16 - Breast

Editors: McPhee, Stephen J.; Papadakis, Maxine A.; Tierney, Lawrence M.

Title: Current Medical Diagnosis & Treatment, 46th Edition

Copyright ©2007 McGraw-Hill

> Table of Contents > 19 - Allergic & Immunologic Disorders

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19

Allergic & Immunologic Disorders

Jeffrey L. Kishiyama MD

Daniel C. Adelman MD

Atopic Disease

Allergic Rhinitis

Essentials of Diagnosis

  • Seasonal or perennial occurrence of nasal pruritus, congestion, rhinorrhea, or paroxysms of sneezing, which may be associated with lower respiratory symptoms, eye erythema, pruritus, irritation, tearing, or eczematous dermatitis.

  • Environmental aeroallergen exposure.

  • Presence of specific-IgE antibody to tested aeroallergens.

Clinical Findings

In addition to the symptoms listed above, up to 40% of patients with allergic rhinitis also manifest lower respiratory symptoms: cough, wheezing, chest tightness, or dyspnea. The physical examination may reveal edematous or inflamed nasal mucosa. In severe cases, the affected mucosa may be pale, boggy, or blue-tinged from vascular engorgement and venous congestion. Nasal symptoms can be nonspecific, however, and the differential diagnosis can include viral rhinitis, bacterial sinusitis, vasomotor rhinitis, nasal polyposis, drug-induced rhinitis, hormonal rhinitis, rhinitis medicamentosa, atrophic rhinitis, gastroesophageal reflux, and systemic disorders such as thyroid disease or Wegener's granulomatosis. Even a basic understanding of regional aeroallergen patterns and seasons can aid the clinician during the evaluation of patients presenting with acute or chronic rhinitis.

Patients with moderate to severe disease, those who are potential candidates for allergen immunotherapy, and those with strong predisposing factors for atopic diatheses (eg, a strong family history of atopy or ongoing exposure to potential sources of allergen) should undergo testing. Since the development of rhinitis precedes the presentation of asthma in over 50% of cases, early intervention may decrease the risk of more severe clinical allergic disease. Patients with comorbidities or associated complications such as allergic asthma, allergic conjunctivitis, chronic cough, sinusitis, polyposis, eczema, or otitis media may also benefit from evaluation by a subspecialist.

Treatment

The three basic principles of allergy management are avoidance of the allergen, symptomatic pharmacologic therapy, and specific allergen immunotherapy. Patients with suboptimal responses to reasonable therapeutic interventions benefit from diagnostic allergy skin testing.

A. Avoidance Therapy

Avoidance is the most effective treatment for any allergic condition but may be limited in its applicability. It cures the clinical manifestations but does not reduce the sensitivity to the allergen.

1. Pollens

Airborne allergens can travel significant distances, but concentrations are highest near their source. Pollen release occurs in the early morning, and airborne levels depend on temperature and wind velocity. Closing windows and remaining in air-conditioned environments can decrease exposure when pollen counts are high.

2. Animal danders

If the allergy is slight, the patient may benefit from merely keeping the animal out of the bedroom; usually, however, it is necessary to remove the animal from the home altogether. Hypersensitivity to animal dander can be exquisite, and passively transferred dander can accumulate to significant levels in “off-limits” areas. Washing or otherwise treating the fur of a live animal has not been proved to reduce allergenicity.

3. House dust and dust mites

The mattress and pillows should be encased in dust mite-proof material, and all other bedding should be washed weekly and dried at high temperature. The bedroom floor should be uncarpeted. The room should be dusted frequently. Electronic air purifiers are of unproved effectiveness for dust mite reduction since the primary source of exposure is the bed. Acaricides are not recommended. Dust mite reduction interventions can be successful adjunctive measures to medical therapy, can significantly

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reduce symptoms, and can reduce bronchial hyperreactivity and medication requirements in sensitized patients.

Table 19-1. Effectiveness of agents used in treatment of allergic disorders.

Drug Class Sneezing Pruritus Rhinorrhea Congestion Inflammation Onset of Action
Antihistamines ++++ ++++ +++ + - Rapid
Sympathomimetics - - + ++++ - Rapid
Corticosteroids +++ +++ +++ ++++ ++++ Slow (days)
Cromolyn-nedocromil sodium ++ + + + ++ Slow (weeks)
Anticholinergics - - ++++ - - Rapid
Immunotherapy ++++ ++++ ++++ ++++ ++++ Slow (months)

4. Mold spores

Out of doors, mold spores are unavoidable during certain seasons. Nevertheless, activities such as gardening and farming can be associated with acute high levels of exposure and should be avoided. Indoor mold contamination can be controlled by repairing leaks, by preventing mold buildup in bathrooms and around windows, and by replacement of mold-contaminated carpeting.

B. Drug Therapy

Three classes of pharmacotherapy are useful for IgE-mediated diseases, based on (1) inhibition of release of mediators from mast cells, (2) inhibition of the action of mediators on their target cells, and (3) reversal of the vascular and inflammatory responses in the target tissues (Table 19-1).

1. Antihistamines

Antihistamine drugs competitively inhibit the binding of histamine to H1 receptors and are useful for the treatment of IgE-mediated allergy. There are a number of such drugs, but the use of first-generation antihistamines (chlorpheniramine, brompheniramine, diphenhydramine, clemastine, hydroxyzine) are limited by sedation, neurocognitive impairment, and dry mucous membranes. Rare complications include seizures and tachyarrhythmias. Second-generation nonsedating histamine H1-receptor-blocking drugs, loratadine, fexofenadine, and desloratadine appear not to be associated with arrhythmias and, along with cetirizine, are the systemic drugs of choice. Cetirizine is mildly sedating, but the incidence of side effects is markedly lower than that of its parent compound, hydroxyzine. Azelastine is a topical antihistamine preparation that is applied intranasally to decrease its systemic side effects. Because of methodologic issues, publication bias, and inability to generalize findings, providing a rank order of potency and clinical efficacy for the available antihistamines is difficult. Clinical tolerance or tachyphylaxis does not occur at prescribed dosages but an incomplete response to antihistamine therapy often indicates the need for combined treatment with a corticosteroid nasal spray. This highlights the necessity to control both the early phase and late phase of the allergic response for optimal symptom control.

Antihistamine therapy only rarely alleviates symptoms of asthma, although it is not contraindicated when used to treat concomitant rhinitis or pruritus. The antipruritic effect of antihistamines may be a useful adjunct in treatment of eczematous diseases.

2. Sympathomimetic drugs

Adrenergic agonists are used for both α-adrenergic (vasoconstricting) and β-adrenergic (bronchodilating) properties. α-Adrenergic agonists can be used orally (pseudoephedrine) or topically (phenylephrine, naphazoline, oxymetazoline) as nasal decongestants and topically as conjunctival vasoconstrictors. Daily use of topical preparations can lead to rapid development of rebound vasodilation (rhinitis medicamentosa). The main side effects of oral decongestants are insomnia, tremor, and tachycardia.

3. Corticosteroids

These drugs have a therapeutic role in virtually all types of allergic diseases because of their anti-inflammatory action rather than by their immunosuppressive effects. Systemic use for the treatment of allergic disease, however, requires close attention to toxicity. Corticosteroids are available in oral, intramuscular, intravenous, intranasal, and bronchial inhalation forms; as eye drops; and in topical formulations for dermatologic use. Short-term systemic burst therapy can be used for treatment of severe asthma, marked allergic rhinitis, allergic fungal sinusitis, and allergic bronchopulmonary aspergillosis. Because of complications, including cataracts, corneal ulceration, keratitis, and glaucoma, the prescription of corticosteroid eye drops should be reserved for ophthalmologists.

Topical corticosteroid nasal sprays are effective and appear safe for long-term use, but epistaxis can occur and nasal septum perforation is a rare complication. Although the dosages and formulations available for the treatment of asthma vary greatly in terms of dosage and clinical potency, intranasal preparations of flunisolide, fluticasone, beclomethasone, mometasone, budesonide, and triamcinolone are similarly efficacious for the treatment of allergic rhinitis. Long-term topical corticosteroid therapy for allergic rhinitis is an essential aspect of management of the inflammatory phase

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of the disease. It may take several days of consistent use before optimal responses are seen, but these compounds have consistently proved superior to antihistamine monotherapy for control of nasal pruritus, sneezing, and nasal congestion. Surprisingly, they may also provide some relief from concomitant eye pruritus and have shown positive effects on sleep, which can be adversely affected in patients with allergic rhinitis. Topical corticosteroids may also be effective for treatment of vasomotor rhinitis and may be used as adjunctive treatment for sinusitis in combination with antibiotic therapy.

4. Cromolyn sodium and sodium nedocromil

Pretreatment with these drugs prevents the response to allergen by stabilizing the mast cell, although the specific molecular mechanisms of action are unknown. Although unrelated, they have similar effects and, because of poor bioavailability, are effective only when applied directly to the involved organ. Their action is short-lived, so that they must be given three or four times a day. Cromolyn is available as a bronchial inhaler, nasal spray, and ophthalmologic preparation; nedocromil is available in metered-dose inhalers. In comparison with topical corticosteroids they appear to be much less potent, but the drugs have very few side effects and wide margins of safety.

5. Anticholinergic agents

Ipratropium bromide is effective as a nasal topical agent for use in rhinitis. Mucous membrane glandular secretion is under cholinergic control and can be inhibited by anticholinergic agents. First-generation antihistamines have systemic anticholinergic activity, but ipratropium is preferred as adjunctive treatment of allergic rhinitis or as primary treatment for many types of nonallergic rhinitis. Ipratropium does not alleviate sneezing, pruritus, or nasal congestion but can be useful for treatment of postnasal drip and rhinorrhea.

6. Leukotriene antagonists

Montelukast is an effective drug for the treatment of asthma. To a much more limited degree, leukotriene antagonists can be efficacious for the treatment of allergic rhinitis, either as monotherapy or combined with an antihistamine. By inhibiting leukotriene-mediated vasodilation vascular permeability and by potentially reducing eosinophilic inflammation, orally administered montelukast can provide symptomatic relief, especially for nasal congestion. It is less effective than intranasal corticosteroids, however.

C. Immunotherapy

Treatment of atopy—especially allergic rhinitis—by the repeated long-term injection of allergen has been shown in many controlled clinical trials to be an effective method for reducing or eliminating symptoms and signs of the allergic disorder.

1. Indications

The severity and duration of a patient's symptoms should be considered when selecting candidates for allergen immunotherapy. This treatment is recommended for patients with severe allergic rhinoconjunctivitis who respond poorly to drug therapy, those seeking to lower their long-term medication requirements, and for those whose allergens are not avoidable. Immunotherapy is unequivocally effective in patients with allergic rhinitis and allergic conjunctivitis who react to pollens, mold, and house dust mites. It reduces immunologic hypersensitivity, symptoms, and medication requirements. In children with documented allergic rhinitis, immunotherapy may reduce the risk of subsequent development of asthma. The efficacy of immunotherapy in allergic asthma is still debated, but a meta-analysis of 20 randomized, controlled trials done by Abramson showed a positive benefit in patients with allergic asthma. The lower clinical response rates observed in asthma have been attributed to the multifactorial nature of the disease. Immunotherapy is of no value in atopic dermatitis.

2. Immunologic effects

“Allergen immunotherapy” is preferable to “desensitization” because the immunologic basis for this treatment has not been clearly elucidated. Nevertheless, certain immunologic changes can be induced by these injections. Circulating levels of IgE antibodies specific to the injected allergens increase slightly during the first few months, then decrease, eventually to substantially lower levels than before treatment. Seasonal rises in IgE antibodies to pollens are blunted or eliminated. IgG blocking antibody is produced. Changes in regulatory T cells favoring suppression of IgE antibody production and apoptosis of antigen-specific T cell clones have been noted. TH2 cytokine responses may be shifted toward TH1 responses in peripheral blood mononuclear cells. Higher thresholds for release of inflammatory mediators and decreases in late-phase allergic reactions might also be related to the reduction in biologic sensitivity of end-organ systems (eyes, nose, bronchi, and skin).

3. Clinical effects

Most patients with allergic rhinitis caused by aeroallergens become more tolerant to natural pollen exposure during successive seasons while receiving immunotherapy. A small minority becomes completely asymptomatic, but most patients enjoy a significant decrease in symptoms and medication usage. Only high-dose injected immunotherapy has been demonstrated to be effective. A beneficial response may persist for years after treatment is stopped. The clinical effects and immunologic responses are antigen-specific, but the treatment may also decrease the risk of developing new environmental sensitivities.

4. Procedure

A sterile aqueous solution of the allergen or allergens responsible for the patient's disease is administered by subcutaneous injection in increasing doses once or twice a week until a maintenance dose is reached, at which time the interval is advanced to every 4 weeks. The maintenance dose is typically one to ten thousand times the starting dose. Ascending doses are used to minimize the risk of systemic allergic reactions during initial stages of immunotherapy. Three to 5 years is a typical course of therapy. Oral immunotherapy remains experimental in the United States, and sublingual or low-dose immunotherapy is unconventional and of unproved efficacy.

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5. Adverse effects

Reactions to treatment may be local or systemic. Localized immediate and late-phase skin reactions occur at injection sites. These are not harmful, but the dose must be adjusted to avoid excessively large or prolonged local reactions. Immediate systemic reactions or anaphylaxis is a potential problem with each injection and must be prevented by monitoring of dosage. The patient remains at the treatment facility for at least 20 minutes after each injection so that drugs and equipment for treating anaphylaxis will be available if needed. No long-term adverse consequences of aqueous allergen extract immunotherapy are known to have occurred in immunocompetent individuals.

Abramson MJ et al: Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2000; CD001186.

Meltzer EO et al: Rhinosinusitis: Establishing definitions for clinical research and patient care. J Allergy Clin Immunol 2004; 114(6 Suppl):155.

Moller C et al: Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002;109:251.

Norman PS: Immunotherapy: 1999–2004. J Allergy Clin Immunol 2004;113:1013.

Togias A: Rhinitis and asthma: Evidence for respiratory system integration. J Allergy Clin Immunol 2003;111:1171.

Anaphylaxis, Urticaria, & Angioedema

Essentials of Diagnosis

  • Anaphylaxis is a systemic reaction with cutaneous symptoms, associated with dyspnea, visceral edema, and hypotension.

  • Urticaria is characterized by large, irregularly shaped, pruritic, erythematous wheals.

  • Angioedema is painless, deep, subcutaneous swelling, often involving periorbital, circumoral, and facial regions.

  • These disorders may be diagnosed clinically, especially in the context of allergen exposure; detection of specific IgE or elevated serum tryptase can confirm the diagnosis.

General Considerations

Certain allergens—especially drugs, insect venoms, and foods—may induce an IgE antibody response, causing a generalized release of mediators from mast cells and resulting in systemic anaphylaxis. This potentially fatal condition affects both nonatopic and atopic persons. Isolated urticaria and angioedema are more common cutaneous forms of anaphylaxis with a better prognosis.

Food allergies cause an estimated 150 fatalities per year in the United States, most cases being due to ingestion of peanuts, tree nuts, shellfish, and fish. Common childhood food allergies such as milk, soy, wheat, and egg are often outgrown over time if strict avoidance is practiced. β-Lactam antibiotics may be involved in 400–800 fatalities per year, and stinging insect venom causes about 50 fatalities per year. Chronic relapsing urticaria, angioedema, and, less commonly, anaphylaxis, however, are not always due to IgE-mediated hypersensitivity. In a minority of cases—perhaps 10% or less—underlying systemic disorders such as systemic mastocytosis or subclinical infection or inflammatory disorders may be manifested by episodic urticaria or angioedema. Idiopathic causes are commonly responsible for chronic or relapsing symptoms, suggesting that some cases may be associated with autoimmune processes including the production of histamine-liberating autoantibodies directed against Fcε mast cell membrane receptors. A review of 593 patients with recurrent episodes of anaphylaxis seeking medical attention at a university medical center revealed that most (70%) anaphylactic episodes in adults were classified as idiopathic in nature. In contrast, the bulk (35–55%) of anaphylactic reactions in children are caused by food allergies. Twenty percent of the population will experience urticaria or angioedema during their lifetime, and the estimated prevalence of idiopathic anaphylaxis is 34,000 patients in the United States.

Clinical Findings

A. Symptoms and Signs

The manifestations are (1) hypotension or shock from widespread vasodilation or dysrhythmia, (2) respiratory distress from bronchospasm or laryngeal edema, (3) gastrointestinal and uterine muscle contraction, and (4) flushing, pruritus, urticaria, and angioedema.

B. Laboratory Findings

In vivo allergy skin testing and in vitro RAST testing can detect allergen-specific IgE for a variety of foods, hymenoptera (bee, wasp, hornet, fire ant) venom, latex, and some medicines. Skin testing for food allergy is appropriate only if the patient has symptoms consistent with IgE-mediated allergy (eg, urticaria, angioedema, or anaphylaxis) within 2 hours after eating the suspect food.

Determination of serum tryptase can be used to identify recent anaphylactic reactions or other reactions due to systemic mast cell activation. Tryptase is a mast cell-derived neutral protease with a half-life of 60–90 minutes. Elevated tryptase levels have been associated with anaphylaxis, systemic mastocytosis, and non-IgE-mediated diseases characterized by mast cell degranulation (“anaphylactoid reactions”). Histamine is released during these disorders and has a very short serum half-life but may be briefly detectable during symptomatic periods.

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If IgE-mediated hypersensitivity is not found and symptoms become relapsing or chronic (over 6 weeks in duration), a screening battery of laboratory tests may be done after a thorough history and physical examination. Appropriate diagnostic testing should follow any positive findings on examination or review of systems. Patients suffering from recurrent angioedema should also be tested for C1-esterase inhibitor deficiency. Measuring a serum C4 level is an easy screening test for C1-esterase inhibitor deficiency/hereditary angioedema because it will be low in most cases.

Treatment

A. Treatment of Anaphylaxis

At the first suspicion of anaphylaxis, airway, breathing, and circulation are assessed. If systemic anaphylaxis is suspected, aqueous epinephrine 1:1000 in a dose of 0.2–0.5 mL (0.2–0.5 mg) is injected intramuscularly. Repeated injections can be given every 5–15 minutes as necessary. Between 40% and 70% of patients suffering from severe anaphylaxis will require more than one injection of epinephrine. Injection in the anterolateral thigh may lead to more predictable and rapid absorption compared with sites in the arm. Epinephrine can stabilize hemodynamics, cause bronchodilation, and prevent further mast cell degranulation. Rapid intravenous infusion of large volumes of fluids (saline, lactated Ringer's injection, plasma, colloid solutions, or plasma expanders) is essential to replace loss of intravascular plasma into tissues in patients with hypotension caused by marked vasodilation. Other vasopressor drugs (high-dose dopamine, norepinephrine, phenylephrine) may be necessary if the patient remains hypotensive.

Airway obstruction is caused by edema of the larynx and hypopharynx or by bronchospasm. The former is treated by maintenance of an airway with endotracheal intubation or tracheostomy. Inhalation of selective β2-adrenergic agonists such as albuterol or terbutaline and intravenous administration of aminophylline (0.5 mg/kg/h IV with 6 mg/kg loading dose over 30 minutes) are effective for bronchospasm.

Antihistamines (H1- and H2-receptor antagonists such as diphenhydramine (25–50 mg orally, intramuscularly, or intravenously every 4–6 hours) and ranitidine (150 mg orally every 12 hours or 50 mg intramuscularly or intravenously every 6–8 hours) may be useful adjuvant therapies for alleviating the cutaneous manifestations of urticaria or angioedema and pruritus and for the gastrointestinal and uterine smooth muscle spasms. Corticosteroids will not reverse respiratory obstruction or shock but may reduce prolonged reactions or relapses. Long-term combined oral antihistamine and prednisone therapy reduces the number and severity of attacks in patients with frequent life-threatening episodes of idiopathic anaphylaxis. Medical therapy does not reliably prevent true IgE-mediated hypersensitivity reactions.

There may be a clinical biphasic or late-phase response in anaphylaxis, causing a recrudescence of symptoms hours (most commonly 6–12 hours) after exposure to the allergen. The incidence of late phase reactions is estimated to be between 1% and 20%. Since this may occur after subsidence of the immediate-phase response, all patients with anaphylaxis should be monitored for up to 24 hours, discharged with injectable epinephrine, and educated about the possible recurrence of symptoms.

Anaphylaxis in a patient being treated with β-adrenergic blocker drugs is a special problem because of refractoriness to epinephrine and selective β-adrenergic agonists. Higher doses of adrenergic drugs are required for the desired effect; glucagon (0.5–1 mg intravenously, intramuscularly, or subcutaneously may be repeated 30 minutes later) in patients taking β-blockers may be beneficial. Patients being treated with angiotensin-converting enzyme inhibitors may suffer from more severe hypotension due to blockade of renin-angiotensin-dependent compensatory mechanisms.

B. Treatment of Urticaria and Angioedema

These disorders are discussed fully in Chapter 6. If urticaria or angioedema is found to be secondary to underlying inflammatory or infectious processes, treatment of the primary disorder can lead to remission of cutaneous symptoms.

C. Venom Immunotherapy

Patients demonstrating immediate hypersensitivity reactions to stinging insects (honey bees, wasps, hornets, yellow jackets, and imported fire ants) with documented venom-specific IgE on allergy skin testing should receive venom immunotherapy for prevention of anaphylaxis. A 5-year course of venom-specific immunotherapy is indicated for persons suffering from generalized urticaria, angioedema, bronchospasm, or hypotension after insect venom exposure. Large isolated local reactions to insect stings are not a predisposing factor for systemic anaphylaxis. Untreated individuals have a 50–60% risk of anaphylactic response to subsequent stings. Venom immunotherapy is highly protective, affording 98% protection from life-threatening reactions on rechallenge. Rarely, anaphylaxis has been associated with other biting insects, including Triatoma and mosquito, but diagnostic reagents and therapeutic extracts are not consistently available for these other species.

Charous BL et al: Natural rubber latex allergy after 12 years: recommendations and perspectives. J Allergy Clin Immunol 2002;109:31.

Kaplan AP: Diagnostic tests for urticaria and angioedema. Clin Allergy Immunol 2000;15:111.

Kemp SF et al: Anaphylaxis: a review of causes and mechanisms. J Allergy Clin Immunol 2002;110:341.

Lieberman P: Anaphylaxis. Med Clin North Am 2006;90:77.

Moffitt JE et al: Stinging insect hypersensitivity: A practice parameter update. J Allergy Clin Immunol 2004;113:1204.

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Drug & Food Allergy

General Considerations

Some drugs are clearly more immunogenic than others, and this can be reflected in the incidence of drug hypersensitivity. A partial list of drugs frequently implicated in drug reactions includes β-lactam antibiotics, sulfonamides, phenytoin, carbamazepine, allopurinol, muscle relaxants used for general anesthesia, nonsteroidal anti-inflammatory drugs, antisera, and antiarrhythmic agents. Many drugs can be associated with recognizable known toxicities, drug interactions, or idiosyncratic reactions that are not immune-mediated. These must be distinguished from true hypersensitivity reactions because the prognosis and management differ. Some estimate that only 10% or less of adverse reactions to drugs are true hypersensitivity reactions. Patients with multidrug hypersensitivity are quite rare, and those reporting “allergies” to more than three distinct classes of drugs should be carefully evaluated since intolerance to many of these drug classes may not be immunologic.

Four foods account for 90% of food allergy in adults: peanuts, tree nuts, fish, and shellfish. Food hypersensitivity must be distinguished from food intolerance, which is more common and more variable in terms of underlying mechanism. An example of food intolerance would be lactose intolerance, which is due to an enzyme deficiency rather than an IgE-mediated hypersensitivity.

Clinical Findings

A. Symptoms and Signs

The development of symptoms and the nature of the adverse drug reaction can suggest whether an immunologic process is responsible for symptoms. Factors to consider include type of symptoms, history of previous drug exposure, time of onset after starting the drug, presence of other systemic involvement, coexisting illness, and concurrent drug use. In previously sensitized individuals, immediate hypersensitivity is manifested by rapid development of urticaria, angioedema, or anaphylaxis. Delayed onset of urticaria accompanied by fever, arthralgias, and nephritis may indicate the development of an immune complex-mediated disorder. Drug fever and Stevens-Johnson syndrome probably act by immune hypersensitivity mechanisms. In genetically slow acetylators and in AIDS patients with depleted hepatic glutathione levels, drugs such as sulfamethoxazole are not rapidly excreted during drug metabolism. This altered drug metabolism favors the generation of haptenated immunoreactive metabolites as well as drug reactions, such as delayed morbilliform eruptions. Other types of immune-mediated dermatologic drug reactions include lupus-like syndromes caused by procainamide, isoniazid, phenytoin, or hydralazine. Drugs that have been associated with the development of systemic or cutaneous vasculitis include leukotriene receptor antagonists, allopurinol, phenytoin, thiazides, nonsteroidal anti-inflammatory drugs, furosemide, cimetidine, gold, hydralazine, and many antibiotics (eg, penicillin, sulfonamides, quinolones, and tetracycline). Cutaneous vasculitides are usually associated with fixed lesions, with histologically-proven immune-complex involvement.

Food hypersensitivity is manifest by immediate hypersensitivity reactions or, more rarely, atopic dermatitis. Onset of allergic food reactions is rapid, usually within minutes to a couple of hours of ingestion, and the reaction is usually quite reproducible. Oral allergy syndrome is a self-limited form of fruit and vegetable hypersensitivity, where symptoms are confined to the oropharynx. Due to cross-reactivity between certain fruit and vegetable allergens and certain seasonal pollens, ingestion of these foods causes pruritus of lips, tongue and palate without systemic anaphylaxis. The most common cross-reacting foods and pollens are apples and carrots, which cross-react with birch pollen; melons and bananas, which cross-react with ragweed pollen. Many of these antigens involved in oral allergy syndrome are heat labile and denature during cooking.

B. Laboratory Findings

1. Allergy testing

Allergy skin testing is only available for a limited number of drugs (penicillin, insulin, streptokinase, chymopapain, heterologous serum), since patients may react to the native drug as well as any metabolite that covalently binds to native protein and becomes immunoreactive. Skin testing is available for patients with suspected immediate hypersensitivity to penicillin or β-lactam antibiotics (see Chapter 37). The degree of cross-reactivity between the cephalosporin antibiotics and penicillins is uncertain. The incidence of IgE-mediated hypersensitivity appears to be less than 5%. There appears to be no allergic cross-reactivity between the monobactam antibiotics (aztreonam) and penicillin or other β-lactam antibiotics. A high degree of cross-reactivity exists between penicillin and the carbapenem, imipenem, so this drug should be given to the penicillin-allergic patient with the same degree of caution as if the patient were to receive penicillin.

If the likelihood of immunologic reaction is low—based on the history and the assessment of likely offending agents—and if no allergy testing is available, judicious test dose challenges may be considered in a monitored setting. If the likelihood of IgE-mediated reaction is significant, these challenges are risky and rapid drug desensitization is indicated.

The gold standard for allergy food testing is skin-prick testing with actual food items, but due to the inconvenience and potential risk for systemic reactions, this form of testing is usually preceded by IgE RAST testing or skin prick testing with commercially available extracts or both.

2. Provocation tests

Occasionally, direct allergen challenge of the target organ or tissue under controlled conditions is required for definitive diagnosis. Such challenges may be bronchial, nasal, conjunctival, oral,

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or cutaneous. A positive test confirms that the test substance can cause the reaction, but it does not prove that an immunologic mechanism is responsible.

a. Bronchoprovocation testing

Natural provocation field testing can be done by having the patient make serial determinations of peak expiratory flow rate using a portable peak flowmeter during periods of natural exposure to a suspected airborne allergen. Bronchoprovocation is not necessary in the routine diagnosis of allergic asthma, but it may be helpful in some cases of occupational asthma. Bronchial provocation with exercise or with inhalation of methacholine, histamine, or cold air can document the presence of nonspecific bronchial hyperreactivity during the diagnostic workup for respiratory symptoms but does not detect allergic sensitivities.

b. Oral provocation

In most cases of suspected allergy to a food or drug, placebo-controlled oral challenge is the definitive test. To be considered a positive result, the reported clinical findings must be reproduced during provocation testing. A blinded provocation test may be preceded by an open challenge (no placebo control), which, if negative, negates the necessity for logistically difficult blinded challenge. Freeze-dried foods in large opaque capsules provide a sufficient dose of allergen for testing. This should not be done in patients with suspected food- or drug-induced anaphylaxis.

Treatment

For IgE-mediated drug hypersensitivity, acute rapid desensitization may allow administration of a drug if there is no suitable alternative treatment regimen. This procedure carries a significant risk and should be undertaken in an intensively monitored setting. This is accomplished by a course of oral or parenteral doses starting with extremely low doses (dilutions of 1 × 10-6 or 1 × 10-5 units) and increasing to the full dose over a period of hours. IgE-mediated reactivity diminishes during the course of this desensitization, creating a temporary drug-specific refractory state. During the refractory period, skin histamine responsiveness is maintained, and mast cells may be activated by other stimuli but the patient may receive the desired drug with a very low risk of anaphylaxis. Acute rapid desensitization may work through cellular mechanisms different from those involved in standard injection immunotherapy, and the refractory period is maintained only throughout the course of uninterrupted therapy.

Various slow desensitization protocols have been developed for patients suffering from late-appearing morbilliform eruptions (eg, AIDS patients with sulfamethoxazole-induced dermatitis). These eruptions are not IgE-mediated, and the slow reintroduction of drug allows for less haptenation during sulfonamide metabolism with generation of less immunoreactive drug metabolites. This form of desensitization is distinct from rapid desensitization of IgE-mediated drug allergy. Desensitization for non-IgE-mediated drug reactions has been successful for aspirin, nonsteroidal anti-inflammatory drugs, and allopurinol.

Any history or finding consistent with toxic epidermal necrolysis or Stevens-Johnson syndrome would be an absolute contraindication for drug readministration.

For any proven food hypersensitivity, strict avoidance is the only rational recommendation. Patients should also be provided with an epinephrine autoinjector (Epi-pen) if indicated.

Clark S et al: Multicenter study of emergency department visits for food allergies. J Allergy Clin Immunol 2004;113: 347.

Grammer LC et al: Drug allergy and protocols for management of drug allergies, 3rd edition. Part II. General principles of prevention of allergic drug reactions. Allergy Asthma Proc 2004; 25:267.

Gruchalla R: Understanding drug allergies. J Allergy Clin Immunol 2000;105(6 Pt 2):S637.

Immune Complex Disease (Serum Sickness)

Essentials of Diagnosis

  • Fever, pruritus, and arthropathy.

  • Reaction is delayed in onset, usually 7–10 days, when specific IgG antibodies are generated against the allergen.

  • Immune complexes found circulating in serum or deposited in affected tissues.

General Considerations

Serum sickness reactions occur when immune complexes are formed by the binding of antigens (eg, drugs, heterologous serum) to antibodies. Deposition of these complexes in tissues or in vascular endothelium can produce immune complex-mediated tissue injury by activation of complement, generation of anaphylatoxins, chemoattraction of polymorphonuclear leukocytes, and tissue injury. The commonly affected organs include skin (urticaria, vasculitis), joints (arthritis), and kidney (nephritis).

Clinical Findings

A. Symptoms and Signs

Constitutional symptoms, such as drug fever, are common.

B. Laboratory Findings

The specific IgG antibody may be present in sufficient quantity in serum to be detected by the precipitin-in-gel method. Detection of these precipitating antibodies

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by gel diffusion can be useful in the diagnosis of allergic bronchopulmonary aspergillosis or hypersensitivity pneumonitis. Enzyme-linked immunosorbent assay (ELISA) will detect antibodies present in lesser amounts.

Circulating antigen-nonspecific immune complexes can be detected in a variety of malignancies and in autoimmune, hypersensitivity, and infectious diseases. Immunohistochemical techniques can identify immune complexes or complement fragments deposited in tissue biopsy specimens. Depressed serum levels of C3, C4, or CH50 may be sought as nonspecific evidence of immune complex disease with consumption of soluble factors.

The erythrocyte sedimentation rate is increased, and other nonspecific laboratory findings may include elevated hepatic aminotransferases or reduced complement levels. Circulating immune complexes may be found, but current assays are limited in sensitivity. Evidence of nephritis may be found by observing red cell casts at urinalysis.

Treatment

This disease is self-limited, so treatment is usually conservative. Aspirin will relieve the arthralgias. Antihistamines and topical corticosteroids will control the dermatitis. Corticosteroid therapy may be necessary for serious reactions—especially glomerulonephritis, neuropathy, and other manifestations of vasculitis.

Pseudoallergic Reactions

These reactions resemble immediate hypersensitivity reactions but are not mediated by allergen-IgE interaction. Instead, direct mast cell activation occurs. Examples of pseudoallergic or “anaphylactoid” reactions include the now rare “red man syndrome” from rapid infusion of vancomycin, direct mast cell activation by opioids, and radiocontrast reactions. In contrast to IgE-mediated reactions, these can often be prevented by prophylactic medical regimens.

Radiocontrast Media Reactions

Reactions to radiocontrast media do not appear to be mediated by IgE antibodies, yet clinically they are similar to anaphylaxis. If a patient has had an anaphylactoid reaction to conventional radiocontrast media, the risk for a second reaction upon reexposure may be as high as 30%. Patients with asthma or those being treated with β-adrenergic blocking medications may be at increased risk. The management of patients at risk for radiocontrast medium reactions includes use of the low-osmolality contrast preparations and prophylactic administration of prednisone (50 mg orally every 6 hours beginning 18 hours before the procedure) and diphenhydramine (25–50 mg intramuscularly 60 minutes before the procedure). The use of the lower-osmolality radiocontrast media in combination with the pretreatment regimen decreases the incidence of reactions to less than 1%.

Immunodeficiency Disorders

The primary immunologic deficiency diseases include congenital and acquired disorders of humoral immunity (B cell function) or cell-mediated immunity (T cell function). Most of these diseases are rare, and since they are genetically determined, are seen primarily in children. Several immunodeficiency disorders affect adults and are discussed below. The WHO classification of immunodeficiency disorders more often affecting adults is set forth in the accompanying box.

Who Classification

  • Primary Immunodeficiency Disorders:

    Selective IgA deficiency.

    Common variable immunodeficiency.

    X-linked agammaglobulinemia.

    Immunodeficiency with normal serum globulins or hyperimmunoglobulinemia.

    Immunodeficiency with thymoma.

  • Secondary Immunodeficiency Disorders (for example, AIDS)

Bonilla FA et al: Primary immunodeficiency diseases. J Allergy Clin Immunol 2003;111:S571.

Buckley RH: Advances in immunology: primary immunodeficiency diseases due to defects in lymphocytes. N Engl J Med 2000;343:1313.

Cooper MA et al: Primary immunodeficiencies. Am Fam Physician 2003;68:2001.

Fischer A: Human primary immunodeficiency diseases: a perspective. Nat Immunol 2004;5:23.

Selective Immunoglobulin A Deficiency

Selective IgA deficiency is the most common primary immunodeficiency disorder and is characterized by the absence of serum IgA with normal levels of IgG and IgM; its prevalence is about 1:500 individuals. Most persons are asymptomatic because of compensatory increases in secreted IgG and IgM. Some affected patients have frequent and recurrent infections such as sinusitis, otitis, and bronchitis. Some cases of IgA deficiency may

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spontaneously remit. When IgG2 subclass deficiency occurs in combination with IgA deficiency, affected patients are more susceptible to encapsulated bacteria and the degree of immune impairment can be more severe. Patients with a combined IgA and IgG subclass deficiency should be assessed for functional antibody responses to glycoprotein antigen immunization.

Atopic disease and autoimmune disorders can be associated with IgA deficiency. Occasionally, a sprue-like syndrome with steatorrhea has been associated with an isolated IgA deficit. Treatment with commercial immune globulin is ineffective, since IgA and IgM are present only in trace quantities in these preparations. Frequent infusions of plasma (containing IgA) or unwashed blood transfusions are hazardous, since anti-IgA antibodies may develop, resulting in systemic anaphylaxis or serum sickness.

Cunningham-Rundles C: Physiology of IgA and IgA deficiency. J Clin Immunol 2001;21:303.

Common Variable Immunodeficiency

Essentials of Diagnosis

  • Defect in terminal differentiation of B cells, with absent plasma cells and deficient synthesis of secreted antibody.

  • Frequent sinopulmonary infections secondary to humoral immune deficiency.

  • Confirmation by evaluation of serum immunoglobulin levels and deficient functional antibody responses.

General Considerations

The most common cause of panhypogammaglobulinemia in adults is common variable immunodeficiency, a heterogeneous immunodeficiency disorder clinically characterized by an increased incidence of recurrent infections, autoimmune phenomena, and neoplastic diseases. The onset generally is during adolescence or early adulthood but can occur at any age. The prevalence of common variable immunodeficiency is about 1:80,000 in the United States.

Clinical Findings

A. Symptoms and Signs

The pattern of immunoglobulin isotype deficiency is variable. Most patients present with significantly depressed IgG levels, but over time all antibody classes (IgG, IgA, and IgM) may be affected. Increased susceptibility to pyogenic infections is the hallmark of the disease. Virtually all patients suffer from recurrent sinusitis, with bronchitis, otitis, pharyngitis, and pneumonia also being common infections. Infections may be prolonged or associated with unusual complications such as meningitis or sepsis.

Gastrointestinal disorders are commonly associated with common variable immunodeficiency, and a sprue-like syndrome, with diarrhea, steatorrhea, malabsorption, protein-losing enteropathy, and hepatosplenomegaly, may develop in patients. Paradoxically, there is an increased incidence of autoimmune disease (20%), although patients may not display the usual serologic markers. Autoimmune cytopenias are most common, but autoimmune endocrinopathies, seronegative rheumatic disease, and gastrointestinal disorders are also commonly seen. Lymph nodes may be enlarged in these patients, yet biopsies show marked reduction in plasma cells. Noncaseating granulomas are frequently found in the spleen, liver, lungs, or skin. There is an increased propensity for the development of B cell neoplasms (50- to 400-fold increase risk of lymphoma), gastric carcinomas, and skin cancers.

B. Laboratory Findings

Diagnosis is confirmed in patients with recurrent infections by demonstration of functional or quantitative defects in antibody production. Serum IgG levels are usually less than 250 mg/dL; serum IgA and IgM levels are also subnormal. Decreased to absent functional antibody responses to protein antigen immunizations establish the diagnosis.

The cause of the panhypogammaglobulinemia in the majority of common variable immunodeficiency patients is an intrinsic B cell defect preventing terminal maturation into antibody-secreting plasma cells. In a small number, excessive suppressor T cell activity that inhibits B cells—or helper T cell activity inadequate to assist B cells to make antibody—has been identified. The absolute B cell count in the peripheral blood in most patients, despite the underlying cellular defect, is normal. A subset of these patients have concomitant T cell immunodeficiency with increased numbers of activated CD8 cells, splenomegaly, and decreased delayed-type hypersensitivity.

Treatment

Patients may be treated aggressively with antibiotics at the first sign of infection. Since antibody deficiency predisposes patients to high-risk pyogenic infections, antibiotic coverage should be sure to cover encapsulated bacteria. Only after the development of bronchiectasis or after sinus surgery do patients become significantly affected by more virulent organisms such as Staphylococcus aureus or Pseudomonas aeruginosa. Maintenance intravenous immune globulin (IGIV) therapy is indicated, with infusions of 300–500 mg/kg of IGIV given at about monthly intervals. Adjustment of dosage or of the infusion interval is made on the basis of clinical responses and steady-state trough serum IgG levels. Such therapy is effective in decreasing the incidence of potentially

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life-threatening infections and increasing quality of life. The yearly cost of monthly infusions can be in excess of $20,000-$30,000.

Cunningham-Rundles C: Immune deficiency: office evaluation and treatment. Allergy Asthma Proc 2003;24:409.

Kokron CM et al: Clinical and laboratory aspects of common variable immunodeficiency. An Acad Bras Cienc 2004;76: 707.

Sneller MC: Common variable immunodeficiency. Am J Med Sci 2001;321:42.

Diseases of Immunoglobulin Overproduction (Gammopathies)

The monoclonal gammopathies include those diseases in which there is a proliferation of a single clone of immunoglobulin-forming cells that produce a homogeneous heavy chain, light chain, or complete molecule. The amino acid sequence of the variable (V) regions is fixed, and only one type (κ or λ) of light chain is produced. Polyclonal gammopathies result from proliferation of many B cell clones, resulting in a diffuse increase of immunoglobulins.

1. Monoclonal Gammopathy of Uncertain Significance

Essentials of Diagnosis

  • M protein in the serum without symptoms or signs of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoma.

  • Less than 10% plasma cells in the bone marrow.

General Considerations

The incidence of monoclonal gammopathy of uncertain significance (MGUS) increases with age and may approach 3% in persons 70 years of age or older. Lymphoid malignancies, amyloidosis, or multiple myeloma will develop in as many as one-third of patients with apparently benign monoclonal gammopathies. No specific therapy is necessary, but close observation is required. MGUS patients should be periodically monitored for changes in serum M proteins, urinary Bence Jones proteins, evidence of renal failure, anemia, hypercalcemia, lytic bone lesions, or bone marrow plasmacytoses. Risk of developing a malignant disorder is 12% at 10 years, 25% at 20 years, and 30% at 25 years. Parameters that suggest a favorable prognosis include (1) concentrations of homogeneous immunoglobulin less than 2 g/dL, (2) no increase in concentration of the immunoglobulin from the time of diagnosis, (3) no decrease in the concentration of normal immunoglobulins, (4) absence of a homogeneous light chain in the urine, and (5) normal hematocrit and serum albumin.

Clinical Findings

A. Symptoms and Signs

No clinical symptoms are associated with MGUS. In patients with MGUS, the quantity of M protein is stable, and the lymphadenopathy, splenomegaly, or bony lesions seen with multiple myeloma are absent.

B. Laboratory Findings

The diagnosis of MGUS is made upon finding of a monoclonal spike on serum protein electrophoresis, confirmed by immunoelectrophoresis to be a homogeneous immunoglobulin with either κ or γ light chains.

Kyle RA et al: A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002;346:564.

Rajkumar SV: MGUS and smoldering multiple myeloma: update on pathogenesis, natural history, and management. Hematology (Am Soc Hematol Educ Program) 2005:340.

2. Multiple Myeloma (See Chapter 13)
3. Waldenström's Macroglobulinemia (See Chapter 13)
4. Amyloidosis

Essentials of Diagnosis

  • The diagnosis is based on clinical suspicion, family history, and preexisting long-standing infection or debilitating illness.

  • Microscopic examination of biopsy (eg, gingival, renal, rectal) or surgical specimens is diagnostic.

  • Fine-needle biopsy of subcutaneous abdominal fat is a simple and reliable method for diagnosing secondary systemic amyloidosis.

General Considerations

Amyloidosis is a group of disorders manifested by impaired organ function due to infiltration with insoluble protein fibrils. Different fibrils can be correlated with the clinical syndromes. In primary amyloidosis (AL), the protein fibrils are monoclonal immunoglobulin light chains, whereas in secondary amyloidosis (AA), protein deposits are derived from acute phase reactant apolipoprotein precursors. Familial amyloidosis syndromes commonly cause infiltrative neuropathies. Other types of amyloidosis may

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also be hereditary. Over 20 types of fibrils have been identified in amyloid deposits. Amyloidosis due to deposition of β2-microglobulin in carpal ligaments occurs in long-term hemodialysis patients.

Clinical Findings

A. Symptoms and Signs

The symptoms and signs of primary amyloidosis are due to amyloid infiltration and subsequent malfunction of the infiltrated organ (eg, nephritic syndrome and renal failure, cardiomyopathy and cardiac conduction defects, Alzheimer's disease, intestinal malabsorption and pseudo-obstruction, carpal tunnel syndrome, macroglossia, peripheral neuropathy, end-organ insufficiency of endocrine glands, respiratory failure, capillary damage with ecchymosis). Secondary amyloidosis is more often limited to the liver, spleen, and adrenals. Familial syndromes commonly cause infiltrative neuropathies.

B. Laboratory Tests

The diagnosis of primary amyloidosis is based on clinical suspicion with corroboration provided by detection of a monoclonal gammopathy on serum protein electrophoresis and microscopic examination of abdominal fat pad aspirates; rectal or gingival biopsies reveal amyloid protein (green birefringence under polarizing microscope after Congo red staining). In systemic disease, rectal or gingival biopsies show a sensitivity of about 80%, bone-marrow biopsy about 50%, and abdominal fat aspiration between 70% and 80%. The latter is a simple and reliable method for diagnosing systemic amyloidosis.

Differential Diagnosis

When evaluating a patient with suspected primary amyloidosis, it is important to consider other causes of the presenting symptoms and signs, including multiple myeloma, hemochromatosis, sarcoidosis, Waldenström's macroglobulinemia, metastatic tumors, and other cause of nephrotic syndrome, such as lupus nephritis.

Treatment

Treatment of localized amyloid tumors is by surgical excision. There is no effective treatment of systemic amyloidosis, and death usually occurs within 1–3 years. Care is generally supportive, although hemodialysis and immunosuppressive therapy may be useful. When concomitant multiple myeloma is found, it is treated in the standard way (see Chapter 13). Secondary disease is usually approached by aggressively treating the predisposing disease, but remission of fibril deposition does not occur. Bone marrow transplant after chemotherapy has been used in selected patients.

5. Heavy Chain Disease (α, γ, µ)

These are rare disorders in which the abnormal serum and urine protein is a part of a homogeneous α, γ, or µ heavy chain. The clinical presentation is more typical of lymphoma than multiple myeloma, and there are no destructive bone lesions. γ Chain disease presents as a lymphoproliferative disorder with autoimmune features. α Chain disease is frequently associated with severe diarrhea and infiltration of the lamina propria of the small intestine with abnormal plasma cells. µ Chain disease is associated with chronic lymphocytic leukemia.

Ando Y et al: A novel tool for detecting amyloid deposits in systemic amyloidosis in vitro and in vivo. Lab Invest 2003;83: 1751.

Gahrton G: New therapeutic targets in multiple myeloma. Lancet 2004;364:1648.

Merlini G et al: Molecular mechanisms of amyloidosis. N Engl J Med 2003;349:583.

Autoimmunity

Autoimmune diseases cannot be explained by a solitary cause or mechanism. Small amounts of autoantibodies are normally produced and may have physiologic roles in cellular interactions. Positive serologic findings may be found years before the development of pathogenic autoimmunity or clinical illness, and in some cases, they represent normal immunity or “benign autoimmunity” without disease. The major theories regarding the development of autoimmune disease are (1) release of normally sequestered antigens; (2) escape from anergy or defective apoptosis (programmed cell death) leading to abnormal autoreactive cellular clones; (3) shared antigens between the host and microorganisms, ie, “molecular mimicry”; and (4) defects in helper or suppressor T cell function. A genetic susceptibility is also a likely determinant of autoimmune disease. In nearly all autoimmune diseases, multiple mechanisms of autoimmunity are operative.

Cell-Mediated Autoimmunity

Certain autoimmune diseases are mediated by T cells that have become specifically immunized to autologous tissues. Cytotoxic or killer T cells generated by this aberrant immune response injure specific organs in the absence of serum autoantibodies. Diminished suppressor T cell activity or loss of clonal anergy results in disordered regulation of immune function and consequent autoreactivity. The immune damage in systemic (non-organ-specific) diseases such as systemic lupus erythematosus may be due to such a mechanism.

Antibody-Mediated Autoimmunity

Several autoimmune diseases have been shown to be caused by autoantibodies in the absence of cell-mediated autoimmunity. The autoimmune hemolytic anemias,

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idiopathic thrombocytopenia, and Goodpasture's syndrome appear to be mediated solely by autoantibodies directed against autologous cell membrane constituents. In these diseases, antibody attaches to cell membranes and fixes complement; the ensuing inflammatory reaction injures the cells.

Anti-receptor antibodies that compete with or mimic physiologic agonists for cellular receptors cause several diseases. In Graves' disease, antibodies are present that bind to thyroid cells' thyroid-stimulating hormone receptors and thereby stimulate thyroid hormone production. In rare instances of type 1 diabetes mellitus, anti-insulin receptor antibodies cause insulin resistance in peripheral target tissues. Antibodies to acetylcholine receptors of the myoneural junction in myasthenia gravis block neuromuscular transmission and produce muscle weakness.

Immune Complex Disease

In this group of diseases (systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, some drug-induced hemolytic anemias, and thrombocytopenias), autologous tissues are injured as “innocent bystanders.” Autoantibodies are not directed against cellular components of the target organ but rather against autologous or heterologous antigens in the serum. The resultant antigen-antibody complexes bind nonspecifically to autologous membranes (eg, glomerular basement membrane) and fix complement. Fixation and subsequent activation of complement components produce a local inflammatory response resulting in tissue injury.

Autoimmune Diseases (See Also Chapter 20)

The diagnosis and treatment of specific autoimmune diseases are described elsewhere in this book. Autoantibodies associated with certain autoimmune diseases may not be pathogenetic but are thought to be markers or by-products of the injury (eg, autoimmune thyroiditis and antithyroglobulin antibody). See Table 19-2 for autoantibody patterns in connective tissue diseases.

Table 19-2. Autoantibodies: Associations with connective tissue diseases.

Suspected Disease State Test Primary Disease Association (Sensitivity, Specificity) Other Disease Associations Comments
CREST syndrome Anticentromere antibody CREST (70-90%, high) Scleroderma (10-15%), Raynaud's disease (10-30%). Predictive value of a positive test is > 95% for scleroderma or related disease (CREST, Raynaud's). Diagnosis of CREST is made clinically.
Systemic lupus erythematosus (SLE) Antinuclear antibody (ANA) SLE (> 95%, low) Rheumatoid arthritis (30-50%), discoid lupus, scleroderma (60%), drug-induced lupus (100%), Sjögren's syndrome (80%), miscellaneous inflammatory disorders. Often used as a screening test; a negative test virtually excludes SLE; a positive test, while nonspecific, increases posttest probability of SLE. Titer does not correlate with disease activity.
Anti-double-stranded-DNA (anti-ds-DNA) SLE (60-70%, high) Lupus nephritis, rarely rheumatoid arthritis, other connective tissue disease, usually in low titer. Predictive value of a positive test is > 90% for SLE if present in high titer; a decreasing titer may correlate with worsening renal disease. Titer generally correlates with disease activity.
Anti-Smith antibody (anti-Sm) SLE (30-40%, high)   SLE-specific. A positive test substantially increases posttest probability of SLE. Test rarely indicated.
Mixed connective tissue disease (MCTD) Anti-ribonucleoprotein antibody (RNP) Scleroderma (20-30%, low), MCTD (95-100%, low) SLE (30%), Sjögren's syndrome, rheumatoid arthritis (10%), discoid lupus (20-30%). A negative test essentially excludes MCTD; a positive test in high titer, while nonspecific, increases posttest probability of MCTD.
Rheumatoid arthritis Rheumatoid factor (RF) Rheumatoid arthritis (50-90%) Other rheumatic diseases, chronic infections, some malignancies, some healthy individuals, elderly patients. Titer does not correlate with disease activity.
Scleroderma Anti-Scl-70 antibody Scleroderma (15-20%, low)   Predictive value of a positive test is > 95% for scleroderma.
Sjögren's syndrome Anti-SS-A/Ro antibody Sjögren's (60-70%, low) SLE (30-40%), rheumatoid arthritis (10%), subacute cutaneous lupus, vasculitis. Useful in counseling women of childbearing age with known connective tissue disease, since a positive test is associated with a small but real risk of neonatal SLE and congenital heart block.
Wegener's granulomatosis Antineutrophil cytoplasmic antibody (ANCA) Wegener's granulomatosis (systemic necrotizing vasculitis) (56-96%, high) Crescentic glomerulonephritis or other systemic vasculitis (eg, polyarteritis nodosa). Ability of this assay to reflect disease activity remains unclear.
CREST = calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia.
Modified, with permission, from Harvey AM et al (editors): The Principles and Practice of Medicine, 22nd ed. Appleton & Lange, 1988; White RH, Robbins DL: Clinical significance and interpretation of antinuclear antibodies. West J Med 1987;147:210; and Tan EM: Autoantibodies to nuclear antigens (ANA): their immunobiology and medicine. Adv Immunol 1982;33:167.

Tests For Autoantibodies Associated With Autoimmune Disease

Agglutination Assays

Red cells are incubated with purified specific antigen (eg, thyroglobulin), which is adsorbed to the cell surface. The antigen-coated cells are suspended in the patient's serum, and antibody is detected by red cell agglutination. Antigen-coated latex particles are substituted for red cells in latex fixation tests.

Enzyme-Linked Immunosorbent Assay

Antibodies to various tissue antigens can be readily detected by these tests. Extracted and purified antigens are fixed to a plastic microtiter well or beads. The patient's serum is added, and excess proteins are removed by washing and centrifugation. Adherent immunoglobulin is then detected when a second antibody coupled to an enzyme (eg, alkaline phosphatase) is added. Finally, the enzyme's substrate is added; color forms and is measured in a spectrophotometer. This test can also be adapted for antigen detection by placing the antibody on the plastic surface. ELISA is very sensitive and less cumbersome than radioimmunoassay techniques.

Immunofluorescence Microscopy

This technique is most frequently used for detection of antinuclear antibody (ANA). Frozen sections of mouse liver or other substrates are cut and placed on glass slides or, alternatively, monolayers of cultured cell lines may be used. A patient's serum is placed over the sections and incubated. Fluorescein-conjugated rabbit anti-human immunoglobulin is then applied and washed. ANA specifically binds to the nucleus, and the fluorescein conjugate binds to the human antibody. Fluorescence of the cell nucleus on microscopy indicates a positive test.

Complement Fixation

Specific antigen, unknown serum, and complement are combined. Sheep red blood cells coated with anti-sheep cell antibody are added for 30 minutes at 37°C. If antigen-specific antibody is present in the patient's serum, complement is bound and consumed, preventing lysis of sheep red cells.

Arbuckle MR: Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003; 349:1526.

Benito-Garcia E et al: Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-Sm and anti-RNP antibody tests. Arthritis Rheum 2004;51:1030.

D'Cruz D: Testing for autoimmunity in humans. Toxicol Lett 2002;127:93.

Newkirk MM: Rheumatoid factors: host resistance or autoimmunity? Clin Immunol 2002;104:1.

Immunogenetics & Transplantation

Associations Between Hla Antigens & Specific Diseases

In humans, very striking associations are observed between particular HLA antigens and specific diseases. Some of these are listed in Table 19-3. In some diseases, the HLA molecule may be implicated in the pathogenesis. In others, the specific HLA allele may be linked to a gene determining immune responsiveness to a particular antigen.

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The standard method for detecting HLA-A, -B, and -C antigens is that of lymphocyte microcytotoxicity. Lymphocytes isolated from peripheral blood or lymph nodes are added to each well of a typing tray filled with sera containing the appropriate cytotoxic alloantibody. When complement is added, cells to which antibody has been specifically bound will have complement activated at the cell surface, resulting in cell death or lysis. It is thus possible to type for all of the known HLA-A, -B, and -C specificities. An appreciable

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majority of typing serum samples are obtained from multiparous women since they form antibodies to fetal alloantigens.

Table 19-3. Association between the presence of various HLA markers and selected autoimmune diseases.

Disease Associated HLA Marker1 Relative Risk of Disease2
Ankylosing spondylitis B27 87.4
Reactive arthropathy, including Reiter's syndrome B27 37.0
Rheumatoid arthritis DR4 4.2
Behçet's syndrome B51 3.8
Systemic lupus erythematosus DR3 5.8
Insulin-dependent (type 1) diabetes mellitus DR3 3.3
DQB1*0201 2.4
DR4 6.4
DQB1*0302 9.5
DR2 0.19
DRB*15013  
DRB*01013  
DQB1*06023 0.15
Idiopathic Addison's disease DR3 6.3
Graves' disease DR3 3.7
Hashimoto's disease DR11 3.2
Postpartum thyroiditis DR4 5.3
Celiac disease DR3 10.8
DQB1*02013  
DQA1*05013  
DR7,11 6.0-10.00
DR7, DQB1*02013  
DR11, DQA1*05013  
Dermatitis herpetiformis DR3 15.9
Sicca syndrome DR3 9.7
Myasthenia gravis DR3 2.5
B8 3.4
Idiopathic membranous glomerulonephritis DR3 12.0
Goodpasture's syndrome DR2 15.9
Multiple sclerosis DR2 4.1
DRB1*15013  
DRB5*01013  
DQB1*06023  
Pemphigus vulgaris (among Ashkenazi Jews) DR4 14.4
Psoriasis vulgaris Cw6 13.3
Birdshot retinochoroidopathy A29 109.0
1Symbols with asterisks indicate alleles, and symbols without asterisks indicate serologically defined antigens. For each disease, the marker or markers with the strongest associations are given. In many cases in which it is difficult to decide whether HLA-DR or -DQ markers are responsible for association, both markers are given.
2The relative risk indicates the frequency of a disease in persons with the HLA marker as compared with persons without the marker. A positive association (ie, when the HLA marker is more frequent in persons with the disease than in those without it) is indicated by a relative risk of more than 1.0, a negative association by a relative risk of less than 1.0, and no association by a relative risk of 1.0.
3The risk has not been assessed separately for this allele.
Reproduced, with permission, from Svejgaard A: MHC and disease associations. In: Herzenberg LA et al (editors). Weir's Handbook of Experimental Immunology, 5th ed. Blackwell Science, 1996.

Typing for the class II antigens HLA-DR and -DQ by serologic methods is technically more difficult. Antigens of the HLA-D, -DR, -DQ, and -DP series may also be detected by in vitro mixed lymphocyte culture. Lymphocytes of one individual (responder cells) will undergo proliferation upon encountering lymphocytes from another individual possessing foreign HLA-DR and -DQ antigens (stimulator cells). Lymphocyte proliferation can be readily measured by DNA incorporation of tritiated thymidine. Responders possessing matching -DR and -DQ antigens will remain nonreactive.

Increasingly, HLA class II typing is being performed by molecular technology. The DNA sequences for the HLA genes and their flanking sequences are known. Selected primers that amplify the gene of interest using the polymerase chain reaction technique are known as sequence-specific primers. HLA typing by PCR provides better resolution than serologic identification because typing is done at the genetic level.

Gonzalez S et al: Immunogenetics, HLA-B27 and spondyloarthropathies. Curr Opin Rheumatol 1999;11:257.

McCurdy D: Genetic susceptibility to the connective tissue diseases. Curr Opin Rheumatol 1999;11:399.

Shiina T et al: An update of the HLA genomic region, locus information and disease associations: 2004. Tissue Antigens 2004;64:631.

Clinical Transplantation

Organ transplants are in widespread use. Limitations include the scarcity of donor organs and expense. Failure to achieve successful grafts is primarily due to histoincompatibility and lack of safe and effective immunosuppressive regimens to halt rejection. Avoiding transmission of infectious agents (eg, HIV, hepatitis B virus, hepatitis C virus, cytomegalovirus) from donor to recipient requires extensive pretransplant serologic testing.

Kidney Transplantation

End-stage renal disease is the indication for kidney transplantation. Factors that determine outcome include antigenic disparity (ABO blood groups and major histocompatibility or HLA) between donor and recipient, the type of immunologic response mounted by the host, and the immunosuppressive regimen used to prevent graft rejection. Nonimmunologic factors that affect the risk of chronic rejection include age and race of recipient; donor age; length of time on dialysis; and coexisting hyperlipidemia, hypertension, or cytomegalovirus infection.

Kidneys from living related donors who are HLA-identical and also red cell ABO-matched grafts have 90% survival at 1 year; grafts from less-well matched relatives and from living unrelated donors have lower rates. Antigens are matched for HLA-A, -B and -DR loci, with -DR compatibility most important for long-term graft survival. Grafts from cadaver donors with zero HLA mismatches have a half-life of 11.3 years. Those with six mismatches have a half-life of 6.8 years, compared with those from HLA-identical siblings, which have a half-life of 23.6 years.

Some donors are highly sensitized to HLA antigens from previous transfusions, ie, possess high panel reactive antibody levels. It may be difficult to find a suitable donor, since a positive cross-match by cytotoxicity testing is likely and would be a contraindication to transplant. Donor screening is performed in all cases to assess suitability, rule out hypertension or anatomic anomalies, and avoid transmission of hepatitis viruses, HIV, and other infectious agents. Owing to the scarcity of related donors, living unrelated donors may be used in certain circumstances. Pretreatment of recipients with blood transfusions from the donor appears to extend graft survival even longer.

Delayed allograft function can be due to hyperacute graft rejection, postischemic acute tubular necrosis, cyclosporine toxicity, or obstructive nephropathy. If conservative measures do not improve function or patients are at high risk for allograft rejection, renal biopsy should be performed for definitive diagnostic purposes. Renal allograft rejection may be due to hyperacute rejection from binding of cytotoxic antibodies and complement activation, acute rejection from cellular immune responses, or chronic rejection. A form of interstitial nephritis secondary to polyomavirus infection is associated with aggressive immunosuppression. Noninvasive methods to diagnose rejection are being developed. To replace the need for renal biopsy, studies of mRNA reveal that the levels of FOXP3 in urinary cells may serve as a mechanistically informative biomarker of acute rejection.

Chronic allograft nephropathy is characterized by vasculopathy and immune-mediated graft obliteration. Previous acute rejection is strongly linked with later chronic rejection, and severity of those episodes has prognostic implications. Cyclosporine-induced nephrotoxicity and recurrent or de novo renal disease are also significant factors affecting long-term survival.

High-Dose Chemotherapy with Hematopoietic Progenitor Cell (Stem Cell) Transplantation

Transient myelosuppression after cancer chemotherapy is a well-established adverse effect of such treatments. For most regimens, it is rapidly reversible and requires no intervention. Some malignancies (eg, many leukemias, lymphomas, and chemotherapy-sensitive breast and small-cell lung carcinomas) may demonstrate a higher cure rate with higher-dose therapy; however, associated with this approach is an increase in hematologic toxicity. Administering the maximal tolerated chemotherapy dose and restoring all hematopoietic functions as rapidly as possible has led to evolution

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of the concept of hematopoietic progenitor cell (HPC) or “stem cell” transplant. HPC transplants have also expanded somewhat into the therapy of certain nonmalignant disorders of hematopoiesis and hematologic function; examples are aplastic anemia, sickle cell anemia, thalassemia, myelodysplasia, amyloidosis, and paroxysmal nocturnal hemoglobinuria.

The sources of HPC are the bone marrow, peripheral blood, and cord blood. They comprise less than 0.5–1% of all nucleated bone marrow cells. Although HPCs are “rare” cells, they can be obtained from the peripheral blood by apheresis. As the peripheral blood has approximately one-fortieth the number of circulating HPCs as the bone marrow, these cells must be “mobilized” by the administration of cytotoxic chemotherapy (with the harvest being performed during the recovery phase) or enriched by the administration of hematopoietic growth factors. The cells are frozen and administered at a later date. Transplantation of HPC from umbilical cord blood can be used in unrelated donors, with a potentially lower rate of graft-versus-host disease, or may be autologous, from frozen stored blood.

Because syngeneic transplants between identical (monozygotic) twins are rare, the two predominant transplants are autologous, where the HPCs are harvested from and returned to the patient; or allogeneic, where the source is an HLA-matched donor, ideally a sibling. The goals of the two procedures—and their associated adverse effects—are frequently different. Allogeneic transplants are most commonly offered to patients with malignant and nonmalignant disorders involving the bone marrow. Chemotherapy is given to ablate the marrow, resulting in maximal suppression or eradication of the recipient's native immune system. The bone marrow is repopulated by infusion of donor cells containing not only HPCs but also functional donor T lymphocytes. These T cells can cause graft-versus-host disease, in which the recipient's tissues are recognized as nonself. While this is occasionally desirable, as in the “graft-versus-leukemia” effect, it is the cause of considerable morbidity and can be fatal. There are two separate phases of graft-versus-host disease: acute, secondary to cytokine-mediated cytotoxicity against the cells of the liver, the mucosa of the gastrointestinal tract, and skin; and chronic, characterized by fibrosis and collagen deposition and resembling autoimmune disease such as scleroderma. The incidence of graft-versus-host disease can be decreased by depleting the donor marrow of T cells, but this is associated with a higher incidence of graft failure and, in the case of leukemia, a higher relapse rate. Allogeneic peripheral HPC transplants have been attempted, and graft-versus-host disease in such cases does not appear to be as severe.

Autologous HPC transplants are performed solely for the treatment of malignancies. In these cases the chemotherapy is intensively myelosuppressive although not necessarily myeloablative. One prominent exception is patients with chronic myelogenous leukemia in blast crisis, who receive their autologous HPC in an effort to return their disease to the chronic phase. Since patients usually have some residual immune function and are receiving their own HPC—and thus do not require posttransplant immunosuppression—the risk of opportunistic infections and immunosuppression-related neoplasia is markedly reduced.

The success rates of HPC transplantation depend mostly on the underlying disease and the associated risk of relapse (in cases of leukemia), the level of matching between donor and recipient (and thus the likelihood of graft-versus-host disease), the age of the recipient, and the complications associated with conditioning (veno-occlusive liver disease and infection). Overall, the survival rates at 1 year are about 60–70% in aplastic anemia and 40–75% in various forms of leukemia and other neoplasms such as non-Hodgkin's lymphomas; results in breast carcinoma are less well defined.

Horwitz ME et al: Chronic graft-versus-host disease. Blood Rev 2006;20:15.

Muthukumar T et al: Messenger RNA for FOXP3 in the urine of renal allograft recipients. N Engl J Med 2005;353:2342.

Nankivell BJ et al: The natural history of chronic allograft nephropathy. N Engl J Med 2003;349:2288.

Sankari BR et al: Immunosuppression after kidney transplantation: current strategies and drug interactions. J Med Liban 2004;52:234.

Shizura JA et al: Hematopoietic stem and progenitor cells. Clinical and preclinical regeneration of the hematolymphoid system. Ann Rev Med 2005;56:509.

Strom TB: Rejection—More than the eye can see. N Engl J Med 2005;353:2394.

Valcarcel D et al: Conventional versus reduced-intensity conditioning regimen for allogeneic stem cell transplantation in patients with hematologic malignancies. Eur J Haematol 2005;74:144.

Mechanism of Action of Immunosuppressive Drugs

The most frequently used immunosuppressive drugs and their modes of action are briefly summarized below.

Corticosteroids

This group of drugs has potent and direct anti-inflammatory effects on immunocompetent cells. Corticosteroids inhibit lymphocyte proliferation and cell-mediated immune responses more severely than they inhibit antibody responses. T helper cells, eosinophils, and monocytes are reduced in peripheral blood. Corticosteroids down-regulate cytokine gene expression through interference with transcription regulation. By inhibition of phospholipase A2, synthesis of inflammatory arachidonic acid metabolites (prostaglandins and leukotrienes) is suppressed. Corticosteroids have been shown to block the activation of T cells by interleukin-1 (IL-1) derived from macrophages. They also inhibit the expression of class II histocompatibility antigens on the macrophage surface, thereby interfering with presentation of antigen

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to T cells. Cumulatively, these cellular changes result in reduced inflammatory responses.

Cytotoxic Drugs

The most frequently used cytotoxic drugs are the anti-metabolites (see below) and cyclophosphamide. Cyclophosphamide is an alkylating agent that damages cells by cross-linking DNA. Although this cycle-specific drug is most effective in killing cells going through the mitotic cycle, it can also cause intermitotic cell injury and death. Cyclophosphamide can inhibit both T and B cell immunity as well as inflammation. Azathioprine and cyclophosphamide are effective inhibitors of the production of serum antibodies.

Antimetabolites

Antimetabolites used for immune modulation include methotrexate, an inhibitor of folic acid synthesis, azathioprine, a structural analog of mercaptopurine and an antagonist of purine synthesis; and leflunomide, an inhibitor of de novo pyrimidine synthesis. Azathioprine is a phase-specific drug that kills rapidly replicating cells. It inhibits proliferation of both T and B cells as well as macrophages. Methotrexate inhibits rapidly proliferating cells in S phase and suppresses both cell-mediated and humoral immunity as well as inflammation. Without immunosuppression, the incidence of graft-versus-host disease after allogeneic HPC transplant is almost 100%; this can be reduced to 20–30% with immunosuppressive therapy, especially the combination of methotrexate and cyclosporine, in addition to corticosteroids. Cyclosporine prevents T cell activation, while methotrexate inhibits the function of T cells that are already activated. When leflunomide is combined with methotrexate for the treatment of rheumatoid arthritis, it is more effective than methotrexate alone but the risk of hepatic toxicity is also increased. As monotherapy, it appears to be comparable to methotrexate or sulfasalazine.

Cyclosporine

This cyclic polypeptide derived from a fungus is used as an immunosuppressive drug in organ transplant recipients. Cyclosporine binds to cyclophilin, a cytoplasmic protein, thereby interfering with calcium-dependent events including secretion of interleukin-2 (IL-2) by T lymphocytes. Since IL-2 is necessary for T cell replication, this drug is a potent inhibitor of T cell proliferation and thereby inhibits T cell-mediated immune responses. Little effect has been shown on direct B cell immune responses or on inflammation. Its toxic effects are primarily on renal and, to a lesser extent, hepatic function. In addition to methotrexate, methylprednisolone has also been used with cyclosporine to treat graft-versus-host disease, although T cell-directed immunotoxins have not proved to be of any benefit. A recently developed microemulsion formulation offers improved oral bioavailability, safety, and efficacy.

Tacrolimus/Sirolimus/Everolimus

Like cyclosporine, tacrolimus also inhibits calcineurin-dependent phosphorylation of nuclear transcription factors, thereby inhibiting T cell activation and subsequent production of IL-2 and interferon-γ. Tacrolimus is approximately 100 times more potent than cyclosporine and, in many cases, is now preferred over cyclosporine. Rates of graft-versus-host disease are lower for tacrolimus-based regimens. Tacrolimus appears to be at least as effective as cyclosporine and possibly better as prophylaxis of acute rejection. The major toxicities include hyperglycemia, nephrotoxicity, and neurotoxicity. Topical formulations are well tolerated and have shown efficacy in the treatment of atopic dermatitis and allergic contact dermatitis.

Sirolimus, a macrocyclic immunosuppressive agent and product of Streptomyces hygroscopicus, inhibits cellular proliferation stimulated by growth factor driven signal transduction in response to alloantigens. It binds to FK506 binding protein 12 (FKBP12), which in turn binds FKBP12-rapamycin associated protein, arresting the cell cycle in the G1 phase. This allows sirolimus to act synergistically with cyclosporine. In particular, sirolimus added to other calcineurin antagonists appears to be less commonly associated with immunosuppression-induced neoplasms or lymphoproliferative diseases. Everolimus, a derivative of sirolimus, has a similar mechanism of action.

Tacrolimus and sirolimus are approved for use in kidney and liver transplantation as primary immunosuppressive agents and as rescue therapy but may also be used to prevent graft-versus-host disease. Everolimus is not approved by the US Food and Drug Administration.

Mycophenolate Mofetil

Mycophenolate mofetil is a prodrug used primarily as an adjunctive agent in kidney transplantation. By blocking lymphocyte production of guanine nucleotides, it inhibits T and B lymphocyte proliferation. Its use in combination with cyclosporine or tacrolimus has led to a lower incidence of acute allograft rejection, reducing the need for high-dose corticosteroids or OKT3 (muromonab-CD3).

Humanized Anti-Interleukin-2 Receptor Antibody

Several humanized monoclonal antibodies directed to the low-affinity IL-2 receptor are approved for use in kidney transplantation. Daclizumab and basiliximab target CD25, the IL-2 receptor, which is expressed on activated T cells. When combined with calcineurin inhibitors, they can be used for induction during transplantation. These antibodies, administered during the first 4–8 weeks following the transplant, result in a reduction of the incidence of acute graft rejection to about 25% when added to standard immunosuppressive therapy. Although the incidence of acute rejection

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is not substantially lower than that of other combinations of immunosuppressive agents, there appears to be a lower incidence and severity of side effects compared with antilymphocyte alternatives.

Muromonab-CD3

A murine monoclonal antibody, muromonab-CD3, is directed against human CD3, the T cell receptor. Indicated for acute graft rejection refractory to corticosteroids, large doses of the drug purge T cells from the systemic circulation. The drug has numerous side effects related to the release of cytokines, including fever, myalgias, dyspnea, and aseptic meningitis, and has also been associated with increased susceptibility to cytomegalovirus infection. Most patients are limited to a single course of therapy since recurrent courses may be associated with the production of neutralizing antibodies or posttransplant lymphoproliferative disease.

Other Monoclonal Antibodies

Rituximab specifically binds to CD20, a pan-B cell marker. Initially approved for use in B cell lymphoma, it is also used for posttransplant lymphoproliferative disease. It is being investigated for other B cell-mediated disorders but does suppress humoral immunity.

Immunomodulating Therapies

Co-Stimulatory Blockade

Abatacept is the first medication in a new class of drugs for the treatment of rheumatoid arthritis that selectively modulate the CD80 or CD86-CD28 co-stimulatory signal required for full T-cell activation. CD80 or CD86 on the surface of an antigen-presenting cell binds to CD28 on the T-cell, facilitating T cell activation. The naturally occurring inhibitory molecule known as cytotoxic T-lymphocyte antigen 4 (CTLA4) is induced on the surface of the T cell. CTLA4 has a markedly greater affinity for CD80 or CD86 than does CD28, thus out competing CD28 for CD80 or CD86 binding. Abatacept is a recombinant fusion protein comprising the extracellular domain of human CTLA4 and a fragment of the Fc domain of human IgG1, which has been modified to prevent complement fixation.

Belatacept differs from abatacept by two specific amino acid substitutions conferring greater binding avidity to CD80 andCD86. In combination with mycophenolate mofetil and corticosteroids after an induction phase with basiliximab, belatacept was found to be noninferior to a cyclosporine-based regimen in kidney transplantation.

Cytokine Therapy

The experimental and clinical applications of cytokines, as biologic response modifiers and therapeutic agents, have been greatly expanded in recent years. Some cytokines, such as tumor necrosis factor and interferon alfa, have direct antitumor activity. Other cytokines affect tumor immune responses by lymphokine-activated killer cells, tumor-infiltrating lymphocytes, and activated natural killer cells. Cytokines have been used to activate immune cells ex vivo prior to adoptive transfer or have been given concurrently with activated effector cells. Clinical trials of cellular adoptive therapy, with IL-2 activated killer cells, for the treatment of renal cell carcinoma and melanoma have demonstrated feasibility and regression of metastasis in some patients. Modest results, significant morbidity, and high cost have hampered widespread adoption of these techniques.

Interferon alfa is used in hairy cell leukemia, chronic myelogenous leukemia, Kaposi's sarcoma, and chronic active hepatitis B and C. Interferon beta is used for multiple sclerosis and interferon gamma for the treatment of chronic granulomatous disease. Constitutional symptoms are common with cytokine therapy, and in some instances toxicity is considerable.

Tumor Necrosis Factor Antagonists

Several approaches are available to mitigate the biologic effects of tumor necrosis factor (TNF), a cytokine produced by macrophages and other antigen-presenting cells. Three molecules have been designed to inhibit binding of TNF to its cellular receptor and thereby reduce its cellular and biologic effects. Etanercept is a dimeric construct—containing the soluble TNF receptor—joined to the Fc domain of a human IgG molecule. Infliximab is a chimeric antibody molecule containing a human Fc domain and a murine variable region. Adalimumab is a recombinant human monoclonal antibody that binds to TNF-α and impairs cytokine receptor binding. All are disease-modifying antirheumatic drugs that have been shown to slow joint destruction and markedly decrease symptoms of rheumatoid arthritis. Etanercept has shown efficacy in ankylosing spondylitis. It must be administered by subcutaneous injection twice weekly; infliximab is given intravenously every 2 months. These TNF antagonists should not be administered to patients with active infection, and the full scope of associated adverse effects is still not clear. Possible association without proven causation has been cited between TNF antagonists and lymphoma, demyelinating syndromes, and hematologic abnormalities. The incidence of ANAs is increased in patients receiving these drugs but frank drug-induced lupus appears rare.

Soluble IL-1 Receptor Antagonist

Anakinra, a recombinant, nonglycosylated soluble IL-1 receptor antagonist, competitively inhibits the binding of IL-1 to its cellular receptor. IL-1 is a major immunomodulatory cytokine, proinflammatory agent, and endogenous pyrogen. Through receptor blockade, anakinra has proved to be anti-inflammatory and efficacious in the treatment of rheumatoid arthritis for patients who have not responded or are unable to tolerate antimetabolites or TNF antagonists. There does

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appear to be an increased incidence of infections in patients receiving anakinra, and hypersensitivity reactions may also occur.

Anti-IgE

Omalizumab is a recombinant, humanized, murine monoclonal antibody with affinity for human IgE. By binding to the Fc-binding domain of circulating serum IgE, omalizumab prevents IgE binding to Fc-receptors on human mast cells. With ongoing subcutaneously injected treatment, tissue mast cells are effectively “disarmed” and less capable of activation through allergen-IgE interactions. Both early and late phase allergic reactions can be suppressed, and omalizumab has shown to be effective for control of symptoms, improvement in pulmonary function, and improvement in quality of life for patients with allergic asthma and allergic rhinitis. Improvement is not sustained after cessation of therapy, and chronic treatment is necessary for long-term disease control.

Intravenous Gamma Globulin

IGIV has numerous immunomodulatory and anti-inflammatory activities and is the standard of care for immunologically mediated disorders such as Kawasaki's syndrome and for antibody replacement in humoral immunodeficiency. When used in humoral immunodeficiency, serum IgG levels can become normal but the IGIV contains virtually no IgM and only traces of IgA.

Each lot of IGIV produced from donated serum contains millions of antibody specificities, reflecting the humoral immune repertoire from thousands of normal blood donors. Most current products undergo numerous purification and viral inactivation steps, including solvent-detergent treatment or pasteurization. The antibody reactivities can be directed against a wide range of foreign and self antigens. In addition to the above disorders, IGIV is effective in Guillain-Barré syndrome, immune-mediated neuropathies, idiopathic thrombocytopenic purpura, pediatric HIV infection, and after bone marrow transplantation. Many other potential indications have been supported only by anecdotal reports or uncontrolled trials.

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