1Center for Clinical Studies, Houston, TX, USA
2University of Texas Medical Branch at Galveston School of Medicine, Galveston, TX, USA
3Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX, USA
Biologic compounds are being used more frequently to treat a multitude of systemic inflammatory conditions. These novel compounds are composed of antibodies or other peptides that act through one of three mechanisms: inhibiting inflammatory cytokine signaling (typically tumor necrosis factor or TNF), inhibiting T-cell activation, or depleting B-cells. The increase in use and ever expanding list of new immune modulating therapies make knowledge of the infectious complications associated with immune modulation even more important. Of particular concern is the risk for developing atypical and opportunistic infections including tuberculosis, herpes zoster, Legionella pneumophila, and Listeria monocytogenes.
adverse effects, anti-tumor necrosis factor-alpha, infections, monoclonal antibodies, psoriasis, risk factors, TNF-α inhibitors
The availability of immune modulating drugs has revolutionized treatment for psoriasis and psoriatic arthritis, as well as a variety of other inflammatory diseases. After approximately one decade of post-marketing surveillance and experience with biologics, they are generally regarded as safe and efficacious therapy for an increasing number of diseases. However, the risk of infection is a concern with long-term immunosuppressive treatment. We review current literature regarding the risk of infection associated with the biologic therapies most commonly used by dermatologists today: tumor necrosis factor-alpha (TNF-α) inhibitors and ustekinumab.
Infliximab (a chimeric monoclonal anti-TNF antibody) (Remicade®), adalimumab (a fully human anti-TNF monoclonal antibody) (Humira®), and etanercept (a recombinant soluble decoy TNF-receptor) (Enbrel®) exert therapeutic effects via the suppression of TNF-α, a cytokine released by macrophages that is central to cell-mediated immunity.
Ustekinumab (Stelara®), an interleukin 12 and interleukin 23 antibody, targets the p40 subunit shared by the two cytokines to prevent receptor interaction, thereby inhibiting signaling and further cytokine production. Pooled data from phase 2 and 3 clinical trials suggest that there is no clear pattern of heightened infection risk compared with controls (placebo, etanercept) for up to 3 years.1 However, ustekinumab has only been US FDA approved since 2009, so knowledge of long-term risk is limited. Some associations have been reported and are outlined below.
Available evidence regarding the risk of herpes zoster (HZ) with TNF-α therapy is conflicting. One retrospective analysis of psoriasis patients treated with anti-TNF therapy, acitretin, cyclosporine, methotrexate, corticosteroids, UVB phototherapy, or PUVA showed an elevated incidence of HZ infection in patients receiving any treatment except alefacept, efalizumab, or adalimumab when compared with controls (patients without any treatment for 1 month or without treatment for 3 months if most recent treatment was infliximab). None of the biologic drugs studied were associated with a clinically significant increased risk of HZ, however, treatment with infliximab approached clinical significance (hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 0.92-3.43).2
Strangfeld et al. demonstrated a significantly higher risk of HZ in rheumatoid arthritis (RA) patients treated with etanercept, infliximab, or adalimumab compared with conventional disease-modifying antirheumatic drugs (DMARDs). The crude incidence rate per 1000 person-years of HZ was 11.1 (95% CI: 7.9-15.1) for infliximab or adalimumab, 8.9 (95% CI: 5.6-13.3) for etanercept, and 5.6 (95% CI: 3.6-8.3) for conventional RA treatments. Adjustments for age, rheumatoid arthritis severity, and glucocorticoid use demonstrated a significantly higher risk with treatment using monoclonal antibodies (HR: -1.82 [95% CI: -1.05-3.15]), but not for etanercept or the anti-TNF-α antagonists as a class.3
While ustekinumab was not included in the aforementioned studies, there is a report of two patients developing severe, mulitdermatomal herpes zoster 1 and 9 months after initiating therapy with usetkinumab. Vaccination against HZ is strongly encouraged before initiating therapy with ustekinumab.4 Currently, there are no clear recommendations regarding HZ vaccine (Zostavax®) administration during treatment with TNF-α inhibitors. Interestingly, results of a recent study suggest that treatment with TNF-α inhibitors may be associated with a lower incidence of postherpetic neuralgia,5 this finding is also supported by Strangfeld’s data3 as noted by Whitley in his editorial discussing the prevalence of herpes zoster during immunosuppressive therapy.6
The risk of latent tuberculosis (TB) reactivation in patients treated with biologics is well-established. A Cochrane review evaluating the adverse reactions of all biologic therapies (all TNF-α inhibitors, anakinra, tocilizumab, abatacept, and rituximab) for any indication found an increased risk of TB reactivation (odds ratio [OR]: 4.68, 95% CI: 1.18-18.60) in comparison with the control treatment group, and a number needed to treat to harm (NNTH) of 681.7 Several of the drugs included in this review are not commonly used by dermatologists. A recent analysis of the risks associated with TNF-α inhibitors in psoriasis patients found that the lifetime risk of TB was 0-17.1% in comparison to 0.3% without the use of TNF-α inhibitors. The authors point out that while there is an increased risk, the risk of tuberculosis is still far lower than the lifetime risk of America’s more common afflictions: cancer (40.4%), heart disease (36.2%), and stroke (18.4%).8
Variation in the risk of TB reactivation in patients treated with TNF-α inhibitors may be expected based on the endemic rates of TB. A recent Spanish study of psoriasis patients receiving any anti-TNF therapy found a 29% incidence of latent TB infection (LTBI), which was comparable to the incidence found in the general population.9 Conversely, a Swedish study found an increased risk of TB infection for RA patients compared with the general population. Treatment with either infliximab or etanercept was associated with a higher risk of TB in RA patients compared with RA patients not treated with TNF-α inhibitors.10
Among all TNF-α inhibitors, infliximab is the agent most heavily associated with greater risk of TB. A study of the FDA Adverse Event Reporting System (AERS) between 1998-2002 concluded an increased risk of developing TB for infliximab and etanercept users (144 per 100,000 infliximab-treated patients compared with 35 per 100,000 etanercept-treated patients, p<0.001) with a rate ratio of 4.17.11 In France, a case-control analysis of newly diagnosed TB associated with anti-TNF agents found that exposure to infliximab or adalimumab versus etanercept was an independent risk factor for TB, OR: 13.3 (95% CI: 2.6-69.0) and OR: 17.1 (95% CI: 3.6-80.6), respectively.12
Infection with the intracellular bacterium Listeria monocytogenes (L. monocytogenes) in patients receiving biologic therapy is well-documented. An assessment of the incidence of Listeria infections in patients using TNF inhibitors was performed by comparing data from the Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases (BIOBADASER) with the Spanish Rheumatoid Arthritis Registry Cohort Study (EMECAR). RA patients treated with TNF-α antagonists had an increased rate of Listeria infection in comparison to RA patients treated with conventional therapy, as well as the general population.13
A recent review described the first case of L. monocytogenes endocarditis associated with infliximab, and identified 92 cases of L. monocytogenes infections related to infliximab treatment in the FDA AERS database. Meningitis was the most common type of infection reported (69 cases, 75%), followed by sepsis (20 cases, 21.7%) and listeriosis (3 cases, 3.3%). Further information was lacking on most of the cases in the AERS database, however, additional immunosuppressive therapy was being used in 22 out of 24 cases detailed in the review.14 Infectious complications with Listeria are seen more frequently in patient treated with infliximab versus etanercept,15 perhaps because of the more versatile binding of infliximab to both soluble and cell surface TNF-α instead of predominantly soluble TNF-α. However, there have been several cases of L. monocytogenes septic arthritis in patients treated with etanercept.15-17 Adalimumab is reported less frequently in association with L. monocytogenes infections, but a case of L. monocytogenes meningitis with this therapy has been documented.18
Legionella pneumophila (L. pneumophila) infections account for up to 15% of cases of community-acquired pneumonia requiring hospitalization.19 Antigenic components of L. pneumophila are potent stimuli of TNF-α production, which along with interferongamma, interleukin-6, and interleukin-1 drive induction of the innate immune response. Inhibiting this response with TNF-α antagonists should predispose to legionellosis.
In France, a registry of 486 multidisciplinary clinical departments was designed by Recherché Axée sur la Tolérance des Biothérapies (RATIO) to prospectively collect data on severe and opportunistic infections in people receiving TNF-α antagonists over a 1-year period. There were 10 cases of L. pneumophila infections; 6 of the patients were treated with adalimumab, 2 with etanercept, and 2 with infliximab. The median duration of therapy when infection occurred was 38.5 weeks. The relative risk of L. pneumophila infection in people receiving anti-TNF therapy was reported as 16.7-21.0 in comparison with the general population. However, this may be an overestimate as 9 out of 10 patients were receiving concomitant immunosuppressive therapy (prednisone, methotrexate, azothioprine, or sulfasalzine), except for one, who was receiving infliximab alone.20 A recent case review of the incidence of legionellosis in patients receiving infliximab included 10 cases19 in addition to those reported by the French registry;20 concomitant immunosuppressive therapy was being used in at least 8 out of 10 of those cases.19 A British study comparing rates of infection in rheumatoid arthritis patients receiving DMARDs therapy versus TNF inhibitors (etanercept, infliximab, adalimumab, and anakinra) found that the rate of serious infection was equal in both cohorts, but a higher rate of infection with intracellular microbes (Legionella, Listeria, and Salmonella) occurred in those using TNF inhibitors.21
While the exact relative risk of developing L. pneumophila during treatment with TNF inhibitors is difficult to predict, there seems to be a clear association in the literature. It is important for clinicians to be mindful of this association and to consider adding floroquinolone or macrolide antibiotics for coverage of Legionella (and other agents of atypical pneumonia) in patients on anti-TNF-α therapy who present with pulmonary symptoms.
In 2008, the FDA issued a ‘black box warning’ to alert clinicians of the risk of endemic mycoses in patients receiving anti-TNF-α therapy. The report included 240 cases of histoplasmosis in patients treated with infliximab, etanercept, or adalimumab. Most cases occurred in areas where the fungus is most prevalent. The most concerning point raised by this report was that in 21 patients, the signs of infection was unrecognized and antifungal therapy was delayed; 12 of those patients died.22 A recent review addressed challenges of diagnosing fungal infections in patients receiving TNF-α antagonists: atypical presentation and symptoms of infection mimicking the underlying disease. The higher incidence of Histoplasmosis capsulatum (H. capsulatum) compared to Blastomyces dermatididis or Coccidiodes spp. in patients taking TNF-α inhibitors is attributed to the wide geographic area of H. capsulatum, as well as the fact that infection with H. capsulatum is contained almost exclusively by cellmediated immunity.23 Multiple cases of aspergillosis have also been associated with TNF-α antagnonists.24
In patients who are starting treatment with TNF-α antagonists, there is no reliable method to predict the risk for acquiring fungal infections. However, patients should be counseled to avoid high-risk activities that may predispose them to exposure to the endemic mycosis in their geographic areas.25 Patients who develop endemic fungal infection while receiving TNF-α inhibitors should immediately discontinue the biologic and initiate therapy with antifungal agents in concordance with the Infectious Diseases Society of America guidelines for treatment of these infections in immunocompromised hosts.23
The risk of infection is always a concern with any immunosuppressive treatment, and such infections are documented with all biologic therapies. Of the TNF inhibitors, infliximab seems to carry the highest risk of infection. In comparison to infliximab, use of etanercept (HR: 0.64, 95% CI: 0.49-0.84), abatacept (HR: 0.68, 95% CI: 0.48-0.96), rituximab (HR: 0.81, 95% CI: 0.55-1.20), and adalimumab (HR: 0.52, 95% CI: 0.39-0.72) was associated with lower rates of hospitalized infections, although the authors attributed variability in patients’ risk of infection to factors other than treatment with biologics.26 Additionally, a 3-year national French registry (RATIO) study comparing incidence of nontuberculosis opportunistic infections (45 cases in 43 patients) between TNF-α inhibitors found that risk factors were infliximab (OR: 17.6 [95% CI: 4.3-72.9]; p<0.0001) or adalimumab (OR: 10.0 [95% CI: 2.3 to 44.4]; p=0.002) versus etanercept.27
Still, it is difficult to predict the true risk to patients commonly seen in the dermatologist’s clinic when: 1) Most reviews of biologics-associated opportunistic infections are comprised of patients being treated for conditions other than psoriasis and 2) Most cases of opportunistic infections associated with biologic therapy occur when additional systemic immunosuppressive therapy is being utilized. Variation in dates of approval for these medications also translates to variation in experience.
The overwhelming majority of evidence supports the idea that biologics are safe for the treatment of psoriasis. Grijalva et al. recently published the results of a US multi-institutional collaboration examining whether or not TNF-α antagonists are associated with an increased risk of serious infections requiring hospitalization in comparison to non-biologic therapy.28 The cohorts studied included 10,484 RA, 2,323 inflammatory bowel disease, and 3,215 psoriasis and spondyloarthropathies. In total, 1,172 serious infections were identified, the majority of which (53%) included pneumonia and skin and soft tissue infections. The conclusion was that TNF-α inhibitors are in fact, not associated with an increased risk for hospitalization for serious infection.28 These findings contradict a general, replicated pattern seen in previous studies evaluating the safety of TNF-α antagonists, i.e., that there is a higher rate of serious infection in patients taking anti-TNF-α therapy compared to patients using non-biologic therapy that decreases with time. Dixon and Felson’s editorial29 addressed the question of why the time-dependent risk of serious infection was not seen in Grijalva’s report. The authors attribute this finding to the unique design of Grijalva’s study, i.e., comparing the risk of serious infections between new user cohorts, not between patients initiating treatment with anti-TNF-α therapy versus those receiving treatment with nonbiologic agents. In other words, the time-dependent risk may disappear when both cohorts are examined at the same point in their course of treatment.29 Of course, this finding has yet to be replicated, but it does warrant a re-evaluation of the safety of anti-TNF-α therapy. Most would agree that the benefits of biologics outweigh the risks and that clinical practice measures such as screening, prevention, and vigilance are effective in limiting the risk of potential opportunistic infections associated with immunotherapy.
- Lebwohl M, Leonardi C, Griffiths CE, et al. Long-term safety experience of ustekinumab in patients with moderate-to-severe psoriasis (Part I of II): Results from analyses of general safety parameters from pooled Phase 2 and 3 clinical trials. J Am Acad Dermatol. 2011 Sep 17.
- Dreiher J, Kresch FS, Comaneshter D, et al. Risk of Herpes zoster in patients with psoriasis treated with biologic drugs. J Eur Acad Dermatol Venereol. 2011 Sep 16.
- Strangfeld A, Listing J, Herzer P, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA. 2009 Feb 18;301(7):737-44.
- Failla V, Nikkels AF. Ustekinumab and herpes zoster. Dermatology. 2011;222(2):119-22.
- Javed S, Kamili QU, Mendoza N, et al. Possible association of lower rate of postherpetic neuralgia in patients on anti-tumor necrosis factor-alpha. J Med Virol. 2011 Nov;83(11):2051-5.
- Whitley RJ, Gnann JW, Jr. Herpes zoster in the age of focused immunosuppressive therapy. JAMA. 2009 Feb 18;301(7):774-5.
- Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011(2):CD008794.
- Kaminska E, Patel I, Dabade TS, et al. Comparing the lifetime risks of TNF-alpha inhibitor use to common benchmarks of risk. J Dermatolog Treat. Epub 2011 Jul 14.
- Sanchez-Moya AI, Dauden E. Incidence of tuberculosis infection in psoriatic patients on anti-TNF therapy: report of a case series with 144 patients. J Eur Acad Dermatol Venereol. 2011 Jun;25(6):730-3.
- Askling J, Fored CM, Brandt L, et al. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum. 2005 Jul;52(7):1986-92.
- Wallis RS, Broder MS, Wong JY, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis. 2004 May 1;38(9):1261-5.
- Tubach F, Salmon D, Ravaud P, et al. Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum. 2009 Jul;60(7):1884-94.
- Pena-Sagredo JL, Hernandez MV, Fernandez-Llanio N, et al. Listeria monocytogenes infection in patients with rheumatic diseases on TNF-alpha antagonist therapy: the Spanish Study Group experience. Clin Exp Rheumatol. 2008 Sep-Oct;26(5):854-9.
- Kelesidis T, Salhotra A, Fleisher J, et al. Listeria endocarditis in a patient with psoriatic arthritis on infliximab: are biologic agents as treatment for inflammatory arthritis increasing the incidence of Listeria infections? J Infect. 2010 May;60(5):386-96.
- Schett G, Herak P, Graninger W, et al. Listeria-associated arthritis in a patient undergoing etanercept therapy: case report and review of the literature. J Clin Microbiol. 2005 May;43(5):2537-41.
- Nadarajah K, Pritchard C. Listeria monocytogenes septic arthritis in a patient treated with etanercept for rheumatoid arthritis. J Clin Rheumatol. 2005 Apr;11(2):120-2.
- Rachapalli S, O’Daunt S. Septic arthritis due to Listeria monocytogenes in a patient receiving etanercept. Arthritis Rheum. 2005 Mar;52(3):987.
- Gil C, Legido J, Cuenca C, et al. [Meningitis due to Listeria monocytogenes during adalimumab therapy]. Gastroenterol Hepatol. 2009 Oct;32(8):587-8.
- Hofmann A, Beaulieu Y, Bernard F, et al. Fulminant legionellosis in two patients treated with infliximab for Crohn’s disease: case series and literature review. Can J Gastroenterol. 2009 Dec;23(12):829-33.
- Tubach F, Ravaud P, Salmon-Ceron D, et al. Emergence of Legionella pneumophila pneumonia in patients receiving tumor necrosis factor-alpha antagonists. Clin Infect Dis. 2006 Nov 15;43(10):e95-100.
- Symmons DP, Silman AJ. The world of biologics. Lupus. 2006;15(3):122-6.
- U.S. Food and Drug Administration. FDA requires stronger fungal infection warning for TNF blockers. Available at: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm107878.htm. Accessed: February 22, 2012.
- Smith JA, Kauffman CA. Endemic fungal infections in patients receiving tumour necrosis factor-alpha inhibitor therapy. Drugs. 2009 Jul 30;69(11):1403-15.
- Nedel WL, Kontoyiannis DP, Pasqualotto AC. Aspergillosis in patients treated with monoclonal antibodies. Rev Iberoam Micol. 2009 Sep 30;26(3):175-83.
- Arnold TM, Sears CR, Hage CA. Invasive fungal infections in the era of biologics. Clin Chest Med. 2009 Jun;30(2):279-86, vi.
- Curtis JR, Xie F, Chen L, et al. The comparative risk of serious infections among rheumatoid arthritis patients starting or switching biological agents. Ann Rheum Dis. 2011 Aug;70(8):1401-6.
- Salmon-Ceron D, Tubach F, Lortholary O, et al. Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry. Ann Rheum Dis. 2011 Apr;70(4):616-23.
- Grijalva CG, Chen L, Delzell E, et al. Initiation of tumor necrosis factor-alpha antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA. 2011 Dec 7;306(21):2331-9.
- Dixon W, Felson DT. Is anti-TNF therapy safer than previously thought? JAMA. 2011 Dec 7;306(21):2380-1.