Allergic and Immunologic Diseases of the Oral Cavity
‘Allergy’ is a broad term used generally to encompass the hypersensitive state acquired by exposure to a specific material, and the altered capacity of the living organism to react upon re-exposure to it. Nearly all cases of allergy depend upon the combination of an antigen, usually but not always a protein or a polysaccharide, with an antibody produced by the host, almost invariably as a result of previous exposure to the antigen.
There are two general types of allergic reactions; and a great diversity of appearance of the various phenomena exists in each group. One type of reaction, the so-called immediate reaction, is that associated with antibodies circulating in the serum of the allergic person and includes anaphylaxis, hay fever and asthma, serum sickness, angioedema, and the wheal-and-erythema skin reaction. The second category of reaction, or delayed reaction, is generally not associated with circulating antibodies since the causative agents are not strictly antigens. They attain antigenic properties by combining with the tissues of the individual. In contrast to the immediate reaction, which develops as soon as the substance is absorbed, the delayed reaction is not manifested clinically for several hours after exposure. Reactions of the latter type include drug allergies, allergies of certain infections, and contact reactions to a vast variety of materials.
Recurrent aphthous stomatitis (RAS) is an unfortunately common disease characterized by the development of painful, recurring solitary or multiple ulcerations of the oral mucosa. Because of the similarity between this disease and herpes simplex infection, with respect to precipitating factors, certain aspects of the clinical appearance of lesions, duration of lesions, recurrence and general failure of response to any form of therapy, the two diseases have been generally confused. A series of intense investigations over the past few years have conclusively established the fact that there is no etiologic relationship between recurrent aphthous stomatitis and herpes simplex infection.
Numerous possible etiologic factors have been suggested in the interesting history of recurrent aphthous stomatitis and these have been adequately reviewed by Ship and his group, and in a workshop on aphthous stomatitis and Behçet’s syndrome at the National Institutes of Health in September 1977, co-chaired by Graykowski and Hooks. However, in the light of present knowledge, it is obvious that there has been considerable confusion in the past between etiologic factors and precipitating factors.
The work of Barile, of Graykowski and of Stanley very strongly implicated a pleomorphic, transitional L-form of an α-hemolytic Streptococcus, Streptococcus sanguis, as the causative agent of the disease. This organism has been consistently isolated from the lesions of patients with typical aphthous ulcers, and microorganisms morphologically consistent with the L-form Streptococcus have been found histologically in the vast majority of aphthous lesions. Once again, it should be emphasized that the herpes simplex virus cannot be isolated from these aphthous ulcers.
The administration of this pleomorphic Streptococcus to guinea pigs and rabbits has produced lesions of the skin and the oral mucosa, which appear clinically and histologically similar to aphthous ulcers in humans. Finally, the work of Graykowski and his associates has shown that patients with recurrent aphthous ulcers, when tested with a Streptococcus vaccine, give a positive delayed type of hypersensitive skin reaction in contrast to patients with no history of aphthae, who give a less frequent and less severe response. Thus, there is some evidence of this disease being an immunologic hypersensitivity reaction to an L-form Streptococcus. It has been suggested that there is a T cell-mediated response to Streptococcus sanguis that produces cross-reaction between streptococcal heat shock protein and oral mucosa, leads to mucosal damage.
As an alternative etiologic factor, Lehner has proposed that the recurrent aphthous ulcer is the result of an autoimmune response of the oral epithelium. Utilizing a fluorescent antibody technique, he has shown both IgG and IgM binding by epithelial cells of the spinous layer of oral mucosa in patients suffering from recurrent aphthous ulcers, while the same cells in healthy control patients or patients with nonspecific ulcers show no such binding.
Normal levels of antinuclear factors and complement levels within normal limits in patients with this disease have been reported by Addy and Dolby and by Lehner. This has led Cohen to suggest that recurrent aphthous stomatitis is not an autoimmune disease arising from a central immunologic fault but rather represents a local immune response against an antigenically altered mucosa. He theorizes, in this context, that the disease is the result of diffusion of bacterial toxins, food, and other substances acting as allergens or haptens, which initiate an immune response. The same substances, he pointed out, could also react with epithelial cell surface antigens to produce a change, resulting in an adverse inflammatory response.
Donatsky has found elevated gamma globulin levels against Streptococcus 2A and M5 by immunofluorescent studies in the serum of patients with recurrent aphthous stomatitis. The detected antibodies in these patients were able to bind serum complement. These investigations have led Antoon and Miller to conclude that the immune system appears actively involved in reaction to bacterial and autoimmune antigens and speculate that L-form streptococci might infect epithelium of the salivary ducts, stimulate formation of antibodies, fix complement and cause cytolysis. They believed that the disease might be further complicated by an autoimmune reaction to released antigens from epithelial tissues.
There has been some evidence that nutritional deficiencies might be of significance in the etiology of recurrent aphthous stomatitis. For example, a study has been reported by Wray and his colleagues in which a series of 330 patients with recurrent aphthae were screened for deficiencies of iron, folic acid, and vitamin B12. A total of 47 deficient patients, or 14.2%, was found: 23 patients were deficient in iron, seven in folic acid, six in vitamin B12 and 11 had combined deficiencies. 39 of these patients were treated with the appropriate replacement therapy, and it was found that 23 had a complete remission of their ulcers, 11 were improved and three were not responded. While the results indicate that a small percentage of patients with recurrent aphthae do have certain nutritional deficiencies, the investigators pointed out that the prompt response to replacement therapy suggested a direct action on oral mucosa, but that it might be reasonably postulated that the presence of a deficiency allows the expression of an unrelated underlying tendency to ulceration and that the deficiency itself does not play a primary role. The failure of response in some patients also might indicate either that the deficiency was coincidental or that the therapy was inadequate. In any event, the role of nutritional deficiencies in the etiology of this disease does not appear to be a major one.
Local trauma has been found to be the precipitating factor in nearly 75% of cases in a series reported by Graykowski and his coworkers. The traumatic incidents included selfinflicted bites, oral surgical procedures, toothbrushing, dental procedures, needle injections, and dental trauma.
It has been recognized for many years that a time relationship exists between the occurrence of the menstrual period and the development of aphthous ulcers. Most series show that the incidence of aphthae is greatest during the premenstrual period. Dolby has similarly shown that ulceration is maximal in the postovulation period and has related this to the blood level of progesterone.
It has also been reported that women may have remission of their aphthous lesions during pregnancy but show eruptions following parturition, sometimes very rapidly. On rare occasions, the onset of the disease has been associated with menarche and menopause.
The role of psychic factors in certain oral diseases is well recognized. In cases of aphthous ulcers, acute psychologic problems appear many times to have precipitated attacks of the disease, although this is a difficult factor to analyze.
Many patients with recurrent aphthous ulcers have a history of asthma, hay fever, or food or drug allergies. This may be a purely fortuitous finding because of the high incidence of allergies in the general population. However, the outbreak of aphthae following the use of certain foods or drugs in the same patients has been reported so frequently that allergy must be considered a precipitating factor.
It is interesting to note that there is negative correlation between aphthous ulcers and smoking. As per Atkin PA and coworkers who measured the nicotine metabolite present in the blood of smokers, the incidence of recurrent aphthous ulcers is significantly lower in smokers.
Apthous ulceration occurs in various systemic diseases like Behçet’s syndrome, cyclic neutropenia, magic syndrome (major aphthous and generalised inflamed cartilage), PFAPA syndrome (periodic fever, aphthae, pharyngitis, and cervical adenitis) and HIV infection.
• Recurrent aphthous major, which is now believed to be simply a more severe form of recurrent aphthous minor but which was thought at one time to represent a separate disease entity known as periadenitis mucosa necrotica recurrens (Mikulicz’s scarring aphthae or Sutton’s disease).
• Recurrent herpetiform ulcerations, which consist of clusters of ulcers resembling herpetic lesions but lacking evidence of the presence of viruses in patients with a low incidence of antibody to oral mucosa.
Recurrent aphthous minor occurs somewhat more frequently in women than in men, and the majority of patients report the onset of the disease between the ages of 10 and 30 years. However, it may commence much earlier in life or not begin until much later. Unfortunately, the disease typically persists with recurring attacks over a period of many years. It is believed that nearly 20% of the general population is affected by this disease at one time or another. It is interesting to note that approximately 55% of a large group of professional school students studied by Ship and his associates gave a positive history of recurrent aphthous ulcers. It is also of interest that a rather remarkable familial tendency for occurrence of the disease has been noted by many workers. For example, in the series of Graykowski and coworkers, over 80% of the affected patients had an additional member or members of their families with a history of aphthae.
The frequency of outbreaks of the aphthae varies remarkably between patients. Some persons will have only one or two attacks a year, while others will have one or two attacks a month, and almost every month for prolonged periods, sometimes years. Occasional patients have continual, repeated outbreaks and are never free of lesions for extended intervals.
The onset of the disease may occur with a variety of manifestations, which are not invariably present in all cases. These include the occurrence of one or more small nodules; burning sensation, erythema, generalized edema of the oral cavity, especially the tongue; paresthesia; malaise; low-grade fever; localized lymphadenopathy; and vesicle-like lesions containing mucus.
The aphthous ulcer begins as a single or multiple superficial erosions covered by a gray membrane (Fig. 16-1). It generally has a necrotic center with clearly defined raised margins surrounded by an erythematous halo. The lesion is typically very painful so that it commonly interferes with eating and speech for several days. At one time it was thought that the aphthous ulcer begins with the formation of a vesicle, as does the lesion of herpes simplex infection. The majority of the evidence now indicates that this is not the case—vesicle formation does not appear to be a stage in the development of the usual aphthous ulcer.
The number of lesions present in any one patient during a single outbreak may vary from one to over 100. However, according to Graykowski and his associates, over 90% of patients have six lesions or less during a single outbreak. They vary in size from 2 to 3 mm to over 10 mm in diameter. The most common sites of occurrence are the buccal and labial mucosa, buccal and lingual sulci, tongue, soft palate, pharynx, gingiva, and all locations of labile mucosa not bound to periosteum. This is in direct contrast to the sites of predilection of recurrent intraoral herpes simplex infection. The ulcers themselves generally persist for 7 to 14 days and then heal gradually with little or no evidence of scarring.
Recurrent aphthous major is characterized by the occurrence of large painful ulcers, usually 1 to 10 in number, on the lips, cheeks, tongue, soft palate, and fauces and cause severe pain and dysphagia (Fig. 16-2). Their incidence is more in patients with HIV infection. These ulcers occur at frequent intervals, and many patients with this disease are seldom free from the presence of at least one ulcer. Usually these lesions occur after puberty and persist up to 20 years or more. Unlike the typical ulcers of recurrent aphthous minor, these lesions may exceed one cm in diameter and persist for up to six weeks and leave a scar upon healing. Not uncommonly, the ulcers recur in waves over a long period of time, so that eventually the oral mucosa may show a great deal of scarring. Patients with these severe major aphthae also occasionally show similar lesions on vagina or penis, rectum, and larynx, with associated rheumatoid arthritis or conjunctivitis.
Recurrent herpetiform ulcers are characterized by crops of multiple small, shallow ulcers, often up to 100 in number, which may occur at any site in the oral cavity. They were first described by Cooke in 1960, while Lehner as well as Brooke and Sapp have expanded our knowledge of this condition. Cooke pointed out the clinical similarities of this disease to the lesions of herpes simplex and that the corresponding histologic changes were not similar, since these lesions resemble the recurrent aphthous ulcer rather than a viral lesion. These lesions have female predisposition with later age of onset and are not associated with herpes virus.
• The herpes simplex virus cannot be cultured from the lesions or demonstrated by electron microscopy, although Sapp and Brooke have demonstrated non-viral intranuclear bodies in adjacent epithelial cells.
Although the exact nature of this disease is unknown, including its etiology and pathogenesis, it is considered appropriate by most investigators to include it as a variant of recurrent aphthous stomatitis and await further clarification.
The minor aphthous ulcer of the oral mucous membrane exhibits a fibrinopurulent membrane covering the ulcerated area. Occasional superficial colonies of microorganisms may be present in this membrane. An intense inflammatory cell infiltration is present in the connective tissue beneath the ulcer, with considerable necrosis of tissue near the surface of the lesion, neutrophils predominating immediately below the ulcer but lymphocytes prevailing adjacent to this. Granulation tissue may be noted near the base of the lesion. Epithelial proliferation is present at the margins of the lesion, similar to that found in any nonspecific ulcer. Accessory salivary gland tissue, commonly present in areas of aphthae, will typically exhibit focal periductal and perialveolar fibrosis, ductal ectasia and mild chronic inflammation. These features may be present in even clinically normal mucosa of the aphthous patient. It has also been found that the aphthous ulcer itself, at least in some cases, begins immediately above the excretory duct of one of these minor glands where there is disruption of this ductal epithelium. The tissue involvement is generally superficial.
Lehner has shown that the histologic findings by light microscopy of the severe oral ulcers in recurrent aphthous major are identical with those described under the recurrent aphthous minor. Electron microscopic studies have confirmed this similarity.
Wood and his associates have described characteristic changes in the nuclei of epithelial cells taken by cytologic smears from around recurrent aphthous ulcers. These have been referred to as Anitschkow cells and consist of cells with elongated nuclei containing a linear bar of chromatin with radiating processes of chromatin extending towards the nuclear membrane (Fig. 16-3). They are quite abundant in patients with recurrent aphthous stomatitis but are not pathognomonic of the disease, since they are also found in patients with sickle cell disease, megaloblastic anemias, and iron-deficiency anemias, in children receiving chemotherapy for cancer, and even in normal people. Their ultrastructure has been described by Haley and his associates, who found that the nuclear chromatin was made up of pleomorphic masses forming an irregular band along the long axis of the nucleus rather than being randomly dispersed.
Recurrent aphthous stomatitis is usually diagnosed by history, clinical findings and exclusion of other diseases. Lesions which may be mistaken for recurrent aphthous stomatitis include herpetic stomatitis, herpangina, erythema multiforme, erosive lichen planus, pemphigus and pemphigoid.
There is no specific treatment for recurrent aphthous ulcers although, over the years, many drugs have been advocated. Graykowski and his coworkers found that a tetracycline mouthwash (250 mg per 5 ml), used four times daily for 5 to 7 days, produced a good response in nearly 70% of the patients tested, by relieving the pain, reducing the size of the lesions, and reducing the healing time. A steroid ointment, 1.5% cortisone acetate, applied locally, and hydrocortisone acetate-antibiotic lozenges also showed some effectiveness but not as great as the tetracycline. Chemical cautery reduced pain but had no other beneficial effects. No significant improvement was found with the use of antihistaminics, gamma globulin, multiple smallpox vaccinations or a Lactobacillus acidophilus-L. bulgaricus preparation, all of which have variously been reported to be effective.
There has also been extensive clinical trial of levamisole, an anthelmintic drug, which has also been found to potentiate the immune response in a variety of ways. The results of a number of these studies in treating recurrent aphthous stomatitis have been reported, some showing a reduction in the duration of symptoms, some showing a decrease in the duration of lesions, some showing a diminished frequency of lesions, but others conclude that the drug had no significant effect on severity or incidence of lesions.
An excellent summary of the many drugs and chemicals which have been used to treat recurrent aphthous stomatitis over the years has been prepared by Antoon and Miller and is shown in Table 16.1. Unfortunately, despite many forms of therapy, there is no known cure for the disease.
Behçet’s syndrome is a multisystemic, chronic disorder, characterized by oral and genital aphthous ulcers, arthritis, and cutaneous lesions, ocular, gastrointestinal and neurological manifestations. It was described by the Greek ophthalmologist Benedict Adamantiades in 1931, but it was in 1937 when the Turkish dermatologist Hulusi Behçet made an extensive study and analyzed it as a triad composed of recurrent aphthous oral ulcers, genital ulcers, and hypopyon uveitis. Behçet’s disease is characterized by exacerbations and remissions. It has a distinct geographical distribution and is common among the Mediterranean and East Asia, where it is a major cause of morbidity. The next highest incidence of the disease is in Turkey, Japan, UK, and USA. Behçet’s disease is usually present in adulthood and is uncommon in children. In Eastern Mediterranean populations, the disease is more common in men, who also experience more severe disease. In Asian populations; however, the sex ratio is reversed. Familial disease is uncommon in Caucasians, but a positive family history is observed in non-Caucasian patients, and the possibility of a sibling risk ratio has been reported in a Turkish study.
The etiology of Behçet’s disease remains obscure but various reports suggested that an infectious trigger with inflammatory mediators and immune deregulation is the causative factor in a genetically succepted host. It is well evidenced in the literature that Behçet’s syndrome is associated with the allele HLA-B*51 (chromosome 6p21), which is relatively common in many ethnic groups. Organophosphates, organochlorides, heavy metal intoxication, and allergens are environmental factors that may trigger initiation or exacerbation of Behçet’s disease. Streptococcus sanguis and S. oralis can be found in the oral microbiota of Behçet’s syndrome patients and other agents include the hepatitis virus, parvovirus B19; some bacteria, including mycobacteria, Borrelia burgdorferi, Escherichia coli, Saccharomyces cerevisiae fungus may be elevated with the occurrence of this disease.
Behçet’s syndrome is characterized by exacerbations and remissions. The duration of attacks ranges between few days to few weeks. Attacks usually end to complete remissions but sequelae can also be left behind. This syndrome is more common in young adults between the ages of 25 and 40 and is 5 to 10 times more common in males.
It is characterized chiefly by oral and genital ulcerations, ocular lesions, and skin lesions. The first manifestation of the disease is usually the appearance of oral and/or genital lesions. The oral lesions are painful and very similar clinically and histologically to that of recurrent aphthous ulcers. They occur in crops at any intraoral site and consist of ulcers ranging in size from several millimeters to a centimeter or more in diameter. These ulcers have an erythematous border and are covered by a gray or yellow exudate. The genital ulcers are small and located on the scrotum, root of the penis or labia majora. The most common sites of oral ulcers are lips, buccal mucosa, tongue, gingiva, palate, tonsils, uvula, and pharynx. It must be emphasized that oral ulcers of Behçet’s Syndrome are usually indistinguishable from ordinary recurrent oral ulcers except in multiplicity and involvement of unusual locations (soft palate and oropharynx). Cutaneous lesions include papulopustular lesions (acneiform) or pseudofolliculitis, erythema nodosum, superficial thrombophlebitis, cutaneous ulcers and nodules, cellulitis type lesions, Sweet’s syndrome, gangrenous pyoderma, other rarer lesions, which occur in addition.
The ocular lesions, beginning as photophobia and irritation, may range in severity from a simple conjunctivitis to uveitis and finally hypopyon. The ocular involvement may lead to blindness. It is more common and severe in men. Inflammation of the eyes is usually episodic and resolves after a few weeks but recurrent attacks eventually cause sequela of blindness. The skin lesions are generally small pustules or papules on the trunk or limbs and around the genitalia. In addition to the various forms of pyoderma, both erythema nodosum and erythema multiforme have been reported to occur. Arthralgia, thrombophlebitis, and CNS involvement, as well as cardiac or pulmonary involvement are occasional complications of the disease.
The intraoral ulcers are entirely nonspecific, and according to Lehner, are remarkably similar to recurrent aphthous ulcers. Endothelial proliferation is reported in the lesions of Behçet’s disease but not in the recurrent aphthous ulcer. Vasculitis also appears to be an essential lesion in Behçet’s disease.
These patients frequently manifest a hypergammaglobulinemia, leukocytosis with eosinophilia, and elevated ESR. Other findings are variable. There is no diagnostic test for Behçet’s disease. ESR, C-reactive protein (CRP), C9 and/or C3, C4 complements may be elevated during the active phases of disease. Immunoglobulins (IgM and IgG) may be elevated and immune complex are also found in serum of some patients. Platelet rosette formation around neutrophils can be seen in acute attacks of disease and disappears after recovery. This phenomenon is relatively specific but nonsensitive.
Reiter’s syndrome is associated with urethritis, balanitis, conjunctivitis, and mucocutaneous lesions. It is a disease of unknown etiology, although there is evidence of an infectious origin. It is one of the most common complications of nonspecific urethritis and, in fact, clinically mimicks gonorrhea, although the urethral discharge is negative for Neisseria. Pleuropneumonia-like organisms (PPLO) have been implicated and, a Bedsonia group virus has also been isolated from patients with the disease. Mycoplasmal and chlamydial species have also been suspected. There is an excellent review of the disease by Weinberger and associates. Currently it is considered to be an immunodysregulated condition. Recent evidence also suggests that this disease may be triggered by infectious agents in genetically susceptible patients. HLA-B27 is considered to be a disease susceptibility factor in Reiter’s syndrome. This disease is also seen frequently in HIV positive patients.
Reiter’s syndrome is more prevalent in young adult men, usually between 20 and 30 years of age. The male to female ratio is 9:1. There is a typical tetrad of manifestations: nongonococcal urethritis, arthritis, conjunctivitis, and mucocutaneous lesions. In any given case, however, the full tetrad is often not present.
Urethritis may be the first sign. The urethral discharge is usually associated with itching and burning sensation. The arthritis is often bilaterally symmetrical and usually polyarticular. Conjunctivitis is often so mild as to be overlooked. The skin lesions are similar to those seen in keratoderma blennorrhagica and consist of red or yellow keratotic macules or papules which eventually desquamate. A possible relationship between Reiter’s syndrome and psoriasis has been discussed by Perry and Mayne.
Oral lesions occur in reported series of cases in less than 5 to about 50% of patients with the disease. The lesions, described by Pindborg and associates, appear as painless, red, slightly elevated areas, sometimes granular or even vesicular, with a white circinate border on the buccal mucosa, lips, and gingiva. They may be mistaken for recurrent aphthous ulcers. The palatal lesions appear as small, bright red purpuric spots which darken and coalesce, while the lesions on the tongue closely resemble ‘geographic’ tongue. Clinically, similar lesions occur on the glans penis, producing a circinate balanitis.
The microscopic findings are not diagnostic. They consist of parakeratosis, acanthosis and polymorphonuclear leukocyte infiltration of epithelium, sometimes with microabscess formation similar to psoriasis. The connective tissue shows a lymphocyte and plasma cell infiltrate.