Blue fingers linked with breathlessness

Ms. O had always been active. She made it a point to exercise at least three times a week — not only for her health but also because she enjoyed the feeling it gave her. She jogged, rode her bicycle, and played tennis in warm weather. Employed as an editorial assistant, she usually walked up the four flights of stairs to her office every day. At 28, Ms. O was a nonsmoker and had never had any health problems. In general, she felt extremely fit. She had regular gynecologic exams but did not see a primary-care clinician.

1. Symptoms

One Thursday, as Ms. O walked up the stairs to her office, she became short of breath after the first flight. She stopped on the landing for about a half minute, then continued. When she arrived at her office, she was winded. For the remainder of the day, she felt well and had no further difficulty.  The next day, she was better, with only a slight sensation of dyspnea on the stairs. Over the weekend, she put it all out of her mind.

On Monday, however, she had a problem with the stairs again. After a brief rest on the first landing, she could barely go up the second flight. She took the elevator to the fourth floor. For the rest of the week, she was unable to walk up the stairs as she once had. Worse, on Wednesday morning, when she usually jogged in the park, she was too short of breath to run. She rested for the remainder of that week, but her symptoms did not disappear. In fact, even grocery shopping was more of an effort than before. In addition, when she was outside, she noticed her fingers occasionally hurt and seemed bluish or purplish in color. Once her fingers turned white, then red, then bluish after she had rearranged some food containers in the freezer. Ms. O decided it was time to see a clinician. 

2. Physical findings

At the time of her visit, her BP, pulse, and temperature were normal. She had no cough or chest pain; there was no history of exposure to any infectious agent or environmental pathogen. Crackling rales were present at both lung bases. The cardiac examination and the remainder of her physical evaluation appeared normal. Her clinician arranged for a tuberculin skin test and obtained blood tests and a chest radiograph. The blood count indicated a very mild anemia, with hemoglobin 11.3 g/dL; a WBC count was normal. An erythrocyte sedimentation rate (ESR) was high (41 mm/hr). Interstitial infiltrates were seen in both lungs, particularly at the bases. A pulmonology consultation was arranged.

Fortunately, Ms. O saw the pulmonologist within the week. Her history and physical findings were unchanged from before, except that now she had an early-morning nonproductive cough, and the painful color changes in the fingers were more prominent. Her tuberculin skin test was negative. She was started on a macrolide antibiotic. A CT scan confirmed the presence of infiltrates without masses. Subsequent bronchoscopy with transbronchial biopsy demonstrated changes of chronic inflammation with interstitial fibrosis and focal intra-alveolar fibrinoid proliferation — findings suggestive of bronchiolitis obliterans with organizing pneumonitis. Cultures for fungi, acid-fast organisms, and other bacteria were all negative. An echocardiogram was normal.

Because of the pulmonary findings in association with prominent signs of Raynaud's disease, Ms. O was referred to me for rheumatologic consultation. When I saw her, vital signs were normal and soft crackling rales were heard at both lung bases. Her skin appeared normal and supple, with marked purplish discoloration of the fingers. There was slight weakness of the neck flexor and hip flexor musculature.

Her creatine kinase was 263 units/L (normal: 135), serum myoglobin 90 ng/mL (normal: 70), and ESR 41. An antinuclear antibody determination was negative. Electromyography demonstrated myopathic changes.

3. Diagnosis

The differential diagnosis of diffuse interstitial pulmonary infiltrates is very broad. In Ms. O's case, extensive testing and questioning had not uncovered any evidence for infectious, occupational, or environmental causative factors. The coincidence of recent-onset Raynaud's disease with the pulmonary findings suggested the possibility of a connective tissue disorder. Among the connective tissue disorders, the differential diagnosis is again quite extensive. Scleroderma, systemic lupus erythematosus, vasculitic syndromes, rheumatoid arthritis, and sarcoidosis are all possibilities. While there was nothing in Ms. O's case to point definitively to one of these disorders, it is always difficult to rule them out absolutely.

The evidence did point to the recently recognized group of disorders known as “myositis synthetase syndrome,” which is characterized by interstitial lung disease, myositis, Raynaud's disease, and other conditions. Arthritis of the small joints of the hands as well as of the wrists, knees, and shoulders may occur, along with fever and skin thickening over the fingers. This syndrome is most common in women near the fifth decade of life and is strongly associated with the genetic HLA type DR3, DRW52. The hallmark of the antisynthetase syndrome is the antibody to one of the t-RNA synthetases. The most common is the antibody to Jo-1, also known as “antihistidyl t-RNA synthetase.” Ms. O had antibody to Jo-1.

The clinical course of patients with the antisynthetase syndrome may be difficult, marked by exacerbations and remissions. However, Ms. O's symptoms and pulmonary findings resolved with corticosteroids. Her laboratory tests have returned to normal, and she remains well after six months. Close observation will be continued.

Dr. Kagen is professor of medicine at Weill Medical College of Cornell University and attending physician at the Hospital for Special Surgery and New York Presbyterian Hospital, all in New York City.

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