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Balancing the Benefits of Biologic Therapy for Autoimmune Disease Against the Risks of Mycobacterial Infections

Management pearls from a new expert review


Since the approval of etanercept in 1998, use of biologic therapy to treat rheumatoid arthritis (RA) and other autoimmune diseases has rapidly expanded. Five tumor necrosis factor-α inhibitors (TNFis) are now available, as well as drugs that target interleukins, Janus kinase (JAK), and CTLA-4.


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These agents have transformed care, but they also are associated with higher risks of serious and opportunistic infections than traditional disease-modifying antirheumatic drugs. A new review provides insights for clinicians on balancing benefits of biologics for RA against risks of tuberculosis (TB) and nontuberculous mycobacterial (NTM) infections.


According to Cassandra Calabrese, DO, who is dual-trained in rheumatology and infectious disease and first author of the review in Infectious Disease Clinics of North America, of all the TNFis, etanercept carries the lowest risk of TB and is the treatment of choice for patients with RA who are at risk for TB, if a TNFi is needed. “It is a soluble receptor fusion protein and causes less complement-mediated cytotoxicity and apoptosis of affected cells than monoclonal TNFis, such as infliximab and adalimumab,” she says.

Few patients with latent TB are seen in Cleveland Clinic’s Department of Rheumatologic & Immunologic Disease because the disease is not endemic to the United States. Risk factors include immigrating from an endemic country or being in close contact with someone with active TB

Of the biologics for RA, rituximab is believed to have the lowest risk of TB. “Reports of TB reactivation in the setting of anti-B-cell therapy are very rare,” says Dr. Calabrese. “JAK inhibitors also have a lower TB signal, as does the CTLA-4 agonist abatacept.”

Nontuberculous mycobacterial infections

In contrast to TB, NTM is ubiquitous in the United States, often found in water and dirt. Because they are not transmittable person-to-person, these infections are not reportable; hence, getting a handle on background incidence is difficult. Some reports do exist, however, linking NTMs with RA and its treatment.

“RA itself may be a risk factor for NTM, which is not surprising because chronic lung disease is common in patients with RA,” says Dr. Calabrese. “Data from population-based studies suggest that incidence of NTM may be upwards of 100 per 100,000 patient-years in individuals with RA who are taking TNFis — double that of RA patients not exposed to the drugs.”

Risk factors for NTM infection include lung disease, diabetes and hypertension. The number one concern, however, is concomitant treatment with steroids. “I can’t stress enough how significantly steroids elevate risk of NTMs (and all infections) in patients with RA when used in conjunction with biologic therapy,” says Dr. Calabrese.

Who is at risk?

There are no formal recommendations for screening for NTM infection prior to starting a patient with RA on biologic therapy. Nevertheless, Dr. Calabrese urges clinicians to be “hypervigilant” about assessing for risk factors and monitoring for symptoms of infection in individuals being treated with the drugs.


“The most common symptom is a chronic cough but disseminated disease can present with cutaneous manifestations,” she says. Diagnostic testing for an NTM includes chest x-ray, computed tomography, sputum culture and a bronchoscopy with cultures and staining. Dr. Calabrese also recommends consultation with an infectious disease specialist.

Balancing benefit and risk

For physicians, the keys to balancing benefit and risk of biologic therapy, says Dr. Calabrese, are the following:

  • Screen patients for latent TB before starting biologic treatment.
  • Assess risk for latent TB according to Centers for Disease Control and Prevention-defined risk factors, such as prolonged time spend in an endemic country, having spent time in a homeless shelter or jail and being a healthcare worker.
  • Counsel patients about the infection risk in the setting of biologics before prescribing.
  • Once patients are on a biologic, have a low threshold for ordering a chest x-ray, if chronic unexplained cough develops.

“I do a lot of counseling with patients about biologics and they are often very afraid of side effects such as infections because they’ve seen the commercials,” says Dr. Calabrese. “But I remind them that RA is a disease that affects the entire body, not just the joints. Having it is almost equivalent to diabetes in terms of cardiovascular risk, increasing risk of heart attack and stroke. Benefits of treating the inflammation with a biologic outweigh the side effects of the drugs, and in particular, the risk of infection.”


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