “lupus diathesis” ( 15). Therefore, both cases probably represent either subclinical SLE or a “lupus diathesis” unmasked by OC therapy rather than idiopathic SLE or true druginduced SLE. The clinical onset of SLE in both patients may have been incidental, but the temporal courses in both strongly suggest a causal relationship. Travers and Hughes’ patient differed from ours because she continued to have symptoms, despite cessation of OC, and continued to have serologic and chemical abnormalities consistent with SLE, requiring low dose corticosteroids, while our patient has been disease-free for 16 months. As noted recently (16), the pathophysiology of SLE is most likely due to multiple factors including naturally occurring or drug-induced hormonal changes in young women or in individuals with Klinefelter’s syndrome (17). Oral contraceptives may facilitate the abnormal immune response of SLE in predisposed individuals, and caution should be employed before prescribing oral contraceptives in women with biological false positive STS.

REFERENCES 1. Elias PM: Erythema nodusum and serological lupus ery-

thematosus. Arch Dermatol 108:716-7 18, 1973

2. Schleicher EM: LE cells after oral contraceptives. Lancet 1~821-822,1968 3. Dubois EL, Strain L, Ehn M, Bernstein G, Friou GJ: LE cells after oral contraceptives. Lancet 2:679, 1968 4. Pimstone BL: LE cells after oral contraceptives. Lancet 1:1153, 1968 5. Spiera H, Plotz CM: Rheumatic symptoms and oral contraceptives. Lancet 1571-572, 1969 6. Chapel TA, Burns RE: Oral contraceptives and exacerbations of lupus erythematosus. Am J Obstet Gynecol 110:366-369, 1971 7. Pimstone B: Systemic lupus erythematosus exacerbated by oral contraceptives. S Afr J Obstet Gynaecol462-63, 1966 8. Travers RL, Hughes GR: Oral contraceptives and systemic lupus erythematosus. J Rheumatol 5.4:448-45 1, 1978 9. Targy BJ, Wauach EE, Myers AK, Garcia C, Zweiman B: Rheumatic disease, abnormal serology, and oral contraceptives. Lancet 2501-503, 1972 10. McKenna CH, Weiman KC, Schulman LE: Oral contraceptives, rheumatic diseases, and autoantibodies (abstract). Arthritis Rheum 12:313-314, 1969 11. Coffen DS, Reynolds WE, Franklin EC, Kukla JP, Ropes MW, Shulman LE, Wallace SL: Preliminary criteria for the classification of systemic lupus erythematosus. Bull Rheum Dis 21:643-648, 1971 12. Zubler RH, Lambert PH: Immune complexes in clinical investigation, Recent Advances in Clinical Immunology. Edited by RA Thompson. New York, Churchill Livingstone, 1977, pp 125-147 13. Lee SL, Chase PH: Drug-induced and systemic lupus erythematosus: a critical review. Semin Arthritis Rheum 5~83-103, 1975 14. Weinstein J: Hypocomplementemia in hydralazine associated systemic lupus erythematosus. Am J Med 65:553556, 1978 15. Sparling PF: Diagnosis and treatment of syphilis. N Engl J Med 248:642-653, 1971 16. Tala1 N: Systemic lupus erythematosus, autoimmunity, sex and inheritance. N Engl J Med 301:838-839, 1979 17. Stern R, Fishman J, Brushman H, Kunkel HG: Systemic lupus erythematosus associated with Klinefelter’s syndrome. Arthritis Rheum 20:18-22, 1977