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Table22.1 Classification ofadverse drug reactions.
Type of reaction Features Examples
A: Dose- related
(Augmented)
● Common
● Related to the pharmacological action of
the drug
● Predictable
● Low mortality
B: Non- dose- related
(Bizarre)
● Uncommon
● Not related to the pharmacological action
of the drug
● Unpredictable
● High mortality
C: Dose- related and
time- related (Chronic)
D: Time- related
(Delayed)
● Uncommon
● Related to the cumulative dose
● Uncommon
● Usually dose- related
● Occurs or becomes apparent sometime
after the use of the drug
E: Withdrawal
(Endofuse)
F: Unexpected failure
of therapy (Failure)
● Uncommon
● Occurs soon after withdrawal of the drug
● Common
● Dose- related
● Often caused by drug interactions
Source: Adapted from Edwards etal.(2).
Anticholinergic effects of
tricyclic antidepressants
Penicillin hypersensitivity
HPA axis suppression by
corticosteroids
Carcinogenesis
Opiate withdrawal syndrome
Parasympathetic control is coordinated by the salivary nuclei in the medulla. Signalling is via efferent fibres of chorda tympani (CN VII) to the sublingual and submandibular glands and the glossopharyngeal (CN IX), auriculotemporal (CN V) and facial (CN VII) nerves. Parasympathetic nerve
fibres from the mandibular, lingual and palatine nerves (CN V) innervate the minor salivary glands.
In the presence of food, the parasympathetic nervous system is stimulated via afferent signalling from the tongue, mouth and nose. Parasympathetic stimulation results in acetylcholine
(ACh) release onto M3muscarinic receptors resulting in increased saliva secretion by the acinar cells; increased bicarbonate secretion by the ductal cells; increased blood flow to salivary
glands secondary to co- transmitter release; and increased rate of saliva expulsion due to contraction of myoepithelial cells. The overall effect is an increased saliva flow, with a watery
composition(4).
The innervation of major salivary glands is depicted in Figure22.1.
22.2.2 Salivary Gland Hypofunction
Oral dryness, or salivary gland hypofunction, is the most commonly reported oral ADR(5). It is
associated with over 500 drugs, with patients taking multiple medications (polypharmacy)
most commonly affected. In this setting, the effect is synergistic and the dryness is often
severe(5).
t.me/Dr_Mouayyad_AlbtousH
22.2 Salivary Gland Involvement
Brain stem
Sublingual gland
Submandibular gland
Th
SSN
379
Parotid gland
C1
C3
ISN
OG
SCG
ACh
NPY
Chorda T.
ACh
VIP
VII
IX
Auriculotemporal N.
Lingual N.
V
ACh
VIP
SP
CGRP
NA
NPY
Parasympathetic fibres
T1
G
ACh
NPY
Carotid
plexus
SG
ACh
VIP
Facial artery
Sympathetic fibres
NA
NPY
ACh
VIP
SP
CGRP
NA
NPY
ACh
VIP
SP
CGRP
Figure22.1 Model of parasympathetic and sympathetic innervation of the adult major salivary glands (in
red and blue, respectively). Neurotransmitters for parasympathetic (red) and sympathetic fibres (blue): ACh,
acetylcholine; NpY, neuropeptide Y; vip, vasoactive intestinal peptide; NA, noradrenaline; Sp, substance p;
cGRp, calcitonin gene- related peptide. Brain stem nuclei: SSN, superior salivatory nuclei; iSN, inferior
salivatory nuclei. Ganglia: ThG, thoracic ganglion; ScG, superior cervical ganglion; OG, otic ganglion; SG,
submandibular ganglion. Spinal cord: c, cervical vertebra; T, thoracic vertebra. Cranial nerves: vii, facial
nerve; iX, glossopharyngeal nerve; v, trigeminal nerve. Source: João N Ferreira etal. (2013)/Taylor & Francis
Group/CC BY- NC 3.0.
There are various mechanisms for drug- related salivary hypofunction, which are as follows(6):
● Many drugs have an anticholinergic or sympathomimetic effect
● Direct damage to salivary gland tissue may occur from the use of cytotoxic agents
● Various drugs cause vasoconstriction of vessels within the salivary glands
● Drugs with a diuretic effect encourage excretion of body fluid and dehydration
The release of ACh from the postganglionic neurons in the parasympathetic (or cholinergic)
nervous system and the resultant binding of muscarinic receptors in the salivary glands form the
main stimulus for saliva secretion. Medications that directly block the binding of ACh to muscarinic receptors will compromise the secretion of saliva. These drugs are broadly categorised as
anticholinergic medications and include tricyclic antidepressants, antipsychotics, anticonvulsants
and bronchodilators.
Many of these drugs exert unwanted effects due to the nonselective antagonism of the muscarinic receptors.
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380
Table22.2 Drug commonly associated withoral dryness.
Medication type Mechanism of action
Gastrointestinal agents,e.g. hyoscine and atropine Block muscarinic receptors
Antiemetics,e.g. prochlorperazine Block dopamine D2, serotonin types 2–4,
histamine type 1 and acetylcholine receptors
Appetite suppressants/stimulants,e.g. phentermine and
sibutramine
Cardiovascular agents,e.g. atenolol, metoprolol, prazosin
Inhibit CNS uptake of norepinephrine,
serotonin and dopamine
Block α
- and β2- adrenergic receptors
1
and clonidine
Urological,e.g. oxybutynin, propantheline, darifenacin,
Block muscarinic receptors and α
solifenacin and tolterodine
Muscle relaxants,e.g. cyclobenzaprine and orphenadrine Act as α
- adrenergic receptor agonists, and
1
H2 histamine blockers
Analgesics,e.g. opioids, tramadol, gabapentin and
pregabalin
Block noradrenaline reuptake in the CNS,
thus inhibiting the salivary reflex
Anticonvulsants,e.g. carbamazepine Act centrally, reduce neurotransmitter release
Sedatives– benzodiazepines and Z- drugs,e.g. zolpidem Enhance GABA effect in CNS, reduce the
salivary secretory reflex, block muscarinic,
α
- and β2- adrenergic receptors
1
Antipsychotics,e.g. olanzapine, clozapine and
Block various neurotransmitter uptake
amisulpiride
Antidepressants,e.g. tricyclics, SSRIs and SNRIs Anticholinergic action; increase serotonin
and noradrenaline at the synaptic cleft.
Bronchodilators,e.g. ipratropium, tiotropium,
salbutamol, salmeterol and eformoterol
Antihistamines (with sedative action), e.g.
diphenhydramine, doxylamine, chlorpheniramine and
2 types: β agonists and antimuscarinic, Block
muscarinic receptors M1 and M3
Central inhibitory action on histamine type 1
and muscarinic receptors
promethazine
CNS stimulants, e.g. caffeine, pseudoephedrine and
α
and α2 agonists
1
amphetamines
- adrenergic
1
Source: Adapted from Villa etal.(6).
Sympathomimetic drugs mimic responses due to stimulation of sympathetic nerves. These
drugs either directly activate adrenergic receptors or indirectly activate them by increasing levels
of the mediators of the sympathetic nervous system, norepinephrine and epinephrine. One of the
main effects of this is a decrease in salivary acinar cell activity and a resultant decrease in saliva
production. Common sympathomimetic drugs that cause salivary hypofunction include selective
serotonin reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors and many
antihypertensives.
Drugs commonly associated with oral dryness are listed in Table22.2.
22.2.2.1 Clinical Presentation
Signs of salivary gland hypofunction include the presence of thick or frothy, sticky saliva; minimal
saliva pooling in the floor of mouth and poor tissue wetting; and atrophy and irritation of the oral
mucosa. Patients may also present with angular cheilosis, dry cracked lips and erythema and
t.me/Dr_Mouayyad_AlbtousH
22.2 Salivary Gland Involvement
depapillation of the tongue. Patients commonly comment on difficulties with speech, swallowing
and eating, with the need to frequently sip water to lubricate the mouth, taste alterations and
halitosis. Denture wearing is very uncomfortable for those with a dry mouth. Additionally, patients
will often develop a burning sensation of the oral mucosa, which may become fragile and easily
traumatised. Salivary gland hypofunction results in a shift in the oral microbiome, often predisposing patients to accelerated dental caries in an atypical pattern commonly affecting smooth surfaces
and incisal edges, periodontal disease and opportunistic infections such as candidosis. Some
patients can also develop ascending sialadenitis of the parotid gland, secondary to stasis and
reduced flushing of the ductal system.
22.2.2.2 Management andPrognosis
Patient education is the key first step in the management of oral dryness. Understanding of the
disease process, drugs implicated and also the sequelae to long- standing salivary gland hypofunction is important.
Identification of drugs which may be xerogenic and consideration of suitable substitutes may be
discussed with the patient’s medical practitioner. Avoidance of dehydrating stimuli such as alcohol
and caffeine should also be discussed.
Objective measures of stimulated and unstimulated salivary flow, together with salivary pH and
buffering capacity, may be helpful in some situations, although not always necessary.
Various over- the- counter oral lubricants in the form of gels and sprays may be helpful to patients
with dry mouth. These moisturise the oral mucosa and provide comfort. Appropriate hydration
should be encouraged.
Additionally, stimulation of existing functional glandular tissue may be achieved with the use of
sugar- free gum and sweets. Muscarinic sialogogues such as pilocarpine and cevimeline may be
prescribed and are effective in increasing saliva flow in a dose- dependent relationship(7). Patients
should be informed of the potential side effects of these drugs. Acupuncture as well as electric
stimulation with handheld devices may also be helpful, although the results are not well
documented(8).
Patients with a dry mouth should be referred to their dentist for regular preventative visits. Use
of high fluoride- containing dental products at home, as well as application of remineralising
agents, will aid in protecting the dentition. Any opportunistic infection should be treated as
appropriate.
Drug- related dry mouth is generally reversible once the offending drug is withdrawn. In
many cases, patients are reliant on medication to manage their medical condition, and so
alleviation of the oral dryness together with management of any oral sequelae is often the
long- term plan.
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22.2.3 Sialorrhoea
Sialorrhoea is an uncommon ADR(9). An increase in saliva amount or flow rate can occur as a
result of some parasympathetic and cholinergic drugs amongst others. Patients often complain of
drooling and the need to constantly swallow copious amounts of saliva.
Parasympathomimetic drugs such as direct muscarinic agonists induce sialorrhoea by increasing cholinergic tone(4). An example of this class of drug is pilocarpine, used to treat wide- angle
glaucoma. An adverse effect of pilocarpine is excess saliva production, and this medication is
commonly prescribed in the management of dry mouth.
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382
Table22.3 Drugs associated withsialorrhoea.
Direct cholinergic/muscarinic agonists Bethanechol, pilocarpine, arecoline and cevimeline
Indirect cholinergic/muscarinic
agonists (acetylcholinesterase
inhibitors)
Antipsychotics Typical (first generation) antipsychotics:
Sedative medications Anticonvulsants- antiepilepticsBenzodiazepines
Adrenergic antagonists (peripheral) Yohimbine
Medications irritating the oesophagus Doxycycline, tetracycline, iron preparations, quinidine,
Poisons and toxins Heavy metals: arsenic, manganese, mercury and
Source: Miranda- Rius etal.(10)/Ivyspring International Publisher/CC BY- NC 4.0.
Edrophonium, neostigmine, physostigmine, pyridostigmine,
metrifonate, donepezil, galantamine, rivastigmine and tacrine
e.g. haloperidol and fluphenazineAtypical (second generation)
antipsychotics:
e.g. clozapine, risperidone, olanzapineReserpine
potassium and non- steroidal anti- inflammatory drugs
thalliumOrganophosphates: insecticides, nerve gases
Illicit drugs: phencyclidine
Indirect muscarinic stimulants generally inhibit the enzyme acetylcholinesterase. These
drugsincrease ACh release, thus stimulating muscarinic and nicotinic receptors, resulting in sialorrhoea. Many of the drugs used to manage Alzheimer’s disease, such as donepezil and galantamine, are known to cause excessive saliva production(10).
Management of drug- induced sialorrhoea is usually symptomatic. Withdrawal of the offending
medication usually results in reversal of the drooling. Some consideration has been given to
reduce the amount of saliva produced to facilitate the patient swallowing it, and several
anticholinergic medications such as scopolamine, benztropine and glycopyrrolate have been
recommended (4, 11, 12). The use of transdermal scopolamine by application of skin patches,
clonidine patches to increase adrenergic tone(13), and botulinum- A injections into the parotid
gland(14) have been suggested as management options in severe cases.
Drugs known to cause sialorrhoea are listed in Table22.3.
22.2.4 Enlargement ofSalivary Glands
Salivary gland enlargement, particularly the parotid glands, has been associated with several medications including iodine- containing drugs such as imaging contrast medium and radioactive
iodine (commonly referred to as ‘iodine mumps’)(15). The enlargement is usually bilateral and
may be of sudden or insidious onset, and on occasions, may be painful. The enlargement usually
subsides after drug cessation.
The pathophysiology of unclear, although is it thought that the presentation results from acute
inflammation due to iodine accumulation in the salivary glands. Administered iodine is mostly
eliminated by the kidney, with only 2% of iodine secreted by the salivary and lacrimal glands. In
patients with impaired renal function, accumulation of iodine within the salivary glands is thought
to be the reason for salivary glands swelling(15).
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22.3 Oral Soft Tissue Involvement
22.3.1 Oral Lichenoid Drug Reactions
Oral lichenoid drug reactions occur uncommonly and are clinically and histologically similar to
oral lichen planus. Oral lichenoid drug reactions are often distinguished by the relationship
between commencing a specific drug and the appearance of oral lesions(16). This timeframe may
vary but averages two to three months(17). Resolution is often noted when the drug is withdrawn.
Drugs most commonly associated with oral lichenoid drug reactions (Table22.4) include antihypertensives (particularly angiotensin- converting enzyme inhibitors [ACEI], and beta blockers),
sulphonamides, penicillamine, non- steroidal anti- inflammatories, antimalarials and some antiretroviral medications.
The aetiopathogenesis of oral lichenoid drug reactions is unknown. There are several mechanisms proposed, including alterations in the route of antigen presentation. For example, penicillamine has been shown to modify surface antigens, and the sulfhydryl groups in captopril cause
alterations to enzyme systems. It is thought that these changes may precipitate an immune
response to epithelial antigens, resulting in the presentation noted clinically. Despite these findings, the exact mechanism by which oral lichenoid drug reactions occur remains unclear(18).
Clinical features range from asymptomatic white striations, plaques and papules to painful erythematous and ulcerative lesions affecting the oral mucosa(16).
Management entails identification and withdrawal of the offending drug if possible, consideration of pharmacological therapy to palliate symptoms and manage inflammation with topical and
systemic corticosteroids and other immunomodulatory medications commonly prescribed. Oral
lichenoid lesions are considered a potentially malignant disorder, and patient education as well as
vigilant follow- up are indicated(17, 19, 20).
383
22.3.2 Erythema Multiforme (EM), Steven- Johnson Syndrome (SJS) and Toxic
Epidermal Necrolysis (TEN)
Erythema multiforme (EM) is a type IV (delayed type) hypersensitivity reaction that may have
cutaneous and mucosal involvement(21). In less than 10% of cases, this reaction is drug- induced,
with non- steroidal anti- inflammatories, sulphonamides, several antibiotics and anticonvulsants
commonly implicated amongst others (Table22.5)(22, 23).
Drug- induced EM expresses tumour necrosis factor- alpha (TNF- α), instead of interferon- gamma
in the case of herpes- associated EM. Drug metabolism is altered and directed towards cytochrome
Table22.4 Drugs associated withoral lichenoid reactions.
Antihypertensive drugs Atenolol, captopril, enalapril, oxprenolol and methyldopa
Immunosuppressants/
immunomodulatory drugs
Non- steroid anti- inflammatory
drugs
Other Carbamazepine, chloroquine, clopidogrel, duloxetine, glimepiride,
Source: Teoh etal.(16)/with permisison of John Wiley & Sons.
Adalimumab, imatinib, infliximab and interferon α
Indomethacin, naproxen
hepatitis B vaccine, lithium, penicillamine, ribavirin, risperidone and
secukinumab
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384
Table22.5 Drug implicated inEM, SJS andTEN.
Commonly
associated
Occasionally
associated
Source: Adapted from Farthing etal.(21).
Allopurinol, carbamazepine, NSAIDS, penicillin, phenytoin and sulphonamides
Busulphan, chlorpropamide, clindamycin, codeine, ethambutol, furosemide, gold,
minoxidil, oestrogens, phenothiazines, phenylbutazone, progestogens, protease
inhibitors, rifampicin, tetracycline, tolbutamide, vancomycin and verapamil
p450- metabolite pathway resulting in the production of reactive and toxic metabolites. Tissue
damage is mainly due to apoptosis and not by inflammatory response(23, 24).
Clinically, oral involvement appears a papular or macular areas of erythema, fluid- filled vesicles,
erosions and ulceration of any mucosal surface, although the gingiva is usually spared. Extensive
lip ulceration and haemorrhagic crusting are common. Patients may also present with targetoid
lesions on the skin, particularly on the extremities. Oral and perioral pain is common, and many
patients have difficulty with oral intake during the acute phase.
Acute illness is often accompanied by fever, flu- like symptoms and malaise. Recovery is usually
within two to six weeks, with some patients requiring systemic corticosteroids and nutritional
support.
Steven- Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) may also be induced by
certain medications and present with oral features similar to EM. These conditions may have more
extensive cutaneous involvement and severe systemic symptoms(25–27).
22.3.3 Drug- Induced Pemphigus
Pemphigus is a group of chronic autoimmune diseases characterised by intra- epithelial blistering,
resulting in superficial vesicles or bullae that easily rupture, leading to ulceration of mucosal and/
or cutaneous sites. Lesions result from autoantibody binding to specific desmosomal proteins on
the surface of the keratinocytes, resulting in loss of cell–cell adhesion, termed acantholysis(28).
Drug- induced pemphigus is well described in the literature (29), and associated drugs are
grouped into three classes: thiols, phenols and non- thiols/non- phenols. The exact pathogenesis
remains unclear, although studies have proposed several mechanisms which may account for the
acantholysis(30, 31).
The sulfhydryl group in thiol drugs acts directly by biochemical modification of the antigens,
leading to inhibition of aggregative enzymes of keratinocytes. This activates acantholytic enzymes
and interferes with cell adhesion due to a thiol–cysteine bond formation rather than a cysteine–
cysteine bond between cells. Acantholysis occurs in the absence of an autoimmune response.
Additionally, the active thiol group may also bind to desmosomal proteins, producing an immunogenic stimulus for autoantibody formation(28).
Phenol drugs stimulate keratinocytes to release proinflammatory cytokines, such as TNF- α and
interleukin (IL)- 1, causing acantholysis via a different mechanism. These cytokines are also
responsible for regulation and synthesis of complement and proteases which are implicated in the
process of acantholysis(32).
Non- thiol/non- phenol drugs trigger intra- epithelial blistering in a variety of ways. Some stimulate the formation of autoantibodies, while others cause alterations and overexpression of keratinocyte target autoantigens. Some drugs potentiate an immune response by facilitating the release of
plasminogen activators by keratinocytes(32).
t.me/Dr_Mouayyad_AlbtousH
Table22.6 Drugs commonly associated withpemphigus.
Ampicillin Oxyphenbutazone
Arsenic Penicillamine
Benzylpenicillin Phenobarbital
Captopril Phenylbutazone
Cefadroxil Piroxicam
Cephalexin Probenecid
Diclofenac Procaine penicillin
Gold Propranolol
Interferon α Rifampicin
Interleukin- 2
Source: Scully etal.(33)/with permission of International &
American Associations for Dental Research.
Clinically, drug- induced oral pemphigus presents as fluid- filled vesicles and bullae that
rupture quickly to form painful shallow ulcers. Drugs most commonly associated with this
reaction are listed in Table22.6. Elimination of the offending drug will result in resolution of
thecondition.
385
22.3.4 Drug- Induced Pemphigoid
Bullous pemphigoid is the most common autoimmune vesiculobullous disease characterised by
subepithelial blistering. These lesions eventually rupture and leave areas of ulceration. The condition commonly affects the skin, although mucosal involvement may also occur.
The pathophysiology of drug- induced pemphigoid is unclear; however, there appears to be
genetic susceptibility, with certain medications acting as triggers of disease(34). It is proposed that
exposure to these medications leads to augmentation of the immune response or alterations in the
antigenic properties of the epidermal basement membrane zone(35). Drugs may bind to molecules in the lamina lucida, thus acting as neoantigens and triggering the formation of antibasement membrane zone antibodies(34, 36). It has also been hypothesised that drugs may cause
structural changes in the cell surface exposing previously hidden epitopes which then stimulate an
immune response(34, 37).
Similar to drug- induced pemphigus, medications that are known to trigger drug- induced pemphigoid largely fall within three functional groups(38):
1) Thiol drugs
2) Phenol drugs
3) Non- thiol and non- phenol drugs
Many thiol drugs contain or release sulfhydryl groups within the precursors or the metabolite.
These drugs are able to modify molecular structure, acting as haptens, or exposing previously hidden epitopes. This results in anti- basement membrane zone antibody formation. In addition,
metabolism of some thiol drugs may result in interactions between the sulfhydryl groups in desmosomes, compromising the integrity of the junction between dermis and epidermis at the basement membrane zone(34, 39).
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386
Certain thiol medications, such as penicillamine, decrease regulatory T- cell activity, resulting in
increased production of autoantibodies directed against basement membrane zone antigens(39).
Phenol drugs, such as cephalosporins and aspirin, contain a phenyl group attached to a hydroxy
group. These drugs have the ability to disrupt the basement membrane zone structure, uncovering
hidden epitopes, and thus triggering the production of autoantibodies. Aspirin has been shown to
act as a hapten, leading to changes in the antigenic properties of the lamina lucida. It can also trigger the formation of autoantibodies by attaching to target site on the cell surface(40).
Certain non- thiol and non- phenol drugs are also linked to the induction of pemphigoid. Drugs
associated with pemphigoid are listed in Table22.7.
Clinically, the features of drug- induced bullous pemphigoid are varied, often leading to a delay
in diagnosis. Affected patients are generally younger than those affected with idiopathic bullous
Table22.7 Drugs associated withpemphigoid.
Likely association Probably association Uncertain association
Alogliptin Actinomycin- D Aldesleukin
Anagliptim Adalimumab Amantadine
Aspirin Amoxicillin Amlodipine
Biostim Ampicillin Anthralin
D- Penicillamine Arsenic Azapropazone
Enalapril Atezolizumab Captopril
Erlotinib Bumetanide Dabrafenib
Etanercept Celecoxib Dabrafenib
Everolimus Cephalexin Doxepin
Ibuprofen Chloroquine Enoxaparin
Levofloxacin Ciprofloxacin Escitalopram
Linagliptin Diclofenac Fluorouracil
Nivolumab Durvalumab Flupenthixol
Pembrolizumab Efalizumab Galantamine hydrobromide
Phenacetin Fluoxetine Iodine
Psoralens with UVA Gabapentin Mesalazine
Rifampicin Friseofluvin Nifedipine
Sirolimus Hydrochlorothiazide Omeprazole
Sitagliptin Infliximab Risperidone
Teneligliptin Lisinopril Sulfonamide
Vildagliptin Metronidazole Valsartan
Penicillin
Rosuvastatin
Spironolactone
Sulfasalazine
Terbinafine
Source: Verheyden etal.(34)/MJS Publishing/CC BY- NC 4.0.
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pemphigoid. There are some histological differences between the two groups, with no specific
antigens noted for drug- induced pemphigoid(40).
There appear to be two divergent clinical pathways. Some patients experience acute, self- limiting
forms, with clear resolution associated with withdrawal of the offending drug. There is also a
chronic form characterised by persistent clinical activity despite removal of the supposed medication. This form usually requires prolonged medical intervention.
22.3.5 Drug- Induced Lupus Erythematosus (DILE)
DILE is a lupus- like immune- mediated condition that occurs with chronic exposure to certain
drugs. It is common for DILE to manifest months to years after commencing drug therapy, and the
condition resolves after cessation of the offending drug. Over 100 drugs from more than 10 different drug groups have been implicated in DILE. The two high- risk drugs are procainamide (20%
risk of developing DILE) and hydralazine (5–8% risk)(41).
Three forms of DILE have been identified: systemic DILE, drug- induced subacute cutaneous
lupus erythematosus (DISCLE) and chronic cutaneous DILE. The latter two may be combined
under the term ‘drug- induced cutaneous lupus erythematosus’ (DICLE)(42).
Some forms of DILE can involve the skin of the face as well as the oral mucosa. Oral lesions
appear as irregular tender areas of erythema, which sometimes ulcerate, and are surrounded by
radiating white striations. The most common oral mucosal sites include the palate, buccal mucosa
and gingiva.
Investigations into the pathophysiology of DILE have mainly focused on reactions to procainamide and hydralazine. Proposed pathogenic mechanisms include genetic predisposition, drug
biotransformation and epigenetic dysregulation of immune cells(41).
Genetic risk factors include certain human leukocyte antigens (HLA) such as HLA- DR4,
HLA- DR0301 and Complement C4 null allele (43). Slow acetylators with genetic deficiency
of N- acetyltransferase are at a higher risk of DILE, especially if exposed to procainamide and
hydralazine(44).
Inhibition of DNA methylation is another contributor to the development of DILE. Demethylation
+
of CD4
T cells incites autoreactivity by upregulating expression of the adhesion molecule LFA- 1.
Autoreactive T cells interact with self- major histocompatibility complex (MHC) class II molecules
on B cells, causing increased autoantibody productions. This induces apoptosis of macrophages
resulting in the release of highly antigenic apoptotic chromatin from the dying macrophages. This
autoantibody production and release of the antigenic macrophage chromatin is thought to contribute to the development of lupus- like autoimmunity(45).
Drugs that have been linked to DILE are listed in Table22.8.
387
Table22.8 Drugs associated withlupus- like reactions.
Ethosuximide Methyldopa Procainamide
Gold Para- amino salicylate Streptomycin
Griseofulvin Penicillin Sulphonamides
Hydralazine Phenytoin Tetracyclines
Isoniazid Phenothiazines
Source: Scully etal.(33)/with permission of International & American
Associations for Dental Research.
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