Gingival enlargement - systemic changes and drug influenced causes

Gingival swellings and gingival enlargement can be caused by a range of different things…4

1. Plaque - induced Inflammation - top

2. Modifying systemic factors - pregnancy - lower

3. Neoplasms ( rare) genetic conditions and systemic diseases,more localised, blood neoplasms - generalised

4. Gingival enlargement associated with specific medications

gingival swellings and gingival enlargements cause…

1. false pocketing - typically from interdental papillae

2. Can be very unsightly

3. Can compromise function - mastication

4. Compromises plaque control

Drug Induced Gingival Enlargement - Terminology

• Drug-Induced Gingival Enlargement (DIGE) - correct term

  • Internationally agreed term following World Workshop 2017

• Drug Induced Gingival Overgrowth (DIGO)

  • Previously widely used term.

• Gingival Hyperplasia - pathological

  • ( implies increased number of cells )

• Gingival Hypertrophy - pathological - NOT what happens in gingival enlargement

  • ( Implies increase in size of gingival cells)

drug induced gingival enlargement is related to 3 different types of medications 3

1. calcium channel blockers - antihypertensive drugs

2. phenytoin - anti-convulsant drug - used to manage epilepsy

3. ciclosporin - an immunosuppresant - used for tissue rejection following transplants

UK subjects taking selected drugs

• With a conservative estimate of DIGE in 20% of these patients there would be a prevalence of around 400 000 people in UK

• note verapimil and diltiazem

• note that the numbers are increasing

PHENYTOIN

• PHT anti-convulsant drug used for management of epilepsy

• plaque control becomes hard to mange - you will see secondary gingival enlargements - redder enlargements

• PHT-induced DIGE reported in early 20th century

• Characterised by fibrous overgrowth of interdental papillae

• Prevalence of approx 40% of those taking the drug

• prevalence and severity associated with dose and serum drug concentrations

• associated with plaque levels

  • but is this cause or effect ?? - possible vicious cycle

FOLATE AND PHENYTOIN INDUCED DIGE

• PHT reduces Folate levels

• Some studies report association of DIGO with folate concentrations

• Others find no association

• Clinical trials of oral folate supplements largely negative

• 1 study of topical folate application showed some benefit in children

OTHER ANTICONVULSIVES AND DIGE

• Sporadic case reports of DIGE with other anti convulsive medications

• Particularly Sodium Valproate

• Systematic investigations do not support the idea that other anticonvulsants cause DIGO

CALCIUM CHANNEL BLOCKERS AND HYPERTENSION

• used to manage high blood pressure and hypertension - swelling coming from the interdental papillae particularly

• probing causes bleeding

CALCIUM CHANNEL BLOCKERS

• Dihydropyridines ( DHPs) incl. Amlodipine, Nifedipine, Felodipine

• Non- Dihydropyridines ( non-DHPs) incl Diltiazem, Verapimil

• Reports of all CCBs causing DIGE

• Reported prevalence of DIGE in CCB patients varies enormously from around 2% to above 50% (!)

SO WHY THE VARIATION IN PREVALENCE?

1. Case definitions of DIGE ?

2. Wide variations in study settings - clinic vs community definitions

3. Wide variations in sample populations

4. Dosing variations

drug induced gingival enlargement AETIOLOGIC FACTORS

• Associated with drug dosage

• Associated with plaque control

• Associated with smoking

• (Potential confounding factors incl diabetes, hypertension ??)

• 4290 subjects from SHIP study examined between 1997 - 2001

• Those taking CCBs had increased pocketing in adjusted models

• In a case-control subset CCB use was associated with increased pocketing but not attachment loss

EFFECTS ON PERIODONTAL DISEASE

• SHIP study and our studies are consistent with CCBs resulting in significant increase in Probing Pocket Depth

• In our studies patients taking CCBs have on average approximately 2 fewer teeth after adjustment for confounders

• Studies with PHT also show increases in PPD but not bone loss

Other Antihypertensive Drugs Do Not Cause DIGE

• ACE Inhibitors eg Ramapril, Enalapril Lisinopril

• AR2P Blockers eg Candesartan, Losartan etc

• Diuretics eg Furosemide

• Betas Blockers eg Propranolol etc

CICLOSPORIN

• Immunosuppressant taken particularly for suppression of graft rejection

• Also used increasingly for other conditions incl Behcets disease, etc

• Post-renal transplant patients often take ciclosporin and a CCB

• Combinations associated with particular severe DIGE

OTHER IMMUNOSUPPRESSIVES DO NOT CAUSE DIGE

• Tacrolimus

• Methotrexate

• Corticosteroids

PHT, CCBS AND CICLOSPORIN

• PHT in use for far longer than other drugs

• When overgrowth was reported there was an implication that this was the same as PHT induced DIGE

• However empirically and experimentally there is good reason to think this is not the case

phenytoin is more fibrous, CCBs are more vascular and the cyclosporin is more inflammatory - slightly different mechanisms at play

Between drugs, clear evidence of differences in: clinical presentation, histological appearance, molecular mechanisms

HISTOLOGY AND MORPHOMETRY

• In PHT, lesions obvious fibrosis, with CTGF (CCN2) expression

• In ciclosporin, very little fibrosis, largely inflammatory lesions

• In CCBs, an intermediate picture with some fibrosis but also increased vascularity

• Evidence of cell proliferation and decreased fibroblast apoptosis ( cell death) ( Uzel et al 2001, Kantarcı et al 2007)

Overall pathogenesis of DIGE remains poorly understood and requires further study

new studies involving collagen synthesis

DIGE - management

• Plaque Control ( would you consider surgical reduction before achieiving perfect plaque control ? - but plaque control will be easier after surgical reduction)

• Other nonsurgical measures - debridement

• Surgical reduction by gingectomy -

• BUT relapse is common with all drugs - reported rates of between 40 -60% within 1 year

INVERSE BEVEL GINGIVECTOMY FOR DIGE

tissue is excised and flap of healthy tissue is sutured back

DO WE NEED TO GET THE DRUG CHANGED ?

• 42 % of patients experienced relapsed soon after treatment

• Pts on CCBs lost 3 times more teeth than others during long term maintenance compared to pts who are not on calcium channel blockers

• Improvement in GO during treatment was not associated with plaque, drug type or dose - suprise

• Replacing the drug significantly reduced GO and improved outcomes

COHORT STUDY OF PERIODONTAL OUTCOME OF CCB PATIENTS

• 30 patients taking CCBs

• Test group - had drug changed

• Control - did not.

• Outcome of initial nonsurgical therapy

CHANGING THE DRUG?

Not your decision - never tell a patient they should have their drug changed;

Letter to Physician requesting an assessment of this

CHANGING THE DRUG? - Phentytoin

• Not a frontline drug for initial management of seizures

• Used by those who have been long term seizure-free

• And in combination with other drugs where seizure control is complex

• Not usually a candidate for drug substitution.

CHANGING THE DRUG? - CICLOSPORIN

• Immunosuppressant taken particularly for suppression of graft rejection

• Post-renal transplant patients often take ciclosporin and a CCB

• Despite availability of Tacrolimus, usually unwise to change this drug

‘very rare’ - no its actually way more common

BRIEF CONSIDERATION OF OTHER CAUSES OF GINGIVAL ENLARGEMENT

• Periodontal Disease

• periodontal disease ± Pregnancy

• Rare Genetic Conditions ( incl Hereditary Gingival Fibromatosis - in children- grows back after surgery)

• Neoplastic Disease Others ( including Sarcoidosis (uncommon), Chronic granulomatous disease, GPA(Wegener's granulomatosis))

• leukaemias - early presentations