systemic medication and the inflammatory cascade

Systemic medication and theinflammatory cascade

AW S AL A N I & RO B I N SE Y M O U R

Inflammation plays a significant role in the patho-

genesis and expression of plaque-induced periodon-

tal disease. The mechanisms whereby inflammatory

mediators contribute to the various processes of

periodontal breakdown are discussed elsewhere in

this volume of Periodontology 2000.

It is widely recognized that our patients are living

for longer and are retaining their teeth into old age.

Part of this increase in life expectancy must be

attributed to improved methods of disease diagnosis

and control. The latter is most frequently mediated

via systemic drug therapy. The range of drugs avail-

able to treat diseases is increasing, and this provides

an opportunity to investigate the effects of such drugs

on the periodontium and on processes involved in

the periodontal diseases. The nature and the patho-

genesis of periodontal disease can be affected by a

variety of drugs, especially those that interact with

immune and inflammatory responses. Obvious

examples include anti-inflammatory agents and im-

munosuppressants.

Early studies, which will be discussed later, ob-

served the effects of such systemic medication on the

periodontium and on the responses of the tissues

to bacterial plaque. Nonsteroidal anti-inflammatory

drugs, which inhibit eicosanoid synthesis by blocking

the cyclooxygenase-1 enzyme system, were particu-

larly relevant in this respect, with an early study

showing that patients on long-term nonsteroidal

anti-inflammatory drug therapy were afforded some

degree of protection against periodontal breakdown

(62). This did indicate that eicosanoids, especially

prostaglandins of the E-series, may be important in

the development and progression of periodontal

disease. In other words, drugs such as nonsteroidal

anti-inflammatory drugs with a known mode of ac-

tion could be used as a �tool� to provide further in-

sight into the role of inflammatory mediators in the

expression of periodontal disease. Consideration was

then given to whether nonsteroidal anti-inflamma-

tory drugs have a therapeutic role to play in the

management of periodontal disease.

In this review, the following categories of medi-

cines are discussed and evidence evaluated regarding

their effect on the inflammatory cascades and how

this relates to periodontal disease:

• corticosteroids.

• cyclooxygenase-1 and cyclooxygenase-2 inhibitors.

• immunosuppressants.

• bisphosphonates.

• anti-cytokines.

• statins.

• omega-3.

The topic of host-modulating agents would also be

applicable to this review. However, as it has been

discussed in a recent volume of Periodontology 2000,

it will not be considered further here (44). In addition

to reviewing the evidence of such drugs on the peri-

odontium, we will also consider their unwanted ef-

fects and, where appropriate, the cost–risk benefit.

Corticosteroids

Corticosteroids are a group of drugs that are

structurally and pharmacologically related to the

endogenous hormone cortisol. There are several

corticosteroids, each with different potencies and

applications. A list of those widely prescribed in

medical practice is given in Table 1. Corticosteroids

are extensively used in many aspects of medicine.

They can be applied topically, by inhalation, orally

and parenterally.

Pharmacological properties

Therapeutic usage of corticosteroids relates mainly to

their anti-inflammatory and immunosuppressive

198

Periodontology 2000, Vol. 64, 2014, 198–210

Printed in Singapore. All rights reserved

� 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

PERIODONTOLOGY 2000

actions. The main anti-inflammatory action is med-

iated via their ability to stimulate the production of a

protein known as lipocortin-1 (annexin A1) (42).

Lipocortin suppresses the enzyme phopholipase A2,

which acts on cell membranes to produce the various

eicosanoids that are discussed elsewhere in this vo-

lume of Periodontology 2000. Thus, corticosteroids,

via stimulation of lipocortin, block production of

prostaglandins and leukotrienes. In addition to this

action, corticosteroids also suppress the enzymes

cyclooxygenase-1 and cyclooxygenase-2, further

reducing eicosanoid synthesis.

Corticosteroid-induced immunosuppression has

many applications in the treatment of a variety of

diseases. Corticosteroids suppress the cell-mediated

response by inhibiting the genes that code for cyto-

kines interleukin-1 to -6, interleukin-8 and inter-

feron-c. Suppression of these cytokines leads to

reduced T-cell proliferation. Humoral immunity is

also suppressed by corticosteroids, resulting in

reductions of B-cells, interleukin-2 synthesis and

expression of interleukin-2 receptors. The outcome

of this suppression is a reduction in B-cell-clone

expansion and antibody synthesis and reduced

activation of T-lymphocytes (27). Corticosteroids

also affect T-cell apoptosis, which is more marked

for immature T-cells that are still present in the

thymus.

The actions of corticosteroids on both inflamma-

tory and immune responses are mediated by activa-

tion of the glucocorticoid receptor. Once activated,

the glucocorticoid receptor up-regulates the expres-

sion of anti-inflammatory proteins and suppresses

the expression of proinflammatory proteins (35).

Corticosteroids and the periodontium

Early animal studies showed that systemic cortisone

injections have a significant effect on periodontal

tissues (53), including induction of alveolar bone loss

and reduction in the numbers of osteoblasts and fi-

broblasts and of the intercellular matrix. This condi-

tion is virtually identical to the bone status seen in

osteoporosis and has been confirmed in further ani-

mal studies, which demonstrated that anti-osteopo-

rotic drugs (calcitonin and alendronate) prevented

corticosteroid-induced osteoporosis (13). Other ani-

mal studies also showed that systemic cortisone

could attenuate the plaque-induced inflammatory

responses in the periodontal tissues.

Human studies on the effects of corticosteroids on

periodontal tissues and disease progression have, for

the most part, been derived from data collected from

patients who have been on long-term steroid therapy

for medical conditions. These very early studies did

demonstrate some anti-inflammatory effects of cor-

ticosteroids on the gingival tissues, but not necessarily

a reduction in the rate of periodontal breakdown. In

other words, it is equivocal whether systemic corti-

costeroid treatment afforded that patient any protec-

tion against periodontal disease progression (53).

More recently, there has been interest in the role of

stress and its effect upon the hypothalamic–pitui-

tary–adrenal axis. Stress would have a direct effect on

the hypothalamic–pituitary–adrenal axis and this

would be mediated by the production of cortisol.

Again, animal studies have provided some insight

into the relationship among stress, cortisol produc-

tion and periodontal breakdown (6). In this study,

Table 1. List of corticosteroids commonly used in medical practice and their indications

Corticosteroid Indication

Hydrocortisone Adrenocortical insufficiency, shock, hypersensitivity reaction, asthma, inflammatory bowel disease,

skin disorders, rheumatic diseases

Cortisone acetate Steroid replacement therapy

Betamethasone Suppression of inflammatory and allergic disorders, congenital adrenal hyperplasia, oral ulceration

Deflazacort Suppression of inflammatory and allergic disorders

Dexamethasone Suppression of inflammatory and allergic disorders, cerebral edema, nausea and vomiting from

chemotherapy, rheumatic diseases

Prednisolone Suppression of inflammatory and allergic disorders, asthma, immunosuppression, rheumatic

diseases

Methylprednisone Suppression of inflammatory and allergic disorders, inflammatory bowel disease, rheumatic

diseases

Triamcinalone Suppression of inflammatory and allergic disorders, skin conditions

199

Systemic medication and the inflammatory cascade

rats that showed a low response to stress developed

significantly less periodontal breakdown than those

that showed a high response. The authors concluded

that hypothalamic–pituitary–adrenal axis hyperacti-

vation is one mechanism by which periodontal

disease susceptibility may be increased. Further

confirmation of the possible role of hypothalamic–

pituitary–adrenal axis hyperactivation has come from

the same group who subsequently demonstrated that

a glucocorticoid receptor antagonist reduced peri-

odontal breakdown in ligature-induced periodontitis

in rats (5). They also demonstrated that neonatal

injection of dexamethasone, which permanently

down-regulates the hypothalamic–pituitary–adrenal

axis, inhibits periodontal disease progression in a

similar manner to the study cited above (4). The au-

thors further emphasized that central nervous system

regulation of inflammatory responses to dental pla-

que may modulate periodontal disease susceptibility

and progression.

Clinical studies have in part confirmed this finding.

Stress and salivary cortisol have been measured in an

adult population suffering from periodontitis (24).

Salivary cortisol levels were positively associated with

an increase in psychological stress and in the extent

and severity of periodontitis. However, it is difficult to

ascertain what role salivary cortisol could play in the

periodontal tissues and in their response to bacterial

plaque.

A more recent investigation has confirmed the

equivocal effects of corticosteroids on the periodontal

tissues and their responses to plaque (48). A ran-

domized trial was completed to evaluate the short-

term effects of a combination of dipyridamole (an

anti-platelet drug) and prednisolone on a variety of

serum proinflammatory markers and clinical signs of

periodontal disease. The findings showed that this

drug combination did reduce the concentrations of

various proinflammatory cytokines, but had no effect

on the periodontal parameters of bleeding on probing

or probing pocket depth. The short-term exposure of

the patients to this drug combination may have con-

tributed to the minimal impact on these periodontal

measures.

Corticosteroids are a very potent and valuable

group of drugs that are used to treat a variety of

medical conditions. Their interest, in periodontal

terms, is on their anti-inflammatory actions and

whether such actions can provide an insight into the

pathogenesis of plaque-induced gingival inflamma-

tion and periodontal disease expression. Therefore,

such drugs have been used as a pharmacological tool

and do not have a place in the management of

periodontal disease.

Unwanted effects of corticosteroids

Steroids have a range of unwanted effects, which are

listed in Table 2. Of particular concern to the

periodontist are the unwanted effects of steroid-

induced osteoporosis and the risk of adrenocortical

suppression.

Table 2. Unwanted effects of systemic corticosteroids

Target Effect

Carbohydrate metabolism Decreased uptake of glucose and increased gluconeogenesis, leading to an increased

riskof diabetes

Protein Decreased protein synthesis and increased protein breakdown, especially in muscles,

causing muscle wasting

Bone Osteoporosis

Gastric mucosa Increased risk of peptic ulceration

Adrenal cortex Suppression leading to an increased risk of an adrenocortical crisis

Fat Redistribution of body fat causing so-called �moon faces� and �Buffalo hump�

Skin Thinning of skin and an increased risk of acne

Wound healing Impaired

Immune system Immunosuppression, increased risk of opportunistic infections

Cardiovascular system Hypertension

Neurological Mood changes and insomnia

Blood vessels Easy bruising

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Alani & Seymour

Corticosteroid-induced osteoporosis

Corticosteroids have a significant effect upon bone

metabolism. They increase bone resorption, inhibit

bone formation, decrease the intestinal absorption of

calcium ions and modify vitamin D metabolism. The

net result is an increased risk of osteoporosis, which

is considered a risk factor for periodontal disease,

especially an increased risk of tooth loss (36). It has

been estimated that 20–30% of patients on long-term

steroid therapy will develop osteoporosis (29). The

risk is higher in patients >60 years of age and also in

women. Corticosteroid-induced osteoporosis can be

managed by dietary supplements of calcium and

vitamin D and also by bisphosphonates. Issues

relating to the use of bisphosphonates and their un-

wanted effects are discussed later.

Corticosteroid-induced adrenalsuppression

Production of cortisol from the adrenal cortex is un-

der the control of the hypothalamic–pituitary axis.

Under normal circumstances, the adrenal cortex

produces 25 mg of cortisol per day. If the levels of

this hormone are increased either from an underlying

disease (Addison�s disease) or from exogenous steroid

medication, then a negative-feedback mechanism is

activated. The consequence of this activation is a

reduction in the release of corticotrophin-release

factor from the hypothalamus, which in turn brings

about a reduction in the release of adrenocortico-

trophic hormone. The final outcome is a reduction in

cortisol secretion, and if this is maintained long-term

there will be atrophy of the adrenal cortex. In such an

event, a patient will be unable to respond to any form

of stress, or will show only a poor response, and this

could lead to an adrenocortical crisis. Such a crisis is

characterized by a significant drop in blood pressure,

and if not treated this will lead to cardiovascular

collapse. The extent of atrophy of the adrenal cortex

will be dependent upon the dose, the duration and

the potency of steroid prescribed. An adrenal crisis is

prevented by either increasing the dose of medicated

steroids or by providing supplementary steroids be-

fore the stressful event.

Case reports have identified that the stress ⁄ anxiety

arising from dental treatment can induce an adre-

nocortical crisis in patients on long-term steroid

medication. However, current evidence suggests that

this problem is very much overstated in the dental

setting. Two studies have shown that both organ-

transplant patients and orthopedic patients on long-

term steroids did not require any steroid supple-

mentation before significant surgical interventions

(7, 18). Of more relevance to dentistry is the placebo-

controlled crossover study on organ-transplant pa-

tients who required two episodes of gingival surgery

and therefore acted as their own controls (55). Blood

pressure and pulse-rate measurements were practi-

cally identical throughout the surgical procedure and

for 2 h afterwards when patients received either

50 mg of intravenous hydrocortisone or placebo.

Subsequently, our center has completed well in ex-

cess of 3000 various dental interventions, including

surgery and extractions, on a diverse group of organ-

transplant patients. During this period there has not

been even a single episode of hypotension that would

indicate the onset of an adrenocortical crisis.

We would advocate that all patients on long-term

steroid therapy, irrespective of their underlying med-

ical condition, should have their blood pressure

monitored before, during and for up to 30 min post-

operatively. If the diastolic pressure falls below 60 mm

or more than 25% from baseline then 100 mg of

intravenous hydrocortisone should be administered.

Cyclooxygenase-1 andcyclooxygenase-2 inhibitors

As their name suggests, these drugs inhibit two

important enzymes involved in the inflammatory

cascade. In brief, cyclooxygenase-1 and cyclooxy-

genase-2 act on arachidonic acid to produce the

eicosanoids (prostaglandins, thromboxane and

prostacyclin). The role of the eicosanoids in the

inflammatory cascade is discussed elsewhere in this

volume of Periodontology 2000.

The cyclooxygenase enzyme system is found in two

forms in humans: cyclooxygenase-1 is a constitutive

enzyme that is responsible for the secretion of mu-

cous in the gastrointestinal mucosa; and cyclo-oxy-

genase-2, which is activated by tissue damage, is re-

garded as an inducible enzyme because it is present

only during injury.

For many years, it has been recognized that drugs

such as aspirin and other nonsteroidal anti-inflam-

matory agents inhibit the cyclooxygenase enzyme

system. Such inhibition not only accounts for their

pharmacological properties, but also for their un-

wanted effects, in particular gastrointestinal irritation

and ulceration.

In the late 1990s, both cyclooxygenase-1 and cy-

clooxygenase-2 were identified, which led to the

evolution of a new range of nonsteroidal anti-

201


inflammatory drugs that selectively blocked cyclo-

oxygenase-2 with little or no action on cyclooxygen-

ase-1. Such drugs (known as cyclooxygenase-2

inhibitors) had, in theory, all the efficacy of conven-

tional nonsteroidal anti-inflammatory drugs without

the unwanted effects (17).

Aspirin and nonsteroidalanti-inflammatory drugs

As mentioned previously, aspirin and nonsteroidal

anti-inflammatory drugs inhibit both cyclooxy-

genase-1 and cyclooxygenase-2 enzyme systems. The

pharmacological properties of these agents are dis-

cussed below.

Analgesia

Both aspirin and nonsteroidal anti-inflammatory

drugs are effective analgesics, especially if the pain

has a significant inflammatory component. Targeting

cyclooxygenase-2 reduces the production of prosta-

glandins, especially those of the E series (e.g. pros-

taglandin E2). Such prostaglandins sensitize free

nerve-endings to the nociceptive actions of further

inflammatory mediators, such as bradykinin and

histamine.

Antipyretic

Aspirin and nonsteroidal anti-inflammatory drugs

will reduce body temperature arising from an infec-

tion. Bacterial or viral infections induce the release of

interleukin-1 from macrophages. Interleukin-1 stim-

ulates the generation of prostaglandin E2 in the

hypothalamus, which results in the elevation of body

temperature. Both drugs block prostaglandin E2

synthesis and hence reduce the body temperature.

These drugs have no action on reducing body tem-

perature if it is raised by exercise or ambient heat.

Anti-inflammatory

Again, this action is mediated by the inhibition of

both prostaglandin E2 and prostacyclin. Such inhi-

bition results in less vasodilatation and less edema

formation.

Antiplatelet

The cyclooxygenase-1 action of aspirin alters the

balance between platelet-derived thromboxane A2,

which promotes platelet aggregation, and prostacy-

clin, which inhibits aggregation. This action reduces

both thromboxane A2 synthesis in platelets and

prostacyclin synthesis in endothelial cells. The action

of aspirin on platelets is irreversible and synthesis

does not recover until the platelet population has

been replaced (usually 7–10 days). By contrast, many

nonsteroidal anti-inflammatory drugs are reversible

inhibitors of platelet thromboxane and their action

only lasts for up to 8 h. The antiplatelet action of

aspirin accounts for its widespread use in the pre-

vention of a variety of thromboembolic disorders.

Cyclooxygenase-1 andcyclooxygenase-2 inhibitors andthe periodontium

Animal studies

As with other drugs, evidence for the possible ther-

apeutic use of anti-inflammatory agents on the

periodontium has come from animal studies. For

example, systemic indomethacin has been shown to

reduce the inflammatory responses and also to

inhibit alveolar bone loss in a ligature-induced

periodontitis model in both beagles and squirrel

monkeys (37, 63). Flurbiprofen (both systemic and

in the form of a topical gel) is a further nonsteroidal

anti-inflammatory drug that has been evaluated in

animal studies in the management of periodontal

disease. Whilst there are some inconsistencies in the

findings from these animal studies, this may be

attributed to different dosing regimens of the drug

(38, 65).

Animal models have also provided opportunities to

compare cyclooxygenase-1 and cyclooxygenase-2

inhibitors on periodontal disease progression in rats

(45). Local and systemic administration of the cy-

clooxygenase-2 inhibitor resulted in a significant

reduction in the loss of fiber attachment and alveolar

bone loss in the ligature-induced periodontitis

model. The cyclooxygenase-1 inhibitor had a similar

outcome on fiber loss in this model, but did not

prevent alveolar bone loss. This outcome suggests

that cyclooxygenase-2 inhibitors may have a more

significant application in the control of periodontal

disease than do cyclooxygenase-1 inhibitors.

Clinical studies

An early indication that nonsteroidal anti-inflam-

matory drugs may attenuate periodontal disease

202

Alani & Seymour

progression came from a cross-sectional study of

patients taking these drugs for the control of mus-

culoskeletal disorders (62). Subjects who had been

taking nonsteroidal anti-inflammatory drugs for

12 months or more had less gingival inflammation

and shallower probing pocket depths than did con-

trol subjects. Other studies of similar design have

likewise confirmed the potentially �protective� effect

of nonsteroidal anti-inflammatory drugs on the

periodontium (15, 47, 61). It has also been demon-

strated, in a group of patients with rheumatoid

arthritis taking a range of anti-inflammatory agents,

that their gingival crevicular fluid levels of interleu-

kin-1beta, interleukin-18 and total elastase were sig-

nificantly lower than those of a control group (31, 32).

Again, this study illustrates the effect of such medi-

cation on a range of inflammatory mediators, which

can influence the response of the periodontal tissues

to bacterial plaque.

Animal studies have already demonstrated the

potential benefits of flurbiprofen on the periodon-

tium. The first clinical study evaluated the efficacy of

systemic flurbiprofen (50 mg, twice daily for

24 months) in a cohort of patients suffering from

chronic periodontitis (65). After 12 and 18 months of

medication, those treated with systemic flurbiprofen

exhibited significantly less alveolar bone loss than

those treated with placebo. At 24 months there was

no difference between the groups and this was

attributed to poor compliance.

Various topical (local) preparations of flurbiprofen

have also been investigated in the management of

various aspects of periodontal inflammation. For

example, topical flurbiprofen was applied via an irri-

gation method in an experimental gingivitis model

(23). In this crossover, placebo-controlled trial, the

local irrigation with flurbiprofen had little or no effect

on the development of gingivitis when compared with

the placebo solution. However, this may have been

caused by the systemic absorption of flurbiprofen

from the oral mucosa. A further study incorporated

flurbiprofen into a toothpaste (1% weight by weight)

and the paste was used an adjunct to nonsurgical

management in patients with chronic periodontitis

(22). After 12 months of use, there was some benefit

from the active paste in terms of sites showing bone

gain. However, this benefit was concluded as small.

The advent of the cyclooxygenase-2 inhibitors has

renewed interest in this group of drugs as possible

adjunctive treatment in the management of peri-

odontal disease. For example, systemic dosing with

the cyclooxygenase-2 inhibitor loxoprofen was shown

to be a useful adjunct to nonsurgical treatment in

patients with chronic periodontitis (43). Loxoprofen

was used for 28 days following a course of scaling and

root planing. Those sites exhibiting deeper probing

depths (>7 mm) appeared to benefit more from this

adjunctive treatment than the shallower sites.

This group of nonsteroidal anti-inflammatory

drugs has also been evaluated in the management of

aggressive periodontitis (2). A short course of etoric-

oxib (120 mg per day for 7 days) was shown to pro-

vide no additional benefits when used as an adjunct

to scaling and root planing. However, a reduction in

the levels of prostaglandin E2 in gingival crevicular

fluid was observed. This apparent failure of treatment

may be related to the nature of the periodontal dis-

ease being treated or the short-term course of

adjunctive treatment.

Later in this article the application of omega-3 fatty

acids in the management of periodontal diseases will

be discussed. A study in rats showed that a combi-

nation of a cyclooxygenase-2 inhibitor (celecoxib)

and an omega-3 fatty acid significantly inhibited the

expression of matrix metalloproteinase-8. Further-

more, rats treated with omega-3 only showed an

increase in expression of tissue inhibitor of metallo-

proteinase-1 (59).

A similar combination (low-dose aspirin with a

dietary supplementation of omega-3 fatty acids) has

been utilized as an adjunct to conventional nonsur-

gical management in a group of patients with chronic

periodontitis (12). At 3 and 6 months after scaling

and root planing, patients receiving the adjunctive

therapy showed a significant reduction in probing

pocket depths and attachment gain when compared

with baseline measurements and with the control

group. The application of dual agents to modify the

response of the periodontal tissues to bacterial pla-

que does open up new vistas in the management of

periodontal disease.

Immunosuppressants

Immunosuppressant drugs, as their name suggests,

are a group of compounds that target the immune

system and suppress various aspects of this system.

They have three main indications in medicine:

• to suppress rejection in organ-transplant patients.

• in the treatment of a variety of chronic inflam-

matory conditions, where suppression of the im-

mune response may help to alleviate symptoms.

• in the management of autoimmune diseases.

There are several drugs that can affect the immune

system and which have therapeutic applications.

203


Those in common usage are shown in Table 3,

together with their particular application.

Antiproliferative immunosuppressants

The two main examples of this category of immu-

nosuppressants are azathioprine and mycophenolate

mofetil.

Azathioprine

Azathioprine is a purine derivative that is not directly

an immunosuppressant, but can be considered as a

prodrug. Azathioprine is first metabolized to 6-mer-

captopurine and further metabolized by the enzyme

thiopurine methyltransferase to the pharmacologi-

cally active 6-thioguanine nucleotide. The latter

suppresses the immune system by inhibiting DNA

synthesis in lymphocytes.

The most common route of administration of

azathioprine is the oral route and the normal dose for

suppression of transplant rejection is 1–5 mg ⁄ kg of

body weight. For autoimmune conditions, the dosage

is slightly lower (1–3 mg ⁄ kg). An intravenous prep-

aration of azathioprine exists; however, this is an

alkaline solution and is irritable to the vasculature

and therefore this preparation is only considered if

the patient is unable to take the drug by mouth.

Unwanted effects. Azathioprine has a range of un-

wanted effects. Of particular concern to the dental

team is the increased susceptibility to infections,

especially opportunistic infections, and bone marrow

suppression. The latter could have significant oral

manifestations or produce lesions on exposed skin,

which could be easily identified. A drug-induced

depression of platelets could lead to petechial hem-

orrhages and also to profuse bleeding from the gin-

gival tissues, especially upon any form of gingival

manipulation. A reduction in the white cell count will

increase the risk of oral ulceration and periodontal

breakdown. There is a cohort of patients who are

particularly susceptible to azathioprine-induced

myelosuppression and such individuals manifest

thiopurine methyltransferase deficiency. Ideally, all

patients medicated with azathioprine should have

their thiopurine methyltransferase activity assessed

before dosing. Azathioprine-induced myelosuppres-

sion is most likely to manifest in the early stages of

treatment and is managed by reducing the dose.

Mycophenolate mofetil

As with azathioprine, mycophenolate mofetil is con-

sidered a prodrug and is hydrolyzed to mycophenolic

acid. Mycophenolic acid reduces both B- and T-cell

proliferation by inhibiting the production of guanine

nucleotide. As both T- and B-cells are inhibited, it has

been suggested that mycophenolate mofetil may be

effective against both acute and chronic organ

rejection (21).

Mycophenolate mofetil is available as an oral

preparation, and a dosage of 1–1.5 g, twice daily, is

used to prevent rejection in organ-transplant patients.

An intravenous preparation is available and this is

mainly used in the early stages of liver transplantation.

As with azathioprine, the most significant un-

wanted effect of mycophenolate mofetil is myelo-

suppression. Platelets seem to be particularly

sensitive to mycophenolate mofetil and the sub-

sequent thrombocytopenia will have an oral mani-

festation that has been described previously. Patients

on this drug will undergo regular hematological

screening and if any form of periodontal surgery is

planned then a blood test should be requested before

the procedure, with specific attention given to the

platelet count. Mycophenolate mofetil is also asso-

ciated with a high prevalence of gastrointestinal

Table 3. List of immunosuppressants used in medical practice and their indications

Immunosuppressant Indication

Azathioprine Transplant patients, inflammatory bowel disease, rheumatoid arthritis, severe refractory

eczema

Mycophenolate mofetil Prophylaxis of acute renal, hepatic and cardiac transplant rejection

Prednisolone Prevention of graft rejection

Cyclosporine Prevention of graft rejection, treatment of graft-vs.-host disease, severe ulcerative colitis,

rheumatoid arthritis, severe skin disorders

Sirolimus Prophylaxis of organ rejection in kidney allograft recipients

Tacrolimus Prophylaxis of organ graft rejection in liver, kidney and heart allograft recipients and for

allograft rejection resistant to conventional immunosuppressant regimens, moderate to

severe eczema

204

Alani & Seymour

problems, especially vomiting. This can readily lead

to dental erosion, and preventative measures need to

be put into place to avoid the outcome of this

unwanted effect.

Calcineurin inhibitors

Calcineurin is a protein phophatase that activates

T-cells of the immune system. It is the target of drugs

such as cyclosporine and tacrolimus.

Cyclosporine

Cyclosporine has had a dramatic effect on patients

undergoing organ-transplant surgery, on subsequent

graft survival and on quality of life. The main mode of

action of cyclosporine is its selective inhibitory effect

on transcription of the interleukin-2 gene. As a con-

sequence of this action, there is decreased clonal

proliferation of T-cells, reduced induction of, and

clonal proliferation of, cytotoxic cells from CD8+

precursor T-cells, reduced function of the effector T-

cells and some reduction in T-cell-dependent B-cell

responses.

From the periodontal perspective, the main inter-

est in cyclosporine is the unwanted effect of gingival

overgrowth. This was first reported in the early 1980s

and has been the subject of extensive research. The

topic of drug-induced gingival overgrowth has been

covered in a previous volume of Periodontology 2000

and the reader is referred to this article (52). Other

unwanted effects of cyclosporine include nephro-

toxicity, hypertension and an increased risk of skin

malignancies.

Tacrolimus

Tacrolimus is a macrolide antibiotic that also inhibits

calcineurin. It is more potent than cyclosporine, and

is now replacing cyclosporine as the treatment of

choice to prevent graft rejection in organ transplan-

tation. Unwanted effects of tacrolimus include

gastrointestinal disturbances, hypertension, nephro-

toxicity and metabolic disturbances.

Immunosuppressants and theperiodontium

Before the advent of cyclosporine, there was an

interest on the effect of immunosuppressant therapy

on the periodontal tissues and their response to

plaque. These early studies, in the 1970s and 1980s,

showed that patients on long-term immunosup-

pressants (usually azathioprine and prednisolone)

were afforded some degree of �protection� against

periodontal breakdown. The more selective immu-

nosuppressants (cyclosporine and tacrolimus) may

not afford the same degree of protection against

periodontal breakdown. However, with cyclosporine,

the unwanted effect of gingival overgrowth will in-

hibit plaque removal and thus create a somewhat

different environment for periodontal disease.

Animal studies have suggested that cyclosporine

can have an adverse effect on alveolar bone homeo-

stasis, resulting in increased osteoclasia and a de-

crease in bone formation (19). The mechanism of

such bone loss is unclear, but it may be mediated by

cyclosporine attenuating some aspect of the inflam-

matory response, which can lead to osteoclast acti-

vation. Whilst this adverse effect has not been widely

recognized in human studies, it has been subse-

quently demonstrated that simvastatin therapy will

significantly reduce cyclosporine-induced alveolar

bone loss in rats (34). The beneficial effects of sim-

vastatin in this model may be mediated by down-

regulation of interleukin-1beta and prostaglandin E2

production.

As with other categories of systemic medication,

there is little or no therapeutic indication for the use

of immunosuppressants in the management of peri-

odontal disease. As with other anti-inflammatory

agents, the main interest in these drugs is what their

pharmacodynamics can tell us about the pathogen-

esis of periodontal disease and periodontal break-

down. Their unwanted effects would exclude any

indication for their use in the management of peri-

odontal disease.

Cytokine modulators

A variety of drugs have now been licenced under this

category (for example, adalimumab, etranercept and

infliximab) for the management of rheumatoid

arthritis and other immune-modulated diseases.

These drugs inhibit the activity of tumor necrosis fac-

tor-a, which is now recognized as an important cyto-

kine in the pathogenesis of periodontal breakdown.

Animal studies have shown that the systemic

administration of recombinant interleukin-11 re-

duced bone loss in a dog model of periodontitis (30),

and etanercept reduced inflammation, tissue injury

and neutrophil infiltration in a rat model of experi-

mental periodontitis (10). Clinical evidence for a

205


possible periodontal benefit of these drugs has come

from investigations of the periodontal status of co-

horts of patients who are receiving such medication

for the management of their rheumatoid arthritis. An

initial study showed that inflxiimab tended to exac-

erbate gingival inflammation in the presence of

existing periodontitis, but paradoxically, these pa-

tients had less attachment loss when compared with

controls (41). The authors suggested that tumor

necrosis factor-a blockade could be beneficial in the

treatment of periodontitis. Other studies of similar

design have confirmed the benefit of tumor necrosis

factor-a blockade in patients with rheumatoid

arthritis who also suffer from periodontitis (30, 39).

Whilst such findings tell us more about the role of

tumor necrosis factor-a in the pathogenesis of peri-

odontal breakdown, it is unlikely, owing to their ad-

verse-effect profile, that the systemic administration

of such drugs would ever have a role in the man-

agement of periodontal disease. Side effects from

these drugs include an increased risk of infection,

gastrointestinal complaints and bone marrow sup-

pression. As with nonsteroidal anti-inflammatory

drugs, a topical or local-delivery application may be

of benefit.

Bisphosphonates

Bisphosphonates are pyrophosphate analogs that

have a common phosphorous-carbon-phosphorous

chemical core. Their potency is partly related to the

existence of a nitrogen side chain. Parenteral and oral

preparations are available with differing potencies.

These drugs have a major impact upon bone

turnover. In brief, they inhibit the digestion of bone

by encouraging osteoclasts to undergo apoptosis or

cell death, thereby slowing bone loss. Bisphospho-

nates are widely used in the management of osteo-

porosis, in Paget�s disease and in the treatment

of secondary bone cancer arising from malignant

disease.

The non-nitrogen bisphosphonates are metabo-

lized in the cell to compounds that replace the ter-

minal pyrophosphate moiety of adenosine triphos-

phate, forming a nonfunctional molecule that

competes with adenosine triphosphate in cellular

energy metabolism. The osteoclast initiates apoptosis

and this leads to an overall decrease in the break-

down of bone (16). Nitrogenous bisphosphonates act

on bone metabolism by binding and blocking the

enzyme farnesyl disphosphate synthetase in the hy-

droxymethylglutaryl-coenzyme-A reductase pathway.

Blockage of this pathway inhibits a process known as

protein prenylation, which may affect proteins in

osteoclasts, leading to osteoclast death (57).

Bisphosphonates and the periodontium

The mode of action of the bisphosphonates indicates

that they may be of benefit in the management of

periodontal disease, especially with an impact on

rates of alveolar bone loss. Initial studies, which were

reviewed by Rocha et al. (49), showed a degree of

promise, with patients on bisphosphonate therapy

exhibiting significantly less alveolar bone loss com-

pared with nonmedicated controls. However, a sub-

sequent systematic review concluded �no meaningful

conclusion can be reached about the benefits of

bisphosphonates in the management of periodontal

disease� (46).

A more recent study (25), of 335 patients who were

medicated with either alendronate or placebo,

showed that there were no differences in alveolar

bone levels after 2 years of medication. It would

therefore seem that the benefits of systemic admin-

istration of bisphosphonates in preventing alveolar

bone loss or as an adjunct to periodontal therapy are

somewhat limited. More significant, however, are the

unwanted effects of these drugs, such as inflamma-

tion and erosion of the esophagus, and more

importantly, in dental practice, the risk of osteone-

crosis of the jaws. There have been several profes-

sional guidelines issued on the prevention and

management of bisphosphonate-induced osteone-

crosis of the jaws, and readers are referred to these

regarding management of their own patients. These

guidelines have also been reviewed and again readers

may find the article of interest (40).

Statins

Statins are a group of drugs used to decrease lipid

levels by inhibiting the enzyme hydroxymethylgluta-

ryl-coenzyme-A reductase, which plays a role in the

production of cholesterol in the liver. A raised cho-

lesterol level has been associated with cardiovascular

diseases, and statins are therefore utilized in the

prevention of this group of conditions. The mode of

action by which statins achieve this is thought to be

multifactorial, one of which is modulation of the

inflammatory response (54, 56, 64). In addition to

their primary mode of decreasing lipid levels, statins

modulate bone metabolism and decrease T-cell

activation. Statins may directly stimulate the

206

Alani & Seymour

expression of bone morphogenetic protein-2 and

increase osteoblast differentiation. There is also some

evidence that they inhibit osteoclast activity and

osteoblast apoptosis (20, 33).

This ability to have a positive effect on the

inflammatory cascade as well as an anabolic effect on

bone formation has been investigated for its effects

on the periodontium and supporting tissues. Seto

et al. (51) examined the topical effect of simvastatin

on alveolar bone recovery in rodents. This study

illustrated the ability of topical simvastatin to recover

ligature-induced bone loss (51). They illustrated the

maintenance of high levels of alkaline phosphatase

and increased bone-nodule formation. It was shown

that this effect was dose dependent and was also

linked to high levels of osteoblastic activity (51). In-

deed, topically applied statins have also shown po-

tential in reducing periodontal tissue breakdown in

rats when compared with controls, although this was

not found to be statistically significant (60).

Retrospective studies examining the effect of sta-

tins in human cohorts have shown some positive

results. Lindy et al. (28) examined 100 (three of whom

did not meet the inclusion criteria) consecutive

chronic periodontitis patients of whom 21 were tak-

ing statin medication. They found that patients on

statin medication were less likely to present with

moderate (4–6 mm) or advanced (>6 mm) peri-

odontal pocket depths than were those who were not

medicated. The authors felt that this decrease in

periodontal inflammation was attributed to the anti-

inflammatory pleiotropic effect of statins. In a retro-

spective study examining 1021 patients, statin use

was attributed to a decreased rate of tooth loss in

patients with chronic periodontitis, although this was

nonsignificant (9). The authors highlighted the diffi-

culties in examining this patient cohort owing to the

confounding variables with which statin users may

present, including smoking and diabetes (9). In

contrast, a retrospective study of 12,631 patients

diagnosed with chronic periodontal disease found

that statin use was associated with increased tooth

loss. Once the results were adjusted for potential

confounders, there was no decreased or increased

association for tooth loss in statin users (50). The

authors felt that a large-scale, long-term, randomized

controlled trial would be required to provide more

definitive evidence about the possible relationship

between statin use and the course of periodontal

disease (50). A subsequent randomized controlled

double-blind study of 38 patients with chronic peri-

odontitis investigated the effect of atrovastatin (14).

Patients were given either a placebo or 20 mg of

atrovastatin, daily, for 3 months, mechanical

periodontal treatment was instigated at baseline and

patients were reviewed for indices at 3 months (14).

Despite improvements in the majority of parameters

in both cohorts, significant improvements in the test

group were only detected in mobility and in the

distance between the crestal alveolar bone level and

the cemento–enamel junction (14). It would seem

pertinent that further investigation into the effect of

statin medication on periodontal tissues is required.

Omega 3

Fish oil is a main source of omega-3 fatty acids, where

the major polyunsaturated fatty-acid components are

eicosapentaenoic acid and docohexaenoic acid. As

mentioned previously, cyclooxygenase-2 inhibitors

reduce inflammation by preventing the synthesis of

arachidonic acid metabolites via the cyclooxygenase-

2 pathway. Eicosapentaenoic acid and docohexaenoic

acid compete with arachidonic acid for the cycloox-

ygenase and lipoxygenase pathways, which result in

the reduced synthesis of highly active arachidonic-

acid metabolites. As a result of this ability to reduce

the synthesis of arachidonic-acid metabolites, omega-

3 has anti-inflammatory, antithrombotic and vaso-

dilator effects. Indeed, Alam and co-workers (1)

demonstrated reductions in the levels of arachidonic

acid, prostaglandin E2 and leukotrienes in the gingival

tissue of rats given a diet rich in omega-3. Similar re-

sults were found in humans with experimental gingi-

vitis (8). Animal studies examining the effects of

omega-3 on experimental periodontitis showed a

reduction in the levels of arachidonic-acid metabo-

lites in gingival tissues compared with those in healthy

tissue (58). When rats were infected with Porphyro-

monas gingivalis, those fed omega-3 fish oil showed

decreased levels of proinflammatory mediators in the

gingival tissues (26). This observation was supported

by the finding that experimental omega-3-fed groups

of rats had less alveolar bone loss than controls when

infected with periodontal pathogens (3).

More recent evidence shows favorable responses in

humans. A recent clinical study of 80 patients re-

vealed interesting results. The control group was

treated with scaling and root planing and a placebo,

whereas the experimental group had the placebo

substituted for fish oil and aspirin, daily, for 26 weeks

(12). Significant reduction in pocket depths and

attachment gain were recorded after 3 and 6 months

(12). These results were mirrored when evaluating

clinical parameters for Class II furcation defects

207


treated with decalcified freeze-dried bone allograft.

One group received a placebo whilst the other re-

ceived aspirin and fish oil on a daily basis for

6 months after the regenerative procedure (11). The

experimental group showed reduced levels of proin-

flammatory mediators, reduction of pocket depth

and attachment-level gain (11).

Conclusions

This review has primarily focused on those drugs that

affect the inflammatory cascade and on the impact, if

any of such medication on plaque-induced inflam-

mation of the periodontal tissues and disease pro-

gression. For the most part, some categories of drugs

do affect periodontal disease progression and can

afford the patient some degree of �protection� against

periodontal breakdown. This information has led to

various developments to explore whether such drugs

could have a therapeutic indication in the manage-

ment of periodontal disease. Apart from host-mod-

ulating agents, the only group that has received

serious development is the group of nonsteroidal

anti-inflammatory drugs. Of these agents, the selec-

tive cyclooxygenase-2 inhibitors appear to offer the

most promise in terms of adjunctive benefit.

A new indication for a drug to manage periodontal

disease should include a balance between any po-

tential benefit of the drug vs. its adverse-effect pro-

file. What is clear for many of the agents discussed

are their unwanted effects, which may outweigh any

periodontal benefit. This should not rule out any

particular drug for future development. However, it is

the unique anatomy of periodontal destruction that

could perhaps open a way forward for further

development. Local or controlled drug delivery does

especially lend itself to the periodontal situation. This

mode of therapy has been dominated by antimicro-

bial agents. Perhaps a way forward is to utilize some

of the drugs cited in a local delivery model. This does

offer exciting opportunities for the future manage-

ment of periodontal diseases.

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