In 2009, a question of proper practices was brought before the Arizona Regulatory Board of Physician Assistants. The patient in question was seen in an emergency department by a PA/physician health care team for complaints of cough and fever at home. In question was the team’s decision to discharge the patient, who had a history of immunosuppression with an anti–tumor necrosis factor (anti-TNF) medication for a chronic joint disorder, without ordering laboratory tests or blood cultures. Although there is textbook instruction for evaluation of patients with infection who use agents in this drug class,1 many clinicians may be unaware that blood cultures should be drawn as part of a proper workup.
In the United States, medications that have anti-TNF-alpha (anti-TNF-a) properties, including adalimumab, etanercept, and infliximab, are approved by the FDA to treat rheumatoid arthritis (RA).2 Many patients take a second medication; others, a combination of medications. Options include methotrexate, cyclosporine, prednisone, and hydroxychloroquine. Typically, anti-TNF medications represent second- or third-line therapy after unsatisfactory response to disease-modifying antirheumatic drugs (DMARDs).
Although anti-TNF medications are effective for treatment of autoimmune diseases like RA, it should be noted that TNF-a is an important component in the proper functioning of the immune system. Accordingly, it is recognized that patients who use anti-TNF medications are at increased risk for infection.3 Indeed, patients with RA are already at greater risk for contracting infectious illnesses, even before immunosuppressive medications are administered.4
TNF is one cytokine that is responsible for humoral activation and subsequent inflammation.5 In RA and certain other diseases (eg, Crohn’s disease, lupus), TNF-a’s interaction with other cytokines is at least partially responsible for the inflammation that leads to RA-associated joint damage.5 Infliximab and adalimumab are monoclonal antibodies developed specifically to bind with TNF-a, thereby neutralizing a pathway for further release of inflammatory cytokines.
In contrast to recombinant soluble receptors, such as etanercept, the site-specific monoclonal antibodies for TNF-a (ie, infliximab, adalimumab) may play a greater role in suppressing macrophages, which contribute significantly to cellular immunity. Macrophage inhibition may further increase the body’s vulnerability to opportunistic infection.6
Anti-TNF Agents: Clinical Trials
The relationship between treatment with immunosuppressive agents (including infliximab and other anti-TNF medications) and serious infection is evident in the literature. In a 2005 study, Listing et al4 followed patients for 12 months after they were started on etanercept, infliximab, anakinra (another cytokine inhibitor), or DMARDs (controls). Ninety-two (26.5%) of the 346 patients who were given infliximab, compared with 6% of 601 controls, developed infection; of these, 20 patients (21.7%) had a determinable serious infection (ie, that was considered life-threatening or resulted in inpatient treatment, significant disability, or death). Thus, serious infection affected 5.8% of the patient population studied who had received infliximab.
Five of the 512 patients who used etanercept were diagnosed with sepsis, but no episodes of bacteremia were recorded among the infliximab patients. The most prevalent serious infections observed were pneumonia, infective arthritis, and various skin and subcutaneous infections (see table4). Less prevalent respiratory tract ailments included bronchitis, lung abscess, and pleural infection. Overall, small numbers of cases of sepsis were reported, making it difficult for the study authors to comment on the disparity of sepsis rates among treatment groups.4
Another prospective study followed 28 patients (median age, 53) who were treated with infliximab between 1999 and 2002.7 Dosages administered ranged from the standard 3 mg/kg every 8 weeks to 10 mg/kg every 4 weeks, with variation in duration of treatment. A 13% higher rate of infection was reported among these patients, compared with patients who received conventional therapy (DMARDs) over a two-year period.
Six patients were determined to have serious, life-threatening infections (ie, requiring hospitalization or IV antibiotic therapy). Of these, two were given a diagnosis of bacteremia via blood cultures. The cultures grew Streptococcus pneumoniae in one patient, who was also diagnosed incidentally with Pneumocystis carinii through bronchial washings, and the other patient had blood cultures positive for Staphylococcus aureus and bilateral necrotizing pulmonary abscesses.
Case Studies
Individual case studies of infection in patients taking infliximab or other anti-TNF agents for RA reveal specific illnesses, their time lines, and relevant patient management. Crum et al2 reported an example of the common pathogen S pneumoniae in a 47-year-old patient who developed a left lower lobe pneumonia. Three of four blood cultures were positive, CBC with differential showed abnormal results, and the patient’s temperature on presentation was 39.5°C.
In a report of two cases of severe abdominal infection during administration of anti-TNF medication, one 40-year-old woman using infliximab for severe RA presented with a temperature of 39.2°C and a three-day history of abdominal pain. Escherichia coli was identified from blood cultures, although urine cultures were negative. CT led to a diagnosis of pyelonephritis. The patient had become septic but improved after 48 hours’ therapy with IV cefuroxime and gentamicin.8