oral health and general health

Our mouths are full of bacteria, various types of plaque, and biofilms. Oral health is an integral part of general health and is essential to the overall health and well being of man. When we have plaque in our mouth, it can play havoc with other parts of our bodies because of bacteria and the infection it can cause. It is the early identification of oral disease that may contribute to early diagnosis and treatment for a number of systemic factors.  Which came first, the gum problems or the systemic problems? If bacteria, plaque, and biofilms live inside your mouth, who is to say these don’t invade the bloodstream through the oral cavity?

CURRENT VIEW OF RISK FACTORS AND PERIODONTAL DISEASES 

 Initially, the bacteria of periodontal disease and the progression of periodontal infections are clearly modified by local and systemic conditions called risk factors. The local factors include pre-existing disease as evidenced by bleeding from gums and plaque retention areas associated with defective restorations.
 Risk factors, which we know to be important, include diabetes mellitus, tobacco use, rheumatoid arthritis, peptic ulcers, respiratory disease, cardiovascular disease, asthma, allergies, cancer, obesity, certain medications, gender (with males having more disease), age (with more disease seen in the elderly), and hereditary factors. Inflammation causes a host response to deal with the infection. When inflammation continues to be present, it can contribute to a number of systemic diseases/conditions.

DIABETES
Diabetes is an important link, because patients with this disease generally have increased susceptibilities to many types of infections. High blood sugar levels help bacteria grow, which can lead to periodontal disease. Many studies have shown a positive relationship between poor glycemic control and increased incidences of periodontitis. The future in medically treating these patients to manage diabetes needs to include a referral to the dental office for a dental/periodontal exam and possible treatment.

CARDIOVASCULAR DISEASE
The body contains 40 billion blood vessels, which makes it simple for harmful inflammatory byproducts to remain anywhere inside arteries, feeding the heart and brain.⁵ An underlying inflammatory response may place an individual at high risk for both periodontal disease and atherosclerosis. An inflammatory process probably has sources that may include systemic inflammation and local infections,inflammation and a higher incidence of heart attack.

PRETERM LOW-BIRTHWEIGHT BABIES 
Bacterial infections that occur with periodontal disease are commonly observed in women of childbearing age.  Premature labor is the consequence of an immune response to infections of the uterus in some women and their infants. Having a healthy mouth can lead to a healthy, full-term pregnancy.

MEDICATIONS

Many of the antianxiety/antidepressant, anti-hypertensive, anti-diabetic drugs can cause dryness of mouth and gums enlargement, which in return may not only cause decay, but can exacerbate gumsdisease.

RHEUMATOID ARTHRITIS AND OSTEOPOROSIS
Rheumatoid arthritis is a disorder in which the body attacks its own healthy cells and tissues. People with rheumatoid arthritis are at increased risk for osteoporosis for many reasons and it can cause bone loss not only systemically, but also in the oral cavity.

RESPIRATORY DISEASES

There is an association between dental plaque, poor oral health, and respiratory diseases. Oral secretions are aspirated along with respiratory pathogens and may affect the adhesion of the organisms to the respiratory epithelium.

PEPTIC ULCERS
Research has now shown that H. pylori strains having similar virulence markers are able to induce different types of gastric inflammation and injury. The entire genome microarray of H. pylori revealed distinctions in the ability of H. pylori strains to induce epithelial cell responses, which are related to inflammation.

TOBACCO USE
This is one risk factor that is preventable. Tobacco use causes chronic systemic inflammation because of toxins found in the body and can stimulate platelets to clump together. The body will go into “high gear” to fight this, causing inflammation that can result in various medical conditions.

CANCER
Cytokines include many types of proteins, which can cause inflammation not only in the mouth but throughout various parts of the body.cytokines have the ability to cause bone loss systemically and orally.

Brushing with toothpaste is important - First and foremost, a toothpaste and a correct brushing action work to remove plaque, a sticky, harmful film of bacteria that grows on your teeth that causes cavities, gum disease and eventual tooth loss if not controlled.

To properly brush your teeth, use short, gentle strokes, paying extra attention to the gumline, hard-to-reach back teeth and areas around fillings, crowns or other restoration. Concentrate on thoroughly cleaning each section as follows:

·         Clean the outer surfaces of your upper teeth, then your lower teeth

·         Clean the inner surfaces of your upper teeth, then your lower teeth

·         Clean the chewing surfaces

·         For fresher breath, be sure to brush your tongue, too

IMPORTANCE OF TOOTH BRUSHING

1. Save money. Prevention is less expensive than cure. Regular daily care of your teeth and gums will prevent problems in the future and leave you with lower dental bills.

2. Fresh Breath. Your mouth will start to smell if you do not clean it regularly. You take the rubbish out regularly so it doesn’t start to stink, clean your mouth out at least twice a day.

3. Prevent gum disease. Gingivitis (inflammation of the gums and the first stage of gum disease) is caused by the plaque build-up around your teeth, leading to swollen gums and teeth that bleed when you brush them. Plaque is an accumulation of food and bacteria, which appears in everyone’s mouth and it needs to be cleaned off regularly .

4. Reduce your chance of a heart attack or stroke. Bacteria from your mouth can make its way into your bloodstream and increase you chance of a heart attack or stroke.

5. Prevent or minimise Diabetes. Any gum disease can make it harder to control your blood glucose. The relationship between serious gum disease and diabetes is two-way. Not only are people with diabetes more susceptible to serious gum disease, but serious gum disease may have the potential to affect blood glucose control and contribute to the progression of diabetes.

6. Have a healthy baby. Gum disease has been shown to increase the chance of premature birth and low birth weight. It can also be one of the many causes of delayed conception and impotence. So get your mouth and gums healthy first.

7. Prevent Dementia. Poor oral health increases your risk of developing dementia .

8. Toothpaste on your brush is the best way to apply minerals and other desensitisers to your teeth.

9. Remove stains. There are mild abrasives in toothpaste that remove debris and surface stains and help to keep your teeth looking fresh, healthy and white.

That 2 minutes brush, twice a day can not only save your teeth and keep your smile looking beautiful it can also literately save your life

Dentinogenesis Imperfecta Type I - A Case report with literature review on nomenclature system.. by Dr. Devaraju .D

Abstract: Significant hereditary anomalies have been diagnosed over the years, among which Dentinogenesis Imperfecta (DI) stands out. DI is an inherited disorder affecting dentin. Defective dentin formation results in discoloured teeth that are prone to attrition and fracture. Till date, mutation in Dentinsialophosphoprotein (DSPP) has been found to cause the dentin disorders DI- I and II (shields II & III). Early diagnosis and treatment are therefore fundamental, aiming at obtaining a favourable prognosis, since late intervention makes treatment even more complex. Here reporting a case with characteristic clinical, radiological and histological features of DI-I. The aetiology and classification followed in literature is confusing since Dentinoenamel junction (DEJ) in DI seems to be structurally and functionally normal and DI is clearly a disorder distinct from Osteogenesis Imperfecta, but we still relate aetiology of DI to DEJ and follow shields classification. So we have briefly reviewed aetiology and nomenclature system of DI.

Key-words: dentin, dentinsialophosphoprotein, osteogenesis imperfecta, tooth anomaly.

Key Messages: Dentinogenesis imperfecta is an autosomal dominant disorder of tooth development characterized by the presence of opalescent dentin, resulting in a dusky blue to brownish discoloration of the teeth.

Text

Introduction:

Dentinogenesis imperfecta was first reported by Tolbot as an autosomal dominant trait. While Hodge and his co-workers suggested the term hereditary opalescent dentin in 1936, Roberts and Schour proposed DI in 1939.¹ DI is described as a localized form of mesodermal dysplasia, observed in histodifferentiation, and which corresponds to a congenital hereditary change, involving deciduous and permanent teeth.

DI-I (shields type II) is transmitted as an autosomal dominant trait, with almost 100% penetrance and an incidence of 1:8000 births.² The defect has been reported to occur widely in the Caucasian race. In Type I, primary and secondary dentitions have typical amber like translucency against reflected light varying from grayish purple to purple brown or yellowish brown and there is often rapid attrition of the teeth. Radiographic features of DI include bulbous crowns with constricted short roots, progressive obliteration of the pulp chambers and periapical radiolucent areas may be noted. Histologically dentinal tubules are irregular and are bigger in diameter and areas of uncalcified matrix are seen.

Case History:

An 18 year old female patient reported with a complaint of pain in her lower right back region of the jaw since 2 months and discoloured teeth. Pain was intermittent and throbbing in nature, non- radiating and aggravated on consuming hot and cold food items. Sleep was disturbed due to pain. Patient’s mother gave a history of discoloured primary teeth and chipping of enamel. She was born from a second degree consanguineous marriage. She has one elder brother, who is not affected and none of the family members have similar complaint. (Figure-1)

The lower facial height was decreased due to severe attrition of maxillary and mandibular teeth and loss of molars (Figure-2). The oral findings include generalized brownish discoloration of teeth with loss of enamel and generalized attrition till the gingival margin. Multiple mobile teeth were present with an intra-oral draining sinus in relation to attached Gingiva of 22 (Figure- 3, 4, 5). Dental caries cannot develop in these cases owing to the absence of dentinal tubules and inability of caries to develop on a surface, where enamel is rapidly being lost due to abrasion and fracture. The case presented here confirms this with the absence of carious lesions.

Full mouth Periapical radiographs and panoramic radiograph showed narrowing of pulp chamber. Periapical radiolucencies in maxillary teeth and mandibular laterals are seen. Enamel of unerupted 38 is normal (Figure-6&7). Electric and Thermal Vitality test revealed non vital maxillary teeth and 42, 32. Ground sectioning of 42 showed dentinal tubules irregular in shape, size and course, increased hypo mineralized interglobular dentin and obliterated pulp chamber (Figure-8, 9&10). Based on the clinical, radiographic and histopathologic features, the case was diagnosed as DI-I.

Emergency treatment involves Endodontic access opening. The treatment carried out was oral prophylaxis; extraction of 12, 16, 22, 42, 46, and 47, followed by endodontic therapy. An over denture is planned, since efficacy of fixed partial denture is less.³

Discussion:

Dentin, the most abundant tissue in teeth, is produced by odontoblasts, which differentiate from mesenchymal cells of the dental papilla. DI is an inherited mesodermal condition affecting the primary and permanent dentition, but is more severe in the primary dentition. Inheritance of dentin defects is typically autosomal dominant, although autosomal recessive and X-linked cases of dentin defects associated with syndromes are reported. Dentin defects occur as a feature in a number of syndromes, including Osteogenesis Imperfecta, Ehlers-Danlos syndrome (EDS), Tumoral calcinosis and Hypophosphatemic rickets.⁴

DI is an inherited disorder affecting dentin. Mutation in Dentinsialophosphoprotein (DSPP) is the cause for this defect. The DSPP gene is located at 4q21.3 in a cluster of dentin and bone matrix genes (Table-II). DSPP encodes both dentin sialoprotein (DSP) and dentin phosphoprotein (DPP) as one precursor protein that is cleaved before secretion. DSP and DPP have different roles in dentinogenesis. DPP serves as a nucleator of mineralization and induces apatite formation.⁵

DI is classified under two systems, one by Witkop and the other by Shields. (Table-II)

These systems are well accepted but not totally satisfactory. The best nomenclature system was suggested by Levin. Extensive pedigrees of individuals with DI have been studied, and none have exhibited other changes suggestive of Osteogenesis Imperfecta (OI). Therefore, DI is clearly a disorder distinct from OI.⁶ So far, no definitive relation between the type of OI and the dental involvement can be established. Familial occurrence of DI with OI cannot be comprehensively explained by mutations in type I collagen genes.⁷ There is no substitute in the present classification for the category designated as DI-I of shields classification. So in present classification there are only two types, Type I - Dentinogenesis Imperfecta without OI & Type II – Brandywine Type with shell tooth. The Diagnosis of DI should be reserved for defective dentin formation with opalescent teeth in the absence of systemic disease. Appropriately, dentin defects associated with the systemic bone disease are termed OI with opalescent teeth.  Some authors classify these disorders as DSPP associated dentin defects, with dentin dysplasia type II representing the mild end of the phenotypic spectrum and DI- II representing the severe end.⁴

         Table – I: Genes underlying dentin defects.

Disorder	location	Gene
DI- I	4q21.3	DSPP
DI- II	4q21.3	DSPP

        Table – II: Various classifications of DI.

Shields8	Witkop9	REvised6,10	Clinical presentation
DI -I	DI	No substitute	Osteogensis Imperfecta with opalescent teeth
DI -II	Hereditary Opalescent Teeth	DI-I	Isolated opalescent teeth
DI -III	Brandywine isolate – found only in a population of southern Maryland(USA)	DI-II	Isolated opalescent teeth

DI-I Clinical presents with amber-brown or blue-grey coloration of teeth with opalescence. The opalescence colour is due not to the pulp showing through but to the collagen structural defect within the dentin, which may reflect either a bluish light through the enamel or a brown color. The enamel tends to chip away from the incisal rim of the anterior teeth and from the occlusal surface of posterior teeth. Originally it was thought that a defective DEJ was resulting in chipping of enamel, but scanning electron microschopic studies have disclosed a normal junction.¹¹ The enamel does not actually fall off the DEJ, as some believe; the DEJ in DI seems to be structurally and functionally normal (Figure-11).

It needs to be appreciated that odontoblasts differentiate in the pre-existing ground substance of the dental papilla and that into this ground substance the first dentin collagen is deposited.¹² Odontoblast differentiation follows three steps a) induction, b) competence and c) terminal differention.¹³ In the first formed dentin (mantle dentin), some of the matrix components are contributed by dental pulp cells beneath the odontoblasts. The odontoblasts are still undergoing the late stage of differentiation as the first layer of dentin matrix is being deposited.¹⁴ The need for an alternate mechanism of mineralization during mantle dentin formation may relate to the fact that odontoblasts are still completing their terminal differentiation at this stage and may not be able to fully exhibit the odontoblast phenotype in terms of expression of dentin specific matrix components.¹³The result is a near normal DEJ because of the less affected mantle dentin. Imperfect primary dentin in DI is because of matrix components which are completely formed by defective odontoblasts. They secrete an abnormal collagen, which is undermineralized and fails to form odontoblastic tubules.

 Some amount of enamel wears off excessively because of hypoplastic hypocalcified areas within the enamel rods. This is presumably due to the fact that the cells of the internal dental epithelium were needed to induce odontoblast and their product, dentin, becomes the initiator for further differentiation of the internal dental epithelial cells in a process of reciprocal induction.¹² The abnormality in dentin formation results secondarily in enamel that is also microscopically somewhat defective.³ The exposed dentin, which is soft, undergoes quick attrition, to such an extent that the dentin becomes smooth and continuous with the gingival tissue

Radiographic feature include bulbous crown with short root, obliteration of pulp chamber and multiple Pseudo periapical radiolucencies with the absence of pulpal exposure or pulpal necrosis. Although the pulp is usually obliterated by excess dentin production, some teeth may show normal sized pulp or pulp enlargement.  Cementum and alveolar bone are normal.²

The histological features include complete absence or reduction in the number of Dentinal tubules. They are irregular in shape, size and course. Hypo mineralized interglobular dentin is increased and cementum is normal. Odontoblasts entrapment may be seen within the dentinal matrix. Large areas of unmineralized dentin and irregular border between the unmineralized and mineralized dentin is seen. The enamel appears defective with subtle hypocalcification defects in the enamel rods just above the DEJ. The DEJ appears flattened although the DEJ appears qualitatively normal.

DI should be differentiated from amelogenesis imperfecta (AI), fluorosis & dentin dysplasia. AI can be recognized by its more clinically apparent enamel defect. AI and fluorosis are associated with normal pulp chambers. Dentin dysplasia type I, has normal coloration of both the primary and permanent dentition, although their pulps are almost completely obliterated. Unlike DI, it almost manifests with extremely short roots and periapical radiolucencies. Type-II does cause a discoloured opalescent primary dentition with obliterated pulp chambers. But the permanent dentition is of normal colour and the pulp chambers are enlarged.³

The goal of the treatment is to establish a more favourable prognosis for such a complex anomaly, and to insure the integrity of the erupting dentition. The treatment should aim to prevent the abrasion of the erupted teeth and to establish the proper vertical dimension. Prosthetic treatment using an overdenture seemed to be preferable in young patients. Once the skeletal development is complete permanent prosthesis is done.¹Contradictory statements were found in the literatures regarding the need for treatment of asymptomatic periapical rarefaction, or whether these are the regions of non infected hypocalcified bone only. In present case the endodontic treatment was carried out for the periapical rarefactions as they were symptomatic. The great challenge to the dentists facing such an anomaly is adequate treatment to achieve functional and aesthetic restoration, thus improving the self esteem and quality of life for these individuals.

Reference:

1. Tanaka T, Murakami T. Radiological Features of hereditary opalescent dentin. Dentomaxillofacial Radiology 1998; 27:251-53.
2. Huch. K,et al., Diagnostic features and pedodontic orthodontic management in Dentinogenesis Imperfecta type II; A case report. Int J pead dent 2002; 12: 316-21.
3. Robert E. marx, Diane stern. Oral And Maxillofacial Pathology 1^st edition Quintessence,2003: Pg 232-234.
4. Suzanne hart P, Thomas C. hart. Disorders of human dentin. Cells tissues organs 2007; 186:70-77.
5. Holappa et al., Splicing site mutations in dentin sialophosphoprotein causing Dentinogenesis Imperfecta type II. Eur J oral sci 2006; 114: 381-84.
6. Brad W.Neville et al., Oral and Maxillofacial Pathology. 2^nd edition. Elsevier; 2005: Pg 94-96.
7. Helena Ranta, Pirjo Liisa Lukinmaa, Janna Waltimo. Heritable dentin defects: Nosology, pathology, and treatment. American Journal of Medical Genetics 1993; 45(2):193–200.
8. Shields ED et al., A proposed classification for heritable human dentin defects with a description of a new entry. Archs oral boil 1973; 18: 543-53.
9. Witkop CJ. Hereditary defects of dentin. Dental clinics of North America 1975; 19: 25-45.
10. Shafer, Hine, Levy. Text book of oral pathology. 5^th edition. Elsevier; 2006: Pg 75-7.
11.   Lewis R. Eversole. Clinical outline of oral pathology: diagnosis and treatment. 4^th edition. PMPH (US); 2001: Pg 363.
12.  Antonio Nanci. Ten Cate’s Oral histology: development, structure, and function. 7^th edition. Mosby; 2008: Pg 191-238.
13. Kenneth M. Hargreaves, Harold E. Goodis. Seltzer and Bender’s Dental Pulp.1^st edition. Quintessence publication; 2002: Pg 31-46.
14. B.K.B. Berkovitz, G.R. Holland and B.J. Moxham. Oral Anatomy, Histology and Embryology. 3^rd edition. Mosby; 2002: Pg 322.

AUTOIMMUNE MUCOCUTANEOUS BLISTERING DISEASES. devaraju d

REVIEW ARTICLE

OVERVIEW OF ORAL BLISTERING DISEASES

ABSTRACT

One of the remarkable characteristics of the normal immune system is that it is capable of reacting to an enormous variety of microbes, but it does not react against each individual's own antigens. This unresponsiveness to self antigens, also called immunological tolerance. Autoantibodies are directed against various constituents of the molecular apparatus that hold epithelial cells together or that bind the surface epithelium to the underlying connective tissue resulting in Autoimmune Blistering Disorders. These autoimmune blistering diseases are potentially life threatening that cause blisters and erosions of the skin and mucous membranes. Despite frequent and significant oral involvement of autoimmune blistering diseases, recognition of the oral presentation of these disorders is low and associated with unnecessary delay in diagnosis and treatment. This text will deal with mucocutaneous features of autoimmune blistering diseases, its classifications, pathophysiology, clinical presentation and advanced treatment options. We have also discussed briefly about various diagnostic methods used.

Keywords: autoantibody, immunofluorescence, desmosome, hemidesmosome.   

INTRODUCTION

Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body really attacks its own cells. This may be restricted to certain organs (e.g. Thyroiditis) or involve a particular tissue in different places. Autoimmune diseases, with the exception of rheumatoid arthritis and autoimmune thyroiditis, are individually rare, but together they affect approximately 5 percent of the population in Western countries. They are a fascinating but poorly understood group of diseases. There are mechanisms which are responsible for one of the cardinal features of the immune system, namely, its ability to discriminate between self and nonself (usually microbial) antigens. If these mechanisms fail, the immune system may attack the individuals own cells and tissues. Such reactions are called autoimmunity, and the diseases they cause are called autoimmune diseases. Oral mucous membranes may be affected by a variety of blistering mucocutaneous diseases. The most common blistering conditions of the oral and perioral soft tissues are viral infections, especially Herpes simplex. Other blistering mucocutaneous diseases include immunological and hereditary diseases. The insuring damage produced by the interaction of these autoantibodies with the host tissue is seen clinically as a disease process.

Autoimmune blistering mucocutaneous diseases can be divided into two subsets: pemphigus subset (Intra epithelial blistering) and pemphigoid subset (subepithelial blistering). Clinically oral mucosa is most often the initial site, and in many cases the only site, of the disease presentation. Affected oral tissues are highly friable with a tendency to bleed and sheer when subjected to minor trauma. Patient affected by these chronic, painful oral ulcers often complaint of discomfort with eating and performing daily oral functions.

The diagnosis of these blistering disorders should be a highly satisfactory exercise. Despite considerable overlap of clinical features a careful evaluation of combined clinical, histological and immunofluorescence data usually enables a correct diagnosis to be made in majority of cases. Clinicopathological correlation is always an essential prerequisite before coming to any final decision.

EPITHELIAL BIOLOGY

A basic knowledge of the biologic character of the stratified squamous epithelium is crucial to the understanding of autoimmune blistering diseases. The function of this adhesive complex is to secure tissue integrity, resist mechanical trauma, prevent microorganisms from entering into the body, and protect from fluid loss.¹ 

The oral mucosa is situated anatomically between skin and intestinal mucosa and shows some properties of each. Hemidesmosomes are complex entities (Fig-1a) containing an array of proteins.If one or more of epithelial basement membrane zone (BMZ) proteins are defective or damaged, the result can be loss of cell-basement membrane adhesion, leading to subepithelial vesiculation and the clinical phenotype of pemphigoid. Desmosomes (Fig-1b) are adhesion proteins that contain a series of proteins, particularly desmogleins and desmocollins. The epithelium thus has a complex structure, and an array of molecules is required for epithelial integrity and health. Damage to the intercellular area leads to separation of the keratinocytes (acantholysis) which, though typical of pemphigus.

 

Fig-1a: Structure of Hemidesmosome.    Fig-1b: Structure of Desmosome. ²

Initiation of Autoreactivity

Even in a genetically predisposed person, some trigger, an environmental exposure or a change in the internal environment is usually required for frank auto reactivity. Studies of genetically similar populations living in different conditions strongly suggest the importance of environmental triggers. For example, the incidence of both type 1 diabetes and multiple sclerosis in a population changes as the members migrate to different regions. That an environmental antigen elicits the antibodies against desmoglein I involved in pemphigus is strongly suggested by epidemiologic studies of pemphigus foliaceus in Brazil, where the incidence of disease declines as the distance from regions where the disease is endemic increases. Such observations, along with the lower-than-expected rate of disease concordance among monozygotic twins, suggest that an environmental factor exposes an autoimmune diathesis. In the case of most autoimmune diseases, however, the trigger is unknown.

CLASSIFICATION

Autoimmune Blistering Mucocutaneous Diseases can be divided into two major subset.²

The pemphigus subset

The pemphigoid subset

Pemphigus vulgaris          Pemphigus vegetans          Pemphigus vegetans of Hallopeau          Pemphigus vegetans of Neumann Pemphigus foliaceus         Pemphigus erythematosus         Endemic pemphigus         Pemphigus herpetiformis         Immunoglobulin A (IgA) Pemphigus foliaceus         Paraneoplastic pemphigus foliaceus         Drug induced Pemphigus foliaceus Paraneoplastic pemphigus IgA pemphigus

Bullous pemphigoid (BP) Mucous membrane pemphigoid (MMP)  Linear IgA disease(LAD) of childhood and adults  Toxic epidermal necrolysis (TEN)  Bullous systemic lupus erythematosus  dermatitis herpetiformis and Epidermolysis bullosa acquisita (EBA).

Pemphigus vulgaris and bullous pemphigoid are the earliest recognized autoimmune blistering diseases and together, they account for about one half of the autoimmune blistering diseases. While most patients with pemphigus vulgaris have oral lesions, only a few patients with bullous pemphigoid have oral lesions. Over the last few decades, many other autoimmune blistering diseases have been delineated, and some of these newly identified diseases have oral manifestations which includes linear immunoglobulin A (IgA) bullous dermatosis, epidermolysis bullosa acquisita, and bullous systemic lupus erythematous.

PEMPHIGUS

Pemphigus is a group of rare, potentially life-threatening autoimmune mucocutaneous diseases that are characterized by blistering that affects stratified squamous epithelium and results in cutaneous or mucosal blistering or both.  It was originally named by wichman in 1791.³ There are several variants of Pemphigus due to autoantibodies directed against the different desmosome constituents and, to the resultant damage of the epithelium at the different levels. Clinical manifestations may vary in these conditions. The susceptibility to develop the autoantibodies that cause pemphigus is genetically determined, but the triggering mechanism that initiates the immune response is unknown. Pemphigus vulgaris is the most common of these disorders (vulgaris is Latin for common). Even so, it is not seen very often. The estimated incidence is one to five cases per million people diagnosed each year in the general population. It accounts for approximately 70% of pemphigus cases. They describe the oral lesions as "the first to show, and the last to go."

Predisposing factors includes strong genetic background to pem­phigus   vulgaris,   and   an   HLA. Most cases are idiopathic, but some have been trig­gered by Medications (captopril and peniciliamine, which contain sulphydryl groups, and rifampicin and di-clofenac), Radiation, Surgery, Certain foods(garlic) and Emotional stress.

Clinical features includes the mucosa and the skin, resulting in superficial blisters and chronic ulceration. Various mucosal surfaces may be involved, including ocular, nasal, oral, pharyngeal, laryngeal, upper respiratory, and anogenital mucous membranes. These lesions contain a thin, watery fluid shortly after development, but this may soon become purulent or sanguineous. These lesions rupture quickly, usually within hours to few days, leaving an erythematous, denuded surface (Fig-2). Infrequently ocular involvement may be seen, usually appearing as bilateral conjunctivitis. Unlike cicatricial pemphigoid, the ocular lesions of pemphigus do not tend to produce scarring and symblepharon formation. The loss of epithelium occasioned by rubbing apparently unaffected skin is termed Nikolsky's sign. It is a characteristic feature of pemphigus and is caused by prevesicular edema which disrupts the dermal-epidermal junction. This test is named after Pyotr Vasilyewich Nikolsky, who first described this sign in 1896. This test is positive in other diseases such as paraneoplastic pemphigus, oral lichen planus, mucous membrane pemphigoid, epidermolysis bullosa, linear IgA disease, lupus erythematosus, dermatomyositis, chronic erythema multiforme, or graft-versus-host disease. Some difficulty may be experienced in differentiating pemphigus from other bullous diseases such as dermatitis herpetiformis, erythema multiforme bullosum, bullous lichen planus, epidermolysis bullosa and other chronic bullous dermatoses such as bullous pemphigoid and cicatricial pemphigoid. Clinical experience, however, aided by the histologic appearance of the lesions, usually suffices to separate the diseases.

Fig-2: Showing ulcers on the floor of the mouth

           Paraneoplastic pemphigus (PNP) was originally described by Anhalt et al. in 1990. Mortality rates approach 90%. Causes of death include sepsis, with resultant multiorgan failure and respiratory failure due to the direct effects of the disease on the respiratory epithelium. The mean age of onset is 60 years. Patients ranging in age from 7-76 years have been reported. With the exception of a few patients, all patients with PNP have had tumors, most of which have been malignant. PNP present as painful oral erosions and these erosions affect all surfaces of the oropharynx and characteristically involve the lateral borders of the tongue and the vermilion of the lips, often with hemorrhagic crusting. Patients present with painful oral erosions, often accompanied by a generalized cutaneous eruption. The eruption can assume a wide variety of morphologies including morbilliform, urticarial, bullous, papulosquamous, or erythema multiforme like lesions. ⁴

Treatment is invariably with systemic corticosteroids 1-1.5 mg/kg/d every morning or in divided doses. Taper as condition improves; single morning dose is safer for long-term use, but divided doses have more anti-inflammatory effect (or plasmapheresis or intravenous immunoglobulins), which typically produce a response within 2 weeks. Systemic corticosteroids reduce the mortality to less than 10%. Some use corticosteroids intravenously, or use steroids with fewer adverse effects – such as deflazacort. Oral lesions may respond poorly but additional topical or intralesional corticosteroids (such as triamcinolone) or other immunosuppressants may help. Emerging treatments includes Intravenous immunoglobulins are successful and safe in steroid-resistant PV, but their mechanism of action is not clear. New drugs include mycophenolate mofetil, though others have no confirmed benefit but offer the hope of relatively safe immunosuppression with no nephrotoxicity or hepatotoxicity. Others under trial include tacrolimus and cholinergic agonists. Treatments aimed at immunoadsorption to remove desmoglein reactive autoantibodies and thought to help include protein A immunoadsorption and a peptide based (Globaffin) adsorber system. Immunomodulation using rituximab (anti-CD20 monoclonal antibody), infliximab, proteinase inhibitors, chimeric molecules for specific recognition and elimination of the autoimmune B cells, and targeting of Dsg3-specific T cells are other strategies. ⁵

BULLOUS PEMPHIGOID

Bullous pemphigoid (BP) is a chronic, autoimmune, subepidermal, blistering skin disease that rarely involves mucous membranes. BP is characterized by the presence of immunoglobulin G (IgG) autoantibodies specific for the hemidesmosomal BP antigens BP230 (BPAg1) and BP180 (BPAg2).⁶ BP primarily affects elderly individuals in the sixth through eighth decades of life, with an average age at onset of 65 years. BP of childhood onset has been reported in the literature. The onset of BP may be either subacute or acute, with widespread, tense blisters. Significant pruritus is frequently present. In some patients, the blisters arise after persistent urticarial lesions. BP has been reported following several nonbullous, chronic, inflammatory skin diseases, such as lichen planus and psoriasis and precipitated by ultraviolet irradiation, x-ray therapy, and exposure to some drugs. Oral lesions occur far less frequently in bullous pemphigoid than in cicatricial pemphigoid, varying from approximately 10-45% in various reported series. These oral lesions of bullous pemphigoid have been reviewed by Shklar and his associates and are usually described as vesicles and areas of erosion and ulceration. An important feature of the oral involvement is the similarity of gingival lesions to those of cicatricial pemphigoid. This gingival involvement generally involves much, if not all, of the gingival mucosa and is exceedingly painful. The gingival tissues appear extremely erythematous and may desquamate as the result of even minor frictional trauma. The vesicles and ultimate erosions may develop not only on the gingival tissues but in any other area such as the buccal mucosa, palate, floor of the mouth the tongue.

MUCOUS MEMBRANE PEMPHIGOID

Mucous membrane pemphigoid (MMP) or Cicatricial pemphigoid (CP) is a chronic, subepithelial autoimmune disease, which predominately affects the mucous membranes, including the conjunctiva, and occasionally the skin. Patients with cutaneous involvement present with tense blisters and erosions, often on the head and the neck or at sites of trauma. Scarring of the mucous membranes is common, hence the designation cicatricial, which can lead to decreased vision, blindness, and supraglottic stenosis with hoarseness or airway obstruction. On a clinical level, MMP involvement may include the eyes, oral cavity, and pharyngeal mucosa of patients usually over the age of 50 years. Although MMP is a blistering disease predominantly involving the mucosal surfaces, up to 30% of patients may also have skin involvement. There are at least 5 subsets of MMP that have been described, each with distinctive clinical features, pattern of immunopathology, and antigenic specificity of autoantibodies.

1. Oral pemphigoid - The first subset of MMP is oral pemphigoid, represented by patients with oral lesions only, with a low frequency of positive indirect immunofluorescence findings and without serologic reactivity to BP antigens or other recognized MMP antigens. The target antigen in these patients with oral pemphigoid is still unclear.

2. Anti-epiligrin pemphigoid - The second subtype of MMP with oral lesions, anti-epiligrin pemphigoid, is quite rare and is characterized by serologic reactivity only to the dermal side of salt-split skin and a low titre of circulating IgG antibodies to BMZ on indirect immunofluorescence; with immunoprecipitation or immunoblotting, these have been recognized as antilaminin 5 (anti-epiligrin) antibodies. The target antigen has been identified as the α3 subunit of laminin 5 (epiligrin) in the BMZ.

3. Anti–BP antigen mucosal pemphigoid - A third subset of MMP with oral lesions includes cases of oral mucosal and skin lesions (with or without other mucosal lesions) with indirect immunofluorescence findings similar to those seen in BP (high frequency of circulating autoantibodies) and a high frequent reactivity to BP antigens.

4. Ocular pemphigoid - A fourth distinct subset of MMP, ocular pemphigoid, includes patients who have ocular lesions (with or without oral lesions) with a low frequency of IgG and C3 and much greater deposits of fibrin in biopsy specimens, negative indirect immunofluorescence on salt-split skin, and negative serology against BP antigens with immunoblotting and immunoprecipitation.

5. Multiple antigens - A fifth MMP group consists of patients with antibodies directed against more than one antigen, as discussed.

Oral MMP usually appears suddenly, is painful, waxes and wanes in severity and lasts for years or may be active throughout the remainder of the patient’s life. Oral lesions are not life threatening, but may be associated with considerable morbidity in severely affected patients who do not respond to medication.⁷ MMP is one of the main causes of desquamative gingivitis (DG). Indeed, DG is the main oral feature of MMP and may be the presenting feature.

Treatment should be individualized for each patient depending on disease severity, age, general state of health, associated medical problems, and contraindications to the use of systemic agents. The main treatments are immunosuppressive and include the systemic and topical corticosteroids in various forms, as well as other immunosuppressive agents. Antibiotics (mainly tetracyclines) and surgery have been advocated by some authors.⁸

Topical corticosteroids remain the mainstay treatment of MMP, especially for localized oral lesions, though some investigators advocate dapsone. The more potent fluorinated steroids, such as fluocinonide 0.025% to 0.05% or clobetasol propionate 0.05% (2-3 applications/day for 9-24 weeks) in an adhesive medium are usually required in as much as triamcinolone acetonide (0.1% to 0.5% aqueous rinse or cream) is rarely adequate to control the disease.⁹

Intralesional therapy with triamcinolone acetonide (in a dilution of 5.0-10 mg/mL), however, has been advocated and can be useful in the treatment of isolated erosions. For gingival lesions, topical corticosteroids are typically more effective when used in a vacuum formed custom tray or veneer. In patients with palatal, pharyngeal, nasal, and esophageal lesions, an aerosol of beclomethasone dipropionate or budenoside (50-200 mcg) may be valuable. If oral lesions continue to develop or extend, or new oral lesions, progressive ocular disease, or laryngeal or oesophageal lesions appear, treatment with a short plasma half-life systemic corticosteroid (eg, prednisone or prednisolone) should be initiated. Prednisolone therapy may be combined with high-potency topical steroids (eg, clobetasol), other immunosuppresive agents, or dapsone. If complete remission is achieved with such a 2-drug regimen, the dosage of the second drug is maintained while the prednisolone is tapered and eventually discontinued, at which point careful tapering of the other drug is attempted. To minimize adverse effects, the following regimen using dapsone has been recommended: 25 mg/day for 3 days, then 50 mg/day for 3 days, then 75 mg/day for 3 days, then 100 mg/day for 3 days; then, to the seventeenth day of therapy, 150 mg daily. However, even with this regimen, intolerance is not uncommon.

LINEAR IGA DISEASE (LAD) OF CHILDHOOD AND ADULTS

Linear immunoglobulin A (IgA) dermatosis (LAD) is an autoimmune subepidermal vesiculobullous disease that may be idiopathic or drug-induced. Children (juvenile dermatitis herpetiformis) and adults are affected, with disease of the former historically referred to as chronic bullous dermatosis of childhood, characterised by linear IgA deposits along the basement membrane zone. The knowledge of this disease is important for the establishment of a correct differential diagnosis in cases of blistering mucocutaneous diseases. The clinical presentation is heterogeneous and appears similar to other blistering diseases, such as bullous pemphigoid and dermatitis herpetiformis.

Clinical features

The mean duration of idiopathic linear IgA dermatosis of childhood is 3.9 years. Remission has been reported to occur in 64% of children, in most cases within 2 years. Disease of adults is more protracted, with a mean duration of 5.6 years, lasting anywhere from 1-15 years. The remission rate in adults is less than that in children (48%). The disease tends to wax and wane in severity. Drug-induced cases typically resolve quickly once the causative agent is identified and withdrawn. Cutaneous lesions usually heal without scarring.

Lesions of the mucous membranes heal with scarring and pose considerable morbidity. Ocular linear IgA dermatosis may be indistinguishable from cicatricial pemphigoid and lead to blindness. Involvement of the pharynx, the larynx, the nose, the rectum, and the esophagus has been reported. In the skin, a vesiculobullous rashes are seen over a normal or erythematous skin characterizes LAD.

Oral Manifestations

Proximately in 80 % of patients mucosal lesions can be observed (oral, ocular, nasal or genital mucous). A 60 – 70 % of LAD patients have oral mucosal lesions. The most frequent oral lesions consist in painful erosive or ulcerative lesions caused by the rupture of bullae. These ulcerative or erosive lesions may appear anywhere in the oral mucous, including vestibular mucous, and the tongue.

Treatment

LAD is usually a chronic disease with periods of exacerbation followed by remission, but the disease can resolve entirely. Up to 52% of patients experience remission. However, the recurrence rate is high, and each episode follows a prolonged course. Dapsone (25-100 mg PO qd )has been found to be effective in the treatment of LAD. Sulfonamide (500 mg PO bid initial; increase by 1 g until disease is controlled) is an orphan drug also approved for the treatment of dermatitis herpetiformis and has been used in LAD patients who cannot tolerate dapsone. Skin lesions are contained within 1 to 2 days after treatment but can recur within 1 to 2 days after treatment is stopped. Mucosal lesions do not respond well and may persist even after the skin lesions are controlled; therefore most patients with mucosal lesions are treated with the combination of a moderate dose of dapsone and a low dose of prednisone. Some studies found that IgA deposits remain after the lesions have resolved.¹⁰

TOXIC EPIDERMAL NECROLYSIS

               Described in 1956 by Alan Lyel¹¹, TEN is a life-threatening skin disorder that is commonly drug-induced. TEN and Stevens-Johnson syndrome (SJS) are severe cutaneous reactions, with more than 90% of cases involving mucosal surfaces. Erythema multiforme (EM) major, once thought to be a mild variant of this disease spectrum, differs from SJS/TEN in its distribution, lesion morphology, and etiology. Although all three are hypersensitivity reactions and give rise to oral bullae, erosions, ulcers, and crusted lips, the skin lesions of SJS and TEN are different from EM. They are more severe and tend to arise on the chest rather than the extremities on erythematous and purpuric macules; these lesions are called "atypical targets" SJS is much more likely to be associated with medication use and Mycoplasma pneumoniae infection and rarely with HSV infection. ^12.13

             Involvement of the oral mucosa results in edema and erythema, followed by blistering. Ruptured blisters may form extensive hemorrhagic erosions with grayish white pseudomembranes or shallow aphthous like ulcers. These lesions resemble oral lesions of paraneoplastic pemphigus, which are long-standing and associated with malignancy. TEN has a mortality rate of 30-50%. Septicemia and multisystem organ failure are the primary causes of death. Complications of SJS/TEN include adhesions and scarring, including stricture formation of mucosal surfaces such as the esophagus, eyelids and cornea, as well as the genitourinary system. 

             The treatment of TEN in burn units has considerably improved patients prognosis and survival because these centres are competent in most aspects of the appropriate care and nursing. Many reports in the literature suggest that the administration of corticosteroids in TEN can be contraindicated (increased mortality owing to septic accidents) and the consideration of other therapeutic solutions would therefore seem to be justified.  Other possible medical therapies for the treatment of TEN that are reported in the literature include the use of plasmapheresis, intravenous immunoglobulins, and cyclosporin.

             In conclusion, it is mandatory: a) To immediately suspend administration of any drug the patient is taking; b) To treat the patient in a burns unit with all the supportive care that these patients need. Having evaluated the drugs used in the treatment of TEN and described in the literature, we believe that cyclosporin presents the most valid rational basis, acting at all the levels of the pathogenetic mechanism (pro-inflammatory cytokines, apoptosis of keratinocytes, T- lymphocyte activation). It is relatively safe at the dosage employed (3-4 mg/kg daily) and inexpensive.

BULLOUS SYSTEMIC LUPUS ERYTHEMATOSUS

             Bullous systemic lupus erythematosus (BSLE) is a rare variant of systemic lupus erythematosus (SLE) which histologically resembles dermatitis herpetiformis (DH) and responds dramatically to dapsone. BSLE is an autoantibody-mediated subepidermal blistering disease that occurs in patients with SLE.¹⁴ Not all blistering eruptions that occur in patients with lupus erythematosus represent BSLE as defined above. Vesiculobullous skin lesions can also develop as a result of extensive damage to the epidermal basal layer (and even suprabasal keratinocytes) due to intense interface dermatitis in the setting of lupus erythematosus specific skin disease. Such patients may present with a severe form of acute or subacute cutaneous lupus erythematosus (SCLE) that resembles erythema multiforme (Rowell syndrome) or TEN. Because EBA and BSLE share the same target antigen, distinguishing between the 2 may be difficult.

Clinical features

In SLE, skin and mucosal lesions are relatively mild and involvement of the skin result in an erythematous rash, classically seen over the malar process and bridge of the nose. When blisters are a clinical feature in SLE, the disease is called BSLE. Primarily young black women are affected, often beginning in the second or third decade of life; however, the disease does occur in both sexes, in many races, and in children.¹⁵ BSLE accounts for 2-3% of cases of autoimmune subepidermal blistering disease, with an estimated incidence of fewer than 0.5 cases per million population per year.

Treatment

             BSLE has a shorter course than EBA with a more favorable prognosis, although the disease is often severe. Dapsone (25-200 mg/d PO) is more effective in the treatment of BSLE than in EBA, and healing of lesions can occur within several days, although dapsone may not have an effect on the systemic aspects of the disease.

CONCLUSION

Patients with an oral mucosal disease characterized by chronic multiple lesions, which  are continuously present, are frequently misdiagnosed for weeks to months since their lesions are frequently confused with other recurrent oral lesions. Because some of these diseases have a high morbidity and mortality, it is extremely important to achieve a definitive diagnosis as expediently as possible and to refer the patient for further medical care. Blistering diseases are challenging to diagnose and require management by a multispeciality team consisting of the dentist, primary care physician, dermatologist, and ophthalmologist.                                                                                                                                                                                                                                                                                                                                          In conclusion Dentists are in a key position to recognize the oral manifestations of autoimmune blistering disorders and contribute to timely diagnosis and therapeutic intervention. So proper knowledge of these diseases helps in early recognition and treatment, which improves therapeutic outcome and disease prognosis.

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