Gingivitis

Introduction

Background

Gingivitis is an inflammatory process limited to the mucosal epithelial tissue surrounding the cervical portion of the teeth and the alveolar processes. Gingivitis has been classified by clinical appearance (eg, ulcerative, hemorrhagic, necrotizing, purulent), etiology (eg, drug-induced, hormonal, nutritional, infectious, plaque-induced), and duration (acute, chronic). The most common type of gingivitis is a chronic form induced by plaque. Gingivitis is shown in the image below.

Moderate chronic gingivitis. Note that the papillae are edematous and blunted. They may bleed with brushing. Note areas of edema overlying some of the root areas. Pallor is seen in these areas. Image courtesy of Robert J. Lindberg, DMD.

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Moderate chronic gingivitis. Note that the papillae are edematous and blunted. They may bleed with brushing. Note areas of edema overlying some of the root areas. Pallor is seen in these areas. Image courtesy of Robert J. Lindberg, DMD.

Compare the image above to a healthy mouth, below.

Healthy mouth and gingiva. Note the healthy light pink color of the gingiva. The intradental papillae are sharp and fill the intradental space. No local edema is present. Image courtesy of Robert J. Lindberg, DMD.

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Healthy mouth and gingiva. Note the healthy light pink color of the gingiva. The intradental papillae are sharp and fill the intradental space. No local edema is present. Image courtesy of Robert J. Lindberg, DMD.

Acute necrotizing ulcerative gingivitis (ANUG, ie, trench mouth) is an acute infectious gingivitis. The term trench mouth was coined in World War I when ANUG was common among trench-bound soldiers.

Pathophysiology

The most common type of gingivitis involves the marginal gingiva and is brought on by the accumulation of microbial plaques in persons with inadequate oral hygiene. Gingivitis proceeds through an initial stage to produce early lesions, which then progress to advanced disease.

The initial stage of an acute exudative inflammatory response begins within 4 or 5 days of plaque accumulation. Both gingival fluid and transmigration of neutrophils increase. Deposition of fibrin and destruction of collagen can be noted in the initial stage. At approximately 1 week, transition to early lesions is marked by the change to predominately lymphocytic infiltrates. Monocytes and plasma cells also may be present. With time, lesions become chronic and are characterized by the presence of plasma cells and B lymphocytes. As chronic local inflammation progresses, pockets develop where the gingiva separates from the tooth. These pockets deepen and may bleed during tooth brushing, flossing, and even normal chewing. As this persistent inflammation continues, periodontal ligaments break down and destruction of the local alveolar bone occurs. Teeth loosen and eventually fall out.

ANUG is a completely different syndrome caused by acute infection of the gingiva with organisms such as Prevotella intermedia, alpha-hemolytic streptococci, Actinomyces species, or any of a number of different oral spirochetes. ANUG may result in accelerated destruction of affected tissues, as well as local or systemic spread of infection.

Noma (cancrum oris) is a syndrome in which ANUG spreads beyond the gingiva. The infection invades local tissues of the mouth and face.

Frequency

United States

Frequency is difficult to determine because of the lack of agreement on measurement criteria. Many people believe that gingivitis begins in early childhood and that 9-17% of children aged 3-11 years have gingivitis. At puberty, prevalence rises to 70-90%. In recent years, periodontal disease, the endpoint of chronic gingivitis, slowly has decreased among adult Americans.

ANUG may be a clinical problem in immunocompromised patients during chemotherapy. Gingivitis and resulting periodontal disease are seen more frequently in patients with either diabetes or HIV.

International

Studies in Australia, Sweden, England, and Switzerland report gingivitis in 48-85% of children aged 3-6 years, but whether this range reflects population differences or whether it is due to different criteria used to define the disease is difficult to know. In adolescence, incidence around the world is comparable to US data (70-90%). ANUG may be found in areas where those at risk, particularly children, face poor living conditions. Recent publications show several cases in areas such as Nigeria, where ANUG and noma were observed in children younger than 14 years.¹

Mortality/Morbidity

Periodontal disease has been shown in some studies to be an associated factor in coronary artery disease (CAD) and cerebrovascular disease/ischemic stroke.^2,3,4 This association with CAD has not been shown in all studies. Periodontal disease in pregnancy has been associated with an increase in preterm birth and adverse pregnancy outcomes.⁵ Periodontitis coexisting with bacterial vaginosis is associated with higher vaginal bacterial counts.⁶ Periodontitis in a person with diabetes has been associated with exacerbation of both conditions.^7,8 Treatment of periodontitis in persons with type 2 diabetes has improved glycemic control.⁹

Severe periodontal disease, as shown in the image below, may occur.

Severe periodontal disease. Loss of the gingival tissue is seen, making the teeth appear long. Even more effacement of the papillae is present. Heaped up ridges are observed in the areas overlying the roots. Image courtesy of Robert J. Lindberg, DMD.

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Severe periodontal disease. Loss of the gingival tissue is seen, making the teeth appear long. Even more effacement of the papillae is present. Heaped up ridges are observed in the areas overlying the roots. Image courtesy of Robert J. Lindberg, DMD.

Chronic gingivitis leads to tooth loss. ANUG may progress into the local soft tissues of the mouth, resulting in noma or cancrum oris, or may spread hematogenously to any other part of the body.

Sex

• Gingivitis is slightly more prevalent in males than in females because females tend to have better oral hygiene.

Age

• Adults are most commonly affected.
• Children from sub-Saharan regions of Africa may be at risk for ANUG because of poor living conditions.

Clinical

History

Historical findings depend on whether the patient has chronic gingivitis or ANUG.

• Chronic gingivitis
  • The most common complaint is bleeding gums. The patient usually notices this when toothbrushing or flossing.
  • Bleeding may be associated with eating, especially foods with a hard consistency, such as apples or crusted bread. These foods may rub against gums.
• Acute necrotizing ulcerative gingivitis
  • Apparently spontaneous bleeding or bleeding in response to very minimal local trauma may occur.
  • ANUG also may produce local pain, malaise, and alterations in taste, such as a metallic flavor.
  • ANUG may produce foul breath.

Physical

• Chronic gingivitis
  • Patients have minimal physical findings aside from local findings at the dental-gingival margins.
  • Gingival pockets may be detected with a periodontal probe. However, the pocket depth may be overestimated when periodontitis is present and underestimated in healthy gums.
  • Mild bleeding from the gum margins may occur with any manipulation.
• Acute necrotizing ulcerative gingivitis
  • Fever, halitosis, marked gingival edema, and ulceration, especially in the interdental papillae, may be present.
  • A grey pseudomembrane may be present.
  • Infection may spread to adjacent soft tissues of the mouth, with noticeable erythema, edema, tenderness, and induration of affected areas.
• Reaction to oral contraceptives (see Causes)

Causes

• Although bacteria play a role in all forms of gingivitis, the primary cause of chronic gingivitis is inadequate oral hygiene.
• Risk factors
  • Use of tobacco or ethanol is thought to be a risk factor.
  • Immune incompetence is observed more frequently in HIV-infected children. As their CD4 counts decline, incidence of gingivitis may increase. Diabetes mellitus increases the risk of gingivitis and periodontitis.
• Drug-induced causes
  • The list of drugs that cause gingivitis and gingival bleeding is extensive.
  • Gingival bleeding may occur with the use of anticoagulants and fibrinolytic agents.
  • Phenytoin, oral contraceptive agents, and calcium channel blockers may cause gingival hyperplasia.
  • Gingivitis has been observed with use of protease inhibitors (eg, saquinavir, ritonavir), vitamin A and analogues, danazol, pentamidine, misoprostol, methotrexate, and gold compounds.
  • Gingivostomatitis has been observed in exposure to arsenic, gold, bismuth, mercury, nickel, sulfur dioxide, lead, thallium, zinc, methyl violet, and topical chlorhexidine.
• Acute necrotizing ulcerative gingivitis
  • Acute necrotizing infection may occur as a complication of chronic gingivitis in situations in which hygiene is abandoned completely or host defenses are weakened.
  • ANUG is the result of soft tissue invasion by ubiquitous organisms and is not believed to be contagious.
  • It is a risk wherever poor sanitation, diet, or oral hygiene is present.
  • Living near livestock is an additional risk factor.
• Other causes
  • Inadequate plaque removal
  • Blood dyscrasias
  • Allergic reactions
  • Chronic debilitating disease
  • Poor nutrition
  • Lack of periodic dental examinations

Facial Pain and Headache

Introduction

Headache and facial pain are common complaints in the emergency and outpatient setting. The lifetime prevalence of headache is greater than 90%.¹ Most patients who present with headache have 1 of the following 3 main headache syndromes: migraine, cluster headache, or tension headache.²

However, headache and facial pain can have numerous other etiologies that are important for the clinician to consider. The reader is referred to the International Headache Society (IHS) classification for an exhaustive compilation of all headache and facial pain etiologies.

In the evaluation of headache and facial pain, the primary goal for the otolaryngologist is to make a distinction between sinogenic and nonsinogenic causes of headache and facial pain.

Relevant Neuroanatomy

The trigeminal nerve (cranial nerve V) and its constituent 3 major branches provide most somatosensory innervation to the head and face region. The trigeminal nerve originates in the lateral pons then divides into the following 3 divisions from the gasserian ganglion: the ophthalmic (V-1), the maxillary (V-2), and the mandibular (V-3) divisions.

The ophthalmic division (V-1) provides sensory innervation to most of the upper third of the head and face, including (but not limited to) the skin of the eyelids, eyebrow, forehead, and nose and part of the mucous membranes of the nasal cavity.³ Ethmoidal branches supply the mucous membranes of the ethmoid sinuses. An intracranial branch called the tentorial nerve of Arnold supplies the tentorium, superior surface of the transverse and straight dural sinuses, and the inferior two thirds of the falx cerebri.⁴

The maxillary division (V-2) innervates several key areas in the midface region including the upper teeth, the floor and anterior region of the nasal cavity, and the skin of the lateral nose and malar region. The sphenopalatine branches innervate the lining of the maxillary sinuses, and the middle meningeal branch supplies portions of the floor of the middle fossa dura.⁵

The mandibular branch (V-3) supplies the teeth and gums of the mandible, the skin of the lower face, the temporomandibular joint (TMJ) and also the dura of the lateral portion of the middle fossa and most of the cranium.⁵

The trigeminal system is the main source for sensory innervation to the supratentorial dura, venous sinuses, and meningeal arteries. The 7th, 9th, and 10th cranial nerves also contain somatosensory pain fibers that synapse with trigeminal pain axons.⁵

Sinogenic Facial Pain and Headache

Sinusitis

The International Headache Society (IHS) classification system lists the following criteria for a diagnosis for sinus headache:⁶

1. Frontal headache that is accompanied by pain in one or more regions of the face, ears, or teeth and that fulfills criteria C and D
2. Clinical, nasal endoscopic, or CT and/or MRI and/or laboratory evidence of acute or acute-on-chronic rhinosinusitis
3. Headache and facial pain that develop simultaneously with the onset or acute exacerbation of rhinosinusitis
4. Headache, facial pain, or both that resolve within 7 days of remission or successful treatment of acute or acute-on-chronic rhinosinusitis

Most sinonasal pain is referred and is deep, aching, and usually nonpulsatile. The location of pain can help localize which sinus may be particularly involved, as follows:⁷

• Frontal sinus - Frontal, vertex, and retro-orbital pain
• Maxillary sinus - Malar region and upper teeth pain
• Ethmoid sinus - Nasion and retro-orbital pain and pain that radiates to the temporal area
• Sphenoid sinus - Vertex, occipital, frontal, and retro-orbital pain

Patients with facial pain secondary to acute sinusitis have coexisting symptoms such as nasal obstruction, hyposmia, or purulent nasal discharge and have endoscopic signs of disease such as purulent drainage, inflammation, and edema.^8,9

Pain severity and radiographic disease severity are not related in patients with sinusitis.¹⁰

Jones et al found that in 679 patients with presumed sinusitis, pain was the presenting symptom for only 119 (18%). Of these patients, 25% had no endoscopic or CT findings of sinusitis.¹¹

Treatment of acute sinusitis consists of antibiotics with systemic or topical decongestants, analgesics, and aggressive hydration. Antibiotic treatment usually consists of amoxicillin or a macrolide antibiotic for 10-14 days. Patients who are poorly responsive, have continued disease at the end of treatment, and those with acute-on-chronic sinusitis may need treatment with second-line medications such as amoxicillin/clavulanate, second- or third-generation cephalosporins, fluoroquinolones, or clindamycin.

Endoscopic sinus surgery (ESS) should be considered for chronic rhinosinusitis in which medical therapy has failed. Studies have shown that facial pain and pressure improve in 56-77% of patients after ESS. Some studies have also reported improvement in facial pain in patients who undergo ESS for nonsinogenic headache and facial pain. However, most of these patients have recurrence of pain within 9 months.¹²

Sinus mucoceles

Sinus mucoceles (mucus-retention cysts) are chronic, slow-growing, cystic lesions. Mucoceles can be a source of pain when they are large enough to cause pressure against the bony walls of the sinus. Maxillary mucocele can cause sinusitis through ostiomeatal obstruction. Frontoethmoidal mucocele is the most clinically significant and can cause frontal headache and orbital pain. Sphenoethmoidal mucocele can cause occipital, vertex, or deep nasal pain. Treatment consists of endoscopic surgical removal or marsupialization.¹³

Contact points

Mucosal contact points within the nasal cavity have also been implicated as a cause for rhinogenic facial pain. Typically, the resolution of symptoms after the placement of a vasoconstrictive agent at a contact point was diagnostic of contact point pain. Controversy exists regarding this etiology for facial pain. In some studies, the prevalence of contact points has been shown to be equal between symptomatic and asymptomatic patients.¹⁴ Conversely, other studies have shown improvements in the pain scores of patients who underwent surgery for a diagnosis of mucosal contact point headache.¹⁵

Primary Headache Syndromes

Tension headache

A tension headache causes mild-to-moderate pain that is typically bilateral and nonpulsatile. Associated features are usually absent, but the headache may improve with physical activity. The most common trigger is stress.²

Relaxation training, stress management, and counseling have been shown to be beneficial.¹⁶ If frequent headache occurs, antidepressant medication is warranted. Acute attacks can be treated with limited usage of analgesics.²

Migraine

Migraine headache is typically considered to be a throbbing, unilateral pain, although up to 40% may have bilateral symptoms.² It is 3 times more common in women, and a positive family history often exists.¹⁷ Classic migraine occurs in 25% of patients with associated symptoms such as nausea, aura, and photophobia. Migraine symptoms can also overlap with those more characteristic of tension, cluster, or so-called sinus headache. Nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line agents for acute attacks. If these are ineffective, then specific medications such as triptans and dihydroergotamine are used. Preventative agents can also be used for those who experience chronic migraine, including beta blockers, tricyclic antidepressants, and anticonvulsants.²

Cluster headache

Cluster headache typically manifests as minutes to hours of severe unilateral temporal headache that occurs in grouped attacks over a period of weeks to months.¹⁶ Periorbital pain with associated rhinorrhea or lacrimation occurs. Cluster headaches most commonly occur in men aged 30-40 years. Acute treatment is oxygen at 7-12 L/min over 15 minutes. The abortive agent of choice is subcutaneous sumatriptan. Preventative agents include corticosteroids or ergotamine titrate.²

Secondary Facial Pain and Headache

Vascular headache

Headache and facial pain can be a presenting sign of a cerebrovascular disorder including, but not limited to, stroke and transient ischemic attack, intracerebral hemorrhage, subarachnoid hemorrhage, arteriovenous malformation, cerebral venous thrombosis, carotid artery dissection and vertebral artery dissection, and postcarotid endarterectomy headache.¹⁸

Temporal arteritis is a chronic vasculitis of medium- and large-sized vessels. Headache is the presenting symptom in 72% of patients.¹⁹ The pain is intense, unilateral or bilateral, and is associated with tenderness over the temporal arteries. Diplopia and jaw claudication can occur. Temporal artery biopsy is performed for diagnosis. Treatment consists of oral corticosteroids.¹⁸

Oral cavity and craniomandibular pain

Pain of dental origin can be referred to many areas of the head and face. Facial pain of dental origin is often caused by caries that progress to infection of the pulp or apical abscess or periodontal disease.²⁰

Temporomandibular joint (TMJ) disorders are known to cause facial pain and headache. Females with TMJ disorders outnumber males, and the onset is in those aged 30-50 years. The TMJ is a diarthrodial joint between the mandibular condyle and the glenoid fossa of the temporal bone. A fibrocartilaginous disc that is attached to the joint capsule allows the condyle to perform both rotational and translational movements.

The 3 main categories of TMJ syndrome are chronic myofascial pain, internal derangement, and degenerative joint disease (DJD).²⁰

• Chronic myofascial pain is most common and is similar in nature to fibromyalgia. The pain is unilateral, dull in character, and localized to the preauricular region. Pain is exacerbated by chewing, yawning, or the stimulation of certain trigger points that are usually located with palpable bands of muscle. Treatment consists of soft diet, analgesics, corticosteroids, local anesthetic blocks, muscle stretching, and treatment of psychological factors.²⁰
• Internal derangement usually consists of an anterior displacement of the disc. A dull preauricular pain with joint tenderness and an audible or palpable joint “click” is present upon examination.²⁰ Treatment consists of a soft diet, orthotic appliances, and physical therapy.²¹ Surgical management can be used in refractory cases, but this is becoming less common.
• DJD is essentially osteoarthritis of the joint and should be treated with a soft diet and NSAIDs.

Miscellaneous

The remaining categories of secondary headache include headaches attributed to head trauma and neck trauma, nonvascular intracranial disorders (eg, hydrocephalus, tumor), substance abuse or withdrawal (eg, caffeine withdrawal), infection (eg, meningitis), homeostasis disorders (eg, hypoxia, hypertension), disorders of cranial and facial structures (eg, orbital pain, otalgia, cervical spine disorders), and psychiatric causes.

Cranial Neuralgias

Facial neuralgias are often sudden, lancinating pains that are unilateral and limited to the distribution of the affected cranial nerve.²²

Trigeminal neuralgia

This is the most common cranial neuralgia, with an incidence of 5 per 100,000.²² It is a brief, paroxysmal, unilateral, stabbing pain in the distribution of one or more of the branches of the fifth cranial nerve. The mandibular branch is most commonly affected. Pain is often triggered by minimal stimulation of the affected area, oftentimes in the location of a “trigger zone.” Most cases are idiopathic, but secondary trigeminal neuralgia (TN) can be caused by vascular or neoplastic compression of the gasserian ganglion or infiltrating lesions.¹⁸ Treatment initially consists of carbamazepine or other antiepileptic drugs.²² Surgical microvascular decompression and also the use of gamma knife radiation have been shown to treat cases caused by compression of the trigeminal nerve from pontine vessels.²³

Glossopharyngeal neuralgia

This is a paroxysmal pain that originates in the tonsillar fossa or tongue base region. The pain can be provoked by swallowing, chewing, yawning, or talking.²³ Hypotension, bradycardia, or syncope can also occur. The etiology is thought to be from intracranial vascular compression of the ninth cranial nerve as it exits the medulla. Initial treatment consists of carbamazepine.²²

Occipital neuralgia

This occurs in the suboccipital region following the distribution of the greater or lesser occipital nerves. It can occur secondary to trauma to the nerves, arthritic changes to the cervical spine, or compression from tumor. Anticonvulsants, antidepressants, local nerve blocks, and surgical cervical root sectioning have all been described as treatments for idiopathic cases.²²

Nervus intermedius neuralgia

This is a lancinating pain in the somatosensory branch of the seventh cranial nerve. The pain is a deep pain in the external auditory canal triggered by stimulation of the canal or by swallowing or talking. Medical management is similar to that for trigeminal neuralgia.²²

Central and Idiopathic Facial Pain and Headache

Two main idiopathic disorders that cause headache and facial pain are midfacial segment pain and atypical facial pain.

Midfacial segment pain

This is a form of tension-type headache of the midface. Pain is a symmetric pressure sensation in the nasion, nasal dorsum, periorbital, or malar region. Hyperesthesia of the skin and soft tissues is also found. Treatment consists of low-dose amitriptyline at 10 mg for 6 months, which may take up to 6 weeks to show effect.²⁴

Atypical facial pain

This is also known as persistent idiopathic facial pain, as classified by the International Headache Society (IHS). The pain is constant, deep, and ill defined, usually crossing recognized dermatomes. The distribution is often unilateral. It occurs most commonly in women older than 40 years. The pain may alter in location, and psychological factors may play a role. The treatment is similar to that for midfacial segment pain.²⁵

Workup and Treatment

History

The onset, duration, quality, location, and exacerbating and relieving factors of the pain are important points to elicit. The clinician should ask about any associated factors such as aura, tearing, rhinorrhea, nausea, and photophobia. A history of rhinitis, recurrent or acute sinusitis, purulent nasal discharge, and hyposmia should be elicited. Comorbid illness such as diabetes, hypertension, dental disease, psychiatric illness, or a history of head or facial trauma or prior surgery should be questioned. A review of systems should include constitutional symptoms such as weight loss, fatigue, fevers, and gastrointestinal complaints. The patient should provide a full list of his or her medications. A social history should include a history of substance abuse, caffeine use, and use of alcohol or tobacco. A family history of migraine, other headache, or head and neck cancer should be noted.

Physical examination

A thorough head and neck examination should be performed, including testing of the cranial nerves, palpation for points of tenderness, trigger points, jaw clicks, and dental pain. If a rhinogenic source is a concern, nasal endoscopy looking for purulence, edema, inflammation, trauma, and tumor should be performed. A neurologic examination should also be performed.

Imaging studies

• Noncontrast CT of the sinuses with axial and coronal sections is the criterion standard for the radiographic diagnosis of sinusitis or possible rhinogenic causes of pain.
• MRI is useful for the evaluation of temporomandibular joint (TMJ) disorders, specifically for internal derangement.
• MRI, and/or magnetic resonance angiography (MRA) of the brain is useful to evaluate for intracranial pathology (tumor, hydrocephalus) and vascular sources of headache. It also is used to assess for microvascular compression of cranial nerve roots.

Treatment

Treatment methods for individual etiologies of headache and facial pain are discussed above. Depending on the clinical suspicion of the possible etiologies of facial pain and headache, the appropriate consultations should be made. For concerns of head and neck lesions or sinus-related headache, an otolaryngologist should be consulted. If a primary headache syndrome or a cranial neuralgia is of concern, the patient should be evaluated by a neurologist. Dentists and oral surgeons should be involved in the care for a patient with a dental or craniomandibular cause of pain. In some cases, a psychiatry referral is appropriate. Any concern for intracranial hemorrhage or meningitis should be evaluated in the emergency setting.

Keywords

headache, head ache, facial pain, head pain, sinusitis, trigeminal neuralgia, temporomandibular joint disorder, TMD, temporomandibular joint, TMJ, migraine, cluster headache, tension headache, sinogenic facial pain, sinogenic headache, rhinosinusitis, sinus mucocele, mucosal contact points, mucus-retention cysts, vascular headache, oral cavity pain, craniomandibular pain

Aphthous Ulcers 2

Introduction

Background

Commonly termed canker sores, aphthous ulcers, or aphthous stomatitis, have been the focus of study and research for many years, although the exact etiology of the lesions has yet to be identified. Categorized as an idiopathic disease, aphthous ulcers are frequently misdiagnosed, treated incorrectly, or simply ignored.

Recurrent aphthous ulcer (RAU), or recurrent aphthous stomatitis (RAS), represents a chronic inflammatory disease characterized by painful oral ulcers recurring with varying frequency. Examples of aphthous ulcers are shown in the images below.

Recurrent aphthae in floor of mouth, showing ovoid ulcer with inflammatory halo.

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Recurrent aphthae in floor of mouth, showing ovoid ulcer with inflammatory halo.

Typical aphthous ulcer in a common site, showing inflammatory halo surrounding a yellowish, round ulcer.

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Typical aphthous ulcer in a common site, showing inflammatory halo surrounding a yellowish, round ulcer.

Children with recurrent aphthous ulcers (canker sores) may reduce their oral food and fluid intake because of the associated pain and subsequently become dehydrated; therefore, aggressive therapy for the lesions can be important.

Recurrent aphthous ulcers (canker sores) may initially appear as erythematous, indurated papules that erode to form sharply circumscribed necrotic ulcers with a gray, fibrinous exudate and an erythematous halo. The 3 categories of recurrent aphthous ulcers (canker sores) are as follows:

• Minor aphthous ulcers (80-85% of recurrent aphthous ulcers [canker sores]) are 1-10 mm in diameter and heal spontaneously in 7-10 days.
• Major aphthous ulcers (also called Sutton disease) constitute 10-15% of recurrent aphthous ulcers (canker sores). These lesions are greater than 10 mm in diameter, take 10-30 days or more to heal, and may leave scars.
• Herpetiform ulcers (5-10% of recurrent aphthous ulcers [canker sores]) are multiple, clustered, 1-mm to 3-mm lesions that may coalesce into plaques. These usually heal in 7-10 days.

Pathophysiology

The pathophysiology of aphthous ulcers remains incompletely understood. The primary disorder appears to be the result of activation of the cell-mediated immune system. Early lesions show a cluster of macrophages and lymphocytes (predominantly cytotoxic and natural-killer T cells) at the preulcerative base, followed by formation of an ulcer with a neutrophilic base and an erythematous lymphocytic ring.

Patients with recurrent aphthous ulcers (canker sores) have increased numbers of cytotoxic CD8⁺ cells and decreased numbers of helper CD4⁺ cells in peripheral blood.¹ Lesions have elevated levels of interferon gamma, tumor necrosis factor-alpha, interleukin (IL)-2, IL-4, and IL-5;² they have a functional deficit of IL-10. Some lesions have also had mast-cell activation and degranulation. In vitro cytotoxicity to oral keratinocyte targets is greater in patients with active recurrent aphthous ulcers (canker sores) than in control subjects or in patients with traumatic ulcers. As expected with this abnormal immunologic activity, corticosteroids are effective therapy.

Aphthous ulcers may have abnormalities in cell communication and epithelial integrity. Lesions have increased expression of an adhesion molecule termed vascular cell adhesion molecule-1 (VCAM-1), E selectin, and keratinocyte intercellular adhesion molecule-1 (ICAM-1).³ Connexins (markers for the presence of gap junctions) are present in the oral mucosa of patients with recurrent aphthous ulcers (canker sores) in amounts similar to those present in normal mucosal tissue. Experimental treatment with irsogladine maleate, which reinforces gap junctional intercellular communication, is effective. Helicobacter pylori may or may not be involved in aphthous ulcer formation.^4,5

Factors predisposing patients to recurrent aphthous ulcers (canker sores) may include trauma, emotional stress,⁶ poor nutritional status, thiamine deficiency,⁷ vitamin B12 deficiency, malabsorption, celiac disease, regional enteropathy, menstruation, food hypersensitivity (eg, cow's milk),⁸ allergic reaction, and exposure to toxins (eg, nitrates in drinking water). Aphthous ulcers (canker sores) are more prevalent in nonsmokers and in smokers who quit but are diminished with nicotine replacement therapy.

Frequency

United States

Although recurrent aphthous ulcers (canker sores) are commonly believed to occur in approximately 20% of the general population, a study of medical and dental students revealed a prevalence of 31-66%.

International

The worldwide incidence is similar to that in the United States. Aphthous ulcers (canker sores) are found in all ethnic groups and geographic locations. The prevalence may be increased in affluent countries and socioeconomic classes.

Mortality/Morbidity

Aphthous ulcers (canker sores) are associated with local pain and discomfort. Symptoms usually last 2-10 days with minor and herpetiform ulcers and as long as 30 days with major ulcers. Most cases are self-limited and heal without sequelae in 7-14 days; however, major ulcers heal slowly (10-30 days or longer).

• Major aphthous ulcers (canker sores) have been known to leave substantial scars.
• The primary morbidity with any type of aphthous ulcer (canker sore) in the pediatric population is dehydration due to poor oral intake.
• Secondary bacterial infections are uncommon.

Race

Race does not appear to influence the frequency or severity of recurrent aphthous ulcers (canker sores).

Sex

Aphthous ulcers (canker sores) may be slightly more common in female individuals than in male individuals. Outbreaks occur most frequently during ovulation or before menstruation, and remissions are common during pregnancy.

Age

Recurrent aphthous ulcers (canker sores) begin in childhood or adolescence, with peak onset in persons aged 10-19 years. Frequency and severity diminish with age. Major aphthous ulcers (canker sores) may begin soon after puberty. Herpetiform recurrent aphthous ulcers (canker sores) tend to affect older persons.

Clinical

History

The diagnosis of aphthous ulcers (canker sores) is primarily clinical. Patients typically describe a prodromal stage of a burning or pricking sensation of the oral mucosa 1-2 days before the ulcer appears. Patients with recurrent aphthous ulcers (RAUs), or canker sores, often mention precipitating factors, such as local trauma or food hypersensitivity.

• During the review of systems, infants and small children should be assessed for decreased feeding, weight, and urine output. Associated symptoms, such as those below, suggest other diagnoses and are not associated with recurrent aphthous ulcers (canker sores).
  • Fever
  • Malaise
  • Myalgias
  • Arthralgias
  • Headache
  • Cough
  • Nausea
  • Vomiting
  • Abdominal pain
  • Diarrhea
  • Sore throat
  • Swollen or painful lymphadenopathy
  • Rash
  • Genital or conjunctival lesions
• Inquire about previous ulcers. The natural history of individual lesions is important because it is the benchmark against which treatment benefits are measured.
  • Age at onset should be noted because major recurrent aphthous ulcers (canker sores) begin after puberty, and herpetiform ulcers are uncommon in children.
  • The duration, location, and size of previous lesions should be noted, as well as the therapy received.
  • Having patients keep an ulcer diary for 1-3 months may be useful.
• Ask the patient about medication use, chemotherapy, radiation therapy, vitamin supplementation, and recent dietary changes.
• Assess for a family history of the following:
  • Aphthous ulcers (canker sores)
  • Inflammatory bowel disease
  • Gluten-sensitive enteropathy
  • Behçet disease
  • Systemic lupus erythematosus
• Review the patient's medical history. Consider Behçet disease; human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS); cancer; Crohn disease; immunocompromised state; cyclic neutropenia; mouth and genital ulcers with inflamed cartilage (MAGIC syndrome); and systemic lupus erythematosus.

Physical

Aphthous ulcers (canker sores) occur on areas of the mouth in which the mucosa is nonkeratinized and loosely attached, particularly the buccal mucosa, the labial mucosa, the floor of the mouth, the ventral surface of the tongue, and the soft palate. Ulcers may appear as single or multiple lesions, and they are easily distinguished from primary or secondary viral infections, bacterial infections (eg, necrotizing ulcerative gingivitis), dermatologic conditions (lichen planus, cicatricial pemphigoid, pemphigus), and traumatic injuries (contusions, lacerations, burns) by the healthy appearance of adjacent tissues and the lack of distinguishing systemic features.

• Minor ulcers are seldom larger than 5 mm but can be as large as 1 cm. They may be single or multiple. The ulcers are round-to-oval, they are covered by a gray or yellowish and fibrinous surface, and they are surrounded by an erythematous border.
• Major recurrent aphthous ulcers (canker sores) can be 1-3 cm in diameter. They are deeper than minor ulcers and often have a raised, irregular, erythematous border. Patients with a history of major recurrent aphthous ulcers (canker sores) often have residual scarring in the oral mucosa from previous lesions.
• Herpetiform aphthous ulcers appear as small (seldom >3 mm in diameter), tightly clustered lesions. They typically number 2-10 but may number as many as 100. They are not related to herpes simplex infections and do not present as or develop into vesicular lesions. The ulcers appear identical to minor aphthous ulcers with the exception of their small size, proximity to other lesions, and increased numbers. Confusion may arise if the lesions coalesce into a large lesion resembling major aphthous stomatitis.
• The rest of the mouth should appear normal. However, halitosis and necrotic, exudative, or bleeding gums may be present with the following: (1) necrotizing ulcerative gingivostomatitis; (2) erythematous tonsils with periodic fever, aphthous pharyngitis, and adenopathy (PFAPA) syndrome;^9,10 and (3) vesicular-ulcerative palatal lesions with coxsackieviral infection.
• Vital signs should be normal. Secondary bacterial infection, PFAPA syndrome, primary viral infection, or rheumatologic disorder may cause fever.
• Clinical evidence of dehydration may include decreased weight, tachycardia, hypotension, cool extremities, delayed capillary refill, depressed fontanelle, dry mucus membranes, decreased skin turgor, or decreased axillary moisture. Plotting the weight and height may reveal a trend toward the low percentiles for age; this finding suggests nutritional deficiency or malabsorption syndrome.
• Skin findings should be normal, but rash may be present with Behçet syndrome, erythema multiforme, hand-foot-and-mouth disease, herpes simplex infection, lichen planus, MAGIC syndrome, pemphigus, pemphigoid, Sweet syndrome, syphilis, systemic lupus erythematosus, varicella (chickenpox), or varicella zoster.
• The joints should be normal, but joints may be tender with effusion, erythema, or decreased range of motion in Reiter syndrome, systemic lupus erythematosus, or MAGIC syndrome.
• The eyes should be normal, but examination may reveal conjunctival lesions in patients with Behçet syndrome or cicatricial pemphigoid. Uveitis or iritis may be present with Reiter syndrome or Behçet syndrome.
• Cervical adenopathy should be minimal. Tender or markedly enlarged lymph nodes suggest PFAPA syndrome.

Causes

Precipitating factors include trauma, salivary gland dysfunction, stress, genetic predisposition, local infections, nutritional deficiencies, GI disorders, systemic disorders, food allergy or hypersensitivity, hormonal fluctuations, and chemical exposure.

• Trauma: Local injury, such as that caused by an accidental bite, dental injection, toothbrush bristle, or ingestion of sharp food, may precipitate aphthous ulcers in individuals who are susceptible. Traumatic piercing uncommonly occurs in keratinized mucosal epithelium, and recurrent aphthous ulcers (canker sores) are rare in keratinized mucosa.
• Stress: Psychological and physiologic stress may increase the risk of aphthous ulcers.⁶ Individuals with aphthous ulcers have had higher-than-average anxiety scores and cortisol levels. Antidepressant therapy may be effective in some patients.
• Genetic predisposition: A family history of recurrent aphthous ulcer (canker sore) is common, though familial penetrance has not been identified as a specific category. recurrent aphthous ulcers (canker sores) may be associated with human leukocyte antigen (HLA) haplotypes B51 (also common in Behçet syndrome), Cn7, A2, B12, and Dr5.
• Local infection: Several infectious agents have been identified in association with aphthous ulcer lesions, including human herpesvirus (HHV)-6,¹¹ HHV-8, varicella zoster virus, human papilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV)-1, HSV-2, Helicobacter species, and L-forms of streptococci.¹² However, authorities generally agree that aphthous ulcers and RAU do not represent acute infections and are not contagious.
• Nutritional deficiencies: Deficiencies of iron; folic acid; zinc; and vitamins B-1, B-2, B-6, B-12, and C have all been implicated in recurrent aphthous ulcers (canker sores). Oxidative stress and diminished antioxidant activity (vitamin E and selenium) may also predispose individuals to recurrent aphthous ulcers (canker sores).¹³
• GI disorders, such as regional enteropathy (Crohn disease), ulcerative colitis, and celiac disease (gluten-sensitive enteropathy), may result in aphthous ulcers. The ulcers may be the only presenting symptom or the only symptom that is evident for a number of years in patients with GI disorders; therefore, a high degree of suspicion should be maintained when patients present with recurrent aphthous ulcers (canker sores).
• Systemic disorders: Disorders such as cyclic neutropenia, Reiter syndrome, Behçet disease, or HIV infection may result in aphthous ulcers (canker sores).
• Food allergy and hypersensitivity: Flavoring agents, essential oils, benzoic acid, cinnamon, gluten, cow's milk,⁸ coffee, chocolate, potatoes, cheese, figs, nuts, citrus fruits, and certain spices have been implicated in some individuals with recurrent aphthous ulcers (canker sores).
• Hormonal fluctuations: In some women, recurrent aphthous ulcers (canker sores) are associated with the menstrual cycle, with outbreaks most commonly occurring during ovulation or before menstruation. A diminished incidence of recurrent aphthous ulcers (canker sores) during pregnancy has been reported.
• Chemical exposures: High levels of nitrates in drinking water have been associated with aphthous ulcers.¹⁴ The nitrates may induce cytochrome b ₅ reductase activity. Sodium lauryl sulfate (SLS), a detergent commonly used in toothpaste, may be a trigger of aphthous ulceration in some individuals.^15,16 Use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with aphthous ulcers.¹⁷ Smoking and nicotine exposure do not increase, and may actually decrease, the risk of aphthous ulcers.
• Significant correlations have been shown between the severity of aphthous stomatitis and hygiene of the oral cavity.¹⁸ Good hygiene reduces not only the number of outbreaks but also the severity.

Aphthous Ulcers

Introduction

Background

Recurrent aphthous stomatitis (RAS) is a common condition, restricted to the mouth, that typically starts in childhood or adolescence as recurrent small, round, or ovoid ulcers with circumscribed margins, erythematous haloes, and yellow or gray floors. A positive family history of similar ulcers is common, and the natural history is typically of resolution in the third decade of life.

Ulcers with similar clinical features but rarely resolving spontaneously with age may be termed "aphthous-like ulcers," and may then be associated with systemic conditions such as Behçet syndrome, auto-inflammatory syndromes, gastrointestinal disease, or immune defects such as HIV/AIDS.

Traumatic ulcer on ventrum/lateral margin of tongue; these must be differentiated from aphthae.

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Traumatic ulcer on ventrum/lateral margin of tongue; these must be differentiated from aphthae.

Pathophysiology

The etiology of recurrent aphthous stomatitis (RAS) is not entirely clear, and aphthae are therefore termed idiopathic. RAS may be the manifestation of a group of disorders of quite different etiology, rather than a single entity.

Despite many studies trying to identify a causal microorganism, RAS does not appear to be infectious, contagious, or sexually transmitted. Immune mechanisms appear at play in persons with a genetic predisposition to oral ulceration.

A genetic basis exists for some RAS. This is shown by a positive family history in about one third of patients with RAS, an increased frequency of HLA types A2, A11, B12, and DR2, and susceptibility to RAS which segregates in families in association with HLA haplotypes. RAS probably involves cell-mediated mechanisms, but the precise immunopathogenesis remains unclear. Phagocytic and cytotoxic T cells probably aid in destruction of oral epithelium that is directed and sustained by local cytokine release.

Patients with active RAS have an increased proportion of gamma-delta T cells compared with control subjects and patients with inactive RAS. Gamma-delta T cells may be involved in antibody-dependent cell-mediated cytotoxicity (ADCC). Compared with control subjects, individuals with RAS have raised serum levels of cytokines such as interleukin (IL)–6 and IL-2R, soluble intercellular adhesion modules (ICAM), vascular cell adhesion modules (VCAM), and E-selectin; however, some of these do not correlate with disease activity.

Cross-reactivity between a streptococcal 60- to 65-kd heat shock protein (hsp) and the oral mucosa has been demonstrated, and significantly elevated levels of serum antibodies to hsp are found in patients with RAS. Lymphocytes of patients with RAS have reactivity to a peptide of Mycobacterium tuberculosis. Some cross-reactivity exists between the 65-kd hsp and the 60-kd human mitochondrial hsp. Monoclonal antibodies to part of the 65-kd hsp of M tuberculosis react with Streptococcus sanguis. RAS thus may be a T cell–mediated response to antigens of S sanguis, which cross-react with the mitochondrial hsp and induce oral mucosal damage. RAS patients have an anomalous activity of the toll-like receptor TLR2 pathway that probably influences the stimulation of an abnormal Th1 immune response.

Predisposing factors found may include any of the following:

• Hematinic deficiency: Up to 20% of patients are deficient of iron, folic acid (folate), or vitamin B.
• Malabsorption in gastrointestinal disorders: About 3% of patients experience these disorders, particularly celiac disease (gluten-sensitive enteropathy) but, occasionally, Crohn disease, pernicious anemia, and dermatitis herpetiformis. HLA DRW10 and DQW1 may predispose patients with celiac disease to RAS.
• Cessation of smoking: This may precipitate or exacerbate RAS in some cases.
• Stress: This underlies RAS in some cases; ulcers appear to exacerbate during school or university examination times.
• Trauma: Biting of the mucosa and wearing of dental appliances may lead to some ulcers; RAS is uncommon on keratinized mucosae.
• Endocrine factors in some women: RAS is clearly related to the progestogen level fall in the luteal phase of the menstrual cycle, and ulcers may then temporarily regress in pregnancy.
• Allergies to food: Food allergies occasionally underlie RAS; the prevalence of atopy is high. Patients with aphthae may occasionally have a reaction to cow's milk, and may have been weaned at an early age.
• Sodium lauryl sulphate (SLS): This is a detergent in some oral healthcare products that may aggravate or produce oral ulceration.
• Immune deficiencies: Ulcers similar to RAS may be seen in patients with HIV, neutropenias and some other immune defects.
• Drugs, especially NSAIDs, alendronate, and nicorandil:¹ These may produce lesions clinically similar to RAS.

Frequency

United States

RAS affects 5-66% of the population. Approximately 1% of children from higher socioeconomic groups in developed countries have RAS; however, 40% of selected groups of children can have a history of RAS, with ulceration beginning before age 5 years and with the frequency of affected patients increasing with age.

Mortality/Morbidity

Most patients with RAS are otherwise well.

Race

RAS have been reported in all races

Sex

A slight female predominance exists.

Age

RAS typically starts in childhood or adolescence.

Clinical

History

The 3 main clinical types of recurrent aphthous stomatitis (RAS) are as follows:

(1) Minor aphthous ulcers (MiAUs, 80% of all RAS)

(2) Major aphthous ulcers (MjAUs)

(3) Herpetiform ulcers.

However, any significance of these distinctions is unclear (ie, they could just be 3 distinct disorders). Diagnosis is based on history and clinical features.

Characteristics of MiAUs (ie, Mikulicz ulcers) include the following:

• They occur mainly in persons 10-40 years of age.
• They often cause minimal symptoms.
• They are small round or ovoid ulcers 2-4 mm in diameter. (MiAUs are round or ovoid in most situations but are often more linear when in the buccal sulcus, a common site.)
• They have an ulcer floor that is initially yellowish but assumes a gray hue as healing and epithelialization proceeds.
• They are surrounded by an erythematous halo and some edema.
• They are found mainly on the nonkeratinized mobile mucosa of the lips, cheeks, floor of the mouth, sulci, or ventrum of the tongue; they are uncommonly seen on the keratinized mucosa of the palate or dorsum of the tongue.
• They occur in groups of only a few ulcers (ie, 1-6) at a time.
• They heal in 7-10 days.
• They recur at intervals of 1-4 months.
• They leave little or no evidence of scarring.

Characteristics of MjAUs (ie, Sutton ulcers, periadenitis mucosa necrotica recurrens [PMNR]) include the following:

• They are larger, of longer duration, of more frequent recurrence, and often more painful than MjAUs.
• They are round or ovoid like MjAUs but are larger and associated with surrounding edema.
• They reach a large size, usually about 1 cm in diameter or even larger.
• They are found on any area of the oral mucosa, including the keratinized dorsum of the tongue or palate.
• They occur in groups of only a few ulcers (ie, 1-6) at one time.
• They heal slowly over 10-40 days.
• They recur extremely frequently.
• They may heal with scarring.
• They occasionally are found with a raised erythrocyte sedimentation rate or plasma viscosity.

Characteristics of herpetiform ulceration (HU) include the following:

• They are found in a slightly older age group than the other RAS.
• They are mainly found in females.
• They begins with vesiculation that passes rapidly into multiple, minute, pinhead-sized, discrete ulcers.
• They involve any oral site, including the keratinized mucosa, increase in size, and coalesce to leave large round ragged ulcers.
• They heal in 10 days or longer.
• They are often extremely painful.
• They recur so frequently that ulceration may be virtually continuous.

Most patients appear to be otherwise well, but a minority have etiologic factors that can be identified by the history. These factors may include the following:

• Dentifrices containing sodium lauryl sulfate
• Trauma
• Stress
• Cessation of smoking
• Menstrual cycle association
• Food allergy

Aphthous-like ulcers may appear in the following diseases and states:

• Hematinic deficiency (eg, iron, folate, vitamin B-12)
• Celiac disease
• Crohn disease
• Behçet syndrome, which may include genital, cutaneous, ocular, or other lesions (The mouth ulcers in Behçet syndrome are often major aphthae, with frequent episodes and long duration to healing.)
• Immunodeficiencies such as human immunodeficiency virus (HIV) infection, and neutropenia (Ulcers appearing on a regular 3-week cycle may indicate cyclic neutropenia.)
• Auto-inflammatory syndromes, such as periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA) in children
• Malignancy (Ulcers appearing for the first time in an older individual may reflect underlying systemic disease [eg, colonic carcinoma with chronic hemorrhage].)
• Drug use (eg, nicorandil, NSAIDs, others)
• Sweet syndrome, a rare immunologically mediated condition that belongs to the group of neutrophilic dermatoses and must be differentiated, particularly from Behçet disease
  • Sweet syndrome is characterized by red-brown plaques and nodules that are frequently painful and occur primarily on the head, neck, and upper extremities.
  • Patients often also have neutrophilia and fever and may have oral ulceration.

Physical

RAS ulcers are recurrent small, round, or ovoid ulcers with circumscribed margins, erythematous haloes, and yellow or gray floors. No specific investigations exist for RAS.

Causes

Some RAS cases involve a familial and genetic basis; approximately 40% of patients with RAS have a familial history, but inheritance may be polygenic with penetrance dependent on other factors.

• Most relevant studies have found hematinic (eg, iron, folic acid, vitamin B-12) deficiencies in as many as 20% of patients with recurrent ulcers. In addition, deficiencies of vitamins B-1, B-2, and B-6 have been noted in some patient cohorts.
• The previously proposed association between recurrent ulcers and celiac disease (gluten-sensitive enteropathy [GSE]) is tenuous, despite some evidence that the haplotype of HLA-DRW 10 and DQW1 may predispose patients with GSE to RAS.
• Hypersensitivity reactions to exogenous antigens other than gluten do not have a significant etiologic role in RAS, and associations with atopy are inconsistent.
• Local physical trauma may initiate ulcers in susceptible people, and RAS is uncommon where mucosal keratinization is present or in patients who smoke tobacco.
• A consistent association between aphthouslike ulceration and psychological illness, zinc deficiency, or sex hormone levels is unlikely.
• Various microorganisms have been examined for a causal association. Latterly, Helicobacter pylori has been detected in lesional tissue of ill-defined oral ulcers, but the frequency of serum immunoglobin G (IgG) antibodies to H pylori is not increased in RAS. Little evidence suggests an etiologic association between viruses and RAS. Human herpesviruses (HHV)–6 and HHV-7 DNA have not been demonstrated in RAS, but HHV-8 DNA is present in HIV-related oral ulcers.

Lupus Erythematosus, Drug-Induced

Introduction

Background

Lupus erythematosus (LE) is an autoimmune disease that can affect the skin, joints, heart, lungs, kidneys, and brain. Drug-induced lupus erythematosus (DILE) is a variant of autoimmune disease that resolves within days to months after withdrawal of the culprit drug in a patient with no underlying immune system dysfunction. Care must be taken to correctly diagnose the symptoms of drug-induced lupus erythematosus and differentiate it from the systemic autoimmune disease, and drug-induced lupus erythematosus should be recognized clinically and serologically for prompt intervention.

Drug-induced lupus erythematosus can arise months to years after exposure to drugs prescribed to treat various medical conditions (eg, antihypertensives, antibiotics, anticonvulsants). The most common drugs that cause drug-induced lupus erythematosus are hydralazine, procainamide, quinidine, isoniazid, diltiazem, and minocycline.¹

Although both systemic lupus erythematosus (SLE) and drug-induced lupus erythematosus are autoimmune disorders and can have similar clinical and laboratory features, research suggests different mechanistic pathways. Guidelines for diagnoses and management of SLE have been established.² Although the pathogenesis of drug-induced lupus erythematosus is not completely understood, a genetic predisposition may play a role, as has been shown with certain drugs metabolized by acetylation, such as procainamide or hydralazine.³ Varying mechanisms leading to the formation of self-recognizing antibodies may explain the differential characteristics of drug effects in persons with drug-induced lupus erythematosus and lupus erythematosus. For example, whereas some drugs can cause drug-induced lupus erythematosus, others may cause a flare of preexisting SLE.

Drugs such as procainamide, chlorpromazine, and quinidine cause the production of antinuclear antibodies against the histone dimer H2A-H2B. Hydralazine forms antinuclear antibodies to H1 and the H3-H4 complex.⁴ Drugs that cause drug-induced lupus erythematosus usually take months to years before the associated symptoms occur, whereas flares of SLE due to drugs may occur within hours to days.

Drug-induced lupus erythematosus is characterized by improvement upon withdrawal of the offending drug or agent in a patient with a previously normal immune system. No specific criteria establish the diagnosis of drug-induced lupus erythematosus, and excluding underlying autoimmune disease is not a simple process. Obvious clinical or serologic evidence of drug-induced lupus erythematosus is not invariably present, even in rare cases of fatal drug-induced lupus erythematosus. Patients who have serologic and clinical findings that normally indicate SLE might actually have drug-induced lupus erythematosus. The symptoms of both drug-induced flares of SLE and drug-induced lupus erythematosus are temporally related to drug exposure, and SLE and drug-induced lupus erythematosus have similar manifestations. Thus, drug-induced lupus erythematosus is typically diagnosed by a process of elimination to rule out SLE.

Although both lupus erythematosus and drug-induced lupus erythematosus can affect multiple organ systems, including the skin, joints, kidneys, and CNS, complications of drug-induced lupus erythematosus that affect the kidneys and CNS are generally considered rare. In drug-induced lupus erythematosus induced by certain drugs, however, the rate of kidney involvement can be significant. For example, the rate of glomerulonephritis in hydralazine-induced drug-induced lupus erythematosus is 5-10%.

Penicillamine is also more likely to be associated with renal disease. Rare cases of death associated with drug-induced lupus erythematosus have been reported as a direct result of renal complications. Thus, a renal biopsy may be necessary to rule out membranous proliferative and necrotizing glomerulonephritis. Hepatic necrosis is another potential serious complication of drug-induced lupus erythematosus and has been documented in cases of minocycline-induced drug-induced lupus erythematosus.

For proper diagnosis, the following factors should be preliminarily confirmed:

• The patient has one or more clinical symptoms of SLE (eg, arthralgias, lymphadenopathy, rash, fever).
• Antinuclear antibodies are present.
• The patient had no history of SLE prior to using the culprit drug.
• The drug was taken anytime from 3 weeks to 2 years prior to the appearance of symptoms.
• Clinical improvement is rapid when the drug is discontinued, whereas antinuclear antibodies and other serologic markers slowly decrease toward more normal levels.

Drugs that cause drug-induced lupus erythematosus are as follows:

• Acebutolol
• Amiodarone
• Atenolol⁵
• Bupropion
• Captopril
• Carbamazepine⁶
• Chlorpromazine
• Diltiazem⁷
• Docetaxel
• Ethosuximide
• Gemfibrozil
• Glyburide
• Gold salt
• Griseofulvin
• Hydantoins
• Hydralazine
• Hydroxychloroquine
• Interferons
• Interleukins
• Isoniazid
• Leuprolide acetate
• Lithium
• Lovastatin
• Mephenytoin
• Methyldopa
• Minocycline⁸
• Nitrofurantoin
• Olanzapine
• Ophthalmic timolol
• Oral contraceptives
• Penicillamine
• Phenytoin
• Practolol
• Procainamide
• Propylthiouracil
• Quinidine
• Reserpine
• Rifampin
• Rifamycin⁹
• Sertraline¹⁰
• Simvastatin
• Sulfasalazine¹¹
• Tetracycline
• Ticlopidine
• Tiotropium bromide inhaler¹²
• Trimethadione
• Tumor necrosis factor-α (TNF α) (etanercept, infliximab, adalimubab)¹³
• Valproate
• Voriconazole

Drugs that cause flares of SLE are as follows:

• Cimetidine
• Hydralazine
• Hydrochlorothiazide
• Mesantoin
• P -Aminobenzoic acid (PABA)
• Penicillin
• Phenylbutazone
• Sulfonamides
• Terbinafine¹⁴

Pathophysiology

Both SLE and drug-induced lupus erythematosus are autoimmune diseases that cause the immune system to manufacture autoantibodies against the patient's own tissues. Which drug characteristics cause the autoantibody formation is unclear, but several theories have been proposed.

One is that the drug serves as a substrate for myeloperoxidase, which is activated in polymorphonuclear neutrophils. This interaction causes the formation of reactive metabolites that directly affect lymphocyte function. A second theory is that with decreased T-cell methylation, an overexpression of lymphocyte function–associated antigen (LFA-1) occurs. T cells with hypomethylated DNA become autoreactive and cause antibody formation. This is the mechanism by which UV light causes flares of lupus. A third theory is that the genetic differences in an individual’s P450 system causes drugs to be metabolized differently, which results in the generation of toxic metabolites that may facilitate autoimmunity.

The medications and other exposures implicated in drug-induced lupus erythematosus and flares of SLE produce autoantibodies more often than systemic autoimmune symptoms. Despite these commonalities, research suggests that drug-induced lupus erythematosus and SLE have separate and distinct mechanistic pathways.

Molecular mimicry between antibodies directed against infectious agents (eg, bacteria, Epstein-Barr virus) and self-antigens has been implicated in SLE. These theories hold that in SLE, the immune system generates autoantibodies to foreign antigens and, in turn, these autoantibodies attack the patient's own tissues.

Autoantibodies in drug-induced lupus erythematosus are thought to be generated by a different mechanism than molecular mimicry. Metabolites of drugs that cause drug-induced lupus erythematosus are subjected to oxidative metabolism by neutrophils, creating reactive metabolites. Virtually all lupus-inducing drugs have been shown to undergo oxidative metabolism, while analogous non–lupus-inducing drugs do not undergo oxidation. The drug metabolite, in turn, is thought to trigger reactions in the thymus that prevent T cells from developing tolerance to the patient's own tissues. In a mouse model, reactive metabolites of procainamide injected into the thymus have been shown to result in lupuslike autoantibodies. Unlike in drug hypersensitivity reactions, this process takes months to years of drug exposure for symptoms to develop.

The production of autoimmune T cells is initiated in the thymus by the capacity of reactive drug metabolites to disrupt central T-cell tolerance. Both mouse model and human studies implicate thymic activity, possibly indicating the persistence of thymic activity into advanced adult life.

Predisposing factors to the development of drug-induced lupus erythematosus include a slow drug-acetylator phenotype and advancing patient age. Slower acetylation may play a role in the greater predisposition for elderly persons to develop drug-induced lupus erythematosus.³ Higher rates of drug-induced lupus erythematosus in elderly persons, however, is also likely due to decreased drug clearance and increased medication usage in these individuals.

Biologics such as interleukins (eg, interleukin 2), interferons (eg, alfa, gamma, beta), and TNF-alpha inhibitors are associated with musculoskeletal symptoms and antibody production suggestive of a lupus-like autoimmune disorder. In one study, approximately 14% of rheumatoid arthritis patients treated with anti–TNF-alpha developed anti-DNA antibodies, while less than 1% developed lupus-like symptoms.

Recognition of DILE in patients receiving anti-TNFα agents can be difficult. Making the diagnosis of DILE is even more challenging because cutaneous reactions with and without evidence of autoimmunity are very common in patients treated with anti-TNFa drugs. Importantly, understand the temporal relationship between the onset of symptoms and the initiation of the medication, which can range from weeks to months. A review by Ramos-Casals et al described 105 patients who developed DILE after starting anti-TNFα therapy, and, in this group, lupuslike symptoms appeared at a mean time of 41 weeks after beginning anti-TNFα therapy.¹³

As TNFα-targeted therapies are being used for an expanding number of autoimmune diseases, the number of reports of their induction of lupuslike syndromes has been growing. When one considers the large number of patients now treated with these biologic agents, the occurrence of anti-TNFα-induced DILE is relatively rare.¹⁵ Most case reports are a result of the use of etanercept or infliximab; adalimumab is less often the inciting agent, which may simply be the result of fewer cumulative patient years of exposure to adalimumab.

Costa et al reported 33 cases of anti-TNFα agents causing DILE. Of these, 21 were due to infliximab, 10 to etanercept, and only 2 cases to adalimumab.¹⁶ Of their 33 patients, 19 had only cutaneous manifestations.¹⁶ Anti-TNFα agents induce a higher prevalence of antibodies to double-stranded DNA, hypocomplementemia, a higher incidence of both cutaneous and systemic disease, particularly renal involvement, than classic DILE caused by other drugs.

Cutaneous findings in TNFα-associated DILE commonly include photosensitivity and the classic cutaneous findings associated with discoid lupus erythematosus and subacute cutaneous lupus erythematosus. Cutaneous manifestations are more frequently observed in patients receiving etanercept, whereas infliximab causes a higher incidence of serositis. Fever is found in similar incidence in both TNFα inhibitor–induced DILE and DILE caused by other categories of medications. Greater than 50% of laboratory results in anti-TNFα–induced DILE patients show low serum complement levels and anti-dsDNA antibodies, which are usually absent or rare findings in classic DILE.

The use of anti-TNFα agents is also associated with the emergence of other autoantibodies, such as anticardiolipin antibodies. Classic DILE is more often associated with antihistone antibodies. DeBandt et al looked at the only case of thrombosis in a patient with anticardiolipin antibodies and anti-TNFα–induced DILE, although half of the anti-TNFα–related DILE patients studied (12) had anticardiolipin antibodies.

The mechanism by which anti-TNFα therapy induces DILE is not understood. One hypothesis is that the binding of the anti-TNFα drug to the cell surface TNFα induces cell apoptosis, which causes the release of antinucleosomal autoantigens and the induction of anti-dsDNA antibodies.¹⁶ A second hypothesis is that the suppression of T-helper type 1 response from the anti-TNFα therapy would generate an exuberant T-helper 2 response, leading to an overproduction of autoantibodies.¹⁷ A third suggestion to the pathogenesis of DILE from these immunosuppressive agents is that patients on these medications may experience more bacterial infections, which are powerful stimulants that boost polyclonal B-lymphocyte activation and autoantibody production.¹⁸

A baseline evaluation, including serology to rule out lupus erythematosus, should be considered in patients prior to the inception of TNFα therapy.¹⁶

Comparison of Findings Between Drug-induced Lupus Erythematosus and Systemic Lupus Erythematosus

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Table

Findings	SLE	Drug-induced Lupus Erythematosus
Clinical	Average age of onset of 20-30 y Affects blacks more than whites Female-to-male ratio of 9:1	Average age of onset of 50-70 y Affects whites more than blacks Female-to-male ratio of 1:1
Laboratory	Antihistone antibodies in 50% Anti-dsDNA present in 80% C3/C4 levels decrease Cutaneous findings in >75% Raynaud phenomenon in 50% Antinuclear antibodies in >95%	Antihistone antibodies in >95% Anti-ssDNA present Anti-dsDNA rare C3/C4 levels normal Cutaneous findings in ~25% Raynaud phenomenon in 25% Antinuclear antibodies in >95%
Immunofluorescence Histopathology	Direct immunofluorescence reveals granular deposition of immunoglobulin G at dermoepidermal junction Lymphohistiocytic interface dermatitis Apoptosis basal vacuolization	Same as SLE Same as SLE

Findings	SLE	Drug-induced Lupus Erythematosus
Clinical	Average age of onset of 20-30 y Affects blacks more than whites Female-to-male ratio of 9:1	Average age of onset of 50-70 y Affects whites more than blacks Female-to-male ratio of 1:1
Laboratory	Antihistone antibodies in 50% Anti-dsDNA present in 80% C3/C4 levels decrease Cutaneous findings in >75% Raynaud phenomenon in 50% Antinuclear antibodies in >95%	Antihistone antibodies in >95% Anti-ssDNA present Anti-dsDNA rare C3/C4 levels normal Cutaneous findings in ~25% Raynaud phenomenon in 25% Antinuclear antibodies in >95%
Immunofluorescence Histopathology	Direct immunofluorescence reveals granular deposition of immunoglobulin G at dermoepidermal junction Lymphohistiocytic interface dermatitis Apoptosis basal vacuolization	Same as SLE Same as SLE

Frequency

United States

As many as 10% of the approximately 500,000 cases of lupus erythematosus may be drug-induced lupus erythematosus.

Mortality/Morbidity

Death from drug-induced lupus erythematosus is extremely rare and may result from renal involvement. In diagnosing drug-induced lupus erythematosus, first excluding the possibility of renal idiopathic lupus rather than drug-induced lupus erythematosus is extremely crucial.

Race

More whites than blacks develop drug-induced lupus erythematosus; more blacks than whites present with SLE.

Sex

In drug-induced lupus erythematosus, no significant statistical difference is apparent in the prevalence for males versus females. In contrast, SLE affects women with considerably higher frequency than men (female-to-male ratio of 9:1).

Age

Patients with drug-induced lupus erythematosus tend to be older (50-70 y) than those with SLE (average age 29 y at diagnosis). Elderly persons generally are more susceptible to drug-induced lupus erythematosus.

Clinical

History

• Most patients with drug-induced lupus erythematosus (DILE) have one or more clinical symptoms of systemic lupus erythematous (SLE), such as arthralgias, lymphadenopathy, rash, and fever, and have had no prior history of autoimmune disease. If a rash is present, it often manifests as a polycyclic, scaling, erythematous rash in sun-exposed areas.
  • Approximately 50% of patients have constitutional symptoms of fever, weight loss, and fatigue.
  • As many as 90% of patients with drug-induced lupus erythematosus have severe but usually noninflammatory joint pain; however, synovitis may be present.
  • Arthralgia is often the only clinical manifestation of drug-induced lupus erythematosus.
• As many as 50% of patients with drug-induced lupus erythematosus experience muscle pain (myalgia).
• The drug was taken anytime from 3 weeks to 2 years prior to the appearance of symptoms. Importantly, note that drug-associated exacerbations of SLE and typical drug hypersensitivities can also be temporally related to drug exposure.
• Clinical improvement is usually rapid when the drug is discontinued, while antinuclear antibodies and other serologic markers slowly decrease toward more normal levels.
• Generally, the absence of CNS and renal involvement is more suggestive of drug-induced lupus erythematosus than SLE. High rates (ie, 5-10%) of glomerulonephritis; however, occur in hydralazine-induced drug-induced lupus erythematosus, and rare cases of death from renal involvement in drug-induced lupus erythematosus have been reported.

Physical

• Extracutaneous physical findings can include the following:
  • Splenomegaly
  • Hepatomegaly
  • Inflammation of the serous membranes that surround the lungs and pleural cavity walls (pleurisy)
  • Fever
  • Inflammation of the fibroserous membranes that cover the heart and the initial part of the great vessels (ie, pericarditis)
  • Cerebritis (rarely)
  • Nephritis (rarely)
• Skin findings are apparent in approximately 25% of all patients diagnosed with drug-induced lupus erythematosus. Importantly, note that certain manifestations typical in persons with SLE are not usually observed in persons with drug-induced lupus erythematosus. Patients with drug-induced lupus erythematosus (unlike patients with SLE) typically do not have the following:
  • Mucosal ulcers
  • Hair loss (alopecia)
  • Circular (discoid) plaques
  • Photosensitivity (with the exception of thiazide-induced subacute lupuslike syndrome)
• Compared with patients who have SLE, patients with drug-induced lupus erythematosus present with a higher prevalence of the following:
  • Purpura
  • Erythema nodosum (painful nodules, usually on the extremities)
  • Erythematous papules (typically on sun-exposed areas, as in the image below)
  • 
    

    

    Erythematous macules and papules are seen on the face, upper chest, and arms in a photodistribution.

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    Erythematous macules and papules are seen on the face, upper chest, and arms in a photodistribution.

• Lymphadenopathy or Raynaud phenomenon is present in approximately 35-50% of patients with SLE but in less than 25% of those with drug-induced lupus erythematosus.
• More than 75% of patients with SLE also have cutaneous findings, versus an average of less than 25% in patients with drug-induced lupus erythematosus. However, in both SLE and drug-induced lupus erythematosus, approximately 75% of patients have arthritis or arthralgia.
• Patients with drug-induced lupus erythematosus also occasionally exhibit skin findings that are analogous to those manifested in patients with subacute cutaneous lupus erythematosus, such as erythematous annular or scaly plaques.

Causes

Drug-induced lupus erythematosus may be induced by medications or caused by other compounds in the environment. The most common drugs that cause drug-induced lupus erythematosus are hydralazine (rate roughly 20%), procainamide (rate roughly 20%, 5-8% if taken for 1 y), quinidine, and minocycline.

• Several broad drug categories have been linked to drug-induced lupus erythematosus, including the following:
  • Antiarrhythmics - Procainamide and quinidine
  • Antibiotics - Minocycline and isoniazid
  • Antifungals - Griseofulvin and voriconazole
  • Anticonvulsants - Valproate, ethosuximide, carbamazepine, and hydantoins
  • Hormonal therapy - Leuprolide acetate
  • Antihypertensives - Hydralazine, methyldopa, and captopril
  • Anti-inflammatories - Penicillamine and sulfasalazine
  • Antipsychotics - Chlorpromazine
  • Cholesterol-lowering agents - Lovastatin, simvastatin, and gemfibrozil
  • Biologics - Interleukins (eg, interleukin 2), interferons (eg, alfa, beta, gamma), and TNFα
  • Inhalers - Tiotropium bromide inhaler
  • Other drug categories - Ophthalmic timolol
• A genetic predisposition may play a role. Hydralazine-induced drug-induced lupus erythematosus has been observed with increased frequency in association with human leukocyte antigen (HLA)-DR4.
• Intrinsic genetic susceptibility may help explain why some patients experience drug-induced lupus erythematosus as a reaction to drug therapies, while others do not. For example, the rate of acetylation is genetically predetermined. In the United States, the population is almost evenly divided between those who are fast acetylators and those who are slow acetylators. Those with slow acetylation rates have a higher prevalence of drug-induced lupus erythematosus than those with faster acetylation rates. In contrast, SLE affects individuals with slow and fast acetylation rates approximately equally.
• Other causes may induce drug-induced lupus erythematosus in certain individuals for no apparent reason, such as sensitivity to the following:
  • Insecticide compounds
  • Certain metallic compounds
  • Eosin (a fluorescent acid dye found in some lipsticks)