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InternalMed_Harrison. Hereditary angioedema is an autosomal dominant disease due to a deficiency of C1INH (type 1) in about 85% of patients and to a dysfunctional protein (type 2) in the remainder. A third type of hereditary angioedema has been described in which C1INH function is normal, and the causal lesion is a mutant form of factor XII, which leads to generation of excessive bradykinin. In the acquired form of C1INH deficiency,thereisexcessiveconsumptiondueeithertoimmunecomplexes formedbetweenanti-idiotypicantibodyandmonoclonalIgGpresented by B cell lymphomas or to an autoantibody directed to C1INH. C1INH blocks the catalytic function of activated factor XII (Hageman factor) and of kallikrein, as well as the C1r/C1s components of C1. During clinical attacks of angioedema, C1INH-deficient patients have elevated plasma levels of bradykinin, particularly in the venous effluent of an involvedextremity,andreducedlevelsofprekallikreinandhigh-molecular-weight kininogen, from which bradykinin is cleaved. The


InternalMed_Harrison

InternalMed_Harrison. plasma levels of bradykinin, particularly in the venous effluent of an involvedextremity,andreducedlevelsofprekallikreinandhigh-molecular-weight kininogen, from which bradykinin is cleaved. The parallel decline in the complement substrates C4 and C2 reflects the action of activated C1 during such attacks. Mice with targeted disruption of the geneforC1INHexhibitachronicincreaseinvascularpermeability.The pathobiology isaggravated byadministrationof anACE inhibitor (captopril) and is attenuated by breeding the C1INH null strain to a bradykinin2receptor(Bk2R)nullstrain.AsACEisalsodescribedaskininase II, the use of blockers results in impaired bradykinin degradation and explains the angioedema that occurs idiosyncratically in hypertensive patients with a normal C1INH. Bradykinin-mediated angioedema, whether caused by ACE inhibitors or by C1INH deficiency, is noteworthy for the conspicuous absence of concomitant urticaria.


InternalMed_Harrison

InternalMed_Harrison. The rapid onset and self-limited nature of urticarial and angioedematous eruptions are distinguishing features. Additional characteristics are the occurrence of the urticarial crops in various stages of evolution and the asymmetric distribution of the angioedema. Urticaria and/or angioedema involving IgE-dependent mechanisms are often appreciatedby historicconsiderationsimplicating specific allergens orphysical stimuli, by seasonal incidence, and by exposure to certain environments. Direct reproduction of the lesion with physical stimuli is particularly valuable because it so often establishes the cause of the lesion. Thediagnosisofanenvironmentalallergenbasedontheclinicalhistory can be confirmed by skin testing or assay for allergen-specific IgE in serum. IgE-mediated urticaria and/or angioedema may or may not be associated with anelevationoftotal IgEorwithperipheral eosinophilia. Fever, leukocytosis, and an elevated sedimentation rate are absent.


InternalMed_Harrison

InternalMed_Harrison. The classification of urticarial and angioedematous states presented in Table 376-1 in terms of possible mechanisms necessarily includes some differential diagnostic points. Hypocomplementemia is not observed in IgE-mediated mast cell disease and may reflect either an acquired abnormality generally attributed to the formation of immune complexes or a genetic or acquired deficiency of C1INH. Chronic recurrent urticaria, generally in females, associated with arthralgias, an elevated sedimentation rate, and normo-or hypocomplementemia suggests an underlying cutaneous necrotizing angiitis. Vasculitic urti-2119 cariatypicallypersistslongerthan 72h,whereasconventionalurticaria often has a duration of 12–36 h. Confirmation depends on a biopsy that reveals cellular infiltration, nuclear debris, and fibrinoid necrosis of the venules. The same pathobiologic process accounts for the urticariainassociationwith suchdiseasesassystemiclupus erythematosus or viral hepatitis with or without associated


InternalMed_Harrison

InternalMed_Harrison. fibrinoid necrosis of the venules. The same pathobiologic process accounts for the urticariainassociationwith suchdiseasesassystemiclupus erythematosus or viral hepatitis with or without associated arteritis. Serum sickness per se or a similar clinical entity due to drugs includes not only urticaria but also pyrexia, lymphadenopathy, myalgia, and arthralgia or arthritis. Urticarial reactions to blood products or intravenous administration of immunoglobulin are defined by the event andgenerally are not progressive unless the recipient is IgA-deficient in the former case or the reagent is aggregated in the latter.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of hereditary angioedema is suggested not only by family history but also by the lack of pruritus and of urticarial lesions, the prominence of recurrent gastrointestinal attacks of colic, and episodes of laryngeal edema. Laboratory diagnosis depends on demonstrating a deficiency of C1INH antigen (type 1) or a nonfunctional protein (type 2) by a catalytic inhibition assay. While levels of C1 are normal, its substrates, C4 and C2, are chronically depleted and fall further during attacks due to the activation of additional C1. Patients with the acquired forms of C1INH deficiency have the same clinical manifestations but differ in the lack of a familial element. Furthermore, their sera exhibit a reduction of C1 function and C1q protein as well as C1INH, C4, and C2. Inborn C1INH deficiency and ACE inhibitor–elicited angioedema are associated with elevated levels of bradykinin. Lastly, type 3 hereditary angioedema is associated with normal levels of complement proteins.


InternalMed_Harrison

InternalMed_Harrison. Urticaria and angioedema are distinct from contact sensitivity, a vesicular eruption that progresses to chronic thickening of the skin with continued allergenic exposure. They also differ from atopic dermatitis, a condition that may present as erythema, edema, papules, vesiculation, and oozing proceeding to a subacute and chronic stage in which vesiculation is less marked or absent and scaling, fissuring, and lichenification predominate in a distribution that characteristically involves the flexor surfaces. In cutaneous mastocytosis, the reddish brown macules and papules, characteristic of urticaria pigmentosa, urticate with pruritus upon trauma; and in systemic mastocytosis, without or with urticaria pigmentosa, there is episodic systemic flushing with or without urtication but no angioedema.


InternalMed_Harrison

InternalMed_Harrison. Identification and subsequent elimination of the etiologic factor(s) provide the most satisfactory therapeutic program; this approach is feasible to varying degrees with IgE-mediated reactions to allergens or physical stimuli. For most forms of urticaria, H1 antihistamines such as chlorpheniramine or diphenhydramine effectively attenuate both urtication and pruritus, but because of their side effects, nonsedating agents such as loratadine, desloratadine, and fexofenadine, or low-sedating agents such as cetirizine or levocetirizine generally are used first. Cyproheptadine in dosages beginning at 8 mg and ranging up to 32 mg daily and especially hydroxyzine in dosages beginning at 40 mg and ranging up to 200 mg daily have proven effective when H1 antihistamines fail. The addition of an H2 antagonist such as cimetidine, ranitidine, or famotidine in conventional dosages may add benefit when H1 antihistamines are inadequate. Doxepin, a dibenzoxepin tricyclic compound with both H1 and H2


InternalMed_Harrison

InternalMed_Harrison. antagonist such as cimetidine, ranitidine, or famotidine in conventional dosages may add benefit when H1 antihistamines are inadequate. Doxepin, a dibenzoxepin tricyclic compound with both H1 and H2 receptor antagonist activity, is yet another alternative. A CysLT1 receptor antagonist such as montelukast, 10 mg/d, or zafirlukast, 20 mg twice a day, can be important add-on therapy.


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InternalMed_Harrison. Topical glucocorticoids are of no value, and systemic glucocorticoids are generally avoided in idiopathic, allergen-induced, or physical urticarias due to their long-term toxicity. Systemic glucocorticoids are useful in the management of patients with pressure urticaria, vasculitic urticaria (especially with eosinophil prominence), idiopathic angioedema with or without urticaria, or chronic urticaria that responds poorly to conventional treatment. With persistent vasculitic urticaria, hydroxychloroquine, dapsone, or colchicine may be added to the regimen after hydroxyzine and before or


InternalMed_Harrison

InternalMed_Harrison. Allergies, Anaphylaxis, and Systemic Mastocytosis 2120 along with systemic glucocorticoids. Cyclosporine can be efficacious for patients with chronic idiopathic or chronic autoimmune urticaria that is severe and poorly responsive to other modalities and/or where a glucocorticoid requirement is excessive. For chronic urticaria induced by autoantibody activation of mast cells and basophils or cold urticaria, monoclonal anti-IgE antibodies such as omalizumab may be considered. The therapy of inborn C1INH deficiency has been simplified by the finding that attenuated androgens correct the biochemical defect and afford prophylactic protection; their efficacy is attributed to production by the normal gene of an amount of functional C1INH sufficient to control the spontaneous activation of C1. The antifibrinolytic agent ε-aminocaproic acid may be used for preoperative prophylaxis but is contraindicated in patients with thrombotic tendencies or ischemia due to arterial atherosclerosis.


InternalMed_Harrison

InternalMed_Harrison. C1. The antifibrinolytic agent ε-aminocaproic acid may be used for preoperative prophylaxis but is contraindicated in patients with thrombotic tendencies or ischemia due to arterial atherosclerosis. Infusion of isolated C1INH protein may be used for prophylaxis or treatment of an acute attack; a bradykinin 2 receptor antagonist and ecallantide, a kallikrein inhibitor, which are administered SC, are each being assessed for amelioration of attacks. Treatment of the underlying hematologic malignancy is indicated for acquired C1INH deficiency.


InternalMed_Harrison

InternalMed_Harrison. Systemic mastocytosis is defined by a clonal expansion of mast cells that in most instances is indolent and nonmalignant. The mast cell expansion is generally recognized only in bone marrow and in the normal peripheral distribution sites of the cells, such as skin, gastrointestinal mucosa, liver, and spleen. Mastocytosis occurs at any age and has a slight preponderanceinmales. Theprevalence of systemicmastocytosis is not known, a familial occurrence is rare, and atopy is not increased.


InternalMed_Harrison

InternalMed_Harrison. A consensus classification formastocytosis recognizescutaneousmastocytosis with variants and four systemic forms (Table 376-2). Cutaneous mastocytosis is the most common diagnosis in children, whereas the form designated as indolent systemic mastocytosis (ISM) accounts for the majority of adult patients; it implies that there is no evidence of an associated hematologic disorder, liver disease, or lymphadenopathy and is not known to alter life expectancy. In systemic mastocytosis associated with clonal hematologic non–mast cell lineage disease (SM-AHNMD), the prognosis is determined by the nature of the associated disorder, which can range from dysmyelopoiesis to leukemia. In aggressive systemic mastocytosis (ASM), mast cell infiltration/proliferation in multiple organs such as liver, spleen, gut, and/or bone results in a poor prognosis; a subset of patients with this form has prominent eosinophilia with hepatosplenomegaly and lymphadenopathy. Mast cell leukemia (MCL) is the rarest


InternalMed_Harrison

InternalMed_Harrison. gut, and/or bone results in a poor prognosis; a subset of patients with this form has prominent eosinophilia with hepatosplenomegaly and lymphadenopathy. Mast cell leukemia (MCL) is the rarest form of the disease and is invariably fatal at present; the peripheral blood contains circulating, metachromatically staining,


InternalMed_Harrison

InternalMed_Harrison. Variants: plaque form, nodular form; telangiectasia macularis Solitary mastocytoma of skin Systemic mastocytosis with an associated clonal hematologic non–mast cell lineage disease (SM-AHNMD) Source: Modified from SH Swerdlow et al (eds): World Health Organization Classification of Tumors: Pathology and Genetics in Tumors of Hematopoietic and Lymphoid Tissues. Lyon, IARC Press, 2008. atypical mast cells. An aleukemic form of MCL is recognized without circulating mast cells when the percentage ofhigh-grade immature mast cells in bone marrow smears exceeds 20% in a nonspicular area. Mast cell sarcoma and extracutaneous mastocytomas are rare solid mast cell tumors with malignant and benign features, respectively.


InternalMed_Harrison

InternalMed_Harrison. A point mutation of A to T at codon 816 of c-kit that causes an aspartic acid to valine substitution is found in multiple cell lineages in patients with mastocytosis, resulting in a somatic gain-in-function mutation. This substitution, as well as other rare mutations of c-kit, is characteristic of patients with all forms of systemic mastocytosis but is also present in some children with cutaneous mastocytosis, as might be anticipated because mast cells are of bone marrow lineage. The prognosis for patients with cutaneous mastocytosis and for almost all with ISM is a normal life expectancy, whereas that for patients with SM-AHNMD is determined by a non–mast cell component. ASM and MCL carry a poorer prognosis. In infants and children with cutaneous manifestations, namely, urticaria pigmentosa or bullous lesions, visceral involvement is usually lacking, and resolution is common.


InternalMed_Harrison

InternalMed_Harrison. The clinical manifestations of systemic mastocytosis, distinct from a leukemic complication, are due to tissue occupancy by the mast cell mass, the tissue response to that mass, and the release of bioactive substances acting at both local and distal sites. The pharmacologically induced manifestations are pruritus, flushing, palpitations and vascular collapse, gastric distress, lower abdominal crampy pain, and recurrent headache. The increase in local cell burden is evidenced by the lesions of urticaria pigmentosa at skin sites and may be a direct local cause of bone pain and/or malabsorption. Mast cell–mediated fibrotic changes occur in liver, spleen, and bone marrow but not in gastrointestinal tissue or skin. Immunofluorescent analysis of bone marrow and skin lesions in ISM and of spleen, lymph node, and skin inASMhasrevealedonlyonemastcellphenotype,namely,scroll-poor cells expressing tryptase, chymase, and CPA.


InternalMed_Harrison

InternalMed_Harrison. The cutaneous lesions of urticaria pigmentosa are reddish-brown macules or papules that respond to trauma with urtication and erythema (Darier’s sign). The apparent incidence of these lesions is ≥80% in patients with ISM and <50% in those with SM-AHNMD or ASM. Approximately 1% of patients with ISM have skin lesions that appear as tan-brown macules with striking patchy erythema and associated telangiectasia (telangiectasia macularis eruptiva perstans). In the upper gastrointestinal tract, gastritis and peptic ulcer are significant problems. In the lower intestinal tract, the occurrence of diarrhea and abdominal pain is attributed to increased motility due to mast cell mediators; this problem can be aggravated by malabsorption, which can also cause secondary nutritional insufficiency and osteomalacia. The periportal fibrosis associated with mast cell infiltration and a prominence of eosinophils may lead to portal hypertension and ascites. In some patients, flushing and recurrent


InternalMed_Harrison

InternalMed_Harrison. and osteomalacia. The periportal fibrosis associated with mast cell infiltration and a prominence of eosinophils may lead to portal hypertension and ascites. In some patients, flushing and recurrent vascular collapse are markedly aggravated by an idiosyncratic response to a minimal dosage of NSAIDs. The neuropsychiatric disturbances are clinically most evident as impaired recent memory, decreased attention span, and “migraine-like” headaches. Patients may experience exacerbation of a specific clinical sign or symptom with alcohol ingestion, temperature changes, stress, use of mast cell–interactive narcotics, or ingestion of NSAIDs.


InternalMed_Harrison

InternalMed_Harrison. Although the diagnosis of mastocytosis is generally suspected on the basis of the clinical history and physical findings, and can be supported by laboratory procedures, it can be established only by a tissue diagnosis. By convention, the diagnosis of systemic mastocytosis depends heavily on bone marrow biopsy to meet the criteria of one major plus one minor or three minor findings (Table 376-3). The bone marrow provides the major criterion by revealing aggregates of mast cells, often in paratrabecular and perivascular locations with lymphocytes and eosinophils, as well as the minor criteria of an abnormal mast cell morphology, an aberrant mast cell membrane immunophenotype, or a codon 816 mutation in any cell type. A serum total tryptase level Major: Multifocal dense infiltrates of mast cells in bone marrow or other extracutaneous tissues with confirmation by immunodetection of tryptase or metachromasia


InternalMed_Harrison

InternalMed_Harrison. Major: Multifocal dense infiltrates of mast cells in bone marrow or other extracutaneous tissues with confirmation by immunodetection of tryptase or metachromasia Minor: Abnormal mast cell morphology with a spindle shape and/or multilobed or eccentric nucleus Aberrant mast cell surface phenotype with expression of CD25 (IL-2 receptor) and CD2 in addition to C117 (c-kit) Detection of codon 816 mutation in peripheral blood cells, bone marrow cells, or lesional tissue aDiagnosis requires either the major criterion and one minor criterion or three minor criteria.


InternalMed_Harrison

InternalMed_Harrison. Detection of codon 816 mutation in peripheral blood cells, bone marrow cells, or lesional tissue aDiagnosis requires either the major criterion and one minor criterion or three minor criteria. and/ora24-hurinecollectionformeasurementofhistamine,histamine metabolites,ormetabolitesofPGD2arenoninvasiveapproachestoconsiderbeforebonemarrowbiopsy.Thepro-β andαformsof tryptaseare elevated in more than one-half of patients with systemic mastocytosis and provide a minor criterion; the fully processed (“mature”) β form is increased in patients undergoing an anaphylactic reaction. Additional studies directed by the presentation include a bone densitometry, bone scan, or skeletal survey; contrast studies of the upper gastrointestinal tract with small-bowel follow-through, computed tomography scan, or endoscopy; and a neuropsychiatric evaluation. Osteoporosis is increased in mastocytosis and may lead to pathologic fractures.


InternalMed_Harrison

InternalMed_Harrison. The differential diagnosis requires the exclusion of other flushing disorders. The 24-h urine assessment of 5-hydroxy-indoleacetic acid and metanephrines should exclude a carcinoid tumor or a pheochromocytoma. Some patients presenting with recurrent mast cell activation symptoms without an obvious increase in mast cell burden in skin or bone marrow have been shown to carry aberrant mast cells with clonality markers of D816C c-kit mutation or surface CD25 expression. Most patients with recurrent anaphylaxis, including the idiopathic group, present with angioedema and/or wheezing, which are not manifestations of systemic mastocytosis.


InternalMed_Harrison

InternalMed_Harrison. The management of systemic mastocytosis uses a stepwise and symptom/sign–directed approach that includes an H1 antihistamine for flushing and pruritus, an H2 antihistamine or proton pump inhibitor for gastric acid hypersecretion, oral cromolyn sodium for diarrhea and abdominal pain, and aspirin for severe flushing with or without associated vascular collapse, despite use of H1 and H2 antihistamines, to block biosynthesis of PGD2. Systemic glucocorticoids appear to alleviate the malabsorption. Mast cell cytoreductive therapy consisting of IFN-α or cladribine is generally reserved for advanced, nonindolent variants of systemic mastocytosis. Their efficacy in ASM is variable, perhaps because of dosage limitations due to side effects. Chemotherapy is appropriate for the frank leukemias. A self-injectable epinephrine prescription is recommended for most patients due to increased incidence of anaphylaxis. Although c-kit is a receptor tyrosine kinase, the gain-in-function mutation of codon


InternalMed_Harrison

InternalMed_Harrison. epinephrine prescription is recommended for most patients due to increased incidence of anaphylaxis. Although c-kit is a receptor tyrosine kinase, the gain-in-function mutation of codon 816 is not susceptible to inhibition by imatinib mesylate.


InternalMed_Harrison

InternalMed_Harrison. Allergic rhinitis is characterized by sneezing; rhinorrhea; obstruction of the nasal passages; conjunctival, nasal, and pharyngeal itching; and lacrimation, all occurring in a temporal relationship to allergen exposure. Although commonly seasonal due to elicitation by airborne pollens, it can be perennial in an environment of chronic exposure to house dust mites, animal danders, or insect products. In North America, the incidence of allergic rhinitis is about 7%. The overall prevalence in North America is nearly 20%, with the peak prevalence of nearly 40% occurring in childhood and adolescence.


InternalMed_Harrison

InternalMed_Harrison. Allergic rhinitis generally occurs in atopic individuals, often in association with atopic dermatitis, food allergy, urticaria, and/or asthma (Chap. 309). Up to 40% of patients with rhinitis manifest asthma, whereas ∼70% of individuals with asthma experience rhinitis. Symptoms generally appear before the fourth decade of life and tend to diminish gradually with aging, although complete spontaneous remissions are uncommon. A relatively small number of weeds that depend on wind rather than insects for pollination, as well as grasses and some trees, produce sufficient quantities of pollen suitable for wide distribution by air currents to elicit seasonal allergic rhinitis. The dates of pollination of these species generally vary little from year to yearinaparticularlocalebutmaybequitedifferentinanotherclimate. In the temperate areas of North America, trees typically pollinate from March through May, grasses in June and early July, and ragweed from mid-August to early October. Molds, which


InternalMed_Harrison

InternalMed_Harrison. In the temperate areas of North America, trees typically pollinate from March through May, grasses in June and early July, and ragweed from mid-August to early October. Molds, which are widespread in nature becausetheyoccurinsoilordecayingorganicmatter,propagatespores in a pattern that depends on climatic conditions. Perennial allergic rhinitis occurs in response to allergens that are present throughout the year, including animal dander, cockroach-derived proteins, mold spores, or dust mites such as Dermatophagoides farinae and Dermatophagoides pteronyssinus. Dust mites are scavengers of human skin and excrete cysteine protease allergens in their feces. In up to one-half of patients with perennial rhinitis, no clear-cut allergen can be demonstrated as causative. The ability of many allergens to cause rhinitisratherthan lower respiratory tract symptoms (particularlypollens) may be attributed to their large size, 10–100 μm, and retention within the nose.


InternalMed_Harrison

InternalMed_Harrison. Episodic rhinorrhea, sneezing, obstruction of the nasal passages with lacrimation, and pruritus of the conjunctiva, nasal mucosa, and oropharynx are the hallmarks of allergic rhinitis. The nasal mucosa is pale and boggy, the conjunctiva congested and edematous, and the pharynx generally unremarkable. Swelling of the turbinates and mucous membranes with obstruction of the sinus ostia and eustachian tubes precipitates secondary infections of the sinuses and middle ear, respectively. Nasal polyps, representing mucosal protrusions containing edema fluid with variable numbers of eosinophils and degranulated mast cells, can increase obstructive symptoms and can concurrently arise within the nasopharynx or sinuses. However, atopy is not a risk factor for nasal polyps, which instead may occur in the setting of the aspirin-intolerant triad of rhinosinusitis and asthma and in patients with chronic staphylococcal colonization, which produces superantigens leading to an intense TH2 inflammatory


InternalMed_Harrison

InternalMed_Harrison. the setting of the aspirin-intolerant triad of rhinosinusitis and asthma and in patients with chronic staphylococcal colonization, which produces superantigens leading to an intense TH2 inflammatory response.


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InternalMed_Harrison. The nose presents a large mucosal surface area through the folds of the turbinates and serves to adjust the temperature and moisture content of inhaled air and to filter out particulate materials >10 μm in size by impingement in a mucous blanket; ciliary action moves the entrapped particles toward the pharynx. Entrapment of pollen and digestion of the outer coat by mucosal enzymes such as lysozymes release protein allergens generally of 10,000–40,000 molecular weight. The initial interaction occurs between the allergen and intraepithelial mast cells and then proceeds to involve deeper perivenular mast cells, both of which are sensitized with specific IgE. During the symptomatic season when the mucosae are already swollen and hyperemic, there is enhanced adverse reactivity to the seasonal pollen. Biopsy specimens of nasal mucosa during seasonal rhinitis show submucosal edema with infiltration byeosinophils, along with somebasophilsand neutrophils.


InternalMed_Harrison

InternalMed_Harrison. The mucosal surface fluid contains IgA that is present because of its secretorypieceandalsoIgE,whichapparentlyarrivesbydiffusionfrom plasma cells in proximity to mucosal surfaces. IgE fixes to mucosal and submucosal mast cells, and the intensity of the clinical response to inhaled allergens is quantitatively related to the naturally occurring pollen dose. In sensitive individuals, the introduction of allergen into thenoseisassociatedwithsneezing,“stuffiness,”anddischarge,andthe fluid contains histamine, PGD2, and leukotrienes. Thus the mast cells of the nasal mucosa and submucosa generate and release mediators Allergies, Anaphylaxis, and Systemic Mastocytosis 2122 through IgE-dependent reactions that are capable of producing tissue edema and eosinophilic infiltration.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of seasonal allergic rhinitis depends largely on an accurate history of occurrence coincident with the pollination of the offending weeds, grasses, or trees. The continuous character of perennial allergic rhinitis due to contamination of the home or place of work makes historic analysis difficult, but there may be variability in symptoms that can be related to exposure to animal dander, dust mite and/or cockroach allergens, fungal spores, or work-related allergens such as latex. Patients with perennial rhinitis commonly develop the problem in adult life, and manifest nasal congestion and a postnasal discharge, often associated with thickening of the sinus membranes demonstrated by radiography. Perennial nonallergic rhinitis with eosinophilia syndrome (NARES) occurs in the middle decades of life and is characterized by nasal obstruction, anosmia, chronic sinusitis, andfrequentaspirinintolerance.Theterm vasomotor rhinitis or perennial nonallergic rhinitis designates a


InternalMed_Harrison

InternalMed_Harrison. middle decades of life and is characterized by nasal obstruction, anosmia, chronic sinusitis, andfrequentaspirinintolerance.Theterm vasomotor rhinitis or perennial nonallergic rhinitis designates a condition of enhanced reactivity of the nasopharynx in which a symptom complex resembling perennial allergic rhinitis occurs with nonspecific stimuli, including chemical odors, temperature and humidity variations, and position changes but occurs without tissue eosinophilia or an allergic etiology. Other entitiestobeexcludedarestructuralabnormalitiesofthenasopharynx; exposure to irritants; gustatory rhinitis associated with cholinergic activation that occurs while eating or ingesting alcohol; hypothyroidism; upper respiratorytractinfection;pregnancywith prominent nasal mucosal edema; prolonged topical use of α-adrenergic agents in the form of nose drops (rhinitis medicamentosa); and the use of certain therapeutic agents such as rauwolfia, β-adrenergic antagonists, estrogens, progesterone,


InternalMed_Harrison

InternalMed_Harrison. topical use of α-adrenergic agents in the form of nose drops (rhinitis medicamentosa); and the use of certain therapeutic agents such as rauwolfia, β-adrenergic antagonists, estrogens, progesterone, ACE inhibitors, aspirin and other NSAIDS, and drugs for erectile dysfunction (phosphodiesterase-5 inhibitors).


InternalMed_Harrison

InternalMed_Harrison. The nasal secretions of allergic patients are rich in eosinophils, and a modest peripheral eosinophilia is a common feature. Local or systemic neutrophilia implies infection. Total serum IgE is frequently elevated, but the demonstration of immunologic specificity for IgE is critical to an etiologic diagnosis. A skin test by the intracutaneous route (punctureorprick) withthe allergensofinterestprovidesa rapid and reliable approach to identifying allergen-specific IgE that has sensitized cutaneous mast cells. A positive intracutaneous skin test with 1:10–1:20 weight/volume of extract has a high predictive value for the presence of allergy. An intradermal test with a 1:500–1:1000 dilution of 0.05 mL may follow if indicated by history when the intracutaneous test is negative, but while more sensitive, it is less reliable due to the reactivity of some asymptomatic individuals at the test dose. Skin testing by the intracutaneous route for food allergens can be supportive of the clinical


InternalMed_Harrison

InternalMed_Harrison. sensitive, it is less reliable due to the reactivity of some asymptomatic individuals at the test dose. Skin testing by the intracutaneous route for food allergens can be supportive of the clinical history. A double-blind, placebo-controlled challenge may document a food allergy, but such a procedure does bear the risk of an anaphylactic reaction. An elimination diet is safer but is tedious and less definitive. Food allergy is uncommon as a cause of allergic rhinitis.


InternalMed_Harrison

InternalMed_Harrison. Newer methodology for detecting total IgE, including the development of enzyme-linked immunosorbent assays (ELISA) employing anti-IgE bound to either a solid-phase or a liquid-phase particle, provides rapid and cost-effective determinations. Measurements of specific anti-IgE in serum are obtained by its binding to an allergen and quantitation by subsequent uptake of labeled anti-IgE. As compared to the skin test, the assay of specific IgE in serum is less sensitive but has high specificity.


InternalMed_Harrison

InternalMed_Harrison. Avoidance of exposure to the offending allergen is the most effective means of controlling allergic diseases; removal of pets from the home toavoidanimaldanders,utilizationofair-filtrationdevicestominimize the concentrations of airborne pollens, elimination of cockroach-derived proteins by chemical destruction of the pest and careful food storage, travel to areas where the allergen is not being generated, and even a change of domicile to eliminate a mold spore problem may be necessary. Control of dust mites by allergen avoidance includes use of plastic-lined covers for mattresses, pillows, and comforters; using a filter-equipped vacuum cleaner; washing bedding and clothes at temperatures>54.5°C(above130°F);andeliminationofcarpetsanddrapes.


InternalMed_Harrison

InternalMed_Harrison. Although allergen avoidance is the most cost-effective means of managing allergic rhinitis, treatment with pharmacologic agents represents the standard approach to seasonal or perennial allergic rhinitis. Oral H1 antihistamines are effective for nasopharyngeal itching, sneezing, and watery rhinorrhea and for such ocular manifestations as itching, tearing, and erythema, but they are less efficacious for the nasal congestion. The older antihistamines are sedating, and they induce psychomotor impairment, including reduced eye-hand coordination and impaired automobile driving skills. Their anticholinergic (muscarinic) effects include visual disturbance, urinary retention, and constipation. Because the newer H1 antihistamines such as fexofenadine, loratadine, desloratadine, cetirizine, levocetirizine, olopatadine, bilastine, and azelastine are less lipophilic and more H1 selective, their ability to cross the blood-brain barrier is reduced, and thus their sedating and anticholinergic side


InternalMed_Harrison

InternalMed_Harrison. olopatadine, bilastine, and azelastine are less lipophilic and more H1 selective, their ability to cross the blood-brain barrier is reduced, and thus their sedating and anticholinergic side effects are minimized. These newer antihistamines do not differ appreciably in efficacy for relief of rhinitis and/or sneezing. Azelastine nasal spray may benefit individuals with nonallergic vasomotor rhinitis, but it has an adverse effect of dysgeusia (taste perversion) in some patients. Because antihistamines have little effect on congestion, α-adrenergic agents such as phenylephrine or oxymetazoline are generally used topically to alleviate nasal congestion and obstruction. However, the duration of their efficacy is limited because of rebound rhinitis (i.e., 7-to 14-day use can lead to rhinitis medicamentosa) and such systemic responses as hypertension. Oral α-adrenergic agonist decongestants containing pseudoephedrine are standard for the management of nasal congestion, generally in


InternalMed_Harrison

InternalMed_Harrison. medicamentosa) and such systemic responses as hypertension. Oral α-adrenergic agonist decongestants containing pseudoephedrine are standard for the management of nasal congestion, generally in combination with an antihistamine. While oral antihistamines typically reduce nasal and ocular symptoms by about one-third, pseudoephedrine must be added to achieve a similar reduction in nasal congestion. These pseudoephedrine combination products can cause insomnia and are precluded from use in patients with narrow angle glaucoma, urinary retention, severe hypertension, marked coronary artery disease, or a first-trimester pregnancy. The CysLT1 blocker montelukast is approved for treatment of both seasonal and perennial rhinitis, and it reduces both nasal and ocular symptoms by about 20%. Cromolyn sodium, a nasal spray, is essentially without side effects and is used prophylactically on a continuous basis during the season. Intranasal high-potency glucocorticoids are the most potent drugs


InternalMed_Harrison

InternalMed_Harrison. sodium, a nasal spray, is essentially without side effects and is used prophylactically on a continuous basis during the season. Intranasal high-potency glucocorticoids are the most potent drugs available for the relief of established rhinitis, seasonal or perennial, and are effective in relieving nasal congestion. They provide efficacy with substantially reduced side effects as compared with this same class of agent administered orally. Their most frequent side effect is local irritation, with Candida overgrowth being a rare occurrence. The currently available intranasal glucocorticoids— beclomethasone, flunisolide, triamcinolone, budesonide, fluticasone propionate, fluticasone furoate, ciclesonide, and mometasone furoate—are equally effective for nasal symptom relief, including nasal congestion; these agents all achieve up to 70% overall symptom relief with some variation in the time period for onset of benefit. Topical ipratropium is an anticholinergic agent effective in reducing


InternalMed_Harrison

InternalMed_Harrison. these agents all achieve up to 70% overall symptom relief with some variation in the time period for onset of benefit. Topical ipratropium is an anticholinergic agent effective in reducing rhinorrhea, including that in patients with perennial symptoms, and it can be additionally efficacious when combined with intranasal glucocorticoids. Local treatment with cromolyn sodium is effective in treating mild allergic conjunctivitis. Topical antihistamines such as olopatadine, azelastine, ketotifen, or epinastine administered to the eye provide rapid relief of itching and redness and are more effective than oral antihistamines.


InternalMed_Harrison

InternalMed_Harrison. Immunotherapy, often termed hyposensitization, consists of repeated subcutaneous injections of gradually increasing concentrations of the allergen(s) considered to be specifically responsible for the symptom complex. Controlled studies of ragweed, grass, dust mite, and cat dander allergens administered for treatment of allergic rhinitis have demonstrated at least partial relief of symptoms and


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InternalMed_Harrison. Intranasal glucocorticoids Past history of allergic rhinitis Treat as allergic rhinitis Wet or sneezy Exclude foreign body and anatomic defect Non-allergic rhinitis No specific allergen identified If negative Topical intranasal antihistamines or oral decongestants No past history of allergic rhinitis Treat as infection (viral vs bacterial) Chronic Anatomic defects, polyps, foreign body, and sinusitis Consider GERD assessment Exclude medication-induced rhinitis Acute Infectious symptoms Present Present Absent Absent Treat medically Consider immune deficiency evaluation if chronic sinusitis Assess for asthma and/or refer to ENT Allergy evaluation History/skin test or blood test for allergen-specific IgE Assess for asthma Oral or intranasal antihistamines, decongestants, intranasal cromolyn, or CysLT1 receptor antagonist Intranasal glucocorticoids (+ antihistamines/decongestants if required and/or + CysLT1 receptor antagonist) Consider nasal saline Allergic rhinitis Specific allergen


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InternalMed_Harrison. or CysLT1 receptor antagonist Intranasal glucocorticoids (+ antihistamines/decongestants if required and/or + CysLT1 receptor antagonist) Consider nasal saline Allergic rhinitis Specific allergen identified Oral glucocorticoids (brief: 3-7 days) If associated with severe asthma, consider omalizumabIpratropium bromide Immunotherapy Blocked nose Oral decongestants


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InternalMed_Harrison. FIGUrE 376-4 Algorithm for the diagnosis and management of rhinitis. ENT, ear, nose, and throat; GERD, gastroesophageal reflux disease.


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InternalMed_Harrison. Allergies, Anaphylaxis, and Systemic Mastocytosis 2124 signs. The duration of such immunotherapy is –5 years, with discontinuation being based on minimal symptoms over two consecutive seasons of exposure to the allergen. Clinical benefit appears related to the administration of a high dose of relevant allergen, advancing from weekly to monthly intervals. Patients should remain at the treatment site for at least 20 minutes after allergen administration so that any anaphylactic conseuence can be managed. Local reactions with erythema and induration are not uncommon and may persist for 1– days. Immunotherapy is contraindicated in patients with significant cardiovascular disease or unstable asthma and should be conducted with particular caution in any patient reuiring adrenergic blocking therapy because of the difficulty in managing an anaphylactic complication. The response to immunotherapy is associated with a complex of cellular and humoral effects that includes a modulation in T cell


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InternalMed_Harrison. because of the difficulty in managing an anaphylactic complication. The response to immunotherapy is associated with a complex of cellular and humoral effects that includes a modulation in T cell cytokine production. Immunotherapy should be reserved for clearly documented seasonal or perennial rhinitis that is clinically related to defined allergen exposure with confirmation by the presence of allergen-specific IgE. Systemic treatment with a monoclonal antibody to IgE (omalizumab) that blocks mast cell and basophil sensitization has efficacy for allergic rhinitis and can be used with immunotherapy to enhance safety and efficacy. However, current approval is only for treatment of patients with persistent allergic asthma not controlled by inhaled glucocorticoid therapy. A seuence for the management of allergic or perennial rhinitis based on an allergen-specific diagnosis and stepwise management as reuired for symptom control would include the following(1) identification of the offending


InternalMed_Harrison

InternalMed_Harrison. of allergic or perennial rhinitis based on an allergen-specific diagnosis and stepwise management as reuired for symptom control would include the following(1) identification of the offending allergen(s) by history with confirmation of the presence of allergen-specific IgE by skin test andor serum assay(2) avoidance of the offending allergenand () medical management in a stepwise fashion (Fig. 376-4). Mild intermittent symptoms of allergic rhinitis are treated with oral antihistamines, oral CysLT1 receptor antagonists, intranasal antihistamines, or intranasal cromolyn prophylaxis. Moderate to more severe allergic rhinitis is managed with intranasal glucocorticoids plus oral antihistamines, oral CysLT1 receptor antagonists, or antihistamine-decongestant combinations. Persistent allergic rhinitis reuiring the daily use of intranasal glucocorticoids with add-on interventions such as oral antihistamines, decongestant combinations, or topical ipratropium merits consideration of


InternalMed_Harrison

InternalMed_Harrison. allergic rhinitis reuiring the daily use of intranasal glucocorticoids with add-on interventions such as oral antihistamines, decongestant combinations, or topical ipratropium merits consideration of allergen-specific immunotherapy. Even a brief course of oral prednisone can be indicated for rapid relief of severe allergic rhinitis symptoms.


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InternalMed_Harrison. autoimmunity and autoimmune Diseases Betty Diamond, Peter E. Lipsky One of the central features of the immune system is the capacity to mount an inflammatory response to potentially harmful foreign mate-377e rials while avoiding damage to self-tissues. Whereas recognition of self plays an important role in shaping the repertoires of immune receptors on both T and B cells and in clearing apoptotic and other tissue debris from sites throughout the body, the development of potentially harmful immune responses to self-antigens is, in general, prohibited. The essential feature of an autoimmune disease is that tissue injury is caused by the immunologic reaction of the organism against its own tissues. Autoimmunity, on the other hand, refers merely to the presence of antibodies or T lymphocytes that react with self-antigens and does not necessarily imply that the self-reactivity has pathogenic consequences. Autoimmunity is present in all individuals; however, autoimmune disease occurs only


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InternalMed_Harrison. that react with self-antigens and does not necessarily imply that the self-reactivity has pathogenic consequences. Autoimmunity is present in all individuals; however, autoimmune disease occurs only in those individuals in whom the breakdown of one or more of the basic mechanisms regulating immune tolerance results in self-reactivity that can cause tissue damage.


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InternalMed_Harrison. Autoimmunity is seen in normal individuals, with a higher frequency among normal older people. Polyreactive autoantibodies that recognize many host antigens are present throughout life. Expression of these autoantibodies may be increased after some inciting events. These antibodies are usually of the IgM heavy chain isotype and are encoded by nonmutated germline immunoglobulin variable region genes. When autoimmunity is induced by an inciting event, such as infection or tissue damage from trauma or ischemia, the autoreactivity is in general self-limited. When such autoimmunity does persist, however, pathology may or may not result. Even in the presence of organ pathology, it may be difficult to determine whether the damage is mediated by autoreactivity. After an inciting event, the development of self-reactivity may be the consequence of an ongoing pathologic process, may be nonpathogenic, or may contribute to tissue inflammation and damage. Individuals with autoimmune disease may


InternalMed_Harrison

InternalMed_Harrison. of self-reactivity may be the consequence of an ongoing pathologic process, may be nonpathogenic, or may contribute to tissue inflammation and damage. Individuals with autoimmune disease may have numerous autoantibodies, only some or even none of which may be pathogenic. Patients with systemic sclerosis may have a wide array of antinuclear antibodies that are important in disease classification but are not clearly pathogenic; patients with pemphigus may also exhibit a wide array of autoantibodies, only one of which (antibody to desmoglein) is known to be pathogenic.


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InternalMed_Harrison. Since Ehrlich first postulated the existence of mechanisms to prevent the generation of self-reactivity in the early1900s, ideas concerning the nature of this prohibition have developed in parallel with a progressive increase in understanding of the immune system. Burnet’s clonal selection theory included the idea that interaction of lymphoid cells with their specific antigens during fetal or early postnatal life would lead to elimination of such “forbidden clones.” This idea was refuted, however, when it was shown that autoimmune diseases could be induced in experimental animals by simple immunization procedures, that autoantigen-binding cells could be demonstrated easily in the circulation of normal individuals, and that self-limited autoimmune phenomena frequently developed after tissue damage from infection or trauma. These observations indicated that clones of cells capable of responding to autoantigens were present in the repertoire of antigen-reactive cells in normal adults and


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InternalMed_Harrison. damage from infection or trauma. These observations indicated that clones of cells capable of responding to autoantigens were present in the repertoire of antigen-reactive cells in normal adults and suggested that mechanisms in addition to clonal deletion were responsible for preventing their activation.


InternalMed_Harrison

InternalMed_Harrison. Currently, three general processes are thought to be involved in the maintenance of selective unresponsiveness to autoantigens (Table 377e-1): (1) sequestration of self-antigens, rendering them inaccessible to the immune system; (2) specific unresponsiveness (tolerance or anergy) of relevant T or B cells; and (3) limitation of potential reactivity by regulatory mechanisms. Derangements of these normal 1. Sequestration of self-antigens 2. Generation and maintenance of tolerance a. Central deletion of autoreactive lymphocytes b. Peripheral anergy of autoreactive lymphocytes c. 3. Regulatory mechanisms a. b. c. d. e.


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InternalMed_Harrison. processes may predispose to the development of autoimmunity (Table 377e-2). In general, these abnormal responses require both an exogenous trigger, such as bacterial or viral infection or cigarette smoking, and the presence of endogenous abnormalities in the cells of the immune system. Microbial superantigens, such as staphylococcal protein A and staphylococcal enterotoxins, are substances that can stimulate a broad range of T and B cells through specific interactions with selected families of immune receptors, irrespective of their antigen specificity. If autoantigen-reactive T and/or B cells express these receptors, autoimmunity may develop. Alternatively, molecular mimicry or cross-reactivity between a microbial product and a self-antigen may lead to activation of autoreactive lymphocytes. One of the best examples of autoreactivity and autoimmune disease resulting from molecular mimicry is rheumatic fever, in which antibodies to the M protein of streptococci cross-react with


InternalMed_Harrison

InternalMed_Harrison. One of the best examples of autoreactivity and autoimmune disease resulting from molecular mimicry is rheumatic fever, in which antibodies to the M protein of streptococci cross-react with myosin, laminin, and other matrix proteins as well as with neuronal antigens. Deposition of these autoantibodies in the heart initiates an inflammatory response, whereas their penetration into the brain can result in Sydenham’s chorea. Molecular mimicry between microbial proteins and host tissues has been reported in type 1 diabetes mellitus, rheumatoid arthritis, celiac disease, and multiple sclerosis. It is presumed that infectious agents may be able to overcome self-tolerance because they possess pathogen-associated molecular patterns (PAMPs). These molecules (e.g., bacterial endotoxin, RNA, or DNA) exert adjuvant-like effects on the immune system by interacting with Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs)


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InternalMed_Harrison. MeChanisMs of autoiMMunity I. Exogenous A. Molecular mimicry B. Superantigenic stimulation C. Microbial and tissue damage–associated adjuvanticity II. A. 1. Loss of immunologic privilege 2. Presentation of novel or cryptic epitopes (epitope spreading) 3. Alteration of self-antigen 4. Enhanced function of antigen-presenting cells a. b. B. 1. 2. C. Increased B cell function 1. 2. D. Apoptotic defects or defects in clearance of apoptotic material E. Cytokine imbalance F. Altered immunoregulation


InternalMed_Harrison

InternalMed_Harrison. b. B. 1. 2. C. Increased B cell function 1. 2. D. Apoptotic defects or defects in clearance of apoptotic material E. Cytokine imbalance F. Altered immunoregulation G. Endocrine abnormalities that increase the immunogenicity and immunostimulatory capacity of the microbial material. The adjuvants activate dendritic cells through TLRs, which in turn stimulate the activation of previously quiescent lymphocytes that recognize both microbial antigens and self-antigens. Similarly, cellular and tissue damage due to the release of damage-associated molecular patterns (DAMPs), including DNA, RNA nucleosomes, and other tissue debris, may activate cells of the inflammatory and immune systems through engagement of the same array of PRRs.


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InternalMed_Harrison. Endogenous derangements of the immune system may also contribute to the loss of immunologic tolerance to self-antigens and the development of autoimmunity (Table 377e-2). Some autoantigens reside in immunologically privileged sites, such as the brain or the anterior chamber of the eye. These sites are characterized by the inability of engrafted tissue to elicit immune responses. Immunologic privilege results from a number of events, including the limited entry of proteins from those sites into lymphatics, the local production of immunosuppressive cytokines such as transforming growth factor β, and the local expression of molecules (including Fas ligand) that can induce apoptosis of activated T cells. Lymphoid cells remain in a state of immunologic ignorance (neither activated nor anergized) with regard to proteins expressed uniquely in immunologically privileged sites. If the privileged site is damaged by trauma or inflammation or if T cells are activated elsewhere, proteins expressed


InternalMed_Harrison

InternalMed_Harrison. with regard to proteins expressed uniquely in immunologically privileged sites. If the privileged site is damaged by trauma or inflammation or if T cells are activated elsewhere, proteins expressed at this site can become immunogenic and also be the targets of immunologic assault. In multiple sclerosis and sympathetic ophthalmia, for example, antigens uniquely expressed in the brain and eye, respectively, become the target of activated T cells.


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InternalMed_Harrison. Alterations in antigen presentation may also contribute to autoimmunity. Peptide determinants (epitopes) of a self-antigen that are not routinely presented to lymphocytes may be recognized as a result of altered proteolytic processing of the molecule and the ensuing presentation of novel peptides (cryptic epitopes). When B cells rather than dendritic cells present self-antigen, they may also present cryptic epitopes that can activate autoreactive T cells. These cryptic epitopes will not previously have been available to effect the silencing of autoreactive lymphocytes. Furthermore, once there is immunologic recognition of one protein component of a multimolecular complex, reactivity may be induced to other components of the complex after internalization and presentation of all molecules within the complex (epitope spreading). Finally, inflammation, environmental agents, drug exposure, or normal senescence may cause a post-transitional alteration in proteins, resulting in the


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InternalMed_Harrison. within the complex (epitope spreading). Finally, inflammation, environmental agents, drug exposure, or normal senescence may cause a post-transitional alteration in proteins, resulting in the generation of immune responses that cross-react with normal self-proteins. For example, the induction and/or release of protein arginine deiminase enzymes results in the conversion of arginine residues to citrullines in a variety of proteins, thereby altering their capacity to induce immune responses. Production of antibodies to citrullinated proteins has been observed in rheumatoid arthritis and chronic lung disease as well as in normal smokers and may contribute to organ pathology. Alterations in the availability and presentation of autoantigens may be important components of immunoreactivity in certain models of organ-specific autoimmune diseases. In addition, these factors may be relevant to an understanding of the pathogenesis of various drug-induced autoimmune conditions. However, the


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InternalMed_Harrison. in certain models of organ-specific autoimmune diseases. In addition, these factors may be relevant to an understanding of the pathogenesis of various drug-induced autoimmune conditions. However, the diversity of autoreactivity manifesting in non-organ-specific systemic autoimmune diseases suggests that these conditions may result from a more general activation of the immune system rather than from an alteration in individual self-antigens.


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InternalMed_Harrison. Many autoimmune diseases are characterized by the presence of antibodies that react with apoptotic material. Defects in the clearance of apoptotic material have been shown to elicit auto-immunity and autoimmune disease in a number of animal models. Moreover, such defects have been found in patients with systemic lupus erythematosus (SLE). Apoptotic debris that is not cleared quickly by the immune system can function as endogenous ligands for a number of PRRs on dendritic cells and B cells. Under such circumstances, dendritic cells and/or B cells are activated, and an immune response to apoptotic debris can develop. In addition, the presence of extracellular apoptotic material within germinal centers of secondary lymphoid organs in patients with SLE may facilitate the direct activation of autoimmune B cell clones or may function to select such clones during immune responses.


InternalMed_Harrison

InternalMed_Harrison. Studies in a number of experimental models have suggested that intense stimulation of T lymphocytes can produce nonspecific signals that bypass the need for antigen-specific helper T cells and lead to polyclonal B cell activation with the formation of multiple autoantibodies. For example, antinuclear, antierythrocyte, and antilymphocyte antibodies are produced during the chronic graft-versus-host reaction. In addition, true autoimmune diseases, including autoimmune hemolytic anemia and immune complex–mediated glomerulonephritis, can be induced in this manner. While such diffuse activation of helper T cell activity clearly can cause autoimmunity, nonspecific stimulation of B lymphocytes can also lead to the production of autoantibodies. Thus, the administration of polyclonal B cell activators, such as bacterial endotoxin, to normal mice leads to the production of a number of autoantibodies, including those to DNA and IgG (rheumatoid factor). A variety of genetic modifications resulting


InternalMed_Harrison

InternalMed_Harrison. such as bacterial endotoxin, to normal mice leads to the production of a number of autoantibodies, including those to DNA and IgG (rheumatoid factor). A variety of genetic modifications resulting in hyperresponsiveness of B cells also can lead to the production of autoantibodies and, in animals of appropriate genetic background, a lupus-like syndrome. Moreover, excess B cell activating factor (BAFF), a B cell survival factor, can cause T cell–independent B cell activation and the development of autoimmunity. SLE can also be induced in mice through exuberant dendritic cell activation, through a redundancy of TLR7 on the Y chromosome (as in BXSB-Yaa mice), or through exposure to CpG, a ligand for TLR9. The ensuing induction of inflammatory mediators can cause a switch from the production of nonpathogenic IgM auto-antibodies to the production of pathogenic IgG autoantibodies in the absence of antigen-specific T cell help. Aberrant selection of the B or T cell repertoire at the time of


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InternalMed_Harrison. of nonpathogenic IgM auto-antibodies to the production of pathogenic IgG autoantibodies in the absence of antigen-specific T cell help. Aberrant selection of the B or T cell repertoire at the time of antigen receptor expression can also predispose to autoimmunity. For example, B cell immunodeficiency caused by an absence of the B cell receptor–associated kinase (Bruton’s tyrosine kinase) leads to X-linked agammaglobulinemia. This syndrome is characterized by reduced B cell numbers. This leads to high levels of BAFF which alter B cell selection and lead to greater survival of autoreactive B cells. Likewise, negative selection of autoreactive T cells in the thymus requires expression of the autoimmune regulator (AIRE) gene that enables the expression of tissue-specific proteins in thymic medullary epithelial cells. Peptides from these proteins are expressed in the context of major histocompatibility complex (MHC) molecules and mediate the central deletion of autoreactive T cells. The


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InternalMed_Harrison. medullary epithelial cells. Peptides from these proteins are expressed in the context of major histocompatibility complex (MHC) molecules and mediate the central deletion of autoreactive T cells. The absence of AIRE gene expression leads to a failure of negative selection of autoreactive cells, autoantibody production, and severe inflammatory destruction of multiple organs. Individuals deficient in AIRE gene expression develop autoimmune polyendocrinopathy–candidiasis– ectodermal dystrophy (APECED).


InternalMed_Harrison

InternalMed_Harrison. Primary alterations in the activity of T and/or B cells, cytokine imbalances, or defective immunoregulatory circuits may also contribute to the emergence of autoimmunity. Diminished production of tumor necrosis factor (TNF) and interleukin (IL) 10 has been reported to be associated with the development of autoimmunity. Overproduction or therapeutic administration of type 1 interferon has also been associated with autoimmunity. Overexpression of costimulatory molecules on T cells similarly can lead to autoantibody production.


InternalMed_Harrison

InternalMed_Harrison. Autoimmunity may also result from an abnormality of immunoregulatory mechanisms. Observations made in both human autoimmune disease and animal models suggest that defects in the generation and expression of regulatory T cell (Treg) activity may allow the production of autoimmunity. It has recently been appreciated that the IPEX (immunodysregulation, polyendocrinopathy, enteropathy X-linked) syndrome results from the failure to express the FOXP3 gene, which encodes a molecule critical in the differentiation of Tregs. Administration of normal Tregs or of factors derived from them can prevent the development of autoimmune disease in rodent models of autoimmunity, and allogeneic stem cell transplantation ameliorates human IPEX. Abnormalities in the function of Tregs have been noted in a number of human autoimmune diseases, including rheumatoid arthritis and SLE, although it remains uncertain whether these functional abnormalities are causative or are secondary to inflammation. One of the


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InternalMed_Harrison. of human autoimmune diseases, including rheumatoid arthritis and SLE, although it remains uncertain whether these functional abnormalities are causative or are secondary to inflammation. One of the mechanisms by which Tregs control immune/inflammatory responses is by the production of the cytokine IL-10. In this regard, children with a deficiency in the expression of IL-10 or the IL-10 receptor develop inflammatory bowel disease that mimics Crohn’s disease and that can be cured by allogeneic stem cell transplantation. Finally, recent data indicate that B cells may also exert regulatory function, largely through the production of IL-10. Deficiency of IL-10producing regulatory B cells can prolong the course of multiple sclerosis in an animal model, and such cells are thought to be functionally diminished in human SLE.


InternalMed_Harrison

InternalMed_Harrison. It should be apparent that no single mechanism can explain all the varied manifestations of autoimmunity or autoimmune disease. Furthermore, genetic evaluation has shown that convergence of a number of abnormalities is often required for the induction of an autoimmune disease. Additional factors that appear to be important determinants in the induction of autoimmunity include age, sex (many autoimmune diseases are far more common in women), exposure to infectious agents, and environmental contacts. How all of these disparate factors affect the capacity to develop self-reactivity is currently being investigated intensively.


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InternalMed_Harrison. Evidence in humans that there are susceptibility genes for auto of twins. Studies in type 1 diabetes mellitus, rheumatoid arthritis, multiple sclerosis, and SLE have shown that ~15–30% of pairs of mono-zygotic twins show disease concordance, whereas the figure is <5% for dizygotic twins. The occurrence of different autoimmune diseases within the same family has suggested that certain susceptibility genes may predispose to a variety of autoimmune diseases. Genome-wide association studies have begun to identify polymorphisms in individual genes that are associated with specific autoimmune diseases. More than 50 genetic polymorphisms associated with one or more autoimmune diseases have been identified to date. It is notable that some genes are associated with multiple autoimmune diseases, whereas others are specifically associated with only one autoimmune condition. Moreover, recent genetic evidence suggests that clusters of genetic risk factors can commonly be found in groups of


InternalMed_Harrison

InternalMed_Harrison. whereas others are specifically associated with only one autoimmune condition. Moreover, recent genetic evidence suggests that clusters of genetic risk factors can commonly be found in groups of autoimmune diseases. Four general clusters have been identified: one group of 6 genetic polymorphisms most frequently associated with Crohn’s disease, psoriasis, and multiple sclerosis; a second cluster of 8 polymor years, genome-wide association studies have demonstrated a variety of 377e-3 other genes that are involved in human autoimmune diseases. Most genes individually confer a relatively low risk for autoimmune diseases and are found in normal individuals. No gene has been identified that is essential for autoimmune diseases. In addition to this evidence from humans, certain inbred mouse strains reproducibly develop specific spontaneous or experimentally induced autoimmune diseases, whereas others do not. These findings have led to an extensive search for genes that determine


InternalMed_Harrison

InternalMed_Harrison. mouse strains reproducibly develop specific spontaneous or experimentally induced autoimmune diseases, whereas others do not. These findings have led to an extensive search for genes that determine susceptibility to autoimmune disease and for genes that might be protective.


InternalMed_Harrison

InternalMed_Harrison. The strongest consistent association for susceptibility to autoimmune disease is with particular MHC alleles. It has been suggested that the association of MHC genotype with autoimmune disease relates to differences in the ability of different allelic variations of MHC molecules to present autoantigenic peptides to autoreactive T cells. An alternative hypothesis involves the role of MHC alleles in shaping the T cell receptor repertoire during T cell ontogeny in the thymus. In addition, specific MHC gene products may themselves be the source of peptides that can be recognized by T cells. Cross-reactivity between such MHC peptides and peptides derived from proteins produced by common microbes may trigger autoimmunity by molecular mimicry. However, MHC genotype alone does not determine the development of autoimmunity. Identical twins are far more likely to develop the same autoimmune disease than MHC-identical nontwin siblings; this observation suggests that genetic factors other than


InternalMed_Harrison

InternalMed_Harrison. development of autoimmunity. Identical twins are far more likely to develop the same autoimmune disease than MHC-identical nontwin siblings; this observation suggests that genetic factors other than the MHC affect disease susceptibility. Studies of the genetics of type 1 diabetes mellitus, SLE, rheumatoid arthritis, and multiple sclerosis in humans and mice have identified several independently segregating disease susceptibility loci in addition to the MHC. Genes that encode molecules of the innate immune response are also involved in autoimmunity. In humans, inherited homozygous deficiency of the early proteins of the classic pathway of complement (C1q, C4, or C2) as well as genes involved in the type 1 interferon pathway are very strongly associated with the development of SLE.


InternalMed_Harrison

InternalMed_Harrison. The mechanisms of tissue injury in autoimmune diseases can be divided into antibody-mediated and cell-mediated processes. Representative examples are listed in Table 377e-3.


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InternalMed_Harrison. phisms most strongly associated with celiac disease, rheumatoid arthritis, and SLE; a third cluster of 7 polymorphisms most Effector Mechanism Target Disease strongly associated with type 1 diabetes, mul-Autoantibody Blocking or inactivation tiple sclerosis, and rheumatoid arthritis; and a fourth cluster of more than 12 polymorphisms most strongly associated with type 1 diabetes, rheumatoid arthritis, celiac disease, Crohn’s disease, and SLE. These results imply that autoimmune diseases with widely differ- ent clinical presentations and patterns of organ involvement could involve similar immunopathogenic pathways. For example, the same allele of the gene encoding PTPN22 is associated with multiple autoimmune dis- eases. Its product is a phosphatase expressed by a variety of hematopoietic cells that down- regulates antigen receptor–mediated stimulation of T and B cells. The risk allele is associated with type 1 diabetes mellitus, rheumatoid arthritis, and SLE in some populations. The


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InternalMed_Harrison. cells that down- regulates antigen receptor–mediated stimulation of T and B cells. The risk allele is associated with type 1 diabetes mellitus, rheumatoid arthritis, and SLE in some populations. The explanation for the association of this polymorphism with autoimmune dis cellular cytotoxicity ishes antigen receptor signaling during lym-T cells Cytokine production phocyte development, permitting escape of autoreactive clones or decreased activation-ease is uncertain, but it is likely that it dimin-


InternalMed_Harrison

InternalMed_Harrison. Cellular cytotoxicity α Chain of the nicotinic Insulin receptor Intrinsic factor TSH receptor (LATS) Proteinase-3 (ANCA) Epidermal cadherin Desmoglein 3 α3 Chain of collagen IV Immunoglobulin Platelet GpIIb:IIIa Rh antigens, I antigen Thyroid peroxidase, thyroglobulin ? ? Myasthenia gravis Insulin-resistant diabetes mellitus Pernicious anemia Graves’ disease Granulomatosis with polyangiitis Pemphigus vulgaris Rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus induced apoptosis of autoantigen-reactive Abbreviations: ANCA, antineutrophil cytoplasmic antibody; LATS, long-acting thyroid stimulator; TSH, thyroid-stimulating lymphocytes in the periphery. In recent hormone. The pathogenicity of autoantibodies can be mediated through several mechanisms, including opsonization of soluble factors or cells, activation of an inflammatory cascade via the complement system, and interference with the physiologic function of soluble molecules or cells.


InternalMed_Harrison

InternalMed_Harrison. In autoimmune thrombocytopenic purpura, opsonization of platelets targets them for elimination by phagocytes. Likewise, in autoimmune hemolytic anemia, binding of immunoglobulin to red cell membranes leads to phagocytosis and lysis of the opsonized cell. Goodpasture’s syndrome, a disease characterized by lung hemorrhage and severe glomerulonephritis, represents an example of antibody binding leading to local activation of complement and neutrophil accumulation and activation. The autoantibody in this disease binds to the α3 chain of type IV collagen in the basement membrane. In SLE, activation of the complement cascade at sites of immunoglobulin deposition in renal glomeruli is considered to be a major mechanism of renal damage. Moreover, the DNAand RNA-containing immune complexes in SLE activate TLR9 and TLR7, respectively, in dendritic cells and promote a proinflammatory, immunogenic milieu conducive to amplification of the autoimmune response.


InternalMed_Harrison

InternalMed_Harrison. Autoantibodies can also interfere with normal physiologic functions of cells or soluble factors. Autoantibodies to hormone receptors can lead to stimulation of cells or to inhibition of cell function through interference with receptor signaling. For example, long-acting thyroid stimulators—autoantibodies that bind to the receptor for thyroid-stimulating hormone (TSH)—are present in Graves’ disease and function as agonists, causing the thyroid to respond as if there were an excess of TSH. Alternatively, antibodies to the insulin receptor can cause insulin-resistant diabetes mellitus through receptor blockade. In myasthenia gravis, autoantibodies to the acetylcholine receptor can be detected in 85–90% of patients and are responsible for muscle weakness. The exact location of the antigenic epitope, the valence and affinity of the antibody, and perhaps other characteristics determine whether activation or blockade results from antibody binding.


InternalMed_Harrison

InternalMed_Harrison. Antiphospholipid antibodies are associated with thromboembolic events in primary and secondary antiphospholipid syndrome and have also been associated with fetal wastage. The major antibody is directed to the phospholipid–β2-glycoprotein I complex and appears to exert a procoagulant effect. In pemphigus vulgaris, autoantibodies bind to desmoglein 3, a component of the epidermal cell desmosome, and play a role in the induction of the disease. These antibodies exert their pathologic effect by disrupting cell–cell junctions through stimulation of the production of epithelial proteases, with consequent blister formation. Cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA), found in granulomatosis with polyangiitis, is an antibody to an intracellular antigen, the 29-kDa serine protease (proteinase-3). In vitro experiments have shown that IgG anti-c-ANCA causes cellular activation and degranulation of primed neutrophils.


InternalMed_Harrison

InternalMed_Harrison. It is important to note that autoantibodies of a given specificity may cause disease only in genetically susceptible hosts, as has been shown in experimental models of myasthenia gravis, SLE, rheumatic fever, and rheumatoid arthritis. Furthermore, once organ damage is initiated, new inflammatory cascades are initiated that can sustain and amplify the autoimmune process. Finally, some autoantibodies seem to be markers for disease but have, as yet, no known pathogenic potential. Manifestations of autoimmunity are found in a large number of pathologic conditions. However, their presence does not necessarily imply that the pathologic process is an autoimmune disease. A number of attempts to establish formal criteria for the classification of diseases as autoimmune have been made, but none is universally accepted. One set of criteria is shown in Table 377e-4; however, this scheme should be viewed merely as a guide in consideration of the problem.


InternalMed_Harrison

InternalMed_Harrison. To classify a disease as autoimmune, it is necessary to demonstrate that the immune response to a self-antigen causes the observed pathology. Initially, the detection of antibodies to the affected tissue in the serum of patients suffering from various diseases was taken as evidence that these diseases had an autoimmune basis. However, such huMan autoiMMune Disease: presuMptive eviDenCe for iMMunoLogiC pathogenesis 1. Presence of autoantibodies or evidence of cellular reactivity to self 2. Documentation of relevant autoantibody or lymphocytic infiltrate in the pathologic lesion 3. a. b. c. 1. 2. 3. Association with other evidence of autoimmunity 4. No evidence of infection or other obvious cause autoantibodies are also found when tissue damage is caused by trauma or infection and in these cases are secondary to tissue damage. Thus, autoimmunity must be shown to be pathogenic before a disease is categorized as autoimmune.


InternalMed_Harrison

InternalMed_Harrison. To confirm autoantibody pathogenicity, it may be possible to transfer disease to experimental animals by the administration of autoantibodies from a patient, with the subsequent development of pathology in the recipient similar to that seen in the patient. This scenario has been documented, for example, in Graves’ disease. Some autoimmune diseases can be transferred from mother to fetus and are observed in the newborn babies of diseased mothers. The symptoms of the disease in the newborn usually disappear as the levels of maternal antibody decrease. An exception, however, is congenital heart block, in which damage to the developing conducting system of the heart follows in utero transfer of anti-Ro antibody from the mother to the fetus. This antibody transfer can result in a permanent developmental defect in the heart.


InternalMed_Harrison

InternalMed_Harrison. In most situations, the critical factors that determine when the development of autoimmunity results in autoimmune disease have not been delineated. The relationship of autoimmunity to the development of autoimmune disease may be associated with the fine specificity of the antibodies or T cells or their specific effector capabilities. In many circumstances, a mechanistic understanding of the pathogenic potential of autoantibodies has not been established. In some autoimmune diseases, biased production of cytokines by helper T (TH) cells may play a role in pathogenesis. In this regard, T cells can differentiate into specialized effector cells that predominantly produce interferon γ (TH1), IL-4 (TH2), or IL-17 (TH17) or that provide help to B cells (T follicular helper, TFH) (Chap. 372e). TH1 cells facilitate macrophage activation and classic cell-mediated immunity, whereas TH2 cells are thought to have regulatory functions and are involved in the resolution of normal immune responses


InternalMed_Harrison

InternalMed_Harrison. TH1 cells facilitate macrophage activation and classic cell-mediated immunity, whereas TH2 cells are thought to have regulatory functions and are involved in the resolution of normal immune responses as well as in the development of responses to a variety of parasites. TH17 cells produce a number of inflammatory cytokines, including IL-17 and IL-22, and seem to be prominently involved in host resistance to certain fungal infections.


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InternalMed_Harrison. cells help B cells by constitutively producing IL-21. In a number of autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, and Crohn’s disease, there appears to be biased differentiation of TH1 and TH17 cells, with resultant organ damage. Studies suggest an accentuated differentiation of TH17 cells associated with animal models of inflammatory arthritis, whereas increased differentiation of TFH cells has been associated with animal models of SLE. The spectrum of autoimmune diseases ranges from conditions specifically affecting a single organ to systemic disorders that involve many organs (Table 377e-5). Hashimoto’s autoimmune thyroiditis is an example of an organ-specific autoimmune disease (Chap. 405). In this


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InternalMed_Harrison. Systemic lupus erythematosus Granulomatosis with polyangiitis disorder, a specific lesion in the thyroid is associated with infiltration of mononuclear cells and damage to follicular cells. Antibody to thyroid constituents can be demonstrated in nearly all cases. Other organ-or tissue-specific autoimmune disorders include pemphigus vulgaris, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Goodpasture’s syndrome, myasthenia gravis, and sympathetic ophthalmia. One important feature of some organ-specific autoimmune diseases is the tendency for overlap, such that an individual with one specific syndrome is more likely to develop a second syndrome. For example, there is a high incidence of pernicious anemia in individuals with autoimmune thyroiditis. More striking is the tendency for individuals with an organ-specific autoimmune disease to develop multiple other manifestations of autoimmunity without the development of associated organ pathology. Thus, as many as 50% of


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InternalMed_Harrison. for individuals with an organ-specific autoimmune disease to develop multiple other manifestations of autoimmunity without the development of associated organ pathology. Thus, as many as 50% of individuals with pernicious anemia have non-cross-reacting antibodies to thyroid constituents, whereas patients with myasthenia gravis may develop antinuclear antibodies, antithyroid antibodies, rheumatoid factor, antilymphocyte antibodies, and polyclonal hypergammaglobulinemia. Part of the explanation may relate to the genetic elements shared by individuals with these different diseases.


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InternalMed_Harrison. Systemic autoimmune diseases differ from organ-specific diseases in that pathologic lesions are found in multiple diverse organs and tissues. The hallmark of these conditions is the demonstration of associated relevant autoimmune manifestations that are likely to have an etiologic role in organ pathology. SLE represents the prototype of these 377e-5 disorders because of its abundant autoimmune manifestations. SLE is a disease of protean manifestations that characteristically involves the kidneys, joints, skin, serosal surfaces, blood vessels, and central nervous system (Chap. 378). The disease is associated with a vast array of autoantibodies whose production appears to be a part of a generalized hyperreactivity of the humoral immune system. Other features of SLE include generalized B cell hyperresponsiveness and polyclonal hypergammaglobulinemia. Current evidence suggests that both hypoand hyperresponsiveness to antigen can lead to survival and activation of autoreactive B cells in


InternalMed_Harrison

InternalMed_Harrison. hyperresponsiveness and polyclonal hypergammaglobulinemia. Current evidence suggests that both hypoand hyperresponsiveness to antigen can lead to survival and activation of autoreactive B cells in SLE. The autoantibodies in SLE are thought to arise as part of an accentuated T cell–dependent B cell response since most pathogenic anti-DNA autoantibodies exhibit evidence of extensive somatic hypermutation.


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InternalMed_Harrison. Treatment of autoimmune diseases can focus on suppressing the induction of autoimmunity, restoring normal regulatory mechanisms, or inhibiting the effector mechanisms. To decrease the number or function of autoreactive cells, immunosuppressive or ablative therapies are most commonly used. In recent years, cytokine blockade has been demonstrated to be effective in preventing immune activation in some diseases or in inhibiting the extensive inflammatory effector mechanisms characteristic of these diseases. New therapies have also been developed to target lymphoid cells more specifically by blocking a costimulatory signal needed for T or B cell activation, by blocking the migratory capacity of lymphocytes, or by eliminating the effector T cells or B cells. The efficacy of these therapies in some diseases—e.g., SLE (belimumab), rheumatoid arthritis (TNF neutralization, IL-6 receptor blockade, CD28 competition, B cell depletion, IL-1 competition), psoriasis (IL-12/23 depletion, TNF


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InternalMed_Harrison. in some diseases—e.g., SLE (belimumab), rheumatoid arthritis (TNF neutralization, IL-6 receptor blockade, CD28 competition, B cell depletion, IL-1 competition), psoriasis (IL-12/23 depletion, TNF neutralization), and inflammatory bowel disease (TNF neutralization, IL-12 neutralization)—has been demonstrated. One major advance in inhibiting effector mechanisms has been the introduction of cytokine blockade that appears to limit organ damage in some diseases, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, and the spondyloarthritides. Small molecules that block cytokine signaling pathways have recently been introduced into the clinic. Biologicals that interface with T cell activation (CTLA-4Ig) or delete B cells (anti-CD20 antibody) have recently been approved for the treatment of rheumatoid arthritis. Therapies that prevent target-organ damage or support target-organ function remain important in the management of autoimmune disease.


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InternalMed_Harrison. Immune-Mediated, Inflammatory, and Rheumatologic Disorders Systemic lupus erythematosus Bevra Hannahs Hahn DEFINITION aND PrEVaLENCE Systemiclupuserythematosus(SLE)isanautoimmunediseaseinwhichorgansandcellsundergodamageinitiallymediatedbytissue-bindingautoantibodiesandimmunecomplexes.Inmostpatients,autoantibod-378 iesarepresent forafewyears beforethefirst clinicalsymptom appears. Ninety percent of patients are women of child-bearing years; people of all genders, ages, and ethnic groups are susceptible. Prevalence of SLE in the United States is 20 to 150 per 100,000 women depending on race and gender; highest prevalence is in African-American and Afro-Caribbean women, and lowest prevalence is in white men.


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InternalMed_Harrison. The proposed pathogenic mechanisms of SLE are illustrated in Fig. 378-1. Interactions between susceptibility genes and environmental factors result in abnormal immune responses, which vary between different patients. Those responses may include (1) activation of innate immunity (dendritic cells, monocyte/macrophages) by CpG DNA, DNA in immune complexes, viral DNA or RNA, and RNA in RNA/ protein self-antigens; (2) lowered activation thresholds and abnormal activation pathways in adaptive immunity cells (mature T and B lymphocytes);(3)ineffectiveregulatoryCD4+andCD8+Tcells,Bcells,and myeloid-derived suppressor cells; and (4) reduced clearance of immune complexesandapoptoticcells.Self-antigens(nucleosomalDNA/protein; RNA/protein in Sm, Ro, and La; phospholipids) are recognized by the immune system in surface blebs of apoptotic cells; thus autoantigens, autoantibodies, and immune complexes persist for prolonged periods of time, allowing inflammation and disease to develop. Immune cell


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InternalMed_Harrison. system in surface blebs of apoptotic cells; thus autoantigens, autoantibodies, and immune complexes persist for prolonged periods of time, allowing inflammation and disease to develop. Immune cell activation is accompanied by increased secretion of proinflammatory type1and2interferons(IFNs),tumornecrosisfactorα(TNF-α),interleukin (IL) 17 and B cell-maturation/survival cytokines B lymphocyte stimulator (BLyS/BAFF), and IL-10. Upregulation of genes induced by 1.Genes


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InternalMed_Harrison. Renal Failure Arthritis Artherosclerosis Leukopenia EPIGENETIC CHANGES Pulm fibrosisCNS dz(DNA hypomethylation, 3.Autoantibodies Stroke miRNA) Clotting Etc. Etc. ?Infection Others EBV


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InternalMed_Harrison. FIGUrE 378-1 Pathogenesis of systemic lupus erythematosus (SLE). Genes confirmed in more than one genome-wide association analysis in northern European whites (several confirmed in Asians as well) as increasing susceptibility to SLE or lupus nephritis are listed (reviewed in SG Guerra et al: Arthritis Res Ther 14:211, 2012). Gene-environment interactions (reviewed in KH Costenbader et al: Autoimmune Rev 11:604, 2012) result in abnormal immune responses that generate pathogenic autoantibodies and immune complexes that deposit in tissue, activate complement, cause inflammation, and over time lead to irreversible organ damage (reviewed in GC Tsokos: N Engl J Med 365:2110, 2011; and BH Hahn, in DJ Wallace, BH Hahn [eds]: Dubois’ Lupus Erythematosus and Related Syndromes, 8th ed. New York, Elsevier, 2013). Ag, antigen; C1q, complement system; C3, complement component; CNS, central nervous system; DC, dendritic cell; EBV, Epstein-Barr virus; HLA, human leukocyte antigen; FcR, immunoglobulin


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InternalMed_Harrison. 2013). Ag, antigen; C1q, complement system; C3, complement component; CNS, central nervous system; DC, dendritic cell; EBV, Epstein-Barr virus; HLA, human leukocyte antigen; FcR, immunoglobulin Fc-binding receptor; IL, interleukin; MCP, monocyte chemotactic protein; PTPN, phosphotyrosine phosphatase; UV, ultraviolet.


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InternalMed_Harrison. IFNsisa genetic “signature”in peripheral blood cells of50–60% ofSLE patients. Decreased production of other cytokines also contributes to SLE: lupus T and natural killer (NK) cells fail to produce enough IL-2 and transforming growth factor beta (TGF-β) to induce and sustain regulatory CD4+ and CD8+ T cells. The result of these abnormalities is sustained production of autoantibodies (referred to in Fig. 378-1 and described in Table 378-1) and immune complexes; pathogenic subsets bind target tissues, with activation of complement, leading to release of cytokines, chemokines, vasoactive peptides, oxidants, and proteolytic enzymes. This results in activation of multiple tissue cells (endothelial cells, tissue-fixed macrophages, mesangial cells, podocytes, renal tubular epithelial cells) and influx into target tissues of T and B cells, monocyte/macrophages, and dendritic cells. In the setting of chronic inflammation, accumulation of growth factors and products of chronic oxidation


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InternalMed_Harrison. and influx into target tissues of T and B cells, monocyte/macrophages, and dendritic cells. In the setting of chronic inflammation, accumulation of growth factors and products of chronic oxidation contribute to irreversible tissue damage, including fibrosis/ sclerosis in glomeruli, arteries, lungs, and other tissues.


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InternalMed_Harrison. SLE is a multigenic disease. Rare single-gene defects confer high hazard ratios (HRs) for SLE (5 to 25), including homozygous deficiencies of early components of complement (C1q,r,s; C2; C4) and a mutation in TREX1 on the X chromosome. In most genetically susceptible individuals, normal alleles of multiple genes each contribute a small amount to abnormal immune/inflammation/tissue damage responses;ifenoughpredisposingvariationsarepresent,diseaseresults. Approximately 45 predisposing genes (examples listed in Fig. 378-1) have been identified in recent genome-wide association studies in different racial groups. Individually, they confer an HR for SLE of 1.5–3 and account for approximately 18% of disease susceptibility, suggesting that environmental exposures and epigenetics play major roles. Predisposing, antigen-presenting human leukocyte antigen (HLA) molecules are most commonly found, in multiple ethnic groups (HLA DRB1 *0301 and *1501, as well as multiple genes across the major


InternalMed_Harrison

InternalMed_Harrison. Predisposing, antigen-presenting human leukocyte antigen (HLA) molecules are most commonly found, in multiple ethnic groups (HLA DRB1 *0301 and *1501, as well as multiple genes across the major histocompatibility complex (MHC) 120-gene region). Other genetic factors in whites include innate immunity pathway gene polymorphisms, especially associated with IFN-α (STAT4, IRF5, IRAK1, TNFAIP3, PTPN22), genes in lymphocyte signaling pathways (PTPN22, PDCD-1, Ox40L, BANK-1, LYN, BLK), genes that affect clearance of apoptotic cellsor immune complexes (C1q, FCRGIIA, FCRGIIIA, CRP, ITGAM), genes that influence neutrophil adherence (ITGAM), and genes that influenceDNArepair(TREX-1).Somepolymorphismsinfluenceclinical manifestations; such as single nucleotide polymorphisms (SNPs) of STAT4 that associate with severe disease, anti-DNA, nephritis, and antiphospholipid syndrome, and an allele of FCGRIIA encoding a receptor that binds immune complexes poorly and predisposes to nephritis. Some gene


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InternalMed_Harrison. with severe disease, anti-DNA, nephritis, and antiphospholipid syndrome, and an allele of FCGRIIA encoding a receptor that binds immune complexes poorly and predisposes to nephritis. Some gene effects are in promoter regions (e.g., IL-10), and others are conferred by copy numbers (e.g., C4A). In addition to genome-encoded susceptibility and protective genes, the influence of certain microRNAs (miRNAs) on gene transcription, as well as posttranscriptional epigenetic modification of DNA (which is hypomethylated in T cells of SLE patients), probably play major roles in disease susceptibility.


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InternalMed_Harrison. Some gene polymorphisms contribute to several autoimmune diseases, such as STAT4 and CTLA4. All of these gene polymorphisms/ transcription/epigenetic combinations influence immune responses to the external and internal environment; when such responses are too high and/or too prolonged and/or inadequately regulated, autoimmune disease results. Female sex is permissive for SLE with evidence for hormone effects, genes on the X chromosome, and epigenetic differences between genders playing a role. Females of many mammalian species make higher antibody responses than males. Women exposed to Antibody Prevalence, % Antigen Recognized Clinical Utility Protein complexed to 6 species of nuclear U1 RNA Protein complexed to U1 RNA Protein complexed to hY RNA, primarily 60 kDa and 52 kDa 47-kDa protein complexed to hY RNA Histones associated with DNA (in nucleosome, chromatin) Phospholipids, β2 glycoprotein 1 (β2G1) cofactor, prothrombin


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InternalMed_Harrison. Phospholipids, β2 glycoprotein 1 (β2G1) cofactor, prothrombin High titers are SLE-specific and in some patients correlate with disease activity, nephritis, vasculitis Not specific for SLE; high titers associated with syndromes that have overlap features of several rheumatic syndromes including SLE; more common in blacks than whites Not specific for SLE; associated with sicca syndrome, predisposes to subacute cutaneous lupus, and to neonatal lupus with congenital heart block; associated with decreased risk for nephritis Usually associated with anti-Ro; associated with decreased risk for nephritis Three tests available—ELISAs for cardiolipin and β2G1, sensitive prothrombin time (DRVVT); predisposes to clotting, fetal loss, thrombocytopenia Measured as direct Coombs test; a small proportion develops overt hemolysis Associated with thrombocytopenia, but sensitivity and specificity are not good; this is not a useful clinical test


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InternalMed_Harrison. Measured as direct Coombs test; a small proportion develops overt hemolysis Associated with thrombocytopenia, but sensitivity and specificity are not good; this is not a useful clinical test In some series, a positive test in CSF correlates with active CNS lupus In some series, a positive test in serum correlates with depression or psychosis due to CNS lupus Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; DRVVT, dilute Russell viper venom time; ELISA, enzyme-linked immunosorbent assay.


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InternalMed_Harrison. Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; DRVVT, dilute Russell viper venom time; ELISA, enzyme-linked immunosorbent assay. estrogen-containingoralcontraceptivesorhormonereplacementhave an increased risk of developing SLE (1.2-to 2-fold). Estradiol binds to receptors on T and B lymphocytes, increasing activation and survival of those cells, thus favoring prolonged immune responses. Genes on theXchromosomethatinfluenceSLE,suchas TREX-1,mayplayarole in gender predisposition, possibly because some genes on the second X in females are not silent. People with XXY karyotype (Klinefelter’s syndrome) have a significantly increased risk for SLE.


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InternalMed_Harrison. Several environmental stimuli may influence SLE (Fig. 378-1). Exposure to ultraviolet light causes flares of SLE in approximately 70% of patients, possibly by increasing apoptosis in skin cells or by altering DNA and intracellular proteins to make them antigenic. Some infections induce normal immune responses that involve certain T and B cells that recognize self-antigens; such cells are not appropriately regulated, and autoantibody production occurs. Most SLE patients have autoantibodies for 3 years or more before the first symptoms of disease, suggesting that regulation controls the degree of autoimmunity for years before quantities and qualities of autoantibodies and pathogenic B and T cells cause clinical disease. Epstein-Barr virus (EBV) may be one infectious agent that can trigger SLE in susceptible individuals. Children and adults with SLE are more likely to be infected by EBV than age-, sex-, and ethnicity-matched controls. EBV contains amino acid sequences that mimic


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InternalMed_Harrison. SLE in susceptible individuals. Children and adults with SLE are more likely to be infected by EBV than age-, sex-, and ethnicity-matched controls. EBV contains amino acid sequences that mimic sequences on human spliceosomes (RNA/protein antigens) often recognized by autoantibodies in people with SLE. Current tobacco smoking increases risk for SLE (odds ratio [OR] 1.5). Prolonged occupational exposure to silica (e.g., inhalation of soap powder dust or soil in farming activities) increases risk (OR 4.3) in African-American women. Thus, interplay between genetic susceptibility, environment, gender, and abnormal immune responses results in autoimmunity (Chap. 377e).


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InternalMed_Harrison. In SLE, biopsies of affected skin show deposition of Ig at the dermalepidermaljunction(DEJ),injurytobasalkeratinocytes,andinflammation dominated by T lymphocytes in the DEJ and around blood vessels and dermal appendages. Clinically unaffected skin may also show Ig deposition at the DEJ.


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InternalMed_Harrison. In renal biopsies, the pattern and severity of injury are important in diagnosisandinselectingthebesttherapy.Mostrecentclinicalstudiesof lupusnephritishaveusedtheInternationalSocietyofNephrology(ISN) and the Renal Pathology Society (RPS) classification (Table 378-2). In the ISN/RPS classification, the addition of “a” for active and “c” for chronic changes gives physicians information regarding the potential reversibility of disease. The system focuses on glomerular disease, although the presence of tubular interstitial and vascular disease is important to clinical outcomes. In general, class III and IV disease, as well as class V accompanied by III or IV disease, should be treated with aggressiveimmunosuppressionifpossible,becausethereisahighriskfor end-stage renal disease (ESRD) if patients are untreated or undertreated. Incontrast,treatmentforlupusnephritisisnotrecommendedinpatients with class I or II disease or with extensive irreversible changes. In the recent Systemic Lupus


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InternalMed_Harrison. patients are untreated or undertreated. Incontrast,treatmentforlupusnephritisisnotrecommendedinpatients with class I or II disease or with extensive irreversible changes. In the recent Systemic Lupus International Collaborating Clinic (SLICC) criteria for classification of SLE, a diagnosis can be established on the basis of renal histology without meeting additional criteria (Table 378-3).


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InternalMed_Harrison. Histologic abnormalities in blood vessels may also determine therapy. Patterns of vasculitis are not specific for SLE but may indicate activedisease:leukocytoclasticvasculitisismostcommon (Chap. 385). Lymph node biopsies are usually performed to rule out infection or malignancies.InSLE,theyshownonspecificdiffusechronicinflammation.