Periodontology 2000, Vol. 76, 2018, 131–149 © 2017 John Wiley & Sons A/S.
y & Sons A/S. Published by John Wiley & Sons Ltd
Printed in Singapore. All rights reserved
Host modulation therapy with
anti-inflammatory agents
P H I L I P M. P R E S H A W
As clinicians, scientists or researchers who are
engaged in the treatment of periodontal diseases, we
share a common goal: the development and utiliza-
tion of the most effective therapies for our patients.
The development of treatment strategies relies heav-
ily on clinical research, and over the last 40–50 years,
there has been an exponential increase in the number
of scientific research publications that address the
management of periodontal diseases. The application
of appropriate and rigorous scientific methodologies,
coupled with correct statistical analysis and interpre-
tation of the results of clinical trials, provides us with
the best available information to make decisions
about how to treat most effectively the highly preva-
lent, chronic inflammatory disease that we refer to as
periodontitis.
Application of the scientific method in modern
periodontal research can be regarded as commenc-
ing with the carefully controlled studies that started
to be published in the 1960s by researchers such as
Lo€ e et al. (75). This research group published a
carefully documented index system for quantifying
gingival inflammation that continues to be widely
used to this day (58). Utilizing this scoring system,
these researchers conducted an experimental gin-
givitis study in which healthy volunteers refrained
from oral hygiene procedures until gingivitis devel-
oped (76). The gingivitis resolved on resumption of
oral hygiene. As well as observing the clinical
changes that occurred as a result of plaque accu-
mulation, the authors also investigated concomitant
changes in the composition of the bacterial plaque,
identifying increases in the number of microorgan-
isms and changes in the proportions of specific
bacterial types. Reinstatement of normal oral
hygiene resulted in re-establishment of the original
bacterial flora. Studies such as this led to the pre-
mise that periodontal diseases are infectious dis-
eases because of the presumed bacterial etiology.
PERIODONTOLOGY 2000
This concept was to hold for the next 25 years or
so, and had a direct impact on how clinicians have
managed the disease. It is interesting to observe,
however, that even in that original publication, the
authors noted ‘the observation that the time neces-
sary to develop clinical gingivitis varied between
individuals could then be a reflection of individual
defence mechanism variability’ (76). In other words,
even back in 1965, researchers were aware of, and
documenting, variations between individuals in
relation to susceptibility to gingival and periodontal
inflammation.
Periodontitis: infection or
inflammation?
Since the 1960s, periodontal research has evolved in
parallel with technological advances, leading to dis-
tinct ‘eras’ in our understanding of periodontal
pathogenesis. For example, in terms of periodontal
microbiology, we have progressed from the nonspeci-
fic plaque hypothesis to the specific plaque hypothe-
sis and, most recently, to the ecological plaque
hypothesis, which holds that accumulation of plaque
biofilm induces environmental changes (such as
altered redox potential and pH, and introduction of
novel host proteins and glycoproteins) that favor the
growth of proteolytic and anaerobic gram-negative
bacteria and the development of an inflammatory
host response (77, 80, 81). Over the same time period,
researchers began to investigate in detail the inflam-
matory response in the gingival and periodontal tis-
sues, with observations, for example, that the levels of
specific inflammatory mediators, such as prostaglan-
din E2, were higher in the gingival crevicular fluid
sampled from sites with periodontitis compared with
gingival crevicular fluid sampled from sites with gin-
givitis (88). Studies of the inflammatory mechanisms
131
Preshaw
associated with periodontal inflammation led to the
concept of the host response as an important deter-
minant of susceptibility to disease (94), and a gradual
increase in awareness that much of the variability in
periodontal disease expression between individuals
derives from variations in the host response to the
subgingival microbiota.
This change in how we perceive periodontal patho-
genesis is neatly captured in various statements from
the periodontal literature. In 2008, the American
Academy of Periodontology held a workshop entitled
‘Inflammation and Periodontal Diseases: a Reap-
praisal’. The findings of the workshop were published
in a supplement to the Journal of Periodontology,
including the statement ‘. . .periodontitis is an inflam-
matory disease initiated by the oral microbial biofilm.
This distinction implies that it is the host response to
the biofilm that destroys the periodontium in the
pathogenesis of the disease’ (127). Similarly, in 2009,
Chapple (17) asserted that ‘periodontitis should prob-
ably not be characterized as an aberrant inflamma-
tory-immune response to pathogenic organisms but
is more accurately categorized as a nonresolving
inflammation that is ineffective in eliminating the
initiating pathogens and that is sustained by the
same’ (36).
So, is periodontitis an ‘infection’ or an ‘inflamma-
tion’? In the 1960s, it was definitely regarded as an ‘in-
fectious disease’ on account of the perceived bacterial
etiology, but that terminology does not seem com-
mensurate with our modern understanding of disease
pathogenesis. Indeed, according to modern under-
standing, an infectious disease is one that we can
‘catch’, usually with a defined microbial etiology. Peri-
odontitis does not fit with this model. It is clear that
the subgingival microbiota initiates and perpetuates
the inflammatory response; however, it is the inflam-
matory response that is responsible for the majority of
tissue breakdown that occurs in affected individuals.
Periodontitis is not an ‘infection’ in the classic sense of
the word. Indeed, this change in focus represents a
paradigm shift in our understanding of this common
inflammatory disease as we move from solely focusing
on mechanistic and antimicrobial approaches to
managing the condition, to considering how to control
the driving force behind disease progression (i.e.
uncontrolled inflammation) (4). As we now recognize
that periodontitis is an inflammatory disease, and that
inflammation results in the majority of the tissue
breakdown that occurs, we are presented with new
opportunities to consider additional methods for
treating the condition that aim to target specific
aspects of the inflammatory response.
132
What is inflammation?
The term ‘inflammation’ is derived from the Latin
word inflammare, ‘to set on fire’. The classical signs
of inflammation were described by the Roman, Aulus
Cornelius Celsus, in the 1st century AD, who referred
to the four cardinal signs of inflammation, namely
rubor, tumor, calor et dolor (redness, swelling, heat
and pain) (112). These reactions are what we would
regard today as the classic inflammatory response to
a traumatic insult or injury. Subsequent researchers
added to the knowledge base, such as Galen in the
2nd century AD who described ‘laudable pus’ (inter-
preting infection and inflammation as being benefi-
cial in wound repair), and Virchow & Cohnheim in
the 1870s, cited in Scott et al. (112), who noted
increased leakiness of vessels permitting the develop-
ment of a fluid and cellular infiltrate in inflamed
tissues. However, many inflammatory conditions do
not result in the appearance of the classic signs of
inflammation, and we now recognize that inflamma-
tion may well be present within tissues at the cellular
level without resulting in all (or even any) of the
classical cardinal signs. This is certainly the case for
gingival and periodontal inflammation (Table 1).
Models of inflammatory processes in the context of
periodontitis have evolved over the years. It is highly
likely that we do not yet understand the full extent of
the molecular and cellular processes involved in
inflammation, and ongoing research will probably
add to the complexity that we perceive. It is certain
that cytokines and other mediators of inflammation
interact functionally in networks in the periodontium
and integrate aspects of innate and adaptive immu-
nity. In the context of periodontal inflammation,
most information available is in relation to the role of
proinflammatory cytokines, such as interleukin-
1beta, tumor necrosis factor-alpha and interleukin-6,
and data are accumulating on T-cell regulatory
cytokines, such as interleukin-12 and interleukin-18,
chemokines and those cytokines that play a role in
bone-cell development and function, for example
RANKL and osteoprotegerin (100). There are clearly
multiple, overlapping and complex functional links
between cytokines, with regulation of expression
being exerted at a number of levels and involving
numerous cell types (both immune cells and resident
cells in the periodontium). A schematic to illustrate
the multiple interactions between cytokines and cel-
lular functions in periodontal inflammation has
been presented previously, with the interpretation
that there is considerable heterogeneity between

Table 1. Cardinal signs of inflammation in gingivitis and periodontitis
Sign Usual cause
Redness Vasodilatation
Swelling Increased vascular
permeability; formation
of granulation tissue
Heat Vasodilatation
Pain Stimulation of nociceptors
Loss of function* Pain; disruption of tissue structure Loss of function is not usually a feature of gingivitis. It may be a
feature of advanced periodontitis, as a result of extensive attachment
and bone loss and subsequent mobility, drifting or sensitivity of teeth
*Loss of function (functio laesa) was added to the four preceding cardinal signs of inflammation, possibly by Galen in the 2nd century AD, but more probably by Vir-
chow in 1871 (105).
individuals in terms of the specifics of their
inflammatory response profile (69). This heterogene-
ity is presumed to explain the marked differences in
susceptibility to periodontitis that we observe in our
patients.
Inflammation is a fundamental homeostatic
response to insult or injury that plays an essential role
in the removal of microorganisms and is important in
the restoration of normal tissue structure and func-
tion. Significantly, however, we now realize that pro-
longed or excessive inflammation can lead to tissue
damage, the signs of which we recognize as disease.
This is certainly the case in periodontitis, in which the
subgingival microbiota initiates and perpetuates the
chronic inflammatory response, resulting in ongoing
tissue destruction and the progression of disease.
Treatment strategies for periodontitis have focused
on reducing the bacterial challenge. Traditionally,
‘scaling and root planing’ was the management strat-
egy of choice for the nonsurgical treatment of
periodontitis. This treatment approach was based
around the concept that ‘infected’ cementum (i.e.
cementum that was impregnated with lipopolysac-
charide) should be removed from root surfaces (along
with plaque and calculus) to enable effective healing,
using a ‘planing’ approach to remove the surface lay-
ers of the cementum. However, we now recognize
Host modulation with anti-inflammatory agents
Evident in gingivitis or periodontitis?
Gingival erythema is present in both gingivitis and periodontitis as
a result of vasodilatation of blood vessels in the soft tissues
Gingival edema is present in both gingivitis and periodontitis as
a result of increased vascular permeability and increased fluid and
cellular infiltrate. In cases of periodontitis, long-standing
inflammation may result in a more fibrotic texture of the swollen
tissues, and granulation tissue may also contribute to tissue swelling
The temperature of the gingival and periodontal tissues is not usually
assessed. Some research studies have identified elevated subgingival
temperatures in cases of gingivitis and periodontitis, but this is not
particularly predictable or reproducible, can vary considerably
(e.g. with location in the mouth, recent food/drink) and is not
a useful indicator of presence of inflammation
Pain that results directly from soft-tissue inflammation is not usually
present in chronic gingivitis or periodontitis (the exception being
acute conditions, such as necrotizing ulcerative gingivitis). If pain is
present in cases of periodontitis, it is usually secondary to
factors such as dentine sensitivity as a result of exposure of root
surfaces following gingival recession
that this approach results in a significant loss of root-
surface structure (both cementum and dentine),
which can result in sensitivity (particularly in patients
undergoing long-term periodontal maintenance care)
and that is not necessary to achieve periodontal heal-
ing. The research of Kieser’s group (85, 119), in the
late 1980s, identified that lipopolysaccharide is not
firmly bound to cementum and is only loosely adher-
ent to root surfaces. He introduced the term ‘root sur-
face debridement’ to indicate a lighter-touch form of
periodontal treatment in which the aim of treatment
is to disrupt and reduce the subgingival biofilm (i.e.
plaque removal) but also to preserve cementum.
Ultrasonic instruments are ideally suited to this task.
The change in the treatment concept from root
planing to root surface debridement fits well with our
modern understanding of the chronic nature of peri-
odontal disease; we accept that patients with peri-
odontitis generally will cycle through episodes of
more active intervention and then periods of peri-
odontal maintenance care, and that periodontal
management should be regarded as a lifelong com-
mitment. Plaque control by the patient is of para-
mount importance, and patients are supported in
this by the regular provision of effective, and non-
damaging, debridement of the root surface by the
clinician. This chronic treatment model maximizes
133
Preshaw
the likelihood of resolution of inflammation but
without causing extensive tissue damage, with the
success of therapy being determined on the basis of
resolution of inflammation (e.g. characterized by
reductions in bleeding on probing, resolution of
inflammation in the tissues and probing-depth
reductions) (21).
Dental clinicians routinely employ risk-manage-
ment strategies, such as smoking-cessation support,
in their periodontal treatment protocols. Smoking
cessation has been shown to result in enhanced peri-
odontal treatment outcomes in those patients who
manage to quit smoking as opposed to those who
continue to smoke (16). The knowledge that peri-
odontitis is a chronic inflammatory disease provides
us with options to consider using anti-inflammatory
agents as therapeutic strategies additional to conven-
tional periodontal treatment (i.e. root surface
debridement) and risk-reduction strategies. This con-
cept has been referred to as host response modula-
tion or host modulation therapy, denoting that the
treatment aims to modify the host response by reduc-
ing those damaging aspects of the inflammatory
response that lead to tissue destruction. A number of
different classes of anti-inflammatory drugs are avail-
able, and some of these have been considered for use
as adjunctive treatments for periodontitis. These will
now be discussed.
Corticosteroids
Corticosteroids (glucocorticoids and mineralocorti-
coids) are a group of drugs, structurally related to the
hormone cortisol, that have a wide variety of applica-
tions in medicine, primarily in relation to their anti-
inflammatory and immunosuppressive properties (2).
Their mechanism of action involves the suppression
of phospholipase A2, the enzyme which acts on cell
membranes to produce eicosanoids. Corticosteroids
therefore block the production of prostaglandins and
leukotrienes and are used for management of a large
variety of chronic inflammatory conditions, such as
arthritis, dermatitis, asthma and inflammatory bowel
disease. Corticosteroids also possess immunosup-
pressive properties: they inhibit the cell-mediated
response (leading to reduced T-cell proliferation) by
inhibiting the transcription of genes that code for var-
ious interleukins and interferon-gamma; and they
also suppress humoral responses, with concomitant
reductions in B-cells and antibody production (2).
Most of the research that has evaluated whether
steroids have an impact on periodontal and gingival
134
inflammation has been carried out in the form of
observational studies of patients who were taking
long-term steroid therapy for other indications (115).
The risk/benefit profile in the context of treatment of
periodontitis is unfavorable – generally no clear bene-
fit of steroid therapy on reducing periodontal inflam-
mation has been noted. Furthermore, steroids are
associated with a range of side effects (including
altered carbohydrate and protein metabolism, osteo-
porosis, peptic ulceration, inhibition of adrenal cortex
function and risk of adrenocortical crisis, drug-
induced Cushing’s syndrome, telangiectasia, hyper-
tension, impaired wound healing and increased risk
of opportunistic infections as a result of immunosup-
pression) (2). Corticosteroids are potent drugs used to
treat a variety of medical conditions and, in view of
the significant risk of unwanted effects associated
with their use, they are clearly not indicated in the
management of periodontitis.
(Conventional) disease-modifying
anti-rheumatic drugs
The conventional disease-modifying anti-rheumatic
drugs are a group of otherwise unrelated drugs used
to slow the progression of rheumatoid arthritis. The
term disease-modifying anti-rheumatic drugs is used
to distinguish these drugs: (i) from the nonsteroidal
anti-inflammatory drugs that reduce inflammation
but which do not necessarily treat the underlying
cause of rheumatoid arthritis; and (ii) from the ster-
oids that reduce the immune and inflammatory
responses but which may not slow progression of the
disease. In other words, whereas nonsteroidal anti-
inflammatory drugs and steroids are also used for
control of symptoms in rheumatoid arthritis, it is only
the disease-modifying anti-rheumatic drugs that
affect disease progression (121). Rheumatoid arthritis
is a systemic inflammatory autoimmune disease that
leads to progressive joint destruction, and it markedly
reduces quality of life. Signs and symptoms include
chronic inflammation of the joints (particularly the
wrists and small joints of the hands and feet) and
impaired function (pain and joint stiffness) as a result
of progressive joint destruction (126).
The disease-modifying anti-rheumatic drugs can be
classified as either conventional disease-modifying
anti-rheumatic drugs (the subject of this section) or
biological disease-modifying anti-rheumatic drugs
(which are discussed below). Conventional disease-
modifying anti-rheumatic drugs are slow-acting drugs
that have efficacy in dampening down the underlying

disease processes in rheumatoid arthritis; these drugs
can result in reductions in the levels of C-reactive
protein and rheumatoid factor, in the erythrocyte
sedimentation rate and of bone and cartilage dam-
age. Conventional disease-modifying anti-rheumatic
drugs include methotrexate, gold salts, sulfasalazine,
cyclosporin, cyclophosphamide and hydroxychloro-
quinone. Methotrexate was first introduced as a
chemotherapy treatment for cancer and is still used
for this indication. However, at lower doses it can be
used in the treatment of inflammatory diseases and is
a first-line treatment for rheumatoid arthritis. The
conventional disease-modifying anti-rheumatic drugs
are potent systemic medications used in the manage-
ment of a significant chronic inflammatory disease
(rheumatoid arthritis), and they have a variety of
unwanted effects. For example, methotrexate may
cause nausea, hair loss, skin rashes, oral ulceration,
vomiting and diarrhea. Therefore, the conventional
disease-modifying anti-rheumatic drugs are clearly
not indicated in the treatment of periodontitis. Bio-
logical disease-modifying anti-rheumatic drugs and
other anti-cytokine drugs are discussed later.
Nonsteroidal anti-inflammatory
drugs
The nonsteroidal anti-inflammatory drugs are a com-
monly used class of drugs indicated as analgesics for
treatment of low/moderate pain, as antipyretic agents
to reduce body temperature and as anti-inflamma-
tory agents. They are used in a wide range of painful
and inflammatory conditions, including arthritis,
gout, dental pain, headaches and dysmenorrhea.
Symptomatic relief of inflammation (reduction of
pain and swelling) results from inhibition of the
cyclooxygenase pathway of arachidonic acid metabo-
lism. Nonsteroidal anti-inflammatory drugs cause
unwanted effects, and there are many patients for
whom these drugs should be used with caution or
avoided altogether. Common adverse reactions
include gastrointestinal effects, renal effects, haemo-
static effects and hypersensitivity reactions, as well as
other symptoms including headaches, dizziness and
vertigo. Gastrointestinal side effects result from inhi-
bition of prostaglandins by the nonsteroidal anti-
inflammatory drugs; that is, prostaglandins protect
the lining of the gastrointestinal tract from acid
attack, and when prostaglandin synthesis is inhibited,
the lining is more vulnerable to ulceration (72). Thus,
nonsteroidal anti-inflammatory drugs can cause gas-
trointestinal tract problems whether taken orally or
Host modulation with anti-inflammatory agents
given parenterally. Further irritation of the gastric
mucosa (when nonsteroidal anti-inflammatory drugs
are taken orally) results from the fact that most nons-
teroidal anti-inflammatory drugs are weak organic
acids (130). Renal effects include salt and fluid reten-
tion (and risk of hypertension) that results from
changes in renal blood flow which is normally modu-
lated by prostaglandins; prostaglandins cause vasodi-
latation of the afferent arterioles to the glomeruli to
maintain normal filtration, and inhibition of prosta-
glandins by nonsteroidal anti-inflammatory drugs
therefore results in reduced renal perfusion pressure
and hence fluid retention. Aspirin is also widely used
at low doses as an anti-platelet aggregation agent as a
result of its inhibitory effect on platelet thromboxane.
Research in the 1970s and 1980s, in which prosta-
glandins began to be implicated in the pathogenesis
of periodontal disease (90, 91), resulted in clinical
studies being carried out to investigate whether nons-
teroidal anti-inflammatory drugs would be of benefit
as an adjunctive treatment for periodontitis. The bio-
logical rationale for this was clear: prostaglandins are
produced by a variety of cell types in the periodon-
tium (neutrophils, macrophages, fibroblasts and
epithelial cells) in response to lipopolysaccharide and
are potent proinflammatory mediators that are rele-
vant to periodontal disease progression; for example,
prostaglandin E2 up-regulates osteoclastic bone
resorption (64, 89). Early evidence to indicate that
nonsteroidal anti-inflammatory drugs may reduce
periodontal disease progression came from studies of
periodontal status in patients who were receiving
long-term nonsteroidal anti-inflammatory drug ther-
apy for the management of musculoskeletal disorders
(135). The patients who had been taking nonsteroidal
anti-inflammatory drugs for prolonged periods
tended to have shallower probing depths and less gin-
gival inflammation than control patients. Subsequent
studies confirmed that both topical and systemic
nonsteroidal anti-inflammatory drugs appeared to
have a ‘protective’ effect on periodontal inflamma-
tion (29, 107, 132). A large number of animal studies
and longitudinal clinical trials were conducted in
which patients received daily administration of oral
nonsteroidal anti-inflammatory drugs for extended
periods of time (up to several years) (62–64, 138–140).
In broad terms, a generally consistent finding was
that the rate of alveolar bone loss was reduced com-
pared with patients who were taking placebo. How-
ever, a high rate of unwanted effects was also noted,
and a further problem was that patients needed to
take the drugs on a daily basis for several years for the
beneficial impact on bone loss to become apparent.
135
Preshaw
The enzyme cyclooxygenase exists in two isoforms
(cyclooxygenase-1 and cyclooxygenase-2); cyclooxy-
genase-1 is constitutively expressed and has cytopro-
tective and antithrombogenic functions, whereas
cyclooxygenase-2 is induced and associated with
inflammatory responses. It is now recognized that
inhibition of cyclooxygenase-1 results in the majority
of the unwanted effects of nonsteroidal anti-inflam-
matory drugs. The development of a class of nons-
teroidal anti-inflammatory drugs which selectively
inhibit cyclooxygenase-2 (and therefore could reduce
inflammation without the unwanted effects of nonse-
lective cyclooxygenase-1 and cyclooxygenase-2 inhi-
bition) offered potential for management of a variety
of chronic inflammatory conditions. A number of
studies were conducted in animals (5, 61) and
humans (131, 141), which indicated that selective
cyclooxygenase-2 inhibitors did modify prostaglandin
production in the periodontal tissues and potentially
enhanced clinical treatment outcomes. However,
separately, these drugs were also identified as causing
significant, life-threatening cardiovascular adverse
events, and most of these drugs were subsequently
withdrawn by their manufacturers (27).
To summarize, the nonsteroidal anti-inflammatory
drugs (including both the nonselective, nonsteroidal
anti-inflammatory drugs and the selective cyclooxy-
genase-2 inhibitors) have been extensively investi-
gated for use as adjunctive anti-inflammatory
treatments for periodontitis, but limited clinical ben-
efits, together with a significant risk of serious
unwanted effects, precludes their use as a drug treat-
ment for periodontitis.
Matrix metalloproteinase inhibitors
Doxycycline, similarly to other members of the tetracy-
cline family of antibiotics, inhibits matrix metallopro-
teinases, which are zinc-dependent enzymes that are
capable of degrading a wide variety of extracellular
matrix proteins, including collagens (108). Matrix met-
alloproteinases play a fundamental role in the tissue
breakdown observed in periodontitis and are secreted
by numerous resident and infiltrating cell types in the
periodontium, including neutrophils, macrophages,
keratinocytes, fibroblasts, osteoclasts and endothelial
cells (54). Regulation of matrix metalloproteinase activ-
ity is exerted by endogenous tissue inhibitors of metal-
loproteinases and alpha-macroglobulins, which form
complexes with precursor and active forms of matrix
metalloproteinases (109). The predominant matrix
metalloproteinases associated with collagen
136
breakdown in periodontitis are matrix metallopro-
teinase-8 and matrix metalloproteinase-9, which are
secreted by the high numbers of infiltrating neutrophils
that are recruited to the inflamed periodontal tissues.
The anti-matrix metalloproteinase properties of the
tetracycline family were first identified in minocycline
(42), and subsequent studies revealed that doxycy-
cline was particularly effective for this purpose (7, 41).
The binding of tetracyclines to matrix metallopro-
teinases occurs via the chelation of structural and cat-
alytic Zn2+ ions within the matrix metalloproteinase
enzyme (49). Doxycycline was identified to be a more
effective inhibitor of matrix metalloproteinase-8 (also
known as collagenase 2 and neutrophil collagenase)
than matrix metalloproteinase-1 (also known as colla-
genase-1 and fibroblast collagenase) (46, 120), there-
fore suggesting that doxycycline could be useful for
reducing pathologically elevated matrix metallopro-
teinase levels without interfering with normal con-
nective tissue turnover. This relative superiority of
doxycycline as a matrix metalloproteinase inhibitor,
compared with tetracycline or minocycline, is a result
of its increased affinity for Zn2+ (49). A number of
potentially useful properties of doxycycline were
identified that were recognized as having relevance in
periodontal pathogenesis, including: direct (cation
chelation dependent) inhibition of active matrix met-
alloproteinases; inhibition of activation of latent
matrix metalloproteinases; inhibition of reactive oxy-
gen species; and reduced osteoclastic activity and
bone resorption (43). These findings led to the intro-
duction of a low-dose formulation of doxycycline
(20 mg, twice daily, referred to as a ‘subantimicrobial
dose’) that was the first (and, to date, has been the
only) host response modulation drug licensed for the
treatment of periodontitis (97).
When using subantimicrobial dose doxycycline as a
host modulation agent, the aim is not to inhibit
matrix metalloproteinase activity completely (as
matrix metalloproteinases play vital roles in various
physiologic, as well as pathologic, processes) but to
modulate (or ‘dampen’) the pathologic levels of
matrix metalloproteinases associated with periodon-
titis. It is used as an adjunct to conventional, nonsur-
gical treatment, with the aim being to enhance the
resolution of inflammation achieved by the conven-
tional therapy. For most patients, a single course of
subantimicrobial dose doxycycline lasting 3 months
(or 12 weeks), with treatment commencing at the
start of the nonsurgical therapy, is prescribed. Suban-
timicrobial dose doxycycline should be avoided in
any patients with a history of allergy to tetracyclines,
and also in pregnant mothers and young children

because of the risk of tetracycline discoloration of the
developing teeth.
Subantimicrobial dose doxycycline, taken for short
durations, was shown to reduce gingival collagenase
activity (40) and to prevent progression of periodonti-
tis (47). Subsequently, large-scale, multicenter, ran-
domized controlled trials were undertaken to
evaluate the efficacy of subantimicrobial dose doxy-
cycline when used as an adjunct to conventional non-
surgical management of periodontitis (12, 13, 98, 99).
These studies, together with a number of smaller clin-
ical trials, have been reviewed previously (11, 97),
with subantimicrobial dose doxycycline being well
tolerated, and evidence of improved periodontal
treatment outcomes in patients who received
adjunctive subantimicrobial dose doxycycline com-
pared with those who received adjunctive placebo. A
systematic review found a statistically significant
mean difference of 0.88 mm (95% confidence inter-
val: 0.08–1.67) for attachment gain in favor of the use
of subantimicrobial dose doxycycline compared with
placebo, although many of the published studies
were excluded from this meta-analysis, which only
included three papers (116).
Most of the studies that have evaluated clinical
changes in periodontal indices following the use of
subantimicrobial dose doxycycline have reported
mean probing depth reductions and/or attachment
gains, typically stratified according to initial probing
depth of the treated sites. This can be somewhat con-
fusing for interpretation because, as clinicians, we do
not routinely report or calculate mean probing depth
changes in our patients. To place the probing depth
reductions that were achieved following use of suban-
timicrobial dose doxycycline into context, it is well
recognized that mean probing depth reductions of
around 1.29 mm are achieved in sites that are initially
4–6 mm deep, and mean probing depth reductions of
around 2.16 mm are achieved in sites that are initially
≥ 7 mm deep, following nonsurgical periodontal ther-
apy alone (19, 20). Similar improvements were noted
in the randomized controlled trials that evaluated the
outcomes of adjunctive subantimicrobial dose doxy-
cycline therapy: for example, in a 2004 study of 210
patients, mean probing depth reductions at sites
which were initially ≥ 7 mm deep were 1.77 mm in
the placebo group (i.e. patients receiving nonsurgical
therapy only) compared with 2.31 mm in the suban-
timicrobial dose doxycycline group (i.e. patients who
received nonsurgical therapy plus subantimicrobial
dose doxycycline for 9 months) (98). In a 2008 study
of 266 patients to evaluate a once-daily modified-
release formulation of subantimicrobial dose
Host modulation with anti-inflammatory agents
doxycycline, the mean probing depth reduction at
sites initially ≥ 7 mm deep in the placebo group was
2.25 mm, compared with 2.74 mm in the subantimi-
crobial dose doxycycline group (99). The mean reduc-
tions observed in the patients treated with adjunctive
subantimicrobial dose doxycycline represent an
improvement of approximately 20–30% in treatment
response compared with the patients who received
nonsurgical therapy plus placebo.
A concern that has sometimes been raised regarding
the use of subantimicrobial dose doxycycline has been
that although statistically significant differences have
been identified between groups of patients treated
with subantimicrobial dose doxycycline and placebo,
are these improvements truly clinically significant?
Some of the published studies have calculated the pro-
portions of sites that improved by certain thresholds
of change that most clinicians would recognize as
being clinically significant (e.g. a probing depth reduc-
tion of ≥ 2 mm). For example, in the 2004 study dis-
cussed in the previous paragraph, 45% of sites with
initial probing depths of ≥ 6 mm demonstrated prob-
ing depth reductions of ≥ 2 mm in the placebo group,
compared with 62% of sites in the subantimicrobial
dose doxycycline group (98). In the 2008 study dis-
cussed in the previous paragraph, 58% of sites with ini-
tial probing depths of ≥ 6 mm demonstrated probing
depth reductions of ≥ 2 mm in the placebo group,
compared with 76% of sites in the subantimicrobial
dose doxycycline group (99). Although it is impossible
to predict, in advance, what the precise benefit of
using adjunctive subantimicrobial dose doxycycline
might be in any specific individual patient, these find-
ings suggest that clinically relevant improvements
may be achieved following adjunctive subantimicro-
bial dose doxycycline therapy.
A further concern regarding the use of subantimi-
crobial dose doxycycline was the potential for devel-
opment of antibiotic resistance when patients are
taking a low dose of doxycycline on a twice-daily basis
for a minimum period of 3 months. However, no evi-
dence of this has been identified in studies that
investigated whether there was any impact of suban-
timicrobial dose doxycycline on the subgingival
(73, 124, 125, 137) or the intestinal (136) microbiota,
even when subantimicrobial dose doxycycline was
taken for prolonged periods of up to 9 months.
To summarize, the use of subantimicrobial dose
doxycycline has been shown to be safe and to result
in improved clinical outcomes when used as an
adjunct to periodontal nonsurgical therapy in care-
fully controlled clinical trials that have been
conducted in secondary care centers such as teaching
137
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dental schools and hospitals. A problem, however, for
many clinicians in routine dental and periodontal
practice is that they are not clear on exactly when
they should use subantimicrobial dose doxycycline.
After all, if it results in clinical benefits, should it be
used in every patient with periodontitis? This was a
viewpoint that seemed to be presented by companies
when the product was first released; clearly, this
would be inappropriate, and this ‘heavy-handed’
approach understandably induced a degree of resent-
ment among the profession. It should also be noted
that randomized controlled trials, by their nature, are
very controlled situations, with careful selection of
participants according to detailed inclusion and
exclusion criteria, very close monitoring of the partic-
ipants during the trial to ensure compliance and care-
fully conducted clinical treatment according to strict
protocols. As yet, no studies have confirmed whether
the improved clinical outcomes that were achieved
with subantimicrobial dose doxycycline therapy in
the published randomized controlled trials could be
replicated in routine clinical practice. Also, in patients
who are particularly at risk of periodontitis (i.e. smok-
ers), a prospective randomized controlled trial did
not reveal evidence of a benefit for using subantimi-
crobial dose doxycycline as an adjunct to nonsurgical
therapy in this disease-susceptible population (86).
A considerable commitment is required of patients
when taking subantimicrobial dose doxycycline, not
only to comply with the requirements involved in the
treatment of their periodontitis (i.e. improved oral
hygiene and attendance for multiple treatment and
maintenance appointments), but also to take a medi-
cation twice daily for a minimum period of 3 months.
Therefore, the decision about prescribing subantimi-
crobial dose doxycycline tends to be based as much
on patient-related factors (e.g. likely motivation, com-
pliance and commitment to the proposed treatment)
as clinical factors (e.g. extent and severity of peri-
odontitis). As previously stated, the decision to use
subantimicrobial dose doxycycline is a matter of indi-
vidual clinical judgment, based on the phase of treat-
ment and the patient’s status and preferences (106).
Chemically modified tetracyclines
As mentioned above, a concern with using subantimi-
crobial dose doxycycline for prolonged periods of
time has been whether there may be development of
antibiotic resistance. Although no evidence of this has
been identified, the chemically modified tetracycline
analogs present a conceptually attractive alternative
to use of doxycycline for inhibition of matrix
138
metalloproteinases, as they possess no antibiotic
properties whatsoever, yet do retain anti-matrix met-
alloproteinase properties (45). This is achieved by
removal of the dimethylamino group on the ‘A’ ring
of the four-ringed tetracycline molecule (44, 49). One
of the most extensively studied has been chemically
modified tetracycline-3 (6-demethyl 6-deoxy 4-dedi-
methylaminotetracycline), which has been shown to
be an inhibitor of matrix metalloproteinase activity
and cytokine production (50). Early studies revealed
an impact of chemically modified tetracycline-3 in
reducing collagenolytic activity induced by Porphy-
romonas gingivalis (48) and in inhibiting matrix met-
alloproteinase-mediated alveolar bone loss in an
animal model (103). Chemically modified tetracy-
cline-3 has also been shown to reduce P. gingivalis
lipopolysaccharide-induced proinflammatory cyto-
kine secretion in an ex vivo human whole-blood
model, although this research did not identify an
impact of chemically modified tetracycline-3 in
reduction of matrix metalloproteinase-8 and matrix
metalloproteinase-9 secretion (14).
Clearly, more research into the efficacy of chemi-
cally modified tetracyclines in modulating periodon-
tal inflammation is required. However, the chemically
modified tetracyclines do appear to offer potential to
reduce connective tissue breakdown in a variety of
pathogenic processes and inflammatory diseases,
such as periodontitis and rheumatoid arthritis, as well
as cancer metastasis and metabolic bone disorders
(1). For example, chemically modified tetracycline-3
has been shown to inhibit tumor-cell-derived matrix
metalloproteinases, as well as to inhibit tumor growth
in models of prostate cancer, melanoma and breast
cancer (78). For now, studies have yet to determine
whether chemically modified tetracycline-3 or other
chemically modified tetracyclines may be of benefit
in the treatment of periodontitis.
Anti-cytokine and biological
therapies
Biological therapies (also referred to as ‘biologics’) are
a range of drugs that are used particularly in the treat-
ment of rheumatoid arthritis, and some are also used
in the treatment of other chronic inflammatory and
autoimmune conditions, such as Crohn’s disease,
ankylosing spondylitis, psoriasis and ulcerative colitis.
In the treatment of rheumatoid arthritis, biological
therapies are often prescribed in combination with
methotrexate in those patients who have had a
limited response to conventional disease-modifying

anti-rheumatic drug therapy. The biologics include a
number of anti-cytokine agents, as shown in Table 2.
These block the activity of specific cytokines, and are
usually monoclonal antibodies that bind to the target
cytokine. They effectively function as immune sup-
pressants, which can result in the major unwanted
effects of these drugs, such as reactivation of serious
infections, such as tuberculosis, or development of
lymphomas and other solid tumors.
Both rheumatoid arthritis and periodontitis are
complex chronic inflammatory diseases with multiple
susceptibility factors (particularly genetic and envi-
ronmental risk factors). A major difference between
the conditions is that periodontitis results from the
inflammation that develops in response to the sub-
gingival microbiota, whereas the inflammation in
rheumatoid arthritis results from an autoimmune
response in which a specific adaptive immune
response is mounted against self-antigen (23). The
inflammation is perpetuated by the continued
bacterial challenge in the case of periodontitis, and
the ongoing autoimmune response in the case of
rheumatoid arthritis, culminating in progressive tis-
sue destruction leading to the signs and symptoms of
disease.
Given the similarities between aspects of the
pathogenesis of periodontitis and rheumatoid arthri-
tis, it is pertinent for the periodontal research com-
munity to be aware of the therapeutic options
available for rheumatoid arthritis. Although the pre-
cise mechanisms that result in breach of immune
tolerance and progression to the clinical signs and
symptoms of rheumatoid arthritis are not known,
the inflammatory cascade plays a key role in all
stages of the pathogenesis of rheumatoid arthritis,
from the initiation of autoimmunity to articular
localization and joint and bone destruction (23).
Tumor necrosis factor-alpha is particularly important
and therefore has been a primary developmental tar-
get for anti-cytokine therapies that have been intro-
duced for the management of rheumatoid arthritis.
Other cytokines that play a role in the pathogenesis
of rheumatoid arthritis include interleukin-1, inter-
leukin-6, interleukin-17 and interleukin-15. In addi-
tion to anti-tumor necrosis factor-alpha treatments,
other biological therapies targeting different cytoki-
nes and aspects of immune cellular function have
also been licensed for the treatment of rheumatoid
arthritis (Table 2).
Regarding the use of biological therapies in the
treatment of periodontitis, animal studies have
revealed potential efficacy for anti-cytokine therapies
in reducing alveolar bone loss in an experimental
Host modulation with anti-inflammatory agents
periodontitis model in primates (87) and for reducing
the inflammatory cell infiltrate in experimental peri-
odontitis in rats (25). The biological rationale for the
use of anti-tumor necrosis factor-alpha treatments as
a modulator of periodontitis expression in experi-
mental animals was confirmed by studies which
showed that tumor necrosis factor-alpha receptor
p55-deficient mice developed less severe periodontal
inflammation (less bone loss and a lower inflamma-
tory reaction) in response to inoculation with Aggre-
gatibacter actinomycetemcomitans (38). Using the
same A. actinomycetemcomitans-induced murine
experimental periodontitis model, the researchers
found that antigen-induced arthritis exacerbated
alveolar bone loss, whereas anti-tumor necrosis fac-
tor-alpha therapies ameliorated the development of
the periodontitis (101, 102).
To date, most research regarding use of anti-cyto-
kine therapies for periodontitis in humans has been
limited to small clinical studies which evaluated peri-
odontal status in patients undergoing treatment for
rheumatoid arthritis. The findings from these studies
have tended to be inconsistent and somewhat con-
fusing, probably because of the small numbers of
patients with a variety of periodontal conditions who
were selected on account of the primary inclusion
criterion being that the patients were receiving anti-
cytokine therapy for rheumatoid arthritis, as opposed
to being purposively recruited on account of their
periodontal status. For example, in one study, intra-
venous therapy with anti-tumor necrosis factor-alpha
(infliximab) of patients with rheumatoid arthritis was
associated with an increase in gingival inflammation
over time, with no effect on probing depths being
observed (95). Another study identified that patients
with rheumatoid arthritis receiving intravenous
infliximab had lower bleeding on probing scores,
lower gingival crevicular fluid tumor necrosis factor-
alpha concentrations and lower mean probing depth
measurements compared with patients with rheuma-
toid arthritis who were not receiving anti-tumor
necrosis factor-alpha therapy and with nonrheuma-
toid arthritis controls (82). A subsequent study of
three groups of patients (those with autoimmune dis-
eases including rheumatoid arthritis who were not
receiving anti-tumor necrosis factor-alpha therapy;
those with rheumatoid arthritis who were receiving
anti-tumor necrosis factor-alpha therapy; and
healthy controls with no autoimmune diseases and
no anti-tumor necrosis factor-alpha therapy) identi-
fied that the patients with autoimmune diseases who
were not receiving anti-tumor necrosis factor-alpha
therapy had more gingival inflammation, more
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Table 2. Biological therapies for the treatment of rheumatoid arthritis

Drug target Drug Comments

Tumor necrosis Infliximab The anti-tumor necrosis factor-alpha properties of these five drugs have been well
factor-alpha Etanercept documented, with demonstrated efficacy in a large number of clinical trials. They are
Adalimumab effective in the majority (~ 70%) of recipients. The main risks are associated with
Golimumab suppressed immune responses, including infection (particularly emergence of latent
Certolizumab infections, such as tuberculosis) and malignancy. Infliximab is a chimeric monoclonal
antibody to tumor necrosis factor-alpha; etanercept is created by fusion of soluble
tumor necrosis factor receptor-2 to an Fc portion of an Ig, giving it anti-tumor necrosis
factor properties and a long half-life; adalimumab and golimumab are monoclonal
antibodies to tumor necrosis factor-alpha; and certolizumab is a PEGylated* Fab
fragment of an anti-tumor necrosis factor-alpha monoclonal antibody
Interleukin-1 Anakinra Recombinant interleukin-1 receptor antagonist that competitively inhibits the binding of
interleukin-1 to its receptor. However, despite being biologically plausible for the
treatment of rheumatoid arthritis, only limited efficacy has been shown in clinical trials.
It carries potential risk of infections as a result of reduced interleukin-1 signaling
Interleukin-6 Tocilizumab A monoclonal antibody to the interleukin-6 receptor, thereby preventing interleukin-6
signaling. Biologically plausible for treatment of rheumatoid arthritis, and good efficacy
in clinical trials
T-cells Abatacept A construct of cytotoxic T-lymphocyte antigen-4 Ig that blocks T-cell activation by
antigen-presenting cells by harnessing the ability of cytotoxic T-lymphocyte antigen-4 to
bind CD80 and CD86 and prevent costimulatory effects of T-cell membrane-associated
CD28. Biologically plausible and demonstrated efficacy in ~ 50% of recipients, but
potential increased risk of infection as a result of suppressed T-cell activation
B-cells Rituximab An anti-CD20 antibody that depletes B-cells. Biologically plausible, efficacy in some
patients (~ 30%), but has potential for increased risk of infection
CD, cluster of differentiation (denotes cell-surface molecules that are used to define different immune-cell lineages, functional phenotypes and stages of develop-
ment); Fab, fragment antigen-binding; Fc, fragment crystallizable.
Adapted from Culshaw et al. (23).
*PEGylation is the process of covalent and non-covalent attachment of polyethylene glycol (PEG) polymer chains to molecules such as drugs.

bleeding on probing, higher mean probing depths
and higher gingival crevicular fluid tumor necrosis
factor-alpha concentrations than the patients in the
other two groups (83). The inference from these find-
ings is that patients with autoimmune disorders (in-
cluding rheumatoid arthritis) have more periodontal
inflammation than do patients who do not have
autoimmune diseases, and that giving anti-tumor
necrosis factor-alpha therapy as a treatment for
rheumatoid arthritis reduces inflammation in the
periodontal tissues.
A further study identified that patients with
rheumatoid arthritis who were also receiving anti-
tumor necrosis factor-alpha therapy demonstrated
statistically significant improvements in probing
depths, bleeding on probing and gingival inflamma-
tion compared with patients who were not receiving
anti-tumor necrosis factor-alpha therapy following
nonsurgical periodontal treatment, though anti-
tumor necrosis factor-alpha therapy alone (i.e. with-
out periodontal treatment) had no significant effect
on the periodontal condition (92). Of interest are
studies in which the presence of antibodies to
P. gingivalis (but not to Prevotella intermedia or to
Fusobacterium nucleatum) was significantly
associated with the presence of rheumatoid arthritis-
related autoantibodies (such as rheumatoid factor
and anti-citrullinated protein antibody) in individuals
categorized as being at high risk of rheumatoid arthri-
tis, suggesting that the presence of P. gingivalis may
be associated with the early loss of tolerance to self-
antigens that occurs in rheumatoid arthritis (84).
To date, no studies have prospectively evaluated
the effect of anti-cytokine therapies as a treatment
specifically for periodontitis. However, periodontal
status has been evaluated in patients before, and
6 months after, commencing anti-cytokine therapy
for the management of rheumatoid arthritis (110). In
this small-scale study, periodontal parameters (pla-
que, gingival bleeding, probing depth and attachment
loss) did not vary significantly from pretreatment to
6 months post-treatment with anti-cytokine drugs,
although improvements in parameters of rheumatoid
arthritis severity (disease activity score, erythrocyte
sedimentation rate and C-reactive protein) did occur
over the same time frame. Of note, these improve-
ments in rheumatoid arthritis parameters tended to
occur in the patients who did not have periodontitis

140

(n = 12), whereas patients who did have periodontitis
(n = 8) did not demonstrate significant improve-
ments in rheumatoid arthritis parameters. Clearly,
this was a small study, involving a low number of
patients, and further research is indicated to investi-
gate the impact (if any) of anti-cytokine drugs on pro-
gression of periodontitis and response to periodontal
treatment, as well as on rheumatoid arthritis parame-
ters in patients with periodontitis.
Lipid mediators of resolution of
inflammation
Resolution of inflammation is a fundamentally
important component of inflammatory responses
(57). Previously, this was believed to be characterized
by a gradual and passive decline in inflammatory pro-
cesses once the initiating stimulus had been elimi-
nated. However, it is now recognized that resolution
of acute inflammation is a highly controlled process,
in which endogenous ‘pro-resolving’ mediators
induce cessation of leukocyte infiltration, reduce vas-
cular permeability and vasodilatation and facilitate
the safe removal and disposal of leukocytes (primarily
by apoptosis) and the removal by macrophages of
apoptotic leukocytes, foreign matter (bacteria) and
necrotic tissue (39). Resolution of inflammation is
important to prevent chronic inflammation; however,
if resolution of inflammation fails, then tissue injury
may result from the perpetuated chronic inflamma-
tory response. Molecules which ‘switch off’ inflam-
mation could theoretically be attractive in the
treatment of inflammatory conditions, such as peri-
odontitis, and potentially could offer advantages over
anti-inflammatory therapies that have significant
unwanted effects. A group of agents that have been
investigated in this regard are the lipoxins, resolvins
and protectins. The identification of these molecules,
which signal the end of the acute inflammatory epi-
sode, has the potential to increase our options for
managing chronic inflammatory diseases (3, 74, 113,
114). The lipoxins are derived from arachidonic acid,
and the resolvins, protectins and maresins are
derived from omega-3 fatty acids found in the diet
(such as in fish oil), including eicosapentaenoic acid
and docosahexaenoic acid. The formation of these
molecules and their numerous anti-inflammatory
functions have recently been reviewed in detail (34).
Animal studies have indicated a potential role for
these molecules in the resolution of periodontal
inflammation (129). In a P. gingivalis-induced
experimental periodontitis model in rabbits, topical
Host modulation with anti-inflammatory agents
application of resolvin E1 resulted in complete
resolution of inflammation and restoration of nor-
mal anatomy of both the hard and soft periodontal
tissues compared with controls (56). Histological
assessment revealed complete regeneration of the
periodontium, together with the complete absence
of osteoclastic cells. In a mouse model of ligature-
induced periodontitis, resolvin E1 resulted in
reduced alveolar bone loss and increased expression
of osteoprotegerin without having an impact on
RANKL, suggesting that resolvin E1 modulates bone
remodeling by direct actions on bone and restora-
tion of a more favorable RANKL:osteoprotegerin
ratio (37).
Relatively few studies have been conducted to
investigate the impact of pro-resolving mediators on
human periodontitis, and this is a developing area of
research. In a clinical study of dietary supplementa-
tion with fish oil and low-dose aspirin as an adjunct
to conventional nonsurgical therapy, greater probing
depth reductions and greater reductions in the sali-
vary levels of RANKL and matrix metalloproteinase-8
were noted in patients receiving the combined
adjunctive treatment compared with controls who
received nonsurgical therapy alone (28). In a cross-
sectional study of 10 individuals with localized
aggressive periodontitis and 10 periodontally healthy,
age-, sex- and race-matched controls, it was noted
that whole-blood samples from the patients with
localized aggressive periodontitis contained signifi-
cantly more platelet–neutrophil and platelet–mono-
cyte aggregates than did samples from the controls,
and that macrophages from the patients with local-
ized aggressive periodontitis exhibited reduced
phagocytosis (33). The addition of resolvin E1, at
levels as low as 1 nM, restored impaired phagocytic
activity in macrophages from patients with localized
aggressive periodontitis to levels that were similar to
those seen in the samples from healthy controls. The
implication of this finding is that although localized
aggressive periodontitis is associated with impaired
phagocytosis, this could potentially be corrected by
the use of resolvin E1.
Small molecule compounds
Recently, interest has focused on a range of small
molecule compounds that target specific cytokine-
mediated processes. A significant benefit of these
small molecules is that they potentially could be
administered orally (or even topically), and therefore
compliance would likely be improved.
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Histone deacetylase inhibitors
Epigenetic control of gene expression occurs via cova-
lent modification of chromatin, including DNA
methylation and histone acetylation. These processes
modify access of transcription factors to coding sec-
tions of DNA and therefore influence gene expression
and protein production. Histone acetylation is con-
trolled by two enzymes: histone acetyltransferase
(which adds acetyl groups to lysine and arginine resi-
dues in histones, leading to exposure of DNA to tran-
scription factors and therefore gene expression); and
histone deacetylases (which remove acetyl groups
from histones, thereby inhibiting gene expression)
(8). Studies of histone deacetylase inhibitors have
identified that they have anti-inflammatory proper-
ties in a number of chronic inflammatory and malig-
nant diseases (133, 134). For example, the histone
deacetylase inhibitors, trichostatin A and suberoy-
lanilide hydroxamic acid, have been shown to have
anti-proliferative and pro-apoptotic activities in can-
cer cells, leading to clinical studies of the use of some
of these molecules as anti-cancer treatments (18, 65,
117). Such studies also led to identification of poten-
tial anti-inflammatory properties of these agents,
probably through inhibition of the nuclear factor-B
pathway and subsequent suppression of inflamma-
tory cytokines as well as inhibition of matrix metallo-
proteinase expression (8, 24, 142). Some studies have
identified both pro- and anti-inflammatory effects of
histone deacetylase inhibitors, and clearly more
research is required to elucidate fully their properties
and potential indications (52, 53).
Of particular relevance in the context of periodon-
tal pathogenesis is the finding that some histone
deacetylase inhibitors appear to be able to regulate
the effects of RANKL on osteoclasts and inflammatory
cells, resulting in inhibition of RANKL-induced osteo-
clastic activity in mouse macrophages and murine
cell lines (68, 123). The inhibition of RANKL-induced
osteoclast formation occurred via suppression of
induction of the osteoclastogenic transcription factor,
c-Fos (68). In human studies, histone deacetylase
inhibitors inhibited osteoclastic bone resorption
in vitro, probably because of reduced expression of
osteoclast transcription factors such as tumor necro-
sis factor receptor associated factor-6, nuclear factor
of activated T-cells and osteoclast associated receptor
during late osteoclast differentiation (10). In a murine
experimental periodontitis model, topical application
of a novel histone deacetylase inhibitor (1179.4b)
resulted in a significant reduction in P. gingivalis-
induced alveolar bone loss, which occurred
142
despite the inhibitor having no effect on reducing
inflammation (9).
The implication of these findings is that histone
deacetylase inhibitors may hold promise as novel
therapeutics in the treatment of diseases character-
ized by bone resorption, such as periodontitis. In the
clinical studies conducted to date (in diseases other
than periodontitis), they have been shown to be well
tolerated and safe, with evidence of clinical efficacy
(32, 35, 55, 96, 104). However, unwanted effects are
certainly a possibility because of the wide-ranging
effects of these molecules in various tissues and cells.
Topical application could therefore be beneficial for
reducing systemic exposure, and periodontitis could
be a useful model for investigating this premise fur-
ther. Development of synthetic histone deacetylase
inhibitors that specifically target those histone
deacetylases that are involved in the disease pro-
cesses of interest may also help to limit unwanted
effects (8).
Other anti-inflammatory
treatments
As drug development and discovery proceeds, a range
of other anti-inflammatory agents have been identi-
fied, some of which may potentially have relevance in
the treatment of periodontitis.
RANKL inhibitors
RANK is a cell-surface receptor expressed by osteo-
clast progenitors and mature osteoclasts. RANKL
binds to RANK and is expressed by bone marrow stro-
mal cells, osteoblasts and fibroblasts, as well as by
other cell types, such as T- and B-lymphocytes (100).
Binding of RANKL to RANK results in osteoclast dif-
ferentiation and activation, leading to bone resorp-
tion. Osteoprotegerin is a decoy receptor for RANKL
and inhibits bone resorption by binding to RANKL,
thereby preventing it from binding to RANK. The
RANK/RANKL/osteoprotegerin axis plays a funda-
mental role in regulating bone metabolism (71), and
increased RANKL:osteoprotegerin ratios are induced
by many cytokines, leading to bone resorption (100).
An anti-RANKL monoclonal antibody (denosumab)
has been developed and is used in the treatment of
bone-resorptive conditions, such as osteoporosis. It is
given via subcutaneous injections, and has been
shown to be clinically effective and well tolerated
(118). To date, there are no reported studies of

denosumab treatment in the context of periodontitis.
In an experimental periodontitis model, however,
exogenous administration of osteoprotegerin to inhi-
bit RANKL resulted in inhibition of alveolar bone
resorption, indicating that RANKL inhibition could be
a potential target in preventing alveolar bone loss
(67).
Bisphosphonates
The bisphosphonates are a class of drugs which dis-
rupt osteoclastic activity and inhibit bone resorption.
Their phosphate–carbon–phosphate structure per-
mits them to bind to metal ions, such as Ca2+, and the
bisphosphonates are able to bind to bone surfaces,
thereby protecting against bone resorption. They are
used extensively in the management of osteoporosis
and other bone-resorptive conditions. A number of
clinical trials were commenced in which the use of
bisphosphonates was evaluated in the treatment of
periodontitis (97). Although initial results appeared
promising, only a relatively small number of studies
showed a benefit (106), and efficacy was not
confirmed in larger clinical trials (66). Furthermore,
the emergence of a severe unwanted effect of
bisphosphonate therapy, bisphosphonate-related
osteonecrosis of the jaw (now referred to as medica-
tion-related osteonecrosis of the jaw), which is char-
acterized by exposure of necrotic bone in the
mandible or maxilla and risk of infection (particularly
following dental procedures such as extractions)
effectively put an end to this line of research (93).
Given the potential for medication-induced
osteonecrosis of the jaw to develop, the use of bis-
phosphonates as an adjunctive treatment for peri-
odontal disease is not indicated.
Toll-like receptor inhibitors
An intriguing possibility could be the development of
therapies which target aspects of toll-like receptor
functioning, as these could have the potential to tar-
get multiple pathways in the inflammatory response
(51, 70). Work is underway to develop ligands to acti-
vate toll-like receptors and antibodies to inhibit them,
in the development of novel therapies that could be
useful in treatment of a range of diseases such as can-
cers, rheumatoid arthritis, inflammatory bowel dis-
ease and systemic lupus erythematosus (59).
However, such research is at a very early stage, and
clearly safety concerns are paramount given the fun-
damental importance of toll-like receptors in infec-
tion and immunity.
Host modulation with anti-inflammatory agents
Combined antibacterial and anti-
inflammatory approaches
As stated previously, periodontal inflammation is ini-
tiated and perpetuated by the bacterial challenge of
the subgingival microbiota, and the majority of tissue
breakdown in periodontitis results from the host
inflammatory response. Thus, drugs that combine
both antibacterial and anti-inflammatory properties
could be of interest in the management of periodonti-
tis. Such a drug is azithromycin, a synthetic ery-
thromycin derivative with a bacteriostatic
antimicrobial action, which is used to treat a variety
of bacterial infections (143). However, azithromycin,
similarly to other macrolide antibiotics, also pos-
sesses anti-inflammatory properties (22), resulting in
inhibition of production of proinflammatory cytoki-
nes, such as interleukin-1beta, interleukin-6, tumor
necrosis factor-alpha and granulocyte–macrophage
colony-stimulating factor, as well as various chemoki-
nes (6, 79). The use of azithromycin as an (antimicro-
bial) adjunct to conventional nonsurgical periodontal
therapy has been evaluated in a small number of
studies, with some evidence of clinical benefit (60),
but no studies have yet evaluated any potential role
for the anti-inflammatory properties of this drug in
the management of periodontitis.
Summary
Host modulation therapy with anti-inflammatories is
not a new concept, and a large number of drugs have
been evaluated for a potential role in the manage-
ment of periodontitis. This research commenced well
over 30 years ago, with early studies involving the use
of nonsteroidal anti-inflammatory drugs prescribed
for long periods as a means to reduce alveolar bone
loss. However, the significant and serious unwanted
effects associated with the long-term use of nons-
teroidal anti-inflammatory drugs preclude their use
as an adjunctive therapy for periodontitis; in other
words, the risks associated with nonsteroidal anti-
inflammatory drug therapy far outweigh any poten-
tial benefits in terms of reductions in alveolar bone
resorption. In the 1990s, a new wave of research
investigated the use of tetracycline compounds,
specifically doxycycline, following identification of its
efficacy as an inhibitor of matrix metalloproteinases.
Carefully conducted randomized controlled trials
confirmed a benefit of using subantimicrobial dose
doxycycline as an adjunct to conventional nonsurgi-
cal treatment with no particular evidence of
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unwanted side effects. To date, this dose of doxycy-
cline (20 mg, twice daily, for 3 months) is the only
available drug therapy that is licensed, as a host mod-
ulation agent, for use in the treatment of periodonti-
tis. However, not all studies have demonstrated the
same magnitude of benefit as seen in the large-scale
clinical trials, and questions still remain about exactly
which patients would benefit and about the out-
comes that can be expected in routine periodontal
practice (as opposed to secondary-care environ-
ments).
Anti-cytokine therapies have a proven track record
in the management of rheumatoid arthritis, and given
the similarities between the pathogenesis of rheuma-
toid arthritis and periodontitis, it is understandable
that the periodontal research community has begun
to look at anti-cytokine therapies as potential host
modulators in the treatment of periodontitis. How-
ever, there are concerns associated with the use of
anti-cytokine drugs, including their well-documented
unwanted effects, such as increased risk of infection
and malignancy. Furthermore, we now recognize that
cytokines function in complex cellular and molecular
networks that integrate aspects of innate and adap-
tive immunity (100). Similarly to other autoimmune
and chronic inflammatory conditions, our under-
standing of the totality of cytokine functioning in
periodontitis is far from complete, and simply inhibit-
ing one specific cytokine might not always be
expected to have a clinically relevant impact on the
disease in question. This concept of redundancy is
based on the fact that many cytokines have very simi-
lar (if not identical) effects on the cells with which
they interact, so inhibiting one cytokine may have no
discernible impact on a disease state because other
cytokines provide the same function as the cytokine
that has been inhibited. Furthermore, although ani-
mal models may indicate which anti-cytokine drugs
may improve diseases such as rheumatoid arthritis,
they cannot predict with accuracy whether the same
efficacy may be achieved in human studies or in indi-
vidual patients (26).
In the treatment of rheumatoid arthritis, inhibition
of tumor necrosis factor-alpha with anti-tumor
necrosis factor-alpha therapies plus methotrexate has
clearly been shown to result in clinical improvements,
probably because tumor necrosis factor-alpha has
such an important, ‘up-stream’ role in the pathogen-
esis of the disease (111). Furthermore, anti-tumor
necrosis factor-alpha therapy in patients with
rheumatoid arthritis results in reductions in other
‘down-stream’ inflammatory mediators, such as
interleukin-1beta and interleukin-6, further
144
enhancing the anti-inflammatory effect (30, 31). Even
so, use of anti-tumor necrosis factor-alpha treatments
does not result in complete eradication of the disease,
and success factors are assessed using composite
scales that take into account percentage improve-
ments in signs and symptoms of the condition. No
studies have, to date, directly investigated the use of
anti-cytokine therapies in the management of peri-
odontitis. However, the high cost and risk of signifi-
cant unwanted effects clearly precludes the use of
currently available anti-cytokine treatments as a
treatment for periodontitis. The mode of administra-
tion (typically, repeated subcutaneous injections or
intravenous infusions) is a further limiting factor. It is
possible that future generations of anti-tumor necro-
sis factor-alpha agents (potentially locally delivered)
could have relevance in the treatment of periodonti-
tis.
Small molecule compounds, such as the histone
deacetylase inhibitors, offer potential in the manage-
ment of diseases characterized by bone resorption.
Many of these appear to inhibit osteoclastic activity
and potentially could be combined with anti-inflam-
matory agents so that both bone resorption and
inflammation are minimized. The development of
specific synthetic histone deacetylase inhibitors that
target those histone deacetylases involved in the dis-
ease process is also of interest. However, it should be
remembered that these agents are likely to have
impacts on multiple aspects of cellular activity, and
further research is required to establish their risk–
benefit profile. It is important to remember that the
mechanisms of action of biologic therapies can be
very different in humans from those that are observed
in animal studies, with potentially harmful conse-
quences when agents are used in humans for the first
time (122). Currently, some histone deacetylase inhi-
bitors are being evaluated in early-stage clinical trials
as cancer therapies and are proving to be effective
and well tolerated.
Pro-resolving lipid mediators appear to offer the
best potential for the development of a new class of
drug therapies that could be used as adjunctive host
modulating therapies in periodontitis. The main ben-
efit of these pro-resolving molecules is that they are
physiological resolution agonists that are produced
endogenously as part of the normal response to
inflammation, as opposed to being inflammation
inhibitors that could compromise host defences (15,
128). Development of drugs that mimic the actions of
inflammation-resolving endogenous mediators could
be useful for the treatment of a range of chronic
inflammatory diseases, including periodontitis;

however, much work remains to be done to demon-
strate safety and efficacy.
Therefore, the immune-modulatory properties of a
number of drug classes and molecules are currently
under investigation to assess which may be applica-
ble for treatment of periodontitis. The challenge
remains to harness the knowledge created from basic
science and animal studies to develop and evaluate
these molecules as new drugs and to evaluate the
risks and benefits associated with their clinical use, as
well as their unwanted effects, interactions and the
variations in response profiles between individuals.
Certainly, however, in the near future we are likely to
see the emergence of a range of new anti-inflamma-
tory and pro-resolving host modulatory therapies that
may have direct relevance as adjunctive agents in the
treatment of periodontitis.
Acknowledgments
The author gratefully acknowledges his colleague, Dr
John Taylor, for his critical review of this paper.
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