Учебники / Otolaryngology - Basic Science and Clinical Review

Figure 3–3 Prevalence patterns for Midwestern pollens and fungi outdoors. Frost occurs from the middle of September through March, and snow occurs from November through February. (From Robert

M. Naclerio & William Solomon; Rhinitis and Inhalant Allergens, JAMA,Vol 278, No22, 1997, 1844. Reprinted with permission)

OCCUPATIONAL ALLERGENS

IgE-mediated reactions to latex have drawn special attention recently because of systemic and respiratory reactions in exposed patients and health care workers. Occupational IgE-mediated reactions can be caused by laboratory animal products, grain (in bakers and agricultural workers), coffee beans, wood dust such as mahogany and western red cedar, chemicals such as platinum dust, and psyllium. Occupational rhinitis may precede the development of occupational asthma.

CLINICAL PRESENTATION

Allergic rhinitis often presents with repetitive sneezing, rhinorrhea, nasal congestion, and itching of the mucous membranes. In severe cases, ear fullness and popping, malaise, and fatigue may be present. The symptoms of nonallergic rhinitis can be similar.

Chronic allergic rhinosinusitis is often a little more difficult to diagnose on clinical history alone. Usual complaints are dull pressure in the face or head, nasal congestion, and postnasal drip, but patients may also report cough, hypo-osmia, sore throat, fetid breath, and malaise. Children frequently have an earache due

to coexisting otitis media. A good history and physical examination play a crucial role in diagnosing allergic rhinitis. Specific timing of symptoms suggests “hay fever” or seasonal allergic rhinitis. One should remember that mold spores can cause seasonal symptoms as well. The link of perennial symptoms with a specific allergen is less obvious and may require special evaluation including in vivo or in vitro allergen testing.

Physical examination is important, but it lacks specificity. Classical clinical signs such as allergic shiners, Dennie-Morgan infraorbital creases, and the “allergic salute” are frequent in children, but they are rarely seen in adults. Examination of the nasal mucosa can reveal pale, swollen nasal turbinates, but some patients may have an erythematous mucosa.After shrinking of swollen mucosa with topical decongestants, polyps can often be readily appreciated.

Allergic rhinitis often coexists with allergic conjunctivitis.The role of allergy in otitis media is controversial, although eustachian tube dysfunction often occurs when rhinitis is prominent.

Other relevant organ system findings include examination of the chest for signs of asthma and the skin for concomitant eczema and atopic dermatitis.

TABLE 3–3 EVALUATION OF AN ALLERGIC PATIENT

History

a.Recent illness

b.Family history

c.Occupational history Physical exam

Skin testing

a.Percutaneous (prick and puncture)

b.Intradermal Laboratory exam

a.Eosinphil count (peripheral blood and nasal lavage)

b.Radioallergosorbent test

DIAGNOSTIC APPROACHES AND ALLERGEN TESTING

Table 3–3 presents the diagnostic approaches to a patient with allergic rhinitis.A careful history and physical exam are the most important steps in the diagnosis of allergic rhinitis. The demonstration of specific IgE antibodies is often useful in diagnosing and better characterizing allergic rhinitis.

Allergy testing is done to identify trigger allergens, reinforce environmental control instructions, and, in some cases, establish a need for direct immunotherapy.Testing is commonly done by one of two ways, skin testing or radioallergosorbent test (RAST).

SKIN TESTING

Skin testing, which requires trained personnel, is usually done in experienced medical facilities because of issues of interpretation and techniques. However, testing is usually safe, and the incidence of adverse reactions is very low. The number of tests depends on the range of local allergens and a particular patient’s exposure. If initial prick test results are negative, the more sensitive intradermal method is usually tried. Overall, skin tests show greater sensitivity than serum assays. They are quick, safe, and cost-effective.

RADIOALLERGOSORBENT TEST

Radioallergosorbent test is an in vitro test assessing serum levels of specific IgE antibodies. It should be utilized in patients who fear skin testing or have dermatographism or extensive skin disease, and in those who must take medications that interfere with skin testing (e.g., antihistamines, certain antidepressants, extensive topical corticosteroids, and possibly beta-blockers). Reliable RAST is now available from

most commercial laboratories. Tests for individual specific allergens can be ordered or can be ordered as panels. The components of panels vary between laboratories.

THERAPY

Effective treatment of allergic rhinitis involves a combination of environmental control and pharmacotherapy. When symptoms persist despite these measures, allergen immunotherapy should be considered.

ENVIRONMENTAL CONTROL

Environmental control is the most useful method of reducing allergy symptoms in most patients and should be instituted in everyone. All surroundings, particularly the bedroom, of the patient should be as free as possible from known and potential asthma triggers. This is the most effective and important step in the treatment of any allergic disease.

PHARMACOTHERAPY

Oral antihistamines are effective in reducing symptoms of itching, sneezing, and rhinorrhea and are the first-line therapy for allergic rhinitis. However, they have little effect on nasal congestion.Therefore, there are a number of antihistamines, both first and second generation, available combined with a decongestant.

Intranasal antihistamines such as Astelin are effective and in contrast with oral preparations may reduce nasal congestion. They are appropriate for use as first-line treatment of allergic rhinitis.

Those with prolonged allergic symptoms should add intranasal corticosteroids. They are the most effective medication class in controlling symptoms of allergic rhinitis. All the newer topically acting agents are generally safe and are not associated with significant systemic side effects in adults. Nasal irritation and bleeding may occur, and very rare cases of nasal septum perforation have been reported. Most reported cases occurred with older preparations

A short course of oral corticosteroids is sometimes used to treat very severe or intractable nasal symptoms or nasal polyps. However, their repeated or prolonged use in allergic rhinitis should be discouraged.

Intranasal cromolyn sodium is effective in some patients and is associated with minimal side effects. It is most useful as a prophylactic agent (i.e., to prevent symptoms when an allergenic exposure is anticipated). Intranasal

anticholinergics (Ipatropium bromide) may also effectively reduce rhinorrhea but usually have no effect on other nasal symptoms.

There is some preliminary evidence that leukotriene antagonists may be useful in allergic rhinitis, but the exact role of this class of drugs remains to be established.

For patients with persistent eye complaints, drops containing cromolyn, antihistamines, or nonsteroidal anti-inflammatory drugs complement oral antihistamines. Intraocular steroids are less often used. They are potentially harmful and require close ophthalmological fol- low-up.

ALLERGEN IMMUNOTHERAPY

Allergen immunotherapy may be highly effective in controlling symptoms of allergic rhinitis. A decision to start immunotherapy is based on the physician’s cost–risk benefits analysis and the patient’s preference. This mode of treatment is usually initiated for several reasons, including severe seasonal or perennial rhinoconjunctivitis in which optimal allergen avoidance and medication have not been sufficiently effective in controlling symptoms; rhinitis caused by allergen that cannot be avoided (e.g., occupational exposure to laboratory animals, pets at home); the use of daily pharmacotherapy, such as systemic corticosteroids for prolonged periods; and intolerable side effects from medications.

Recent studies suggest that immunotherapy may prevent further development of asthma in patients with allergic rhinitis.Allergen immunotherapy can be stopped in most patients after 3 to 5 years with persistence of therapeutic effects.

INVESTIGATIONAL TREATMENTS

As IgE regulation has become better understood, more possible therapeutic strategies are emerging. For example, signaling through the IL-4 receptor is mediated by the activation of STAT6, so the development of STAT6 blocking agents is being actively pursued by several groups.

Several studies are ongoing to evaluate the action of anti-IgE antibodies in allergic rhinitis. Two different approaches have been proposed: producing antibodies to the membrane portion of IgE, but not secreted IgE, and developing antibodies against the IgE-binding site for the high-affinity IgE receptor Fc(RI).The first approach is predicated on the existence of a structurally different IgE isoform and is aimed at the ablation of surface IgEbearing cells. The second relies on preventing IgE from binding to its receptor.

Finally, anti-CD4 monoclonal antibody has been reported to be beneficial in the animal models of allergic disorders.

SUMMARY

Allergic rhinitis is a very common disease, which is increasing in frequency throughout the developed world. Proper knowledge of disease pathogenesis and underlying immune mechanisms, as well as familiarity with current treatment guidelines, is essential for the proper differential diagnosis and management of allergic rhinitis. The latter should begin with simple environmental control measures to prevent the patient from inhaling potentially allergenic substances. After that, drug therapy should be instituted. Although intranasal corticosteroids are the most effective in this regard, oral and intranasal antihistamines and blockers of mast cell degranulation such as cromolyn can be used as first-line therapy, especially in children.

Initial referral to a specialist may be helpful for a majority of patients, to establish the diagnosis, identify and eliminate causative allergens, and develop a therapeutic plan.A limited response to pharmacotherapy and severe allergic symptoms most of the year are indications for allergen immunotherapy.

SUGGESTED READINGS

Beaven MA, Metzger H. Signal transduction by Fc receptors. Immunol Today 1993;14:222–226

Costa JJ, Galli SJ. Mast cells and basophils. In: Rich R, Fleicher TA, Shwartz BD, ShearerWT, StroberW, eds. Clinical Immunology: Principles and Practice. St. Louis: Mosby-Year Book; 1996: 408–430

Irani AA, Schechter NM, Craig SS, et al.Two types of human mast cells that have distinct neutral pretease compositions. Proc Natl Acad Sci U S A 1986;83:4464

Klinck M, Cline MG, Halonean M, et al. Problems in defining normal limits for serum IgE. J Allergy Clin Immunol 1990;85:440

Lemanske RFJ, Kaliner MA. Late phase allergic reactions. In: Middleton E Jr, Reed CE, Ellis EF, Adkinson NF,Yunginger JW, Buse WW, eds. Allergy: Principles and Practice, 4th ed. St. Louis: Mosby-Year Book; 1993:320–361

Malone DC, Lawson AA, Smith DH,Arrighi HM, Battista C.A cost of illness study of allergic rhinitis in the United States. J Allergy Clin Immunol 1997;99:22–27

Murray JJ,TonelAB, BrashAR, et al. Release of prostaglandin D2 into human airways during acute antigen challenge. N Engl J Med 1986;315:800

Ogasawara H,Asakura K, Saito H, Kataura A. Role of CD4-positive cells in the pathogenesis of nasal allergy in the murine model. Int Arch Allergy Immunol 1999;118:37–43

Pipkorn U, Proud D, Lichenstein LM, et al. Inhibition of mediator release in allergic rhinitis by pretreatment with topical glucocorticosteroids. N Engl J Med 1987;316:1506

Sanderson CJ. Interleukin-5, eosinophils and disease. Blood 1992; 79:3101–3109

Valone FH, Boggs JM, Goetzl EJ. Lipid mediators of hypersensitivity and inflammation. In: Middleton E Jr, Reed CE, Ellis EF, Adkinson NF, Yunginger JW, Busse WW, eds. Allergy: Principles and Practice. 4th ed. St. Louis: Mosby-Year Book; 1993:302–319

SELF-TEST QUESTIONS

For each question select the correct answer from the lettered alternatives that follow.To check your answers, see Answers to Self-Tests on page 715.

1.The synthesis of immunoglobulin E (IgE), which plays a central role in allergic disease, is induced by the following:

A.IL-4, IL-5, IL-6, and IL-13, produced by Th2 cells

B.Interferon andTNF- , produced byTh1 cells

C.IL-4, IL-12, and IL-13

D.IL-4 and IL-13, produced by Th2 cells

E.IL-4 and IL-13, produced by Th1 cells

2.Which of the following statements is true?

A.Histamine is the major mediator of an earlyphase allergic reaction, and is contained in a preformed state within the granules of mast cells and basophils.

B.Prostaglandin D is formed in human mast cells from the metabolism of arachidonic acid through the cyclooxygenase pathway, and plays a role in maintaining acute and late allergic responses.

C.Leukotrienes are the products of arachidonic acid metabolism through the cyclooxygenase

pathway, and they are the major mediators of late and chronic allergic reactions.

D.Tryptase, chymase, mast cell carboxypeptidase, and cathepsin G are located in both the mucosal mast cells and connective tissue mast cells.

E.The major proteoglycans in mast cells are histamine, heparin, and chondroitin sulfate A.

3.Which of the following statements regarding allergens is true?

A.Food and drug allergies are the common causes of allergic rhinitis.

B.The majority of plants in the northern United States produce windborne pollen and cause nasal allergy.

C.Almost all of the major mite allergens, which are the major cause of perennial allergic rhinitis throughout the world, are contained in mite fecal pellets.

D.Molds are highly ubiquitous outdoor allergens and usually cause only seasonal allergic rhinitis.

E.Ideal growing conditions for dust mites are low humidity, a temperature around 55 F, and the presence of shed human skin, which is their major food source.

4.Management of allergic rhinitis may include

IEnvironmental control

IIOral and intranasal antihistamines

III Intranasal steroids

IV Oral steroids

A.I, II, and III

B.I and III

C.II and IV

D.All the above

This chapter will focus primarily on systemic rheumatological diseases that often significantly affect and can even initially present in the head and neck region.These include the collagen vascular or connective tissue diseases (e.g., rheumatoid arthritis and systemic lupus erythematosus) and the vasculitides (e.g., polyarteritis nodosa and Cogan’s syndrome). There will also be a discussion of two organ-specific diseases (autoimmune thyroiditis and myasthenia gravis) and a brief overview of the head and neck manifestations of acquired immunodeficiency syndrome (AIDS). Preceding this review is a discussion of basic immunity, autoimmunity, and the unique immunology of the inner ear. The primary immunodeficiencies such as DiGeorge’s syndrome (T-cell deficiency) and Bruton’s agammaglobulinemia will not be covered in this chapter, nor will the association between upper airway malignancies and immunosuppression. Comprehensive reviews of these topics from an otolaryngologist’s perspective have been covered by Harris and associates (Harris and Penn, 1981; Harris and South, 1982). Previous reviews have covered the head and neck manifestations of collagen vascular diseases (Standefer and Mattox, 1986) and autoimmune diseases (Campbell et al, 1983), as well as the association between systemic autoimmune diseases and hearing loss (Berrettini et al, 1998). Comprehensive reviews for head and neck surgeons of Wegener’s granulomatosis (Devaney et al, 1998), scleroderma (Weisman and Calcaterra, 1978), giant cell arteritis and polymyalgia rheumatica (Ferguson et al, 1987), thyroiditis (Morinaka, 1995), and AIDS (Moazzez and Alvi, 1998; Riederer et al, 1996) are also available.

BASIC IMMUNITY

Although a comprehensive description of the underlying mechanisms that make up our immune system is beyond the scope of this chapter, an outline of the major components and their function is warranted.

There are two types of immunity: natural and acquired. Natural immunity, also called native or innate, refers to the defense mechanisms present prior to an individual’s exposure to foreign molecules. This includes physicochemical barriers (mucous membranes), circulating molecules (complement), and phagocytic cells (macrophages and neutrophils). This discussion will emphasize the acquired immunity mediated by lymphocytes (T and B cells).

There are two types of acquired immune responses, humoral and cellular. Humoral responses are mediated by antibodies that are synthesized by B lymphocytes. Cellular responses are mediated by T lymphocytes. Antibodies are proteins found in the blood, lymphoid tissue, and

mucosal tissue that specifically recognize and eliminate antigens. Antigens are molecules that elicit an antibody response.They include bacterial toxins such as lipopolysaccharides and viral proteins.Antigens are typically foreign molecules; however, this is not always the case (see Autoimmunity that follows).Although a humoral response can be transferred to a “naive” or unimmunized individual with cell-free portions of the blood (e.g., plasma or serum), an effective cellular response is required for a comprehensive humoral response. For example, an individual B cell clonally expands when the antibody on its surface recognizes its ligand (the specific binding site or epitope of an antigen). However, B cell proliferation and differentiation into a mature, secreting plasma cell require support from direct cell-to-cell interaction with accessory leukocytes (e.g., T helper cells and macrophages), as well as with soluble factors secreted by these cells.

The bone marrow is the site of origin of all lymphoid stem cell lines.The four primary classes of white blood cells (leukocytes) are lymphocytes, mononuclear phagocytes, dendritic cells, and granulocytes. Lymphocytes are divided into B cells,T cells, and natural killer cells. B cells continue to differentiate in the bone marrow and complete maturation in the peripheral circulation and lymphoid tissue. B cells are responsible for antibody production.T cells mature in the thymus and are divided into helper T cells, suppressor T cells, and cytotoxic T cells. Helper T cells stimulate B cells and are required for a comprehensive antibody response.They also activate macrophages and secrete cytokines. Cytotoxic T cells lyse virus-infected cells and tumor cells. Suppressor T cells modulate and downregulate the immune response. Natural killer cells perform antibody-dependent cellular cytotoxicity (ADCC). Mononuclear phagocytes include the bone marrow–derived circulating monocytes and their tissue-resident counterparts, macrophages. They phagocytose foreign material, present antigen to B and T cells, and secrete cytokines. Dendritic cells include the Langerhans cells and are important in the induction of an immune response. Finally, granulocytes are key players in the acute inflammatory response. Granulocytes include neutrophils or polymorphonuclear leukocytes (PMN), eosinophils, basophils, and the tissue-resident counterparts of basophils, histamine-containing mast cells. They respond to cytokines and antibody-coated material, leading to phagocytosis and the release of granules containing cytotoxic compounds (e.g., peroxides and superoxide anion).This oxidative burst can damage host tissue as well as foreign, invading cells.

There are three phases of immune responses: cognitive, activation, and effector. The cognitive phase describes

the specific recognition of antigen by soluble antibodies, antibodies on the surface of B cells, or T-cell receptors.T-cell receptors are surface molecules onT cells that bind specific peptide sequences from cellularly processed antigens when expressed in association with self-surface molecules, major histocompatibility complex (MHC). Class I MHC is found on all cells and is recognized by cytotoxic T cells expressing clusters of differentiation (CD)8 surface molecules. Class II MHC is expressed only by antigen-presenting cells (APCs) and is recognized by helper T cells expressing CD4 on their surface. APCs include macrophages, B cells, dendritic cells, and endothelial cells.

The activation phase of an immune response is the proliferation and differentiation induced in lymphocytes following the recognition of antigen. This phase requires the presence of helper T cells and/or APCs. In the effector phase, activated lymphocytes function to eliminate antigen. For example, antibodies opsonize microbes, making them more attractive for phagocytosis. Antibodies also neutralize toxins and activate the complement cascade pathway leading to bacterial lysis.

Soluble protein hormones secreted by helper and accessory cells are crucial in the activation and effector phases.These molecules are collectively called cytokines or lymphokines [e.g., interleukin (IL), interferon, and tumor necrosis factor (TNF)]. Helper T cells initially secrete IL-2, which serves as a growth factor for activated B and T cells. In the presence of IL-12 from B cells, a subset of helper T cells develops called Th1. Th1 cells continue to produce IL-2 and also make interferon and TNF- . A Th1 response is largely cellular, prompting the activation of macrophages, natural killer cells, and cytotoxic T cells. If helper T cells are initially exposed to IL-4 from mast cells, they differentiate into Th2 cells, making ILs-4, 5, 9, and 10. This milieu supports a humoral response. Other lymphokines increase vascular permeability and function as chemotactants, causing leukocyte migration. Macrophages secrete IL-1, which stimulates resting B and T cells, and TNF- , which activates neutrophils and also functions as a broad-based inflammatory mediator. TNFproduces fever and upregulates adhesion molecules on the endothelial cells of postcapillary high endothelial venules (HEVs).The adhesion molecules on endothelial cells are termed addressins (e.g., glycosylation-dependent cell adhesion molecule-1 (GlyCAM) and vascular cell adhesion molecule-1 [VCAM]). The complementary ligands on T cells are called homing receptors (e.g., selectins and integrins). This process of upregulation of adhesion molecules and homing receptors leads to the

margination and recruitment of circulating leukocytes at the site of an immune response.

AUTOIMMUNITY

The hallmark of acquired immunity is the ability to distinguish between self and nonself. When this ability breaks down, autoimmunity results.A complex series of deoxyribonucleic acid (DNA) rearrangements and posttranslational modifications in the variable regions of the immunoglobulin (Ig; e.g., antibody) and T-cell receptor genes results in the vast array of unique B andT cells we have at birth. It is estimated that we possess the ability to recognize over one billion different molecular targets via these unique variable regions. Essential to this process is the “education” or selection during fetal development in favor of cells that can recognize and thus be stimulated by their accessory counterpart cells (i.e., positive selection) and against cells that recognize self too strongly (i.e., negative selection). One theory that describes how an antigen can be a molecule from the host is through a loss of this negative selection. This is termed a loss of central tolerance.

Autoimmunity can also develop from a loss of peripheral tolerance called clonal anergy. Peripheral tolerance is the inhibitory effect that costimulatory-deficient APCs are thought to exhibit on peripheral T cells.With local infection or inflammation,APCs are stimulated and in turn can stimulate a resident T cell not specific for the original antigen. An example of this theory is the organspecific disease autoimmune thyroiditis, which can be induced in animals administered thyroglobulin with a strong adjuvant.

As opposed to an organ-specific autoimmune disease, systemic autoimmune diseases such as lupus erythematosus and Sjögren’s syndrome are thought to develop following polyclonal lymphocyte activation. Molecules such as bacterial lipopolysaccharides stimulate B cells irrespective of a specific antigen. Self-reactive B cells, which had been present but anergic, can be turned on in this situation. It also has been postulated that certain bacterial superantigens can activate polyclonal T cells by binding portions of the T-cell receptor and MHC on APCs, thus forming a stimulatory bridge in the absence of any processed peptide.

If a foreign antigen bears enough resemblance to a self-antigen (or autoantigen), a cross-reactivity can ensue. The classic example of this process is rheumatic fever and subsequent valvular heart disease. Following repeated infections with group A streptococcus, individuals develop antistreptococcal antibodies that also recognize myocardial proteins.This leads to a chronic inflammatory state that can scar the valves and cause stenosis.

Three possible mechanisms exist for tissue damage in autoimmune responses. First, autoantibodies can directly recognize host antigens, either natural or modified. The subsequent binding of the carboxyl terminus of the antibody (fragment crystallizable [Fc] portion) by Fc receptors on PMNs and macrophages leads to phagocytosis. Complement lysis is also initiated by exposed Fc. Second, antigen– antibody immune complexes from a distant site can deposit in filtering tissues (e.g., glomeruli) without binding any antigen, still causing tissue damage secondary to migration of PMNs and monocytes. Third, cytotoxic T cells can damage tissue after being recruited by the release of cytokines from activated APCs and helper T cells.

IMMUNOLOGY OF THE INNER EAR

The inner ear contains the immune cells and mediators necessary for an immune response, and the endolymphatic sac is apparently involved in immunoregulation because it contains a resident population of lymphocytes.The inner ear can also mount a primary immune response against exogenous antigen introduced into the perilymph. This response is as effective as peritoneal presentation and more effective than middle ear presentation in eliciting systemic immunity. Furthermore, when antigen was injected into the inner ear of an animal previously sensitized by systemic immunization, an inflammatory infiltration of immunocompetent cells, production of local antibody, and cochlear damage were observed.When the endolymphatic sac is surgically destroyed or the duct obstructed, there is reduced inflammation and cochlear damage, thus further emphasizing the sac’s role. Interestingly, the lymphocytes that appear in the inner ear during an immune response do not originate from the endolymphatic sac, and the cochlea has no resident leukocytes. These cells have been shown to enter from the circulation via the spiral modiolar vein (SMV), which behaves as a high endothelial venule during a secondary immune response. The issue of autoimmune reactivity to inner ear tissue was first addressed in a guinea pig model, where immunization with heterologous (bovine) inner ear tissue led to hearing loss in roughly 30% of the animals, along with histopathological evidence of inner ear degenerative changes and a mononuclear cell infiltration (Harris, 1987). Sera from these animals contained immunoglobulins against a 68 kilodilation (kDa) inner ear protein, which has been shown to be present in 33% of progressive sensorineural hearing loss (PSNHL) patients and 30% of Meniere’s patients but only 5% of controls (Gottschlich et al, 1995). The clinical entity

autoimmune inner ear disease (AIED) has been described as an idiopathic bilateral PSNHL. Patients with AIED have a positive Western blot against 68 kDa protein and are often responsive to steroid treatment. An autoimmune etiology for AIED has also been suggested because AIED patients have an increased risk of developing a systemic autoimmune disease on follow-up.

RHEUMATOID ARTHRITIS

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease with a typically insidious onset and progressive, fluctuating course of polyarthropathy leading to thickened synovial membranes and eventual damage of subchondral bone and cartilage. There is symmetrical involvement of small hand joints [proximal interphalangeal (PIP) joints and metacarpophalangeal (MCP)] joints, wrists, ankles, and elbows. In advanced forms of disease, there is subluxation and ulnar deviation of the MCP joints and swan neck deformity in the fingers. Pulmonary involvement includes diffuse interstitial fibrosis, parenchymal nodules, and pleural effusion. Splenomegaly is found in 10% of patients. Prevalence is roughly 1 to 3%, and onset is more common in women between 25 and 50 years of age. A pathognomonic feature, the rheumatoid nodule, is a necrobiotic granuloma usually found at subcutaneous sites subject to trauma (e.g., the extensor surface of the forearm). Laboratory findings include an elevated erythrocyte sedimentation rate (ESR) and positive rheumatoid factor (RF), which indicates the presence of antibodies reactive to the Fc portion of IgG molecules.Although a positive RF is a sensitive test, it is also found in other chronic inflammatory states such as lupus, tuberculosus, and sarcoid.

Otological manifestations of RA include an increased incidence of sensorineural hearing loss (SNHL), with reported prevalence rates varying from 29 to 48%. A prospective study of 45 RA patients found a mild SNHL in 44% of patients, 36% with bilateral involvement (Kastanioudakis et al, 1995). Audiometric analysis was predominantly normal.There was no correlation between hearing loss and age, sex, disease duration, systemic involvement, autoantibodies, or treatment regimen. It is important to note that no temporal bone studies have been reported confirming the relationship between inner ear dysfunction and RA. Conductive hearing loss rates varying from 13 to 38% have been reported in RA patients. Loosening of the transducer mechanism secondary to erosion of the ossicles by inflammatory synovitis is one proposed mechanism.

Laryngeal manifestations, especially cricoarytenoid involvement, are common in RA. They have been reported in 26 to 80% of patients investigated. In the

acute phase synovitis and effusion can lead to dysphonia, hoarseness, odynophagia, and dysphagia. There can also be a sense of throat fullness (globus) and in severe cases dyspnea or stridor if limitation of vocal cord abduction via the posterior cricoarytenoid occurs.There have been numerous reports of an increased incidence of vocal cord nodules in RA patients, usually presenting as hoarseness and dysphonia. After cordotomy and removal of the subcordal masses, a patient’s dysphonia typically resolves.

The temporomandibular joint (TMJ) is commonly involved in RA. TMJ arthritis can lead to symptoms of jaw, face, or ear tenderness and pain, malocclusion with limited jaw mobility ( 45 mm), and even dysphagia. TMJ involvement has been found in as many as 78% of RA patients evaluated with radiographic evidence that typically demonstrates flattening of the anterior portion of the condylar head. Additionally, RA can affect the nose, leading to nasal septum perforation. Arthritic involvement of the cervical spine in RA has a predilection for the atlantoaxial and apophyseal joints, and it has also been implicated in cervical myelopathy.

Treatment of RA is traditionally done with a medication pyramid. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line agent of choice. In intermediate RA or if early RA is refractory to NSAIDs, second-line agents such as methotrexate are often initiated. Other second-line agents include antimalarials, gold, D-penicillamine or sulfasalazine, and immunosuppressives such as cyclophosphamide and cyclosporine. Oral glucocorticosteroids can be substituted or added to the regimen usually at no more than 10 mg per day. Flares are often treated with pulse methylprednisolone boluses. Many studies have shown a benefit in combination therapy with disease-modifying antirheumatic drugs (DMARDs) such as methotrexate and cyclophosphamide or methotrexate and cyclosporine. New treatments include drugs that inhibit TNFreceptors such as Etanercept, a soluble TNF receptor. This approach presumably works in part by preventing the activation of neutrophils and upregulation of adhesion molecules.

HIGHLIGHTS

Arthritis of the cricoarytenoid joints is very common in RA patients. Symptoms are usually hoarseness, dysphonia, and dysphagia; however, life-threatening upperairway obstruction can occur if the cords become fixed in adduction.Vocal cord nodules are easily treated with cordotomy.TMJ arthritis is also a frequent finding, leading to jaw, face, and ear pain, as well as malocclusion and limited jaw mobility. Of note, one third to one half of RA patients have significant, demonstrable hearing loss.

Sensorineural hearing loss is more common than conductive, and both unilateral and bilateral presentations are common. Novel drugs targeting theTNFreceptor appear to be a promising treatment.

SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus (SLE) is an inflammatory, multisystem disease affecting connective tissue, blood vessels, mucous membranes, and serosal surfaces. Onset may be sudden or insidious (often with fevers and malaise) and predominantly occurs in young women. Ninety percent of patients report articular symptoms (polyarthralgia, arthritis).The characteristic malar “butterfly” rash is pathognomonic but not common. Other findings include pleuritis, pericarditis, endocarditis, generalized adenopathy, splenomegaly, neuritis, meningitis, headaches, epilepsy, cerebral vascular accidents, scleritis, retinal degeneration, glomerulonephritis, and inflammatory bowel disease. Positive antinuclear antibodies (ANAs) occur in 98% of patients with SLE; however, false-positives may be seen in 5 to 10% of cases. High titers of more specific anti-DNA antibodies (e.g., Farr test) can confirm an SLE diagnosis.

In a retrospective study of 673 patients with systemic vasculitides, 80 patients reported subjective audiological disturbances; of these patients, 14 had evidence of PSNHL by audiometry. Of the 69 patients diagnosed with SLE, there were no patients with PSNHL (Berrettini et al, 1998). However, others have reported SNHL in controlled studies of SLE patients as well as hearing loss with additional otologic manifestations such as chronic otitis media with necrotizing vasculitis and dysequilibrium. In a study of 84 patients with SLE, 26 patients (31%) reported aural symptoms. Fifty percent of these described unilateral hearing loss, and 50% bilateral with or without tinnitus.Although audiometry was offered to all subjects, only 10 completed testing, and seven of these had abnormal pure-tone thresholds (Sperling et al, 1998).Temporal bone histopathologic studies from SLE patients have shown evidence of new bone formation and fibrosis throughout the inner ear. A mechanism for these findings has been postulated using an animal model, where systemic immunization followed by local deposition of the same antigen in the inner ear led to inflammation of the spiral modiolar vein, leukocyte infiltration, cochlear fibrotic changes, and osteogenesis.

Head and neck manifestations have been reported in as many as 76% of patients with SLE by Rothfield (1981). This same author found that oral mucosal lesions, including palatal ulcers and hyperkeratosis, appeared as the first sign of disease in roughly 40% of

patients. Laryngeal involvement in SLE has been reported with an incidence between 0.3 and 12.8%. Less frequent ear, nose, and throat (ENT) manifestations of SLE include TMJ arthritis, auricular chondritis in patients with associated relapsing polychondritis,and nasal septal perforations. Necrotizing tracheitis and parotid gland enlargement were found in roughly 10% of SLE patients in a different study. Additional findings (Ropes et al. [1976]) included a roughly 15% associated cranial neuropathy rate, with the trigeminal nerve and facial nerve most commonly involved.

Preventive treatment is critical with SLE and includes avoidance of sun exposure because of photosensitivity, routine laboratory screening to detect early renal and hematologic complications (e.g., chemistries, complete blood count, urinalysis, and immune studies), birth control, and infection monitoring.The initial pharmacotherapy, as with RA, is NSAIDs. Oral corticosteroids and antimalarials play an important role in long-term reduction of flares. Azathioprine, cyclophosphamide, and methotrexate are investigational drugs. Although cyclophoshamide has been shown to be more efficacious than azathioprine, azathioprine is considered safer. Side effects common to both drugs are gastrointestinal intolerance and bone marrow suppression. Numerous studies have demonstrated an advantage of combination oral prednisone and intravenous cyclophosphamide over oral prednisone alone in preventing nephritis. Intravenous corticosteroids are the drug of choice for acute flares.

HIGHLIGHTS

SLE will usually involve the head and neck region (three quarters of patients). Oral mucosal lesions are the most prevalent finding and are often the presenting symptom of disease. As many as one third of SLE patients will complain of aural symptoms, and SNHL can be demonstrated in the majority of those tested.Additional findings include trigeminal and facial nerve neuropathies, parotiditis, tracheitis, laryngeal manifestations, andTMJ arthritis.

PROGRESSIVE SYSTEMIC SCLEROSIS

Progressive systemic sclerosis (PSS) is a degenerative disease characterized by diffuse fibrosis and vascular changes in the skin (scleroderma), joints, and internal organs. There are two types: localized (most common in children) and systemic (usually manifest in adults). The incidence rate of systemic scleroderma is roughly 20 per million per year in the United States, and the prevalence is 240 per million.There is a 5:1 female to male ratio in PSS, and the 2-year survival rate is reportedly between 40 and 80%. Initial findings are commonly Raynaud’s phenomenon (an

intermittent pallor or cyanosis of acral parts, typically digits, secondary to vasospasm), polyarthralgia, gastrointestinal (GI) complaints (dysphagia, dyspepsia), and occasionally dyspnea. Progression can be rapid or prolonged before full manifestation of the CREST syndrome (calcinosis of fingertips and bony eminences, Raynaud’s, esophageal dysfunction, sclerodactyly, and telangiectasia). Visceral involvement includes GI (reflux with Barrett’s metaplasia in one third of patients), cardiorespiratory (pulmonary fibrosis and cardiac failure), and renal systems (malignant hypertension and renal insufficiency).

In the Berrettini et al (1998) study of 673 patients with systemic vasculitis disease, 252 patients (37%) had systemic scleroderma. None of these patients had audiovestibular abnormalities as measured by audiometry, tympanometry, brainstem auditory evoked response (BAER), or electronystagmography (ENG); however, it is important to note that only those patients with subjective complaints were tested (80 of 673).

In a review of 71 PSS patients, head and neck manifestations were reported in 80% of those studied (Weisman and Calcaterra, 1978). Thirty percent of these patients had complaints in the head and neck region as the initial presentation. Dermatologic involvement included a tight, masklike facies secondary to a progression of the fibrosis (35%); telangiectasias of the face, lips, and tongue (18%); hyperpigmentation (7%); and calcinosis (3%). Investigators also found decreased opening of the mouth (28%), neck stiffness or pain (14%), xerostomia (8%), dysphonia (6%), keratoconjunctivitis sicca (2%), diminished taste (1%), and parotitis (1%). Additional oral mucosal changes in PSS include gingivitis, tongue atrophy, and thickening of the periodontal membrane.

Dysphagia, dyspepsia, and reflux are common complaints in PSS. Reported rates of dysphagia are roughly 40%, and abnormal esophagrams are present in 20% of PSS patients. An investigation of esophageal function in 125 scleroderma patients revealed that 45 patients (36%) had endoscopic evidence of esophagitis. Manometry revealed that 80% of those tested had abnormalities correlating with severity of disease (Bassotti et al, 1997).

Disease-modifying agents for PSS include drugs affecting vascular changes such as prostacyclin, drugs affecting immune response such as cyclosporin A, and drugs inhibiting fibroblast activity such as D-penicillamine and interferon- . Although D-penicillamine and interferonare effective in slowing the rate of skin thickening, aggressive physical therapy, analgesics, and reconstructive surgery are also used. Esophageal dysmotility in PSS is managed like reflux disease from other causes with smaller meals, avoidance of late-night meals, eating upright, and histamine-2 receptor antagonist (H2) blockers or