Myopathy for the general internist: Statins and much more

CASE 5: FEVER, UNDIAGNOSED LUNG DISEASE, NO MYOSITIS

In January 2001, a 39-year-old woman was admitted to the hospital after 5 weeks of fever (temperatures 103°–104°F) and myalgias. An extensive workup was negative except for low-titer antinuclear antibody and for mild basilar fibrosis noted on chest radiography. She left the hospital against medical advice because of frustration with a lack of a specific diagnosis (“fever of unknown origin”).

Two months later, at a follow-up rheumatology consult, she reported more myalgias and arthralgias, as well as fever. Chest radiography now showed pleural effusions. Her fingers had color changes consistent with Raynaud phenomenon. At that time, I diagnosed an undifferentiated connective tissue disease and told her that I suspected an autoimmune condition that would need time to reveal itself. In the meantime, I treated her empirically with prednisone.

In April, she returned, much more short of breath and with more prominent diffuse pulmonary infiltrates. Physical examination revealed subtle Gottron changes. Testing revealed poor pulmonary function: forced vital capacity (FVC) 56%, forced expiratory volume in 1 second (FEV₁) 52%, and diffusing capacity for carbon monoxide (Dlco) 40%. Blood testing was positive for anti-PL-12 antibody, one of the non-Jo-1 antisynthetase antibodies. At this time, we treated her with glucocorticoids and tacrolimus.

More than 15 years later, this patient is doing well. Her skin rash, joint symptoms, and fever have not returned, and interestingly, she never developed myositis. Her Raynaud symptoms are mild. Her most recent pulmonary function test results (January 2018) were FVC  75%, FEV₁ 87%, and Dlco 78%. Although these results are not normal, they are much improved and allow her to be completely functional without supplemental oxygen. Echocardiography showed  normal pulmonary artery systolic pressure (25 mm Hg). She was still taking tacrolimus and prednisone. When we tried to stop tacrolimus after she had done well for many years, her condition flared.

Non-Jo-1 antisynthetase syndrome: Bottom line

Patients with a non-Jo-1 antisynthetase syndrome often present without myositis symptoms and may never manifest myositis symptoms. Likely because of this presentation, diagnosis of a specific connective tissue disorder is delayed, perhaps leading to increased mortality risk from pulmonary disease. Chronic immunosuppression is often required for these autoimmune conditions.

CASE 6: DERMATOMYOSITIS, RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE

A 58-year-old woman presented in the summer of 2012 with a photosensitive rash. The following January, she returned with polyarthritis, mild muscle weakness, and a dermatomyositis-pattern rash. Her CK level was normal, and her antinuclear antibody and Sjögren syndrome antibody test results were negative. She improved on low-dose prednisone and methotrexate.

She was originally referred to me in May of that year for worsening rash and mild weakness. She denied pulmonary symptoms, but examination revealed faint basilar crackles. I increased her prednisone dosage to 20 mg/day and started mycophenolate mofetil mainly for the mild cutaneous and myositis features. I also recommended high-resolution CT of the lungs and pulmonary function tests, which she underwent in early June. High-resolution CT showed nonspecific mild infiltrates with minimal ground-glass opacities.

On July 1, she presented to her local emergency department with severe shortness of breath, requiring oxygen 12 L/min. She had a palmar rash. Repeat high-resolution CT showed dramatic worsening compared with the scan the previous month. Because of continued inadequate oxygenation, she was transferred to our center. A blood test later was positive for antimelanoma differentiation-associated gene 5 (MDA-5) autoantibody, previously known as anticlinically amyopathic dermatomyositis (anti-CADM)-140 antibody (based on immunoprecipitation results).

She died on the third day after transfer, just 2 months after I had originally seen her, at which time she had had no pulmonary symptoms.

Clinically amyopathic dermatomyositis

Anti-CADM-140, first reported from Asia,^18–20 is an autoantibody-associated disease but not an antisynthetase. It is associated with dermatomyositis; patients often have a “vasculopathy” with cutaneous ulcerations and palmar papules.

MDA-5 is a cytoplasmic protein that “senses” viral RNA and induces production of type 1 interferon. It is involved in the innate immune defense against viruses.

Anti-MDA-5 positivity is associated with a poor pulmonary outcome.²¹ In our cohort from the University of Pittsburgh, many patients died within 3 years, compared with about a 40% survival rate in patients with dermatomyositis who tested negative for this antibody. That being said, many patients with anti-MDA-5 do not develop rapidly progressive interstitial lung disease.

Autoimmune interstitial lung disease: Bottom line

Autoimmune interstitial lung disease is easy to miss, especially in the case of a non-Jo-1 syndrome, for 3 important reasons:

• The autoimmune features may initially be subtle (eg, Raynaud phenomena, mild dermatomyositis rash, undifferentiated connective tissue disease)
• Autoantibody testing is not often ordered, is not standardized, or may be unavailable 
• Providers are mistakenly reassured that a patient who tests negative for antinuclear antibody does not have an autoimmune condition.

To emphasize the last point, in a cohort of 202 patients who tested positive for an antisynthetase antibody, only half were antinuclear antibody-positive, but nearly three-quarters demonstrated anticytoplasmic staining on indirect immunofluorescence (due to the location of the autoantigen in the cytoplasm), making the latter a better screening test for an antisynthetase antibody. For scleroderma, 99% were antinculear antibody-positive, but for myositis, this test is much less sensitive.²²