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Systemic Vasculitis TABLf 3?. lnfectiousArthritisTreatment Based on Suspected Pathogen Likely or ldentified Pathogen First-Line Therapy Second-Line Therapy Comments Gram-Positive Cocci MRSA Vancomycin Clindamycin; Narrow treatmentto MSSA coverage daptomycin; linezolid as appropriate based on sensitivity data

TABLf 3?. lnfectiousArthritisTreatment Based on Suspected Pathogen Likely or ldentified Pathogen First-Line Therapy Second-Line Therapy Comments Gram-Positive Cocci MRSA Vancomycin Clindamycin; Narrow treatmentto MSSA coverage daptomycin; linezolid as appropriate based on sensitivity data MSSA Nafcillin; cefazolin Gram-Negative Bacilli Enteric gram-negative bacilli Th ird-generation Fluoroquinolones cephalosporin (e.9., ceftriaxone or ce{otaxime) Pse u d o m o n a s a e ru g i n osa Ceftazidime; cefepime; Carbapenems; aareonam; pi peracillin-tazobactam fluoroq uinolones Gram-Negative Cocci Neisseria gonorrhoeae lV ceftriaxone for >7 days Fluoroquinolones (only if ln absence of specific culture culture sensitivities sensitivity data, "stepping down" to Oral doxycycline, 100 mg confirm susceptibility) oral therapy is no longer orally twice daily for 7 days if recommended because of increasing Chlamydia infection not resistance of N. gonorrhoeaeto excluded commonly used oral agents Suspected Bacterial lnfection, No Gram Stain Always initiate therapy with Vancomycin; vancomycin + Appropriate to start with broad coverage for MRSA; consider third-generation antibiotic coverage; narrow coverage patient risk factors and cephalosporin; or if culture data become available community patterns of infection; vancomycin + consider coverage for gram- antipseudomonal antibiotic negative organism if patient is immunocompromised and at risk for gonococcal infection Confirmed Diagnosis Bo r re I i a b u rg d o rf e ri (Ly me Oral doxycycline, amoxicillin, lf inadequate response, lV arthritis) or cefuroxime axetil x 28 days ceftriaxone x 2-4 wk M ycob a cte ri u m tubercu/osis 3- or 4-drug treatment (e.9., Duration mayvaryfrom 6 months or isoniazid, pyrazinamide, longer depending on drug regimen ri{ampin, ethambutol, (shortertreatment if rifampin is used) streptomycin) Fungal infections Amphotericin B, Prolonged treatment courses of echinocandin, or azoles several months may be needed; (f luconazole, itraconazole, maintenance therapy may be voriconazole, posaconazole) required in high-risk patients depending on suspected organism or culture data

MSSA Nafcillin; cefazolin Gram-Negative Bacilli Enteric gram-negative bacilli Th ird-generation Fluoroquinolones cephalosporin (e.9., ceftriaxone or ce{otaxime) Pse u d o m o n a s a e ru g i n osa Ceftazidime; cefepime; Carbapenems; aareonam; pi peracillin-tazobactam fluoroq uinolones Gram-Negative Cocci Neisseria gonorrhoeae lV ceftriaxone for >7 days Fluoroquinolones (only if ln absence of specific culture culture sensitivities sensitivity data, "stepping down" to Oral doxycycline, 100 mg confirm susceptibility) oral therapy is no longer orally twice daily for 7 days if recommended because of increasing Chlamydia infection not resistance of N. gonorrhoeaeto excluded commonly used oral agents Suspected Bacterial lnfection, No Gram Stain Always initiate therapy with Vancomycin; vancomycin + Appropriate to start with broad coverage for MRSA; consider third-generation antibiotic coverage; narrow coverage patient risk factors and cephalosporin; or if culture data become available community patterns of infection; vancomycin + consider coverage for gram- antipseudomonal antibiotic negative organism if patient is immunocompromised and at risk for gonococcal infection Confirmed Diagnosis Bo r re I i a b u rg d o rf e ri (Ly me Oral doxycycline, amoxicillin, lf inadequate response, lV arthritis) or cefuroxime axetil x 28 days ceftriaxone x 2-4 wk M ycob a cte ri u m tubercu/osis 3- or 4-drug treatment (e.9., Duration mayvaryfrom 6 months or isoniazid, pyrazinamide, longer depending on drug regimen ri{ampin, ethambutol, (shortertreatment if rifampin is used) streptomycin) Fungal infections Amphotericin B, Prolonged treatment courses of echinocandin, or azoles several months may be needed; (f luconazole, itraconazole, maintenance therapy may be voriconazole, posaconazole) required in high-risk patients depending on suspected organism or culture data lV = intravenous; MRSA = methicillin-resistant Staphy/oco ccus aureus; MSSA = methicillin sensitive Staphyloco ccus aureus.

MSSA Nafcillin; cefazolin Gram-Negative Bacilli Enteric gram-negative bacilli Th ird-generation Fluoroquinolones cephalosporin (e.9., ceftriaxone or ce{otaxime) Pse u d o m o n a s a e ru g i n osa Ceftazidime; cefepime; Carbapenems; aareonam; pi peracillin-tazobactam fluoroq uinolones Gram-Negative Cocci Neisseria gonorrhoeae lV ceftriaxone for >7 days Fluoroquinolones (only if ln absence of specific culture culture sensitivities sensitivity data, "stepping down" to Oral doxycycline, 100 mg confirm susceptibility) oral therapy is no longer orally twice daily for 7 days if recommended because of increasing Chlamydia infection not resistance of N. gonorrhoeaeto excluded commonly used oral agents Suspected Bacterial lnfection, No Gram Stain Always initiate therapy with Vancomycin; vancomycin + Appropriate to start with broad coverage for MRSA; consider third-generation antibiotic coverage; narrow coverage patient risk factors and cephalosporin; or if culture data become available community patterns of infection; vancomycin + consider coverage for gram- antipseudomonal antibiotic negative organism if patient is immunocompromised and at risk for gonococcal infection Confirmed Diagnosis Bo r re I i a b u rg d o rf e ri (Ly me Oral doxycycline, amoxicillin, lf inadequate response, lV arthritis) or cefuroxime axetil x 28 days ceftriaxone x 2-4 wk M ycob a cte ri u m tubercu/osis 3- or 4-drug treatment (e.9., Duration mayvaryfrom 6 months or isoniazid, pyrazinamide, longer depending on drug regimen ri{ampin, ethambutol, (shortertreatment if rifampin is used) streptomycin) Fungal infections Amphotericin B, Prolonged treatment courses of echinocandin, or azoles several months may be needed; (f luconazole, itraconazole, maintenance therapy may be voriconazole, posaconazole) required in high-risk patients depending on suspected organism or culture data lV = intravenous; MRSA = methicillin-resistant Staphy/oco ccus aureus; MSSA = methicillin sensitive Staphyloco ccus aureus. TEY ?OIilIS Systemic Vasculitis . For patients suspected of having infectious arthritis, blood and synovial cultures must be obtained before Overview treatment, but empiric antibiotic therapy should be Vasculitis is inflammation of blood vessels, including capillar started pending culture results. ies, arteries, and/or veins. Clinical manifestations result from o In addition to antibiotic therapy, an infected joint must tissue ischemia in the affected areas. Vasculitis can be primary also be adequately drained by needle aspiration or sur- secondary to another underlying autoimmune disease, or gical drainage. triggered by other causes (Table 38). Vasculitis mimics must be considered in the differential diagnosis (Table 39). Primary . Many patients with prosthetic joint infections require autoimmune vasculitis disorders are discussed in this removal ofthe orthopedic device as part ofa two-stage section. procedure, with reimplantation of a new device after an Vasculitis is not one disease, but many. These conditions appropriate course of intravenous antibiotics. are typically grouped into distinct categories according to

TEY ?OIilIS Systemic Vasculitis . For patients suspected of having infectious arthritis, blood and synovial cultures must be obtained before Overview treatment, but empiric antibiotic therapy should be Vasculitis is inflammation of blood vessels, including capillar started pending culture results. ies, arteries, and/or veins. Clinical manifestations result from o In addition to antibiotic therapy, an infected joint must tissue ischemia in the affected areas. Vasculitis can be primary also be adequately drained by needle aspiration or sur- secondary to another underlying autoimmune disease, or gical drainage. triggered by other causes (Table 38). Vasculitis mimics must be considered in the differential diagnosis (Table 39). Primary . Many patients with prosthetic joint infections require autoimmune vasculitis disorders are discussed in this removal ofthe orthopedic device as part ofa two-stage section. procedure, with reimplantation of a new device after an Vasculitis is not one disease, but many. These conditions appropriate course of intravenous antibiotics. are typically grouped into distinct categories according to 78

Systemic Vasculitis TABLE 38. Causes of Secondary Vasculitis Medications Common causes: antimicrobial agents (e.g., minocycline, sulfadiazine); antithyroid agents (propylthiouracil 180y"-907o1, methimazole, carbimazole, benzylthiouracil [10o/o-20%; not available in the United States]); cardiovascular drugs (hydralazine); tumor necrosis factor inhibitors Rare causes: vaccines; antiepileptic agents; antiarrhythmic agents; diuretics; anticoagulants; antineoplastic agents; hematopoietic growth factors; NSAIDs; psychotropic drugs; sympathomimetic agents; allopurinol; interferon alfa; levamisole (associated with cocaine) lnfections Hepatitis A, B, and C viruses; HIV; bacterial endocarditis; parvovirus 819 Neoplasms Hairy cell leukemia (associated with polyarteritis nodosa); other hematologic and solid malignancies Autoimmune Diseases Systemic lupus erythematosus; rheumatoid arthritis; Sjogren syndrome; inflammatory myopathies; systemic sclerosis; relapsing polychondritis; inflammatory bowel disease; primary biliary cirrhosis clinical presentation and pathophysiolo$r A well-established including the external carotid, subclavian, axilIary temporal, classification scheme focuses on size ofinvolved vessels. Vessel ophthalmic, ciliary occipital, and vertebral arteries. The vessel size can provide insight into processes and presentations, but involved dictates the clinical symptoms. conditions and vessel sizes may overlap. Clinical Manifestations and Diagnosis Common GCA symptoms include headache (typically tempo I

clinical presentation and pathophysiolo$r A well-established including the external carotid, subclavian, axilIary temporal, classification scheme focuses on size ofinvolved vessels. Vessel ophthalmic, ciliary occipital, and vertebral arteries. The vessel size can provide insight into processes and presentations, but involved dictates the clinical symptoms. conditions and vessel sizes may overlap. Clinical Manifestations and Diagnosis Common GCA symptoms include headache (typically tempo I t, Large-Vessel Vascu Iitis ral but occasionally more diffuse), constitutional symptoms, L Giant Cell Arteritis concomitant polymyalgia rheumatica (PMR), and scalp ten I Epidemiolory and Pathophysiolory derness over the temporal artery. Symptoms can be unilateral Giant cell arteritis (GCA; also called temporal arteritis) usually or bilateral. Jaw aching and fatigue with cherning indicate affects patients older than 50 years (peak incidence, 70 B0 years). ischemia (claudication) of the muscles of mastication. The GCA is more common in White persons (incidence in Europe, most feared complication of GCA is ischemic optic neuropathy 10-20/100,000). The female to male ratio is about 3:1. due to occlusion of the posterior ciliary or occasionally the Histologically, GCA is characterized by granulomatous ophthalmic artery which can cause irreversible blindness. inflammation of large and medium-sized arteries, with infil- Early recognition and treatment of any visual change (e.g., tration of CD4 positive lymphocytes, macrophages, and mult reversible diplopia or visual defect) are critical. Intracranial inucleated giant cells. Inflammatory disruption of the internal ischemic strokes are rare. elastic lamina is common. Involved vessels include the aortar Extracranial disease involving great vessels in the chest its major branches olfthe arch; and secondary branch vessels, and arms occurs in up to 50'/" of patients but is usually

t, Large-Vessel Vascu Iitis ral but occasionally more diffuse), constitutional symptoms, L Giant Cell Arteritis concomitant polymyalgia rheumatica (PMR), and scalp ten I Epidemiolory and Pathophysiolory derness over the temporal artery. Symptoms can be unilateral Giant cell arteritis (GCA; also called temporal arteritis) usually or bilateral. Jaw aching and fatigue with cherning indicate affects patients older than 50 years (peak incidence, 70 B0 years). ischemia (claudication) of the muscles of mastication. The GCA is more common in White persons (incidence in Europe, most feared complication of GCA is ischemic optic neuropathy 10-20/100,000). The female to male ratio is about 3:1. due to occlusion of the posterior ciliary or occasionally the Histologically, GCA is characterized by granulomatous ophthalmic artery which can cause irreversible blindness. inflammation of large and medium-sized arteries, with infil- Early recognition and treatment of any visual change (e.g., tration of CD4 positive lymphocytes, macrophages, and mult reversible diplopia or visual defect) are critical. Intracranial inucleated giant cells. Inflammatory disruption of the internal ischemic strokes are rare. elastic lamina is common. Involved vessels include the aortar Extracranial disease involving great vessels in the chest its major branches olfthe arch; and secondary branch vessels, and arms occurs in up to 50'/" of patients but is usually TABLE 39. Differential Diagnosis (lncluding Mimics) of Vasculitis Disease Comments lnfection (sepsis, endocarditis, hepatitis) Rash and/or musculoskeletal symptoms can occur.

t, Large-Vessel Vascu Iitis ral but occasionally more diffuse), constitutional symptoms, L Giant Cell Arteritis concomitant polymyalgia rheumatica (PMR), and scalp ten I Epidemiolory and Pathophysiolory derness over the temporal artery. Symptoms can be unilateral Giant cell arteritis (GCA; also called temporal arteritis) usually or bilateral. Jaw aching and fatigue with cherning indicate affects patients older than 50 years (peak incidence, 70 B0 years). ischemia (claudication) of the muscles of mastication. The GCA is more common in White persons (incidence in Europe, most feared complication of GCA is ischemic optic neuropathy 10-20/100,000). The female to male ratio is about 3:1. due to occlusion of the posterior ciliary or occasionally the Histologically, GCA is characterized by granulomatous ophthalmic artery which can cause irreversible blindness. inflammation of large and medium-sized arteries, with infil- Early recognition and treatment of any visual change (e.g., tration of CD4 positive lymphocytes, macrophages, and mult reversible diplopia or visual defect) are critical. Intracranial inucleated giant cells. Inflammatory disruption of the internal ischemic strokes are rare. elastic lamina is common. Involved vessels include the aortar Extracranial disease involving great vessels in the chest its major branches olfthe arch; and secondary branch vessels, and arms occurs in up to 50'/" of patients but is usually TABLE 39. Differential Diagnosis (lncluding Mimics) of Vasculitis Disease Comments lnfection (sepsis, endocarditis, hepatitis) Rash and/or musculoskeletal symptoms can occur. Dru g toxicity/poisoni ng Cocaine, amphetamines, ephedra alkaloids, and phenylpropanolamine may produce vasospasm, resulting in ischemia. Coagulopathy Thrombotic diseases (disseminated intravascular coagulation; antiphospholipid syndrome; thrombotic thrombocytopenic purpura)can produce ischemic symptoms. Malignancy Paraneoplastic vasculitis is rare. Any organ system may be affected, but the skin and nervous system are the most common. Vasculitic symptoms may precede, occur simultaneously with, or follow diagnosis of cancer. Lymphoma occasionally may involve the blood vessels and mimic vasculitis. Consider malignancy in patients with incomplete or no response to therapy for idiopathic vasculitis. Atrial myxoma Classic triad of symptoms is embolism, pulmonary congestion or heart failure, and constitutional symptoms (fatigue; weight loss; fever). Skin lesions can be identical to i

Dru g toxicity/poisoni ng Cocaine, amphetamines, ephedra alkaloids, and phenylpropanolamine may produce vasospasm, resulting in ischemia. Coagulopathy Thrombotic diseases (disseminated intravascular coagulation; antiphospholipid syndrome; thrombotic thrombocytopenic purpura)can produce ischemic symptoms. Malignancy Paraneoplastic vasculitis is rare. Any organ system may be affected, but the skin and nervous system are the most common. Vasculitic symptoms may precede, occur simultaneously with, or follow diagnosis of cancer. Lymphoma occasionally may involve the blood vessels and mimic vasculitis. Consider malignancy in patients with incomplete or no response to therapy for idiopathic vasculitis. Atrial myxoma Classic triad of symptoms is embolism, pulmonary congestion or heart failure, and constitutional symptoms (fatigue; weight loss; fever). Skin lesions can be identical to i I those seen in leukocytoclastic vasculitis. i I Cholesterol emboli Typically seen in patients with severe atherosclerosis. Embolization may occur after I abdominaltrauma, aortic surgery, or angiography. May also occur after heparin, l l warfarin, orthrombolytictherapy. Patients may have livedo reticularis, petechiae and purpuric lesions, and localized skin necrosis. 79

Systemic Vasculitis subclinical; it only sometimes results in upper extremity clau dose. Mild flares can be managed with modest increases of dication. Severe but uncommon complications include aortic prednisone and slower tapering. The addition of low-dose aneurysm and dissection. Up to 50% of patients with GCA methotrexate may facilitate glucocorticoid tapering and may have PMR, which may occur before, concurrent with, or after be considered in patients with significant glucocorticoid diagnosis of GCA (see Polymyalgia Rheumatica). contraindications, although data are limited. At treatment Physical examination may reveal scalp or temporal artery initiation, all patients should undergo bone densitometry tenderness and induration, reduced peripheral pulses, and to stratify risk for glucocorticoid-induced osteoporosis and bruits. Laboratory studies almost always show elevated ery.th receive prophylaxis. rocyte sedimentation rate (ESR) and/or C reactive protein GCA is self-limited (2-6 years) in some patients but may (CRP). Rarely, however, the inflammatory markers may be be chronic in others. It also may recur. Appropriate and timely normal. Nonspecific evidence of inflammation may include treatment can reduce risk for blindness. anemia, elevated serum ferritin level, and thrombocytosis. Serologic testing reveals no specific autoantibodies (although Polymyalgia Rheumatica low-level antinuclear antibody levels and rheumatoid factor Epidemiologr and Pathophysiolory are common in older patients). Although not a vasculitis, PMR is an inflammatory disorder GCA is suspected on the basis of clinical presentation that frequently (up to 50'7, of cases) accompanies GCA. PMR and should be confirmed, when possible, by temporal and GCA likely reflect the clinical spectrum of a single artery biopsy and/or imaging of the great vessels. New or disease process, although PMR occurs 3 to 10 times more atypical headache, jaw claudication, or visual changes in a frequently. Patients presenting with PMR should be asked patient older than 50 years, especially with concurrent about arteritis symptoms because 107, to 20% have con PMR, should raise suspicion. Temporal artery biopsy is comitant GCA. diagnostic, but false-negative results are common because of skip lesions; adequate biopsy sampling (>1-cm length of Clinical Manifestations and Diagnosis temporal artery) is crucial; although bilateral temporal The classic picture of PMR is pain and stiffness of the shoul artery biopsy can slightly increase the yield, unilateral der girdle and hip girdle. Symptoms may affect some or all of biopsy is recommended. Temporal artery biopsy findings these areas; symmetric presentation is classic. Pain and stiff remain abnormal for up to 4 weeks after initiation of glu ness are most pronounced in the morning. Peripheral arthri cocorticoids. Given the risk for blindness. treatment should tis, generally mild and affecting the knees and wrists, may therefore be initiated first and biopsy performed within occur. Synovitis in the hands and feet is uncommon. 2 weeks. If the pretest likelihood of disease is high, treat Constitutional symptoms and laboratory findings resemble ment may be continued even in the presence of a negative those of GCA, although normal inflammatory markers are biopsy result. more common in PMR than GCA. PMR is diagnosed clini cally. Temporal artery biopsy should be performed only if Management GCA is suspected. Suspected GCA should be treated immediately to prevent visual loss. Beginning high-dose prednisone (1 mg/kg/d, up Management to 80 mg) is recommended. Intravenous pulse methylpre- Unlike GCA, PMR responds dramatically to moderate dose dnisolone for 3 days is recommended for acute visual loss; prednisone (12.5 20 mg/d); lack of a rapid response should however, data on this approach are limited, and estab- prompt consideration of alternate diagnoses. Prednisone lished blindness is usually irreversible. Prednisone plus the taper is initiated 4 weeks after symptoms resolve and requires interleukin 6 inhibitor tocilizumab is conditionally recom- months to years. Monitoring of recurrence is managed simi- mended as initial therapy because the combination is superior larly to the approach used for GCA. For relapses, guidelines to prednisone alone and typically permits faster glucocorti for the management of PMR (developed by the American coid taper. Symptoms and inflammatory markers usually College of Rheumatologz and the European League Against respond rapidly to treatment; lack of response should prompt Rheumatism) recommend increasing the prednisone dose to reconsideration of the diagnosis. High dose prednisone is the last pre relapse dose at which the patient was doing well, maintained for 2 to 4 weeks. Once symptoms resolve and followed by a gradual reduction within 4 to 8 weeks to the inflammatory markers normalize, prednisone is tapered as relapse dose. Methotrexate can be used in select cases as a tolerated, with a goal of reaching 20 mg/d within 2 to weak glucocorticoid-sparing agent. 3 months, at which point tapering is slowed. Glucocorticoids Prognosis is good, although periodic recurrences are should be discontinued, when possible, within 6 months, but common. If PMR treatment is initiated properly, patients longer treatment may be warranted as dictated by disease whose PMR is not accompanied by GCA rarely progress to activity. Patients should be monitored for symptom recur GCA. Several studies suggest the benefit of tocilizumab for rence. ESR and/or CRP should be monitored monthly but treating PMR in the absence of GCA, but the agent is not should not be the sole indication for adjusting glucocorticoid approved for this purpose.

subclinical; it only sometimes results in upper extremity clau dose. Mild flares can be managed with modest increases of dication. Severe but uncommon complications include aortic prednisone and slower tapering. The addition of low-dose aneurysm and dissection. Up to 50% of patients with GCA methotrexate may facilitate glucocorticoid tapering and may have PMR, which may occur before, concurrent with, or after be considered in patients with significant glucocorticoid diagnosis of GCA (see Polymyalgia Rheumatica). contraindications, although data are limited. At treatment Physical examination may reveal scalp or temporal artery initiation, all patients should undergo bone densitometry tenderness and induration, reduced peripheral pulses, and to stratify risk for glucocorticoid-induced osteoporosis and bruits. Laboratory studies almost always show elevated ery.th receive prophylaxis. rocyte sedimentation rate (ESR) and/or C reactive protein GCA is self-limited (2-6 years) in some patients but may (CRP). Rarely, however, the inflammatory markers may be be chronic in others. It also may recur. Appropriate and timely normal. Nonspecific evidence of inflammation may include treatment can reduce risk for blindness. anemia, elevated serum ferritin level, and thrombocytosis. Serologic testing reveals no specific autoantibodies (although Polymyalgia Rheumatica low-level antinuclear antibody levels and rheumatoid factor Epidemiologr and Pathophysiolory are common in older patients). Although not a vasculitis, PMR is an inflammatory disorder GCA is suspected on the basis of clinical presentation that frequently (up to 50'7, of cases) accompanies GCA. PMR and should be confirmed, when possible, by temporal and GCA likely reflect the clinical spectrum of a single artery biopsy and/or imaging of the great vessels. New or disease process, although PMR occurs 3 to 10 times more atypical headache, jaw claudication, or visual changes in a frequently. Patients presenting with PMR should be asked patient older than 50 years, especially with concurrent about arteritis symptoms because 107, to 20% have con PMR, should raise suspicion. Temporal artery biopsy is comitant GCA. diagnostic, but false-negative results are common because of skip lesions; adequate biopsy sampling (>1-cm length of Clinical Manifestations and Diagnosis temporal artery) is crucial; although bilateral temporal The classic picture of PMR is pain and stiffness of the shoul artery biopsy can slightly increase the yield, unilateral der girdle and hip girdle. Symptoms may affect some or all of biopsy is recommended. Temporal artery biopsy findings these areas; symmetric presentation is classic. Pain and stiff remain abnormal for up to 4 weeks after initiation of glu ness are most pronounced in the morning. Peripheral arthri cocorticoids. Given the risk for blindness. treatment should tis, generally mild and affecting the knees and wrists, may therefore be initiated first and biopsy performed within occur. Synovitis in the hands and feet is uncommon. 2 weeks. If the pretest likelihood of disease is high, treat Constitutional symptoms and laboratory findings resemble ment may be continued even in the presence of a negative those of GCA, although normal inflammatory markers are biopsy result. more common in PMR than GCA. PMR is diagnosed clini cally. Temporal artery biopsy should be performed only if Management GCA is suspected. Suspected GCA should be treated immediately to prevent visual loss. Beginning high-dose prednisone (1 mg/kg/d, up Management to 80 mg) is recommended. Intravenous pulse methylpre- Unlike GCA, PMR responds dramatically to moderate dose dnisolone for 3 days is recommended for acute visual loss; prednisone (12.5 20 mg/d); lack of a rapid response should however, data on this approach are limited, and estab- prompt consideration of alternate diagnoses. Prednisone lished blindness is usually irreversible. Prednisone plus the taper is initiated 4 weeks after symptoms resolve and requires interleukin 6 inhibitor tocilizumab is conditionally recom- months to years. Monitoring of recurrence is managed simi- mended as initial therapy because the combination is superior larly to the approach used for GCA. For relapses, guidelines to prednisone alone and typically permits faster glucocorti for the management of PMR (developed by the American coid taper. Symptoms and inflammatory markers usually College of Rheumatologz and the European League Against respond rapidly to treatment; lack of response should prompt Rheumatism) recommend increasing the prednisone dose to reconsideration of the diagnosis. High dose prednisone is the last pre relapse dose at which the patient was doing well, maintained for 2 to 4 weeks. Once symptoms resolve and followed by a gradual reduction within 4 to 8 weeks to the inflammatory markers normalize, prednisone is tapered as relapse dose. Methotrexate can be used in select cases as a tolerated, with a goal of reaching 20 mg/d within 2 to weak glucocorticoid-sparing agent. 3 months, at which point tapering is slowed. Glucocorticoids Prognosis is good, although periodic recurrences are should be discontinued, when possible, within 6 months, but common. If PMR treatment is initiated properly, patients longer treatment may be warranted as dictated by disease whose PMR is not accompanied by GCA rarely progress to activity. Patients should be monitored for symptom recur GCA. Several studies suggest the benefit of tocilizumab for rence. ESR and/or CRP should be monitored monthly but treating PMR in the absence of GCA, but the agent is not should not be the sole indication for adjusting glucocorticoid approved for this purpose. 80

Systemic Vasculitis Takayasu Arteritis t Epidemiolory and Pathophysiolory Takayasu arteritis (TA) causes inflammation of the large ves- sels, most commonly the aorta, followed by the subclavian, common carotid, and renal arteries; the pulmonary arteries may also be involved. TA is rare, with a prevalence of 40 per million in Japan and up to 8 per million elsewhere. Although # vascular involvement and clinical features overlap some- E # what with GCA, TA predominantly affects younger women. Arterial lesions are often stenotic ("pulseless disease"), and one third are aneurysmal. Histopathology is similar to that ol GCA. Clinical Manifestations and Diagnosis TA manifestations include new onset hypertension, Iimb clau- dication, postprandial abdominal pain due to mesenteric ischemia, reduced pulses, arterial bruits, and blood pressure discrepancies between the arms. Heart failure related to aortic insufficiency or coronary artery disease may occur. Neurologic manifestations include transient ischemic attack, stroke, and acute visual changes. As with GCA, laboratory studies are non specific and reveal anemia as well as elevated ESR and CRP. Angiography may demonstrate arterial stenosis or aneurysm (Figure 52). Management Primary treatment of TA is high dose oral glucocorticoids (1 mg/kg/d, up to 80 mg/d) with a slow taper. Guidelines con

Clinical Manifestations and Diagnosis TA manifestations include new onset hypertension, Iimb clau- dication, postprandial abdominal pain due to mesenteric ischemia, reduced pulses, arterial bruits, and blood pressure discrepancies between the arms. Heart failure related to aortic insufficiency or coronary artery disease may occur. Neurologic manifestations include transient ischemic attack, stroke, and acute visual changes. As with GCA, laboratory studies are non specific and reveal anemia as well as elevated ESR and CRP. Angiography may demonstrate arterial stenosis or aneurysm (Figure 52). Management Primary treatment of TA is high dose oral glucocorticoids (1 mg/kg/d, up to 80 mg/d) with a slow taper. Guidelines con ditionally recommend adjunctive treatment with nonbiologic immunosuppressive medications (e.g., methotrexate, Iefluno- mide, mycophenolate mofetil, azathioprine, and cyclophos- phamide) to mitigate glucocorticoid exposure. For refractory t I G U R E 5 2. Aortic angiogram from a patient with Takayasu arteritis. Note the high-grade stenosis of the proximal right subclavian artery (white arrcw) as well as disease, adding a tumor necrosis factor inhibitor is preferred the left su bclavian artery just below the origin of the left v erlebral arhery (black anow\. over adding tocilizumab. Endovascular or reconstructive vas- lncidentally noted is an anatomic variation with a common origin of the right cular procedures are sometimes required; if possible, these brachiocephalic artery and the left common carotid artery.

ditionally recommend adjunctive treatment with nonbiologic immunosuppressive medications (e.g., methotrexate, Iefluno- mide, mycophenolate mofetil, azathioprine, and cyclophos- phamide) to mitigate glucocorticoid exposure. For refractory t I G U R E 5 2. Aortic angiogram from a patient with Takayasu arteritis. Note the high-grade stenosis of the proximal right subclavian artery (white arrcw) as well as disease, adding a tumor necrosis factor inhibitor is preferred the left su bclavian artery just below the origin of the left v erlebral arhery (black anow\. over adding tocilizumab. Endovascular or reconstructive vas- lncidentally noted is an anatomic variation with a common origin of the right cular procedures are sometimes required; if possible, these brachiocephalic artery and the left common carotid artery. should be performed during periods of inactive disease. The leading cause ofdeath is heart failure; stroke and cardiovascu lar disease also contribute to morbidity. The 1O-year survival Mediu m-Vessel Vascu litis rate is 90'l". Polyarteritis Nodosa Epidemiolory and Pathophysiolory I(EY POITTS Polyarteritis nodosa (PAN) is a rare systemic necrotizing vascu- . Giant cell arteritis should be suspected in a patient litis that affects medium-sized and sometimes small-sized older than 50 years with new or atypical headache, jaw arteries. Prevalence is approximately 31 per million but declin claudication, or visual changes. ing. Average age at onset is 50 years. HVC . Suspected giant cell arteritis should be treated immedi- Historically, PAN has been strongly associated with hep- ately with prednisone to prevent visual loss; diagnosis atitis B virus (HBV). Because HBV prevalence has declined can still be confirmed with temporal artery biopsy with the advent of the HBV vaccine and antiviral treatment, within 2 weeks after initiation of prednisone. the proportion of patients with HBV-associated PAN has HVC r Polymyalgia rheumatica is associated with pain and declined from 36% to less than 5'/. of all PAN cases; most stiffness ofthe neck, shoulder, and pelvic girdles; it contemporary cases are autoimmune. Pathophysiologr is not responds dramatically to moderate-dose prednisone. well understood. . Takayasu arteritis occurs in younger women and causes Clinical Manifestations and Diagnosis inflammation of the aorta and other major noncranial PAN most commonly affects the skin and peripheral nerv vessels. ous system, as well as the gastrointestinal tract and kidneys.

should be performed during periods of inactive disease. The leading cause ofdeath is heart failure; stroke and cardiovascu lar disease also contribute to morbidity. The 1O-year survival Mediu m-Vessel Vascu litis rate is 90'l". Polyarteritis Nodosa Epidemiolory and Pathophysiolory I(EY POITTS Polyarteritis nodosa (PAN) is a rare systemic necrotizing vascu- . Giant cell arteritis should be suspected in a patient litis that affects medium-sized and sometimes small-sized older than 50 years with new or atypical headache, jaw arteries. Prevalence is approximately 31 per million but declin claudication, or visual changes. ing. Average age at onset is 50 years. HVC . Suspected giant cell arteritis should be treated immedi- Historically, PAN has been strongly associated with hep- ately with prednisone to prevent visual loss; diagnosis atitis B virus (HBV). Because HBV prevalence has declined can still be confirmed with temporal artery biopsy with the advent of the HBV vaccine and antiviral treatment, within 2 weeks after initiation of prednisone. the proportion of patients with HBV-associated PAN has HVC r Polymyalgia rheumatica is associated with pain and declined from 36% to less than 5'/. of all PAN cases; most stiffness ofthe neck, shoulder, and pelvic girdles; it contemporary cases are autoimmune. Pathophysiologr is not responds dramatically to moderate-dose prednisone. well understood. . Takayasu arteritis occurs in younger women and causes Clinical Manifestations and Diagnosis inflammation of the aorta and other major noncranial PAN most commonly affects the skin and peripheral nerv vessels. ous system, as well as the gastrointestinal tract and kidneys. 81

Systemic Vasculitis ir: :r:, ,-li,' Clinical Features of Polyarteritis Nodosa Organ System Symptoms Frequency Comments Constitutional Fever; malaise; weight loss 65% Musculoskeletal Arthralgia; myalgia 55% Skin Purpura; nodules; necrotic ulcers 50%-600a Neurologic Mononeuritis multiplex; peripheral neuropathy 79"/" Wrist drop; foot drop Kidney Hypertension; hematuria; proteinuria 40% Renal artery microaneurysms with tissue infarcVhematoma; no glomerulonephritis Gastrointestina I Mesenteric ischemia; intestinal perforation; 38% One third of gastrointestinal cases manifest pancreatitis; cholecystitis; appendicitis; as acute abdomen gastrointestinal bleeding Testicular Orchitis 17% Usually unilateral, due to testicular artery involvement Other Sensorineural hearing loss Case reports Bilateral; symmetric; sudden onset; rapidly progressive Laboratory Elevated erythrocyte sedimentation rate in 82%; elevated C-readive protein; leukocytosis; anemia; thromboqytosis; increased liver chemistrytest result in 33%

ir: :r:, ,-li,' Clinical Features of Polyarteritis Nodosa Organ System Symptoms Frequency Comments Constitutional Fever; malaise; weight loss 65% Musculoskeletal Arthralgia; myalgia 55% Skin Purpura; nodules; necrotic ulcers 50%-600a Neurologic Mononeuritis multiplex; peripheral neuropathy 79"/" Wrist drop; foot drop Kidney Hypertension; hematuria; proteinuria 40% Renal artery microaneurysms with tissue infarcVhematoma; no glomerulonephritis Gastrointestina I Mesenteric ischemia; intestinal perforation; 38% One third of gastrointestinal cases manifest pancreatitis; cholecystitis; appendicitis; as acute abdomen gastrointestinal bleeding Testicular Orchitis 17% Usually unilateral, due to testicular artery involvement Other Sensorineural hearing loss Case reports Bilateral; symmetric; sudden onset; rapidly progressive Laboratory Elevated erythrocyte sedimentation rate in 82%; elevated C-readive protein; leukocytosis; anemia; thromboqytosis; increased liver chemistrytest result in 33% Table 4O lists the clinical and laboratory findings of PAN. Management The disease does not involve the lungs. When present, kid- Intravenous pulse glucocorticoids and ryclophosphamide are ney involvement is renovascular rather than glomerular indicated for severe organ-threatening disease; glucocorti and often leads to hypertension. Cutaneous PAN is a vari- coids and disease-modirying antirheumatic drugs are used for ant confined to the skin. Cutaneous features of medium- milder disease. HBV-associated PAN is treated with short-term vessel vasculitis include livedo reticularis (Figure 53) and glucocorticoids, antiviral medication, and plasmapheresis if painful deep ulcers and skin necrosis due ischemic infarc- necessary. The S-year survival rate for treated PAN is 80%, and tion (Figure 54). Because of the intense inflammation of the relapse rate is 10% to 2O%. medium-sized vessels, subcutaneous nodules may be palpable. PrimaryAngiitis of the Central Nervous System Diagnosis is often confirmed via angiography of the mes- Epidemiolory and Pathophysiolory enteric and/or renal vasculature, which demonstrates saccular Primary angiitis of the central nervous system (PACNS) is a microaneurysms and areas of narrowing in medium-sized rare small- and medium-vessel vasculitis of the central nerv- vessels. The gold standard for diagnosing PAN is histologic ous system; it affects the brain parenchyma, spinal cord, and identification of focal segmental panmural necrotizing inflam- leptomeninges. Incidence is 2.4 per 100,000. Median age at mation of a medium-sized vessel, obtained on biopsy of involved, easily accessible tissue (e.g., skin or a superficial nerve).

Table 4O lists the clinical and laboratory findings of PAN. Management The disease does not involve the lungs. When present, kid- Intravenous pulse glucocorticoids and ryclophosphamide are ney involvement is renovascular rather than glomerular indicated for severe organ-threatening disease; glucocorti and often leads to hypertension. Cutaneous PAN is a vari- coids and disease-modirying antirheumatic drugs are used for ant confined to the skin. Cutaneous features of medium- milder disease. HBV-associated PAN is treated with short-term vessel vasculitis include livedo reticularis (Figure 53) and glucocorticoids, antiviral medication, and plasmapheresis if painful deep ulcers and skin necrosis due ischemic infarc- necessary. The S-year survival rate for treated PAN is 80%, and tion (Figure 54). Because of the intense inflammation of the relapse rate is 10% to 2O%. medium-sized vessels, subcutaneous nodules may be palpable. PrimaryAngiitis of the Central Nervous System Diagnosis is often confirmed via angiography of the mes- Epidemiolory and Pathophysiolory enteric and/or renal vasculature, which demonstrates saccular Primary angiitis of the central nervous system (PACNS) is a microaneurysms and areas of narrowing in medium-sized rare small- and medium-vessel vasculitis of the central nerv- vessels. The gold standard for diagnosing PAN is histologic ous system; it affects the brain parenchyma, spinal cord, and identification of focal segmental panmural necrotizing inflam- leptomeninges. Incidence is 2.4 per 100,000. Median age at mation of a medium-sized vessel, obtained on biopsy of involved, easily accessible tissue (e.g., skin or a superficial nerve). F I G U R E 5 4 . Retiform purpura on the lower legs due to vasculitis characterized FIGU RE 5 3 . Livedo reticularis on the feet, recognized as a red-blue, reticulated by dark red or purple net-like, branching, or stellate configuration. Skin necrosis and vascular network. ulceration may occur.

F I G U R E 5 4 . Retiform purpura on the lower legs due to vasculitis characterized FIGU RE 5 3 . Livedo reticularis on the feet, recognized as a red-blue, reticulated by dark red or purple net-like, branching, or stellate configuration. Skin necrosis and vascular network. ulceration may occur. 82

Systemic Vasculitis onset is 50 years. The three histologic presentations have a Sma I l-Vessel Vascu I itis patchy distribution: granulomatous (most common), lympho ANCA-Associated Vascu litis cytic, and necrotizing. ANCA-associated vasculitis includes three diseases character- Clinical Manifestations and Diagnosis ized by the presence of ANCA (Table 4f), granulomatosis with Patients with PACNS usually present with gradual and progres polyangiitis, microscopic polyangiitis, and eosinophilic granu sive symptoms of headache, cognitive impairment, neurologic lomatosis with polyangiitis. (ANCA associated glomerulone deficits, transient ischemic attacks, and strokes. Laboratory phritis is discussed in MKSAP 19 Nephrologr.) The presence of findings are normal. Cerebrospinal fluid is abnormal but non- ANCA can be detected on serologic testing and helps to define specific in 80'2, to 90% of patients, with elevated protein, lym the diseases. phocltic pleocy.tosis, and occasional oligoclonal bands. MRI The two types of vasculitis associated ANCA are p ANCA (perinuclear, directed against the neutrophil enzyme myelo shows nonspecific white and gray mafter changes and infarcts. Magnetic resonance angiography and CT angiography have peroxidase) and c ANCA (cl,toplasmic, directed against the limited usefulness because of poor resolution. Cerebral angiog neutrophil proteinase 3). Perinuclear and cytoplasmic refer to raphy may demonstrate vessel "beading" (alternating dilations patterns of immunofluorescent staining; enzyme linked and stenoses) but has limited sensitivity and specificity. Brain immunosorbent assays against myeloperoxidase and protein- biopsy should be performed in any patient in whom the diag- ase 3 are used to confirm antibody positivity and in some cases

onset is 50 years. The three histologic presentations have a Sma I l-Vessel Vascu I itis patchy distribution: granulomatous (most common), lympho ANCA-Associated Vascu litis cytic, and necrotizing. ANCA-associated vasculitis includes three diseases character- Clinical Manifestations and Diagnosis ized by the presence of ANCA (Table 4f), granulomatosis with Patients with PACNS usually present with gradual and progres polyangiitis, microscopic polyangiitis, and eosinophilic granu sive symptoms of headache, cognitive impairment, neurologic lomatosis with polyangiitis. (ANCA associated glomerulone deficits, transient ischemic attacks, and strokes. Laboratory phritis is discussed in MKSAP 19 Nephrologr.) The presence of findings are normal. Cerebrospinal fluid is abnormal but non- ANCA can be detected on serologic testing and helps to define specific in 80'2, to 90% of patients, with elevated protein, lym the diseases. phocltic pleocy.tosis, and occasional oligoclonal bands. MRI The two types of vasculitis associated ANCA are p ANCA (perinuclear, directed against the neutrophil enzyme myelo shows nonspecific white and gray mafter changes and infarcts. Magnetic resonance angiography and CT angiography have peroxidase) and c ANCA (cl,toplasmic, directed against the limited usefulness because of poor resolution. Cerebral angiog neutrophil proteinase 3). Perinuclear and cytoplasmic refer to raphy may demonstrate vessel "beading" (alternating dilations patterns of immunofluorescent staining; enzyme linked and stenoses) but has limited sensitivity and specificity. Brain immunosorbent assays against myeloperoxidase and protein- biopsy should be performed in any patient in whom the diag- ase 3 are used to confirm antibody positivity and in some cases nosis is seriously considered; however, the patchy distribution to replace immunolluorescence testing. of findings results in a 50'/n false-negative rate. ANCA may play a direct role in disease propagation by Evaluation also focuses on ruling out other conditions, activating primed endothelial cells and neutrophils, leading including infection, malignancy (e.g., intravascular CNS lym- to vessel damage. The granulomatous inflammation in phoma), and reversible cerebral vasoconstriction syndrome. some forms of ANCA associated vasculitis suggests a role for cell-mediated immunity. Although most cases of ANCA- Management associated vasculitis are idiopathic. a few are drug induced; PACNS is treated with high dose glucocorticoids and cyclo several drugs can cause this rare reaction, including pro- phosphamide. Patients often have permanent disability from pylthiouracil and levamisole (an adulterant often found in neurologic damage, and the recurrence rate is 27"/,,. cocaine). See MKSAP 19 Nephrologr for details on kidney involve

nosis is seriously considered; however, the patchy distribution to replace immunolluorescence testing. of findings results in a 50'/n false-negative rate. ANCA may play a direct role in disease propagation by Evaluation also focuses on ruling out other conditions, activating primed endothelial cells and neutrophils, leading including infection, malignancy (e.g., intravascular CNS lym- to vessel damage. The granulomatous inflammation in phoma), and reversible cerebral vasoconstriction syndrome. some forms of ANCA associated vasculitis suggests a role for cell-mediated immunity. Although most cases of ANCA- Management associated vasculitis are idiopathic. a few are drug induced; PACNS is treated with high dose glucocorticoids and cyclo several drugs can cause this rare reaction, including pro- phosphamide. Patients often have permanent disability from pylthiouracil and levamisole (an adulterant often found in neurologic damage, and the recurrence rate is 27"/,,. cocaine). See MKSAP 19 Nephrologr for details on kidney involve Kawasaki Disease ment in ANCA associated vasculitis. Kawasaki disease is a medium vessel vasculitis and the most common type of vasculitis in children. It presents as fever, Granulomatosis With Polyangiitis rash, cervical lymphadenopathy, conjunctival congestion, and EpidemiologA and Pathophy siology mucositis. Coronary vessel vasculitis is the most feared compli- Granulomatosis with polyangiitis (GPA) is the most common cation and may leave permanent vasculopathy if not treated ANCA-associated vasculitis. with an annual incidence of 7 to promptly. Although Kawasaki disease almost never develops in 12 per million.

Kawasaki Disease ment in ANCA associated vasculitis. Kawasaki disease is a medium vessel vasculitis and the most common type of vasculitis in children. It presents as fever, Granulomatosis With Polyangiitis rash, cervical lymphadenopathy, conjunctival congestion, and EpidemiologA and Pathophy siology mucositis. Coronary vessel vasculitis is the most feared compli- Granulomatosis with polyangiitis (GPA) is the most common cation and may leave permanent vasculopathy if not treated ANCA-associated vasculitis. with an annual incidence of 7 to promptly. Although Kawasaki disease almost never develops in 12 per million. adulthood, adults who had Kawasaki disease as a child may have residual coronary aneurysms that require monitoring and man- Clinical Manifestations and Diognosis agement. Recently a Kawasaki like syndrome (multisystem GPA affects the small vessels of the upper and lower airways inflammatory syndrome in children) has been identified in (sinuses, lungs), kidneys, eyes (scleritis), skin, and peripheral patients (rarely, adults) who have been infected with COVID-l9. nerves. At least 50'X, of,patients have constitutional symptoms. More than 95'7, of patients are ANCA positive, with antibodies r(EY POll{I5 overwhelmingly (>SO'2, of cases) directed against proteinase 3 r Polyarteritis nodosa most commonly affects the skin (anti PR3 antibodies; c ANCA). and peripheral nervous system, as well as the gastroin- GPA presents as systemic or localized disease. The sys testinal tract and kidneys; the gold standard for diagno- temic form is more common, involves major organs, and is sis is focal segmental panmural necrotizing inflamma- associated with positivity for anti PR3 antibodies. Patients tion of a medium-sized vessel on biopsy. with localized disease are more likely to be younger and . Patients with primary angiitis of the central nervous female; have mainly ear, nose, and throat involvement; and are system usually present with gradual and progressive less likely to be PR 3 positive. See Table 41 for clinical features symptoms of headache, cognitive impairment, neuro- ofGPA. logic deficits, transient ischemic attacks, and strokes. Cutaneous leatures of GPA include petechiae or palpable r Adults who had Kawasaki disease as a child may have purpura (both of which are nonblanching lesions; Figure 55), hemorrhagic bullae, and superficial ulcers. However, any residual coronary aneurysms that require monitoring and management. of the small vessel vasculitides may present with these findings.

adulthood, adults who had Kawasaki disease as a child may have residual coronary aneurysms that require monitoring and man- Clinical Manifestations and Diognosis agement. Recently a Kawasaki like syndrome (multisystem GPA affects the small vessels of the upper and lower airways inflammatory syndrome in children) has been identified in (sinuses, lungs), kidneys, eyes (scleritis), skin, and peripheral patients (rarely, adults) who have been infected with COVID-l9. nerves. At least 50'X, of,patients have constitutional symptoms. More than 95'7, of patients are ANCA positive, with antibodies r(EY POll{I5 overwhelmingly (>SO'2, of cases) directed against proteinase 3 r Polyarteritis nodosa most commonly affects the skin (anti PR3 antibodies; c ANCA). and peripheral nervous system, as well as the gastroin- GPA presents as systemic or localized disease. The sys testinal tract and kidneys; the gold standard for diagno- temic form is more common, involves major organs, and is sis is focal segmental panmural necrotizing inflamma- associated with positivity for anti PR3 antibodies. Patients tion of a medium-sized vessel on biopsy. with localized disease are more likely to be younger and . Patients with primary angiitis of the central nervous female; have mainly ear, nose, and throat involvement; and are system usually present with gradual and progressive less likely to be PR 3 positive. See Table 41 for clinical features symptoms of headache, cognitive impairment, neuro- ofGPA. logic deficits, transient ischemic attacks, and strokes. Cutaneous leatures of GPA include petechiae or palpable r Adults who had Kawasaki disease as a child may have purpura (both of which are nonblanching lesions; Figure 55), hemorrhagic bullae, and superficial ulcers. However, any residual coronary aneurysms that require monitoring and management. of the small vessel vasculitides may present with these findings. 83

Systemic Vasculitis TABLE 4'l . Clinical Features of ANCA-Associated Vasculitis Diseases Granulomatosis With Microscopic Polyangiitis Eosinophili< Granulomatosis Polyangiitis With Polyangiitis ANCA c-ANCA (antiprotei nase-3 p-ANCA (anti myeloperoxidase p-ANCA (anti myeloperoxidase antibodies) (>957o) a ntibodies) (507"-7 5"/") antibodies) (-50%) Vascular histology Pauci-immune necrotizing Pauci-immune nongranulomatous Pauci-i m mu ne necrotizing granulomatous vasculitis necrotizing vasculitis granulomatous vasculitis with eosinophilic infiltration of vessel walls and tissues; extravascular granu lomas Cardiac Pericarditis; myoca rd itis; Pericarditis; endomyocarditis; conduction disorder (<1 0%) conduction disorder; heart failure (27"/o-47"/")

TABLE 4'l . Clinical Features of ANCA-Associated Vasculitis Diseases Granulomatosis With Microscopic Polyangiitis Eosinophili< Granulomatosis Polyangiitis With Polyangiitis ANCA c-ANCA (antiprotei nase-3 p-ANCA (anti myeloperoxidase p-ANCA (anti myeloperoxidase antibodies) (>957o) a ntibodies) (507"-7 5"/") antibodies) (-50%) Vascular histology Pauci-immune necrotizing Pauci-immune nongranulomatous Pauci-i m mu ne necrotizing granulomatous vasculitis necrotizing vasculitis granulomatous vasculitis with eosinophilic infiltration of vessel walls and tissues; extravascular granu lomas Cardiac Pericarditis; myoca rd itis; Pericarditis; endomyocarditis; conduction disorder (<1 0%) conduction disorder; heart failure (27"/o-47"/") Ea rslnose/th roat Crusting; rhinorrhea; sinusitis; Sinusitis; sensorineural hearing Nasal polyps; rhinitis; sinusitis otitis media; chond ritis of ears and loss (9%-30%) (prodromal) nose with saddle nose deformity; septal perforation (7 0"/"-1 00"/") Gastrointestinal Ulceration; perforation (5"/"-1 1%l Abdominal pain; bleeding Abdominal pain; bleeding (30%-s8%) Kidney Pauci-immune necrotizing Pauci-immune necrotizing Pauci-immune necrotizing glomeru lonephritis (40%- 1 00%) glomerulonephritis (80%- 1 00%) g lome ru loneph ritis (25o/"\

Ea rslnose/th roat Crusting; rhinorrhea; sinusitis; Sinusitis; sensorineural hearing Nasal polyps; rhinitis; sinusitis otitis media; chond ritis of ears and loss (9%-30%) (prodromal) nose with saddle nose deformity; septal perforation (7 0"/"-1 00"/") Gastrointestinal Ulceration; perforation (5"/"-1 1%l Abdominal pain; bleeding Abdominal pain; bleeding (30%-s8%) Kidney Pauci-immune necrotizing Pauci-immune necrotizing Pauci-immune necrotizing glomeru lonephritis (40%- 1 00%) glomerulonephritis (80%- 1 00%) g lome ru loneph ritis (25o/"\ Lung Alveolar hemorrhage; nodules; Alveolar hemorrhage; pulmonary Asthma (prodromal, >90%); trachea l/su bg lottic stenosis infiltrates; pulmonary fibrosis nodular opacities; infiltrates (500/"-907o) (25%-55"/") (257o-86o/"\ Ocular Scleritis; episcleritis; retinal vasculitis; retro-orbital pseudotumor; dacryoadenitis (14"/"-60%)

Lung Alveolar hemorrhage; nodules; Alveolar hemorrhage; pulmonary Asthma (prodromal, >90%); trachea l/su bg lottic stenosis infiltrates; pulmonary fibrosis nodular opacities; infiltrates (500/"-907o) (25%-55"/") (257o-86o/"\ Ocular Scleritis; episcleritis; retinal vasculitis; retro-orbital pseudotumor; dacryoadenitis (14"/"-60%) Skin Petechiae/purpura; painful skin Petechiae/purpura; painful skin Petechiae/purpura; painful skin lesions; maculopapular rash; lesions; maculopapular rash; lesions; maculopapular rash; livedo reticularis; ulcers livedo reticularis; ulcers livedo reticularis; ulcers Neurologic Mononeuritis multiplex, Distal symmetric polyneuropathy; Sensori motor peripheral sensorimotor peripheral m o n o ne u riti s m ulti pl ex (37 "/"-7 2"/"1 neuropathy, mononeu ritis neuropathy (33%) multiplex (70%) Central nervous system Centra I nervous system involvement pachymeningitis; cerebral (pachymeningitis) (<5%) hemorrhage; infaras (<20%)

Skin Petechiae/purpura; painful skin Petechiae/purpura; painful skin Petechiae/purpura; painful skin lesions; maculopapular rash; lesions; maculopapular rash; lesions; maculopapular rash; livedo reticularis; ulcers livedo reticularis; ulcers livedo reticularis; ulcers Neurologic Mononeuritis multiplex, Distal symmetric polyneuropathy; Sensori motor peripheral sensorimotor peripheral m o n o ne u riti s m ulti pl ex (37 "/"-7 2"/"1 neuropathy, mononeu ritis neuropathy (33%) multiplex (70%) Central nervous system Centra I nervous system involvement pachymeningitis; cerebral (pachymeningitis) (<5%) hemorrhage; infaras (<20%) In the setting ofa classic clinical presentation and positiv- GPA is common (historically, >50'X, after initial remission). ity for c-ANCA/anti-PR3 antibodies, diagnosis of GPA is Glucocorticoids alone are insufficient to control GPA. Patients straightforward. However, because of significant risks of treat- with limited presentations of GPA (such as arthropathy or ment, biopsy of involved tissue is usually recommended if upper airway disease) without organ threatening disease can possible. Histopathologz of most tissues demonstrates pauci- sometimes be treated with glucocorticoids plus methotrexate; immune necrotizing granulomatous vasculitis; pauci-immune such patients should be carefully monitored for treatment necrotizing glomerulonephritis without granulomas is seen failure or development of kidney or other organ threatening on kidney biopsy. disease, necessitating a more aggressive regimen. With use of these approaches, GPA mortality has declined from 90'ln to Management around 10%. Kidney failure and infection remain the main To induce remission in severe organ-threatening or life- causes ofdeath. threatening disease, treatment of GPA consists of high-dose oral glucocorticoids or intravenous glucocorticoids plus Microscopic Polyangiitis rituximab (preferred) or cyclophosphamide; selected patients Ep idemiologA ond P ot ho p hg s iology may benefit from plasma exchange. Once remission is The annual incidence of microscopic polyangiitis (MPA) is achieved, patients should receive maintenance therapy con- estimated al 2.7 per million in Europe and lower elsewhere. sisting of rituximab, methotrexate, or azathioprine; rituxi- Average age at onset is 50 to 60 years, with a predilection mab appears to be most effective for preventing relapse and for men over women (1.8:1). Compared with GPA, ANCAs are is preferred. It remains unclear whether suppressive mainte- Iess prevalent (507, 75'X,) and usually directed against nance therapy can be fully withdrawn because relapse in myeloperoxidase.

In the setting ofa classic clinical presentation and positiv- GPA is common (historically, >50'X, after initial remission). ity for c-ANCA/anti-PR3 antibodies, diagnosis of GPA is Glucocorticoids alone are insufficient to control GPA. Patients straightforward. However, because of significant risks of treat- with limited presentations of GPA (such as arthropathy or ment, biopsy of involved tissue is usually recommended if upper airway disease) without organ threatening disease can possible. Histopathologz of most tissues demonstrates pauci- sometimes be treated with glucocorticoids plus methotrexate; immune necrotizing granulomatous vasculitis; pauci-immune such patients should be carefully monitored for treatment necrotizing glomerulonephritis without granulomas is seen failure or development of kidney or other organ threatening on kidney biopsy. disease, necessitating a more aggressive regimen. With use of these approaches, GPA mortality has declined from 90'ln to Management around 10%. Kidney failure and infection remain the main To induce remission in severe organ-threatening or life- causes ofdeath. threatening disease, treatment of GPA consists of high-dose oral glucocorticoids or intravenous glucocorticoids plus Microscopic Polyangiitis rituximab (preferred) or cyclophosphamide; selected patients Ep idemiologA ond P ot ho p hg s iology may benefit from plasma exchange. Once remission is The annual incidence of microscopic polyangiitis (MPA) is achieved, patients should receive maintenance therapy con- estimated al 2.7 per million in Europe and lower elsewhere. sisting of rituximab, methotrexate, or azathioprine; rituxi- Average age at onset is 50 to 60 years, with a predilection mab appears to be most effective for preventing relapse and for men over women (1.8:1). Compared with GPA, ANCAs are is preferred. It remains unclear whether suppressive mainte- Iess prevalent (507, 75'X,) and usually directed against nance therapy can be fully withdrawn because relapse in myeloperoxidase. 84

Systemic Vasculitis Clinical Manifestations ond Diognosis The typical patient with EGPA has a prodromal history of difficult-to-treat asthma (96% 7oo'k), rhinitis, and/or atopy. A phase with increased peripheral and tissue eosinophilia follows, with migratory pulmonary infiltrates and, Iess com- monly, endomyocardial infiltration and gastrointestinal disease. The subsequent acute vasculitic phase includes mononeuritis multiplex or peripheral sensorimotor neuropathy (70'X,), kidney involvement (2s'2,), and skin involvement (60'l,,). The vasculitis phase is often associated with improvement of asthma. See Table 41 for the clinical features of EGPA. Laboratory findings show peripheral eosinophiiia of more than 10'1,, or more than 1500/pL (1.5 x 10e/L). Only about 407, to 60'l. of patients have a positive ANCA result, mostly directed against myeloperoxidase. Diagnosis is based on typical clinical findings, eosino philia, and biopsy specimens demonstrating fibrinoid necrosis and eosinophilic infiltration of vessel walls, as well as extravas cular granuloma formation.

Clinical Manifestations ond Diognosis The typical patient with EGPA has a prodromal history of difficult-to-treat asthma (96% 7oo'k), rhinitis, and/or atopy. A phase with increased peripheral and tissue eosinophilia follows, with migratory pulmonary infiltrates and, Iess com- monly, endomyocardial infiltration and gastrointestinal disease. The subsequent acute vasculitic phase includes mononeuritis multiplex or peripheral sensorimotor neuropathy (70'X,), kidney involvement (2s'2,), and skin involvement (60'l,,). The vasculitis phase is often associated with improvement of asthma. See Table 41 for the clinical features of EGPA. Laboratory findings show peripheral eosinophiiia of more than 10'1,, or more than 1500/pL (1.5 x 10e/L). Only about 407, to 60'l. of patients have a positive ANCA result, mostly directed against myeloperoxidase. Diagnosis is based on typical clinical findings, eosino philia, and biopsy specimens demonstrating fibrinoid necrosis and eosinophilic infiltration of vessel walls, as well as extravas cular granuloma formation. Management In EGPA, glucocorticoids alone may be sufficient for mild disease without major organ involvement. With kidney, gastrointestinal, cardiac, or neurologic involvement, cyclophos phamide had been indicated in the past. However, mepoli zumab, a monoclonal antibody that binds interleukin 5, has been FDA approved for EGPA and has a more favorable safety FIGU RE 5 5. Small-vessel vasculitis manifesting as palpable purpura and profi le than cyclophosphamide. petech iae. I\4ortality for EGPA is the lowest among all forms of ANCA associated vasculitis. The S-year survival is 977,, and Clinical Manifestations ond Dicgnosis the relapse rate is 2B%. If not treated early, neuropathy may Like GPA, MPA characteristically affects the lungs and kid- become permanent. neys, along with other organ systems. In contrast to GPA, I( EY PO I ilTS MPA tends to spare the upper airways, and lung involve ment is not granulomatous on biopsy. See Table 41 for the . Granulomatosis with po$angiitis affects the upper and clinical f'eatures of MPA. Diagnosis is suspected on the basis Iower airways, kidneys, eyes, skin, and peripheral nerves; of typical clinical findings and positivity for myeloperoxi induction of remission in severe organ threatening or dase ANCA, although negativity for ANCA does not rule out life threatening disease consists ofhigh dose glucocor the diagnosis. The diagnostic gold standard is a biopsy ticoids rituximab (pref'erred) or cyclophosphamide. specimen demonstrating necrotizing pauci-immune vas r l\4icroscopic polyangiitis characteristically affects the culitis of small vessels in any afl'ected tissue or pauci- lungs and kidneys; treatment is the same as that for immune necrotizing crescentic glomerulonephritis in the granulomatosis with polyangiitis. kidney. Absence of granulomas distinguishes MPA from . Eosinophilic granulomatosis with polyangiitis is associ- GPA. ated with asthma, rhinitis, sinusitis, atopy, peripheral and tissue eosinophilia, migratory pulmonary infil Management trates, and mononeuritis multiplex or peripheral senso Treatment of MPA is similar to that of GPA. rimotor neuropathy; treatment consists of glucocorti- coids for mild disease, with mepolizumab or Eosinophilic Granulomatosis With Polyangiitis cyclophosphamide added for more severe disease. Ep id e mi olo gU ond P atho phy s io lo gy Eosinophilic granulomatosis with polyangiitis (EGPA) is the rarest ANCA associated vascuiitis. with an annual lmmune Complex-Mediated Vasculitis incidence of 0.11 to 2.66 per million. Eosinophil infiltra Immune complexes develop from cross linking of multiple tion, activation, and degranulation participate in disease antigens and antibodies. Immune complexes can deposit pathogenesis. in small vessels, Ieading to complement and neutrophil

Management In EGPA, glucocorticoids alone may be sufficient for mild disease without major organ involvement. With kidney, gastrointestinal, cardiac, or neurologic involvement, cyclophos phamide had been indicated in the past. However, mepoli zumab, a monoclonal antibody that binds interleukin 5, has been FDA approved for EGPA and has a more favorable safety FIGU RE 5 5. Small-vessel vasculitis manifesting as palpable purpura and profi le than cyclophosphamide. petech iae. I\4ortality for EGPA is the lowest among all forms of ANCA associated vasculitis. The S-year survival is 977,, and Clinical Manifestations ond Dicgnosis the relapse rate is 2B%. If not treated early, neuropathy may Like GPA, MPA characteristically affects the lungs and kid- become permanent. neys, along with other organ systems. In contrast to GPA, I( EY PO I ilTS MPA tends to spare the upper airways, and lung involve ment is not granulomatous on biopsy. See Table 41 for the . Granulomatosis with po$angiitis affects the upper and clinical f'eatures of MPA. Diagnosis is suspected on the basis Iower airways, kidneys, eyes, skin, and peripheral nerves; of typical clinical findings and positivity for myeloperoxi induction of remission in severe organ threatening or dase ANCA, although negativity for ANCA does not rule out life threatening disease consists ofhigh dose glucocor the diagnosis. The diagnostic gold standard is a biopsy ticoids rituximab (pref'erred) or cyclophosphamide. specimen demonstrating necrotizing pauci-immune vas r l\4icroscopic polyangiitis characteristically affects the culitis of small vessels in any afl'ected tissue or pauci- lungs and kidneys; treatment is the same as that for immune necrotizing crescentic glomerulonephritis in the granulomatosis with polyangiitis. kidney. Absence of granulomas distinguishes MPA from . Eosinophilic granulomatosis with polyangiitis is associ- GPA. ated with asthma, rhinitis, sinusitis, atopy, peripheral and tissue eosinophilia, migratory pulmonary infil Management trates, and mononeuritis multiplex or peripheral senso Treatment of MPA is similar to that of GPA. rimotor neuropathy; treatment consists of glucocorti- coids for mild disease, with mepolizumab or Eosinophilic Granulomatosis With Polyangiitis cyclophosphamide added for more severe disease. Ep id e mi olo gU ond P atho phy s io lo gy Eosinophilic granulomatosis with polyangiitis (EGPA) is the rarest ANCA associated vascuiitis. with an annual lmmune Complex-Mediated Vasculitis incidence of 0.11 to 2.66 per million. Eosinophil infiltra Immune complexes develop from cross linking of multiple tion, activation, and degranulation participate in disease antigens and antibodies. Immune complexes can deposit pathogenesis. in small vessels, Ieading to complement and neutrophil 85

Systemic Vasculitis activation, with consequent inflammation and tissue Clinical Monifestations and Diognosis damage. Although any tissue or organ may be affected, the Cutaneous symptoms (palpable purpura, digital ischemia, classic finding is invariably in the skin. Inflammation and ulcers, necrosis, and livedo reticularis) are seen in about 90% erythrocyte extravasation from damaged vessels result in of patients. Other common manifestations include peripheral nonblanching palpable purpura, usually in dependent areas neuropathy, arthralgia without arthritis, and glomerulone- (Figure s6). The various immune complex mediated vascu- phritis (usually membranoproliferative). Pulmonary and/or litides are distinguished by the antigen that drives them, the gastrointestinal involvement is rare. Testing for cryoglobulins class of antibody generated, and differences in clinical requires that a sample of blood be maintained at 37.0 "C presentations. (98.6 'F) until clotting is complete to avoid incorporation of the cryoglobulins into the clot. In addition to detection of Cryoglobulinemic Vasculitis cryoglobulins, laboratory abnormalities frequently include Cryoglobulins cause an immune complex mediated small depressed C4 complement and low CH50 levels. Patients vessel vasculitis primarily affecting the skin, peripheral nerv- with type II and type III cryoglobulinemia have positivity for ous system, and kidneys. CNS involvement may rarely occur. rheumatoid factor. A false-negative cryoglobulin result is not There are three types of cryoglobulins. Type I occurs as a unusual given the complexity of cryoglobulin testing. consequence of malignant monoclonal gammopathies and B-cell lymphoma. Types II and III are polyclonal and "mixed" Management in nature. Each is formed from the interaction of antigen Treatment of cryoglobulinemia requires first addressing the targeted antibodies with rheumatoid factor; tlpe II cryoglobu- cause of the disease, such as instituting antiviral therapy for lins include a monoclonal IgM rheumatoid factor, whereas in hepatitis C virus related cryoglobulinemia. When the conse type III cryoglobulins the rheumatoid lactor is a polyclonal IgM. quences of the cryoglobulinemia are severe (e.g., glomerulo The ability olrheumatoid factor to directly bind other antibod nephritis, ulcerating cutaneous lesions, digital gangrene), the ies facilitates the formation of immune complexes even in the vasculitis itself must also be treated. Glucocorticoids and absence of persistent antigen. In addition to their ability to rituximab in combination are the standard first line therapy. form immune complexes, all cryoglobulins demonstrate the unique feature of precipitating in the cold. See MKSAP 19 IgA Vasculitis Hematologz for details on type I cryoglobulins and the differ- See MKSAP 19 Nephrologr for information on IgA nephropa entiation of cryoglobulinemia from cold agglutinin disease. thy and on kidney involvement in IgA vasculitis.

activation, with consequent inflammation and tissue Clinical Monifestations and Diognosis damage. Although any tissue or organ may be affected, the Cutaneous symptoms (palpable purpura, digital ischemia, classic finding is invariably in the skin. Inflammation and ulcers, necrosis, and livedo reticularis) are seen in about 90% erythrocyte extravasation from damaged vessels result in of patients. Other common manifestations include peripheral nonblanching palpable purpura, usually in dependent areas neuropathy, arthralgia without arthritis, and glomerulone- (Figure s6). The various immune complex mediated vascu- phritis (usually membranoproliferative). Pulmonary and/or litides are distinguished by the antigen that drives them, the gastrointestinal involvement is rare. Testing for cryoglobulins class of antibody generated, and differences in clinical requires that a sample of blood be maintained at 37.0 "C presentations. (98.6 'F) until clotting is complete to avoid incorporation of the cryoglobulins into the clot. In addition to detection of Cryoglobulinemic Vasculitis cryoglobulins, laboratory abnormalities frequently include Cryoglobulins cause an immune complex mediated small depressed C4 complement and low CH50 levels. Patients vessel vasculitis primarily affecting the skin, peripheral nerv- with type II and type III cryoglobulinemia have positivity for ous system, and kidneys. CNS involvement may rarely occur. rheumatoid factor. A false-negative cryoglobulin result is not There are three types of cryoglobulins. Type I occurs as a unusual given the complexity of cryoglobulin testing. consequence of malignant monoclonal gammopathies and B-cell lymphoma. Types II and III are polyclonal and "mixed" Management in nature. Each is formed from the interaction of antigen Treatment of cryoglobulinemia requires first addressing the targeted antibodies with rheumatoid factor; tlpe II cryoglobu- cause of the disease, such as instituting antiviral therapy for lins include a monoclonal IgM rheumatoid factor, whereas in hepatitis C virus related cryoglobulinemia. When the conse type III cryoglobulins the rheumatoid lactor is a polyclonal IgM. quences of the cryoglobulinemia are severe (e.g., glomerulo The ability olrheumatoid factor to directly bind other antibod nephritis, ulcerating cutaneous lesions, digital gangrene), the ies facilitates the formation of immune complexes even in the vasculitis itself must also be treated. Glucocorticoids and absence of persistent antigen. In addition to their ability to rituximab in combination are the standard first line therapy. form immune complexes, all cryoglobulins demonstrate the unique feature of precipitating in the cold. See MKSAP 19 IgA Vasculitis Hematologz for details on type I cryoglobulins and the differ- See MKSAP 19 Nephrologr for information on IgA nephropa entiation of cryoglobulinemia from cold agglutinin disease. thy and on kidney involvement in IgA vasculitis. Epi demiolo gA a nd P athophy s iol ogy Ep ide miologA and Potho phy s iology Mixed cryoglobulinemia, which accounts for 75% to 90'l" of all IgA vasculitis (Henoch-Schonlein purpura) is a common vas cases of cryoglobulinemic vasculitis, is rare, with an estimated culitis of childhood that rarely occurs in adults. Estimated prevalence of 1in 100,000. About two thirds of mixed cryoglo annual incidence in adults is 14 per million. Onset is usually bulinemia (type II and type III) cases are related to hepatitis C preceded by upper respiratory tract infection, often with virus infection. Autoimmune diseases, such as systemic lupus streptococcal bacteria. erythematosus and Sjdgren syndrome, more typically cause type I I I cryoglobulinemia. Clinical Manifestations o nd Diognosis Patients with IgA vasculitis typically present with palpable purpura in dependent areas. Other common findings include abdominal pain or gastrointestinal bleeding (50'1,), arthritis and arthralgia (oo%), and glomerulonephritis. Although pro- gressive renal damage may occur, 90% of adults with kidney involvement fully recover. There are no specific laboratory tests for diagnosis. Diagnosis is confirmed by demonstrating IgA tissue deposi tion, generally in the skin, by immunofluorescent microscopy. Skin biopsy demonstrates leukocy.toclastic vasculitis with healy deposits of IgA and complement on immunofluorescent staining. Although rarely necessary renal histolory shows IgA deposition within the mesangium.

Epi demiolo gA a nd P athophy s iol ogy Ep ide miologA and Potho phy s iology Mixed cryoglobulinemia, which accounts for 75% to 90'l" of all IgA vasculitis (Henoch-Schonlein purpura) is a common vas cases of cryoglobulinemic vasculitis, is rare, with an estimated culitis of childhood that rarely occurs in adults. Estimated prevalence of 1in 100,000. About two thirds of mixed cryoglo annual incidence in adults is 14 per million. Onset is usually bulinemia (type II and type III) cases are related to hepatitis C preceded by upper respiratory tract infection, often with virus infection. Autoimmune diseases, such as systemic lupus streptococcal bacteria. erythematosus and Sjdgren syndrome, more typically cause type I I I cryoglobulinemia. Clinical Manifestations o nd Diognosis Patients with IgA vasculitis typically present with palpable purpura in dependent areas. Other common findings include abdominal pain or gastrointestinal bleeding (50'1,), arthritis and arthralgia (oo%), and glomerulonephritis. Although pro- gressive renal damage may occur, 90% of adults with kidney involvement fully recover. There are no specific laboratory tests for diagnosis. Diagnosis is confirmed by demonstrating IgA tissue deposi tion, generally in the skin, by immunofluorescent microscopy. Skin biopsy demonstrates leukocy.toclastic vasculitis with healy deposits of IgA and complement on immunofluorescent staining. Although rarely necessary renal histolory shows IgA deposition within the mesangium. F IG U R E 5 6. Palpable purpura is the classic rash of any small-vessel, immune Management complex-mediated vasculitis. The Iesions are nonblanching and represent extravasations of blood from damaged vessels. Purpuric lesions are typically more Although IgA vasculitis in children tends to be self-limited, prominent 0n the lower exlremities, a consequence of the superimposed eflect of adults are more likely to develop persistent nephropathy and gravity on hydrostatic pressure. may require glucocorticoids. Despite lack of evidence, some

F IG U R E 5 6. Palpable purpura is the classic rash of any small-vessel, immune Management complex-mediated vasculitis. The Iesions are nonblanching and represent extravasations of blood from damaged vessels. Purpuric lesions are typically more Although IgA vasculitis in children tends to be self-limited, prominent 0n the lower exlremities, a consequence of the superimposed eflect of adults are more likely to develop persistent nephropathy and gravity on hydrostatic pressure. may require glucocorticoids. Despite lack of evidence, some 86

Other Rheumatologic Diseases patients may require additional immunosuppression (cyclo- Mediterranean. Prevalence is highest in Turkey (20-600/ phosphamide or rituximab). 100,000). Outside of endemic areas, Behqet syndrome tends to be less severe. The main genetic risk factor is the Hypersensitivity Vasculitis major histocompatibility complex I antigen HLA-B51, sup Epidemiology and Pathophg siology porting Behqet syndrome as an autoimmune disease. Hypersensitivity vasculitis is a small vessel vasculitis medi- However, many experts believe that the condition repre ated by immune complex deposition confined to the skin. It sents mixed mechanisms involving both autoimmunity may be triggered by an antigen, such as a drug or infection; in and autoinflammation. Most patients with Behqet syn- 50'/u of cases, the antigen is unknown. Men and women and drome present with painful oral and/or genital ulcers people of all ages are aflected. (Figure 57). Genital ulcers typically occur on the scrotum and vulva and tend to scar. Clinical Manifestations ond Diognosis Gastrointestinal involvement may be present, making the The most common presentation of hypersensitivity vasculi distinction between Behqet syndrome and Crohn disease dif tis is palpable purpura in dependent regions, often develop ficult. Eye disease includes panuveitis, optic neuritis, and ing 7 to 10 days after exposure to a triggering antigen; Iesions retinal vasculitis. Arthritis and enthesitis may be present. appear in "crops" and resolve over a few weeks after the Cutaneous manifestations include pustular lesions, skin antigen is removed. Internal organs are unaffected. Skin ulcers, and erythema nodosum. Vascular involvement is seen biopsy with immunofluorescence demonstrates leukocyto in both the arterial and venous systems. In the arterial bed, clastic vasculitis without heavy IgA deposits. Evaluation both aneurysms and thrombosis may be seen. The pulmonary should be guided by clinical signs and symptoms and may bed may be affected, and Budd Chiari syndrome can occur. require only a complete blood count, basic chemistries, and The most common form of venous disease is thrombosis. urinalysis. which occurs in the lower extremities but may also occur in the cerebral and cardiac circulations. Central nervous system Management disease may include parenchymal brain involvement, espe Removal of the antigen (if identified) and supportive care are cially in the brainstem. Pyramidal, motor, and behavioral usually sufficient. Resolution within a month is the rule. If changes may occur. symptoms persist or recur, anti-inflammatory agents, topical Diagnosis of Behqet syndrome is based on the presence of or low dose systemic glucocorticoids, colchicine, or dapsone the characteristic signs and symptoms (Table 42). The pres- may be helpful. ence of patherry-accumulation of a pustular neutrophilic infiltrate after disruption of the skin with a sterile needle XEY POIXTS strongly suggests Behget syndrome (Figure 58). However, o Mixed cryoglobulinemia is associated with cutaneous results of pathergz tests are often negative, particular\ in symptoms, peripheral neuropathy, arthralgia without nonendemic areas. lmaging may define typical, but nonpath- arthritis, and glomerulonephritis, with two thirds of ognomonic, patterns of vascular involvement. cases related to hepatitis C virus infection. Management involves selecting agents appropriate to the o IgA vasculitis (Henoch-Sch6nlein purpura) is character- type and severity of clinical involvement. For oral ulcers, both ized by palpable purpura and abdominal pain or gastro topical and systemic glucocorticoids may be used. Apremilast, intestinal bleeding and occurs mainly in children. a phosphodiesterase 4 inhibitor, is FDA approved for oral I o The most common presentation of hypersensitivity vas- culitis is palpable purpura, developing 7 to 10 days after exposure to a triggering antigen.

patients may require additional immunosuppression (cyclo- Mediterranean. Prevalence is highest in Turkey (20-600/ phosphamide or rituximab). 100,000). Outside of endemic areas, Behqet syndrome tends to be less severe. The main genetic risk factor is the Hypersensitivity Vasculitis major histocompatibility complex I antigen HLA-B51, sup Epidemiology and Pathophg siology porting Behqet syndrome as an autoimmune disease. Hypersensitivity vasculitis is a small vessel vasculitis medi- However, many experts believe that the condition repre ated by immune complex deposition confined to the skin. It sents mixed mechanisms involving both autoimmunity may be triggered by an antigen, such as a drug or infection; in and autoinflammation. Most patients with Behqet syn- 50'/u of cases, the antigen is unknown. Men and women and drome present with painful oral and/or genital ulcers people of all ages are aflected. (Figure 57). Genital ulcers typically occur on the scrotum and vulva and tend to scar. Clinical Manifestations ond Diognosis Gastrointestinal involvement may be present, making the The most common presentation of hypersensitivity vasculi distinction between Behqet syndrome and Crohn disease dif tis is palpable purpura in dependent regions, often develop ficult. Eye disease includes panuveitis, optic neuritis, and ing 7 to 10 days after exposure to a triggering antigen; Iesions retinal vasculitis. Arthritis and enthesitis may be present. appear in "crops" and resolve over a few weeks after the Cutaneous manifestations include pustular lesions, skin antigen is removed. Internal organs are unaffected. Skin ulcers, and erythema nodosum. Vascular involvement is seen biopsy with immunofluorescence demonstrates leukocyto in both the arterial and venous systems. In the arterial bed, clastic vasculitis without heavy IgA deposits. Evaluation both aneurysms and thrombosis may be seen. The pulmonary should be guided by clinical signs and symptoms and may bed may be affected, and Budd Chiari syndrome can occur. require only a complete blood count, basic chemistries, and The most common form of venous disease is thrombosis. urinalysis. which occurs in the lower extremities but may also occur in the cerebral and cardiac circulations. Central nervous system Management disease may include parenchymal brain involvement, espe Removal of the antigen (if identified) and supportive care are cially in the brainstem. Pyramidal, motor, and behavioral usually sufficient. Resolution within a month is the rule. If changes may occur. symptoms persist or recur, anti-inflammatory agents, topical Diagnosis of Behqet syndrome is based on the presence of or low dose systemic glucocorticoids, colchicine, or dapsone the characteristic signs and symptoms (Table 42). The pres- may be helpful. ence of patherry-accumulation of a pustular neutrophilic infiltrate after disruption of the skin with a sterile needle XEY POIXTS strongly suggests Behget syndrome (Figure 58). However, o Mixed cryoglobulinemia is associated with cutaneous results of pathergz tests are often negative, particular\ in symptoms, peripheral neuropathy, arthralgia without nonendemic areas. lmaging may define typical, but nonpath- arthritis, and glomerulonephritis, with two thirds of ognomonic, patterns of vascular involvement. cases related to hepatitis C virus infection. Management involves selecting agents appropriate to the o IgA vasculitis (Henoch-Sch6nlein purpura) is character- type and severity of clinical involvement. For oral ulcers, both ized by palpable purpura and abdominal pain or gastro topical and systemic glucocorticoids may be used. Apremilast, intestinal bleeding and occurs mainly in children. a phosphodiesterase 4 inhibitor, is FDA approved for oral I o The most common presentation of hypersensitivity vas- culitis is palpable purpura, developing 7 to 10 days after exposure to a triggering antigen. L Other Rheumatologic Diseases Behget Syndrome i Behqet syndrome, a systemic vasculitis, consists of a constel- lation of characteristic signs and symptoms, including oral and genital ulcers and inflammatory eye disease. Less com- mon but more ominous features include vascular and central FIGURE 57. Recurrent,painful genital mucosal ulcerationsareacharacteristic nervous system disease. Epidemiologr varies widely; endemic clinical leature of BehEet syndrome. ln women, they typically appear on the vulva, areas are along the historic Silk Route from East Asia to the as shown, and may heal with disfiguring scarring.

L Other Rheumatologic Diseases Behget Syndrome i Behqet syndrome, a systemic vasculitis, consists of a constel- lation of characteristic signs and symptoms, including oral and genital ulcers and inflammatory eye disease. Less com- mon but more ominous features include vascular and central FIGURE 57. Recurrent,painful genital mucosal ulcerationsareacharacteristic nervous system disease. Epidemiologr varies widely; endemic clinical leature of BehEet syndrome. ln women, they typically appear on the vulva, areas are along the historic Silk Route from East Asia to the as shown, and may heal with disfiguring scarring. 87