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Systemic lupus erythematosus presenting as chronic serositis with no demonstrable antinuclear antibodies
Systemic Lupus Erythematosus Presenting As Chronic Serositis with No Demonstrable Antinuclear Antibodies
JULIO E. FERREIRO, M.D. WILLIAM M. REITER, M.D. MARIO J. SALDANA,
M.D.
Miami, Florida
From the Departments of Medicine and Pathology. University of Miami School of Medicine, Miami, Florida. Requests for reprints should be addressed to Dr. Julio E. Ferreiro, Department of Medicine R-60, P.O. Box 016960, Miami, Florida 33101.
Manuscript acceptedJune23, 1963.
1100
June 1984
Approximately 5 percent of patients with systemic lupus erythematosus by clinical and pathologic criteria have no demonstrable antinuclear antibodies. This figure is likely to be an underestimate, as it does not include the antinuclear antibody-negative patients wtth limited manifestations in whom the diagnosis of systemic lupus erythematosus is missed. A 23-year-old woman is described who had a history of perplexing bilateral pleural effusions with development of peritoneal effusion after 18 months and positive antinuclear antibody results after 22 months. Tissue pathologic features, initially interpreted as nonspecific, on review revealed striking lymphocytic pertarteritis with endothelial swelling and leukocytoclastic vasculitis often seen in systemic lupus. A selective defect in the suppression of T cell effector function, such as direct cell-mediated cytotoxicity, with intact suppressor systems for B cell effector function, such as antibody production, can be postulated in this patlent. This would explain the active cellular tissue pathology with the lack of prominent antinuclear antibody production. Osler [l] in 1895 emphasized that “erythema exudativum” (systemic lupus erythematosus) was a systemic disease with variable visceral manifestations that need not be accompanied by dermatologic findings. Much had been learned by 1935, allowing Baeher et al [2] to publish an extensive clinical and pathologic description of this disease. However, it was not until the discovery of the lupus erythematosus cell phenomenon by Hargraves et al [3] in 1948 that the diagnosis could be extended to patients in whom the full clinical picture of systemic lupus erythematosus was not present. In a 1953 report of the first large series to make clinical use of the lupus erythematosus cell, Dubois [4] stated that “There is no classic pattern of this illness, and the diagnosis must be based on an over-all view of the entire clinical picture with the aid of the lupus erythematosus test. Because of its varied forms, many of these cases are at present masquerading under other diagnoses.” The lupus erythematosus test has gradually been replaced by direct assays for antinuclear antibodies [5,6], increasing sensitivity and allowing recognition of even earlier and more subtle forms of this disease. Although the presence of antinuclear antibodies is no longer considered specific for systemic lupus erythematosus, their detection remains almost a sine qua non of diagnosis. However, it has become apparent that approximately 5 percent of patients with systemic lupus by clinical and pathologic criteria have no demonstrable antinuclear antibodies [7-g]. This figure is likely to be an underestimate, as it does not include the antinuclear antibody-negative patients with limited or
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unusual presentations in whom the diagnosis of systemic lupus has been missed as in the time before the lupus erythematosus cell test. These patients continue to present a diagnostic challenge. The following case report records the two-year search for the elusive cause of recurrent pleural and peritoneal effusions in a young woman and the difficulties in arriving at the diagnosis of systemic lupus erythematosus. It may also provide clinical and pathologic correlation for recent advances in the elucidation of the immunopathogenesis of this intriguing disease. CASE REPORT In March 198 1, a 23-year-old Caucasian woman presented to a community hospital with a three-month history of intermittent pleuritic chest pain and generalized chest aching. She denied antecedent trauma or respiratory illness and was without cough, sputum production, dyspnea, fever, weight loss, or malaise. There was no significant past medical history. Her father had had tuberculosis. Physical examination showed no abnormalities except for a grade II/IV systolic ejection murmur at the left sternal border and diminished breath sounds and dullness at the lung bases. Results at laboratory evaluation, including erythrocyte sedimentation rate and antinuclear antibody level, were normal. A tuberculin skin test (5 TU of PPD) produced a 10 mm reaction. Chest x-ray revealed bilateral pleural effusions without infiltrate, adenopathy, or mass lesions. Results of echocardiography and gallium scanning were normal. Bilateral thoracentesis with pleural biopsy was performed. The fluid was reported as an exudate with a normal glucose level showing prominent neutrophils, eosinophils, and lymphocytes without malignant cells. The biopsy specimens reportedly showed nonspecific pleuritis. All culture results were negative. The patient was then transferred to Jackson Memorial Hospital. After review of the initial data and repeated examination and serologic studies, she was discharged in May 198 1 to begin a course of isoniazid and ethambutol for possible tuberculous pleuritis. Over the subsequent year, she was seen frequently by one of us (JEF). She continued to have episodic chest discomfort poorly responsive to analgesics and nonsteroidal anti-inflammatory agents. Bilateral pleural effusions reaccumulated and persisted. No pertinent physical fihdings developed and laboratory evaluation, including erythrocyte sedimentation rate and antinuclear antibody determination, remained unrevealing. There was one episode, by history, of transient left arm weakness, but subsequent radioisotope brain scanning showed nothing abnormal. In May 1982, she was evaluated with thoracoscopy and repeated biopsy. There were no new findings. By November, she continued to have chest pain and also noted abdominal discomfort. Physical examination again revealed signs of pleural effusions, but ascites and a right adnexal mass were present as new findings. The erythrocyte sedimentation rate was noted to be elevated to 42 mm per hour for the first time, and antinuclear antibodies were again not found. Ultrasound examination revealed a cystic mass in the left pelvis, and
IN SYSTEMIC
LUPUS ERYTHEMATOSUS-FERREIRO
ET AL
computed tomography revealed a solid mass in the right pelvis. Exploratory laparotomy revealed healed right pelvic inflammatory disease and a left hemorrhagic corpus luteum. The surface of the uterus and the area of the terminal ileum had an unusual gelatinous appearance, but biopsy of these tissues and of the peritoneum showed anly nonspecific inflammation. There was no evidence of pelvic abcesses or suppuration consistent with active pelvic inflammatory disease. By January 1983, malaise, anorexia, and weight loss had developed. There were no other new symptoms. She was again admitted to hospital. On physical examination, her blood pressure was 130180 mm Hg, pulse 80 beats per minute, and temperature 98.8”F. There was no alopecia, skin and mucous membranes were without lesions, and there was no lymphadenopathy. Dullness and decreased breath sounds were noted at the lung bases; a pleural rub was not heard. There was mild diffuse chest wall tenderness. There was no jugular venous distention, heart sounds were normal with a grade II/VI early systolic ejection murmur at the lower left sternal border without radiation, and there was no pericardial rub. The abdomen was distended, with shifting dullness and mild diffuse tenderness without rebound. The liver span was 9 cm, and the spleen was not palpable. The joints were normal, and results of neurologic examination were normal. Chest x-ray revealed bilateral pleural effusions and pleural reaction (Figure 1). Computed tomography of the abdomen revealed ascites without organomegaly or masses. Fluid from paracentesis was an exudate with 290 blood cells (30 percent polymorphonuclear leukocytes and 70 percent monocytes). There were no malignant cells. Blood chemistry and hematologic parameters and results of urinalysis were all normal. Serologic tests for syphilis and rheumatoid factor gave negative results. The erythrocyte sedimentation rate was 72 mm per hour, the C3 level was 222 mg/dl (normal 101 to 189) and the C4 level was 43 mg/dl (normal 21 to 63). An-
Figure sions.
June 1984
1.
Chest x-ray showing
bilateral
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tinuclear antibody assay gave positive results in a speckled pattern. Results had previously been negative eight times over 22 months. Specific antibodies to native DNA (nDNA), ribonuclear protein (RNP), Smith (Sm), Sjogren’s antigen A @S-A or Ro), and Sjogren’s antigen 6 (SS-B or La) were not detected. Results of assays for circulating immune complexes by the Clq and conglutinin methods were negative. Review of all tissue specimens obtained previously was undertaken. Pleural samples obtained in March 1981 and May 1982 were identical and revealed moderate to dense focal inflammatory cell infiltrates composed of lymphocytes, monocytes, and eosinophils in the submesothelial fibroconnective tissue space. They had a characteristic distribution in and around conglomerates of arteriolar and capillary vessels (Figure 2A). In one specimen, a small area of fibrinoid necrosis was noted (Flgure 28). The capillaries had marked
swelling of the endothelium frequently occluding their luminae (Figure 3). Several fragments of intercostal muscle showed many discrete foci of myositis with necrosis of muscle fibers (Figure 4). The cytologic composition of the pleural fluid was remarkable for its high content of eosinophils with lesser numbers of lymphocytes, polymorphonuclear leukocytes, and reactive mesothelial cells. The biopsy specimens of pelvic peritoneum and terminal ileum showed extensive leukocytoclastic vasculitis. Involved vessels were arterioles and capillaries showing dense polymorphonuclear leukocytic infiltration and eosinophilia (Figure 5). The eosinophils were present both within the confines of the vessels and in the perivascular space. The patient began receiving prednisone, with relief of chest and abdominal pain, disappearance of pleural and peritoneal effusions, return of the erythrocyte sedimentation rate to normal, and reversion of the antinuclear antibody results to negative. In summary, the patient was a 23-year-old woman with a history of perplexing pleuritis with effusion, myositis, and predominantly lymphocytic periarteritis who, after 18 months,
Figure 2. Biopsy of pleura (A) showing proliferation of capillaries with distinct “cuffing” by lymphocytes. Eosinophi/s, present in the fibrotic stroma, were far more numerous in the pleural exudate. Focus of “fibrinoid” necrosis (B) is associated with polymorphonuclear leukocytes and eosinophils undergoing kariolysis (hematoxylin and eosin stain; original magnification X 79, reduced by 30 percent).
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Figure 3. Higherpower view of a focus of capillary prolifera tion as illustrated inFigure 2 A. Due to the marked endothe/la/swelling, the capillary luminae are difficulf to discern (L) (hematoxylin and eosin stain; original magnification X 760, reduced by 30 percent).
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had polyserositis with peritonitis and peritoneal effusion, leukocytoclastic vasculitis, and, after 22 months, positive antinuclear antibody results. A diagnosis of systemic lupus etythematosus was made, and there was complete response of the clinical illness to corticosteroid therapy. COMMENTS Recurrent pleuritis is a frustrating diagnostic challenge, A in many cases, conveyed by the term “idiopathic.” report on the use of thoracoscopy in cases of undiag-
nosed pleural effusion [lo] described evaluation of 18 patients, nine of whom were found to have malignancy, two infection, and seven nonspecific inflammatory findings. In a report on the follow-up study of 27 patients in whom the cause of pleural effusion remained indeterminate after extensive initial evaluation [ 111, diagnosis was eventually made in 16, including one with systemic lupus erythematosus, but could not be reached in 11. In a review of the Mayo Clinic experience with longpleural effusion undiagnosed after thoracotomy, term follow-up study of 5 1 patients was reported [ 121. A diagnosis was eventually made in 18, including two with systemic lupus erythematosus. One of these patients was initially suspected of having systemic lupus, but the antinuclear antibody result did not become positive until nine months after surgery. In the remaining 33 patients, the pleural effusion was said not to recur, and no disease became apparent. Undiagnosed effusions of possible collagen vascular cause that are said not to recur must be viewed in light of the observation that approximately 35 percent of patients with systemic lupus erythematosus have spontaneous remissions lasting up to eight years [4,13]. Pleural effusions occur with great frequency in the collagen vascular autoimmune diseases such as systemic lupus erythematosus; however, in our patient, the absence of other clinical features and the negative serologic results initially reduced the likelihood of these possibilities. Over time, as the other possible processes were excluded and mutisystem involvement developed, a clinical diagnosis of systemic lupus became more reasonable. The development of the positive speckled antinuclear antibody result at the time when the disease seemed most active was decisive in providing evidence of an autoimmune process. Review of the pathologic specimens provided additional support for a diagnosis of systemic lupus erythematosus. There was the finding of lymphocytic periarteritis with endothelial swelling often described in systemic lupus [ 2,4,14,15], the unexpected finding of myositis and finally the observation of leukocytoelastic vasculitis. Usually recognized as a dermatologic finding, leukocytoclastic vasculitis can be part of a number of systemic diseases [ 161; of all of these, systemic lupus erythematosus is the one compatible
IN SYSTEMIC
LUPUS ERYTHEMATOSUS--FERREIRO
ET AL
with this patient’s other findings and clinical course. It should be pointed out that the pathologic findings in this case were not reported by several pathologists involved in the initial study of the biopsy material, suggesting that once malignancy and granulomatous disease are ruled out, relatively subtle inflammatory changes may easily be overlooked. It was only after the clinical problem began to unravel that the need for a more critical review of the biopsy material arose and led to the recognition of the changes described. This experience underscores the need for close collaboration between the clinician and the pathologist in the interpretation of “nonspecific” inflammatory changes in cases of obscure pleural or peritoneal disease. Pleuritis, manifested as pleurisy or pleural effusion, is a common finding in systemic lupus erythematosus, being present at some time in approximately 50 percent of patients [4,17-191. As an initial manifestation, it occurs in only 3 percent [4,18]. In an extensive clinical
Figure 4. Microscopic view of intercostal muscle with intense cellular infiltrate mainly composedof lymphocytesand eosinophils. These foci of myositis were numerous and showed distorted and necrotic skeletal muscle fibers (M) (hematoxylin and eosin stain; original magnification X 760, reduced by 30 percent).
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analysis of systemic lupus erythematosus, Fries and Holman [ 171 stated that chest pain is vaguely characterized or predominantly pleuritic. The finding of intercostal muscle myositis as well as pleuritis in our patient may explain this kind of vague chest discomfort. Myositis tends not to be emphasized as a part of systemic lupus, but it is reported as a major clinical finding with objective documentation in 5 percent of one series [ 181 and noted to be a common finding in pathologic studies
patients, but he stated that it did not occur in the absence of congestive heart failure or renal failure, neither of which was present in our patient. Other authors report peritoneal serositis in 16 percent of their patients [ 181; furthermore, Reifenstein and colleagues [20] found areas of peritonitis in 72 percent of an autopsy series. The evaluation of antinuclear antibodies has moved from the simple detection of antibodies reactive with uncertain nuclear antigens to identification of some of the specific antigens. Although there appears to be a group of patients with systemic lupus who are antinuclear antibody-negative by conventional assay techniques, this does not prove they lack autoantlbody production. These patients may have antibodies that are reactive with antigens not present in the usual assay systems employed. In a review of 66 patients with antinuclear antibody-negative systemic lupus erythematosus [9] 41 were found to have antibodies to Ro, 21 of whom also had antibodies to La. An additional 18 patients had antibodies to single-stranded DNA. Only seven had no antibody-antigen reaction identified. When serum samples from patients with anti-80 antibodies were assayed for antinuclear antibodies using KB human epithelioid cells as substrate rather than the usual mouse liver slices, most showed a positive speckled nuclear or cytoplasmic fluorescent pattern corresponding to the locations of the Ro and La antigens in this substrate. Anti-R0 antibodies are found in approximately 30 percent of antinuclear antibody-positive patients with systemic lupus erythematosus patients but are rare in normal subjects or patients without collagen vascular disease [21]. Their practical utility derives from the support that give to the diagnosis of a collagen vascular autoimmune disease when clinical features are suspicious but insufficient for diagnosis and routine antinuclear antibody assay gives negative results. Among the possible clinical differences between groups of antinuclear antibody-positive and antinuclear antibody-negative patients, the negative group seems to have more prominent dermatologic findings and less prominent renal involvement [ 7-91. The validity of this might be questioned in light of the intrinsic utility of dermatologic findings in suggesting the diagnosis of systemic lupus erythematosus despite negative antibody results. The close connection postulated among autoantibodies, circulating immune complexes, and renal disease may suggest an explanation for the scarcity of renal involvement in patients who seem to have less active or different autoantibody production. Within the antinuclear antibody-negative group, particular serologic findings do not seem to correlate with clinical features. In our patient, who was without dermatologic or renal involvement, assays for nDNA, RNP, Sm, Ro, and La
1151. Abdominal pain, generally believed to be secondary to visceral vasculitis, has been noted at some time in approximately 35 percent of patients [4,18]. It is an initial finding only very rarely [4]. Ascites is rarely reported. It was noted by Dubois [4] in 24 percent of his
Two’high-power views of the severe leukocyfoFigure 5. elastic vasculitis in the peritoneal biopsy specimen. The walls of the vessels are densely infiltrated by polymorphonuclear leukocytes and eosinophils, almost obscuring the vascular luminae (L) (hematoxylin and eosin stain; original magnification X 1,240, reduced by 30 percent).
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antibodies and circulating immune complexes gave negative results, even when the antinuclear antibody results were positive. The implication may be that this patient’s antinuclear antibodies were directed against as yet unidentified nuclear antigens, either without great propensity for the formation of circulating complexes or with intact mechanisms for the rapid clearance of such complexes. From early hope that work on the biochemistry behind the lupus erythematosus cell phenomenon would unravel the cause of the disease has come the realization that antinuclear antibodies may be important only as an epiphenomenon, perhaps contributing to the complications of systemic lupus erythematosus but not of primary pathogenic significance. In an elegant discussion of immune regulation in systemic lupus, Steinberg [22] provided fascinating information that allowed a coherent explanation of variable serologic findings and clinical activity. In patients with systemic lupus, anti-T cell antibodies have been described that selectively kill subpopulations of T cells involved in suppression and control of 6 and T cell functions. In
some patients, antibodies kill only T cells that suppress other T cell effector functions, such as direct cellmediated cytotoxicity, but not T cells responsible for suppression of B cell effector functions, such as antibody production. In systemic lupus, antinuclear antibody production could be correlated with defects in the T suppressor system for B ceil effector functions. This aspect of the suppressor system would be functionally ineffective before florid autoantibody production could occur. The selective T suppressor cell defect for T effector function alone can be postulated in our patient, explaining both the absence of prominent autoantibody production and the active cellular tissue findings, which can be considered analogous to the lymphocytic infiltrates seen in early acute T cell-mediated rejection of tissue transplants 123,241. Further studies are certainly needed on the mechanisms of tissue damage and immune regulation in systemic lupus erythematosus. ACKNOWLEDGMENT We thank Dr. Laurence B. Gardner for his help and suggestions in the preparation of this manuscript.
REFERENCES
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3.
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5.
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7.
8. 9.
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Osler W: On the visceral complications of erythema exudativum multiforme. Am J Med Sci 1895; 110: 629-646. Baeher G, Klemperer P, Schifrin A: Diffuse disease of the peripheral circulation usually associated with lupus erythematosus and endocarditis. Trans Assoc Am Physicians 1935; 50: 139-155. Hargraves MM, Richmond H, Morton R: Presentation of two bone marrow elements: the “tart” cell and the “LE” cell. Proc Staff Meet Mayo Clin 1948; 23: 25-28. Dubois EL: The effect of the LE cell test on the clinical picture of systemic lupus erythematosus. Ann Intern Med 1953; 38: 1265-1294. Schur PH, Sandson J: Immunologic factors and clinical activity in systemic lupus erythematosus. N Engl J Med 1968; 278: 533-538. Sharp GC, Irvin WS, LaRoque RL, et al: Association of autoantibodies to different nuclear antigens with clinical patterns of rheumatic disease and responsiveness to therapy. J Clin Invest 1971; 50: 350-359. Gladman DD, Chalmers A, Urowitz MB: Systemic lupus erythematosus with negative LE cells and antinuclear factor. J Rheumatol 1978; 5: 142-147. Fessel WJ: ANA-negative systemic lupus erythematosus. Am J Med 1978; 64: 80-86. Maddison PJ, Provost TT, Reichlin M: Serological findings in patients with “ANA-negative” systemic lupus erythematosus. Medicine (Baltimore) 1981; 60: 87-94. Boushy SF, North LB, Helgason AH: Thoracoscopy: technique and results in eighteen patients with pleural effusion. Chest 1978; 74: 386-389. Gunnels JJ: Perplexing pleural effusions. Chest 1978; 74: 390-393. Ryan CJ, Rodgers RF, Unni KK, Hepper NGG: The outcome of patients with pleural effusion of indeterminate cause at
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thoracotomy. Mayo Clin Proc 1981; 56: 145-149. Harvey AM, Shulman LE. Tumulty PA, et al: Systemic lupus erythematosus: review of the literature and clinical analysis of 138 cases. Medicine (Baltimore) 1954; 33: 291-439. Klemperer P, Pollack AD, Baeher G: On the nature of acute lupus erythematosus. NY State J Med 1942; 42: 2225 2226. Lowman EW, Slocumb CH: The peripheral vascular lesions of lupus erythematosus. Ann Intern Med 1952; 36: 1206-1216. Callen JP: Cutaneous vasculitis and its relationship to systemic disease. DM 1981; 28: 20-21. Fries JF, Holman HR: Systemic lupus erythematosus; a clinical analysis. Philadelphia: WB Saunders, 1975. Estes D, Christian CL: The natural history of systemic lupus erythematosus by prospective analysis. Medicine (Baltimore) 1971; 50: 85-95. Dubois EL, Tuffanelli DL: Clinical manifestations of systemic lupus erythematosus. JAMA 1964; 190: 104- 111. Reifenstein EC, Reifenstein EC Jr, Reifenstein GH: A variable symptom complex of undetermined etiology with fatal termination. Arch Intern Med 1939; 63: 553-574. Maddison P, Mogavero M, Provost TT, Reichlin M: The clinical significance of autoantibodies to soluble cytoplasmic antigen in systemic lupus erythematosus and other connective tissue diseases. J Rheumatol 1979; 6: 189-195. Steinberg AD: Studies of immune regulation. In: Decker JL, moderator. Systemic lupus erythematosus: evolving concepts. Ann intern Med 1979; 91: 587-604. Fowles RE, Mason JW: Endomyocardial biopsy. Ann Intern Med 1982; 97: 885-894. Lindquist RR, Guttmann RD. Merrill JP, et al: Human renal allografts: interpretation of morphologic and immunohistochemical observations. Am J Pathol 1968; 53: 851-881.
The American Journal of Medicine
Volume 78
1105
JULIO E. FERREIRO, M.D. WILLIAM M. REITER, M.D. MARIO J. SALDANA,
M.D.
Miami, Florida
From the Departments of Medicine and Pathology. University of Miami School of Medicine, Miami, Florida. Requests for reprints should be addressed to Dr. Julio E. Ferreiro, Department of Medicine R-60, P.O. Box 016960, Miami, Florida 33101.
Manuscript acceptedJune23, 1963.
1100
June 1984
Approximately 5 percent of patients with systemic lupus erythematosus by clinical and pathologic criteria have no demonstrable antinuclear antibodies. This figure is likely to be an underestimate, as it does not include the antinuclear antibody-negative patients wtth limited manifestations in whom the diagnosis of systemic lupus erythematosus is missed. A 23-year-old woman is described who had a history of perplexing bilateral pleural effusions with development of peritoneal effusion after 18 months and positive antinuclear antibody results after 22 months. Tissue pathologic features, initially interpreted as nonspecific, on review revealed striking lymphocytic pertarteritis with endothelial swelling and leukocytoclastic vasculitis often seen in systemic lupus. A selective defect in the suppression of T cell effector function, such as direct cell-mediated cytotoxicity, with intact suppressor systems for B cell effector function, such as antibody production, can be postulated in this patlent. This would explain the active cellular tissue pathology with the lack of prominent antinuclear antibody production. Osler [l] in 1895 emphasized that “erythema exudativum” (systemic lupus erythematosus) was a systemic disease with variable visceral manifestations that need not be accompanied by dermatologic findings. Much had been learned by 1935, allowing Baeher et al [2] to publish an extensive clinical and pathologic description of this disease. However, it was not until the discovery of the lupus erythematosus cell phenomenon by Hargraves et al [3] in 1948 that the diagnosis could be extended to patients in whom the full clinical picture of systemic lupus erythematosus was not present. In a 1953 report of the first large series to make clinical use of the lupus erythematosus cell, Dubois [4] stated that “There is no classic pattern of this illness, and the diagnosis must be based on an over-all view of the entire clinical picture with the aid of the lupus erythematosus test. Because of its varied forms, many of these cases are at present masquerading under other diagnoses.” The lupus erythematosus test has gradually been replaced by direct assays for antinuclear antibodies [5,6], increasing sensitivity and allowing recognition of even earlier and more subtle forms of this disease. Although the presence of antinuclear antibodies is no longer considered specific for systemic lupus erythematosus, their detection remains almost a sine qua non of diagnosis. However, it has become apparent that approximately 5 percent of patients with systemic lupus by clinical and pathologic criteria have no demonstrable antinuclear antibodies [7-g]. This figure is likely to be an underestimate, as it does not include the antinuclear antibody-negative patients with limited or
The American Journal of Medicine Volume 78
CHRONIC SEROSITIS
unusual presentations in whom the diagnosis of systemic lupus has been missed as in the time before the lupus erythematosus cell test. These patients continue to present a diagnostic challenge. The following case report records the two-year search for the elusive cause of recurrent pleural and peritoneal effusions in a young woman and the difficulties in arriving at the diagnosis of systemic lupus erythematosus. It may also provide clinical and pathologic correlation for recent advances in the elucidation of the immunopathogenesis of this intriguing disease. CASE REPORT In March 198 1, a 23-year-old Caucasian woman presented to a community hospital with a three-month history of intermittent pleuritic chest pain and generalized chest aching. She denied antecedent trauma or respiratory illness and was without cough, sputum production, dyspnea, fever, weight loss, or malaise. There was no significant past medical history. Her father had had tuberculosis. Physical examination showed no abnormalities except for a grade II/IV systolic ejection murmur at the left sternal border and diminished breath sounds and dullness at the lung bases. Results at laboratory evaluation, including erythrocyte sedimentation rate and antinuclear antibody level, were normal. A tuberculin skin test (5 TU of PPD) produced a 10 mm reaction. Chest x-ray revealed bilateral pleural effusions without infiltrate, adenopathy, or mass lesions. Results of echocardiography and gallium scanning were normal. Bilateral thoracentesis with pleural biopsy was performed. The fluid was reported as an exudate with a normal glucose level showing prominent neutrophils, eosinophils, and lymphocytes without malignant cells. The biopsy specimens reportedly showed nonspecific pleuritis. All culture results were negative. The patient was then transferred to Jackson Memorial Hospital. After review of the initial data and repeated examination and serologic studies, she was discharged in May 198 1 to begin a course of isoniazid and ethambutol for possible tuberculous pleuritis. Over the subsequent year, she was seen frequently by one of us (JEF). She continued to have episodic chest discomfort poorly responsive to analgesics and nonsteroidal anti-inflammatory agents. Bilateral pleural effusions reaccumulated and persisted. No pertinent physical fihdings developed and laboratory evaluation, including erythrocyte sedimentation rate and antinuclear antibody determination, remained unrevealing. There was one episode, by history, of transient left arm weakness, but subsequent radioisotope brain scanning showed nothing abnormal. In May 1982, she was evaluated with thoracoscopy and repeated biopsy. There were no new findings. By November, she continued to have chest pain and also noted abdominal discomfort. Physical examination again revealed signs of pleural effusions, but ascites and a right adnexal mass were present as new findings. The erythrocyte sedimentation rate was noted to be elevated to 42 mm per hour for the first time, and antinuclear antibodies were again not found. Ultrasound examination revealed a cystic mass in the left pelvis, and
IN SYSTEMIC
LUPUS ERYTHEMATOSUS-FERREIRO
ET AL
computed tomography revealed a solid mass in the right pelvis. Exploratory laparotomy revealed healed right pelvic inflammatory disease and a left hemorrhagic corpus luteum. The surface of the uterus and the area of the terminal ileum had an unusual gelatinous appearance, but biopsy of these tissues and of the peritoneum showed anly nonspecific inflammation. There was no evidence of pelvic abcesses or suppuration consistent with active pelvic inflammatory disease. By January 1983, malaise, anorexia, and weight loss had developed. There were no other new symptoms. She was again admitted to hospital. On physical examination, her blood pressure was 130180 mm Hg, pulse 80 beats per minute, and temperature 98.8”F. There was no alopecia, skin and mucous membranes were without lesions, and there was no lymphadenopathy. Dullness and decreased breath sounds were noted at the lung bases; a pleural rub was not heard. There was mild diffuse chest wall tenderness. There was no jugular venous distention, heart sounds were normal with a grade II/VI early systolic ejection murmur at the lower left sternal border without radiation, and there was no pericardial rub. The abdomen was distended, with shifting dullness and mild diffuse tenderness without rebound. The liver span was 9 cm, and the spleen was not palpable. The joints were normal, and results of neurologic examination were normal. Chest x-ray revealed bilateral pleural effusions and pleural reaction (Figure 1). Computed tomography of the abdomen revealed ascites without organomegaly or masses. Fluid from paracentesis was an exudate with 290 blood cells (30 percent polymorphonuclear leukocytes and 70 percent monocytes). There were no malignant cells. Blood chemistry and hematologic parameters and results of urinalysis were all normal. Serologic tests for syphilis and rheumatoid factor gave negative results. The erythrocyte sedimentation rate was 72 mm per hour, the C3 level was 222 mg/dl (normal 101 to 189) and the C4 level was 43 mg/dl (normal 21 to 63). An-
Figure sions.
June 1984
1.
Chest x-ray showing
bilateral
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ET AL
tinuclear antibody assay gave positive results in a speckled pattern. Results had previously been negative eight times over 22 months. Specific antibodies to native DNA (nDNA), ribonuclear protein (RNP), Smith (Sm), Sjogren’s antigen A @S-A or Ro), and Sjogren’s antigen 6 (SS-B or La) were not detected. Results of assays for circulating immune complexes by the Clq and conglutinin methods were negative. Review of all tissue specimens obtained previously was undertaken. Pleural samples obtained in March 1981 and May 1982 were identical and revealed moderate to dense focal inflammatory cell infiltrates composed of lymphocytes, monocytes, and eosinophils in the submesothelial fibroconnective tissue space. They had a characteristic distribution in and around conglomerates of arteriolar and capillary vessels (Figure 2A). In one specimen, a small area of fibrinoid necrosis was noted (Flgure 28). The capillaries had marked
swelling of the endothelium frequently occluding their luminae (Figure 3). Several fragments of intercostal muscle showed many discrete foci of myositis with necrosis of muscle fibers (Figure 4). The cytologic composition of the pleural fluid was remarkable for its high content of eosinophils with lesser numbers of lymphocytes, polymorphonuclear leukocytes, and reactive mesothelial cells. The biopsy specimens of pelvic peritoneum and terminal ileum showed extensive leukocytoclastic vasculitis. Involved vessels were arterioles and capillaries showing dense polymorphonuclear leukocytic infiltration and eosinophilia (Figure 5). The eosinophils were present both within the confines of the vessels and in the perivascular space. The patient began receiving prednisone, with relief of chest and abdominal pain, disappearance of pleural and peritoneal effusions, return of the erythrocyte sedimentation rate to normal, and reversion of the antinuclear antibody results to negative. In summary, the patient was a 23-year-old woman with a history of perplexing pleuritis with effusion, myositis, and predominantly lymphocytic periarteritis who, after 18 months,
Figure 2. Biopsy of pleura (A) showing proliferation of capillaries with distinct “cuffing” by lymphocytes. Eosinophi/s, present in the fibrotic stroma, were far more numerous in the pleural exudate. Focus of “fibrinoid” necrosis (B) is associated with polymorphonuclear leukocytes and eosinophils undergoing kariolysis (hematoxylin and eosin stain; original magnification X 79, reduced by 30 percent).
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Figure 3. Higherpower view of a focus of capillary prolifera tion as illustrated inFigure 2 A. Due to the marked endothe/la/swelling, the capillary luminae are difficulf to discern (L) (hematoxylin and eosin stain; original magnification X 760, reduced by 30 percent).
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had polyserositis with peritonitis and peritoneal effusion, leukocytoclastic vasculitis, and, after 22 months, positive antinuclear antibody results. A diagnosis of systemic lupus etythematosus was made, and there was complete response of the clinical illness to corticosteroid therapy. COMMENTS Recurrent pleuritis is a frustrating diagnostic challenge, A in many cases, conveyed by the term “idiopathic.” report on the use of thoracoscopy in cases of undiag-
nosed pleural effusion [lo] described evaluation of 18 patients, nine of whom were found to have malignancy, two infection, and seven nonspecific inflammatory findings. In a report on the follow-up study of 27 patients in whom the cause of pleural effusion remained indeterminate after extensive initial evaluation [ 111, diagnosis was eventually made in 16, including one with systemic lupus erythematosus, but could not be reached in 11. In a review of the Mayo Clinic experience with longpleural effusion undiagnosed after thoracotomy, term follow-up study of 5 1 patients was reported [ 121. A diagnosis was eventually made in 18, including two with systemic lupus erythematosus. One of these patients was initially suspected of having systemic lupus, but the antinuclear antibody result did not become positive until nine months after surgery. In the remaining 33 patients, the pleural effusion was said not to recur, and no disease became apparent. Undiagnosed effusions of possible collagen vascular cause that are said not to recur must be viewed in light of the observation that approximately 35 percent of patients with systemic lupus erythematosus have spontaneous remissions lasting up to eight years [4,13]. Pleural effusions occur with great frequency in the collagen vascular autoimmune diseases such as systemic lupus erythematosus; however, in our patient, the absence of other clinical features and the negative serologic results initially reduced the likelihood of these possibilities. Over time, as the other possible processes were excluded and mutisystem involvement developed, a clinical diagnosis of systemic lupus became more reasonable. The development of the positive speckled antinuclear antibody result at the time when the disease seemed most active was decisive in providing evidence of an autoimmune process. Review of the pathologic specimens provided additional support for a diagnosis of systemic lupus erythematosus. There was the finding of lymphocytic periarteritis with endothelial swelling often described in systemic lupus [ 2,4,14,15], the unexpected finding of myositis and finally the observation of leukocytoelastic vasculitis. Usually recognized as a dermatologic finding, leukocytoclastic vasculitis can be part of a number of systemic diseases [ 161; of all of these, systemic lupus erythematosus is the one compatible
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with this patient’s other findings and clinical course. It should be pointed out that the pathologic findings in this case were not reported by several pathologists involved in the initial study of the biopsy material, suggesting that once malignancy and granulomatous disease are ruled out, relatively subtle inflammatory changes may easily be overlooked. It was only after the clinical problem began to unravel that the need for a more critical review of the biopsy material arose and led to the recognition of the changes described. This experience underscores the need for close collaboration between the clinician and the pathologist in the interpretation of “nonspecific” inflammatory changes in cases of obscure pleural or peritoneal disease. Pleuritis, manifested as pleurisy or pleural effusion, is a common finding in systemic lupus erythematosus, being present at some time in approximately 50 percent of patients [4,17-191. As an initial manifestation, it occurs in only 3 percent [4,18]. In an extensive clinical
Figure 4. Microscopic view of intercostal muscle with intense cellular infiltrate mainly composedof lymphocytesand eosinophils. These foci of myositis were numerous and showed distorted and necrotic skeletal muscle fibers (M) (hematoxylin and eosin stain; original magnification X 760, reduced by 30 percent).
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analysis of systemic lupus erythematosus, Fries and Holman [ 171 stated that chest pain is vaguely characterized or predominantly pleuritic. The finding of intercostal muscle myositis as well as pleuritis in our patient may explain this kind of vague chest discomfort. Myositis tends not to be emphasized as a part of systemic lupus, but it is reported as a major clinical finding with objective documentation in 5 percent of one series [ 181 and noted to be a common finding in pathologic studies
patients, but he stated that it did not occur in the absence of congestive heart failure or renal failure, neither of which was present in our patient. Other authors report peritoneal serositis in 16 percent of their patients [ 181; furthermore, Reifenstein and colleagues [20] found areas of peritonitis in 72 percent of an autopsy series. The evaluation of antinuclear antibodies has moved from the simple detection of antibodies reactive with uncertain nuclear antigens to identification of some of the specific antigens. Although there appears to be a group of patients with systemic lupus who are antinuclear antibody-negative by conventional assay techniques, this does not prove they lack autoantlbody production. These patients may have antibodies that are reactive with antigens not present in the usual assay systems employed. In a review of 66 patients with antinuclear antibody-negative systemic lupus erythematosus [9] 41 were found to have antibodies to Ro, 21 of whom also had antibodies to La. An additional 18 patients had antibodies to single-stranded DNA. Only seven had no antibody-antigen reaction identified. When serum samples from patients with anti-80 antibodies were assayed for antinuclear antibodies using KB human epithelioid cells as substrate rather than the usual mouse liver slices, most showed a positive speckled nuclear or cytoplasmic fluorescent pattern corresponding to the locations of the Ro and La antigens in this substrate. Anti-R0 antibodies are found in approximately 30 percent of antinuclear antibody-positive patients with systemic lupus erythematosus patients but are rare in normal subjects or patients without collagen vascular disease [21]. Their practical utility derives from the support that give to the diagnosis of a collagen vascular autoimmune disease when clinical features are suspicious but insufficient for diagnosis and routine antinuclear antibody assay gives negative results. Among the possible clinical differences between groups of antinuclear antibody-positive and antinuclear antibody-negative patients, the negative group seems to have more prominent dermatologic findings and less prominent renal involvement [ 7-91. The validity of this might be questioned in light of the intrinsic utility of dermatologic findings in suggesting the diagnosis of systemic lupus erythematosus despite negative antibody results. The close connection postulated among autoantibodies, circulating immune complexes, and renal disease may suggest an explanation for the scarcity of renal involvement in patients who seem to have less active or different autoantibody production. Within the antinuclear antibody-negative group, particular serologic findings do not seem to correlate with clinical features. In our patient, who was without dermatologic or renal involvement, assays for nDNA, RNP, Sm, Ro, and La
1151. Abdominal pain, generally believed to be secondary to visceral vasculitis, has been noted at some time in approximately 35 percent of patients [4,18]. It is an initial finding only very rarely [4]. Ascites is rarely reported. It was noted by Dubois [4] in 24 percent of his
Two’high-power views of the severe leukocyfoFigure 5. elastic vasculitis in the peritoneal biopsy specimen. The walls of the vessels are densely infiltrated by polymorphonuclear leukocytes and eosinophils, almost obscuring the vascular luminae (L) (hematoxylin and eosin stain; original magnification X 1,240, reduced by 30 percent).
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antibodies and circulating immune complexes gave negative results, even when the antinuclear antibody results were positive. The implication may be that this patient’s antinuclear antibodies were directed against as yet unidentified nuclear antigens, either without great propensity for the formation of circulating complexes or with intact mechanisms for the rapid clearance of such complexes. From early hope that work on the biochemistry behind the lupus erythematosus cell phenomenon would unravel the cause of the disease has come the realization that antinuclear antibodies may be important only as an epiphenomenon, perhaps contributing to the complications of systemic lupus erythematosus but not of primary pathogenic significance. In an elegant discussion of immune regulation in systemic lupus, Steinberg [22] provided fascinating information that allowed a coherent explanation of variable serologic findings and clinical activity. In patients with systemic lupus, anti-T cell antibodies have been described that selectively kill subpopulations of T cells involved in suppression and control of 6 and T cell functions. In
some patients, antibodies kill only T cells that suppress other T cell effector functions, such as direct cellmediated cytotoxicity, but not T cells responsible for suppression of B cell effector functions, such as antibody production. In systemic lupus, antinuclear antibody production could be correlated with defects in the T suppressor system for B ceil effector functions. This aspect of the suppressor system would be functionally ineffective before florid autoantibody production could occur. The selective T suppressor cell defect for T effector function alone can be postulated in our patient, explaining both the absence of prominent autoantibody production and the active cellular tissue findings, which can be considered analogous to the lymphocytic infiltrates seen in early acute T cell-mediated rejection of tissue transplants 123,241. Further studies are certainly needed on the mechanisms of tissue damage and immune regulation in systemic lupus erythematosus. ACKNOWLEDGMENT We thank Dr. Laurence B. Gardner for his help and suggestions in the preparation of this manuscript.
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