Side effects observed with anti TNF α biologics? How can these toxicities be limited?
1. Injection site and infusion reactions.
• All injectable TNF inhibitors: injection site reaction (up to 40% of patients) lasting 3 to 5 days. Some cause “bee sting” pain due to the preservative in the liquid. Treat with topical steroid or antihistamine. Rotate the injection sites. Usually reactions stop after 3 months of continued use. Citrate-free formulations cause less injection site pain. If problems persist, lyophilized ETN or certolizumab pegol can be used, which seem to have fewer injection site reactions.
• INF: moderate infusion reactions occur in <6% of patients. Common complaints include headache (20%), nausea (15%), flushing, and dyspnea. Treat by stopping the infusion and restarting at a slower rate. If the patient has more than three drug allergies or has an infusion reaction, premedicate with Allegra (180 mg) 45 minutes before infusion; may also premedicate with aspirin (better than acetaminophen) and, if necessary, Solu-Cortef (100–125 mg IV).
• Serious bacterial infections: the overall prevalence of serious infections is 3% to 4% and overall relative risk is two to three times compared with csDMARDs alone. However, when disease severity, comorbidities, and corticosteroid use are controlled for, the risk of serious infections may not be much higher than with other csDMARDs. Infections tend to be pneumonias which occur more commonly within the first 6 months of use. TNF inhibitors should be stopped in all patients who develop a febrile infection, except for the “common cold.” Patients with an open skin wound are most prone to develop cellulitis, so stopping the TNF inhibitor until the wound is healed is prudent. TNF inhibitors should be avoided in patients with chronic ongoing infections such as osteomyelitis and bronchiectasis with recurrent pneumonias. Although controversial, the risk of infection may be reduced if surgery is performed after waiting at least 1 to 1.5 dosing cycles from the last dose (7–10 days for ETN; 14–21 days for ADA and certolizumab; 4–6 weeks for golimumab; and 6 weeks for INF).
• Opportunistic infection (TB): TNF is important for granuloma formation and integrity. Therefore, all TNF inhibitors can cause reactivation of latent TB (risk increased 2.4 to 8.7×). Owing to long half-life and blood levels, INF may cause more of these infections than subcutaneous formulations. Anti-TNF monoclonal antibodies are more likely (3–4×) than ETN to reactivate latent TB. Patients who reactivate their TB typically do so within 6 to 12 months of starting a TNF inhibitor. In >50% of cases, the reactivation is at a site other than the lung (lymph nodes commonly). Therefore, all patients should be screened for risk factors for TB exposure and should be screened with a PPD or ex vivo testing for TB and chest radiograph before starting a TNF inhibitor. This should be repeated yearly in patients at risk for further TB exposure. Because patients are on immunosuppressants, a PPD ≥5 mm is considered positive even in patients who have received a bacillus Calmette–Guérin (BCG) vaccine previously. The ex vivo IGRA (QuantiFERON-TB Gold and T-SPOT.TB) may be a better screening test for TB than PPD since the skin test is only 70% sensitive. The IGRA test is particularly useful in patients with a history of previous BCG vaccination, which can cause a false-positive PPD, and in patients on immunosuppressive medications, which have a high false-negative rate for PPD skin testing. However, an indeterminant and/or false-negative IGRA can also occur in patients on moderate doses of corticosteroids. Note that the T-SPOT.TB test is more sensitive than the QuantiFERON-TB test in patients on immunosuppressives. If one IGRA test is indeterminate, the other test should be performed. If either test is positive, the patient should be considered to have latent TB. Patients who have a positive TB screening test need treatment with a Centers for Disease Control and Prevention-recommended anti-TB prophylaxis regimen. After 4 weeks of therapy, the TNF inhibitor can be started. In patients with active TB, patients should complete anti-TB therapy before starting a TNF inhibitor; however in some cases it could be started sooner if necessary.
• Opportunistic infections (hepatitis B/C): all TNF inhibitors increase the risk of hepatitis B reactivation. Patients with resolved hepatitis (HBsAg–, HBcAb + , undetectable viral load) have <2% risk of reactivation. As a result of this low rate, these patients can receive TNF inhibitors and have their symptoms, hepatic enzyme tests, and viral DNA loads checked periodically. Alternatively, patients with chronic and inactive hepatitis B (HBsAg + ) should either not receive TNF inhibitors or must receive concomitant antiviral prophylaxis (lamivudine, other) starting 2 to 4 weeks before and continuing while on TNF inhibitors. Patients with hepatitis C can receive TNF agents without antiviral therapy but need hepatic enzyme and viral RNA load monitoring.
• Opportunistic infections (other): TNF inhibitors increase risk of nontuberculous mycobacterial infections, Pneumocystis jirovecii , Listeria monocytogenes , Legionella , herpes zoster, cytomegalovirus, and fungal infections. Patients with previous or current exposure to endemic fungi ( Histoplasmosis , Coccidioidomycosis , others) need to be evaluated for these infections if they develop a febrile illness. INF may be associated with increased risk of fungal infections compared with SC-administered TNF inhibitors.
TNF is important for inducing apoptosis in tumor cells. However, it is unclear if TNF inhibitors increase the risk of malignancy, particularly lymphoma. Studies vary and state that the relative risk may or may not be increased for lymphoma. However, most large studies report that it is not increased over the increased baseline risk (2–3×) of lymphoma associated with the underlying autoimmune disease being treated. Solid tumors are not increased. Melanoma and other skin cancers may be increased (relative risk 1.79× and 1.45×, respectively). Patients who develop a cancer (other than melanoma) while receiving a TNF inhibitor do not have worse histology, more widespread disease, or worse prognosis. Whether or not patients with active cancer or recently treated cancer can safely receive a TNF inhibitor is controversial, although it should not be used in patients with melanoma or lymphoma. Some experts recommend not starting these agents until a patient is cancer-free for 5 years, while others will use TNF inhibitors in any patient with a previously treated solid organ malignancy.
4. Demyelinating syndromes.
Brain demyelination (multiple sclerosis-like), optic neuritis, Guillain–Barré syndrome, myelitis, polyradiculopathy, and peripheral demyelinating neuropathy have been reported rarely. Most are reversible when the TNF inhibitor is stopped. Therefore, TNF inhibitors should not be given to patients with a history of multiple sclerosis, optic neuritis, or other demyelinating disorder. Some experts recommend brain magnetic resonance imaging in patients with a strong family history of demyelinating disease to look for occult lesions. If silent lesions are present, do not give TNF inhibitors to the patient.
5. Autoimmune phenomenon.
Between 10% and 50% of patients on TNF inhibitors will develop a positive antinuclear antibody, 5% to 10% patients develop anti-dsDNA antibodies (usually IgM isotype), and a small number (0.2%–0.4%) develop drug-induced lupus (DIL; aka TNF-α inhibitor-induced lupus-like syndrome). A few patients have developed antiphospholipid antibodies and antineutrophil cytoplasmic antibodies (ANCAs) that are rarely clinically significant. Patients who develop DIL have mild symptoms of arthritis, cytopenias, and serositis that resolve with TNF inhibitor discontinuation. Small-vessel leukocytoclastic vasculitis has rarely been reported. Concomitant use of MTX does not lessen the frequency of these manifestations. Pretreatment and/or routine monitoring of autoantibody levels is not indicated in the absence of symptoms.
• Antidrug antibodies: over 20% of patients treated with INF will develop HACAs. Patients who develop HACAs may lose their response to INF (i.e., neutralizing antibodies) and/or experience more severe infusion reactions. Concomitant MTX therapy in RA patients (not spondyloarthropathy patients) is recommended to decrease the risk of developing HACAs. Less than 10% of patients receiving SC formulations of TNF inhibitors develop antidrug antibodies. This is decreased to <1% with concomitant MTX use. These antibodies are rarely neutralizing but may bind and increase the clearance, making the TNF inhibitor less effective. Drug levels/activity and antidrug antibodies can be measured in patients on INF or ADA.
• Congestive heart failure (CHF): avoid TNF inhibitors (especially INF) in patients with class III or IV CHF.
• Hematologic: neutropenia, thrombocytopenia, and pancytopenia have rarely been reported. Monitoring with periodic CBC (every 3–6 months) is recommended.
• Palmoplantar psoriasis: less than 1% patients develop worsening psoriasis on palms and soles. Not prevented by using MTX. Etiology unknown but may be attributable to increased IFN-α production. Patients with SAPHO (acronym for synovitis, acne, pustulosis, hyperostosis, and osteitis) or pustular psoriasis are more likely to get this with INF or ADA.
• Additional toxicities: sarcoidosis, subacute cutaneous lupus-like rash, seizures, colonic perforations, increased liver enzymes > three-fold elevation (2%–4%), severe hepatotoxicity (rare but most common with INF), and noninfectious pulmonary infiltrates have been reported.