Tumor Necrosis Factor Inhibitors

Questions

Q26.1 What is the rationale strongly supporting the role of TNF-α in the pathogenesis of psoriasis? (Pg. 288)
Q26.2 How does TNF-α relate to the Th17 and Th22 pathways? ( Fig. 26.1 ) (Pg. 288)
Q26.3 Of the four TNF-α inhibitors discussed in this chapter, which are the most immunogenic? (Pgs. 290, 292, 293x3, 294, 295, 296)
Q26.4 How do the maximum PASI-75 rates compare between the four TNF-α inhibitors? (Pgs. 291x2, 293, 295, 297)
Q26.5 What is the risk of reactivation of hepatitis B or hepatitis C virus in patients treated with TNF-α inhibitors? (Pgs. 292, 299)
Q26.6 What are the key variables regarding the likelihood and the management of injection site reactions with etanercept and adalimumab? (Pgs. 292, 296)
Q26.7 What are the potential advantages of the chemical structure of certolizumab-pegol in relation to pregnancy? (Pg. 297)
Q26.8 Is the risk of lymphoma in patients receiving TNF-α inhibitors elevated compared with the baseline risk in autoimmune diseases, such as psoriasis and rheumatoid arthritis? (pg. 298)
Q26.9 Why is it important to order a baseline PPD or interferon-γ release assay (such as Quantiferon Gold or Tspot TB) before initiation of TNF-α inhibitor therapy? (Pg. 299)
Q26.10 Concerning the potential for demyelinating diseases, (1) what are several examples of demyelinating diseases ‘associated with’ TNF-α inhibitors, and (2) has a causal association been definitively established? (Pg. 300)

Abbreviations used in this chapter

AE

Adverse effect(s)

ANA

Antinuclear antibody

CBC

Complete blood count

CMP

Comprehensive metabolic panel

CYP

Cytochrome P-450

FDA

US Food and Drug Administration

GVHD

Graft-versus-host disease

HBV

Hepatitis B virus

IBD

Inflammatory bowel disease

IFI

Invasive fungal infection

IFN

Interferon

LFT

Liver function test(s)

LT

Lymphotoxin

NDBRD

National Data Base Rheumatic Disease

NMSC

Nonmelanoma skin cancer

OR

Odds ratio

PASI

Psoriasis Area Severity Index

PGA

Physicians Global Assessment

PPD

Purified protein derivative

RA

Rheumatoid arthritis

RCT

Randomized controlled trial(s)

SEER

Surveillance Epidemiology End Result

SIR

Standardized incidence ratio

TB

Tuberculosis

Th

T-helper

TNF

Tumor necrosis factor

Introduction—Psoriasis Pathogenesis

On first inspection, the clinical and histological changes of psoriasis are dominated by the proliferation and altered maturation of involved keratinocytes compared with normal-appearing skin. In addition to the alteration in keratinocytes, neutrophils, T cells, dendritic cells (DC), and macrophages are all found infiltrating the skin, accompanied by hyperplastic dilated blood vessels. There are over 1000 different gene products upregulated in a psoriasis plaque, suggesting that the inflammation in psoriasis is a complicated, cross-activated system that is stimulated and regulated on many different levels, from T cells to keratinocytes. Although classically considered a T-helper (Th)1 cytokine, tumor necrosis factor (TNF)-α is not only produced by many cells in the inflammatory cascade, but also works synergistically with many other cytokine effectors in psoriasis ( Fig. 26.1 ).

Q26.1 There are a number of lines of circumstantial evidence that implicate specific cytokines in the pathogenesis of psoriatic disease. Involved skin has increased TNF-α compared with nonlesional skin. Importantly, increased lesion and serum TNF-α levels correlate with severity of the disease. TNF-α also upregulates intracellular adhesion molecules on the surface of endothelial cells and is chemotactic for neutrophils.

With the advent of biologic therapies and the TNF-α inhibitors, our understanding of the pathogenesis of psoriasis has greatly increased. Numerous other cytokines, including interleukin (IL)-17 and IL-23, have recently been targeted, and have demonstrated the importance of the Th17 cell pathway. Th17 cells are primarily proinflammatory cells found to be active in very specific disease states, including immune-mediated diseases and specific microbial infections. This cell type is present in active psoriatic plaques, and primarily produces Il-17 and IL-22. IL-22 is also made by a distinct T-cell population, the Th22 cell, a cell that is found in the epidermis of the psoriatic plaque and again is active in only a few other specific disease states.

Q26.2 Much of the TNF-α found in the psoriasis plaque is produced by CD11c dermal DC and CD-163 macrophages. TNF-α clearly potentiates the Th1 response in inflammatory reactions, but also seems to play an important role in the extensive cross-activation of multiple inflammatory mediators. TNF-α may play a critical role in the activation of DC and their production of IL-23, an important cytokine in the activation of the Th17 system. In addition, it is induced by IL-17, and acts synergistically with IL-22 to increase keratinocyte proliferation about fivefold compared with IL-22 alone. Activated keratinocytes in psoriasis produce CCL20, an important chemokine to attract DC and Th17 cells. IL-17, IL-22, and TNF-α all help to stimulate CCL20 expression, and likely promote a positive feedback loop to continue inflammation. TNF-α also stimulates the IL-22R.

TNF-α is initially an active 26-kDa membrane-bound protein that can be cleaved by a TNF-α converting enzyme to its more potent, soluble form ( Table 26.3 ). TNF-β, also known as lymphotoxin-α or LT-α , goes through a similar process of cleavage but usually remains on the cell surface. TNF-α and LT-α both bind to the two TNF receptors (TNFR), p55 and p75. Although the p55 receptor has a fivefold higher affinity for TNF-α, the dissociation rate is high. The majority of the responses attributed to TNF are mediated by the p55 receptor and it is found in most tissues, including epidermal cells. The p75 TNFR is found only on cells of the immune system. The ligand-receptor complex of bound TNF to TNFR is internalized into the cell and activates transcription factors, such as nuclear factor (NF)κB.

Table 26.3

Tumor Necrosis Factor-α Inhibitors—Comparison of Immunologic Properties

Drug Name	Source	Monoclonal Ab versus Receptor	Components	TNF Binding	Injection Site Reactions	Antidrug Antibodies
Etanercept	Fully human	Receptor (TNF), with MW 150 kDa	Dimeric fusion protein, p75 TNF receptor linked to Fc IgG ₁	Binds to both TNF-α and TNF-β; binding to soluble and membrane bound TNF-α	14%	Rare
Infliximab	Chimeric (25% mouse, 75% human)	Monoclonal Ab, with MW 150 kDa	IgG ₁ κ	TNF-α only, inhibits binding to soluble and transmembrane TNF receptor	( Infusion reactions 20%, most minor)	About 10% of RA patients ^a
Adalimumab	Fully human	Monoclonal Ab, with MW 148 kDa	IgG ₁	TNF-α only, inhibits TNF binding to p55 and p75 transmembrane TNF receptor	6%	Rare, 5% with low titers ^b
Certolizumab	Recombinant, humanized	Antibody fragment, with MW ∼91 kDa	Fab’ antibody conjugated with polyethylene glycol	TNF-α only; binding to soluble and membrane bound TNF-α	Rare	About 7% of RA patients, 8%–19% of psoriasis patients

Ab , Antibody; IgG , immunoglobulin G; MW , molecular weight; RA , rheumatoid arthritis; TNF , tumor necrosis factor.

a The neutralizing antidrug antibodies may reduce efficacy of infliximab in a minority of patients.

b No effect of these antidrug antibodies on the efficacy of adalimumab.

This chapter will examine the role of TNF-α inhibitor therapy in dermatology, with particular emphasis on the treatment of psoriasis. At present, there are four TNF-α inhibitors available in the United States for psoriasis and psoriatic arthritis: etanercept, infliximab, adalimumab, and certolizumab. All of these medications have been used extensively for various nonpsoriatic indications, including rheumatoid arthritis (RA), other inflammatory joint diseases, and Crohn disease. Importantly, many of the safety data available on these medications are derived from nonpsoriatic indications and suggest, but do not prove, the overall favorable safety profile of these drugs in patients with psoriasis.

Etanercept

Pharmacology

Q26.3 Etanercept (Enbrel) is a dimeric, fully human fusion protein (produced in Chinese hamster ovary cells) consisting of two ligand-binding domains of the p75 TNFR fused to the Fc portion of human immunoglobulin (Ig)G ₁ . It is 150 kDa, making it about 10 times the size of insulin. Etanercept binds to both soluble and membrane-bound TNF-α, thereby preventing the cytokine from binding to any cell surface receptors. In addition, it can bind to TNF-β (also known as LT-α ). Etanercept can bind to two TNF molecules at once and has about a 100-fold greater affinity for TNF-α than either of the soluble, naturally occurring TNFR. Although it has a much higher affinity for soluble TNF-α than other monoclonal antibodies, it also releases the TNF-α quickly, with 90% of the bound cytokine released after 2 to 3 hours.

In vitro studies have shown that plasma, supplemented with slightly higher than normal physiologic concentrations of LT-α and TNF-α and incubated with pharmacologic doses of etanercept, reduces the concentration of these molecules by 80% and 50%, respectively.

The IgG tail of etanercept helps to stabilize the molecule and gives it a half-life of 4.8 days. After subcutaneous administration, it is absorbed slowly, reaching a peak level in about 2 days. The absolute bioavailability of subcutaneous etanercept is 58%. The etanercept–TNF-α complex is believed to be metabolized by proteolysis, with the byproducts eliminated in bile, urine, or both.

Decreased liver function has not seemed to change the efficacy of etanercept, as proved in some small studies for patients with liver disease (active hepatitis C infection and moderate-to-severe alcoholic hepatitis). Key pharmacology concepts for TNF-α inhibitors are given in Table 26.2 .

Table 26.1

Tumor Necrosis Factor-α Inhibitors

Generic Name	Trade Name	FDA Approved Biosimilar	Manufacturer	How Supplied	Standard Psoriasis Dosage Range
Etanercept	Enbrel	Erelzi (etanercept-szzs)	Amgen	25 mg/0.5 mL prefilled syringes, 50 mg/mL single-use prefilled SureClick Autoinjector, 25 mg multiple use vial (not prefilled), and Enbrel Mini 50 mg/mL single dose prefilled cartridge with reusable AutoTouch autoinjector	50 mg twice weekly for 3 months, 50 mg weekly
Infliximab	Remicade	Inflectra (infliximab-dyyb); Renflexis (infliximab-abda); Ixifi (infliximab-qbtx)	Janssen	100 mg powder in 20 mL single use vials	3–5 mg/kg per injection; typically given at baseline, 2 weeks, 6 weeks, then every 8 weeks thereafter
Adalimumab	Humira	Amjevita (adalimumab-atta);Hyrimox (adalimumab-adaz);Cyltezo (adalimumab-adbm)	AbbVie	80 mg/0.8 mL, 40 mg/0.8 mL, and 40 mg/0.4 mL single-use pens; 10–80 mg doses in single-use, prefilled syringe; single-use institutional use vial of 40 mg/0.8 mL	80 mg loading dose at week 0, 40 mg at 1 week, then 40 mg every other week thereafter
Certolizumab pegol	Cimzia	None	UCB, Inc.	200 mg lyophilized powder in single use vial; 200 mg/1 mL single-dose prefilled syringe	400 mg every 2 weeks; 200 mg every 2 weeks can be considered for patients <90 kg in weight (after initial loading dose)

FDA, US Food and Drug Administration.

Table 26.2

Key Pharmacology Concepts—Tumor Necrosis Factor-α Inhibitors

Drug Name	Absorption and bioavailability			Elimination
Drug Name	Peak Levels	Bioavailability (%)	Protein Binding	Half-Life	Metabolism	Excretion
Etanercept	About 2 days	58	N/A	4.8 days (mean terminal half-life)	Proteolysis	Fragments into bile and urine
Infliximab	At time of infusion	100	N/A	7 days (5 mg/kg dosing), 9 days (10 mg/kg dosing)	Proteolysis	Fragments into bile and urine
Adalimumab	About 5.5 days	64	N/A	14 days (mean terminal half-life)	Proteolysis	Fragments into bile and urine
Certolizumab pegol	About 2–7 days	∼80%	N/A	14 days for all doses tested	Unknown	PEG component possibly excreted in urine after cleavage from Fab

PEG , Polyethylene glycol.

Clinical Use

US Food and Drug Administration-Approved Indications

The US Food and Drug Administration (FDA) approved etanercept for the treatment of RA in November 1998. Since then, the drug has been approved for use in psoriatic arthritis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, and psoriasis.

Plaque Psoriasis

Etanercept for plaque psoriasis has been studied in four large trials. After two smaller studies demonstrated efficacy, two larger, Phase III studies continued to show the clinical efficacy of etanercept. In the first study, etanercept monotherapy was used in patients with moderate-to-severe psoriasis, with a mean Psoriasis Area Severity Index (PASI) score of 18. However, alternative dosing schedules were also evaluated. For the first 12 weeks of therapy, enrolled subjects were treated with placebo, etanercept 25 mg once weekly, etanercept 25 mg twice weekly, or etanercept 50 mg twice weekly. The PASI-75 for 12 weeks of therapy was 4% for placebo, 14% in the lowest dose, 34% in the 25 mg twice-weekly group, and 49% in the 50 mg twice-weekly group. Subjects were continued on their therapy for another 12 weeks, with PASI-75 response rates increasing to 25% in the low-dose, 44% in the middle-dose, and 59% in the high-dose groups.

Another large trial with 580 patients showed similar results. In this study, the first 12 weeks had a placebo arm, plus a 25 mg twice-weekly group and a 50 mg twice-weekly group. After 12 weeks all patients were changed to 25 mg twice weekly. Q26.4 The patients on the high dose initially showed a PASI-75 of 49%; even after the decrease in dose to etanercept, 25 mg twice weekly, some patients continued to improve with a PASI-75 of 54% at 24 weeks. Further, 77% of those patients who achieved a PASI-75 in the first 12 weeks maintained their PASI-75 at the end of 24 weeks despite the decreased dose. In addition, 33% of patients who did not reach their PASI-75 initially were able to finally reach the PASI-75 level, while on the ‘maintenance’ dose of etanercept. Overall, this study demonstrated that about 20% of patients required etanercept 50 mg twice weekly to maintain clearance of their psoriasis. The net result is that many patients can be given this higher ‘induction’ dose of etanercept, and after 3 months can maintain their clearance with only 25 mg twice weekly of etanercept.

For those that do respond with a PASI-75, there have been additional studies to evaluate withdrawal and rechallenge with etanercept. The mean time to relapse (defined as a reduction of the maximal improvement from baseline by 50%) of plaque psoriasis after discontinuation of etanercept was 84 days. There were no reports of a change of morphology of the patients’ psoriasis (no transition to pustular or erythrodermic psoriasis) during treatment or after withdrawal. There were no reports of rebound flare (defined as worsening of the PASI to 125% of the patient’s baseline) or tachyphylaxis after restarting etanercept. Also, no patients demonstrated neutralizing antibodies to the drug.

Long-term safety in combined Phase III trials in a 72-week open-label extension showed no difference in the adverse effect (AE) profile between the 50 mg twice weekly and the 25 mg twice weekly dosing patterns. Patients who stopped and then restarted medication continued to show improvement. This was also seen in post-hoc analysis of 226 patients who had received 50 mg twice weekly, until clinical response was achieved, and then paused treatment until relapse. Patients were then restarted on 25 mg twice weekly of etanercept, and 83% of those patients achieved a Physician Global Analysis (PGA) of 2 or less (2 = mild, 1 = almost clear, 0 = clear) without any new safety concerns during retreatment.

One unique aspect of etanercept is that it is approved for treatment in pediatric populations. A 48-week study of 211 patients (ages 4–17 years) underwent weekly dosing of 0.8 mg/kg (up to 50 mg) for 12 weeks. Patients were then entered into an open-label portion of the study. Q26.4 At week 12, 57% of patients achieved a PASI-75, compared with 11% of patients on placebo, and at week 36 (after 24 weeks of open-label treatment), about 65% of patients had achieved a PASI-75.

The long-term extension portion of this trial followed 182 patients, 140 of whom completed the week-96 follow-up and 69 completed 264 week follow-up. PASI responses were similar at the end of the trial compared with the 12-week data, and 40% to 50% of patients maintained a clear/almost clear PGA.

Off-Label Dermatologic Uses ( Table 26.4 )

There have been case reports and small clinical trials that have suggested the efficacy of etanercept in other inflammatory conditions of interest in dermatology. Larger clinical trials ideally should be performed before widespread use of etanercept for these conditions. The dermatoses treated with etanercept include:

1.
Neutrophilic dermatoses: Behçet disease — multiple case reports, small, randomized, controlled clinical trial of 40 male patients that received etanercept or placebo twice weekly for 4 weeks and found a significant reduction in papulopustular lesions, oral ulcers, and nodular lesions (all secondary endpoints of the study) in the treatment group, but no reduction in joint complaints or pathergy (primary endpoint). Another small, single center prospective observational trial found that for refractory Behcet’s disease, adding etanercept to traditional immunosuppressive therapy led to resolution of symptoms in 15 of 15 patients at 8 weeks. Reports of efficacy for aphthous stomatitis pyoderma gangrenosum (PG) —including reports of efficacy with topical use, subcorneal pustular dermatosis, and Sweet syndrome in association with RA.
2.
Granulomatous dermatoses : generalized granuloma annulare, cutaneous sarcoidosis case reports, but a small Phase II trial for pulmonary sarcoidosis was terminated early because of excessive treatment failure despite five of 17 patients considered treatment successes.
3.
Vasculitis: case reports for use in refractory giant cell arteritis (GCA), deficiency of adenosine deaminase 2 disease, polyarteritis nodosa, and Takayasu arteritis. A small randomized controlled trial showed a trend towards efficacy and decrease in corticosteroid requirements with use of etanercept for long-standing GCA, but the findings were not statistically significant.
4.
Severe drug reactions: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS-TEN)—one randomized, controlled trial found etanercept superior to corticosteroids for treatment of moderate-to-severe SJS-TEN patients, in regard to skin-healing time and risk of gastrointestinal (GI) hemorrhage.

Table 26.4

Levels of Evidence for US Food and Drug Administration-Approved and Off-Label Dermatologic Indications for Tumor Necrosis Factor-Alpha Inhibitors.

Data from Phillips B, Ball C, Sackett D, et al. Oxford Centre for Evidence-based Medicine – Levels of Evidence. Centre for Evidence-Based Medicine (website). Available at: https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/2018 . Accessed March 22, 2019.

Dermatologic Indication	Etanercept Level of Evidence	Infliximab Level of Evidence	Adalimumab Level of Evidence	Certolizumab Level of Evidence
Psoriasis	1 ^a	1 ^a	1 ^a	1 ^a
Psoriatic arthritis	1 ^a	1 ^a	1 ^a	1 ^a
Hidradenitis suppurativa	2	2	1 ∗	N/A
Aphthous stomatitis	4	4	4	N/A
Behçet disease	2	2	2	4
Pyoderma gangrenosum	4	1	4	4
Cutaneous sarcoidosis	4	2	2	N/A
Systemic vasculitis	4	2	2	N/A
Stevens-Johnson syndrome/ toxic epidermal necrolysis	1	4	N/A	N/A
Pityriasis rubra pilaris	4	2	4	N/A

Levels of evidence: Level 1, Randomized, controlled trials (RCT), systematic reviews of RCT, or meta-analyses of RCT; Level 2, Nonrandomized controlled trials, cohort studies, systemic reviews of cohort studies, subanalyses of RCT; Level 3, Case-control studies, systematic reviews of case-control studies; Level 4, Retrospective observational studies, case-series and case-reports

a US Food and Drug Administration-approved indication.

In addition, etanercept has had anecdotal success with pityriasis rubra pilaris. A small randomized, controlled clinical trial failed to show significant efficacy for use in hidradenitis suppurativa (HS), but there are some case reports and few open label small trials of success.

Contraindications

( Box 26.1 ) Contraindications to use of etanercept include sepsis or other active infections, known hypersensitivity to etanercept, and concurrent administration with anakinra or other biologic disease-modifying antirheumatic drug (DMARD). Relative contraindications include congestive heart failure (CHF) and a personal or family history of demyelinating disease.

Box 26.1

Drug Risks Profile—Tumor Necrosis Factor Inhibitors—Etanercept (E) and Adalimumab (A)

Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. ( https://www.wolterskluwercdi.com/facts-comparisons-online/ ).

Contraindications
None listed
Boxed Warnings
Infections—invasive fungal, TB reactivation, opportunistic bacteria, viruses (see text)	Malignancies—lymphoma, including hepatosplenic T-cell lymphoma (see text)
Warnings & Precautions ^a
Infections ^a Infections (same list as with “Boxed Warning”) ^a Active TB, including reactivation of latent TB ^a Be sure immunizations current before rx (esp. live vaccines) Monitor closely for infections with surgeries (see text) Malignancies Malignancies—“impact not fully defined” (see text)	Hypersensitivity Reactions May rarely cause anaphylaxis, angioedema ^a Positive ANA and “lupus-like syndrome” reported Cardiovascular ^a Worsening or new onset heart failure Other Major Adverse Effects Rare cases pancytopenia/aplastic anemia reported Demyelinating diseases “reported” (see text)
Pregnancy Prescribing Status
Traditional US Food and Drug Administration rating —category B	Newer rating ^b —(A) probably compatible, (E) low risK

a Under “Warnings & Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid.

b See Chapter 65 , Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings.

ANA, Antinuclear antibody; TB , tuberculosis; TNF , tumor necrosis factor.

Q26.5 Although its effect on patients with renal or liver failure is not known, it has been shown to be effective in patients with active hepatitis C infection, without any AE or elevation of the liver enzymes, and even one case of successful treatment of psoriatic arthritis in the setting of active human immunodeficiency virus (HIV) and hepatitis C has been reported. There have been cases of fulminant hepatitis (hepatitis B virus [HBV]) reactivation with most anti-TNF agents, and although the etanercept patients were successfully treated with lamivudine, caution is advised and antiviral therapy, even without active disease, is advised in some cases. A small clinical trial with 45 patients showed that etanercept increased mortality in patients with moderate to severe alcoholic hepatitis.

There have been multiple case reports showing effectiveness when etanercept is used in patients with HIV. A phase I study in 16 patients with HIV-associated tuberculosis (TB) were treated with etanercept, 25 mg twice weekly for 4 weeks, in addition to standard TB therapy. Etanercept-treated patients seemed to trend towards even a superior response to pulmonary TB.

Etanercept is traditional pregnancy category B. The newer FDA pregnancy category is summarized as “probably compatible.” It has been detected at low levels in breast milk.

Adverse Effects

The universal AE of the TNF-α inhibitors will be discussed at the end of this chapter.

Etanercept to date has been studied in over 20,000 patients in clinical trials. The majority of the patients in etanercept trials had RA. It has been given to over 500,000 patients worldwide across indications, with postmarketing surveillance of AE.

Antidrug Antibodies

Q26.3 About 2% of patients on etanercept will develop antidrug antibodies (ADA), but these are not neutralizing, nor have they been found in association with ineffective treatment or AE. There have been three small (around 150 patients) adult studies and one pediatric study showing that around 70% to 80% of patients recapture a response (measured by either a PGA ≤ 2 or PASI 50/75) after relapse from pausing treatment.

Injection Site Reactions

Q26.6 Injection site reactions are by far the most common AE, occurring in about 14% of patients. Histology shows perivascular cuffing with predominantly CD8 T cells. The injection site reactions are thought to be a delayed-type hypersensitivity, and continued use of etanercept after 4 weeks lessens the incidence and severity of the reaction. Treatment includes warm compresses, topical corticosteroids, and oral antihistamines. Once the inflammation has subsided at that site, it may be used again for injection.

Drug Interactions

Because etanercept is metabolized by proteolysis, it is unlikely to interfere with the metabolism or excretion of most drugs. Trials with an IL-1 antagonist (anakinra), used in conjunction with etanercept, have shown an increased risk of serious infections. Patients on etanercept should not receive live vaccines.

Monitoring Guidelines

Like the AE, universal monitoring guidelines will be discussed at the end of this chapter.

Therapeutic Guidelines

Etanercept is supplied in four major formulations. The first is a sterile, preservative-free, lyophilized powder that is reconstituted by the patient with 1 mL of supplied bacteriostatic water. It should be stored in the refrigerator and should not be frozen. Each vial contains 25 mg etanercept, 10 mg sucrose, 40 mg mannitol, and 1.2 mg tromethamine. Once reconstituted, it is stable for up to 14 days in the refrigerator. There is also a prefilled, single-use syringe containing either 25 mg (0.51 mL) or 50 mg (0.98 mL) etanercept, a 50 mg/mL single-use prefilled SureClick Autoinjector, and the Enbrel Mini 50 mg/mL single dose prefilled cartridge, with reusable AutoTouch autoinjector. These should also be stored in the refrigerator and not frozen. Before injecting, it should be allowed to return to room temperature for about 15 minutes, to reduce injection-related pain. Of note, a latex derivative is found in the needle cover of the SureClick autoinjector, Enbrel Mini cartridge, and prefilled syringe, so caution should be taken in patients with latex allergy.

For psoriasis, the recommended initial dose should be 50 mg twice weekly for 3 months. The dose is then stepped down to 50 mg once weekly. The recommended dose for psoriatic arthritis is 50 mg once weekly, with or without methotrexate. Etanercept is approved for children ages 2 to 17 years, for polyarticular juvenile idiopathic arthritis and psoriasis. Their dose is 0.8 mg/kg per week in divided doses. Patients should rotate injection sites to at least 1 inch away from the last site of injection.

Biosimilars

There is currently one FDA-approved etanercept biosimilar, Erelzi (etanercept-szzs). A phase III equivalence trial conducted in 531 adult patients with psoriasis comparing Erelzi to etanercept demonstrated noninferiority of Erelzi. Further, this study demonstrated that switching between the two did not impact safety.

Infliximab

Pharmacology

Q26.3 Infliximab (Remicade) is a chimeric (25% mouse and 75% human) IgG ₁ monoclonal antibody specific for TNF-α only. It neutralizes soluble TNF-α and blocks membrane-bound TNF-α. This protein can fix complement and induce complement-mediated cytotoxicity in vitro, in cells that have been transgenically modified to express large quantities of TNF on their surface. There is no evidence that this effect has any physiologic significance. Infliximab has a molecular weight of 150 kDa. Concentrations in the serum are directly related to dosing, and do not seem to correlate with age. The half-life is about 7 days in the 5 mg/kg group, and 9 days in the 10 mg/kg group. It is assumed that it is metabolized by proteolysis, because case reports have shown efficacy in patients with either renal failure or hepatic failure (see Table 26.2 ).

Clinical Use

US Food and Drug Administration-Approved Indications

Plaque Psoriasis

Infliximab was approved for the treatment of Crohn disease in 1998, and has since been approved for the treatment of RA (in combination with methotrexate), ankylosing spondylitis, ulcerative colitis, psoriatic arthritis, and plaque psoriasis.

Three major trials have looked at the efficacy of infliximab in plaque psoriasis. The first was a 249-patient trial in patients with moderate-to-severe psoriasis, with a mean PASI score of about 20. Q26.4 Subjects were treated with placebo, 3 mg/kg infliximab, or 5 mg/kg infliximab, with three separate infusions over a 6-week period. The PASI-75 rate again was around 80% in both dosing groups, with over one-half of the patients essentially clearing with a PASI-90. The placebo showed a PASI-75 of 6%. The majority maintained PASI-75 until 3 to 4 months after the last infusion, showing a long remission period for psoriasis.

An international phase III trial, EXPRESS I, again looked at patients with moderate-to-severe psoriasis with a mean PASI score of around 21. They received infliximab 5 mg/kg or placebo at weeks 0, 2, and 6 (induction), followed by maintenance therapy every 8 weeks. At week 24, placebo patients crossed over to infliximab induction and maintenance therapy for a 50-week study. At week 10, the PASI-75 was 80% (3% placebo), and 71% continued to have PASI-75, until week 50 (with 77% in the crossover placebo/infliximab patients). Q26.3 Of note, ADA to infliximab were measured in the initial 276 patients who received infliximab at the beginning of the trial, and found at the end of the trial that 64% were ADA negative, 27% were ADA positive, and 10% were inconclusive. Of those patients who achieved a PASI-75 at week 10, 39% who had positive ADA maintained a PASI-75 through week 50, compared with 81% ADA negative patients and 96% ADA inconclusive patients.

A 48-week phase III trial performed in North America, EXPRESS II, focused on determining whether infliximab performed better as a maintenance therapy or could be used on an intermittent, as-needed (PRN) basis. A total of 835 patients with mean PASI of around 18 were given placebo, 3 mg/kg, or 5 mg/kg of infliximab at weeks 0, 2, and 6. At week 14, patients were rerandomized to receive either every 8 week maintenance or PRN treatment through week 48. At week 16, placebo patients crossed over to 5 mg/kg induction, followed by every 8 week scheduled maintenance. A PASI-75 at week 10 was achieved by 70% of patients in the 3 mg/kg group, 75% in the 5 mg/kg group, and 2% of the placebo group. The PASI-75 responders maintained a better response through week 50 in the maintenance group, compared with the PRN group, with the median of the average percent PASI improvement being 89% and 76% in the 5 mg/kg group and 80% and 72% in the 3 mg/kg group. Of those who did not reach a PASI-75% response, 59% achieved a PASI-75 at some point in the maintenance phase through week 50.

Q26.3 ADA to infliximab were detected in about 38% of patients in the 5 mg/kg group through week 66, and 48% in the 3 mg/kg group. Across all maintenance groups, patients who developed ADA were less likely to, but not entirely precluded from, maintaining a PASI-75 response at week 50.

Off-Label Dermatologic Uses

Infliximab

It is critical to consider that for the following conditions, there is documentation of successful infliximab use, primarily through case reports and small case series (see Table 26.4 ). Clinical trials ideally should be performed before widespread use of infliximab for these conditions. The dermatoses treated with infliximab include the following:

1.
HS : Multiple case reports and a phase II trial support use of infliximab for HS. A total of 38 patients were randomized to infliximab, 5 mg/kg or placebo at week 0, 2, and 6. At week 8, more patients in the treatment group attained 50% or greater decrease in HS Severity Index (HSSI) than placebo, around 27% versus around 5% respectively, but this difference did not reach statistical significance. However, patients in the treatment group had significantly greater improvement in terms of Dermatology Life Quality Index (DLQI), Visual Acuity Score (VAS), and PGA score compared with placebo at week 8.
2.
Neutrophilic dermatoses ; PG—one double-blind, randomized trial with 29 patients showed 46% improved compared with 6% of placebo. Additional case reports, including one success with topical infliximab, and another reporting use for an infant. Behçet disease has just anecdotal evidence and small trials. One open-label trial showed efficacy for use of infliximab in intestinal, neurologic, and vascular Behçet disease, another showed efficacy for refractory posterior uveitis, with complete response in 68% of patients. Also there has been reported success with infliximab in aphthous stomatitis/refractory oral ulcerations.
3.
Vasculitis : Multiple open label trials have shown efficacy of infliximab for treatment of systemic vasculitis. It has also been reported as third-line therapy for refractory Kawasaki disease. Some case series have shown efficacy for use in Takayasu arteritis, whereas others have shown no utility.
4.
Granulomatous dermatoses : There are multiple case reports of success for cutaneous sarcoidosis, including anecdotal success in a family with Blau syndrome. One small, phase II trial enrolled patients with chronic corticosteroid-dependent pulmonary sarcoidosis and found that infliximab was more effective for extrapulmonary sarcoidosis, in conjunction with corticosteroids or other immunosuppressive medications, compared with placebo at 24 weeks. Another subset analysis of a small, randomized, controlled trial evaluating use of infliximab in chronic pulmonary sarcoidosis found that the treatment groups had significantly more improvement in desquamation and induration of chronic cutaneous sarcoidosis lesions, compared with placebo, whereas there was no significant difference in the outcomes of erythema and percentage of area involved.

In addition, infliximab has shown efficacy for use in pityriasis rubra pilaris, including one small, open trial which showed complete remission in four patients treated with infliximab, and in TEN.

Contraindications

( Box 26.2 ) Infliximab should not be given to any patient with a known hypersensitivity to murine proteins, infliximab, or to any inactive components of infliximab. In trials conducted in CHF, there was a significant increase in mortality and hospitalization in the patients that received 10 mg/kg (but not those who received the 5 mg/kg dose). Therefore, infliximab is contraindicated at doses >5 mg/kg in patients with moderate to severe (New York Classification III or IV) CHF. Given that the dosage range for psoriatic arthritis and psoriasis is from 3 to 5 mg/kg, this complication is unlikely.

Box 26.2

Infliximab Contraindications

Contraindications

Absolute

Known hypersensitivity to infliximab or murine proteins
Concurrent administration with anakinra (IL-1 receptor antagonist)
Avoid with active infections
Chronic or localized infections—including TB

Relative

Moderate to severe (New York Classification III or IV) congestive heart failure (OK with doses ≤5 mg/kg)
Family history of demyelinating disease (including multiple sclerosis)

Pregnancy Prescribing Status

—category B

IL , Interleukin; IV , intravenous; TB , tuberculosis.

Although it should not be started in patients with active infections, there have been two retrospective studies, one open-label study, and several case reports of patients tolerating infliximab well in controlled HIV (low viral loads and normal CD4 counts).

Infliximab is pregnancy category B and has been found to be absent from breast milk and serum of infants of nursing mothers.

Adverse Effects

Infliximab is most commonly used for fistulizing Crohn disease or refractory RA (in combination with methotrexate in RA patients). The majority of the safety data are also from these two populations. Please refer to the end of this chapter for universal TNF-α inhibitor AE.

Infusion Reactions

Infusion reactions are defined as any AE during infusion and up to 3 hours posttransfusion. The most common symptoms include headache, flushing, nausea, dyspnea, infusion site infiltrations, and taste perversion. Approximately 20% (vs. 10% of the placebo group) experienced infusion reactions. Less than 1% of patients with infusion reactions experienced serious reactions, including hypotension, chest pains, dyspnea, anaphylaxis, and convulsions. Typically, symptoms resolve with a decrease in infusion rate and with adjunctive medications, such as acetaminophen and antihistamines. These drugs can also be given before treatment to reduce the likelihood of a reaction. Epinephrine and systemic corticosteroids are given for serious reactions.

Antidrug Antibodies

Q26.3 As seen in the clinical trials for plaque psoriasis, these ADA corresponded to an increased clearance rate of infliximab, an increased incidence of infusion reactions, and reduced efficacy. However, higher ADA titers did not correlate with severity of infusion reactions or serious infectious complication. Approximately 25% of patients without any detectable ADA will have an infusion reaction. As previously mentioned, concomitant immunomodulatory therapy (such as with methotrexate) may reduce the incidence of ADA. Other ways to combat the formation of these ADA are through premedication with oral corticosteroids, continuing with maintenance dosing after induction, and either increasing the dose per kilogram or shortening the interval between doses.

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