From Grand Rounds from HSS: Management of Complex Cases | Volume 8, Issue 3
A 36-year-old previously healthy man presented with progressive shortness of breath and dry cough for 3 months and intermittent fevers for 2 weeks. He had no Raynaud’s phenomenon, joint pain, muscle weakness, or skin changes. A chest radiograph demonstrated bilateral basilar infiltrates. Computed tomography (CT) angiography showed bilateral basilar ground-glass opacities, traction bronchiectasis, and a dilated thickened esophagus without pulmonary embolism. He was treated with antibiotics without improvement. A bronchoscopy with biopsy was performed, and pathology from the small sample was read initially as organizing pneumonia. Prednisone 60 mg daily was started. His cough and fevers resolved; however, he subsequently experienced worsening dyspnea, 15-lb. weight loss, dysphagia, and proximal muscle weakness. On the 6-minute-walk-test (6MWT), he desaturated to 90%, with a Borg dyspnea score of 4 (“somewhat severe”). Repeat CT demonstrated worsening ground-glass opacification (Fig. 1).
Figure 1A: Initial CT scan of the lungs demonstrates bilateral ground-glass opacities and peribronchovascular consolidation.
Figure 1B: Follow-up CT scan, 8 months later, demonstrates significant improvement in the areas of ground-glass and consolidation with persistent mid- to lower-lobe traction bronchiectasis consistent with fibrotic non-specific interstitial pneumonia without progression.
The patient was readmitted for pulmonary disease progression despite high-dose steroids. Bacterial cultures and tests for respiratory viruses, aspergillus, Pneumocystis jiroveci pneumonia, HIV, and tuberculosis were negative. Antinuclear antibody titer was 1:80 (speckled). Other serologic tests were negative including rheumatoid factor and autoantibodies against cyclic citrullinated peptide, Ro (SSA), La (SSB), double-stranded DNA, ribonucleoprotein (RNP), myeloperoxidase, proteinase-3, Jo-1, Scl-70, anticentromere, RNA polymerase III, and anti–glomerular basement membrane. With steroid therapy, creatine phosphokinase level was normal, and aldolase level was mildly elevated (9.2 U/L; upper limit: 8.1). The patient had an isolated urinalysis with hematuria that resolved on repeat study. On re-evaluation of the small initial biopsy sample, there was concern for capillaritis. Repeat lung biopsy was pursued given diagnostic uncertainty and showed mixed cellular and early fibrotic non-specific interstitial pneumonia (NSIP) (Fig. 2). Cyclophosphamide was given by IV, and eventually a myositis-specific serologic panel was positive for anti-PL-12 (alanyl-tRNA synthetase) antibody.
Figure 2: Right lower lobe lung biopsy demonstrates mixed cellular and early fibrotic non-specific interstitial pneumonia (image courtesy of Alain Borczuk, MD).
The patient was diagnosed with antisynthetase syndrome and received monthly IV cyclophosphamide for 6 months, with an excellent response, evidenced by clinically significant improvement in 6MWT distance (92 m) and Borg dyspnea score (2-unit improvement). Steroids were tapered, and mycophenolate was initiated for maintenance. Eight-month CT imaging improved significantly (Fig. 1). After 12 months of treatment, forced vital capacity was 94% predicted (from 89% 3 months post-treatment), and diffusing capacity for carbon monoxide was 62% predicted (from 57% 3 months post-treatment). Eighteen months after diagnosis, the patient had no pulmonary, musculoskeletal, or gastrointestinal symptoms.
Clinical features of antisynthetase syndrome include myositis, interstitial lung disease (ILD), arthritis, fever, and Raynaud’s phenomenon . The most common radiographic ILD patterns are NSIP and organizing pneumonia . Autoantibodies in antisynthetase syndrome include anti-Jo-1 (most common), anti-PL-7, anti-PL-12, anti-EJ, anti-OJ, anti-KS, anti-Zo, anti-SC, anti-JS, and anti-YRS . Differences in disease features by antisynthetase antibody have been observed. Specifically, anti-PL-12 positivity is associated with amyopathic dermatomyositis and isolated ILD , and patients with anti-PL-12 antibody (vs. anti-Jo-1 antibody) have more severe ILD and worse prognosis . Accordingly, among 202 patients with antisynthetase syndrome, 5-year survival was better in patients with than those without anti-Jo-1 antibody (90% vs. 75%, respectively; p < 0.005) .
Randomized controlled trials testing therapies in antisynthetase syndrome are lacking. Steroids are considered first-line treatment; however, steroid monotherapy is associated with frequent disease flares. Other immunosuppressive agents used off-label include azathioprine, mycophenolate, tacrolimus, rituximab, and cyclophosphamide . In a systematic review, data was pooled from 12 nonrandomized studies that included 141 patients with idiopathic inflammatory myopathy–associated ILD treated with cyclophosphamide . Cyclophosphamide was associated with forced vital capacity and diffusing capacity for carbon monoxide improvement in 58% and 64% of patients, respectively . Our case illustrates symptomatic and radiographic improvement of antisynthetase syndrome treated with cyclophosphamide with durable response at 18 months on mycophenolate maintenance therapy.
Assistant Attending Physician, Hospital for Special Surgery
Assistant Professor of Medicine, Weill Cornell Medical College
Xiaoping Wu, MD, MS
Assistant Attending Physician New York-Presbyterian Hospital
Instructor of Medicine Weill Cornell Medicine
Associate Attending Physician, Hospital for Special Surgery
Associate Professor of Medicine, Weill Cornell Medical College