68-Year-Old Woman With Dyspnea and Chest Pain

Residents' Clinic 68-Year-Old Woman With Dyspnea and Chest Pain STEVEN

A. VERNINO, M.D., PH.D.,*

AND KEVIN

G. MODER, M.D.t

A 68-year-old woman sought medical advice because of 5 months of worsening fatigue and dyspnea on exertion, weight loss, and chest pains. She had a 6-year history of joint and systemic complaints thought to be due to rheumatoid arthritis (RA). One month earlier, she had been admitted to her local hospital because of shortness of breath and chest pain. At that time, congestive heart failure and rheumatoid lung disease were diagnosed, and furosemide was prescribed. She was admitted to our institution for further evaluation. Her chest symptom was a brief stabbing pain that increased with deep inspirations. It was located over the left lateral chest area but occasionally involved the anterior, substernal, and right lateral chest area. It did not worsen with exertion; on several occasions, it reportedly resolved with the sublingual use of nitroglycerin. The patient also reported a 22.7-kg loss of weight over the past 2 years and recurrent fevers and night sweats during the past several weeks. She described herself as depressed. The patient's past medical history was significant for mild RA diagnosed 6 years earlier. She had received orally administered prednisone for the past 3 years and was treated briefly with methotrexate, which was discontinued because of anemia 6 months before admission. She had a long history of hypertension, which had been well controlled by methyldopa therapy for more than 10 years. She had undergone a subtotal thyroidectomy for multinodular goiter and was taking thyroid hormone replacement therapy.

1. Which one of the following is the least likely cause of this patient's chest pain? a. Pericarditis b. Pneumonia c. Pulmonary embolism d. Rheumatoid pleurisy e. Myocardial ischemia *Resident in Neurology, Mayo Graduate School of Medicine, Mayo Clinic Rochester, Rochester, Minnesota. tAdviser to resident and Senior Associate Consultant in Rheumatology, Mayo Clinic Rochester, Rochester, Minnesota. See end of article for correct answers to questions. Address reprint requests to Dr. K. G. Moder, Division of Rheumatology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo Clin Proc 1996; 71:485-488

The differential diagnosis of chest pain encompasses disorders of many organ systems, including cardiac, pulmonary, gastrointestinal, and connective-skeletal tissues. The most helpful features in narrowing the diagnosis are the character and timing of the pain, Brief stabbing pain that intensifies with respiration is typical of pleural or pericardial irritation, such as may occur in pericarditis, pneumonia, pleural effusion, pulmonary embolism, or pulmonary infarction. Rheumatoid pleurisy should also be considered, even though chronic asymptomatic pleural effusions are more commonly encountered. Although myocardial ischemia must always be considered when chest pain is evaluated, anginal pain usually does not have a pleuritic component and, more commonly, has dull pressurelike features rather than a sharp quality. Physical examination revealed an ill-appearing woman with labored respirations (24 breaths/min) who had severe kyphosis. She was afebrile and normotensive. Decreased breath sounds in the right lung base and fine crackles in both lung bases were noted. A soft apical holosystolic murmur was present. The jugular veins were flat, and she had no peripheral edema. Findings on abdominal examination were unremarkable; no organomegaly was evident. A stool sample was negative for occult blood. Examination of the joints revealed reducible, nontender swan-neck deformities of the second and fourth digits of both hands. The patient had no active synovitis. The joint findings did not support the diagnosis of active RA. A chest roentgenogram revealed a small right pleural effusion (Fig. 1). Because the pleural effusion was small, thoracentesis was not performed. We believed that her chest pain was a consequence of pleural irritation. Although her constitutional symptoms suggested the presence of an underlying systemic illness, our preliminary assessment raised doubt about the diagnosis of RA and congestive cardiac failure.

2. Which one of the following is least likely to help in confirming the diagnosis ofrheumatoid arthritis in this patient? a. Symptoms of the patient b. Physical examination c. Rheumatoidfactor d. Examination of synovial fluid e. Plain roentgenogram of the hands 485

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0.77 X 109 ; lymphocytes, 0.32 X 109 ; and monocytes, 0.08 X 109 ) , and platelet count of 149 X 109/L. These findings indicated either a hematologic disorder or a reflection of a nonhematologic systemic illness.

3. Which one of the following tests is least likely to help identify the cause of this patient's leukopenia and anemia? a. Peripheral blood smear b. Folate and vitamin B l 2 studies c. Serum iron studies d. Reticulocyte count e. Erythrocyte sedimentation rate

Fig. 1. Chest roentgenogram, showing small right pleural effusion and hiatal hernia.

RA is a chronic systemic illness that is characterized primarily as a symmetric polyarthritis. Systemic symptoms, such as fatigue and weight loss, may be seen before the development of articular disease. On questioning, most patients admit the presence of morning stiffness and joint swelling. On examination, evidence of active synovitis or evidence of prior arthritis with joint deformities is usually noted. Typically, the small joints of the hands and feet are affected, but any joint may be involved. The distal interphalangeal joints of the hands, however, are usually spared. Rheumatoid nodules may also be seen on extensor surfaces.' The test for rheumatoid factor is positive in 80% of patients. High titers of rheumatoid factor tend to correlate with more aggressive disease and the presence of extra-articular manifestations. If synovial fluid from an actively involved joint is examined, it may show many inflammatory cells, but this finding is not specific for RA. Our patient had no clinical evidence of ongoing synovitis; thus, joint aspiration was not warranted. On roentgenography of the hand, joint space narrowing, periarticular osteoporosis, soft tissue swelling, and marginal erosions may be evident. These changes are often best seen in the small joints of the hands and feet. Our patient had a negative test for rheumatoid factor. She was seronegative and had neither rheumatoid nodules nor erosive changes on roentgenograms. These findings would be unusual in a patient with long-standing RA and pulmonary involvement. Laboratory studies revealed a hemoglobin concentration of 8.1 g/dL, mean corpuscular volume of 93.0 fL, total leukocyte count of 1.2 X 109/L (differential: neutrophils,

Microscopic examination of a peripheral blood smear can establish the morphologic characteristics of the deficient erythrocytes or the presence of immature or dysmorphic leukocyte forms in the peripheral blood. Because automated cell counting systems can occasionally have systematic errors, the smear is also important to confirm the presence of cytopenia. Folate and vitamin B 12 are required for effective erythropoiesis. Severe megaloblastic anemia due to deficiencies of these vitamins can be associated with leukopenia and thrombocytopenia because of disordered bone marrow function. In contrast, iron deficiency causes a hypochromic, microcytic anemia but is not a cause of pancytopenia. The reticulocyte count is useful for evaluating the response of the bone marrow to a low hemoglobin level. An inappropriately low reticulocyte level suggests that the anemia is due, at least in part, to a failure of the bone marrow. Bone marrow dysfunction can be attributable to many causes and often results in deficiencies of all blood elements. A normochromic, normocytic anemia is frequently present in a patient with a systemic inflammatory condition such as RA. The combination of RA, leukopenia (specifically, neutropenia with an absolute granulocyte count of less than 2.0 X 109/L), and splenomegaly constitutes Felty's syndrome. A substantially increased erythrocyte sedimentation rate, weight loss, recurrent fevers, and evidence of other extraarticular manifestations of RA are often present. This aggressive syndrome of RA occurs in less than 1% of patients with RA and generally in patients who have had RA for years.' As previously indicated, our patient did not have convincing evidence to support the diagnosis of RA or Felty's syndrome. Felty's syndrome manifests with neutropenia (rather than lymphopenia) and splenomegaly (which was absent in our patient).' Our patient's peripheral blood smear demonstrated pancytopenia with severe lymphocytopenia. Serum folate and vitamin B I2 levels were within the normal range. The reticulocytes were 1.19% despite her anemia. The erythrocyte sedimentation rate was increased (63 mm in 1 hour). Direct Coombs' test was weakly positive. Routine labora-

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tory studies revealed a serum sodium of 133 mEq/L, potassium of 3.4 mEq/L, and creatinine of 0.9 mg/dL and a low sensitive thyroid-stimulating hormone level (0.2 mIU/L). An electrocardiogram showed no abnormalities. Echocardiography revealed an ejection fraction of 70% and no evidence of valvular disease. On the basis of her history, our patient had derived minimal benefit from therapy with furosemide and prednisone. We were concerned that side effects from medications may have complicated the clinical picture. Because of her hyponatremia and hypokalemia, the furosemide therapy was discontinued. We were also concerned that her antihypertensive medication (methyldopa) may have been responsible for some of her other symptoms.

4. Which one ofthe following clinical features or complications in our patient is least likelY to result from the antihypertensive drug that she had been taking for a decade? a. Anemia b. Depression c. Arthralgias d. Thyroid dysfunction e. Chest pain Coombs' -positive hemolytic anemia may be induced by certain medications, including methyldopa, penicillin, and quinidine. In 10 to 30% of methyldopa-treated patients, Coombs' test will be positive, whereas overt hemolytic anemia occurs in less than 1% of such patients." Methyldopa has been associated with a variety of adverse reactions, including hepatitis, black tongue, depression, and arthralgias. It has not been reported to cause thyroid dysfunction. Methyldopa is one causative agent in medication-induced lupus erythematosus (MILE). Positive antinuclear antibodies (ANA) occur in up to 18% of patients receiving methyldopa, and a small proportion of these cases will fulfill the current criteria for diagnosis of systemic lupus erythematosus (SLE).5 Pleuropulmonary involvement in MILE is common, and pleuritic chest pain associated with exertional dyspnea has been reported as the initial symptom ofMILE. 6 Our patient's history of inflammatory but seronegative, nonerosive arthritis is more consistent with SLE than with RA. Her chief complaint of pleuritic chest pain was consistent with a lupus pleuritis. In fact, she did have defining symptoms that met four of the criteria established by the American Rheumatism Association (ARA) for the diagnosis of SLE (arthritis, pleuritis, lymphocytopenia, and a positive ANA titer). ANA studies showed positive results in a homogeneous pattern at a titer of 1:10,240. At this point, we thought that this patient had MILE.

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5. On the basis of the clinical diagnosis, which one of the following is least likely to be found in our patient? a. Normal renal and neurologic function b. Very high titer of antinuclear antibodies c. Presence of antihistone autoantibodies d. Presence of anti-double-stranded DNA (dsDNA) autoantibodies e. Normal serum complement levels The characteristics of MILE differ substantially from those of idiopathic SLE. The prominent symptoms of MILE tend to be musculoskeletal (myalgias and arthritis), constitutional (fever and weight loss), and pleuropulmonary (pleuritis and pleural effusions). Renal and nervous system involvement is rarely seen in MILE. 5.7 A consistent finding in patients with MILE is a positive test result for ANA, often in high titer. In most patients, antihistone autoantibodies are present; however, patients with idiopathic SLE may also demonstrate autoantibodies to histone. Anti-dsDNA autoantibodies are rarely seen in MILE; when present, they support the diagnosis of idiopathic SLE. Other laboratory abnormalities associated with SLE (including hypocomplementemia and false-positive result of a rapid plasma reagin test) are seldom noted in MILE. 5 In our patient, autoantibodies to dsDNA and extractable nuclear antigens were absent. Antihistone autoantibodies were present. Complement levels were normal. This combination of a high ANA titer with a negative anti-dsDNA and positive antihistone antibodies is consistent with the diagnosis of MILE. The methyldopa therapy was discontinued, and the patient received a tapering dose of prednisone. On telephone follow-up 1 month after dismissal, the patient reported resolution of her chest pain and diminished fatigue. DISCUSSION SLE is an autoimmune disease that can affect many organ systems. Idiopathic SLE predominates in young women, with a higher prevalence in racial minorities. The variability and multisystem nature of SLE led the ARA in 1982 to develop epidemiologic criteria for identifying SLE.8 Although these criteria were not intended to be applied to individual patients, these signs and symptoms are ones commonly observed clinically. The 11 ARA criteria are malar rash, photosensitivity, erythematous discoid rash, hematologic disorder (hemolytic anemia, lymphocytopenia, thrombocytopenia), oral or nasopharyngeal ulcers, serositis, nonerosive arthritis, neurologic disorder, proteinuria or active urine sediment, abnormal titer of ANA, and a positive lupus test (LE cells, anti-DNA antibodies, anti-Sm antibodies, false-positive syphilis test). A case of SLE is identified when 4 or more of these 11 criteria are met.

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MILE is most commonly associated with procainamide and hydralazine. Methyldopa was first reported to cause a lupus syndrome in 1982.9 Phenytoin, isoniazid, quinidine, penicillamine, propylthiouracil, and sulfasalazine have also been implicated.Y In addition, all these medications as well as others (including ~-adrenergic blockers, ethosuximide, levodopa, and lithium) can produce a positive ANA test result without clinical disease.Y The epidemiology of MILE differs from that of idiopathic SLE. MILE has no female or racial predominance, and the age at onset tends to be in the fifth or sixth decade of life, which corresponds to the population most likely to be taking the offending medications. Typically, recovery from MILE occurs spontaneously after discontinuation of the causative medication. Resolution of the disease may, however, be prolonged, and ANA positivity may persist for years after discontinuation of the offending agent. In patients with a new-onset inflammatory arthropathy, the differential diagnosis includes both SLE and RA. Occasionally, distinction between these two conditions--especially early in the course of the disease-s-can be difficult. Laboratory studies are only occasionally helpful, and the clinical manifestations are usually more important diagnostic elements. Rheumatoid factor and ANA can be detected in both conditions. Anti-dsDNA and anti-Sm antibodies are more specific for SLE but are present in less than 70% and 30%, respectively, of patients with SLE. 1O Antihistone antibodies may be present in MILE, idiopathic SLE, and sometimes RA in cases of Felty's syndrome. 11 In summary, this case illustrates several key points about the differential diagnosis of an inflammatory polyarthritis, which includes SLE, MILE, and RA. This case also demonstrates that iatrogenic disease due to side effects or idiosyncratic reactions of medications can cause severe morbidity.

For proper recognition of these problems, careful review of the medication history in each new patient and adequate clinical suspicion are necessary.

REFERENCES 1. 2. 3.

4. 5. 6. 7. 8.

9. 10.

11.

Moder KG. A working guide to joint examination in rheumatoid arthritis. J Musculoskeletal Med 1995 Nov; 12:17-20; 27-28; 30; 33-34 Dillon AM. Felty's syndrome. Minn Med 1987; 70:411; 413 Rosenstein ED, Kramer N. Felty's syndrome and pseudoFelty's syndromes. Semin Arthritis Rheum 1991; 21:129142 Petz LD. Drug-induced autoimmune hemolytic anemia. Transfus Med Rev 1993; 7:242-254 Skaer TL. Medication-induced systemic lupus erythematosus. Clin Ther 1992; 14:496-506 Smith PR, Nacht RI. Drug-induced lupus pleuritis mimicking pleural space infection. Chest 1992; 101:268-269 Yung RL, Richardson Be. Drug-induced lupus. Rheum Dis Clin North Am 1994 Feb; 20:61-86 Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et ai. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25:1271-1277 Nordstrom DM, West SG, Rubin RL. Methyldopa-induced systemic lupus erythematosus. Arthritis Rheum 1989; 32:205-208 Notman DD, Kurata N, Tan EM. Profiles of antinuclear antibodies in systemic rheumatic diseases. Ann Intern Med 1975; 83:464-469 Cohen MG, Webb J. Antihistone antibodies in rheumatoid arthritis and Felty's syndrome. Arthritis Rheum 1989; 32:1319-1324

Correct answers: 1. e, 2. d, 3. c, 4. d, 5. d

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