¹Center for Clinical Studies, Houston, TX, USA
²Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX, USA

ABSTRACT
In the past three decades, major advances have been made in understanding the pathogenesis of psoriasis. The currently accepted theory is that T-cell mediated immune dysregulation triggers keratinocyte hyperproliferation in psoriasis. Recent research indicates that the Th17/interleukin (IL)-23 pathway plays a prominent role in the amplification phase of psoriasis. The discovery of the Th17/ IL-23 pathway provides targets for new drug development. This review focuses on the role of IL-23 in psoriasis pathogenesis and the current therapies targeting IL-23 that are in clinical trials.

Key Words:
cytokine, interleukin-23, IL-23, guselkumab, tildrakizumab, Th17, psoriasis

Introduction

In the past three decades, major strides have been made in understanding the pathogenesis of psoriasis. While psoriasis pathogenesis originally focused on keratinocyte hyperproliferation, the currently accepted theory is that of T-cell mediated immune dysregulation.^1,2 While the T helper cell (Th) 1/interferon-gamma (IFN-γ) pathway was originally heavily implicated in the amplification phase, recent research indicates that the Th17/interleukin (IL)-23 pathway plays the more dominant role.³ This review focuses on the role of IL-23 in psoriasis pathogenesis and the current therapies targeting IL-23 that are in clinical trials.

IL-23

IL-23 is composed of two subunits, p19 and p40, which are linked by a disulfide bond. The p19 subunit is a unique component of IL-23. Alternatively, the p40 subunit is a component of IL-12 as well.⁴ IL-23 is produced by keratinocytes and activated antigen-presenting cells (APCs), specifically Langerhans cells, macrophages and dendritic cells. IL-23 is expressed by APCs in the presence of Toll-like receptor (TLR) agonists (lipopolysaccharde, CpG and PolyI:C).⁵ The IL-23 receptor is present on memory T cells, natural killer (NK) T cells, macrophages, dendritic cells and naïve T cells.⁶

IL-23 is the key cytokine that propels naïve T cell differentiation to Th17 cells.⁶ It is essential in bridging the innate and adaptive immune responses and orchestrating the early local immune response. When IL-23 binds to the IL-23 receptor, the complex activates Jak2 and Tyk, members of the Janus family of tyrosine kinases, leading to phosphorylation of the receptor complex and eventually phosphorylation of signal transducer and activator of transcription 3 (STAT3). STAT3 phosphorylation triggers differentiation to Th17 cells.⁷ Transforming growth factor-beta (TGF-β), IL-6, IL-1β and IL-21 are also needed to coordinate production of Th17 cells.⁸ However, IL-23 appears to be the main cytokine in this process as studies have shown that IL-6, IL-1β and TGF-β in the absence of IL-23 result in production of regulatory T cells that inhibit inflammation.⁹

The Th17/IL-23 Pathway in the Immunopathogenesis of Psoriasis

In considering the pathophysiology of psoriasis, it can be divided into two distinct immune-mediated phases: the initial and amplification phases.⁵ In the initial phase, trauma to keratinocytes or stimulation of TLR receptors in genetically predisposed skin leads to activation of the innate immune system. This cataclysm of macrophages, dendritic cells and diverse cytokines triggers the production of IL-12 and IL-23. These two cytokines provide the bridge to the amplification phase, which is characterized by the adaptive immune response.⁵ The intricacies of this amplification have been the source of much debate over the last three decades, specifically in regards to which Th pathway drives this phase.

In the 1990s, clinical studies demonstrated elevated levels of the p40 subunit in psoriatic lesions. At the time, the high expression of p40 was correlated to elevated levels of IL-12 (a component of the Th1 pathway) because IL-23 had not yet been discovered.¹⁰ This theory further propagated the theory that the Th1 pathway is key in orchestrating the amplification phase of psoriasis. However, recent evidence has revealed that the elevated p40 level in psoriasis is due to IL-23, not IL-12. In a study done by Lee and colleagues, p40 and p19 mRNA were elevated in psoriatic lesions, but p35 mRNA, which is specific to IL-12, was not increased in lesional skin.³ Another study highlighted the presence of IL-23- staining cells in palmoplantar pustulosis, hyperkeratotic hand dermatitis and lesional psoriasis biopsies. Furthermore, IL-23 levels in psoriatic skin appear to correspond with the clinical course of the patient.¹¹ IL-23 injections in mice skin have also induced histological changes seen in psoriatic skin, specifically epidermal acanthosis and parakeratosis. IL-12 injections did not have the same effect.¹² Finally, many genetic studies in psoriasis patients have demonstrated a strong association with genetic loci encoding the IL-23 p19 subunit and IL-12/23 p40 subunit, but not the IL-12 p35 subunit.^13,14 Taken together, this data points to the prevailing role of the Th17/IL-23 pathway in psoriatic disease.

The Th17/IL-23 pathway promotes chronic inflammation. Th17 cells secrete two IL-17 cytokines, IL-17A and IL-F, and also IL-21, IL-22, IL-26 and IFN-γ. All of these cytokines activate the inflammatory cascade and provoke irregular cellular replication and maturation in psoriasis.¹⁵ IL-17A is a potent pro-inflammatory cytokine that triggers keratinocyte production of pro-neutrophilic chemokines, including CXCL1, CXCL5, and CXCL8. These chemokines orchestrate neutrophilic migration into psoriatic lesions, which stimulates keratinocyte proliferation.¹⁶ IL-17 also inhibits neutrophil apoptosis, stimulates angiogenesis, augments tissue remodeling and synergistically with tumor necrosis factor-alpha enhances inflammation.¹⁷ IL-22 causes keratinocyte hyperproliferation and increases keratinocyte production of antimicrobial proteins. It is because of these antimicrobial proteins that psoriatic skin lesions are rarely infected.¹⁷ Both IL-17A and IL-22 have also been found to stimulate keratinocyte production of CCL20, a chemokine overproduced in psoriasis. It is hypothesized that CCL20 promotes maintenance of psoriatic lesions by enhancing chemotaxis of CCR6+ Th17 and dendritic cells to diseased skin.¹⁸

Although there is convincing data about the significant role the Th17/IL-23 pathway plays in late-stage psoriasis, there remain many questions. It is still unclear why IL-23 is preferentiallyproduced in psoriatic skin. Is it a genetic predisposition or a dysregulation of the innate immune response? Furthermore, it is unclear what the specific antigen is that dendritic cells present to antigen-specific Th17 cells. Hypotheses have ranged from an external antigen to an autoantigen.¹⁷

Psoriasis Therapies Targeting IL-23

Given the initial discovery of elevated p40 levels in psoriatic skin, novel biologics, specifically ustekinumab and briakinumab, were developed to target this p40 subunit. These agents target the p40 subunit of IL-12 and IL-23 and, thus, both the IL-12/Th1 and Th17/IL-23 pathways.¹⁰ Despite the efficacy and favorable safety profile of ustekinumab, drug development has moved towards solely targeting the IL-23/Th1 pathway given its dominant role in psoriatic disease and the theoretical risk of blocking the IL-12/Th1 pathway.

Tildrakizumab

Tildrakizumab, alternatively known as MK-3222 or SCH900222, is a human immunoglobulin G1 (IgG1) monoclonal antibody that targets only the p19 portion of IL-23. Since tildrakizumab does not target the p40 subunit of IL-23, it does not affect IL-12 activity.¹⁹

The results of a Phase IIb randomized, controlled, dose-ranging study for tildrakizumab were presented at the American Academy of Dermatology 71st Annual Meeting in March 2013. In this study, 335 patients with moderate to severe plaque psoriasis were randomized to receive tildrakizumab 5 mg, 25 mg, 100 mg, 200 mg or placebo at weeks 0, 4, and then every 12 weeks for 52 weeks. The primary endpoint, PASI-75 at week 16, was attained by 33%, 64%, 66%, 74%, and 4% of the 5 mg, 25 mg, 100 mg, 200 mg, and placebo groups respectively. The secondary endpoint, achieving a physician global assessment (PGA) of “clear” or “minimal” at week 16, was achieved by 33%, 58%, 62%, 74%, and 2% of the 5 mg, 25 mg, 100 mg, 200 mg, and placebo groups respectively. The adverse event rate in the treatment groups ranged from 60% to 71% compared to 69% in the placebo group. The most common adverse event was nasopharyngitis. Serious adverse events (including one death) were rare, occurring in only four patients. None of the serious adverse events were linked to tildrakizumab.^19,20

Of note, data from the proof of concept study demonstrated that 18% of patients treated with three doses of tildrakizumab developed antidrug antibodies. Of these patients with antibodies, 55% had decreased serum drug levels in contrast to patients without antidrug antibodies. However, patients with antidrug antibodies still attained PASI improvement comparable to patients without antidrug antibodies. Similarly, the safety profile did not differ either.²¹

Tildrakizumab is the first anti-IL-23 therapy for psoriasis to enter Phase III trials. There are currently two Phase III trials underway. The projected date for final collection of primary outcome data is June or July 2015 for both trials. This data has yet to be published. The study completion date for both studies is 2019.^21,22

Guselkumab

Guselkumab, or CNTO 1959, is a humanized IgG1 monoclonal antibody that targets the p19 subunit of IL-23.²³

The results of X-PLORE, a Phase IIb randomized, controlled, doseranging study for guselkumab, were presented at the American Academy of Dermatology 72nd Annual Meeting in March 2014. In this study, patients with moderate to severe plaque psoriasis were randomized to receive either guselkumab 5 mg, 15 mg, 50 mg, 100 mg or 200 mg, placebo or adalimumab. The guselkumab was given at weeks 0, 4 and then every 12 weeks. The patients in the adalimumab group received an initial dose of 80 mg and then 40 mg every other week (starting one week after the initial dose). The primary endpoint, patients achieving a PGA of “clear” or “minimal” at week 16, was met by 34%, 61%, 79%, 86%, 83%, and 7% of patients in the guselkumab 5 mg, 50 mg, 15 mg, 100 mg, 200 mg, and placebo groups respectively. At week 16, PASI-75 was achieved by 44%, 76%, 81%, 79%, 81%, and 5% of the patients receiving guselkumab 5 mg, 15 mg, 50 mg, 100 mg, 200 mg, and placebo respectively. PASI 90 was achieved by 34%, 34%, 45%, 62%, 57%, and 2% of guselkumab 5 mg, 15 mg, 50 mg, 100 mg, 200 mg, and placebo-treated patients respectively. Comparatively, in the adalimumab group, 58%, 70%, and 44% of patients attained a PGA of “clear” or “minimal”, PASI-75 and PASI-90 respectively at week 16. At week 52, adverse events occurred in 66% of patients treated with guselkumab. Serious adverse events were experienced by 3% of guselkumab treated patients. Three patients had either a myocardial infarction or cerebrovascular accident but these were not linked to guselkumab treatment. No serious or opportunistic infections occurred in patients on guselkumab. One patient on guselkumab reported a malignancy (cervical cancer).²⁴

Based on the above promising Phase II results, Phase III trials to further asses the efficacy of guselkumab are planned.^25-27 Currently, there is a Phase II trial evaluating guselkumab for palmoplantar pustulosis as well as a Phase I trial to evaluate the pharmacokinetics of guselkumab in lyophilized versus liquid formulations.^28,29 The estimated primary completion date for the palmoplantar pustulosis study is August 2014.²⁸

Other Drugs Targeting IL-23 in the Pipeline

BI655066, manufactured by Boehringer Ingelheim Pharmaceuticals, is another drug targeting IL-23 that is currently in Phase II trials for psoriasis.³⁰ It is a human IgG1 monoclonal antibody. MP-196, another monoclonal antibody targeting IL-23, is manufactured by TcL Pharma and is in preclinical development for psoriasis. Finally, there are several IL-23 receptor antagonists that have been patented but not tested in pre-clinical or clinical trials. Neutralization of the IL-23 receptor is a promising approach for psoriasis management as the IL-23 is only present on developing Th17 cells. Thus, blocking the IL-23 receptor can prevent activation of STAT3 and naïve T cell differentiation to a Th-17 cell.⁵

Conclusion

The discovery of the Th17/IL-23 pathway adds to the complexity of psoriasis pathogenesis and provides targets for new drug development. Not only are there upstream IL-23 p19 and IL-23 receptor neutralizing drugs in development, there are currently also downstream IL-17 antagonists in trials as well. Although these drugs are still years away from being FDA approved, they offer promise of more targeted, efficacious and safe psoriasis therapy in the future.

References

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9. Fitch E, Harper E, Skorcheva I, et al. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep. 2007 Dec;9(6):461-7.
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11. Lee E, Trepicchio WL, Oestreicher JL, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004 Jan 5;199(1):125-30.
12. Levin AA, Gottlieb AB. Specific targeting of interleukin-23p19 as effective treatment for psoriasis. J Am Acad Dermatol. 2014 Mar;70(3):555-61.
13. Lowes MA, Kikuchi T, Fuentes-Duculan J, et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol. 2008 May;128(5):1207-11.
14. Nair RP, Stuart PE, Kullavanijaya P, et al. Genetic evidence for involvement of the IL23 pathway in Thai psoriatics. Arch Dermatol Res. 2010 Mar;302(2):139-43.
15. Nakajima K. Critical role of the interleukin-23/T-helper 17 cell axis in the pathogenesis of psoriasis. J Dermatol. 2012 Mar;39(3):219-24.
16. Novelli L, Chimenti MS, Chiricozzi A, et al. The new era for the treatment of psoriasis and psoriatic arthritis: perspectives and validated strategies. Autoimmun Rev. 2014 Jan;13(1):64-9.
17. Quatresooz P, Hermanns-Le T, Pierard GE, et al. Ustekinumab in psoriasis immunopathology with emphasis on the Th17-IL23 axis: a primer. J Biomed Biotechnol. 2012 2012:147413.
18. Singh TP, Lee CH, Farber JM. Chemokine receptors in psoriasis. Expert Opin Ther Targets. 2013 Dec;17(12):1405-22.
19. MedPage Today. Psoriasis yields to IL-23 drug. Source reference: Papp K, et al. Dose-dependent improvement in chronic plaque psoriasis following treatment with anti-IL-23p19 humanized monoclonal antibody (MK-3222). Presented at: 71st Annual Meeting of the American Academy of Dermatology, Maimi Beach, FL, March 1-5, 2013. Available at: http://www.medpagetoday.com/MeetingCoverage/AAD/37664. Accessed January 19, 2015.
20. PeerView Press. Investigational drug provides significant symptom improvement in chronic plaque psoriasis: presented at AAD.
21. Merck Sharp & Dohme Corp. A 64-week, phase 3, randomized, placebocontrolled, parallel design study to evaluate the efficacy and safety/ tolerability of subcutaneous tildrakizumab (SCH 900222/MK-3222), followed by an optional long-term safety extension study, in subjects with moderate-to-severe chronic plaque psoriasis (protocol no. MK-3222-010). In: ClinicalTrials.gov, Identifier: NCT01722331. Last updated November 24, 2014. Available at http://clinicaltrials.gov/ct2/show/NCT01722331. Accessed January 19, 2015.
22. ClinicalTrials.gov. US National Institutes of Health. Search results for tildrakizumab.
23. Skin & Allergy News. Psoriasis drug pipeline extrudes progress.
24. Johnson & Johnson. Press release dated March 24, 2014. Anti-interleukin-23 monoclonal antibody guselkumab shows significant efficacy in treatment of moderate to psoriasis plaque psoriasis. Results from phase 2b X-PLORE study through week 40 report efficacy of guselkumab across multiple dosing regimens and compared with adalimumab.
25. Janssen Research & Development, LLC. A phase 3, multicenter, randomized, double-blind, placebo and active comparator-controlled study evaluating the efficacy and safety of guselkumab for the treatment of subjects with moderate to severe plaque-type psoriasis with randomized withdrawal and retreatment (VOYAGE 2). In: ClinicalTrials.gov, Identifier: NCT02207244. Last updated December 30, 2014.
26. Janssen Research & Development, LLC. A phase 3, multicenter, randomized, double-blind study to evaluate the efficacy and safety of guselkumab for the treatment of subjects with moderate to severe plaque-type psoriasis and an inadequate response to ustekinumab (NAVIGATE). In: ClinicalTrials.gov, Identifier: NCT02203032. Last updated December 31, 2014.
27. Janssen Research & Development, LLC. Phase 3, multicenter, randomized, double-blind, placebo and active comparator-controlled study evaluating the efficacy and safety of guselkumab in the treatment of subjects with moderate to severe plaque-type psoriasis (VOYAGE 1). In: ClinicalTrials.gov, Identifier: NCT02207231. Last updated: January 5, 2015.
28. Janssen Pharmaceutical K.K. A multicenter, randomized, double-blind, placebo-controlled, parallel group study to assess the efficacy, safety and tolerability of CNTO 1959, a human anti-IL 23 monoclonal antibody, following subcutaneous administration in subjects with palmoplantar pustulosis. In: ClinicalTrials.gov, Identifier: NCT01845987. Last updated: November 18, 2014.
29. Janssen Research & Development, LLC. Phase 1, open-label, randomized, parallel study to assess the pharmacokinetic comparability of 2 formulations and to evaluate pharmacokinetic comparability of guselkumab (CNTO1959) delivered by 2 different devices in healthy subjects. In: ClinicalTrials.gov, Identifier: NCT01866007. Last updated: March 10, 2014.
30. Boehringer Ingelheim. A 48 weeks study of three different dose regimens of BI 655066 administered subcutaneously in patients with moderate to severe chronic plaque psoriasis (randomised, dose-ranging, activecomparator- controlled (ustekinumab), double-blind within dose groups of BI 655066). In: ClinicalTrials.gov, Identifier: NCT02054481. Last updated: January 7, 2015.

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

ABSTRACT
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.

Key Words:
adverse effects, anti-tumor necrosis factor-alpha, infections, monoclonal antibodies, psoriasis, risk factors, TNF-α inhibitors

Background

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.

Herpes Zoster

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

Tuberculosis

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

Listeria monocytogenes

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

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.

Fungal Infections

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

Conclusion

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.

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