Nancy Hueppchen, M.D., M.S.

• Associate Dean for Curriculum, School of Medicine
• Associate Professor of Gynecology and Obstetrics

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0009047/nancy-hueppchen

Such food allergen epitopes are typically conformational (rather than linear) medicine 503 discount zyprexa express, and more easily destroyed by heat (cooking) medications over the counter order zyprexa canada, by acid in the stomach medications janumet 2.5mg zyprexa with mastercard, or by proteases in the intestines medications not to crush purchase zyprexa 10mg fast delivery, and thus rarely progress to systemic reactions medicine werx purchase zyprexa master card. Aspirin medicine express purchase 7.5mg zyprexa otc, nonsteroidal anti-inflammatory drugs, and alcohol also act to increase intestinal permeability and may help trigger food-induced anaphylaxis. Hymenoptera families primarily responsible for sting venom-triggered anaphylactic reactions include the Apidae (honey bees and bumble bees), Vespidae (hornets, yellow jackets, and paper wasps), and Formicidae (fire ants). Major allergens of honey bees include phospholipase A2 (Api m 1), hyaluronidase (Api m 2), and melitin (Api m 4). Bumble bee venom proteins exhibit immunologic cross-reactivity with those of the honey bee, but lack melitin. Vespid venoms cross-react among themselves and include phospholipase and hyaluronidase, the latter allergen cross-reacting with bee hyaluronidase. Fire ant venom contains various alkaloids that are not allergenic, but produce sterile pustules, and various allergenic proteins that cross-react with vespid allergens such as phospholipase and scorpion venom allergens. Allergens from biting insects of the Diptera order (mosquitoes, gnats, midges, true flies) are salivary in origin and do not cross-react with Hymenoptera venom allergens. Anaphylaxis to these salivary proteins appears to be uncommon, but precise epidemiologic data are problematic because people are often unaware of a mosquito bite, and commercial diagnostic reagents of high quality are not yet available. These include radiocontrast dyes, most narcotics except for fentanyl, and vancomycin. The dose and rate of administration and individual variations in reactivity are determinants of severity. For radiocontrast dyes, those of low ionic strength and iso-osmolarity are less likely than those of high ionic strength and hyper-osmolarity to elicit a systemic reaction. These reactions usually are avoided by reducing the rate of administration of the antibiotic, thereby reducing peak levels. Endogenous mast cell activators include neuropeptides such as substance P, neurokinin A, and calcitonin gene-related peptide, defensins, and the complement anaphylatoxins C3a and C5a. Aspirin and Nonsteroidal Anti-inflammatory Drugs Insect Sting Venom Aspirin hypersensitivity typically manifests as either a respiratory reaction with bronchospasm, nasal congestion, and rhinorrhea or a cardiovascular reaction with hypotension and urticaria, although sometimes overlap occurs, including gastrointestinal signs and symptoms. Less commonly, sensitivity occurs to only one of the drugs within this class, a clue that IgE against a unique chemical moiety on that particular drug is involved. Physical Stimuli Physical stimuli may precipitate urticaria or systemic anaphylaxis in certain individuals. Episodes can occur in response to exercise, heat, solar radiation, vibration, pressure, or cold. Exercise-dependent anaphylaxis is sometimes associated with ingestion of any food, regardless of whether sensitivity to the food can be documented, occurring within several hours of ingestion and might be avoided by delaying exercise until several hours after eating. In some cases of familial cold- or vibration-triggered urticaria, genetic defects have been found. Irritant dermatitis is the most frequent contact reaction and does not involve acquired immunity. In contrast, IgE-dependent immediate hypersensitivity occurs against latex proteins, seen with cutaneous (elastic materials), mucosal or intravascular (catheters), oral (balloon), and inhaled (powdered latex gloves) routes of exposure, eliciting signs and symptoms within minutes. Instead, Some patients experience spontaneous bouts of anaphylaxis without an obvious exogenous stimulus. A corollary of this is that systemic anaphylaxis to a Hymenoptera insect sting may be a presenting manifestation of these conditions, particularly if a baseline serum tryptase level is elevated. Hereditary alpha tryptasemia, an autosomal dominant disorder, presents with an elevated serum tryptase level (8-100 ng/mL) and multiple-organ signs and symptoms, including cutaneous flushing, pruritus and vibratory urticaria, dysautonomia with irritable bowel syndrome, hyperextensible joints, anaphylaxis, and/or retained primary dentition. An increase in the acute serum tryptase level (collected 30 min to 4 hours after clinical onset) of at least 2 + 1. Although an increased serum total tryptase level is quite specific for anaphylaxis, the sensitivity is low for detecting anaphylaxis triggered by food ingestion, or, in general, if anaphylactic severity is either modest (no hypotension) or local (laryngeal edema), or if the acute sample was collected outside of the optimal times. Whether there are anaphylactic IgE-dependent pathways not involving mast cell activation, but instead involving basophil activation, is unknown, but has been considered for anaphylaxis triggered by food allergen ingestion. Baseline tryptase levels in serum are stable in healthy subjects, reflecting genetic rather than environmental factors, and range from 1 to 11 ng/mL. Baseline levels above 20 ng/mL occur in most patients with systemic mastocytosis (Chapter 240), representing a minor criterion for that diagnosis, and greater than 8 ng/mL in all patients diagnosed to date with hereditary alpha tryptasemia. However, urinary N-methylhistamine levels also may reflect overall levels of released histamine, accumulating in urine during anaphylaxis and stored in the bladder until micturition. However, levels are affected by ingested histamine-containing foods, histamine-producing mucosal bacteria, and variability in histamine metabolism. Autoimmune progesteronemediated anaphylaxis, catamenial anaphylaxis, tends to occur just before menses, and may respond to medical or surgical interventions that prevent menses. They arise from bone marrow progenitors and complete their development in peripheral tissues, primarily under the influence of stem cell factor, the ligand for the tyrosine kinase receptor called Kit. This may be important in the defense against certain microbes such as helminths that elicit a strong IgE response or to protein toxins that are destroyed by mast cell proteases. Antigen-specific IgE, indicating sensitization, is precisely measured by either laboratory or skin tests. Such tests should be delayed for at least 2 weeks after an anaphylactic event to prevent false-negative results. IgE sensitization is necessary but not sufficient to diagnose allergic disease, because many subjects sensitized to an aeroallergen, particularly at a low antigen-specific IgE level, do not have symptoms when exposed. When food allergy is suspected but not confirmed by IgE testing, oral food challenges can be performed, using protocols to minimize the risk for severe systemic anaphylaxis. Vasovagal syncope causes diaphoresis, nausea, hypotension, and bradycardia, but without urticaria and tachycardia. Rapid onset after exposure to a likely allergen of 2 of the following: Diagnosing systemic anaphylaxis I. Acute onset of systemic anaphylaxis in the apparent absence of allergen exposure means that the signs and symptoms, once they begin, develop over minutes to an hour, whereas rapid onset after exposure to a likely or known allergen means that these signs and symptoms begin to occur within minutes to several hours after that exposure. Second symposium on the definition and management of anaphylaxis: summary report-second national institute of Allergy and infectious disease/Food Allergy and Anaphylaxis network symposium. Histamine, formed from histidine by histidine decarboxylase, is the sole biogenic amine stored in the secretory granules of human mast cells and basophils but is also made by other cell types. Histamine released by mast cells or basophils diffuses freely and interacts with H1, H2, H3, and H4 receptors. Activating H1 receptors found on endothelial cells, smooth muscle cells, and sensory nerves causes bronchial and gastrointestinal smooth muscle contraction, vascular smooth muscle relaxation, increased permeability of postcapillary venules, coronary artery vasoconstriction, and pruritus, signs and symptoms often associated with systemic anaphylaxis. Stimulating H2 receptors on gastric parietal cells can increase acid production in the stomach, leading to peptic ulcer disease if histamine levels are chronically elevated, as in systemic mastocytosis, but also modulates inflammatory and vascular responses. H4 receptors, found on most hematopoietic inflammatory cells, may modulate certain aspects of inflammation, such as eosinophil recruitment and pruritus. Histamine, after its secretion from mast cells and basophils, is rapidly metabolized to inactive methylhistamine and methylimidazole acetic acid. Sulfidopeptide leukotrienes stimulate bronchoconstriction, mucus secretion, eosinophil recruitment, vasopermeability, vasoconstriction of coronary and peripheral arteries, vasodilation of venules and a burning cutaneous wheal and flare response, and diminish cardiac contractility. Sphingosine-1-phosphate (S1P), generated from sphingosine by sphingosine kinases in activated mast cells and in other cell types, may affect the vascular response during systemic anaphylaxis. Mast cells are the principal source of heparin proteoglycan and certain proteases. All express /-tryptases, and a subset also expresses chymase, mast cell carboxypeptidase A3, and cathepsin G (like neutrophils and monocytes). Although not selectively produced by these cells, their vasoactive and inflammatory potential could affect the severity, character, and duration of anaphylaxis. Panic attacks and vocal cord dysfunction can be a challenge to distinguish from anaphylaxis, especially by history alone, but nevertheless must be considered. Acute attacks of angioedema caused by C1 esterase inhibitor deficiency are not associated with pruritus or urticaria and evolve slower and persist longer than attacks of anaphylaxis. Shock due to complement activation, generating complement anaphylatoxins, or to activation of the contact system leading to the production of bradykinin, can occur without involving mast cell activation. Scombroidosis occurs 5 to 60 minutes after ingestion of histamine, typically in poorly stored fish, and manifests with flushing, palpitations, headache, and gastrointestinal symptoms. The condition lasts several hours, both duration and severity depending on the amount of histamine ingested, and usually responds to H1-receptor and H2-receptor antihistamines, but occasionally requires epinephrine and intravenous fluids. Acute serum sickness, various cell activation syndromes, endotoxin-mediated septic shock, and superantigen-mediated toxic shock syndromes manifest with fever, which is not characteristic of anaphylaxis by itself. Also, hypoglycemia, seizure, and primary pulmonary or cardiac events should be considered. Systemic mastocytosis (Chapter 240) and hereditary alpha tryptasemia are important conditions to consider in the setting of anaphylaxis. Both disorders can be precisely diagnosed by specific genetic tests and can present with systemic anaphylaxis particularly when spontaneous or elicited by an insect sting. Diagnostic tests for systemic mastocytosis are discussed in detail in Chapter 240. Alternatively, calibrated intravenous administration of a solution of epinephrine (1 mg/100 mL solution starting at 30 to 100 mL/hour) and titrated to the lowest effective rate of infusion can be considered. Epinephrine relaxes bronchial smooth muscle and improves vascular tone and permeability, thereby counteracting bronchospasm, hypotension, and tissue edema. Although there is no absolute contraindication to its use for treating systemic anaphylaxis, the benefits of epinephrine need to be weighed against its disadvantages in elderly subjects and in those with cerebrovascular or coronary artery disease, hypertension, diabetes, hyperthyroidism, cardiomyopathy, or narrow-angle glaucoma, in whom adverse events such as myocardial infarction, stroke, or pulmonary edema can be precipitated. Evidence to support use of glucocorticosteroids to treat anaphylaxis is lacking and in an emergency department setting does not appear to affect relapse rate. B = bronchospasm; h1r = h1 histamine receptor; h2r = h2 histamine receptor; im = intramuscular; le = laryngeal edema. Patients who have experienced an anaphylactic reaction are at greatest risk for another episode. Such individuals should wear a Medic-Alert bracelet, carry an epinephrine autoinjector. In subjects with recurrent anaphylaxis, prophylactic use of H1- and H2-receptor antihistamines is beneficial. A leukotriene antagonist and cyclooxygenase inhibitor theoretically would provide additional prophylactic benefit. Cyclosporine A (5 mg/kg/day) might be considered in difficult cases of recurrent anaphylaxis because of its ability to inhibit mast cell activation. Glucocorticosteroids do not inhibit mast cell activation in vitro or immediate skin test wheal/flare responses to allergens in vivo; whether of benefit in selected patients with recurrent anaphylaxis is anecdotal. Anti-IgE therapy in peanut-allergic subjects can increase the threshold of sensitivity, on average, from the equivalent of half a peanut to almost nine peanuts, A2 thereby providing protection against accidental exposures. Experimental oral A3 or epicutaneous A4 biologic immunotherapies have also shown promising results. Insect venom allergy can be treated by venom immunotherapy, dramatically decreasing the risk of anaphylaxis to future stings. A5 Reactions to radiocontrast media can be prevented or attenuated by prior administration of H1- and H2receptor antihistamines. Patients who are hypersensitive to penicillin should avoid -lactam antibiotics in general, but can be desensitized if an antibiotic in this class is critically needed. However, desensitization is temporary; once the drug has cleared, sensitivity is likely to return. However, most people with a history of penicillin or amoxicillin allergy lose their sensitivity, which can be determined by allergy skin testing and oral challenge. Patients with systemic mastocytosis, in addition to prophylactic pharmacologic measures, should avoid using direct mast cell agonists such as vancomycin and most narcotics with the exception of fentanyl. Aspirin-intolerant asthmatics with sinus polyps can be desensitized to aspirin and placed on a daily dose to maintain desensitization status, resulting in better control of asthma, shrinkage of polyps, and reduction of hyposmia. A5 Future research should yield more effective therapeutic interventions to achieve longer-lasting clinical tolerance. Ongoing research will provide more precise diagnostic tools for delineating different pathways of systemic anaphylaxis, indicating which cell types and biochemical pathways are involved, thereby revealing the most appropriate treatments. Consequently, interventions that reduce this risk (including better desensitization regimens) and that more effectively reverse the signs and symptoms of this potentially fatal disorder will be developed. Emergency department corticosteroid use for allergy or anaphylaxis is not associated with decreased relapses. Current knowledge and management of hypersensitivity to perioperative drugs and radiocontrast media. Factors increasing the risk for a sever reaction in anaphylaxis: an analysis of data from the European Anaphylaxis Registry.

Both of these mechanisms have been demonstrated to cause endothelial injury in in vitro assays employing sera from patients with systemic vasculitis symptoms kidney stones order 7.5 mg zyprexa with visa. The ability of these antibodies to damage endothelial cells is an appealing argument for their potential role in forms of vasculitis in which the endothelium is the focus of the inflammation (as opposed to the more external vessel wall layers) symptoms yeast infection women order zyprexa online pills. Takayasu arteritis has been termed "pulseless disease" because of its ability to obliterate peripheral pulses (particularly in the upper extremities) medications safe during breastfeeding order 5mg zyprexa fast delivery. Exuberant collateral circulation develops over time in response to the gradual narrowing of major arteries pretreatment buy 10 mg zyprexa amex, making the loss of digits or limbs from ischemia extremely rare treatment 1st 2nd degree burns order zyprexa with a mastercard. The extensive development of collateral circulation usually renders unnecessary any attempts to revascularize stenoses of primary aortic branches treatment 11mm kidney stone cheap zyprexa 7.5mg on line, such as the subclavian artery. The pulmonary circulation is involved in approximately 50% of cases of Takayasu arteritis. Patients with severe narrowing of the aortic arch vessels supplying the head may develop Takayasu retinopathy, the hypotensive retinopathy leading to neovascularization originally described by Takayasu. In contrast, patients with prolonged hypertension associated with renal artery stenosis demonstrate the classic ocular features of hypertension: "copper wiring" and multiple retinal infarctions. This complication is particularly difficult to diagnose1 and dangerous because vascular narrowings of large arteries to the arms and legs often lead to underestimations of the true central aortic pressure. Takayasu arteritis involvement of the ascending aorta may lead to aortic dilation, aortic regurgitation, aneurysm formation, and aortic rupture. The toxicity of high doses of glucocorticoids in young women, however, urges the early consideration of alternative agents. A2 Patients can be treated with tocilizumab, administered either intravenously (8 mg/kg each month) or subcutaneously (162 mg each week). Once tocilizumab has been initiated, prednisone should be tapered to low doses (10 mg daily or less) within 3 months and ultimately discontinued altogether, if possible. Consideration may be given to tapering (to either 4 mg/kg intravenously each month or 162 mg subcutaneously every other week) after one year. Large-vessel imaging may be useful in guiding decisions regarding the duration of therapy. About 50% of patients will relapse within 10 years,3 so some Takayasu arteritis patients may require chronic treatment with tocilizumab plus (possibly) low-dose glucocorticoids. Overt signs of vasculitis may not occur until weeks or months after onset of the first symptoms. Skin lesions of polyarteritis nodosa include livedo reticularis, subcutaneous nodules, ulcers, and digital gangrene. A majority of patients with polyarteritis nodosa (>80% in some series) have vasculitic neuropathy, typically in the pattern of a mononeuritis multiplex. The typical renal manifestation of polyarteritis nodosa is vasculitic involvement of the medium-sized intrarenal arteries, leading to renin-mediated hypertension and renal infarctions. Cardiac lesions, which usually remain subclinical, may lead to myocardial infarction or congestive heart failure. Symptoms suggestive of a neuropathy can be confirmed by electrodiagnostic studies that demonstrate a sensorimotor axonal neuropathy, often in a mononeuritis multiplex pattern. The pathologic changes in polyarteritis nodosa are limited to the arterial circulation, and the lesions are segmental, favoring the branch points of arteries. In gross pathologic specimens, aneurysmal bulges of the arterial wall may be visible. Histologic sections reveal infiltration and destruction of the blood vessel wall by inflammatory cells, accompanied by fibrinoid necrosis. B, Fibrinoid necrosis (arrows) in a jejunal artery from a patient who required surgical resection of necrotic bowel. Patients with idiopathic polyarteritis nodosa and multiorgan involvement require high-dose glucocorticoid treatment initially. Approximately half of patients with idiopathic polyarteritis nodosa achieve remissions or cures with high doses of glucocorticoids alone. Severe cases of multiorgan disease, particularly vasculitic neuropathy, should be treated with cyclophosphamide (2 mg/kg/day, adjusted for renal dysfunction). For patients with idiopathic polyarteritis nodosa limited to the skin, tumor necrosis factor inhibitors may be effective glucocorticoidsparing agents. Because of its striking mucocutaneous findings and lymphadenopathy, Kawasaki disease is also known as mucocutaneous lymph node syndrome. Features of Kawasaki disease include high fevers, cervical adenopathy, conjunctival congestion, buccal erythema, prominence of the tongue papillae ("strawberry tongue"), a polymorphous truncal rash, erythema of the palms and soles, and desquamation of skin from the fingertips occurring days to weeks into the illness. In a small number of patients with Kawasaki disease, panvasculitis in the coronary vessels leads to acute cardiac complications. Coronary arteritis leads to narrowing of the vessel lumen by the migration of myointimal cells from the media through the fragmented internal elastic lamina. Direct complications include aneurysmal dilation and thrombosis of the coronary arteries, leading to myocardial infarction and possibly to death (in 1 to 2% of patients with Kawasaki disease during the acute illness). Late mortality from myocardial infarction may occur from the thrombosis of coronary artery aneurysms formed during the initial inflammatory stage. Such myocardial infarctions have been reported in middle-aged individuals who had febrile illnesses consistent with Kawasaki disease in childhood. Buerger disease has a remarkably strong yet poorly understood association with cigarette smoking. The vessels affected by Buerger disease are the distal medium-sized arteries and veins, particularly vessels at the levels of the ankles and wrists. The disease is characterized by thrombotic obliterations that begin distally and proceed proximally. Buerger disease tends to be segmental in nature, involving 5- to 10-cm lengths of blood vessels. Arterial obliteration leads to the development of collateral vessels with a "corkscrew" appearance on angiography. Vascular occlusion in Buerger disease often leads to the loss of digits and, if smoking persists, to loss of larger amounts of tissue. Despite the intense involvement of the extremities in Buerger disease, internal organ disease almost never occurs. Failure to stop smoking is associated with a dramatic increase in the risk of limb loss by amputation. No other therapeutic interventions, including glucocorticoids and anticoagulation, have dramatic effects on Buerger disease. Cartilaginous inflammation may lead to nasal septal perforation and collapse of the nasal bridge ("saddle nose" deformity). Orbital masses ("pseudotumors" that develop behind the eye), scleritis, and peripheral ulcerative keratitis are the most dangerous ocular lesions. The most common radiographic findings are pulmonary infiltrates, nodules, and cavitary lesions. Large-airway disease leading to bronchial narrowing is a challenging diagnosis to establish because patients present with few symptoms until advanced disease is present. The presenting complaint is frequently arthralgias or an oligoarthritis that is migratory in nature. Cutaneous nodules over the extensor surfaces of joints, particularly the elbow, may mimic rheumatoid nodules. These lesions are known as cutaneous extravascular necrotizing granulomata or Churg-Strauss lesions. An alternative dosing regimen of rituximab, 1 g times two separated by 2 weeks, may also be effective. A7 In patients with end-stage renal disease, renal transplantation can substantially reduce subsequent mortality. Many cases of small-vessel vasculitis once regarded as polyarteritis nodosa are now classified more properly as microscopic polyangiitis. The combination of rituximab and glucocorticoids is the treatment regimen of choice for most patients with microscopic polyangiitis. The disease is associated with necrotizing vasculitis of small to mediumsized vessels. The addition of mepolizumab, 300 mg subcutaneously each month, has also been shown to have an important glucocorticoid-sparing role. The lesions of urticarial vasculitis must be distinguished from the far more common chronic idiopathic urticaria (Chapters 237 and 411). Unlike idiopathic urticaria, the lesions of urticarial vasculitis last more than 48 hours, often have a purpuric component. In urticarial vasculitis, lesions associated with vasculitis are often accompanied by stinging or burning. Urticarial vasculitis affects the capillaries and postcapillary venules, showing leukocytoclastic vasculitis on light microscopy. Direct immunofluorescence studies reveal both immunoglobulin and complement deposition in or around blood vessels of the upper dermis or the dermoepidermal junction. The histopathologic findings are those of a leukocytoclastic vasculitis with IgA deposition. Cryoglobulins are antibodies that precipitate from serum under conditions of cold and resolubilize on rewarming. Type I cryoglobulins, which are monoclonal but lack rheumatoid factor activity, are associated with certain hematopoietic malignant neoplasms. Vasculitis results from the deposition of cryoglobulin-containing immune complexes within blood vessel walls and the activation of complement. Ninety percent of patients with vasculitis secondary to mixed cryoglobulins are hypocomplementemic, with C4 levels characteristically more depressed than C3. The efficacy of glucocorticoids in the glomerulonephritis associated with this condition is controversial. For patients with severe cutaneous ulcers, mononeuritis multiplex, glomerulonephritis, or other manifestations of severe disease, glucocorticoids, rituximab, and possibly a short course of plasma exchange may be indicated. Variable-Vessel Vasculitides Hypocomplementemic Urticarial Vasculitis At least three subtypes of urticarial vasculitis are known: (1) normocomplementemic, a form that is generally idiopathic and benign (which may be viewed as a manifestation of cutaneous leukocytoclastic angiitis); (2) hypocomplementemic, a form that is often associated with a systemic inflammatory disease; the variable-vessel vasculitides have no predominant type of vessel involved but rather can affect vessels of any size (small, medium, and large) and any type (arteries, veins, and capillaries). Cogan Syndrome the combination of inflammatory eye disease and vestibuloauditory dysfunction is the sine qua non of Cogan syndrome. Although the ocular manifestations vary, the classic presentation is the combination of interstitial keratitis and sensorineural hearing loss. Although intervals as long as 1 to 2 years have been described between the start of disease in one organ and the appearance of disease in the other, the time between disease manifestations in these organs is usually only a matter of months. Patients usually present with photophobia and blurry vision, sometimes accompanied simultaneously by auditory or vestibular dysfunction. The vascular disease associated with Cogan syndrome remains poorly described but typically involves the primary branches of the thoracic or abdominal aorta. Cyclophosphamide, mycophenolate mofetil, and biologic agents such as tumor necrosis inhibitors or rituximab can be considered for patients with suboptimal responses to glucocorticoids who still have salvageable hearing. Nevertheless, attempts at treatment are begun too late in some patients, and it is important to realize when the risk of further immunosuppression outstrips the likelihood of longterm benefit. Cutaneous leukocytoclastic angiitis has also been termed hypersensitivity vasculitis. Cutaneous leukocytoclastic angiitis is the preferred name because no hypersensitivity or allergy is evident in many cases. Although it is occasionally associated with synovitis, other signs of systemic involvement are absent. The skin lesions in cutaneous leukocytoclastic angiitis occur in "crops," coinciding with some period of elapsed time following exposure to the inciting antigen. The usual time between the exposure and the onset of clinically evident vasculitis is 10 to 14 days. The lesions typically occur first in dependent regions, such as on the lower extremities or buttocks. The rash may be asymptomatic but is usually accompanied by burning or tingling sensations. For patients in whom a precipitant can be identified, elimination of the offending agent usually leads to resolution of the vasculitis within days to weeks. The type, intensity, and duration of therapy for cutaneous leukocytoclastic angiitis are based on the degree of disease severity. Mild cases may be treated simply with leg elevation, H1 antihistamines, or lowdose prednisone. For persistent disease not associated with cutaneous gangrene, colchicine, hydroxychloroquine, or dapsone may be tried. For severe cases, high doses of glucocorticoids are indicated to suppress inflammation quickly and prevent skin ulceration. The triad of recurrent mouth ulcers, genital ulcers, and eye inflammation is the classic presentation. Venous complications include thromboses of the deep venous system, vena cava, portohepatic vein, and cerebral sinus.

Loose connective tissue fills spaces between muscle sheaths symptoms 6dpiui 5 mg zyprexa otc, encases blood and lymphatic vessels medications breastfeeding discount 5 mg zyprexa otc, and holds fibroblasts that synthesize collagen fibers symptoms 8 days before period cheap zyprexa 10 mg with mastercard. A broadbased set of rheumatic disease classifications can provide an overall construct for consideration of a multitude of possible rheumatic diseases treatment 4 pink eye purchase zyprexa 10mg without prescription. Classifications based on pathogenic mechanisms as well as clinical features facilitate identification of specific symptoms and signs and guide a further line of investigation treatment 247 generic zyprexa 20 mg visa. Although all rheumatic diseases will not fit within this classification osteoporosis treatment cheap zyprexa online american express, a systematic and directed analysis will facilitate making the correct diagnosis of the patient. However, considering these in a classification schema can aid in the approach to a patient in whom these disorders are being considered (see Table 241-1). These diseases are ubiquitous and for the most part have a similar incidence and prevalence throughout the world (Table 241-2). Each is associated with characteristic immune aberrations and mechanisms of inflammatory damage, although the cause and reasons for chronicity still remain unknown. Autoimmune rheumatic diseases are also among the leading causes of death and morbidity in the industrial world, in part related to associated comorbid diseases, particularly cardiovascular disease. Increasing evidence points to risks for their genesis relating to environmental factors, socioeconomic factors, and exposure to infectious agents, ultraviolet radiation, and pollutants. In some cases, geographic clusters of a rare autoimmune disease indicate specific genetic determinants. For example, with systemic sclerosis, higher incidence, prevalence, and mortality rates have been reported in African American populations compared with white populations, and the prevalence has been reported as higher in southern Europe, particularly Italy (prevalence of 7 to 33 per 100,000). Additionally, social and demographic factors may contribute to the epidemiology of rheumatic diseases. Inflammatory arthropathies, including rheumatoid arthritis and ankylosing spondylitis, have a higher prevalence in North American Native populations. Primary care and hospital-based health care providers are often the first to evaluate a patient with an evolving rheumatic disease, and they need to be attuned to the presenting features to make a timely diagnosis. In many cases, the presentation could signal a life- or organ-threatening condition. Evaluation of constitutional, systemic, and joint symptoms should always include rheumatic disease in the differential diagnosis. The pattern of joint involvement, particularly duration and timing of maximal symptoms, can help the health care provider diagnose patients who present with spondyloarthropathy or any inflammatory arthritis, regardless of pathogenetic classification. For instance, joint pain that is worse in the morning, is associated with prolonged stiffness, and improves with activity is a classic presentation of inflammatory pain. In contrast, pain that is worse with activity, better with rest, and associated with a very short period of stiffness signals that it most likely has a degenerative etiology. However, pain with an inflammatory pattern localized to the spine or an enthesis (site of ligament insertion) is more likely to indicate a seronegative spondyloarthropathy. Thus, the pattern of joint involvement is central to the evaluation and diagnosis of any rheumatic disease. Thus, a working knowledge of nonarticular patterns of disease presentation is important. Systemic features such as myalgias or fatigue are common to almost all rheumatic diseases regardless of their classification, whereas true weakness may be the only presenting complaint of an inflammatory myopathy. Renal involvement is common to seropositive systemic autoimmune diseases and vasculitis and can present with anasarca if proteinuria is severe or prolonged. Consequently, specific and nonspecific features associated with various connective tissue diseases must be identified to develop correctly a differential diagnosis that fits within the classification described in Table 241-1. Features may evolve sequentially over time; thus, rheumatic diseases from more than one category must often be considered in a patient whose disease has not yet fully manifested before diagnosis, leaving the patient with a label of a nonspecific or undifferentiated connective tissue disease. When these are not yet met, features are considered in the context of the broad classifications, and terms such as undifferentiated inflammatory polyarthritis or undifferentiated spondyloarthropathy may be used in the interim to aid in diagnosis and management. Cutaneous Manifestations Joint Symptoms as a Common Presenting Feature Almost all rheumatic diseases can manifest with joint-related symptoms as a significant and frequently presenting feature. A nonblanching purpuric rash can indicate a vasculitis, and rashes involving specific extensor regions are common to dermatomyositis. Algorithm for identification of undifferentiated peripheral inflammatory arthritis. Algorithm for identification of undifferentiated peripheral inflammatory arthritis: a multinational collaboration through the 3e initiative. These tend to be present for days and are often palpable, and a tissue biopsy of the lesions is very helpful in diagnosis. In adult-onset Still disease (an adult form of systemic inflammatory arthritis classified as an autoinflammatory disease), patients present with daily spiking fevers, peaking late in the day, associated with a salmon-colored evanescent blanching rash lasting only 1 to 2 hours. Psoriasis is almost always present in psoriatic arthritis (a spondyloarthropathy variant). Although psoriasis is often widespread, involving extensor surfaces, it can be missed if there are very few lesions or if it is located in areas that are not easily seen (intertriginous regions, such as in the ear, umbilicus, buttock creases, or scalp) or if it only involves the nails. The rash of psoriasis can be seen in any of the variants of the spondyloarthropathies. Occasionally rheumatoid arthritis manifests with nodules over the extensor surfaces or rashes in the same areas, but this is increasingly rare. However, the presence of nodules over extensor surfaces may also indicate gouty tophi. In systemic sclerosis, distal tightening of the skin, presence of telangiectasias, and digital ulcers can be seen. These should also be sought in the context of Raynaud syndrome, characterized by vascular spasm in the hands. Pattern of Onset of Rheumatic Diseases by Category Most rheumatic diseases appear spontaneously and often insidiously or with a subacute onset. Not all will manifest with all typical features at the time of presentation, and a diagnosis can take time to make as defining features present themselves. Almost all rheumatic diseases have had classification criteria published that account for the typical and specific features of the disease. However, in an individual patient a diagnosis can be made without meeting all classification criteria because some features of a rheumatic disease are highly specific and are not associated with other diseases. The natural history of each rheumatic disease is related to the severity of presentation, the specific additional organs that become involved, and the development of comorbidities. Rheumatoid arthritis may present with one or two swollen joints or pain in the forefoot. Autoimmune and vascular rheumatic diseases are associated with high morbidity and mortality when left untreated, and efforts to investigate for all manifestations early on are warranted. Degenerative Rheumatic Diseases these refer to rheumatic diseases commonly associated with advancing age. Degenerative joint disease is usually thought to include osteoarthritis and degenerative disc disease. Degenerative joint disease is heralded by breakdown of articular collagenous structures (cartilage or intervertebral discs) and development of bony hypertrophy. Resultant pain from varying causes contributes to immobility, secondary comorbidities, and disability. Degenerative joint disease represents, by far, the most common of the rheumatic diseases and is described in detail in Chapter 246. In general, these diseases are not associated with rashes or nonspecific constitutional symptoms. Raynaud phenomenon, although not specific to systemic sclerosis, frequently precedes its onset, often by many years. Skin tightness can go on to involve the face, arms, and, in the case of diffuse systemic sclerosis, the trunk, back, and legs. When features of rheumatic diseases present as the classical phenotype, making the diagnosis is straightforward. One or more of certain features, including constitutional disturbances such as fatigue, fever, weight loss, arthralgia, arthritis, and myalgias, are commonly seen in almost all rheumatic diseases. Overlap of symptoms expands the differential diagnosis, and a clear distinction is often not readily apparent, even after serologic testing. They involve multiple organ systems and are therefore heterogeneous in clinical manifestations. Each symptom presentation is associated with specific signs and should be further characterized by additional investigations (Table 241-3), including measurement of characteristic autoantibodies in serum. Defined autoantibody specificities can discern subtypes of rheumatic diseases (Chapter 242; see Table 241-3). As noted, cutaneous manifestations, sicca symptoms (of dry eyes or mouth), mucosal ulceration, fevers, alopecia, and Raynaud syndrome are common and often described by patients. Rheumatoid arthritis (Chapter 248) has a female-to-male ratio of approximately 3: 1 and typically has its onset in the later adult decades, with symmetrical small-medium joint synovitis as the classic presenting feature. Skin tightness is the hallmark of systemic sclerosis (Chapter 251), often referred to as scleroderma, which most often involves the extremities. Skin manifestations initially present with swelling of the digits, Ankylosing spondylitis (Chapter 249) manifesting with lower spine disease and earlier spinal fusion is more common in males than females. Disease in females may present more atypically with cervical or thoracolumbar symptoms in the primary presentation. Localization of symptoms to the neck and thoracolumbar spine, sacroiliac joints, and large upper and lower extremity "root" joints can be used to differentiate ankylosing spondylitis from rheumatoid arthritis. The typical presence of psoriatic skin lesions in patients with psoriatic arthritis can be a distinguishing feature from rheumatoid arthritis. Spinal inflammation can also be associated with inflammatory bowel disease, not infrequently in the mid or upper spine as opposed to the sacroiliac joints. Forms of Vasculitis There are many vasculitis syndromes, and these are generally grouped based on vessel size (Chapter 254). Polymyalgia rheumatica (Chapter 255) is a common inflammatory rheumatic disease of the elderly and shares many pathogenetic and epidemiologic features with giant cell arteritis, a form of older-onset vasculitis. For suspected crystal disease, perform aspiration of synovial fluid or tophus and examine under polarized light microscopy. In complex regional pain syndrome, tendonitis, or enthesitis, specific physical findings and imaging can facilitate diagnosis. Moreover, questions regarding recent illnesses, travel, exposure to possible infectious pathogens, and presence or absence of systemic features such as fever, fatigue, or weight loss will provide important clues. Appreciation of signs and symptoms indicating extra-articular features, particularly cutaneous, pulmonary, renal, neurologic, or vascular manifestations, will guide the differential diagnosis, and further investigations will help to determine the definitive diagnosis as well as the prognosis and required intensity of therapy. The presence of one rheumatic disease can be associated with comorbid manifestations unrelated to connective tissue. For example, myocardial infarction is more common in many patients with rheumatic diseases. Immobility or treatment-related factors leading to obesity can increase risks for diabetes and lower joint degeneration. Recent diagnostic classification criteria are based on the typical clinical presentation and laboratory evidence of acute phase reactants. Mimics of polymyalgia rheumatica can include elderly onset rheumatoid arthritis; thus, tests to exclude this may be indicated. When considering polymyalgia rheumatica, it is important to include giant cell arteritis in the differential diagnosis, particularly when acute phase reactants are very high or there are nonmusculoskeletal symptoms or manifestations. A high index of suspicion for temporal artery inflammation or large vessel disease involving the aorta is needed because clinical consequences of associated vascular inflammation in giant cell arteritis can be damaging, sometimes leading to blindness or stroke, or to more severe vascular destruction and organ ischemia, which can be life-threatening. Autoinflammatory Diseases Rare autoinflammatory diseases are based on mutations in genes involved in inflammatory pathways. They are more typically diagnosed in children and are covered in detail in Chapter 245. Gout (Chapter 257) is the most common and prototypical autoinflammatory disease, occurring more often in middleaged and older men, and is increasing in prevalence. Exquisitely painful joint and periarticular erythema and swelling are presenting features. High serum uric acid is associated with gout, although levels may lower during acute attacks. Factors in the Medical History that Contribute to Diagnosis and Prognosis Age and Gender Pain and Pain Syndromes Pain (also see Chapter 27) is a common and nonspecific, but very important, symptom central to nearly all rheumatic diseases. Location, distribution, and patterns should be elicited along with temporal features, triggers, migratory or alleviating features, and prior history of physical or psychological trauma. In regional pain syndromes, the distribution of pain is the key clue to the diagnosis. Diffuse pain without evidence of underlying pathology associated with inordinate levels of fatigue, difficulty coping, and intricately detailed descriptions of pain using colorful analogies herald fibromyalgia (Chapter 258). Fibromyalgia is defined as widespread pain involving the right and left sides and upper and lower extremities, as well as the neck and back. For instance, a regional pain syndrome relating to a mechanical neck and shoulder syndrome will result in the patient having pain in the involved neck and shoulder but also the trapezius, upper chest, axilla, and upper and/or lower arm and hand. A large proportion of patients presenting with musculoskeletal pain will have regional pain relating to muscular imbalances, postural factors with or without underlying degenerative arthritis, tendinopathy, or enthesopathy. As an example, pain syndromes in the trapezial region, referring down the arm to the deltoid and even forearm, can be multifactorial and associated with a combination of muscular spasm, underlying degenerative arthritis in the cervical spine, or rotator cuff impingement, not infrequently relating to repetitive activities. Pain in a distal extremity after trauma or surgery associated with a cold, shiny extremity is suggestive of complex regional pain syndrome. The etiology of these will become apparent with taking a careful history of pain features along with a medical history, physical examination, and exclusion of "red flags" or factors that indicate an underlying pathology specific to a related organ from which pain can be referred. Pain in the setting of a history of malignancy should suggest the possibility of metastases. Most pain syndromes warrant a full medical evaluation before making a definitive diagnosis. A comprehensive history is needed to complete an evaluation of a patient with a rheumatic disease.

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