Erythema nodosum, a “red flag” during anti‐TNF therapy

Dear Editor, A 72-year-old woman was diagnosed with psoriatic arthritis 26 years ago at another center. She had a factor VIII deficit and did not tolerate nonsteroidal antiinflammatory drugs (NSAIDs), although she was occasionally taking aceclofenac. In January 1996 she had two tender and four swollen joints, a limited range of motion in four peripheral joints and in the cervical spine, joint deformities in the hands (distal interphalangeal joints, DIP) and feet (first metatarsophalangeal joint, MTP). She had extensive cutaneous lesions from psoriasis. Plain-film X-rays showed erosions in her hands and tarsal bones, bilateral grade four sacroiliitis, and left scapulohumeral osteoarthritis. She had an erythrocyte sedimentation rate (ESR) of 28 mm/h. In a step-up approach, she was treated with oral sulfasalazine (2 g/day) and methotrexate (15 mg/week) as tolerated. In March 2003, she had herpes zoster on the right side at the level of L4. In June 2005, she presented with clinical and biological (ESR 49 mm/h) impairment. She had no known past history of tuberculosis (TB). Tuberculosis skin test, purified protein derivative or PPD (booster), was negative, the chest plain-film was normal, and etanercept was prescribed (50 mg/week subcutaneously) with good response (ESR 27 mm/h). In April 2008, mild renal insufficiency (serum creatinine 1.47 mg/100 mL; normal 0.50–1.00 mg/100 mL), arterial hypertension and vitamin D deficiency were detected; we prescribed furosemide (40 mg/day), manidipine (20 mg/day), and calcidiol (0.266 mg every other week). In May 2008, etanercept was discontinued because of a huge cutaneous injection site reaction that disapeared in weeks. Then, taking into account the different pharmacological profile, adalimumab was commenced and the same response was maintained. In May 2009, adalimumab was also discontinued because of tender erythematous swelling on the front of legs, compatible with erythema nodosum, followed by fever, persistent dry cough, lymph node enlargement, asthenia and anemia due to iron deficiency. A thoracic and abdominal computed tomography (CT) scan with oral contrast agent showed several large right inguinal (maximum of 22 mm in diameter) and smaller retroperitoneal and iliac lymph nodes. Chest X-ray was normal. The lungs high-resolution CT (HRCT) scan was normal. Relevant blood test results were: ESR, 28 mm in the first hour; red blood cell count 3.23 m/mm (normal 3.80–5.50 m/mm); hemoglobin, 6.4 g/mL (normal 12.0–16.0 g/mL); mean corpuscular volume, 72 pg (normal 78–100 pg), which required blood transfusion. Fecal occult blood was positive. Upper gastrointestinal tract endoscopy and colonoscopy revealed chronic gastritis and colonic diverticulosis and hemorrhoids. Serum calcium, phosphorus and angiotensin-converting enzyme (ACE) were normal. Purified protein derivative was now strongly positive (20 mm/72 h). Histologic study of an inguinal lymph node (20 mm in diameter) found caseating granulomata. Periodic acid Schiff (PAS) and Ziehl–Nielsen stains were negative. We assumed that the patient had tuberculous adenitis and prescribed triple therapy (isoniazid, rifampin, ethambutol) for 2 months (May–July 2009) followed by double therapy (isoniazid, rifampin) for 5 months (July– December 2009). The erythema nodosum resolved in weeks. In December 2009, an abdominopelvic CT scan with oral contrast agent showed only a single right inguinal lymph node (19 mm in diameter) and again, in March 2010, there was a little asymptomatic right inguinal lymph node.