A 25-year-old Caucasian female presented to the emergency department with intermittent joint pains for four weeks and hemoptysis. She reported first symptoms of difficulty making a fist, first with the right hand and then progressing to the left hand. She reported migratory joint pain that affected her bilateral elbows and shoulders. Each joint pain episode lasted approximately 36 hours before migrating to different joints. Three days before admission while she was traveling in the Midwest United States, she had three bouts of small-volume hemoptysis, approximately one teaspoon each time, which prompted her to come to the hospital. A review of systems was notable for an unexplained 15-pound weight loss in one year. She has a past medical history of migraine and a history of Achilles tendon infection in 2019. She took sarecycline daily for acne for two months before admission. She works with chimpanzees in the laboratory. Her physical examination was significant for non-blanchable purpuric rash on the left elbow and toes and swelling and erythema of the left knee (Figure 1 and Figure 2). Her nasal and otoscopic examination was unremarkable.
Her presenting blood investigation was notable for normocytic anemia, low iron levels, and hypereosinophilia (eosinophils 9%) (normal range: 0%-5%). She had mildly elevated total bilirubin and C-reactive protein (CRP). Her urine analysis was positive for ketones and red blood cells (RBCs). Initial chest X-ray showed confluent airspace disease, prominent in the lower lobe, and right greater than left (Figure 3).
In summary, the patient presented with migratory joint pain, purpuric rash, weight loss, anemia, low iron levels, indirect hyperbilirubinemia, hypereosinophilia, microscopic hematuria, and mild hemoptysis. Due to the subacute course and systemic involvement, an autoimmune process such as systemic vasculitis was highly suspected. Within the differential, infectious and paraneoplastic processes were also considered. Infectious workup, including human immunodeficiency virus (HIV), hepatitis B and C panels, Histoplasma, parvovirus, Mycoplasma pneumoniae, tuberculosis, Pneumocystis jirovecii, Cytomegalovirus, herpes simplex virus (HSV)-1, and HSV-2, were all negative. Transthoracic echocardiogram did not show evidence of endocarditis or atrial myxoma. Vasculitis diseases such as ANCA-associated vasculitis and immune complex vasculitis were highly suspected. We sent autoimmune laboratory results for ANCA and other autoimmune diseases that could be related to immune complex vasculitis such as cryoglobulins vasculitis, lupus, and rheumatoid arthritis. Goodpasture's syndrome and sarcoidosis were also in the differential diagnosis, which could be obtained by bronchoscopy. Anti-glomerular basement membrane (GBM) antibody was sent for possible Goodpasture's syndrome. The sarecycline that the patient used before admission has never been reported to be associated with ANCA-associated vasculitis before.
Finally, a skin biopsy was suggested and did not show vasculitis. However, it revealed dermal blood vessels with intravascular thrombi without evidence of vasculitis. Because of the increased risk of hypercoagulable states from intravascular thrombi and concern for hemolytic anemia, hematology was consulted. The patient underwent multiple hematology workups, including prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, beta-2 glycoprotein, cardiolipin antibody, cryoglobulins, lupus anticoagulant, protein C, protein S, antithrombin III, and factor V Leiden, which were all negative. She had mildly elevated D-dimer (592 ng/mL) (normal range: <281 ng/mL), which did not support any specific diagnosis. Her direct and indirect Coombs tests were negative, suggesting that this was less likely to be autoimmune hemolytic anemia. Her peripheral blood smear did not show evidence of schistocytes, and her lactic dehydrogenase (LDH), haptoglobin, was negative, which helped rule out microangiopathic hemolytic anemia.
Pulmonology was consulted due to an unclear diagnosis, and bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy was performed. The bronchoscopy revealed erythematous lesions on the tracheal mucosa (Figure 4). Cytology from BAL was negative for malignancy. Biopsy showed airway wall fibrosis, chronic inflammation, and scattered eosinophils with no definitive evidence of vasculitis. Fragments of lung parenchyma with hemosiderin-laden macrophages and focal intra-alveolar fibrin were seen. The findings were consistent with diffuse alveolar hemorrhage. Hypersensitivity pneumonitis was less likely due to a negative test. Acute eosinophilic pneumonia was less likely due to low numbers of eosinophils from BAL.
Later in her hospitalization, the autoimmune laboratory results came back. Antinuclear antibody (ANA), anti-GBM antibody, and cyclic citrullinated peptide (CCP) were negative. Rheumatoid factor was 19.5 IU/mL (normal range: <12 IU/mL). Her anti-PR3 antibody and cytoplasmic ANCA (c-ANCA) titer were positive at 1:320. Given the positive anti-PR3 antibody and c-ANCA, ANCA-associated vasculitis, especially GPA, microscopic polyangiitis (MPA), was the most likely diagnosis. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) is more associated with anti-myeloperoxidase (MPO) antibody than PR-3 antibody and thus less likely to be the cause. The patient was treated with 1 g methylprednisolone for three days before transitioning to prednisone 60 mg daily for presumptive vasculitis.
Nephrology was consulted for microscopic hematuria. Her urine sediment showed multiple white blood cells, dysmorphic RBC, and RBC casts raising concerns of renal involvement from systemic disease. Since the diagnosis remained unclear even after a skin biopsy and a bronchoscopy, a kidney biopsy was performed. Finally, a kidney biopsy showed pauci-immune necrotizing and crescentic glomerulonephritis involving about 20% of intact glomeruli and minimal (1% of glomeruli) chronic changes of the parenchyma (focal global glomerulosclerosis). A diagnosis of granulomatosis with polyangiitis with articular, pulmonary, renal, and skin involvement was made. Due to her fertile age, rituximab was chosen instead of cyclophosphamide to avoid side effects as it was not an inferior option. The patient eventually received one dose of IV rituximab at 375 mg/m2 and was discharged with outpatient rheumatology follow-up.