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Systemic Sclerosis TABLE 28. American College of Rheumatology/European League Against Rheumatism Classification Criteria for Systemic Sclerosis Manifestation Add:tional Manifestations WeighVScore" Skin thickening of fingers of both hands extending I proximalto the MCPs Skin thickening of the fingers (count higher score Puffy fingers 2 only) Sclerodactyly of fingers distal to the MCPs but proximal to PlPs 4 Fingertip lesions Digitaltip ulcers 2 Fingertip pitting scars 3 Tela ngiectasia 2 Abnormal nailfold capillaries 2 Pu lmonary hypertension and/or interstitial lung Pulmonary hypertension 2 disease (maximum score is 2) lnterstitial lung disease 2 Raynaud phenomenon 3 SSc-related autoantibodies (maximum score is 3) Anticentromere ) Anti-Scl-70 (antitopoisomerase-1 ) 3

SSc-related autoantibodies (maximum score is 3) Anticentromere ) Anti-Scl-70 (antitopoisomerase-1 ) 3 Anti-RNA polymerase lll 3 MCP = metacarpophalangeal; PIP = proximal interpha angeal; SSc = systemic sclerosis. uThe total score is determined by adding the maximum weight (score) in each category- A score of 9 or more equates to definite systemic sclerosrs. From van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 201 3 classification criteria for systemic sclerosis: an American College of Rheumatology/ European League Against Rheumatism Collaborative lnitiative. Ann Rheum Dis 201 3;72: T 747-55. doi:1 0.1 1 36/ann rheumdis-20 1 3-204424. IP MID: 240926821 Copyright 201 3, American College of Rheumatology. Adapted with permission from BMJ Publishing Group Ltd.

From van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 201 3 classification criteria for systemic sclerosis: an American College of Rheumatology/ European League Against Rheumatism Collaborative lnitiative. Ann Rheum Dis 201 3;72: T 747-55. doi:1 0.1 1 36/ann rheumdis-20 1 3-204424. IP MID: 240926821 Copyright 201 3, American College of Rheumatology. Adapted with permission from BMJ Publishing Group Ltd. (LcSSc), diffuse cutaneous systemic sclerosis (DcSSc), and Cl inica I Ma nifestations systemic sclerosis sine scleroderma (internal organ involve- ment only). Specific long term complications may be more and Diagnosis likely in one subtype than another; however, overlap is com The diagnosis of SSc depends on the presence of specific clini mon. LcSSc, formerly known as the CREST syndrome, is less cal findings and autoantibodies, which are present in 90'l, to commonly accompanied by fibrosis of internal organs than is 95"1, of patients (Table 30). DcSSc but is more commonly associated with pulmonary arte- rial hypertension. Patients with LcSSc have manifestations Cutaneous lnvolvement that can include calcinosis, Raynaud phenomenon, esopha The skin is the organ most commonly involved in SSc, with the geal dysmotility, sclerodactyly, and telangiectasia (CREST); all hands being universally affected. In LcSSc, the skin over the five conditions may not be present. fingers/hands, face, and neck is typically affected. In DcSSc, Various disorders may present with skin thickening and skin involvement is more extensive and additionallv includes other manifestations that overlap with SSc findings; these the upper arms, trunk, and lower extremities. conditions should be considered in the differential diagnosis of The earliest skin manifestations in DcSSc are often dif SSc (Table 29). These conditions are not typically associated fusely swollen fingers/hands. This will later give way to thick with Raynaud phenomenon, and the absence of Raynaud phe- ened, bound down, atrophic skin. Skin thickening in LcSSc nomenon in a patient with skin thickening makes SSc unlikely. may be more subtle than in DcSSc, and the inability to tent the skin over the fingers (sclerodactyly) may be an important clue. t(EY port{Ts The skin changes can lead to joint contractures (Figure 39). . Systemic sclerosis is a multiorgan disease characterized Small mat-like telangiectasias are common in LcSSc and occa by fibrosis and vasculopathy; the skin is the principal sionally occur in DcSSc. They are found on the hands and face target, and Raynaud phenomenon is one ofthe earliest and can also be seen on the oral mucosal side of the lips. They manifestations. blanch with light pressure. Poikiloderma can occur in areas of . Systemic sclerosis is divided into three subtypes based fibrosis and consists of areas of hyperpigmentation mixed on the extent of skin involvement: limited cutaneous with hypopigmentation that give the skin a salt-and pepper systemic sclerosis, diffuse cutaneous systemic sclerosis, appearance. Facial skin involvement can lead to limitation of and systemic sclerosis sine scleroderma. the oral aperture and difficulty eating. In addition, the face is o The absence of Raynaud phenomenon in a patient with typically devoid of wrinkles. Calcinosis occurs in approximately 25% of patients with skin thickening makes systemic sclerosis unlikely. SSc, typically in the hands, forearms, elbows, gluteal region,

(LcSSc), diffuse cutaneous systemic sclerosis (DcSSc), and Cl inica I Ma nifestations systemic sclerosis sine scleroderma (internal organ involve- ment only). Specific long term complications may be more and Diagnosis likely in one subtype than another; however, overlap is com The diagnosis of SSc depends on the presence of specific clini mon. LcSSc, formerly known as the CREST syndrome, is less cal findings and autoantibodies, which are present in 90'l, to commonly accompanied by fibrosis of internal organs than is 95"1, of patients (Table 30). DcSSc but is more commonly associated with pulmonary arte- rial hypertension. Patients with LcSSc have manifestations Cutaneous lnvolvement that can include calcinosis, Raynaud phenomenon, esopha The skin is the organ most commonly involved in SSc, with the geal dysmotility, sclerodactyly, and telangiectasia (CREST); all hands being universally affected. In LcSSc, the skin over the five conditions may not be present. fingers/hands, face, and neck is typically affected. In DcSSc, Various disorders may present with skin thickening and skin involvement is more extensive and additionallv includes other manifestations that overlap with SSc findings; these the upper arms, trunk, and lower extremities. conditions should be considered in the differential diagnosis of The earliest skin manifestations in DcSSc are often dif SSc (Table 29). These conditions are not typically associated fusely swollen fingers/hands. This will later give way to thick with Raynaud phenomenon, and the absence of Raynaud phe- ened, bound down, atrophic skin. Skin thickening in LcSSc nomenon in a patient with skin thickening makes SSc unlikely. may be more subtle than in DcSSc, and the inability to tent the skin over the fingers (sclerodactyly) may be an important clue. t(EY port{Ts The skin changes can lead to joint contractures (Figure 39). . Systemic sclerosis is a multiorgan disease characterized Small mat-like telangiectasias are common in LcSSc and occa by fibrosis and vasculopathy; the skin is the principal sionally occur in DcSSc. They are found on the hands and face target, and Raynaud phenomenon is one ofthe earliest and can also be seen on the oral mucosal side of the lips. They manifestations. blanch with light pressure. Poikiloderma can occur in areas of . Systemic sclerosis is divided into three subtypes based fibrosis and consists of areas of hyperpigmentation mixed on the extent of skin involvement: limited cutaneous with hypopigmentation that give the skin a salt-and pepper systemic sclerosis, diffuse cutaneous systemic sclerosis, appearance. Facial skin involvement can lead to limitation of and systemic sclerosis sine scleroderma. the oral aperture and difficulty eating. In addition, the face is o The absence of Raynaud phenomenon in a patient with typically devoid of wrinkles. Calcinosis occurs in approximately 25% of patients with skin thickening makes systemic sclerosis unlikely. SSc, typically in the hands, forearms, elbows, gluteal region, 50

l L Systemic Sclerosis I ; TABLE 29. Common Manifestations/Features of Scleroderma Spectrum Disorders Disorder Ma nifestation/Feature Comments Systemic Sclerosis t Diffuse cutaneous Distal and proximal skin thickening (face, chest, Skin involvement is extensive and is commonly systemic sclerosis abdomen; proximalto elbows and knees); commonly accompanied by internal organ fibrosis and ILD l (DcSSc) has visceral organ involvement Limited cutaneous Distal (face, neck, hands, feet), but not proximal, skin More likely to develop PAH and Raynaud systemic sclerosis thickening; typically not accompanied by internal phenomenon early in the disease and frequently (LcSSc) organ fibrosis develop calcinosis cutis, telangiectasia, and esophageal dysmotility i, Systemic sclerosis Fibrosing organ involvement without skin thickening Difficult to diagnose; prognosis may be similar to sine scleroderma LcSSc t Localized Scleroderma Morphea Focal plaques of skin thickening, generally on the Systemic manifestations or Raynaud phenomenon is trunk extremely rare Linear scleroderma Streaks/lines of thickened skin Same as morphea

Localized Scleroderma Morphea Focal plaques of skin thickening, generally on the Systemic manifestations or Raynaud phenomenon is trunk extremely rare Linear scleroderma Streaks/lines of thickened skin Same as morphea Scleroderma-like Conditions" Eosinophilic fasciitis Orange peel induration (peau d'orange) of proximal Full-thickness skin biopsy demonstrates lymphocytes, extremities with sparing o{ hands and face; peripheral plasma cells, and eosinophils infiltrating the deep eosinophilia; skin retraction overthe superficial veins fascia; glucocorticoids are mainstay of treatment may be more apparent with elevation of an affected limb Nephrogenic Secondary to gadolinium in patients with kidney Skeletal muscle fibrosis with contractures and/or systemic fibrosis disease; brawny, wood-like induration of extremities, cardiac muscle involvement can occur, with sparing the digits cardiomyopathy and increased mortality; changes in use and formulation of gadolinium have reduced incidence Scleredema lndurated plaques/patches on back, shoulder girdle, Typically seen in long-standing diabetes mellitus and neck Scleromyxedema Waxy, yellow-red papules overthickened skin of face, Associated with paraproteinemia (lgG)") and may upper trunk, neck, and arms; deposition of mucin with therefore occur in the setting of multiple myeloma or large numbers of stellate fibroblasts in the dermis AL amyloidosis; more frequent in men

Scleroderma-like Conditions" Eosinophilic fasciitis Orange peel induration (peau d'orange) of proximal Full-thickness skin biopsy demonstrates lymphocytes, extremities with sparing o{ hands and face; peripheral plasma cells, and eosinophils infiltrating the deep eosinophilia; skin retraction overthe superficial veins fascia; glucocorticoids are mainstay of treatment may be more apparent with elevation of an affected limb Nephrogenic Secondary to gadolinium in patients with kidney Skeletal muscle fibrosis with contractures and/or systemic fibrosis disease; brawny, wood-like induration of extremities, cardiac muscle involvement can occur, with sparing the digits cardiomyopathy and increased mortality; changes in use and formulation of gadolinium have reduced incidence Scleredema lndurated plaques/patches on back, shoulder girdle, Typically seen in long-standing diabetes mellitus and neck Scleromyxedema Waxy, yellow-red papules overthickened skin of face, Associated with paraproteinemia (lgG)") and may upper trunk, neck, and arms; deposition of mucin with therefore occur in the setting of multiple myeloma or large numbers of stellate fibroblasts in the dermis AL amyloidosis; more frequent in men Chronic graft-versus- Lichen planus-like skin lesions, or localized or Occurs most commonly after hematopoietic stem cell host disease generalized skin thickening transplantation; may occasionally be seen after blood transfusion in immunocompromised host Drug and toxin Can produce scleroderma-like tissue changes Examples: bleomycin, docetaxel, pentazocine, exposure L-tryptophan, organic solvents

Chronic graft-versus- Lichen planus-like skin lesions, or localized or Occurs most commonly after hematopoietic stem cell host disease generalized skin thickening transplantation; may occasionally be seen after blood transfusion in immunocompromised host Drug and toxin Can produce scleroderma-like tissue changes Examples: bleomycin, docetaxel, pentazocine, exposure L-tryptophan, organic solvents ILD = interstitial lung disease; PAH = pulmonary arterial hypertension. oScieroderma-like skin changes may also be a manifestation of systemic endocrine, kidney, or infiltrative disorders. TABLE 30. Autoantibodies and Their Associations in Systemic Sclerosis Autoantibody MainClinicalAssociations Comments Antinuclear antibodies DcSSc; LcSSc Overall prevalence in SSc, 70oZ; not associated with specific manifestations Anticentromere ( kinetochore proteins) LcSSc with or without PAH Overall prevalence in SSc, <30%; highly associated (>90%) with LcSSc Anti-Scl-70 (DNA topoisomerase-1 ) DcSSc; ILD Overall prevalence in SSc, <30%; highly associated with DcSSc Anti-RNA polymerase lll DcSSc; scleroderma renal crisis Useful in DcSSc with negativity for anti-Scl-70 Anti-U3-RNP (fibrillarin) DcSSc; PAH; myositis Associated with poor outcome; more common in Black men

TABLE 30. Autoantibodies and Their Associations in Systemic Sclerosis Autoantibody MainClinicalAssociations Comments Antinuclear antibodies DcSSc; LcSSc Overall prevalence in SSc, 70oZ; not associated with specific manifestations Anticentromere ( kinetochore proteins) LcSSc with or without PAH Overall prevalence in SSc, <30%; highly associated (>90%) with LcSSc Anti-Scl-70 (DNA topoisomerase-1 ) DcSSc; ILD Overall prevalence in SSc, <30%; highly associated with DcSSc Anti-RNA polymerase lll DcSSc; scleroderma renal crisis Useful in DcSSc with negativity for anti-Scl-70 Anti-U3-RNP (fibrillarin) DcSSc; PAH; myositis Associated with poor outcome; more common in Black men Anti-PM-Scl Myositis Associated with overlap syndrome and polymyositis Anti-Ku Myositis Rare Anti-Th/To LcSSc; PAH Ra re PAH = pulmonary arterial hypertension; DcSSc = diffuse cutaneous systemic sclerosis; ILD - interstitial lung disease; LcSSc = limited cutaneous systemic sclerosis; RNP = ribonucleoprotein; SSc = systemic sclerosis. : 61

Systemic Sclerosis l'2, and 5'X, of patients have a rheumatoid arthritis-SSc over lap. with positivity for anti cyclic citrullinated antibodies and classic rheumatoid arthritis manifestations along with those of SSc. Patients with SSc may develop acro osteolysis. or resorption of the terminal bony tuft of the fingers and, less commonly. the toes; the prevalence is as high as 20'7, to 4O"/, in more severe disease (Figure 41). This manifesta- tion is typically seen in patients with significant distal vascular involvement, including ulceration. ischemia, and calcinosis. Tendon rubs can be felt or heard with a stethoscope because fibrosis affects tendons or tendon sheaths. These occur in about 10'7, ol patients with DcSSc. SSc-associated myositis occurs in 10'1, to 15% of patients. t I G U R E 3 9. Hands of a 35-year-old woman with diffuse cutaneous systemic Myalgia and proximal muscle weakness are common symp sclerosis. Note the shortening of fingers and tight atrophic appearance of the skin toms. Serum creatine kinase and/or serum aldolase levels are This patient is unable to make a full fist. elevated, and electromyogram demonstrates myopathic changes. There is a strong association between SSc-associated and iliac crest (Figure 4O). These deposits can be seen or felt myositis and myocardial involvement. The presence of anti and are easily detected on radiographs. PM Scl antibodies identifies patients with an overlap between polymyositis and SSc. These patients usually have less skin and Musculoskeletal lnvolvement gastrointestinal involvement but have more calcinosis and Joint involvement occurs in 12'2, to 65'7, of patients with SSc; it lung disease. is mainly polyarticular and can be erosive, with hand/wrist predominance. SSc is one of the few forms of inflammatory Vascular lnvolvement arthritis that affects the distal interphalangealjoints. Between Raynaud phenomenon occurs in approximately 95'2, of patients with SSc; it is the most common early manifestation of SSc, typically occurring years before recognizable SSc. Raynaud phenomenon is initially episodic, but with'uascular fibrosis, the blood supply becomes permanently restricted. SSc will develop in approximately 80'7, of patients with the combination of Raynaud phenomenon, an SSc-associated autoantibody, and nailfold capillary changes in an SSc pattern (Figure 42).

l'2, and 5'X, of patients have a rheumatoid arthritis-SSc over lap. with positivity for anti cyclic citrullinated antibodies and classic rheumatoid arthritis manifestations along with those of SSc. Patients with SSc may develop acro osteolysis. or resorption of the terminal bony tuft of the fingers and, less commonly. the toes; the prevalence is as high as 20'7, to 4O"/, in more severe disease (Figure 41). This manifesta- tion is typically seen in patients with significant distal vascular involvement, including ulceration. ischemia, and calcinosis. Tendon rubs can be felt or heard with a stethoscope because fibrosis affects tendons or tendon sheaths. These occur in about 10'7, ol patients with DcSSc. SSc-associated myositis occurs in 10'1, to 15% of patients. t I G U R E 3 9. Hands of a 35-year-old woman with diffuse cutaneous systemic Myalgia and proximal muscle weakness are common symp sclerosis. Note the shortening of fingers and tight atrophic appearance of the skin toms. Serum creatine kinase and/or serum aldolase levels are This patient is unable to make a full fist. elevated, and electromyogram demonstrates myopathic changes. There is a strong association between SSc-associated and iliac crest (Figure 4O). These deposits can be seen or felt myositis and myocardial involvement. The presence of anti and are easily detected on radiographs. PM Scl antibodies identifies patients with an overlap between polymyositis and SSc. These patients usually have less skin and Musculoskeletal lnvolvement gastrointestinal involvement but have more calcinosis and Joint involvement occurs in 12'2, to 65'7, of patients with SSc; it lung disease. is mainly polyarticular and can be erosive, with hand/wrist predominance. SSc is one of the few forms of inflammatory Vascular lnvolvement arthritis that affects the distal interphalangealjoints. Between Raynaud phenomenon occurs in approximately 95'2, of patients with SSc; it is the most common early manifestation of SSc, typically occurring years before recognizable SSc. Raynaud phenomenon is initially episodic, but with'uascular fibrosis, the blood supply becomes permanently restricted. SSc will develop in approximately 80'7, of patients with the combination of Raynaud phenomenon, an SSc-associated autoantibody, and nailfold capillary changes in an SSc pattern (Figure 42). F I G UR E 4 0. Calcinosis seen in limited cutaneous systemic sclerosis.Ihis F I G UR E 4 1 . Posteroanterior radiograph of the hands in a patient with systemic patient has deposits of calcium in the subcutaneous tissues around the elbow. sclerosis and acro-osteolysis. Note the destruction of the distal phalanges, particularly Calcinosis often occurs in the hands and forearms but can also affect other locations, of the first and second digits bilaterally, which will eventually result in clinical such as the trunk or lower extremities. shortening of the affeoed digits.

F I G UR E 4 0. Calcinosis seen in limited cutaneous systemic sclerosis.Ihis F I G UR E 4 1 . Posteroanterior radiograph of the hands in a patient with systemic patient has deposits of calcium in the subcutaneous tissues around the elbow. sclerosis and acro-osteolysis. Note the destruction of the distal phalanges, particularly Calcinosis often occurs in the hands and forearms but can also affect other locations, of the first and second digits bilaterally, which will eventually result in clinical such as the trunk or lower extremities. shortening of the affeoed digits. 62

Systemic Sclerosis Approximately B0% of patients with SSc have involve ment of the lower two thirds (smooth muscle portion) of the esophagus, manifesting primarily as symptoms of dysmotility and/or gastroesophageal reflux disease. Esophageal involve- ment is associated with an increased risk for Barrett esopha gus and adenocarcinoma. A dilated esophagus on chest imaging is a clue to esophageal involvement. Gastric symptoms also result mainly from dysmotility. Patients describe early satiety and may report nausea and vomiting as a result of delayed gastric emptying. Gastric antral vascular ectasia is most common in patients with DcSSc and those with anti RNA polymerase III antibodies. Bleeding ecta sias can cause significant blood loss. Small intestinal bacterial overgrowth is common and can cause malabsorption and diarrhea. The diarrhea is described as explosive and t1pically follows a meal. Diagnosis is established by a hydrogen breath test, although an empiric trial of rotating antibiotics is often used. Small intestine dys motility can result in pseudo-obstruction. Large intestine dysmotility may lead to constipation, and vascular ectasia can occur in the large intestine. Some patients may develop fecal incontinence.

Approximately B0% of patients with SSc have involve ment of the lower two thirds (smooth muscle portion) of the esophagus, manifesting primarily as symptoms of dysmotility and/or gastroesophageal reflux disease. Esophageal involve- ment is associated with an increased risk for Barrett esopha gus and adenocarcinoma. A dilated esophagus on chest imaging is a clue to esophageal involvement. Gastric symptoms also result mainly from dysmotility. Patients describe early satiety and may report nausea and vomiting as a result of delayed gastric emptying. Gastric antral vascular ectasia is most common in patients with DcSSc and those with anti RNA polymerase III antibodies. Bleeding ecta sias can cause significant blood loss. Small intestinal bacterial overgrowth is common and can cause malabsorption and diarrhea. The diarrhea is described as explosive and t1pically follows a meal. Diagnosis is established by a hydrogen breath test, although an empiric trial of rotating antibiotics is often used. Small intestine dys motility can result in pseudo-obstruction. Large intestine dysmotility may lead to constipation, and vascular ectasia can occur in the large intestine. Some patients may develop fecal incontinence. Kidney lnvolvement Scleroderma renal crisis affects 5% of patients with DcSSc and 2% of patients with LcSSc. Scleroderma renal crisis was previ- ously the chiefcause ofdeath in SSc. Risk factors for sclero derma renal crisis include DcSSc, use of glucocorticoids (>z.s mg/d), andthe presence of anti-RNA polymerase III anti- bodies. The more recent lower incidence of scleroderma renal crisis is ascribed to the avoidance ofglucocorticoids in SSc and the use ofcalcium channel blockers, which are renal protec- FIGU RE 4 2 . Capil lary loops n systemic sclerosis. Iop, Early cha nges with loss i

Kidney lnvolvement Scleroderma renal crisis affects 5% of patients with DcSSc and 2% of patients with LcSSc. Scleroderma renal crisis was previ- ously the chiefcause ofdeath in SSc. Risk factors for sclero derma renal crisis include DcSSc, use of glucocorticoids (>z.s mg/d), andthe presence of anti-RNA polymerase III anti- bodies. The more recent lower incidence of scleroderma renal crisis is ascribed to the avoidance ofglucocorticoids in SSc and the use ofcalcium channel blockers, which are renal protec- FIGU RE 4 2 . Capil lary loops n systemic sclerosis. Iop, Early cha nges with loss i of capillary loop density (or drop out) with marked dilatation of the remaining tive, to treat Raynaud phenomenon. capillary loops. Bottom, Late changes with extensive loss of capillary loops. Digital ulcers occur in about 15% of patients with SSc, typically on the extensor surfaces and tips of the fingers (Figure 43) and toes but also on the dorsum of hands and feet and even on the lower extremities. Vascular changes in the extremities may indicate similar involvement of internal organs. Cardiac lnvolvement Myocardial fibrosis is a consequence of microvascular disease and a cause of early death. It results from repetitive ischemia- reperfusion injury of the myocardium. Myocardial involve- ment may lead to heart failure, intraventricular conduction block, and arrhlthmias. Diastolic dysfunction is more com mon than systolic dysfunction, and a right bundle branch block is a predictor of early mortality in SSc.

Cardiac lnvolvement Myocardial fibrosis is a consequence of microvascular disease and a cause of early death. It results from repetitive ischemia- reperfusion injury of the myocardium. Myocardial involve- ment may lead to heart failure, intraventricular conduction block, and arrhlthmias. Diastolic dysfunction is more com mon than systolic dysfunction, and a right bundle branch block is a predictor of early mortality in SSc. Gastrointestina I I nvolvement Symptoms of esophageal dysmotility and reflux are common in all forms of SSc and may offer an early clue to the diagnosis t I G U R E 4 3. Digital pitting (soft'tissue defects and scarring in the pulp space when associated with other symptoms. 0f the di$al phalanges) in a patient with systemic sclerosis. 63

Systemic Sclerosis Scleroderma renal crisis occurs within 4 years of SSc f,tY PotxTs onset in 75'2, of cases. Patients characteristically present with . Raynaud phenomenon is the most common early mani- manifestations of hypertensive emergency, including head- festation of systemic sclerosis. ache, encephalopathy, seizures, and hypertensive retinopathy. Rarely, a normotensive form of scleroderma renal crisis can . The earliest skin manifestations of systemic sclerosis are often diffusely swollen fingers/hands; with time, the skin occur. Risk factors for a poor prognosis include male sex, older becomes thickened, atrophic, and immobile. age, and heart failure. Changes in blood pressure from ambu- latory baseline measurements may alert physicians to an . Symptoms of esophageal dysmotility and reflux are impending renal crisis. common in all forms of systemic sclerosis and may offer Laboratory fi ndings include microangiopathic hemoly'tic an early clue to the diagnosis when associated with anemia, thrombocytopenia, and proteinuria. The serum cre- other symptoms. atinine level is typically elevated and may remain so for some . Patients with scleroderrna renal crisis characteristically time aflter blood pressure is controlled. Abnormalities in the present with manifestations of h)?ertensive emergency. renin angiotensin-aldosterone system and in endothelin 1 o Lung involvement in systemic sclerosis includes pul are thought to contribute to the pathophysiologz. Although monary arterial hypertension and interstitial lung dis- ACE inhibitors have dramatically improved the outcome of ease (lLD); ILD is the main cause of disease-associated patients with scleroderma renal crisis, prophylactic use of mortality. ACE inhibitors may actually worsen scleroderma renal crisis outcomes and is not recommended even in high-risk patients.

Scleroderma renal crisis occurs within 4 years of SSc f,tY PotxTs onset in 75'2, of cases. Patients characteristically present with . Raynaud phenomenon is the most common early mani- manifestations of hypertensive emergency, including head- festation of systemic sclerosis. ache, encephalopathy, seizures, and hypertensive retinopathy. Rarely, a normotensive form of scleroderma renal crisis can . The earliest skin manifestations of systemic sclerosis are often diffusely swollen fingers/hands; with time, the skin occur. Risk factors for a poor prognosis include male sex, older becomes thickened, atrophic, and immobile. age, and heart failure. Changes in blood pressure from ambu- latory baseline measurements may alert physicians to an . Symptoms of esophageal dysmotility and reflux are impending renal crisis. common in all forms of systemic sclerosis and may offer Laboratory fi ndings include microangiopathic hemoly'tic an early clue to the diagnosis when associated with anemia, thrombocytopenia, and proteinuria. The serum cre- other symptoms. atinine level is typically elevated and may remain so for some . Patients with scleroderrna renal crisis characteristically time aflter blood pressure is controlled. Abnormalities in the present with manifestations of h)?ertensive emergency. renin angiotensin-aldosterone system and in endothelin 1 o Lung involvement in systemic sclerosis includes pul are thought to contribute to the pathophysiologz. Although monary arterial hypertension and interstitial lung dis- ACE inhibitors have dramatically improved the outcome of ease (lLD); ILD is the main cause of disease-associated patients with scleroderma renal crisis, prophylactic use of mortality. ACE inhibitors may actually worsen scleroderma renal crisis outcomes and is not recommended even in high-risk patients. Lung lnvolvement Management Lung involvement in SSc includes pleuritis and pleural effu Treatment options for systemic sclerosis are mainly sympto sions, interstitial lung disease (lLD), pulmonary arterial matic and organ system specific. Table 31 outlines treatment hypertension (PAH), bronchiolitis, pulmonary veno occlusive options for manifestations of SSc. disease, respiratory muscle weakness, and skin involvement of ACE inhibitors (typically captopril) can be lifesaving in the trunk that restricts chest wall movement. Patients are also patients with scleroderma renal crisis and should be titrated to at increased risk for lung cancer. control blood pressure. Dialysis may be needed temporarily for Significant ILD occurs in 50'7, of patients with DcSSc (857, scleroderma renal crisis. ACE inhibitor therapy should be con of patients with anti-Scl-70 antibodies) and 35% of patients tinued in scleroderma renal crisis even in the presence of a with LcSSc and is the main cause of disease associated death. rising serum creatinine level and the need for dialysis because In patients with SSc, men are more likely than women to late improvement may occur. The addition of plasma exchange develop ILD, and Black persons tend to have more severe to ACE inhibitors in patients with scleroderma renal crisis and disease than other ethnic groups. The most common high microangiopathic features has been suggested; angiotensin resolution CT pattern is nonspecific interstitial pneumonitis receptor blockers should be considered only when ACE inhibi- followed by usual interstitial pneumonitis. An abnormal FVC tors are not tolerated. early in the disease course (within the first 5 years) is highly The Scleroderma Lung Study ll compared cyclophospha- predictive of the development of more severe disease, as is mide for 1 year versus mycophenolate mofetil over 2 years for fibrosis of more than 20% of lung volume on baseline high- ILD in SSc. With both agents, FVC improved in approximately resolution CT. There is a strong association between ILD and 75"/,, to BO"/,, and FVC worsened in 2O"1, to 25% of patients. In gastroesophageal reflux disease, but whether the latter contrib 7o"/,, of patients in each group (especially those with DcSSc). utes to ILD (through aspiration) is uncertain. All patients should skin scores improved significantly. Mycophenolate was better undergo pulmonary function testing and high resolution CT at tolerated and has become a mainstay of therapy in these the time of initial SSc diagnosis, and pulmonary function test patients. ing with Dlco should be repeated every 6 to 12 months for Nintedanib (a tyrosine kinase inhibitor) significantly 5 years. A 10% decline in FVC or l5'1, decline in DLCo within slowed the decline in lung function among patients with 12 months should raise concern for progression. ILD associated with SSc but did not affect other disease PAH has a prevalence of 10'7, in SSc. Patients with PAH manifestations. The combination of nintedanib plus present with exertional dyspnea. With more advanced disease, mycophenolate resulted in the slowest rate of decline in FVC they may have chest pain and lower extremity edema. Patients per year. with SSc should undergo echocardiography annually. and for Rituximab is a promising agent in SSc. In a controlled trial new or concerning symptoms. Pulmonary function testing comparing rituximab versus cyclophosphamide for ILD asso can provide a clue to underlying PAH; an FVC/Dr-co ratio of 1.6 ciated with SSc, rituximab improved FVC and skin score to a or greater suggests the diagnosis. See MKSAP 19 Pulmonary greater degree than did cyclophosphamide. Autologous hemat- and Critical Care Medicine for further discussion of diagnosis opoietic stem cell transplantation has been studied for several and treatment. years in patients with rapidly progressive, severe SSc; one third

Lung lnvolvement Management Lung involvement in SSc includes pleuritis and pleural effu Treatment options for systemic sclerosis are mainly sympto sions, interstitial lung disease (lLD), pulmonary arterial matic and organ system specific. Table 31 outlines treatment hypertension (PAH), bronchiolitis, pulmonary veno occlusive options for manifestations of SSc. disease, respiratory muscle weakness, and skin involvement of ACE inhibitors (typically captopril) can be lifesaving in the trunk that restricts chest wall movement. Patients are also patients with scleroderma renal crisis and should be titrated to at increased risk for lung cancer. control blood pressure. Dialysis may be needed temporarily for Significant ILD occurs in 50'7, of patients with DcSSc (857, scleroderma renal crisis. ACE inhibitor therapy should be con of patients with anti-Scl-70 antibodies) and 35% of patients tinued in scleroderma renal crisis even in the presence of a with LcSSc and is the main cause of disease associated death. rising serum creatinine level and the need for dialysis because In patients with SSc, men are more likely than women to late improvement may occur. The addition of plasma exchange develop ILD, and Black persons tend to have more severe to ACE inhibitors in patients with scleroderma renal crisis and disease than other ethnic groups. The most common high microangiopathic features has been suggested; angiotensin resolution CT pattern is nonspecific interstitial pneumonitis receptor blockers should be considered only when ACE inhibi- followed by usual interstitial pneumonitis. An abnormal FVC tors are not tolerated. early in the disease course (within the first 5 years) is highly The Scleroderma Lung Study ll compared cyclophospha- predictive of the development of more severe disease, as is mide for 1 year versus mycophenolate mofetil over 2 years for fibrosis of more than 20% of lung volume on baseline high- ILD in SSc. With both agents, FVC improved in approximately resolution CT. There is a strong association between ILD and 75"/,, to BO"/,, and FVC worsened in 2O"1, to 25% of patients. In gastroesophageal reflux disease, but whether the latter contrib 7o"/,, of patients in each group (especially those with DcSSc). utes to ILD (through aspiration) is uncertain. All patients should skin scores improved significantly. Mycophenolate was better undergo pulmonary function testing and high resolution CT at tolerated and has become a mainstay of therapy in these the time of initial SSc diagnosis, and pulmonary function test patients. ing with Dlco should be repeated every 6 to 12 months for Nintedanib (a tyrosine kinase inhibitor) significantly 5 years. A 10% decline in FVC or l5'1, decline in DLCo within slowed the decline in lung function among patients with 12 months should raise concern for progression. ILD associated with SSc but did not affect other disease PAH has a prevalence of 10'7, in SSc. Patients with PAH manifestations. The combination of nintedanib plus present with exertional dyspnea. With more advanced disease, mycophenolate resulted in the slowest rate of decline in FVC they may have chest pain and lower extremity edema. Patients per year. with SSc should undergo echocardiography annually. and for Rituximab is a promising agent in SSc. In a controlled trial new or concerning symptoms. Pulmonary function testing comparing rituximab versus cyclophosphamide for ILD asso can provide a clue to underlying PAH; an FVC/Dr-co ratio of 1.6 ciated with SSc, rituximab improved FVC and skin score to a or greater suggests the diagnosis. See MKSAP 19 Pulmonary greater degree than did cyclophosphamide. Autologous hemat- and Critical Care Medicine for further discussion of diagnosis opoietic stem cell transplantation has been studied for several and treatment. years in patients with rapidly progressive, severe SSc; one third 64

Systemic Sclerosis TABLE 31. Treatment Options for Common Manifestations of Systemic Sclerosis Manifestations Treatment Cutaneous manifestations Methotrexate, mycophenolate, cyclophosphamide, and rituximab have been shown to improve skin For pruritus, antihistamines can be tried; low-dose prednisone can also help but doses >7.5 mg/d should be used with caution because of risk for scleroderma renal crisis. Laser therapy can be used for telangiectasias. Musculoskeletal NSAlDs, intra-articular or low-dose prednisone, hydroxychloroquine, or methotrexate can be used {or ma nifestations a rth ra I g iala rth ritis. Methotrexate, azathioprine, or mycophenolate can be used for significant myositis. Raynaud phenomenon Cold avoidance; gloves; central warmth Calcium channel blockers; sildenafil; losartan; prazosin Topical nitrates; low-dose aspirin Digital sympathectomy for refractory cases Gastroesophageal refl ux Avoid eating close to bedtime; head-of-bed elevation disease H2 blockers; proton pump inhibitors Surgical fundoplication Gastrointesti na I dysmoti ity I Metoclopramide (avoid long-term use); domperidone (investigational limited-access program), erythromycin; cisapride (investigational limited-access program) Gastric antral vascular ectasia Ablation laser therapy Small intestine bacterial Rotating antibiotics; if fat malabsorption, cholestyramine overgrowth Pseud o-obstruction Promotility agent such as domperidone can be tried; if resistant, octreotide may be useful. Constipation Fiber; stool softeners; polyethylene glycol Scleroderma renal crisis ACE inhibitors (typically captopril), plasma exchange Dialysis

Surgical fundoplication Gastrointesti na I dysmoti ity I Metoclopramide (avoid long-term use); domperidone (investigational limited-access program), erythromycin; cisapride (investigational limited-access program) Gastric antral vascular ectasia Ablation laser therapy Small intestine bacterial Rotating antibiotics; if fat malabsorption, cholestyramine overgrowth Pseud o-obstruction Promotility agent such as domperidone can be tried; if resistant, octreotide may be useful. Constipation Fiber; stool softeners; polyethylene glycol Scleroderma renal crisis ACE inhibitors (typically captopril), plasma exchange Dialysis lnterstitial lung disease Mycophenolate mofetil; cyclophosphamide; nintedanib; rituximab; stem cell transplant in rapidly progressive cases Lung transplantation Pulmonary arterial Supplemental oxygen; treat right-sided heart failure hypertension Calcium channel blockers (if positive response to vasoreactivity testing); prostanoids; endothelin receptor antagonists; phosphodiesterase-5 inhibitors; soluble guanylate cyclase stimulator Combination therapy (ambrisentan and tadalafil); lung transplantation

lnterstitial lung disease Mycophenolate mofetil; cyclophosphamide; nintedanib; rituximab; stem cell transplant in rapidly progressive cases Lung transplantation Pulmonary arterial Supplemental oxygen; treat right-sided heart failure hypertension Calcium channel blockers (if positive response to vasoreactivity testing); prostanoids; endothelin receptor antagonists; phosphodiesterase-5 inhibitors; soluble guanylate cyclase stimulator Combination therapy (ambrisentan and tadalafil); lung transplantation to one half of patients had significant improvement in lung weight. A meta-analysis of pregnancies in patients with SSc function, skin thickening, and antibody status. However, suggested that although disease manifestations, including cost and potential toxicity limit the utility of stem cell digital ulcers, may improve, 14'X, of patients may develop new transplantation. manifestations or worsening of current disease during preg- nancy; in another 10'/., disease will worsen in the first r( Ev P0 t 1{Ts 6 months postpartum. Contraindications to pregnancy in . Treatment options for systemic sclerosis are mainly patients with SSc include PAH and severe restrictive lung symptomatic and organ system specific. disease (FVC <1 L). r ACE inhibitors can be lifesaving in patients with sclero- derma renal crisis and should be titrated to control t(EY P0ilaTS blood pressure even in the presence of rising serum . Pregnant patients with systemic sclerosis may experience creatinine. hypertensive disease, preeclampsia, preterm delivery and low birth weight.

to one half of patients had significant improvement in lung weight. A meta-analysis of pregnancies in patients with SSc function, skin thickening, and antibody status. However, suggested that although disease manifestations, including cost and potential toxicity limit the utility of stem cell digital ulcers, may improve, 14'X, of patients may develop new transplantation. manifestations or worsening of current disease during preg- nancy; in another 10'/., disease will worsen in the first r( Ev P0 t 1{Ts 6 months postpartum. Contraindications to pregnancy in . Treatment options for systemic sclerosis are mainly patients with SSc include PAH and severe restrictive lung symptomatic and organ system specific. disease (FVC <1 L). r ACE inhibitors can be lifesaving in patients with sclero- derma renal crisis and should be titrated to control t(EY P0ilaTS blood pressure even in the presence of rising serum . Pregnant patients with systemic sclerosis may experience creatinine. hypertensive disease, preeclampsia, preterm delivery and low birth weight. Pregnancy o Contraindications to pregnancy in patients with systemic sclerosis include pulmonary arterial hypertension and Pregnant patients with SSc may experience hypertensive severe restrictive lung disease. disease, preeclampsia, preterm delivery and low birth 55

\ Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease Mixed Connestive Cli nical Manifestations Tissue Disease and and Diagnosis See Table 32 for details on the clinical manifestations and Undifferentiated diagnosis of MCTD. Raynaud phenomenon and pulmonary involvement are common features; pufff hands and inflam Connective Tissue Disease matory arthritis are also seen. Pulmonary arterial hyperten- Overview sion is the major cause of death; severe kidney and neurologic diseases are uncommon. Although antinuclear antibodies, Most patients with rheumatologic disease have well estab rheumatoid factor, and anti-cyclic citrullinated peptide anti lished and well classified diagnoses. However, given the com bodies are often present, the presence of anti double mon underlying processes of autoimmunity and inflamma- stranded DNA, anti-Smith, or anti-Ro/SSA antibodies makes tion, it is not surprising that some patients have features of primary SLE a more likely diagnosis. more than one rheumatologic disease simultaneously or sequentially (overlap syndromes). Other patients present with signs and symptoms that are autoimmune in nature (often including Raynaud phenomenon) but do not rise to the level of Management a specific rheumatologic condition; such patients have undif- Treatment for MCTD is directed at the specific organ system ferentiated connective tissue disease (UCTD). Mixed connec involved in the individual patient and is guided by the man tive tissue disease (MCTD) is a specific variant of overlap syn- agement of these manifestations as would occur in the "par- drome that includes clinical manifestations meeting a dual or ent" condition (see Table 32). triple diagnosis of systemic lupus erythematosus (SLE), auto- immune myositis, and/or systemic sclerosis. MCTD is associ- ated with positivity for anti Ul-ribonucleoprotein (RNP) Prognosis antibodies. Prognosis of MCTD depends on the spectrum and severity of See Table 32 for a comparison of MCTD and UCTD. organ involvement. Patients with initially mild disease may develop nelv and more severe manifestations over decades, including interstitial lung disease and pulmonary arterial Epidemiology and hypertension. As in patients with other systemic inflamma- Pathophysiology tory disorders, patients with MCTD are at increased risk for MCTD is rare, and B0% of patients are women. B-cell abnor atherosclerotic cardiovascular disease. malities and an association with anti-U1-RNP antibody have UCTD usually remains mild and stable but in a minority been described. The antibody binds to the 70 kD epitope of of patients may evolve into a more specific autoimmune the RNP complex, but its actual role in pathogenesis is not disorder, most commonly SLE. Most patients with UCTD understood. Genetic risk alleles include HLA DRBI-04:01 who develop a more specific disease do so within the first 2 and HLA-B-O8, underlining the autoimmune nature of the to 5 years after presentation. A definite disease is more likely condition. to develop in patients with cytopenias; antibodies to

Mixed Connestive Cli nical Manifestations Tissue Disease and and Diagnosis See Table 32 for details on the clinical manifestations and Undifferentiated diagnosis of MCTD. Raynaud phenomenon and pulmonary involvement are common features; pufff hands and inflam Connective Tissue Disease matory arthritis are also seen. Pulmonary arterial hyperten- Overview sion is the major cause of death; severe kidney and neurologic diseases are uncommon. Although antinuclear antibodies, Most patients with rheumatologic disease have well estab rheumatoid factor, and anti-cyclic citrullinated peptide anti lished and well classified diagnoses. However, given the com bodies are often present, the presence of anti double mon underlying processes of autoimmunity and inflamma- stranded DNA, anti-Smith, or anti-Ro/SSA antibodies makes tion, it is not surprising that some patients have features of primary SLE a more likely diagnosis. more than one rheumatologic disease simultaneously or sequentially (overlap syndromes). Other patients present with signs and symptoms that are autoimmune in nature (often including Raynaud phenomenon) but do not rise to the level of Management a specific rheumatologic condition; such patients have undif- Treatment for MCTD is directed at the specific organ system ferentiated connective tissue disease (UCTD). Mixed connec involved in the individual patient and is guided by the man tive tissue disease (MCTD) is a specific variant of overlap syn- agement of these manifestations as would occur in the "par- drome that includes clinical manifestations meeting a dual or ent" condition (see Table 32). triple diagnosis of systemic lupus erythematosus (SLE), auto- immune myositis, and/or systemic sclerosis. MCTD is associ- ated with positivity for anti Ul-ribonucleoprotein (RNP) Prognosis antibodies. Prognosis of MCTD depends on the spectrum and severity of See Table 32 for a comparison of MCTD and UCTD. organ involvement. Patients with initially mild disease may develop nelv and more severe manifestations over decades, including interstitial lung disease and pulmonary arterial Epidemiology and hypertension. As in patients with other systemic inflamma- Pathophysiology tory disorders, patients with MCTD are at increased risk for MCTD is rare, and B0% of patients are women. B-cell abnor atherosclerotic cardiovascular disease. malities and an association with anti-U1-RNP antibody have UCTD usually remains mild and stable but in a minority been described. The antibody binds to the 70 kD epitope of of patients may evolve into a more specific autoimmune the RNP complex, but its actual role in pathogenesis is not disorder, most commonly SLE. Most patients with UCTD understood. Genetic risk alleles include HLA DRBI-04:01 who develop a more specific disease do so within the first 2 and HLA-B-O8, underlining the autoimmune nature of the to 5 years after presentation. A definite disease is more likely condition. to develop in patients with cytopenias; antibodies to TAALE 32. Comparison of Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease Condition Typical Clinical Features Diagnosis Treatment Mixed Raynaud phenomenon (bi- or Positivity for anti- Treatment determined by the management of connective tricolor); puffy fingers; inflammatory U1-RNP antibodies, the specific disease diagnoses and organs tissue disease a rthritis; sclerodactyly; serositis; 7O-kD protein involved; may include anti-inflammatory esophageal dysmotility; myositis; immunomodulatory and biologic agents Fulfills diagnostic interstitial lung disease; PAH criteria for at least two Vasodilators for PAH and Raynaud phenomenon of the following: SSc, PPI for esophageal disease autoimmune myositis, SLE

TAALE 32. Comparison of Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease Condition Typical Clinical Features Diagnosis Treatment Mixed Raynaud phenomenon (bi- or Positivity for anti- Treatment determined by the management of connective tricolor); puffy fingers; inflammatory U1-RNP antibodies, the specific disease diagnoses and organs tissue disease a rthritis; sclerodactyly; serositis; 7O-kD protein involved; may include anti-inflammatory esophageal dysmotility; myositis; immunomodulatory and biologic agents Fulfills diagnostic interstitial lung disease; PAH criteria for at least two Vasodilators for PAH and Raynaud phenomenon of the following: SSc, PPI for esophageal disease autoimmune myositis, SLE Undifferentiated Variable; most common include Does not meet Same as for mixed connective tissue disease connective Raynaud phenomenon (bi- or diagnostic criteria for tissue disease tricolor), particularly with abnormal any specific connective nailfold capillaroscopy, persistent tissue disease; usually inf la m matory a rth ritis/a rth ra g ia I positivity for ANA, with unexplained by other diagnoses, titer >1 :80 skin rash, cytopenias, and serositis

Undifferentiated Variable; most common include Does not meet Same as for mixed connective tissue disease connective Raynaud phenomenon (bi- or diagnostic criteria for tissue disease tricolor), particularly with abnormal any specific connective nailfold capillaroscopy, persistent tissue disease; usually inf la m matory a rth ritis/a rth ra g ia I positivity for ANA, with unexplained by other diagnoses, titer >1 :80 skin rash, cytopenias, and serositis PAH = pulmonary arterial hypertension; PPI = proton pump inhibitor; RNP = ribonucleoprotein; SLE = systemic lupus erythematosus; SSc = systemic sclerosis. 65

Crystal Arthropathies extractable nuclear antigens; anticentromere, anti-Ro/SSA, Pathophysiology or antiphospholipid antibodies; and/or abnormal nailfold Uric acid is the end product of purine metabolism, and about capillaries. two thirds ofurate production derives from cellular turnover of rTY POIT{15 nucleic acids; the remainder is derived from dietary intake. A o ]\rtixed connective tissue disease includes clinical small proportion ofpatients overproduce urate on an inherited manifestations of systemic lupus erythematosus, metabolic basis. Unlike most mammals, humans do not express

extractable nuclear antigens; anticentromere, anti-Ro/SSA, Pathophysiology or antiphospholipid antibodies; and/or abnormal nailfold Uric acid is the end product of purine metabolism, and about capillaries. two thirds ofurate production derives from cellular turnover of rTY POIT{15 nucleic acids; the remainder is derived from dietary intake. A o ]\rtixed connective tissue disease includes clinical small proportion ofpatients overproduce urate on an inherited manifestations of systemic lupus erythematosus, metabolic basis. Unlike most mammals, humans do not express autoimmune myositis, and/or systemic sclerosis; uricase, an enzyme that converts urate into highly soluble anti-Ul-ribonucleoprotein antibodies are gzpically allantoin. Urate therefore accumulates and can precipitate as present. crystals in joints and other tissues if serum concentrations exceed the saturation point. At normal body temperature and o Treatment for mixed connective tissue disease is pH, the saturation point of urate is 6.8 mg/dl (0.40 mmol/L). directed at the specific disease states and organ At lower temperatures and more acidic environments (e.g., in systems involved. the distal extremities), the saturation concentration is lower. r Undifferentiated connective tissue disease does not Almost all serum urate is filtered at the glomerulus, but meet criteria for a specific rheumatologic condition; approximately 90% is reabsorbed in the proximal tubule; in most cases are mild, but a minority of patients develop most patients with gout, hereditary underexcretion of uric acid a more specific autoimmune disorder. is the primary cause of hyperuricemia (Table 33). Not all patients with hyperuricemia develop gout. The factors that lead to the development of gout in hyperuricemia are unclear, but

autoimmune myositis, and/or systemic sclerosis; uricase, an enzyme that converts urate into highly soluble anti-Ul-ribonucleoprotein antibodies are gzpically allantoin. Urate therefore accumulates and can precipitate as present. crystals in joints and other tissues if serum concentrations exceed the saturation point. At normal body temperature and o Treatment for mixed connective tissue disease is pH, the saturation point of urate is 6.8 mg/dl (0.40 mmol/L). directed at the specific disease states and organ At lower temperatures and more acidic environments (e.g., in systems involved. the distal extremities), the saturation concentration is lower. r Undifferentiated connective tissue disease does not Almost all serum urate is filtered at the glomerulus, but meet criteria for a specific rheumatologic condition; approximately 90% is reabsorbed in the proximal tubule; in most cases are mild, but a minority of patients develop most patients with gout, hereditary underexcretion of uric acid a more specific autoimmune disorder. is the primary cause of hyperuricemia (Table 33). Not all patients with hyperuricemia develop gout. The factors that lead to the development of gout in hyperuricemia are unclear, but Crystal Arthropathies degree ofelevation in serum urate level is predictive. A serum urate Ievel greater than 10 mg/dl (0.59 mmol/L) is associated Gout with a 30'/o likelihood of an initial gout flare within 5 years. A gout flare (acute gouty arthritis) is triggered when resi Epidemiology dent synovial macrophages ingest monosodium urate crystals, Gout is characterized by intermittent painful flares of inflam Ieading to activation of the NLRP3 inflammasome and genera- matory arthritis in response to crystals formed in joints tion of interleukin (lL)-18. IL 1p causes local vasodilation, caused by excessive serrrm levels of urate. Gout is increas triggers production of other inflammatory cytokines, and ingly common, with a U.S. prevalence of approximately 4'l.. recruits and activates neutrophils. Complement activation Factors contributing to this increase include dietary changes, on the surface of urate crystals also promotes neutrophil increasing obesity, and an aging population. Nearly all recruitment. patients with gout experience comorbidities, including hypertension, coronary artery disease, hyperlipidemia, dia betes mellitus, and chronic kidney disease (CKD). Some Clinical Manifestations comorbidities (e.g., CKD) contribute to hyperuricemia; all Three requirements generally must be f'ulfilled for onset of comorbidities complicate treatment by posing relative con clinically apparent gout: (1) hyperuricemia; (2) monosodium traindications for appropriate therapeutics (e.g., NSAIDs in urate deposition in joints and/or soft tissues; and (3) a reaction patients with CKD). to phagocytosed crystals that leads to an acute inflammatory Men reach a steady state serum urate level after puberty, response. whereas premenopausal women are generally protected from hyperuricemia by estrogenic effects. Men can have their flrst Gout Flares gout flare in the third to fifth decade; women are more likely Ear$ acute gout flares are typically monoarticular, and at least to experience the first flare after menopause. 50% of first flares in men involve the first metatarsophalangeal

Crystal Arthropathies degree ofelevation in serum urate level is predictive. A serum urate Ievel greater than 10 mg/dl (0.59 mmol/L) is associated Gout with a 30'/o likelihood of an initial gout flare within 5 years. A gout flare (acute gouty arthritis) is triggered when resi Epidemiology dent synovial macrophages ingest monosodium urate crystals, Gout is characterized by intermittent painful flares of inflam Ieading to activation of the NLRP3 inflammasome and genera- matory arthritis in response to crystals formed in joints tion of interleukin (lL)-18. IL 1p causes local vasodilation, caused by excessive serrrm levels of urate. Gout is increas triggers production of other inflammatory cytokines, and ingly common, with a U.S. prevalence of approximately 4'l.. recruits and activates neutrophils. Complement activation Factors contributing to this increase include dietary changes, on the surface of urate crystals also promotes neutrophil increasing obesity, and an aging population. Nearly all recruitment. patients with gout experience comorbidities, including hypertension, coronary artery disease, hyperlipidemia, dia betes mellitus, and chronic kidney disease (CKD). Some Clinical Manifestations comorbidities (e.g., CKD) contribute to hyperuricemia; all Three requirements generally must be f'ulfilled for onset of comorbidities complicate treatment by posing relative con clinically apparent gout: (1) hyperuricemia; (2) monosodium traindications for appropriate therapeutics (e.g., NSAIDs in urate deposition in joints and/or soft tissues; and (3) a reaction patients with CKD). to phagocytosed crystals that leads to an acute inflammatory Men reach a steady state serum urate level after puberty, response. whereas premenopausal women are generally protected from hyperuricemia by estrogenic effects. Men can have their flrst Gout Flares gout flare in the third to fifth decade; women are more likely Ear$ acute gout flares are typically monoarticular, and at least to experience the first flare after menopause. 50% of first flares in men involve the first metatarsophalangeal TA,8LE 33. Causos of Hyperuricemia Primary renal uric acid underexcretion (hereditary, renaltubular basis) Chronic kidney disease of any cause (secondary uric acid underexcretion) Uric acid overproduction due to primary defea in purine metabolism: PRPP synthetase overactivity; HPRT deficiency

Crystal Arthropathies degree ofelevation in serum urate level is predictive. A serum urate Ievel greater than 10 mg/dl (0.59 mmol/L) is associated Gout with a 30'/o likelihood of an initial gout flare within 5 years. A gout flare (acute gouty arthritis) is triggered when resi Epidemiology dent synovial macrophages ingest monosodium urate crystals, Gout is characterized by intermittent painful flares of inflam Ieading to activation of the NLRP3 inflammasome and genera- matory arthritis in response to crystals formed in joints tion of interleukin (lL)-18. IL 1p causes local vasodilation, caused by excessive serrrm levels of urate. Gout is increas triggers production of other inflammatory cytokines, and ingly common, with a U.S. prevalence of approximately 4'l.. recruits and activates neutrophils. Complement activation Factors contributing to this increase include dietary changes, on the surface of urate crystals also promotes neutrophil increasing obesity, and an aging population. Nearly all recruitment. patients with gout experience comorbidities, including hypertension, coronary artery disease, hyperlipidemia, dia betes mellitus, and chronic kidney disease (CKD). Some Clinical Manifestations comorbidities (e.g., CKD) contribute to hyperuricemia; all Three requirements generally must be f'ulfilled for onset of comorbidities complicate treatment by posing relative con clinically apparent gout: (1) hyperuricemia; (2) monosodium traindications for appropriate therapeutics (e.g., NSAIDs in urate deposition in joints and/or soft tissues; and (3) a reaction patients with CKD). to phagocytosed crystals that leads to an acute inflammatory Men reach a steady state serum urate level after puberty, response. whereas premenopausal women are generally protected from hyperuricemia by estrogenic effects. Men can have their flrst Gout Flares gout flare in the third to fifth decade; women are more likely Ear$ acute gout flares are typically monoarticular, and at least to experience the first flare after menopause. 50% of first flares in men involve the first metatarsophalangeal TA,8LE 33. Causos of Hyperuricemia Primary renal uric acid underexcretion (hereditary, renaltubular basis) Chronic kidney disease of any cause (secondary uric acid underexcretion) Uric acid overproduction due to primary defea in purine metabolism: PRPP synthetase overactivity; HPRT deficiency Conditions of increased cellturnover leading to purine/urate generation: leukemia/lymphoma/other myeloproliferative disorders; psoriasis; hemolytic a nemia; polycythemia vera Drug-induced hyperuricemia (agents reducing renal glomerularfiltration and/ortubular urate excretion): thiazide and loop diuretics; cyclosporine; tacrolimus; low-dose salicylates; ethambutol; pyrazinamide; lead ingestion/toxicity; alcohol; nicotinic acid Diet-induced hyperuricemia (agents high in purines or inducing purine/urate biosynthesis): alcohol; shellfish; red meat; high-fructose corn syrup-sweetened beverages and foods; impact on serum urate generally is limited in the absence of other causes

Conditions of increased cellturnover leading to purine/urate generation: leukemia/lymphoma/other myeloproliferative disorders; psoriasis; hemolytic a nemia; polycythemia vera Drug-induced hyperuricemia (agents reducing renal glomerularfiltration and/ortubular urate excretion): thiazide and loop diuretics; cyclosporine; tacrolimus; low-dose salicylates; ethambutol; pyrazinamide; lead ingestion/toxicity; alcohol; nicotinic acid Diet-induced hyperuricemia (agents high in purines or inducing purine/urate biosynthesis): alcohol; shellfish; red meat; high-fructose corn syrup-sweetened beverages and foods; impact on serum urate generally is limited in the absence of other causes HPRT = hypoxanthine-guanine phosphoribosyltransferase; PRPP = phosphoribosylpyrophosphate 67