Development of active tuberculosis following initiation of infliximab despite appropriate prophylaxis

Sir, Prospective cohort studies have demonstrated an increased risk of active tuberculosis in patients treated with tumor necrosis factor antagonists (anti-TNF agents) [1]. Current guidelines support chemoprophylaxis with isoniazid (INH) for 6–9 months prior to the initiation of anti-TNF agents in patients with evidence of latent tuberculosis [2]. We present two rheumatoid arthritis patients who had positive tuberculin skin tests (TST). Despite receiving an adequate course of INH for latent tuberculosis infection, both patients developed active tuberculosis after initiation of infliximab. Patient 1 is a 58-yr-old male Chinese immigrant with a 3 yr history of seropositive rheumatoid arthritis who was admitted to the hospital with three weeks of fevers, chills, productive cough, night sweats and altered mental status. His medical history was otherwise notable for chronic inactive hepatitis B and chronic obstructive pulmonary disease. Three yrs prior, he had a positive TST. Chest computed tomography (CT) revealed emphysematous changes and multiple calcified granulomas consistent with prior tuberculosis. He was treated with a 9 month course of INH, 300 mg/day. Despite treatment with methotrexate and sulfasalazine, his rheumatoid arthritis remained active, requiring frequent intra-articular steroid injections and oral corticosteroids. Fourteen months prior to admission he started infliximab infusions (6 mg/kg) in addition to methotrexate and sulfasalzine, and was successfully tapered off corticosteroids. On admission, the patient was ill appearing and thin. He had a temperature of 102.6° with normal respiratory rate and oxygen saturation. The breath sounds were decreased and there were diffuse expiratory wheezes in all the lung fields. There was no lymphadenopathy. Initial investigations included normal complete blood counts, electrolytes, liver and renal function tests, as well as negative tests for HIV, hepatitis C and rapid plasma reagent. Sputum stains for acid-fast bacilli, pneumocystis carinii and legionella species were negative. A chest radiograph and chest CT scan demonstrated no new infiltrates or pathological lymphadenopathy. A CT scan of the abdomen and pelvis revealed enlarged mesenteric and retro-peritoneal nodes. Bone marrow biopsy and right inguinal lymph node biopsy did not show evidence of malignancy or granulomatous disease. Given the high level of concern for tuberculosis, the patient was empirically started on INH, rifampin, pyrizinamide and ethambutol. Nine days after discharge the sputum cultures grew mycobacterium tuberculosis, with sensitivity to ethambutol, INH, pyrazinamide, rifampin and streptomycin. He has since made a full recovery. Patient 2 is a 77-yr-old woman originally from Trinidad with seronegative rheumatoid arthritis treated with infliximab who was admitted to the hospital with a three week history of worsening weakness and fatigue. One week prior to admission she developed a non-productive cough, fevers and chills. On the day of admission she was profoundly weak and was noted by family members to have slurred speech. Her medical history was also notable for sickle cell trait, glucose-6-phosphate dehydrogenase deficiency, sideroblastic anaemia and a single episode of bilateral pulmonary embolism. Ten yrs prior she had a positive TST; chest radiographs did not show any abnormalities suggestive of tuberculosis at the time. Seven yrs prior to admission she was treated with a 7 month course of INH after starting prednisone. She had a negative TST 4 yrs prior. She had previously failed methotrexate and subsequently failed combination therapy with leflunomide. She was started on treatment with infliximab at 4 mg/kg every 6 weeks 4 months earlier. Medications on admission included methotrexate (17.5 mg orally once per week), prednisone (5 mg/day), infliximab, warfarin and oxycodone. On admission, her temperature was 103 F and oxygen saturation was 92%. On chest auscultation, there were inspiratory crackles at the left lower lung base. She had right hip pain with very limited range of motion. Initial laboratory evaluation was notable for a white blood cell count of 2600 cells, with 59% neutrophils and 9% bands. Serum electrolytes were normal; blood and urine cultures were negative. A chest radiograph was consistent with left lower lobe pneumonia and the patient was initially treated for community-acquired pneumonia with levofloxacin. By the fourth hospital day she had failed to improve; a chest CT demonstrated bilateral multiple small pulmonary nodules consistent with miliary tuberculosis. A right hip joint aspiration yielded sterile, non-inflammatory synovial fluid. A bone marrow biopsy showed normal myeloid elements. On the ninth hospital day a sputum sample was positive by gen-probe amplified mycobacterium tuberculosis direct test. Treatment was started with rifampin, INH, ethambutol and pyrazinamide. The following day she developed respiratory failure requiring mechanical ventilation for the next 9 days. She gradually recovered and was discharged to a rehabilitation facility after a 34 day hospital course. Eventually, sputum cultures grew mycobacterium tuberculosis, with sensitivity to ethambutol, INH, pyrazinamide, rifampin and streptomycin.