Anti-tumor necrosis factor-α therapy in uveitis.

Accepted Manuscript Anti-Tumor Necrosis Factor-α Therapy in Uveitis Miguel Cordero-Coma, MD, PhD, FEBOphth, Lucia Sobrin, MD, MPH PII:

S0039-6257(15)00111-3

DOI:

10.1016/j.survophthal.2015.06.004

Reference:

SOP 6575

To appear in:

Survey of Ophthalmology

Received Date: 22 July 2014 Revised Date:

14 June 2015

Accepted Date: 15 June 2015

Please cite this article as: Cordero-Coma M, Sobrin L, Anti-Tumor Necrosis Factor-α Therapy in Uveitis, Survey of Ophthalmology (2015), doi: 10.1016/j.survophthal.2015.06.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Anti-Tumor Necrosis Factor-α Therapy in Uveitis

Miguel Cordero-Coma, MD, PhD, FEBOphth Head of the Uveitis Unit. University Hospital of León, León, Spain.

Lucia Sobrin, MD, MPH

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Associate Professor of Ophthalmology, Harvard Medical School

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Instituto Biomedicina (IBIOMED), University of León, León, Spain.

Boston, Massachusetts, USA

Corresponding Author: Miguel Cordero-Coma, MD

c/ Altos de Nava s/n

León, SPAIN.

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24080

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Hospital Universitario de León

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Uveitis and Retina Services, Massachusetts Eye and Ear Infirmary

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Tel: (+34) 987-233041

Fax: (+34) 987-233322

Email: [email protected]

KEYWORDS: Uveitis; Tumor necrosis factor-alpha; Infliximab; Adalimumab; Etanercept; Golimumab; Certolizumab; Serum levels of anti-TNF-α drug; Anti-drug antibodies; Pharmacogenomics of anti- TNF-α therapy; Immune-mediated uveitis; Non-infectious uveitis; Uveitis treatment.

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Abstract

Since the first reported use in 2001 of an anti-tumor necrosis factor-alpha (TNF-α) agent,

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infliximab, for the treatment of uveitis, several new anti-TNF-α agents have emerged for the treatment of refractory non-infectious uveitides, although their use remains off-label in the United States. These agents have demonstrated remarkable clinical anti-inflammatory

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efficacy and a potential immunoregulatory role in selected uveitis patients, but it is currently unclear whether they can modify the natural history of disease. We review the rationale and

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clinical indications for this therapy, the differences between agents, how to manage dosing and intervals, and how to screen for and identify potential side effects. We also present a summary of the science behind the use of anti-TNF-α agents in ocular inflammation and the

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evidence for their efficacy.

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I. Introduction

Systemic immunomodulatory therapy (IMT) has been employed for the last several decades

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for treatment of selected non-infectious uveitis patients. The primary need for IMT in uveitis is as a corticosteroid-sparing agent. Even in patients controlled on oral corticosteroids, a

chronic daily dose above 7.5 mg often produces long-term adverse events. Contemporary

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management of patients with severe and refractory ocular inflammation includes the

therapeutic option of biologic agents. These agents generally include monoclonal antibodies

forms of naturally inhibitory molecules.

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and fusion proteins directed against selected cell surface glycoproteins, and recombinant

Among potential targets of biologic agents, tumor necrosis factor-alpha (TNF-α), is a

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proinflammatory master cytokine produced by several cell types, is implicated in the pathogenesis of many immune-mediated diseases. TNF-α is an important mediator of the intraocular tissue damage observed in uveitis patients and is associated with the pathogenesis

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of sight-threatening uveitis complications, including cystoid macular edema (CME) and

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choroidal neovascularization. During the last decade, TNF-α antagonists have become well accepted as useful agents in the treatment armamentarium of refractory uveitis; however, this therapeutic option requires a thorough knowledge of the differences between currently available agents, their mechanism of action, how to manage dosing and intervals, and how to screen for and identify potential side effects.

II. Tumor Necrosis Factor-alpha

A. Biology of TNF-α

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TNF-α is initially synthesized as a monomeric trans-membrane protein.83 TNF-α-converting enzyme processes the membrane TNF-α, releasing the soluble fraction.83,104 Both the soluble and membrane-bound TNF-α are functional as trimers (formed by three molecules).83 TNF-α

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interacts with specific membrane receptors (TNF Receptors I and II) that are expressed,

depending on the type of target cell, as signals of cell death, activation or proliferation.83 These receptors are also present as soluble receptors, capable of binding TNF-α. This

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interaction between TNF-α and its soluble receptors keeps the amount of TNF-α below

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pathological limits. 83

In the eye, TNF Receptors I and II are expressed by the pigment epithelial cells of the iris, ciliary body, and retina.75 Moreover, these cells are able to produce TNF-α and metalloproteases, which may cleave TNF-α from the cell membrane.75 TNF-α is essential in

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the intraocular immune response called anterior-chamber associated immune deviation (ACAID) and in the auto-regulation of the physiological apoptosis of resident ocular

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cells.49,50

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B. Physiology of TNF-α

In addition to its key role as a mediator of inflammation, which will be further discussed, TNF-α is a potent, pleiotropic, multifunctional cytokine that exerts crucial homeostatic functions in the immune system, including:75,93

1. host defense from infections: TNF-α is particularly crucial in host´s immune response against certain pathogens like viruses (hepatitis A and B) as well as bacteria (particularly Mycobacterium tuberculosis).

ACCEPTED MANUSCRIPT 2. formation of lymphoid tissue, principally at the lymph nodes, which is essential for the immune response. 3. induction of apoptosis, or programmed cell death

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Under normal physiological conditions, TNF-α is produced by almost all immune system cells and many other cell types. Although there is this constitutive production of TNF-α, the cytokine is consumed in normal physiological functions, and there are typically no detectable

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serum levels in healthy humans.93 If an inflammatory stimulus occurs (e.g. trauma or an

immune-mediated process), activated tissue macrophages, T- and NK-lymphocytes, mast

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cells, and endothelial cells begin producing TNF-α in larger quantities. Under these pathologic conditions, there may besignificant serum levels of TNF-α.93

C. Potential mechanisms of action

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Preclinical studies provide evidence that TNF-α blockade is an appropriate approach for the treatment of uveitis patients. Inhibition of TNF-α in experimental models of uveitis ameliorates intraocular inflammation and leads to decreased interferon-gamma (IFN-γ) and

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increased interleukin-4 (IL-4) production by T-cells infiltrating the retina. This suggests that blocking TNF-α production causes deviation of the immune response towards a Th2 type

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response in parallel with lessening disease activity.38

Neutralizing TNF-α clearly suppresses inflammation. Human studies have tried to determine whether this approach may be also be immunomodulatory, i.e. redirect the immune system away from autoimmunity. Greiner et al. found an increased fraction of peripheral blood CD4+ T cells expressing IL-10 in those patients treated with a TNF-α blocker, which correlated with recovery of visual function.60 Higher ocular tissue levels of IL-10 seem to

ACCEPTED MANUSCRIPT confer a higher threshold of resistance to uveitis.133 TNF-α antagonism may also diminish IL22 levels, which correlates with decreased disease activity.28 Increased levels of IL-22 have been associated with systemic disease and uveitis activity in Behçet disease patients.16 In addition, treatment with TNF-α inhibitors has been associated with elevation of T-regulatory

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lymphocytes levels.18,128 Diminished numbers and impaired function of T-regulatory cells are found in non-infectious uveitis,151 active Behçet disease,63 and Vogt-Koyanagi-Harada uveitis.24 Indeed T-regulatory cells are considered an important part of the regulatory

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mechanisms that limit uveitis.20

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The data from the studies in humans, however, focus on peripheral blood changes. Alterations in peripheral T-cells and cytokines could be related to modulation of ocular inflammation, but could also be systemic effects of TNF-α inhibition that do not correlate

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with ocular immunomodulation.

III. Role of TNF-α in uveitis

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A. Experimental models

Experimental autoimmune uveoretinitis (EAU) models demonstrate an increased expression

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and production of TNF-α that is essential to the induction (afferent) phase.100,118 This increased expression of TNF-α is occurs not only in the typical inflammatory infiltrates that characterize EAU, but also in some retinal cells such as the retinal pigment epithelium and Müller cells.34 EAU models reveal that TNF- α is produced by macrophages, activated Tcells, and some intraocular resident cells.39 Moreover, this intraocular production of TNF-α might decisively influence the course of EAU.33 TNF-α is crucial in:39

ACCEPTED MANUSCRIPT 1. leukocyte recruitment to the eye in the initial phases of the disease by producing chemokines and inducing an increased adhesion of leukocytes to vascular endothelium 2. maturation of dendritic cells, increasing their ability to present antigens to T-cells

4. activation of effector function of infiltrating T-cells

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3. activation of macrophages

5. increasing apoptosis of resident ocular cells and infiltrating cells

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Through these actions, TNF-α exerts a critical role in the pathogenesis of EAU.98 TNF- α

in the afferent phase of the disease.15

B. Clinical studies

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blockade in the EAU model reduces the incidence and severity of the disease if administered

TNF-α levels are elevated both in the serum and aqueous humor of patients with uveitis, and

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these increased levels correlate with disease status.2,101,117 T-cells extracted from the aqueous humor of non-infectious uveitis patients spontaneously produce significant levels of TNFα.115 As previously seen in experimental models, persistent production of TNF-α is associated

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with tissue damage via reactive oxygen species, promotion of angiogenesis, and breakdown

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of the blood-ocular barrier.75 A new T-helper cell population, Th22, has recently been identified as distinct from the previously characterized Th1, Th2, and Th17 populations. This Th22-type T-cell clone produces large amounts of TNF-α and IL-22.127 These cytokines seem to play a key role in the pathogenesis of uveitis in Behçet disease127 and also in other types of uveitis.28

TNF-α has also been associated with sight-threatening uveitis complications such as CME and choroidal neovascularization. This could be related to the TNF-α’s interaction with

ACCEPTED MANUSCRIPT vascular endothelial growth factor (VEGF) since TNF-α is known to up-regulate VEGF production in choroidal endothelial cells.57,64 TNF-α blockade in uveitis patients leads to a reduction in serum VEGF levels.18 This effect on VEGF levels by TNF-α blockers may

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explain successful outcomes when anti-TNF-α agents are used specifically to treat CME.86

IV. TNF-α Inhibitors

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A. History

The first reported use of anti-TNF-α agents comes from the 1980s in animal models of

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sepsis;11,140 however, subsequent clinical trials in sepsis patients yielded controversial results.17 In 1991, Keffer and co-workers provided a pre-clinical rationale for a causal role of TNF in the development of arthritis and the effectiveness of anti-TNF therapy against immune-mediated human arthritides were reported.73 This was later confirmed in clinical

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trials94 and led to the approval of etanercept, the first biological therapy for rheumatoid arthritis (RA), by the U.S. Food and Drug Administration (FDA) in 1998.

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B. Similarities and differences among agents

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The inhibition of TNF-α can be achieved with a monoclonal antibody (mAb) or with a circulating receptor fusion protein. There are four commercially available monoclonal antiTNF-α antibodies: infliximab (Remicade), adalimumab (Humira), golimumab (Simponi), and certolizumab pegol (Cimzia). Infliximab, adalimumab and golimumab are full-length bivalent IgG mAbs, whereas certolizumab is a monovalent fragment antigen-binding antibody covalently linked to polyethylene glycol.139 Adalimumab and golimumab are fully human mAbs whereas infliximab is a chimeric protein containing approximately 25% mousederived and 75% human-derived amino acids.139 Certolizumab is a humanized protein

ACCEPTED MANUSCRIPT containing amino acid sequences in the complementarity-determining regions derived from a mouse anti-TNF mAb.139 There is only one commercially available receptor fusion protein: etanercept (Enbrel). Etanercept is a genetically engineered fusion protein composed of a dimer of the extracellular portions of TNF Receptor 2 fused to the Fc (Fragment,

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crystallizable) portion of human immunoglobulin G-1.139 Figure 1 shows simplified diagrams of the molecular structures of the various TNF antagonists.

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C. Dosages and routes of administration

Table 1 shows the characteristics of the five commercially available TNF inhibitors.

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Infliximab is the only anti-TNF-α agent administered intravenously, whereas the remaining four are administered subcutaneously. The different dosage regimens represent the optimal schedule for each agent to achieve trough levels.89 Despite infliximab having a half-life of up to 9.5 days, it is typically administered every 4 - 8 weeks in the maintenance treatment phase,

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compared with adalimumab, which is administered every other week, but has a longer halflife of approximately 14 days. The biologic effects of infliximab extend beyond its serum half-life, which explains the dosing interval that exceeds its half-life significantly. The

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linkage of certolizumab to polyethylene glycol theoretically may prolong its presence in

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serum (half-life is 14 days) and therefore its duration of action. Both infliximab and certolizumab require a loading dose prior to the standard maintenance dosing; however, a loading dose may be also beneficial when using other agents.112

Although these are the recommended dosages, other therapeutic regimens appear in the literature for treatment of uveitis, particularly for infliximab.43 Most uveítis specialists believe that the treatment of uveítis requires higher doses of infliximab and shorter intervals between doses than those used for rheumatologic or gastrointestinal disorders. Infliximab

ACCEPTED MANUSCRIPT doses are weight-based for both adults and children. When using the subcutaneous anti-TNFα agents in children, it is important to adjust the dose according to weight. As in other immune-mediated diseases such as RA and inflammatory bowel disease (IBD), different approaches for dose intensification with anti-TNF agents are often attempted for uveitis that

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is refractory to, or relapses with, typical doses.43,72 For example, for infliximab, the starting dose for both adults and children is usually 5 mg/kg but it can be increased incrementally, typically by 2 or 3 mg/kg, until a complete response is achieved. The maximum dose listed

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on the medication label approved by the FDA is 10 mg/kg, and that is usually the highest dose attempted in adults. In children, there are reports in the literature that doses as high as

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20 mg/kg have been used successfully for JIA.70,136

D. Approved indications

In the United States, the FDA has not yet approved any anti-TNF-α agent for the treatment of

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ocular inflammation. The drugs are approved for many other systemic autoimmune conditions (Table 2), all of which have been associated with uveitis and/or scleritis. Therefore, the use of these agents for ocular inflammation is considered off-label in the

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United States. Obtaining approval from third-party payers is facilitated if the patient

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concomitantly has one of the systemic disease diagnoses for which the medications are approved. If the patient does not have one of these indications, the request for coverage should be supplemented by evidence from the many articles in the literature demonstrating efficacy for ocular inflammation.

E. Safety 1. Potential side effects and safety concerns The most reliable data on safety are derived from large clinical trials and data sets in the rheumatologic and gastroenterology literature. These data are thought to be generally

ACCEPTED MANUSCRIPT applicable to the use of these agents for uveitis. There is one study that found a higher rate of infliximab toxicity when treating uveitis compared to what had been previously reported for other disorders.132 The authors hypothesized that patients with isolated ocular disease may not have the elevated systemic levels of TNF-α that are seen in systemic autoimmune

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conditions. The adverse effects of TNF blockade might thus have affected uveitis patients to a greater degree than patients with systemic conditions. Subsequent studies have not found rates of side effects higher than in the rheumatologic literature.76,126,135 Below are the side

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effects that have been associated with the use of anti-TNF-α agents:

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a. Infections

TNF-α is crucial to the host´s immune response against infections, particularly against intracellular pathogens such as hepatitis viruses (HV) and tuberculosis (TB).87,143 Anti-TNF-α treatment therefore may promote TB and HV reactivation. These agents also generally

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increase the risk of any type of infection. A meta-analysis of the randomized clinical trials including patients treated with anti-TNF-α agents showed that there is an increased risk for severe infection from a variety of pathogens, particularly after 6 months of therapy, and this

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has been subsequently corroborated.6,12 The rates of newly acquired bacterial infections are elevated in patients on these agents. There is also higher risk of invasive fungal infections

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including histoplasmosis.148 Pneumococcal and influenza vaccines should also be considered prior to therapy. Of note, patients should not receive live virus vaccines while receiving antiTNF-alpha agents because of the risk of disseminated infection with the live virus.22,84 b. Cancer/neoplasms The risk for developing malignancies after this therapy is much less clear than that of infections. The meta-analyses in the rheumatologic and gastrointestinal literature generally do not find an increased risk for malignancy in the short term;13,105,147 however, there is an

ACCEPTED MANUSCRIPT increased incidence of lymphoma and melanoma in patients taking these agents in some health authorities´ registries.5 It is not clear if the increased risk of malignancy is due to the drug itself or to the underlying disease for which it is indicated. Kempen et al performed a critical analysis of published studies of patients receiving anti-TNF-α agents for treatment of

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ocular inflammatory disorders and concluded that TNF-inhibitors may accelerate diagnosis of cancer in the first six to 12 months, but probably do not increase long-term cancer risk.74 In

there is an increased risk for malignancy.

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c. Demyelinating disease and other neuropathies

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counseling patients, it is important to disclose that there is conflicting evidence about whether

Patients receiving anti-TNF-α agents may development central and peripheral neuropathies, including demyelinating and vasculitic neuropathies. The pathogenesis of this association is unclear, and the incidence is also difficult to determine precisely, although it appears to be

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low (just 27 reported cases as of 2009).82 In one series, over 50% of the peripheral neuropathy complications were Guillain-Barre syndrome (GBS), and short follow-up of these cases shows a good prognosis after treatment withdrawal.82 Twenty-three cases of GBS with

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TNF-alpha therapy have been reported in the literature as of 2013. There have also been

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central nervous demyelinating lesions like those seen in multiple sclerosis.110 The potential risk for inducing or aggravating a demyelinating disorder should be considered before prescribing TNF-α inhibitors for treatment of pars planitis, since up to 15% of patients with pars planitis may eventually develop MS.23 Before initiating anti-TNF-α therapy in a patient with pars planitis, magnetic resonance imaging (MRI) of the brain could be performed to exclude multiple sclerosis.23 However, it should be explained to the patient that a normal MRI prior to therapy initiation does not rule-out the possibility of future demyelinating disease.

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d. Cardiovascular alterations There are potential beneficial cardiovascular effects of anti-TNF-α agents, including protective effects against ischemia and myocarditis as well as an anti-hypertensive effect.

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There are, however, also potential cardiovascular adverse events such as a propensity for atherosclerosis formation and promotion of atheroma plaque rupture, as well as hypertrophy and heart failure from contractile myocardial dysfunction.114 The New York Heart

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Association (NYHA) recommends that anti-TNF-α therapy be avoided in patients with heart failure grades III and IV, but this recommendation is not supported by all epidemiological

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studies.32

e. Hypersensitivity reactions and autoimmunity

The presence of some mouse-derived amino acids in infliximab explains the increased

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incidence of acute hypersensitivity reactions appearing during its infusion and up to two hours afterwards. This is a relatively frequent occurrence that varies depending on the study’s follow-up length,78 with 3-22% of patients receiving infliximab developing some form of the

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reaction. This side effect probably explains the higher number of adverse event-related

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treatment withdrawals with infliximab.123 Development of autoantibodies against anti-TNF-α drugs is further discussed under Clinical Response. Hypersensitivity reactions occur with the use of other anti-TNF-α agents, and most of these cases are delayed, mild, and self-limited, consisting of local cutaneous eruption (eczematous-like) at the site of injection.8

Anti-TNF-α agents may also induce of autoimmunity, including formation of antinuclear, anti-DNA, and anti-cardiolipin antibodies, among others.9 There is also a rare lupus-like syndrome associated with this therapy. For example, sixteen new cases of systemic lupus

ACCEPTED MANUSCRIPT erythematosus were reported after etanercept treatment to the FDA over a three-year period91 but it is difficult to differentiate drug-induced from a primary diagnosis of lupus.51 All antiTNF-α agents, but particularly etanercept, have been associated with the onset of sarcoidosis, both pulmonary and extra-pulmonary.45,59 The pathogenesis of this potential effect is unclear,

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but points to a crucial role of TNF-α in the pathogenesis of this disease.152 Other autoimmune diseases that have been infrequently reported as side effects are cutaneous vasculitis

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(leukocytoclastic vasculitis) and interstitial pulmonary diseases.92,106

f. Other safety concerns

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Transient and mild elevation of hepatic enzymes occur in up to 18% of patients receiving anti-TNF-α therapy.25 Most of these cases, however, do not develop hepatotoxicity or even autoimmune hepatitis, and the subsequent need for treatment discontinuation is rare.25,107 Most hematological side effects reported are mild leukopenia and/or thrombocytopenia

reported.14,35

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although some exceptional cases with severe pancytopenia and/or medullar aplasia have been

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For pregnant women, these drugs are classified as Category B (no evidence of harm in

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animals, but no adequate human studies). In a systematic meta-analysis, the risk of pre-term birth and low birth weight was slightly higher in women on these agents compared to the national average, but the risk of spontaneous abortion was generally no different.40 There is, however, a paucity of studies with long-term follow-up. In general, treatment with anti-TNFα therapy should be discontinued during the third trimester to minimize late fetal exposure that may lead to fetal death.22,67 In addition, vaccination with live viruses should be delayed in the post-natal period until serologic levels of anti-TNF-α are undetectable.40

ACCEPTED MANUSCRIPT 2. Screening history and laboratory tests before therapy initiation58,137 All patients selected for treatment with anti-TNF-α therapy should be screened initially and then monitored regularly for prevention and early detection of side effects. A patient who is

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about to start treatment with an anti-TNF-α agent should be evaluated for:

a. an active infection

Presence of an active infection should delay or contraindicate this therapy. A thorough

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screening for active and latent TB is required, with tuberculosis skin testing or an interferon release assay (IRA). Unlike TB skin tests, IRA tests are not confounded by prior BCG

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vaccination and thus are particularly useful in that patient population. A chest X ray may have already been done as part of the initial targeted work up for uveitis, but if it has not been done, a chest X ray for patients with positive TB skin or IRA testing is indicated. An expert

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panel has recommended one month of TB treatment before starting anti-TNF-alpha agents.80

b. past history of malignancy

Past history of malignancy requires discussion with the oncologist and the patient regarding

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the potential risk of recurrence.

c. heart failure

Patients with well-compensated mild CHF (NYHA classes I and II) and a concomitant indication for the use of TNF-alpha blockers should be evaluated at baseline and then be closely monitored for any clinical signs of worsening heart failure. Patients with NYHA class III or IV heart failure should not be treated with TNF-alpha blockers.

d. cytopenias/hematological disorders

ACCEPTED MANUSCRIPT Treatment should be delayed until they are resolved.

e. demyelinating disease Treatment with anti-TNF-α therapy should be avoided in patients with a history of

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demyelinating disease. If there is a family history of demyelinating disease, this potential side effect should be thoroughly discussed with the patient before therapy initiation.

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f. antibody testing for Hepatitis B and C infection

If a patient has serologic evidence of a hepatitis virus infection, they will require concomitant

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hepatitis virus prophylaxis during the anti-TNF-α treatment to prevent reactivation. In addition, all patients initiating anti-TNF-α therapy with negative markers for HBV should be vaccinated against HBV.

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3. side effect monitoring labs during therapy58,137

The practitioner who has prescribed treatment with anti-TNF-α therapy must personally

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monitor for potential side effects; however, all involved health personnel--including infusion

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nurses, primary care physician--and the patients themselves should be educated about side effects and participate in this monitoring. If the ophthalmologist has not received training on the use of these agents, which usually only occurs as part of a uveitis fellowship, then the ophthalmologist should co-manage the patients with an experienced rheumatologist. This monitoring should include:

a. a general clinical evaluation to rule out the appearance of infections (including TB), cytopenias, demyelinating disease, cancer, worsening of heart failure, and pneumonitis.

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b. serologic testing including a complete blood count and a comprehensive metabolic profile performed every month for the first three months and at least every 2 to 4 months thereafter, although some uveitis specialists continue to check these tests every 4-6 weeks even past the

F. Clinical response

1. serum drug levels and anti-drug antibodies

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initial 3 months.

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Anti-TNF-α agents are not initially effective in all patients with non-infectious uveitis, and some have a diminished response or become intolerant over time.36,96 Immunogenicity is defined as the potential for an antigen to induce an immune response after being recognized by a preexisting T-cell or B-cell receptor.21 Immunogenicity to anti-TNF-α agents may occur

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and be a reason for treatment failure.1,132 This is usually manifested as lower drug levels than expected and/or the appearance of serum anti-drug antibodies (ADAs).

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It is not currently common practice to monitor drug levels regularly for uveítis patients, but

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this should be considered in cases where the clinical response is less than expected.111 There is some evidence from the RA and IBD literature that regular monitoring of biologic drug serum levels may optimize treatment decision making.7,26 There are also some preliminary studies regarding potential utility of serum drug levels in uveítis.1,129 Behcet disease patients who did not have any uveítis recurrences had a higher mean serum infliximab concentration at 8 weeks post infusion compared with patients who did have relapses (7.3 µg/ml vs. 3.4 µg/ml, respectively). Currently there is no clear consensus on the drug trough levels that correlate with clinical response in uveitis. In inflammatory bowel disease a cut-off trough

ACCEPTED MANUSCRIPT level between 3 and 5.8 µg/ml for adalimumab may have the optimal sensitivity, specificity and positive likelihood ratio for prediction of clinical response.48,88 In general, high serum concentrations of anti-TNF agents, measured just before the administration of the next dose, are associated with clinical improvement, whereas low levels are associated with poor

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responses.7,26

All exogenous proteins are capable to induce immunogenicity. The development of

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immunogenicity depends on intrinsic patient factors, characteristics of the drug being used, and route of administration.21 This development of ADAs may signal reduced efficacy and

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safety issues in uveitis patients.1 These ADAs are also referred to as human anti-chimeric antibodies (HACAs) when they occur with infliximab. Anti-TNF-α concentrations are usually reduced in the presence of ADAs and formation of these antibodies correlate with a shorter-lived response to treatment.41,68 Clinical data from studies regarding other immune-

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mediated diseases have given rise to suggested algorithms for revising biologic therapy in patients with ongoing inflammation or uncontrolled disease (Figure 2). Again, monitoring of ADAs has not been definitively shown to improve treatment outcomes, and thus it is not

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typical practice among uveítis specialists to monitor for their development.

2. Use of concomitant immunomodulatory agents The use of anti-TNF-α agents for refractory non-infectious uveitis not only is efficacious for inflammation suppression, but also can allow for a significant reduction in concomitant immunosuppressive medications.37,141 Patients with vision-threatening uveitis who are candidates for anti-TNF-α therapy have usually shown a partial response to conventional IMT agents. In this setting, the practitioner has to decide whether to continue the previous IMT therapy with TNF-α agent initiation. There are two reasons to consider continuing the

ACCEPTED MANUSCRIPT previous agent. The first is for the potentially synergistic anti-inflammatory effect. The second is to prevent formation of ADAs that can diminish the effect of the anti-TNF-α agent.

The reported experience in other immune-mediated diseases such as RA or Crohn disease

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generally supports the higher efficacy of combined therapy when compared with anti-TNF-α therapy alone although some studies do not show an advantage.27,42,48 Unfortunately, there are no randomized, prospective studies comparing both therapeutic options in patients with

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uveitis. The existing information suggests that concomitant therapy may achieve better inflammation control and a reduction in immunogenicity associated with anti-TNF-α

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therapy.120,150 A concomitant IMT agent should therefore be considered particularly in those cases associated with a worse prognosis such as juvenile idiopathic arthritis (JIA) and Behcet-associated uveitides.69,77

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3. Pharmacogenetics

A substantial proportion of patients (approximately 30-40%) fail to respond to anti-TNF-α therapy for non-uveitis indications.103 The largest studies in uveitis report a non-response rate

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of approximately 20%.76,131 Treatment response is likely dependent on many factors,

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including age, location and severity of uveitis, and type of TNF-α blocker employed.79 Genetic differences might also explain some of the variation. Pharmacogenetic studies for anti-TNF-α therapy have been done in patients with immune-mediated diseases other than uveitis such as RA, psoriasis, or sarcoidosis.54,142,145 Genetic polymorphisms associated with response to anti-TNF treatment are present in TNF receptors and TNF promoter regions. Emerging genome-wide association studies suggest that there may be a number of genes with modest effects on treatment response rather than a few genes of large effect;103 however, these results are preliminary and need to be validated in larger cohorts before they can be

ACCEPTED MANUSCRIPT incorporated into clinical practice.

V. Anti-TNF-α therapy in uveitis: Reported clinical experience

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1. Infliximab

Infliximab is currently the anti-TNF-α agent used more often for the treatment of immunemediated uveitis.80 The number of studies is particularly large for uveitis associated with two

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underlying conditions: Behçet disease and JIA.31 There is substantial good-quality evidence to support the use of infliximab for Behçet-associated uveitis.80 Infliximab has been shown to

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be effective for Behçet disease-associated uveitis resistant to other immunosuppressants and is even superior to those therapies in naïve patients in some reports.141,149 In addition, infliximab is associated with quality of life improvement in Behcet disease patients.116 There is also substantial good-quality evidence for infliximab in the treatment of uveitis associated

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with JIA.80 It can achieve a reduction in the requirement for topical and systemic steroids as well as systemic IMT.70,121 As mentioned previously, in JIA-associated uveitis, doses as high

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as 20 mg/kg have been used successfully.70,136

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Infliximab is also successfully used for treatment of uveitis associated with other systemic immune-mediated conditions such as spondyloarthritides (strong recommendation, goodquality evidence), IBD (discretionary recommendation, moderate-quality evidence), and sarcoidosis (discretionary recommendation, moderate-quality evidence).31,126 Moreover, there is moderate-quality evidence for the efficacy in immune-mediated conditions confined to the eye such as birdshot retinochoroidopathy and sympathetic ophthalmia.4,61,80

2. Adalimumab

ACCEPTED MANUSCRIPT Adalimumab is the anti-TNF-α agent with the second largest number of publications for the treatment of uveitis.31,80,130 There is good-quality evidence for the use of adalimumab in spondyloarthropathy-associated uveitis, HLA-B27-associated uveitis, and JIA-associated uveitis.31,52,80,113 Adalimumab is quite efficacious in suppressing inflammation in these

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disorders. For example, it achieved an approximately 50% reduction in uveitis flares in

ankylosing spondylitis patients.52,113 One small prospective study suggested better efficacy for adalimumab over infliximab in maintaining remission of chronic childhood uveitis,

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however the dose of infliximab employed was lower than that typically used in children and this has not been confirmed in large randomized trials.122 There is moderate-quality evidence

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for adalimumab in the treatment of pars planitis, idiopathic posterior uveitis, and Behçet disease-associated uveitis.10,37,80,97 As with infliximab, adalimumab allows for a significant reduction in the mean immunosuppression load and the mean corticosteroid dose in immunemediated uveitis.37 Interestingly, one prospective study found that adalimumab induces a

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reduction in plasma VEGF levels that correlates with clinical improvement.18 Since VEGF plays a role in the pathogenesis of CME,144 this inhibitory effect could explain the successful outcomes of adalimumab for uveitic macular edema in the largest prospective study

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evaluating this therapy in uveitis to date.37

3. Etanercept

Use of etanercept for treatment of immune-mediated uveitis has been particularly focused on patients with JIA-associated uveitis.31 Although preliminary studies showed promising results,109 long-term studies reflected lower rates of treatment success.108,124 Subsequently, the clear inferiority of etanercept when compared to adalimumab and infliximab for treatment of JIA-associated uveitis was established in evidence-based studies.66,80 Moreover, etanercept has been associated with development of uveitis in JIA patients119 and in patients with other

ACCEPTED MANUSCRIPT types of uveitis.53,125 While the exact pathogenesis of this association remains unclear, clinical observations indicate that etanercept may have immunodysregulatory and even proinflammatory effects in the eye.71 Etanercept additionally has been specifically associated with the development and worsening of granulomatous uveitis in the setting of sarcoidosis

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and the development of other sarcoid-like granulomas.65,138 and should, therefore, be avoided for the treatment of sarcoid-associated uveitis and JIA-associated uveitis.80 Patients receiving

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this drug for other indications should be monitored for the development of uveitis.80

4. Golimumab

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The reported experience on the use of golimumab for treatment of immune-mediated uveitis is limited to a few retrospective case series including patients who had been resistant to previous treatment with other TNF-α blockers.29,30,44,90,146 Most of these studies include patients with Behçet disease, JIA, and HLA-B27+ associated uveitides. Although the results

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of these initial studies are encouraging, the reported experience on the use of golimumab for

5. Certolizumab

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uveitis is too scarce to make any conclusions about its efficacy for uveitis.

The reported experience on the use of certolizumab for treatment of immune-mediated uveitis

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is currently limited to one retrospective case series of seven patients.81 Therefore, data is too limited to make any substantial comments regarding this agent in uveitis.

VI. Local use of anti-TNF-α therapy in uveitis

A. Infliximab Two prospective, non-comparative case series have studied intravitreal infliximab for the treatment of uveitis in 22 eyes of 22 patients, collectively.46,47,85 One study employed a single

ACCEPTED MANUSCRIPT intravitreal injection of 1.5 mg/0.15 mL infliximab.46,47 The other also employed a single intravitreal injection of infliximab with a different dose, 1 mg/0.05 mL.85 A single intravitreal injection of infliximab produced a significant improvement in visual acuity, vitreous inflammation scores, and central macular thickness (CMT) at one month in both studies;

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however, these results were not maintained at the 6-month end-point. This suggests a

temporary effect and the need for repeated injections. Although there were some concerns about intravitreal infliximab being retinotoxic when used in the treatment of non-uveitic

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diseases,56 toxicity was not noted in the aforementioned trials.

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B. Adalimumab

There are only two reports of intravitreal adalimumab for treatment of uveitis.3,62 One study included patients with persistent CME, despite control of their ocular inflammation, who failed previous therapies for CME. A total of 8 patients, 5 with an associated systemic

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immune-mediated disease, were evaluated. The follow-up period was 6 months. The initial injection dose was 0.5-mg/0.05 mL, and reinjections with a higher dose of 1 mg/0.05 mL were given for a total of 4 injections. These four intravitreal injections of adalimumab did not

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improve VA or reduce CMT; however, a recent case series of patients with active non-

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infectious uveitis yielded positive results.62 Seven out of 12 eyes had improvement of at least two lines of vision, and nine of 10 eyes with vitreous haze had zero haze at 26 weeks.

VII. Summary of recommendations for the use of anti-TNF-α therapy in uveitis

Given the substantial data accumulated on the use of anti-TNF-α agents for treatment of uveitis, other groups have previously summarized the evidence regarding effectiveness and safety of this therapy.31,102 Recently, an expert panel provided evidence-based guidelines for

ACCEPTED MANUSCRIPT the use of these drugs for treatment of uveitis.80 We summarize recommendations for these agents’ use in uveitis in a series of answers to questions commonly posed by clinicians.

1. Which anti-TNF-α agent should be chosen?

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Although there is more literature to date regarding the use of infliximab in the treatment of uveitis, infliximab and adalimumab can be highly effective, depending on the dose and

intervals used, on prior exposure, and on the specific uveitis entity being treated.31,80 Of

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course, this cannot be definitively stated without evidence from a randomized clinical trial comparing the two, but such a clinical trial will likely never be done. The two drugs share a

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similar mechanism of action, but have different routes of administration, immunogenic potential, and price. These factors usually play a role in which is chosen. For example, a patient may have a preference for route of administration.

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Etanercept is associated with lower rates of treatment success and in some cases can induce ocular inflammation.31,80 In general, etanercept should not be used for uveitis or scleritis, although there are individual cases where it may be efficacious.109 The clinical efficacy of

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golimumab and certolizumab needs to be further demonstrated and these agents currently should be considered only as alternatives in those patients who have failed both infliximab

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and adalimumab.31

2. What are the main indications for this therapy in uveitis?80 The vast majority of uveitis will not require TNF-α blockade as first-line therapy. There is good-quality evidence for infliximab and moderate-quality evidence for adalimumab as a second-line therapy for patients with ophthalmic manifestations of Behçet disease.80 There is also good-quality evidence for using either infliximab or adalimumab as second-line IMT for

ACCEPTED MANUSCRIPT treatment of JIA-associated uveitis refractory to methotrexate alone.80 In such cases, methotrexate is often continued along with the anti-TNF-α agent, unless medically contraindicated. There is good-quality evidence for both infliximab and adalimumab as corticosteroid-sparing treatments for patients with chronic uveitis secondary to seronegative

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spondyloarthropathy. A common clinical scenario where anti-TNF-α agents are used is for patients with vision-threatening, corticosteroid-dependent uveitides of any etiology who have failed first-line IMT such as antimetabolites or calcineurin inhibitors. For this highly

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heterogeneous group of patients, there are many case series and open-label prospective trials

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that support this practice.126,130-132

3. How do I choose and manage dosing and intervals?

Each anti-TNF-α agent has a recommended dose and a maintenance dose frequency as shown in Table 1. The standard regimen of infliximab therapy is intravenous infusion at a dose of 5

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mg/kg at weeks 0, 2, and 6 and then every 8 weeks. Only infliximab and certolizumab pegol require a loading dose, although evidence-based guides for the use of anti-TNF-α agents for treatment of other immune-mediated conditions such as Crohn disease also recommend the

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use of a loading dose when using adalimumab.112 Adalimumab and etanercept require a

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dosage adjustment based on weight in children.

The time needed to determine if there is treatment response is somewhat variable and is probably influenced by many factors such as the underlying condition, location and severity of uveitis, the type of anti-TNF-α agent, the doses used (with or without loading dose), and concomitant immunomodulatory treatment.19,76 In general, significant improvement in ocular inflammation is observed within 1 or 2 infusions of infliximab99,132 and 2 injections of adalimumab.18 In our experience, 2-3 months of anti-TNF-α therapy are usually sufficient to

ACCEPTED MANUSCRIPT assess the response to treatment. In patients who do not respond to maximal doses of antiTNF-α therapy (e.g. 10 mg/kg monthly for infliximab or 40 mg weekly for adalimumab for adults) after at least 2 months, we recommend switching to another anti-TNF-α agent or

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another immunosuppressant with a different mechanism of action.

Once improvement in the uveitis is achieved, management of concomitant

1) Concomitant immunosuppressive therapy:

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immunosuppressive therapy and anti-TNF-α dosing intervals becomes relevant:

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1.A. Steroids: Corticosteroids should be tapered as a main goal of any IMT is to spare the patient their long-term side effects of steroids. The manyany steroid tapering schedules used are beyond the scope of this review. In the vast majority of patients, corticosteroids can be discontinued altogether, and inability to wean completely off of steroids is a clear indication

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to increase anti-TNF-α dose.19,37

1.B. Other immunosuppressants. In general, treatment with concomitant immunosuppressants

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(with methotrexate, mycophenolate mofetil, azathioprine being the most commonly used)

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may be slowly tapered and eventually discontinued.19,37,135 There is some data, however, that maintaining an immunosuppressant along with an anti-TNF-α agents has advantages as explained in section IV F-2. Unfortunately, there are no randomized, prospective studies comparing both therapeutic options in patients with uveitis.

2) Treatment regimen with anti-TNF-α: If a patient has a partial response or has a recurrence of inflammation after quiescence on an anti-TNF-α, there are several different management strategies that may be employed. The first strategy we usually attempt is decreasing the

ACCEPTED MANUSCRIPT interval of maintenance administration to every 4-6 weeks for infliximab and to every week for adalimumab. Other options are to increase the anti-TNF-α dose, add a new concomitant immunosuppressive medication, or increase the concomitant immunosuppression dose.135 Restarting steroids (either topical or systemic) is an option for short-term inflammation

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control. Those patients resistant to these strategies may require switching to another antiTNF-α drug or even to a different family of immunosuppressants.19 Monitoring of serum

cases as explained in section IV.7,26

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4. How long should anti-TNF-α therapy be maintained?

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drug concentrations may help treatment decision-making in these particularly challenging

There is a paucity of data for making recommendations regarding this issue. In the largest studies in uveitis with long term follow up the initial clinical remission rates were 81.8% and 77% respectively.76,131 but the rate decreased to 53.4% at 24 months for one study of

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infliximab.76 When initiating therapy, we tell the patient that this therapy is potentially indefinite, but that we will try to eventually discontinue therapy if they have a prolonged period of quiescence. For example, in patients whose disease is completely controlled for at

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least 2 years after cessation of steroids, many uveitis specialists will attempt a gradual

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lengthening of the interval between infliximab infusions. If the disease is well controlled with a long interval between infusions, generally 4 months or more, we consider discontinuation. Although it is unclear whether anti-TNF-α should be tapered or withdrawn in such patients,95 the potential adverse effects from the agents with long-term use and costs of the therapy are two reasons to attempt discontinuation. Data on clinical outcomes after discontinuation of anti-TNF-α therapy are scarce so it is difficult to quantitate the risk of uveitis reactivation. 19, 76, 141 Therefore, we suggest continued, close monitoring of patients who discontinue anti-TNF-α therapy.

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5. In which situations should this therapy be avoided? There is a controversy regarding the contraindications to anti-TNF-α therapy.5 In general, anti-TNF-α drugs are not recommended during pregnancy and lactation or in patients with

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active infection, cancer, demyelinating disease, optic neuritis, heart failure, interstitial

pneumonitis, severe cytopenia and/or other serious conditions that are known to be induced or worsened by this therapy. Anti-TNF-α agents, however, may sometimes be used in

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VIII. The future of anti-TNF-α therapy in uveitis

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selected cases with these pre-existing conditions at the discretion of the physician.40,55

The off-label use of TNF-α inhibitors for the treatment of clinically relevant uveitides has widely increased over the past decade based on their remarkable efficacy; however, there are many unresolved issues to explore. We have discussed the potential utility of monitoring

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serum drug concentrations and ADAs.41,68,129 Incorporating these measures into clinical practice may be relevant for the challenging therapeutic decision-making involved in these cases.129 These measures may also help minimize the time required to establish the optimal

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therapy for a patient, as well as minimize adverse events. Identification of genetic

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polymorphisms associated with response to anti-TNF therapies may also help to optimize management.

Identification and routine use of biomarkers of clinical response and risk of relapse will also be crucial when managing this treatment in patients with non-infectious uveitis. A current dilemma in clinical practice is how long to continue therapy once the uveitis is controlled. Biomarkers may help identify those patients with disease under apparent control (no ophthalmological signs of active inflammation) but at high risk of relapse. For example, low

ACCEPTED MANUSCRIPT levels of T-regulatory lymphocytes have been associated with uveitis relapses,24 whereas high levels of these cells are associated with the regression phase of uveitis.18,128,134

The local (intraocular) use of these agents is not well studied. Whether this route of

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administration may be comparable or even co-adjuvant to systemic use of TNF-α inhibitors remains unclear. Local delivery may maximize results and minimize potential side-effects

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although preliminary results have not been very encouraging.3,46,47,85

In general, we need larger randomized studies with longer follow-up that include more

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homogeneous groups of uveitis patients. There are still many unanswered questions about the use of anti-TNF-α therapy for non-infectious uveitis.

IX. Conclusions

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The use of TNF-α blockers for treatment of selected cases of non-infectious uveitis has become increasingly common over the last decade. There are substantial data in the literature supporting this therapy, although its use for treatment of uveitis remains off-label in most

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countries. Despite the unresolved issues, there is a clear rationale for their use in severe and

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selected cases of non-infectious uveitis. Given their potential for severe side effects, however, a thorough knowledge of these agents is mandatory for all practitioners prescribing these drugs. Several clinical trials evaluating anti-TNF-α agents are ongoing in uveitis, and we expect these will increase our ability to use these agents in the most efficacious and safe manner.

X. Methods of literature search

ACCEPTED MANUSCRIPT A systematic literature search was performed in PubMed (January 1961 until December 2014) using the combinations of keywords including: Uveitis; Tumor necrosis factor-alpha; Infliximab; Adalimumab; Etanercept; Golimumab; Certolizumab; Serum levels of anti-TNFα drug; Anti-drug antibodies; Pharmacogenomics of anti-TNF-α therapy. The search was

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confined to articles written in English. A manual literature search among the cited references

XI. Disclosures The authors have made the following disclosures:

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in the manuscripts from the systematic literature search was performed as well.

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Miguel Cordero Coma – Speaker honoraria from Abbvie, MSD, Allergan.

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Lucia Sobrin – Scientific advisory board for Santen.

ACCEPTED MANUSCRIPT Figure Legends

Figure 1. Simplified diagrams of the molecular structures of five TNF antagonists. Adalimumab and golimumab are fully human IgG1 monoclonal anti-TNF antibodies.

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Infliximab is a mouse/human chimeric monoclonal anti-TNFantibody of IgG1 isotype. Etanercept is a fusion protein of TNFR2 (p75) and the Fc region of human IgG1.

Certolizumab is a PEGylated Fab' fragment of a humanized IgG1 monoclonal anti-TNF

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antibody. Adapted with permission from Tracey et al.38

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Figure 2. Flow chart for revising biologic therapy in patients with ongoing inflammation.

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This flow chart is a proposal and has not been validated in any studies.

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ACCEPTED MANUSCRIPT

Table 1. Characteristics of Anti-Tumor Necrosis Factor-alpha Antagonists Etanercept Fused receptor and antibody fragment

Adalimumab Monoclonal antibody

Golimumab Monoclonal antibody

Certolizumab Pegylated monoclonal Antibody

Nature of antibody

Mouse-human chimeric

Human fusion protein

Fully human

Fully human

Humanized

Route of administration

Intravenous

Subcutaneous

Subcutaneous

Subcutaneous

Subcutaneous

Loading dose employed

5 mg/kg at weeks 0,4, and 6

Standard maintenance dose* Maintenance dose frequency

5 mg/kg

For patients with underlying psoriasis, 50 mg twice weekly for the first three months 50 mg

For some underlying diseases, the first dose is higher: 80 mg (for psoriasis) or 160 mg (for Crohn’s disease) 40 mg

If there is underlying Yes: 400 mg at weeks ulcerative colitis, 0, 2, and 4 200 mg at week 0, and 100 mg at week 2 50 mg 200 mg

Every 4 to 8 weeks

Weekly

Every 2 weeks

Monthly

Every 2 weeks

Pediatric dose

5 mg/kg

0.8 mg/kg up to a maximum of 50 mg per week

24 mg/m2 body surface area up to a maximum of 40 mg every 2 weeks

N/A

N/A

Usual maximal dose

10mg/kg for adults, 20 mg/kg for children every 4 weeks 9.5

50 mg weekly

40 mg weekly

100 mg monthly

200 mg every 2 weeks

3

14

12

14

Half-life (days)

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Structure

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Infliximab Monoclonal antibody

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N/A= not available * Although only infliximab doses are weight-based for adults, patients with higher weights may require increased doses of other anti-TNF α agents as well.

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Table 2. United States Federal Drug Administration-Approved Indications for Tumor Necrosis Factor Antagonists as of June 2014 Federal Drug Administration-Approved Indications Rheumatoid arthritis Juvenile idiopathic arthritis Psoriatic arthritis Ankylosing spondylitis Crohn’s disease Ulcerative colitis Plaque psoriasis

Certolizumab

Crohn’s disease Rheumatoid arthritis Psoriatic arthritis Ankylosing spondilitis

Etanercept

Rheumatoid arthritis Polyarticular juvenile idiopathic arthritis in patients aged 2 years or older Psoriatic arthritis Ankylosing spondylitis Plaque psoriasis

Golimumab

Rheumatoid arthritis in combination with methotrexate Psoriatic arthritis Ankylosing spondylitis Ulcerative colitis

Infliximab

Crohn’s disease Pediatric Crohn’s disease Ulcerative colitis Pediatric ulcerative colitis Rheumatoid arthritis in combination with methotrexate Ankylosing spondylitis Psoriatic arthritis Plaque psoriasis

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Medication Adalimumab

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Figure 1. Simplified diagrams of the molecular structures of five TNF antagonists. Adalimumab and golimumab are fully human IgG1 monoclonal anti-TNF antibodies. Infliximab is a mouse/human chimeric monoclonal anti-TNFantibody of IgG1 isotype. Etanercept is a fusion protein of TNFR2 (p75) and the Fc region of human IgG1. Certolizumab is a PEGylated Fab' fragment of a humanized IgG1 monoclonal anti-TNF antibody. Adapted with permission from Tracey et al.38

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Uveitis patient unresponsive to anti-TNF-alpha therapy

Low serum drug trough concentration

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Intensify therapy (increase dose or decrease dosing interval)

High anti-drug antibody levels

Change to different anti-TNF agent and/or add concomitant immunosuppressant

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Low anti-drug antibody levels

High serum drug trough concentration

Low anti-drug antibody levels

Change to treatment with a different mechanism of action

High anti-drug antibody levels

Optimal management strategy is unclear. Could add concomitant immunosuppressant and/or change to different anti-TNF agent

Predicting durable response or resistance to antitumor necrosis factor therapy in inflammatory bowel disease.

Q Fever Risk in Patients Treated with Chronic Antitumor Necrosis Factor-Alpha Therapy.

Effects of Antitumor Necrosis Factor Therapy on Osteoprotegerin, Neopterin, and sRANKL Concentrations in Patients with Rheumatoid Arthritis.

Uveitis Reactivation in Children Treated With Tumor Necrosis Factor Alpha Inhibitors.

Outcome of patients with serology suggestive of past hepatitis B virus infection during antitumor necrosis factor therapy for psoriasis.

Prospective comparison of preference and efficacy of adalimumab and infliximab for treating ulcerative colitis naive to antitumor necrosis factor therapy.

[Therapy of ascites with tumor necrosis factor in ovarian cancer].

[Surgical therapy of uveitis].

[Therapy of intermediate uveitis].

Screening for latent tuberculosis before tumour necrosis factor antagonist therapy.

Sensory neuronopathy associated with tumor necrosis factor inhibitor therapy.

Anti-tumor necrosis factor therapy abrogates autoimmune demyelination.

Screening for latent tuberculosis before tumour necrosis factor antagonist therapy.

Alopecia secondary to anti-tumor necrosis factor-alpha therapy.

Comparing the risk of developing uveitis in patients initiating anti-tumor necrosis factor therapy for ankylosing spondylitis: an analysis of a large US claims database.

Combination of Gold Nanoparticle-Conjugated Tumor Necrosis Factor-α and Radiation Therapy Results in a Synergistic Antitumor Response in Murine Carcinoma Models.

Tumor necrosis factor, tumor necrosis factor inhibition, and cancer risk.

Recalcitrant psoriatic uveitis and anti-tumor necrosis factor-α monoclonal antibodies: experience from a psoriasis referral center.

Predictive value of early restoration of quality of life in Crohn's disease patients receiving antitumor necrosis factor agents.

CD40 ligand-engineered mesenchymal stem cells greatly enhanced the antitumor immune response and lifespan in mice.

Antitumor necrosis factor α is more effective than conventional medical therapy for the prevention of postoperative recurrence of Crohn's disease: a meta-analysis.

Tumor necrosis factor-alpha.

Antitumor effect of recombinant human interleukin-1 beta alone and in combination with natural human tumor necrosis factor-alpha.

Withdrawal of anti-tumour necrosis factor α therapy in inflammatory bowel disease.