Anti-helminthic drugs in recurrent apthous stomatitis: A short review.

Recurrent aphthous stomatitis (RAS) is a common mucosal condition producing painful ulcerations in the oral cavity and considerable clinical morbidity. The etiology remains obscure, though local trauma, psychologic stress, hematinic deficiencies and immune dysregulation have been implicated. Though the primary goals of therapy are symptomatic relief of pain, the clinicians are aiming toward reducing the frequency, duration, number of ulcerations and increasing ulcer free periods with systemic drug therapy if topical medications appear ineffective. Levamisole, an antihelminthic drug has been tried with promising results in patients with severe RAS providing long-term benefits.

Recurrent aphthous stomatitis (RAS) is a common clinical condition seen world-wide[1] producing painful ulcerations in the oral cavity.[2]

The etiology is unclear and management remains unsatisfactory as most treatments modalities only reduce the symptoms but do not stop recurrence.[1] Immunomodulatory drugs have been tried lately to reduce the frequency duration and severity of this mucosal disorder causing sometimes severe morbidity to the patient.

RAS

RAS is a disorder characterized by recurring ulcers confined to the oral mucosa in patients with no other signs of disease but many investigators believe that immunologic disorders, hematologic deficiencies and allergic or psychological abnormalities may play a role.[3]

RAS are classified as minor (<1 cm in size) ulcers healing faster without scars and major (>1 cm in size) which take longer time to heal and often scar. The third type is herpetiform ulcers which manifests as recurrent crops of dozens of small ulcers throughout the oral mucosa.[3]

RAS minor composes from 70% to 87% of all forms of RAS and a recent study places its frequency rate at 17.7% in the general population. The remaining 7-10% cases are apthous major and herpatiform type each.[45] RAS is characterized by multiple, recurrent, small, round, or ovoid ulcers with circumscribed margins, erythematous haloes and yellow or grey floors, it usually presents first in childhood or adolescence and then can occur later in adult life.[1] Apthous ulcers, which usually occur on the non-keratinized oral mucosa, can cause considerable pain and may interfere with eating, speaking and swallowing.[6]

Etiopathogenesis of Recurrent Apthous Stomatitis

Patients with recurrent apthous stomatitis are predisposed to develop ulcers at sites of trauma. Investigators drew an analogy between ulcers developing at sites of trauma and the positive pathergy reaction in Bechet's disease.[7] Hence one of the most likely precipitating factors are local trauma and stress. Other associated factors include systemic diseases and nutritional deficiencies, food allergies, genetic predisposition, immune disorders, the use of certain medications and human immunodeficiency virus infection.[6] About 50% of first-degree relatives of patients with recurrent apthous stomatitis also have the condition suggesting genetics as one of the associated factors in its etiology.[8]

The clinician should routinely perform a blood test to rule out iron, vitamin B12 or folate deficiency as well as a complete blood count. Elimination diets or dietary supplementation if a hematinic deficiency is involved may resolve symptoms completely.[9]

Differential Diagnosis of RAS

RAS and recurrent intraoral herpes are the two most commonly encountered recurring oral lesions in the dental office.[10] Because the general frequency and clinical similarity of these conditions often make it difficult to distinguish one from the other, therapeutic intervention may be inappropriate since the former is an autoimmune phenomenon and the latter is a viral infection.[11]

Aphthous ulcers are one of the most common oral diseases world-wide but oral lesions similar to aphthous ulcers may be present in several systemic diseases.[12] There are several diseases that should be included in the differential diagnosis of a patient who presents with a history of recurring ulcers of the mouth such as Behçet's syndrome, recurrent herpes simplex virus infection, recurrent erythema multiforme and cyclic neutropenia so a thorough history and clinical evaluation of the patient is must.[3]

Diagnosis is on clinical grounds alone and must be differentiated from other causes of recurrent ulceration, particularly Behçet disease - a systemic disorder in which aphthous-like ulcers are associated with genital ulceration and eye disease (particularly posterior uveitis).[1]

Levamisole

Levamisole is a levisomer of tetramisole ((-)-2,3,5,6-tetrahydro-6-phenylimidazole [2,1-6] thiazole monohydrochloride) and has been used as a broad spectrum anti-helminthic drug since 1966.[13]

This drug commonly used by gastroenterologists, having a wide range of immunomodulatory actions, has been used successfully as monotherapy and an adjunct to treatment in a variety of diseases. It has been successfully used in the treatment of parasitic, viral and bacterial infections including inflammatory skin diseases. It has also been used in combination with other drugs for treating a number of dermatologic disorders, e.g. in combination with cimetidine for treating recalcitrant warts, with prednisolone for treating lichen planus, erythema multiforme and aphthous ulcers of the oral cavity.[14]

Levamisole has been tried in multiple chronic oral ulcerative lesions such as mucous membrane pemphegoid, oral lichen planus (OLP) and pemphigus vulgaris with varied results. In one study conducted by Lu et al., all patients were given 150 mg/day of levamisole and 15 mg/day of prednisolone for 3 consecutive days each week, along with topically applied dexamethasone orobase. The addition of levamisole to prednisolone produced improved results in the management of above stated mucocutaneous disorders.[15]

In yet another study, it has also been concluded that for erosive OLP patients, the combination therapy is superior to the single therapy of levamisole or of Chinese medicinal herbs as studied by serum levels of squamous cell carcinoma associated antigen determined by a microparticle enzyme immunoassay.[16] Adverse affects of levamisole are mild and infrequent and include rash, nausea, abdominal cramps, taste alteration, alopecia, arthralgia and a flu-like syndrome and rarely cause agranulocytosis.[14] Agranulocytosis is commonly seen in those patients with human leukocyte antigen-B27 positivity and in those patients who have undergone long-term levamisole therapy. For this reason, levamisole is usually recommended for intermittent use.[17]

Anemia is estimated to affect nearly a third of the global population. It is more widespread in South Asia (53%) than in other regions of the world.[18] It was concluded in one study that routine administration of intestinal anthelmintic agents results in a marginal increase in hemoglobin (1.71 g/l), which could translate on a public health scale into a small (5-10%) reduction in the prevalence of anemia in populations with a relatively high prevalence of intestinal helminthiasis.[19] Since RAS is commonly associated with hematinic deficiencies, this drug can be used as an adjunct for its management.

Immunology and Levamisole

A study published in 1978, Renoux et al. have reported that levamisole increased cellular immunity and has been approved for many autoimmune and inflammatory diseases.[20] There is good evidence that patients with RAS show signs of immune dysregulation. Histologically, RAS are mucosal ulcerations with a mixed inflammatory infiltrate and large granular lymphocytes predominating in the preulcerative and healing phases and OKT8 cells predominating in the ulcerative phase.[21] Increased adherence of neutrophils may help perpetuate the ulceration and release of tumor necrosis factor (TNF) has also been reported.[22]

As recurrent aphthous ulcerations (RAU) are common oral inflammatory lesions, TNF-alpha plays an important inflammatory mediator and a critical cytokine for adequate host defense. A study by Sun concluded that a significantly higher than normal serum level of TNF-alpha (normal 3.8 pg/ml) can be detected in 20-39% of patients in the ulcerative stage of major, minor or herpetiform ulcerations. The serum TNF-alpha level may be associated with the severity and the stage of RAS. It has been concluded that levamisole can modulate serum TNF-alpha levels in RAS patients.[23]

Interleukin-6 (IL-6) is a pro-inflammatory cytokine that has effects on cellular and humoral immunities and levamisole and levamisole plus Chinese medicinal herbs can modulate the serum IL-6 level in RAS patients. The therapeutic effect of RAS can be monitored by a reduction of serum IL-6 level in RAU patients. It was also suggested that the combination therapy is superior to the single therapy of levamisole only.[24]

In a study conducted to evaluate the effect of levamisole on the immune system of patients with RAS or OLP, it was found a significant improvement in clinical symptoms and normalization of the decreased CD4/CD8 ratio in RAU patients after levamisole treatment. Moreover, the decreased CD4/CD8 ratio, which persisted until the remission stage in the untreated RAS patients, reverted to normal in the active late stage in the levamisole-treated patients. This reversion of aberrant cellular immunity in an earlier stage of the ulcer cycle may explain why RAS patients experience symptom improvement after antihelminthic drug therapy.[25]

Management of RAS

RAS are often recurrent and periodic lesions that cause clinically significant morbidity. Topical medications such as antimicrobial mouth-washes and topical corticosteroids (dexamethasone) can achieve the primary goal to reduce pain and to improve healing time but do not improve recurrence or remission rates. In severe conditions of major apthous stomatitis, systemic medications can be tried if topical therapy is ineffective.[26]

Cases of major ulcers that are characterized by pain and dysphagia and that are recurrent usually require systemic therapy. Several systemic drugs have been used to treat major ulcers including systemic corticosteroids, dapsone, colchicine, thalidomide, pentoxifylline, low-dose interferon-α and levamisole.[27]

The therapeutic choice of drug depends on the severity of the disease, the number of ulcers, their location and duration and the level of associated orofacial pain.[28]

However, despite detailed clinical, immunologic, hematologic and microbiologic investigation, the etiology of RAS remains unknown. At present, topical steroids and antimicrobial mouth rinses are the mainstays of treatment, but there is still no means of preventing recurrence of the oral ulceration.[29]

Though the primary goals of therapy for RAS are relief of pain, reduction of ulcer duration and restoration of normal oral function, secondary goals include reduction in the frequency and severity of recurrences and maintenance of remission with levamisole showing variable efficacy. Thus, RAS can be effectively managed with a variety of topical and systemic medications.[6]

Levamisole hydrochloride may reduce healing time and reduce the number of ulcers, but an older study found only subjective improvement.[30] This drug has proven to increase hemoglobin concentration of the patient along with regulating immune system of the RAS patients. Prolonged use of this drug should be avoided due to its adverse side-effects especially agranulocytosis.[14]

Conclusion

Recurrent apthous stomatitis is a multifactorial condition and it is likely that immune-mediated destruction of the epithelium is the final common pathway in RAU's pathogenesis. Symptomatic and definitive treatment ranges from antimicrobial rinses corticosteroids to systemic immunomodulating agents. Levamisole hydrochloride may reduce healing time and reduce the number of ulcers with its immune regulation and improve hematologic picture and thus can be considered as one of drugs for the treatment modality of recurrent apthous stomatitis.