Review Article
An Overview on Biologic Medications and Their Possible Role
in Apical Periodontitis
Elisabetta Cotti, DDS, MS,* Elia Schirru, DDS, MS,* Elio Acquas, PhD, and Paolo Usai, MD
Abstract
Introduction: Apical periodontitis (AP) is the expres-
sion of a deficient balance between infection and the
host immune response. Methods: If reducing the bacte-
rial load from the root canal and preventing its rein-
fection may lead to clinical success, then the integrity
of the nonspecific immune system has a relevant influ-
ence on the outcome of endodontic treatment. Results:
Compromised immune systems and/or genetic alter-
ations of the hosts response may as well play an impor-
tant role on the development, progression, and healing
of AP. Thus, immunomodulatory drugs might have the
potential to influence both the severity of AP and the
outcome of endodontic treatment. Biologic medications
are a new class of drugs of monoclonal antibodies or
fusion proteins that include fragments of a peculiar cyto-
kine receptor. Specific inflammatory molecules or cells,
such as tumor necrosis factor, interleukins, and T or
B cells, are the selective targets of these drugs. They
modulate the altered immune response and perform
an important role in the short-term treatment of chronic
inflammatory diseases such as rheumatoid arthritis, re-
fractory Crohn disease, or ulcerative colitis. Despite
the clinical positive outcomes and their widespread
use, the consequences of administering biologic medi-
cations on the development of the dental diseases
have not been adequately investigated. Conclusions:
The aim of this review was to give an overview of bio-
logic medications, their composition, their mechanisms
of action, and their possible implications on endodontic
and other dental diseases. (J Endod 2014;40:1902
1911)
Key Words
Apical periodontitis, biologic drugs
From the *Department of Conservative Dentistry and End-
odontics, School of Dentistry, Department of Life and Environ-
mental Sciences, School of Pharmacology, and Department of
Gastroenterology, School of Medicine, University of Cagliari,
Italy; and the Department of Endodontology, Kings College
Dental Institute, London, United Kingdom.
Address requests for reprints to Dr Elisabetta Cotti, Depart-
ment of Conservative Dentistry and Endodontics, University of
Cagliari, School of Dentistry, 09124 Cagliari, Italy. E-mail
address: cottiend@tin.it
0099-2399/$ - see front matter
Copyright 2014 American Association of Endodontists.
http://dx.doi.org/10.1016/j.joen.2014.08.013
1902 Cotti et al.
T he aim of endodontic therapy is to treat or to prevent apical periodontitis (AP). AP is
a coordinated sequence of host responses to the presence of a microbial infection
originated from the root canal system and invading the local tissues (1). If reducing the
microbiota from the root canal and preventing its reinfection may lead to clinical suc-
cess, then host factors must have a critical role in determining the severity of the disease
as well as in determining how a specific patient responds to treatment (1).
The so-called integrity of the nonspecific immune system has an influence on the
outcome of endodontic treatment, which may be as important as other patient- and
treatment-related variables (ie, technical quality of root canal treatment) (2). The
role of the immune system may be reflected in the delayed or impaired resolution of
AP, the response to treatment of immunocompromised patients, diabetic patients,
and the degree of severity of the clinical manifestations of AP (28). Within this
overall scenario, genetic factors from the host that influence immune modulation
must also play a very important role on the development, progression, and healing
of AP (911).
Strindberg (4) had already included in his classic study the general health status
of the patient as an explanatory variable, but he had not found a significant impact of
this variable on periapical health.
Marending et al (2) for the first time in recent years assessed the importance of the
immune system on endodontic initial treatment and retreatment outcome in 132 teeth of
subjects seeking endodontic therapy within a medical center in Switzerland.
They scored periapical health using the periapical index (PAI) system, had the
same operator perform the standardized treatments on teeth, and followed up patients
for an average of 46 months. Their overall success (defined as a PAI score at recall #2
without symptoms) was 88% with a recall rate of 79%. Using a regression model, 3 sig-
nificant predictors for treatment outcome were found in that cohort:
1. Integrity of the nonspecific immune system (P = .05)
2. Dichotomized initial PAI score (P = .04)
3. Quality of root filling (P = .01)
The stepwise logistic regression analysis indicated an odds ratio of 8.25 for the
role of immune system versus an odds ratio of 12.77 for the quality of root canal filling;
this is a remarkable finding because it suggests that the status of the immune system is
almost as important as the technical quality of endodontic treatment.
Fouad and Burleson (5) in a retrospective study on diabetic versus nondiabetic
patients have come to similar conclusions, showing that diabetic patients with pre-
operative AP had significantly reduced success on endodontic treatment. Studies
have shown the trend toward a higher risk for the spreading of periapical infection
and for the development of larger periapical lesions on immunocompromised
animals (6, 7).
Furthermore, in terms of the host response, the delayed or impaired resolution of
periapical lesions has been attributed to the persistent state of activation of macro-
phages after the initial cause of AP has been removed with the consequent continuous
production of bone-resorbing cytokines (8).
Genetic factors were first associated with the development of symptomatic apical
abscesses (9), with the occurrence of external root resorption (12), and in a recent
case-control study on AP refractory to endodontic treatment. Morsani et al (10) found
that a specific genotype in the interleukin (IL)-1b gene cluster is associated with the
persistence of AP. Because monocytes from people homozygous for the IL-1b gene
JOE Volume 40, Number 12, December 2014

(allele 2) produce 4 times more IL-1b and heterozygous cells produce
2-fold more IL-1b (11), this situation could contribute to the creation
of a stronger immune-inflammatory response at the periapical area of a
tooth affected by AP and the consequent persistence of AP even after a
state-of-the-art root canal treatment.
Although the importance of the initial periapical status and the
technical quality of the root canal treatment on endodontic success
has been reviewed several times, the most important conclusion from
these studies is the definite impact that an impaired nonspecific immune
system has on the efficacy of endodontic treatment (3).
The clinical implications of these conclusions suggest the novel
concept that new immunomodulatory drugs have the potential to influ-
ence endodontic treatment outcome. This review provides a foundation
to understand this new hypothesis for the modulation of endodontic
outcome.
Models for Chronic Inammatory Diseases
Inflammation is the usual response to harmful exogenous or
endogenous elements. It is a protective response that helps to destroy,
dilute, or wall off detrimental agents, and at the same time it initiates a
variety of events that generate the healing and repair or replacement of
the damaged tissue. Inflammation and repair are also potentially harm-
ful; the inflammatory response is the cause of hypersensitive reactions
and a variety of diseases ranging from asthma to rheumatic pathologies.
The current belief is that inflammation represents part of the nonspe-
cific immune response with typical signs that include alteration of blood
flow, vasodilation, upraising of cellular metabolism, release of cellular
mediators, cellular influx, and extravasation of fluids (13).
Mediators are the major effector system of innate inflammatory re-
action; they come from plasma proteins, inflammatory cells, and tissue
cells. Mediators from plasma proteins are kinins, proteases activated
during coagulation and activation of the complement; mediators from
inflammatory cells are histamine, serotonin, prostaglandins, leukotri-
enes, platelet-activating factor (PAF), reactive oxygen species, nitric ox-
ide, neuropeptides, chemokines, and cytokines (Table 1) (1420).
Major cytokines include tumor necrosis factor (TNF), IL-1/12,
and interferon gamma (14). TNF-a is a cytokine released by activated
monocytes, macrophages, and T lymphocytes that contributes to the im-
mune response, growth regulation, differentiation, survival, and physi-
ological function of a variety of different cells together with the
production of other cytokines, inflammatory mediators, and enzymes
(21, 22). It is a potent inducer of bone resorption, which stimulates
the differentiation and activation of osteoclasts (23). TNF-a functions
are mediated by 2 receptors: TNF-R1 (receptor type 1, CD120a, and
p55/60), which is expressed in most tissues, and TNF-R2 (receptor
type 2, CD120 b, and p75/80), which is highly regulated and typically
expressed in immune system cells (22) (Table 2) (2435).
Acute inflammation is a prompt response designed to support a
site of damage with leukocytes and plasma proteins. Chronic inflamma-
tion is a complex event characterized by the simultaneous presence of
active inflammation, the tissue injury and healing process, vascular
changes, and infiltration of white blood cells; it represents the base
of complex pathologies (14, 36).
AP is an inflammatory disease. The pathologic changes of the peri-
apical tissues in AP are caused by microbes, their toxins, and metabolic
byproducts; these irritants are capable of either inducing nonantigenic
pathways or serve as antigens to activate adaptive responses. Thus, the
pathogenesis of AP involves an innate and adaptive immune response
(3739) (Fig. 1). The development of acute AP reflects the innate im-
mune response and represents the immediate defense reaction to irri-
tants; characteristic features of acute AP are similar to typical acute
JOE Volume 40, Number 12, December 2014
Review Article
inflammation. If pathogens in the root canal are not defeated, acute
AP progresses to chronic inflammation (3739). The specific
conditions from the infected pulp tissue and root canal play a
regulatory role in controlling the local immune-inflammatory process
(40). Primary endodontic infection is a potent activator of toll-like re-
ceptor-4 (TLR-4) and stimulates macrophages to produce cytokines
that establish different network interrelationships implicated in the
development of the variety of clinical and radiographic features of AP
(41, 42). IL-6 and IL-10 have been positively associated with the radio-
graphic size of the lesion and with the inflammation of the periodontal
ligament. Higher levels of TNF-a were correlated to the presence of
exudation; on the other hand, IL-10, which counterbalances the pro-
duction of inflammatory cytokines, was negatively correlated to the
presence of clinical symptoms (41, 42). The network between
different cytokines regulates the formation of both initial and chronic
AP. Chronic inflammatory forms of AP are characterized by a balance
between anti- and proinflammatory cytokines (41). The response of
periapical tissues to injuries is similar to that of the other connective
tissues in the body and the other inflammatory diseases. The role of
IL-6 in human resorptive chronic diseases such as rheumatoid arthritis
(RA) has been reported (43).
RA and Crohn disease (CD) are, in fact, well-known models of
pathologies strongly related to chronic inflammation (4345). RA
affects 0.3%1% of the entire worlds population (46, 47), and it
presents, as a major feature, the excessive production of
proinflammatory cytokines, their primary localization into synovia,
and their eventual spread to the entire joints. TNF seems to be the
predominant cytokine involved in the pathogenesis of RA (48); the
other cytokines implicated in this disease are the allelic variations
of IL-1 and IL-1Ra (receptor antagonist), noticeable in animals but
still controversial in humans, (49, 50), and IL-6 (51). Inflammatory
cells are represented by T cells, dendriticlike cells, and macrophages.
The progression of RA also includes the degeneration process of carti-
lage and bone through the activation of the receptor activator of nu-
clear factor kB (Rank)receptor activator of nuclear factor kB ligand
(RankL) system. Rank-RankL system is based on 3 different elements:
Rank, its ligand RankL, and osteoprotegerin (52). Rank is a mem-
brane protein receptor expressed on preosteoclasts; RankL is a pro-
tein of the TNF superfamily expressed by stromal cells, synovial
fibroblasts, and T cells (53).
Once secreted, RankL binds to its own receptor RANK on osteo-
clast progenitor cells (preosteoclasts) (54); the activated receptor
then stimulates the differentiation of the osteoclasts and eventually the
resorption of bone (55). RANKL activity is regulated by osteoprotegerin,
a decoy receptor of RANKL that blocks osteoclastic formation. Thus,
cytokines such as TNF-a, IL-1, IL-6, and IL-17; hormones; and growth
factors increase the expression of RANKL in the joints and promote
osteoclastogenesis (56).
CD involves potentially the whole alimentary tract with a predilec-
tion for the distal small bowel and proximal large bowel. The defective
production of defensins in patients and the IL-23 pathway are associated
with this disease (57). IL-12 and IL-23 promote the differentiation of
naive CD4+ T cells into Th1 effector cells (that produce interferon
gamma), the generation of memory T cells, and the differentiation of
Th17 cells (58). T-cell products IL-2 and activated antigen-
presenting cells amplify the immune response with the production of
IL-2 (T-cell growth factor), IL-1, and TNF. Besides inflammation, aph-
thous ulcers and granulomas are the early clinical hallmark of CD; CD
granulomas are sarcoidlike lesions with epithelioid histiocytes and in-
flammatory cells, and TNF is the key cytokine involved in its formation
(57). Genetics and environment have been advocated as important fac-
tors in the pathogenesis of rheumatic diseases (RA) (59, 60); yet, the
Biologic Medications and AP 1903
Review Article
TABLE 1. Mediators of Inflammation
Products Cell types General effects Pulp/periapex effects
Cell derived
PAF Activated inflammatory cells, Vasodilation, aggregation of Stimulates production of PGI2
endothelial cells, injured platelets, degranulation of and TXA2 in rats
tissue cells serotonin, alteration of
vascular permeability,
oxidative burst, adhesion cells
expression (integrins)
Prostanoids  Mast cells predominantly PGD2 1. Vasodilation PGE2 increases bradykinin-
1. Prostacyclin  Macrophages PGE2, TXA2 Vascular permeability evoked release of
PGI2  Platelets TXA2 Pain immunoreactive CGRP and
PGD2  Endothelial cells PGI2 2. Vasoconstriction production of hepatocyte
PGE2 Platelet aggregation growth factor (it stimulates
PGF2a DNA synthesis)
2. Thromboxane (TXA2)
Leukotrienes Neutrophils, macrophages, mast Chemotaxis, stimulation of Reduce or increase spontaneous
LTA4 cells, basophils smooth muscle contraction, and evoked nerves excitability
LTB4 vascular permeability, (contrasting data)
LTC4 leukocyte aggregation, and
LTD4 adhesion
LTE4
Lipoxins Platelets, neutrophils. Negative regulator of No data
leukotrienes, chemotaxis, and
adhesion of neutrophils
Cytokines*(further details  Macrophages/monocytes pre- Endothelial cells activation to IL-1 reduces pain threshold; IL-1
in Table 2) dominantly IL-1, -6, -8, TNF-a, T express adhesion molecules and TNF-a have a protective
IL-1 (and subspecies) cells, IL-6, -10, -13, INF-g and production of reactive role against the spread of the
IL-6  Epithelial cells IL-1, -8 oxygen species; aggregation infection
IL-8  Lymphocytes TNF-b of neutrophils; fever; antiviral;
IL-10  NK cells INF-g leukocytes activation
IL-13
TNF-a
TNF-b
INF- a
INF- b
INF-g
Chemokines Leukocytes; epithelial cells; Leukocytes chemotaxis and Chemotaxis, proangiogenesis in
CCLs endothelial cells; activated activation inflamed pulp; proangiostasis
CXCLs macrophages in healthy pulp
XCLs
CX3CLs
ROS Endothelial cells; leukocytes Cell injury; bacterial toxicity; Superoxide reduces pulpal blood
Superoxide (neutrophils) protein crosslinking; DNA flow
Nitric oxide breaks; peroxidation of lipid
Hydrogen peroxide membrane
Hydroxyl radical
Serotonin Platelets Platelets aggregation Induces release of CGRP in
Vasodilation, increased women
vascular permeability,
recruitment of neutrophils
Histamine Basophils; mast cells; platelets Vasodilation, increased vascular High concentration in pulp
permeability, endothelial polyps
activation
Plasma derived
Hageman factor Plasma Conversion plasminogen to Exacerbates inflammatory
plasmin, prekallikrein to response
kallikrein; activation of
alternative pathway of the
complement and coagulation
system
Complement Plasma Phagocytosis; leukocyte Minor effects on pulp
chemotaxis and activation,
vasodilation; opsonization
CCLs, C-C motif ligand; CGRP, calcitonin gene-related peptide; IL, interleukin; INF, interferon; PGE, prostaglandin E; TNF, tumor necrosis factor.

role of bacteria, specifically oral bacteria, has been proposed to the number of species and their concentrations are significantly higher
participate in its early causative processes as well (61). in synovial fluids of patients with RA when compared with controls (in
DNA from oral bacterial species can be isolated in serum and sy- this case, patients with osteoarthritis) (61). A further finding to support
novial fluids from patients with various forms of arthritis. In addition, these data is the presence in RA of antibodies against cyclic citrullinated

1904 Cotti et al. JOE Volume 40, Number 12, December 2014
 TABLE 2. Cytokines
Ligands (L) Chr L Receptors (R) Chr R Cell type Action Action on pulp
IL-1a, b 2q14 IL-1RI 2q12 Macrophages, monocytes, Pyrogen agent, stimulates Stimulates resorption of
IL-1RII lymphocytes, differentiation of the periapical bone but
keratinocytes, TH17 cells, also has a protective
microglia, hematopoiesis role against infection
megakaryocytes, spread; inhibits pulp
neutrophils, fibroblasts
fibroblasts, synovial proliferation; induces
lining cells expression of
collagenase
IL-1Ra 2q14.2 IL-1RI 2q12 Monocytes, macrophages, Antagonist of IL-1 May have a crucial role in
IL-1RII fibroblasts, the progression of the
neutrophils, apical lesions

JOE Volume 40, Number 12, December 2014

endothelial and
epithelial cells,
keratinocytes
IL-2 4q26-q27 IL-2R 10p15-p14 CD4+ and CD8+ activated Proliferation of effector T Proinflammatory effects;
T cells, dendritic cells, and B cells, comparable levels of IL-
NK cells development of Treg 2 have been found in
cells, differentiation normal, inflamed, and
and proliferation of NK necrotic pulps
cells and growth factor
for B cells
IL-4 5q31.1 IL-4RI 16p12.1-p11.2 TH2 cells, basophils, induction of TH2 May stabilize the
IL-4RII eosinophils, mast cells, differentiation, IgE dimensions of the
NKT cells, g/d T cells class switch, up- chronic lesions
regulation of class II
MHC expression on
B cells, up-regulation of
CD23 and IL-4R, survival
factor for B and T cells,
role in tissue adhesion
and inflammation
IL-6 7p21 IL-6 1q21 Endothelial cells, Synthesis of acute phase May stabilize the
sIL-6R fibroblasts, monocytes/ proteins; stimulates dimensions of chronic
macrophages activation and lesions;
trafficking of proinflammatory and
leukocytes; anti-inflammatory
differentiation, effects; it increases in
activation, survival of teeth with symptomatic
T cells; B cell: pulpitis
differentiation and
production of IgG, IgM,
IgA; hematopoiesis
IL-10 1q31-q32 Complex of IL-10R1/ 11q23; 21q22.11 T cells, B cells, monocytes, Immune suppression Inhibitory effect against
IL10R2 macrophages, dendritic bone resorption
cells
IL-12A, B 3q25.335q31.1-q33.1 IL-12Rb1 10p15-p14; 19p13.1 Monocytes, macrophages, Induce TH1-cell Correlations to bone-
IL-12Rb2 neutrophils, microglia, differentiation and resorptive processes

Biologic Medications and AP

dendritic cells, B cells cytotoxicity
(Continued )

1905
Review Article
 TABLE 2. (Continued )

1906
Ligands (L) Chr L Receptors (R) Chr R Cell type Action Action on pulp
IL-13 5q31 IL-13R1a1 Xq13.1-q28 T cells, NKT cells, mast Switching to IgG4 and IgE; Inhibits resorption
IL-13R1a2 cells, basophils, up-regulation of CD23,
eosinophils MHC-II on B cells;

Cotti et al.
induction of CD11 b,
CD11c, CD18, CD29;
Review Article

CD23, and MHC-II on

monocytes; activation
of eosinophils and mast
cells; recruitment and
survival of eosinophils
IL-17 6p12 IL-17RA 22q11.1 T cells Induces production of IL-6 Induces IFN-g production;
and -8 increases production of
CXCL1 and CXCL5
chemokines
IL-18 11q22.2-q22.3 IL-18R 2q12 Macrophages, astrocytes, Induction of IFN-g in Proinflammatory effects,
Kupffer cells, presence of IL-12; similar to IL-12
keratinocytes, enhances NK cell
osteoblasts, dendritic cytotoxicity; promoting
cells TH1 or TH2cell
responses depending
cytokine enviroment
IFN-g 12q14 INFGR1 + INFGR2 6q23.3; 21q22.11 CD8+ and CD4+ T cells, Activation of Proinflammatory effects,
activated NK cells macrophages; induces might have a crucial
MHC class II protein protective effect on the
expression; inhibits IL- pathogenesis of late
4dependent class II periapical bone
expression on B cells; resorption in vivo
regulates TH1 cells
development;
regulates
immunoglobulin class
switching
TNF-a 6p21.3 TNFR1/2 12p13.2; 1p36.22 Macrophages, monocytes, Cell cytotoxicity; Promotes bone
astrocytes, B cells, improvement of the resorption; protective
basophils, cardiac function of NK cells; role against spread of
myocytes, eosinophils, fever; anorexia; infection
fibroblasts, glial cells, essential role in septic
granulosa cells, shock
keratinocytes, mast
cells, neurons,
neutrophils, tumor cells
LT-a (TNF b) 6p21.3 TNFR1 (DR1) 12p13.2 NK, T, and B cells Mediates inflammatory, Proinflammatory effects
immunostimulatory
and antiviral responses;
plays a role in apoptosis
Ig, immunoglobulin; IL, interleukin; NK, natural killer; NKT, natural killer T cells.

JOE Volume 40, Number 12, December 2014


Figure 1. Adaptive and innate immune responses in AP: the production of cytokines, immunoglobulins, and up-regulation of the bone resorption process. Ags,
antigens; APC, antigen presenting cell; Bc, B lymphocyte; Igs, immunoglobulins; MAC, macrophage; MHC II, major histocompatibility complex II; MLT-OSTC, multi-
nucleated osteoclast; OPG, osteoprotegerin; OSB, osteoblast; OSTC, osteoclast; PAMP, pathogen-associated molecular patterns; PLC, plasma cell; PMN, polymor-
phonuclear leukocyte; RANK-L, Rank ligand; Tc, T lymphocyte; Th1-2, T helper cells.
peptide. Citrullination is the post-translation deamination process that
converts arginine residuals to citrulline by the enzyme peptidyl arginine
deaminase, and Porphyromonas gingivalis has been shown to express
peptidyl arginine deaminase proteins (59, 60).
The current therapeutic approach of these pathologies strongly
related to chronic inflammation is mainly focused on the blockage of
inflammation by reducing the high levels of cytokines produced. RA
has been treated with nonsteroidal anti-inflammatory drugs (54);
disease-modifying antirheumatic drugs (DMARDs), a class of medicines
that include methotrexate (48, 54) (a drug that inhibits the stimulated
neutrophil function and the production of several proinflammatory
cytokines) (62); and glucocorticoids (48, 54, 63). The management
of CD has included the use of sulfasalazine, other 5-aminosalicylic
acid agents, glucocorticoids, azathioprine, 6-mercaptopurine purine
analogues, and DMARDs.
In recent years, biologic dugs, a revolutionary class of drugs
created by genetic engineering, have been prescribed for patients
affected by these chronic inflammatory diseases in which the classic
pharmacologic approach has been unsuccessful (48, 54, 57, 6466).
Biologic Drugs
The active ingredients of biologic agents are genetic engineered
molecules, mostly monoclonal antibodies or fusion proteins containing
a portion of the cytokines receptors (6782). Every different active
ingredient of biologic agents is directed against a specific target such
as TNF-a, IL-1, IL-6, T cells, or B cells, and its aim is either to reduce
or block the activity of these targets (54). The most common target for
these new medicines is TNF-a. The US Food and Drug Administration
and European Medicines Agency have to date approved 5 RA biologic
agents called TNF inhibitors: adalimumab, infliximab, etanercept, cer-
tolizumab pegol, and golimumab (Table 3) (8391).
In 1975, Kohler and Milstein (Nobel Prize winners in 1984) pub-
lished original research on the production of large quantities of anti-
bodies against specific targets. They had created monoclonal
antibodies as a result of the association between heavy and light chains
from 2 different parental lines. They described the derivation of a num-
JOE Volume 40, Number 12, December 2014
Review Article
ber of tissue culture cell lines that secrete antisheep red blood cell an-
tibodies. The cell lines were obtained by fusion of mouse myeloma and
mouse spleen cells from an immunized donor. The resulting cells,
called a hybridoma, had the antibody production capability inherited
from lymphocytes (from the spleen) and the ability to grow
continuously like malignant cancer cells (from myeloma cell line).
This research was an outbreak because cell fusion techniques repre-
sented a new and powerful tool to produce antibodies directed against
a predetermined antigen on animals (67). During the early 1990s, orig-
inal studies were focused on the creation of new molecules that could
interact with the mechanisms of chronic inflammation in humans
(6880). In 1992, a chimeric mouse-human antibody was raised
against the human CD4 antigen and showed an enhanced activity in
mediating antibody-dependent cell-mediated cytotoxicity using human
CD4+ target and effector cells and represented a considerable promise
for the treatment of allograft rejection and RA (48). In 1994, Elliott et al
(81) introduced a human open-label clinical trial based on the compar-
ison between a chimeric monoclonal antibody against TNF-a and a pla-
cebo in the treatment of RA. This trial showed that the blockade of
TNF-a was highly effective and had a safe outcome in the short-term
treatment of RA. Collectively, this study formed the beginning of a
new direction in the treatment of rheumatic diseases with the new bio-
logic drugs.
All biologics have several adverse effects; they could increase the
risk of infection or permit reactivation of previous infections. Contrain-
dications for the use of this class of drugs include sepsis or risk of
sepsis, pre-existing tuberculosis, opportunistic infections, hepatitis B
reactivation, hepatitis B virus infection (92, 93), and hepatitis C
infection. All patients treated with biologic agents should be screened
annually for tuberculosis (8486, 89, 9294) and receive vaccines
against pneumococcus (92), annual influenza (95), and hepatitis
B virus (9294). Furthermore, after the long-term administration of
biologic drugs, cases have been reported on the onset of various malig-
nancies (including breast and lung carcinoma, lymphoma, melanoma,
and nonmelanoma skin cancer) (94), rare cases of jaundice, noninfec-
tious hepatitis, and isolated cases of liver failure resulting in liver trans-
plantation or death (94).
Biologic Medications and AP 1907
Review Article
TABLE 3. Biologic Drugs
Target Nature Mechanism of action
Adalimumab TNF-a inhibitor Recombinant human Inhibits the binding of TNF-a to TNF-a
monoclonal antibody IgG receptors (p55, p75)
Infliximab TNF-a inhibitor Chimeric human-murine IgG1 antibody Forms a durable complex with TNF-a,
leading to loss of TNF activity
Etanercept TNF-a inhibitor Human fusion protein TNF receptor Inhibits the TNF binding to its cell
p75 (TNF receptor2+Fc domain of surface receptor
IgG1)
Certolizumab pegol TNF-a inhibitor Monoclonal antibody Binds and neutralizes both soluble and
transmembrane TNF-a and inhibits
signaling through both the p55 and
p75 TNF a receptors in vitro
Golimumab TNF-a inhibitor Monoclonal antibody IgG1k Forms a stable complexes with TNF-a,
excluding TNF-a receptor binding.
Neutralizes the expression of
e-selectin, VCAM-1, ICAM-1
Canakinumab IL-1 b inhibitor Human monoclonal antibody IgG1/k Binds to human IL-1b
isotype)
Rilonacept IL-1 inhibitor Dimeric fusion protein (binding Binds and blocks IL-1a and -b
domain of IL1+ IL1 accessory
receptor protein)
Anakinra IL-1 a and b inhibitor Inhibits competitively the binding of
IL-1a and -b to IL-1 type 1 receptor
Natalizumab Integrin a4-subunit inhibitor Humanized monoclonal antibody Blocks interaction of a4b1 or a4b7
integrin on leukocytes to their
counter receptors (VCAM and
MAdCAM) and ligand (fibronectin)

Ig, immunoglobulin; IL, interleukin; MAdCAM, mucosal addressin cell adhesion molecule; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule.

The use of TNF blockers has also been associated with the exacer-
bation of clinical symptoms of central nervous system demyelinating
disorders, including multiple sclerosis and peripheral demyelinating
disorders (9294). Patients with mild heart failure (New York Heart
Association class I/II) should be closely monitored if treated with
TNF blockers, and if they develop new symptoms or they show
worsening symptoms of heart failure, TNF therapy must be
interrupted (84).
Today, biologic drugs are administered both alone or in combina-
tion with other DMARDs for ulcerative colitis, ankylosing spondylitis,
psoriatic arthritis, plaque psoriasis, and cryopirin-associated syn-
drome. At the moment, there are no references to any endodontic
pathosis regarding biologic drugs.
Biologic Drugs and Their Possible Role
in Dental Diseases and AP
Despite their powerful biological effects and widespread use, the
consequences of the use of biologic medications on the progress of
various dental diseases have not been extensively investigated yet. The
use of biologic drugs may be reflected in lower periodontal indices
and the inhibition or reduction of the loss of periodontal bone connec-
tive tissue attachment, both directly and indirectly (96100).
Mayer et al (96) evaluated the periodontal status in patients
affected by RA and treated with antiTNF-a. Twenty patients with RA
were enrolled in the study and divided into 2 equal groups: the patients
in the first group received an infusion of infliximab (200 mg every
8 weeks), and the patients in the second group were treated without us-
ing biologic agents. A third group of 10 healthy subjects was selected as
the control group. The results showed that the patients receiving anti-
TNF exhibited lower periodontal indices.
Assuma et al (97) used an animal model consisting of 14 Macaca
fascicularis with periodontitis induced tying a silk ligature with Por-
phyromonas gingivalis around the posterior mandibular teeth. Two
of the animals were treated by injecting a soluble receptor to IL-1
and TNF (3 times per week for 6 weeks), and 3 animals were injected
with the vehicle alone (sterile phosphate buffered saline). The site of
inoculation was the interdental papillae between the first and the
second molar. Additional animals were included in the study in order
to identify the induced progression of events over time. Three animals
were sacrificed at 0, 2, and 4 weeks. Mandibular posterior sextants were
dissected surgically, and each specimen was processed for histopatho-
logic examination. Three sites of interests were analyzed on each section
at 500 magnification:
1. Close proximity to the oral epithelium (box 1)
2. Proximity to the bone surface (box 2)
3. Coronal periodontal ligament (box 3)
In this study, the treatment with IL-1 and TNF blockers was in-
hibited by approximately 80% the recruitment of inflammatory cells
to bone, 67% the formation of osteoclasts, and 60% the amount of
bone loss. In addition to that, the recruitment of new leukocytes was
decreased. These data suggest that periodontal disease is initiated
when the inflammatory stimulus spreads to the deep gingival connective
tissue stimulating the recruitment of leukocytes and that biologic drug
blockade of IL-1 and TNF may inhibit periodontal bone loss.
Delima et al (98), using a similar animal model, found that the
loss of connective tissue attachment was reduced respectively by 51%
and the loss of the height of the alveolar bone was reduced by almost
91% in those animals treated with IL-1 and TNF blockers. In a second
study with a similar design, the same researchers observed that the
amount of inflammatory cells in the alveolar bone and in the deep
connective tissue was reduced from 50%70% in the animals treated
with IL-1 inhibitors (99). Cirelli et al (100) delivered a vector con-
taining the TNF receptor gene to rats with previously induced peri-
odontitis and bone loss sustained by P. gingivalis

1908 Cotti et al. JOE Volume 40, Number 12, December 2014

lipopolysaccharide (LPS). They observed that a single administration
of this vector led to a long-term expression and secretion of the TNF
receptor and a statistically noticeable anti-inflammatory effect in the
prevention of linear bone resorption and a low level of IL-6 and
IL-10, RANK ligand, and osteoprotegerin. These data show the poten-
tial for biologic drugs to modulate the host immune-inflammatory
response in periodontal disease.
Furthermore, in a study conducted on 40 patients affected by RA
with concomitant severe periodontitis, all patients were treated
with DMARDs, and 20 of them were treated with the addition of
antiTNF-a biologic drugs. They were divided into 4 groups of 10:
1. Periodontal treatment only
2. No periodontal treatment and no antiTNF-a
3. Periodontal treatment and antiTNF-a
4. No periodontal treatment and anti TNF-a
At the end of the study, patients with RA and periodontal disease
had benefits regarding the decrease of serum levels of TNF-a both
when periodontal treatment was performed alone and when it was per-
formed in association with TNF blockers. Importantly, treatment with
biologic medications alone did not improve the periodontal condition
of the patients (101).
These findings suggest that if biologic drugs exhibit a positive in-
fluence on periodontal disease, they still must be considered in
conjunction with periodontal treatment and, therefore, do not represent
an alternative to appropriate dental care. It is possible that the suppres-
sion of proinflammatory cytokines might prove beneficial also in con-
trolling AP in humans and in experimental animals.
Several cytokines and chemokines are involved in the protective
and destructive immune responses that take place during the devel-
opment and healing of AP (102). Significantly increased TNF-a
(103) as well as high levels of IL-1b are associated with symptomatic
periapical abscesses and endodontic treatment failures (9, 10).
Activated macrophages can be considered the main source of IL-
1a, IL-1b, and TNF-a in the development of AP. If the activation of
macrophages persists, it maintains the osteoclastic activity. A
possible treatment strategy may be to turn off the activated
macrophages and, consequently, lower the local production of IL-1
and TNF-a in AP (8). When the teeth of knockout mice (TLR-4 defi-
cient) are subjected to anaerobic pathogens, there is a reduction of
the expression of IL-1 and IL-12, which results in the decrease of peri-
radicular bone destruction (104). A conspicuous reduction of bone
resorption in AP of rats is also achieved using adeno-associated virus
(AVV)-RNAi silencing of cathepsin K, an enzyme involved in the degra-
dation of the collagen matrix of the bones, followed by the consequent
decrease of inflammatory cytokine expression (105). Therefore, the
modulation of the availability of cytokines may influence a periapical
healing response if supported by an adequate disinfection of the en-
dodontium.
Conclusions
Bacteria cause AP as well as periodontal disease, and inflammation
is a common trait in these pathologies; yet, other factors may determine
the severity of the disease as well as how a specific patient responds to
treatment (1, 5, 810, 106).
Because AP and PD are not pathologies of a narrow and limited
area of the human body but integral processes of a whole system, a
new outline has to be drawn. Although new treatments are used to
cure chronic diseases, the dentist, in general, and the endodontist, in
particular, should become aware of the way these new class of medica-
tions may affect the different phases of their treatment.
JOE Volume 40, Number 12, December 2014
Review Article
Acknowledgments
The authors deny any conflicts of interest related to this study.
References
1. Nair PNR. Pathogenesis of apical periodontitis and the causes of endodontic fail-
ures. Crit Rev Oral Biol Med 2004;15:34881.
2. Marending M, Peters OA, Zehnder M. Factors affecting the outcome of orthograde
root canal therapy in a general dentistry hospital practice. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 2005;99:11924.
3. Ng YL, Mann V, Rahbaran S, et al. Outcome of primary root canal treatment: a sys-
tematic review of the literaturepart 2. Influence of clinical factors. Int Endod J
2008;41:631.
4. Strindberg LZ. The dependence of the results of pulp therapy on certain factors. An
analytical study based on radiographic and clinical follow-up examinations. Acta
Odontol Scand 1956;14:1175.
5. Fouad AF, Burleson J. The effect of diabetes mellitus on endodontic treatment
outcome: data from an electronic patient record. J Am Dent Assoc 2003;134:
4351.
6. Fouad A, Barry J, Russo J, et al. Periapical lesion progression with controlled mi-
crobial inoculation in a type I diabetic mouse model. J Endod 2002;28:816.
7. Konsaka T, Kumazawa M, Yamasaki M, et al. Periapical lesions in rats with
streptozocin-induced diabetes. J Endod 1996;22:41821.
8. Metzger Z, Huber R, Slavescu D, et al. Healing kinetics of periapical lesions
enhanced by the apexum procedure: a clinical trial. J Endod 2009;35:1539.
9. De Sa AR, Moreira PR, Xavier GM, et al. Association of CD 14, IL1B, IL6, IL10 and
TNFA functional gene polymorphisms with symptomatic dental abscesses. Int
Endod J 2007;20:56372.
10. Morsani JM, Aminosharie A, Han YW, et al. Genetic predisposition to persistent
apical periodontitis. J Endod 2011;37:4559.
11. Pociot F, Molvig J, Wogensen L, et al. A Taq I Polymorphism in the human
interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro.
Eur J Clin Invest 1992;22:396402.
12. Iglesias-Linares A, Yanez-Vico RM, Ortiz-Ariza E, et al. Postorthodontic external
root resorption in root-filled teeth is influenced by interleukin-1b polymorphism.
J Endod 2012;38:2837.
13. Ferrero-Miliani L, Nielsen OH, Andersen PS, et al. Chronic inflammation: impor-
tance of Nod2 And Nalp3 in interleukin-1b generation. Clin Exp Immunol
2007;147:22735.
14. Kumar V, Abbas AK, Fausto N, et al. Robbins and Cotran Pathologic Basis Of Dis-
ease, 8th ed. Philadelphia: Saunders/Elsevier; 2010.
15. Rubin R, Strayer DS, Rubin E. Rubins Pathology: Clinicopathologic Founda-
tions of Medicine, 6th ed. Philadelphia: Wolters Kluwer/Lippincott Williams &
Wilkins; 2011.
16. Hargreaves KM, Goodis HE, Tay FR. Seltzer and Benders Dental Pulp, 2nd ed.
Chicago: Quintessence Publishing; 2012.
17. Bendall L. Chemokines and their receptors in disease. Histol Histopathol 2005;20:
90726.
18. Duerschmied D, Suidan GL, Demers M, et al. Platelet serotonin promotes the
recruitment of neutrophils to sites of acute inflammation in mice. Blood 2013;
121:100815.
19. Loyd DR, Sun XX, Locke EE, et al. Sex differences in serotonin enhancement of
capsaicin-evoked calcitonin gene-related peptide release from human dental
pulp. Pain 2012;153:20617.
20. Sattari M, Haghighi AK, Tamijani HD. The relationship of pulp polyp with the pres-
ence and concentration of immunoglobulin E, histamine, interleukin-4 and inter-
leukin-12. Aust Endod J 2009;35:1648.
21. Bradley JR. TNF-mediated inflammatory disease. J Pathol 2008;2014:14960.
22. Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death
Differ 2003;10:4565.
23. Steeve KT, Marc P, Sandrine T, et al. IL-6, RANKL, TNF-alpha/IL-1: interrelations
in bone resorption pathophysiology. Cytokine Growth Factor Rev 2004;15:
4960.
24. Gallin JI, Snyderman R. Inflammation: Basic Principles and Clinical Correlates,
3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1999.
25. Akdis M, Burgler S, Crameri R, et al. Interleukins, from 1 to 37, and interferon-g:
receptors, functions, and roles in diseases. J Allergy Clin Immunol 2011;127:
70121.
26. Kawashima N, Stashenko P. Expression of bone-resorptive and regulatory cyto-
kines in murine periapical inflammation. Arch Oral Biol 1999;44:5566.
27. Shimauchi H, Takayama S, Imai-Tanaka T, et al. Balance of interleukin-1b and
interleukin-1 receptor antagonist in human periapical lesions. J Endod 1998;
24:1169.
Biologic Medications and AP 1909
Review Article
28. Anderson LM, Dumsha TC, McDonald NJ, et al. Evaluating IL-2 levels in human
pulp tissue. J Endod 2002;28:6515.
29. Sasaki H, Hou L, Belani A, et al. IL-10, but not IL-4, suppresses infection-stimulated
bone resorption in vivo. J Immunol 2000;165:362630.
30. Queiroz-Junior CM, Silva MJB, Corr^ea JD, et al. A controversial role for IL-12 in
immune response and bone resorption at apical periodontal sites. Clin Dev Immu-
nol 2010;2010:327417.
31. Hahn CL, Liewehr FR. Update on the adaptive immune responses of the dental pulp.
J Endod 2007;33:77381.
32. Gaffen SL. An overview of IL-17 function and signaling. Cytokine 2008;43(3):4027.
33. Colic M, Gazivoda D, Vucevic D, et al. Proinflammatory and immunoregulatory
mechanisms in periapical lesions. Mol Immunol 2009;47:10113.
34. Feghali CA, Wright TM. Cytokines in acute and chronic inflammation. Front Biosci
1997;2:d1226.
35. de Sa AR, Pimenta FJG, Dutra WO, et al. Immunolocalization of interleukin 4, inter-
leukin 6, and lymphotoxin a in dental granulomas. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 2003;96:35660.
36. Serhan CN, Ward PA, Gilroy DW. Fundamentals of Inflammation. New York:
Cambridge University Press; July 2010.
37. Lin LM, Huang GTJ. Pathobiology of the periapex. In: Hargreves KM, Cohen S,
Berman LH, eds. Cohens Pathways of the Pulp Expert Consult, 10th ed. St Louis:
Mosby Elsevier; 2011:52958.
38. Hahn CL, Liewehr FR. Innate immune responses of the dental pulp to caries.
J Endod 2007;33:64351.
39. de Brito LC, Teles FR, Teles RP, et al. T-lymphocyte and cytokine expression in
human inflammatory periapical lesions. J Endod 2012;38:4815.
40. Martinho FC, Chiesa WM, Leite FR, et al. Correlation between clinical/radiographic
features and inflammatory cytokine networks produced by macrophages stimu-
lated with endodontic content. J Endod 2012;38:7405.
41. Martinho FC, Leite FR, Chiesa WM, et al. Signaling pathways activation by primary
endodontic infectious contents and production of inflammatory mediators.
J Endod 2014;40:4849.
42. Al-Balaghi S, Strom H, Moller E. B cell differentiation factor in synovial fluid of pa-
tients with rheumatoid arthritis. Immunol Rew 1984;78:723.
43. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid
arthritis. N Engl J Med 2001;344:90716.
44. Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet 2012;380:160619.
45. Dagfinrud H, Kvien TK, Hagen KB. The Cochrane review of physiotherapy interven-
tions for ankylosing spondylitis. J Rheumatol 2005;32:1899906.
46. Cross M, Smith E, Hoy D, et al. The global burden of rheumatoid arthritis: estimates
from the Global Burden of Disease 2010 study. Ann Rheum Dis 2014;73:131622.
47. Gabriel SE, Michaud K. Epidemiological studies in incidence, prevalence, mortality,
and comorbidity of the rheumatic diseases. Arthritis Res Ther 2009;11:229.
48. Firestein GS, Budd RC, Gabriel SE, et al. Kelleys Textbook Of Rheumatology, 9th
ed. Philadelphia: Elsevier/Saunders; 2013.
49. Ohmura K, Johnsen A, Ortiz-Lopez A, et al. Variation in IL-1b gene expression is a
major determinant of genetic differences in arthritis aggressivity in mice. Proc Nat-
lAcad Sci U S A 2005;102:1248994.
50. Johnsen AK, Plenge RM, Butty V, et al. A broad analysis of IL1 polymorphism and
rheumatoid arthritis. Arthritis Rheum 2008;58:194757.
51. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med
2011;365:220519.
52. Geusens P. The role of Rank ligand/osteoprotegerin in rheumatoid arthritis. Ther
Adv Musculoskelet Dis 2012;4:22533.
53. Boyce BF, Xing L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther
2007;9:S1.
54. Longo D, Fauci A, Kasper D, et al. Harrisons Principles Of Internal Medicine,
18th ed. New York: Mcgraw-Hill Professional; 2011.
55. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature
2003;423:33742.
56. Lorenzo J, Horowitz M, Choi Y. Osteoimmunology: interactions of the bone and
immune system. Endocr Rev 2008;29:40340.
57. Feldman M, Friedman LS, Brandt LJ. Sleisenger and Fordtrans Gastrointestinal
and Liver Disease, 9th ed. Philadelphia: Saunders; 2010.
58. Glas J, Seiderer J, Wagner J, et al. Analysis of IL12B gene variants in inflammatory
bowel disease. PLoS One 2012;7:e34349.
59. Persson GR. Rheumatoid arthritis and periodontitis: inflammatory and infectious
connections. Review of the literature. J Oral Microbiol 2012;4
http://dx.doi.org/10.3402/jom.v4i0.11829.
60. Han JY, Reynolds MA. Effect of anti-rheumatic agents on periodontal parameters
and biomarkers of inflammation: a systematic review and meta-analysis.
J Periodontal Implant Sci 2012;42:312.
61. Moen K, Brun JG, Valen M, et al. Synovial inflammation in active rheumatoid
arthritis and psoriatic arthritis facilitates trapping of a variety of oral bacterial
DNAs. Clin Exp Rheumatol 2006;24:65663.
1910 Cotti et al.
62. Cronstein BN, Naime D, Ostad E. The antiinflammatory mechanism of metho-
trexate. Increased adenosine release at inflamed sites diminishes leukocyte accu-
mulation in an in vivo model of inflammation. J Clin Invest 1993;92:267582.
63. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guide-
lines. Guidelines for the management of rheumatoid arthritis: update. Arthritis
Rheum 2002;46:32846.
64. Agarwal SK. Biologic agents in rheumatoid arthritis: an update for managed care
professionals. J Manag Care Pharm 2011;17:148.
65. Pearson DC, May GR, Fick G, et al. Azathioprine for maintaining remission of
Crohns disease. Cochrane Database Syst Rev 2000;2:CD000067.
66. Wilkins T, Jarvis K, Patel J. Diagnosis and management of Crohns disease. Am Fam
Physician 2011;84:136575.
67. Kohler G, Milstein C. Pillars article: continuous cultures of fused cells secreting
antibody of predefined specificity. Nature 1975;256:4957.
68. Looney JE, Knight DM, Arevalo-Moore M, et al. High-level expression and charac-
terization of a mouse-human chimeric CD4 antibody with therapeutic potential.
Hum Antibodies Hybridomas 1992;3:191200.
69. Sany J. Immunological treatment of rheumatoid arthritis. Clin Exp Rheumatol
1990;8:818.
70. Emmrich F, Horneff G, Becker W, et al. An anti-CD4 antibody for treatment of
chronic inflammatory arthritis. Agents Actions Suppl 1991;32:16570.
71. Horneff G, Winkler T, Kalden JR, et al. Human anti-mouse antibody response
induced by anti-CD4 monoclonal antibody therapy in patients with rheumatoid
arthritis. Clin Immunol Immunopathol 1991;59:89103.
72. Lipsky PE. Immunopathogenesis and treatment of rheumatoid arthritis.
J Rheumatol Suppl 1992;32:924.
73. Kirkham BW, Thien F, Pelton BK, et al. Chimeric CD7 monoclonal antibody therapy
in rheumatoid arthritis. J Rheumatol 1992;19:134852.
74. Verwilghen J, Kingsley GH, Ceuppens JL, et al. Inhibition of synovial fluid T cell
proliferation by anti-CD5 monoclonal antibodies. A potential mechanism for their
immunotherapeutic action in vivo. Arthritis Rheum 1992;35:144551.
75. Wendling D, Racadot E, Wijdenes J. Treatment of severe rheumatoid arthritis by
anti-interleukin 6 monoclonal antibody. J Rheumatol 1993;20:25962.
76. Strand V, Lipsky PE, Cannon GW, et al. Effects of administration of an anti-CD5 plus
immunoconjugate in rheumatoid arthritis. Results of two phase II studies. The CD5
Plus Rheumatoid Arthritis Investigators Group. Arthritis Rheum 1993;36:62030.
77. Moreland LW, Pratt PW, Sanders ME, et al. Experience with a chimeric monoclonal
anti-CD4 antibody in the treatment of refractory rheumatoid arthritis. Clin Exp
Rheumatol 1993;11:1539.
78. Kinne RW, Becker W, Schwab J, et al. Comparison of 99Tcm-labelled specific murine
anti-CD4 monoclonal antibodies and nonspecific human immunoglobulin for imag-
ing inflamed joints in rheumatoid arthritis. Nucl Med Commun 1993;14:66775.
79. Elliott MJ, Maini RN, Feldmann M, et al. Treatment of rheumatoid arthritis with
chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum
1993;36:168190.
80. Van der Lubbe PA, Reiter C, Breedveld FC, et al. Chimeric CD4 monoclonal anti-
body cM-T412 as a therapeutic approach to rheumatoid arthritis. Arthritis Rheum
1993;36:13759.
81. Elliott MJ, Maini RN, Feldmann M, et al. Randomised double-blind comparison of
chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus pla-
cebo in rheumatoid arthritis. Lancet 1994;344:110510.
82. Purcell RT, Lockey RF. Immunologic responses to therapeutic biologic agents.
J Investig Allergol Clin Immunol 2008;18:33542.
83. Annex I. Summary of Product Characteristics. European Medicine Agency: Humira
product information. Available at: http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Product_Information/human/000481/WC500050870.
pdf. Accessed June 29, 2014.
84. Annex I. Summary of Product Characteristics. European Medicine Agency: Remicade
product information. Available at: http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Product_Information/human/000240/WC500050888.
pdf. Accessed June 29, 2014.
85. Annex I. Summary of Product Characteristics. European Medicine Agency: Enbrel
product information. Available at: http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Product_Information/human/000262/WC500027361.
pdf. Accessed June 29, 2014.
86. Annex I: Summary of Product Characteristics. European Medicine Agency: Cimzia
product information. Available at: http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Product_Information/human/001037/WC500069763.
pdf. Accessed June 29, 2014.
87. Annex I: Summary of Product Characteristics. European Medicine Agency: Simponi
product information. Available at: http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Product_Information/human/000992/WC500052368.
pdf. Accessed June 29, 2014.
88. Annex I: Summary of Product Characteristics. European Medicine Agency. Ilaris
product information. Available at: http://www.ema.europa.eu/docs/en_GB/
JOE Volume 40, Number 12, December 2014

document_library/EPAR_-_Product_Information/human/001109/WC500031680
.pdf. Accessed June 29, 2014.
89. Annex I: Summary of Product Characteristics. European Medicine Agency: Arcalyst
product information. Available at: http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Product_Information/human/001047/WC500026510
.pdf. Accessed June 29, 2014.
90. Annex I: Summary of Product Characteristics. European Medicine Agency: Kineret
product information. Available at: http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Product_Information/human/000363/WC500042310.
pdf. Accessed June 29, 2014.
91. Annex I: Summary of Product Characteristics. European Medicine Agency: Tysabri
product information. Available at: http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Product_Information/human/000603/WC500044686.
pdf. Accessed June 29, 2014.
92. Label and approval history: Enbrel. US Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103795s5507lbl.pdf. Ac-
cessed June 29, 2014.
93. Label and approval history: Humira. US Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125057s232lbl.pdf. Ac-
cessed June 29, 2014..
94. Label and approval history: Remicade. US Food and Drug Administration. Available
at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103772s5295lbl.pdf.
Accessed June 29, 2014.
95. Label and approval history: Ilaris. US Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125319s0054.pdf. Ac-
cessed June 29, 2014.
JOE Volume 40, Number 12, December 2014
Review Article
96. Mayer Y, Balbir-Guman A, Machetei EE. Anti-tumor necrosis factor alpha therapy
and periodontal parameters in patients with rheumatoid arthritis. J Periodontol
2009;80:141420.
97. Assuma R, Oates T, Cochran D, et al. IL-1 and TNF antagonists inhibit the inflammatory
response and bone loss in experimental periodontitis. J Immunol 1998;160:4039.
98. Delima AJ, Oates T, Assuma R, et al. Soluble antagonists to interleukin-1 (IL-1) and
tumor necrosis factor (TNF) inhibits loss of tissue attachment in experimental
periodontitis. J Clin Periodontol 2001;28:23340.
99. Delima AJ, Karatzas S, Amar S, et al. Inflammation and tissue loss caused by periodontal
pathogens is reduced by interleukin-1 antagonists. J Infect Dis 2002;186:5116.
100. Cirelli JA, Park CH, MacKool K, et al. AAV2/1-TNFR: Fc gene delivery prevents peri-
odontal disease progression. Gene Ther 2009;16:42636.
101. Ortiz P, Bissada NF, Palomo L, et al. Periodontal therapy reduces the severity of
active rheumatoid arthritis in patients treated with or without tumor necrosis factor
inhibitors. J Periodontol 2009;80:53540.
102. Marton IJ, Kiss C. Overlapping protective and destructive regulatory pathways in
apical periodontitis. J Endod 2014;40:15563.
103. Henriques LC, de Brito LC, Tavares WL, et al. Cytokine analysis in lesions refractory
to endodontic treatment. J Endod 2011;37:165962.
104. Hou L, Sasaki H, Stasehnko P. Toll-like receptor 4-deficient mice have reduced
bone destruction following mixed anaerobic infection. Infect Immun 2000;68:
46815.
105. Gao B, Chen W, Hao L, et al. Inhibiting periapical lesions through AAV-RNAi
silencing of cathepsin k. J Dent Res 2013;92:1806.
106. Kornman KS, di Giovine FS. Genetic variations in cytokine expression: a risk factor
for severity of adult periodontitis. Ann Periodontol 1998;3:32738.
Biologic Medications and AP 1911