dysfunction, trauma ( capillary/skin fragility, e.g., chronic steroid use), hemophilia, a nticoagulation, and hereditary connective tissue diseases (e.g., Ehlers-Danlos \200\224see Chapter 16). Palpable purpura suggests vasculitis, including drug-induced (see Chapter 15). Widespread telangiectasias occur in limited cutaneous scleroderma (see Chapter 13), hereditary hemorrhagic telangiectasia, and dermatomyositis. Ulcers and ulcerating rashes Ulcers are de \201 ned as a loss or defect of dermis and epid ermis produced by sloughing of necrotic tissue: SKIN DISORDERS AND RHEUMATIC DISEASE 199 Cutaneous polyarteritis nodosa may cause painful ulcerating lesions in the lower extremitie s, as can other forms of systemic vasculitis that affect the medium-sized vessels. Cutaneous ulceration may have more than one cause in autoimmune diseases. For example, vasc ulitis, venous stasis in an immobile patient, and ulceration over nodules or pressure point s may all contribute to the same set of lesions. Trauma may be an important cause of cutane ous ulcers in a patient who is already predisposed towards forming these lesions. A painful, indurated, expanding, plum-colored plaque or acneiform pustule that then ulcerates suggests pyoderma gangrenosum. The ulcer has irregular, bluish margins. Neurotropic ulcers are a classic sequelae of diabetes, but they can also occur in associati on with mononeuritis multiplex (from vasculitis) and other rheumatic diseases. Severe widespread ulceration developing rapidly in a child may suggest dermatomyositis. Vasculitic ulcers in the context of livedo reticularis and antibodies to phospholipids (e.g., cardiolipin) may be indicative of the antiphospholipid antibody syn drome (APS) (see Chapter 11). Textural abnormalities Abnormalities of the texture of the skin may be dif \201 cult to di scern. Atrophy and thinning, laxity, thickening, and induration may all be associ- ated wit h disease. \200 Generalized skin atrophy and thinning is an age-related process, but this can be accelerated by chronic steroid use; heritable diseases of connective tissue should also be considered. Skin laxity can best be demonstrated over elbow and knee extensor surfaces. Generalized laxity of connective tissue may result in varicose veins and internal organ prolapse. True acral and digital puf \201 ness in a patient with Raynaud \200\231s is suggestive of scleroderma. Skin thickening has a variety of causes (see below). Scleroderma and scleroder ma-like skin may be localized, limited, or diffuse \200\224this distinction is important (s ee Table 4.1). Diagnostic issues in patients with skin thickening \200 Raynaud \200\231s phenomenon (RP) invariably precedes the onset of systemic sclerosis (scleroderma), but is not a characteri stic of morphea, linear scleroderma, or scleroderma mimics. In patients with RP, abnormal nailfold capillaries on capillaroscopy may indicate the presence of scleroderma or \200\234prescleroderma \200\235 (see Plate 4). The speci \201 cities of autoantibodies are often predictive of the scleroderma subtype. In patients with RP, the ANA has predictive value for identifying pati ents who may progress to scleroderma; anticentromere antibodies are associated with limited cutaneous scleroderma; anti-topoisomerase I (SCL-70) and anti-RNA polymerase III antibodie s are linked with progression to diffuse cutaneous scleroderma. CHAPTER 4 The spectrum of presentation 200 Patients with diffuse cutaneous scleroderma have a preponderance of visceral organ involvement in the \201 rst 5 years of disease; screening investigation s should include pulmonary function tests, an echocardiogram, and a high-resolution CT of t he chest to screen for pulmonary hypertension and pulmonary \201 brosis. Eosinophilic fasciitis may occur as a paraneoplastic syndrome, and is associated with hemat ologic malignancies. Clinically, eosinophilic fasciitis is associated with skin that takes on the appearance of an orange peel ( peau d \200\231orange ). Linear scleroderma in children can produce lifelong deformities because limbs to develop correct length and bulk. Scleroderma-like syndromes may occur secondarily to exposure to some industrial chemicals: vinyl chloride, chlorinated organic solvents, and silicon and ep oxy resins. SKIN DISORDERS AND RHEUMATIC DISEASE 201 Table 4.1 Pattern recognition in patients with skin thickening Classi \201 cation Skin features Early small skin areas affected (itchy). Progression to hidebound skin, typically on trunk (areola spared) and legs. Lesions become waxy and hypo/ hyperpigmented guttate (small <10 m m) papules usually on neck and anterior chest Morphea may be localized (guttate) or generalized Linear scleroderma Linear bandlike pattern often in dermatomal distribution. Atrophy of muscles is common. Fix ed joint deformities and growth abnormalities can occur \200\234Coup de saber \200\235 Linear scleroderma on the face/scalp can be depressed; ivory in appearance. Hemiatrophy can occur Systemic sclerosis (early) Early morning \200\234puf \201 ness \200\235 in hands and feet, facial \200\234tightness . \200\235 Nonpitting edema of intact dermal and epidermal appendages. High degree of suspi cion needed Systemic sclerosis (classic) Firm, taut, hidebound skin proximal to MCP joints. Skin may be coarse, pigmented, and dry. Epidermal thinning, loss of hair, and sweating can occur. Telangiectasias and skin calcinos is become obvious. Skin creases disappear. Such change proximal to elbows or knees in the l imbs or below the clavicles (in those with face and neck involvement) classi \201 es disea se as diffuse as opposed to limited systemic sclerosis Systemic sclerosis (late) 2 \200\22315 years after onset of classical phase, skin softens but pigmentation changes re main. Skin becomes atrophic and can ulcerate Eosinophilic fasciitis Phases: early \200\224pitting edema; progressive \200\224 peau d \200\231orange; late \200 \224induration ( \200\234woody feel \200\235) with venous guttering when limb elevated. Arm s and legs most commonly affected but \201 ngers mainly spared. Synovitis and low-grade m yositis may occur. Eosinophilia is usually striking but not always present Lipodermatosclerosis Fibrotic induration of lower legs associated with venous stasis ( \200\234champagne-bottle legs \200\235) Diabetes Waxy thickening of extremities. Insidious progression. Joints of the hands become stiff, th e tendons can thicken. Skin changes proximal to wrist and on the face very unlikely but sti ffening of elbow and shoulder joints not uncommon Dependent lymphedema Feet/ankles/lower legs. Often pitting. Chronic presence may give hyperkeratosis. Main cause s: R- or L-sided heart failure, renal failure, nephrotic syndrome, and low-protein states CHAPTER 4 The spectrum of presentation 202 Skin vasculitis in adults Background There are a variety of ways in which systemic vasculit is may present, including fever of unknown origin, organ infarction, gastrointestinal bleed - ing, and high acute phase reactants in a generally unwell patient. However, a vasculitic skin rash is one of the most common presenting features of systemic vasculitis, and can be an important diagnostic clue. When to consider a diagnosis of vasculitis (see also Chapters 15 and 22) \200 Systemic va sculitis is rare. Overall, the annual incidence is about 40 per million. Cutaneous vasculitis, however, is not rare; it can follow viral or bacterial illness, can b e triggered by drugs, and is associated with malignancy. Biopsy generally demonstrates degranulation of neutrophils ( \200\234leukocytoclasis \200 \235) and evidence of vessel destruction. The list of causes is long (see Table 4.2); however, in about 50% of cases, no cause may be found. Cutaneous vasculitis may also occur in association with another autoimmune disease not normally characterized by vasculitis, including SLE, rheumatoid arth ritis, and Sj gren \200\231s syndrome. Important considerations (see Table 4.3) The following important points of clinical assessm ent should be followed in patients with possible vasculitic rashes. \200 Determine whethe r the patient has been taking a new drug. Many antibiotics, including penicillins, sulfonam indes, and cephalosporins, commonly cause cutaneous vasculitis. Evaluate the patient for evidence of chronic infection; Hepatitis B, Hepatitis C, and HIV a ll are worth considering. Endocarditis should also be considered in the right host (e.g., t he elderly, or patients who use intravenous drugs). Look for evidence of a primary autoimmune disorder that may be associated with cutaneous va sculitis. In \202 ammatory bowel disease, for example, can occasionally cause a leukocytoc lastic vasculitis in addition to oral ulcerations and pyoderma gangrenosum. Because SLE is common, it may be worthwhile to check ANA and serum complements as well. Look for evidence of cryoglobulinemic vasculitis. Serum cryoglobulins tests are often mishandled, leading to false-negative results. Rheumatoid factor is detecte d in 80% of patients with mixed essential cryoglobulinemia, and may be a better screening t est. Age-appropriate screening for malignancy should be performed. Serum and urine electrophoresis with immuno \201 xation may be of value. Urinalysis may demonstrate an \200\234active sediment \200\235; evidence of hematuria, proteinuria, or red blood cell casts may be the \201 rst clue that a patient h as a systemic vasculitis. SKIN VASCULITIS IN ADULTS 203 Table 4.2 Precipitants and associations of hypersensitivity (allergic) small vessel vasculi tis Drugs Sulfonamides and penicillins, for example \200\224there are many Infections Hepatitis B, hepatitis C, HIV B -hemolytic streptococcus e.g., serum sickness Foreign protein Autoimmune disease Rheumatoid arthritis Sj gren \200\231s syndrome (antiRo positive) Systemic lupus erythematosus In \202 ammatory diseases Sarcoid Crohn \200\231s disease, ulcerative colitis Chronic active hepatitis Malignancy Myelo- and lymphoproliferative disorders Solid tumors Cryoglobulinemia Table 4.3 Laboratory tests in patients with suspected vasculitis Hematology CBC, ESR Chemistries Electrolytes, BUN, creatinine Liver function enzymes, serum ACE CRP, urine toxicology (cocaine) Serum and urine protein electrophoresis Microbiology Blood cultures Hepatitis B and C serology. Consider HIV Streptococcal antibodies Immunology Immunoglobulins, cryoglobulins, complement ANA (ENAs), rheumatoid factor ANCA (when relevant) CHAPTER 4 The spectrum of presentation 204 Systemic vasculitis \200 Untreated primary systemic vasculitis is generally characterized by in \202 ammation; many patients will complain of B-type symptoms, including fevers, we ight loss, and night sweats. Patients with idiopathic cutaneous vasculitis, on the other hand, often feel quite well The extracutaneous signs and symptoms may provide clues to the correct diagnosis: \200 Henoch-Sch nlein purpura: colicky abdominal pain \200 Churg- Strauss syndrome: adult-onset asthma, eosinophilia \200 Wegener \200\231s granulomatosis: chronic sinusitis \200 Microscopic polyangiitis: hemoptysis, red blood cell casts \200 Mononeuritis multiplex, which presents as a \200\234wrist drop \200\235 or \200\234foot drop \200\235, is pathognomic for systemic vasculitis in a nondiabetic patient. Diagnostic procedures Skin biopsy \200 Try to discuss the case with the pathologist \201 rst. \200 Punch biopsy is simple, and may be suf \201 cient to yield a diagnosis. E lliptical biopsy provides more tissue, and may increase yield. \200 Use a needle to lift the skin sample \200\224this avoids forceps-induced damage. Biopsy should extend to the subcutaneous fat, which generally includes the arterioles and venules affected by primary systemic vasculitis. Idiopathic leukocytocla stic vasculitis affects the capillaries but generally spares the arterioles and venules. Biopsy should be sent for routine histology and for direct immuno \202 uorescence, which may yield important clues regarding the underlying cause: \200 IgA: Henoch-Sch nlein purpura \200 IgM, C3: Cryoglobulinemic vasculitis \200 I gG, IgM, IgA, C3: SLE \200 Minimal immunoreactant staining: ANCA-associated vasculitis \200 Samples for immuno \202 uorescence should be snap frozen in liquid N 2 or dry ice or transported immediately to the laboratory, ideally in PBS. Immuno \202 uores cence cannot be performed on samples that have been treated with formalin. This page intentionally left blank CHAPTER 4 The spectrum of presentation 206 Skin vasculitis in children and adolescents Epidemiology \200 Classi \201 cation of chil dhood vasculitis is dif \201 cult. A system that has clinical utility is shown in Table 4.4. Statistically, the most common form of vasculitis is HSP, followed by hypersensitivity angiitis. Kawasaki disease (KD) affects primarily children under 5 years of age. Clues from the history \200 All of the systemic vasculitides may be associated with featu res such as fatigue, fever, gastrointestinal symptoms, lymphadenopathy, myalgias, and arthr algias. Drugs or infection are often identi \201 ed as a precipitant of a cutaneous leukocytoclastic vasculitis. Granulomatosis with polyangiitis (Wegener \200\231s granulomatosis) is rare. As in adults, it may be characterized by a limited localized form involving the respi ratory tract. Subglottic stenosis, nasal septum disease, and respiratory infections may all have occurred. Testicular pain is a rare though fairly speci \201 c feature for polyarteritis nodosa. This can also occur with Wegener \200\231s granulomatosis. \200 Abdominal pain is not speci \201 c. Gut bleeding can occur in Henoch- Sch nlein purpura (HSP) and juveni le dermatomyositis especially. \200 Vasculitis can occur in association with familial Med iterranean fever. Examination Characteristic examination features of the rash \200 Erythematous rash with s welling progressing to desquamation of palms and soles of the feet is typical of KD. Lower limb and buttock palpable purpura is typical of, but not speci \201 c for, HSP and hypersensitivity angiitis. Skin nodules are not speci \201 c but are common in cutaneous polyarteritis nodosa and frequently occur in hypersensitivity vasculitis. A nodular, painful rash on the medial sides of the ankles is frequent in cutaneous polyarteritis nodosa. Extensive necrotic and ulcerative rash with notable muscle pains suggests dermatomyositis. Periungual erythema and both eyelid and nail bed telangiectasias are typical. Livedo reticularis is a feature of cutaneous polyarteritis nodosa (often with painful skin nodules), but also occurs with SLE and the antiphospholipid syndro me (see Chapters 10 and 11 respectively). Other typical or speci \201 c examination features \200 Bilateral conjunctival injection , lip/oral/buccal in \202 ammation, and acute nonpurulent cervical lymphadenopathy are typ ical features of KD. \200 The incidence of cardiovascular manifestations is 35% in KD. Mu rmurs, gallop rhythm, and coronary artery aneurysms (30%) can occur. Pulselessness may suggest a large vessel vasculitis. SKIN VASCULITIS IN CHILDREN AND ADOLESCENTS 207 Table 4.4 A classi \201 cation of childhood vasculitis Polyarteritis Macroscopic Microscopic Kawasaki disease (mucocutaneous lymph node syndrome) Granulomatous vasculitis Granulomatosis with polyangiitis (Wegener \200\231s granulomatosis) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) Leukocytoclastic vasculitis Henoch \200\223Sch nlein purpura Hypersensitivity angiitis Cutaneous polyarteritis nodosa Vasculitis and autoimmune connective tissue disease SLE JIA Mixed connective tissue disease Dermatomyositis Scleroderma Large vessel vasculitis Takayasu \200\231s disease Miscellaneous vasculitides Severe oral aphthous ulceration raises the possibility of Beh et \200\231s syndrome. It is rare, but does occur in children. Investigations \200 Leukocytosis, thrombocytosis, anemia, and an acute phase response are typical in all forms of systemic vasculitis and are not speci \201 c. ECG and echocardiography are essential in suspected KD. \200 In patients suspected of hav ing a small vessel vasculitis, glomerulonephritis should be ruled out (urinalysis, urine microscopy, spot urine protein/cr eatinine ratio). In patients with an active sediment, or other unexplained renal abnormalities (e.g., worsening proteinuria or serum creatinine) kidney biopsy can be valuab le to con \201 rm the diagnosis. ANCA is not speci \201 c for vasculitis, but C-ANCA with antibodies to proteinase-3 (PR3-A NCA) in appropriate patients is highly suspicious for granulomatosis with polyangiitis (Weg ener \200\231s granulomatosis), while P-ANCA with antibodies to myeloperoxidase (MPO-ANCA) is suggestive of microscopic polyangiitis or eosinophilic granulomatosis with polyangiitis (the Churg-Strauss syndrome). Biopsy of the skin rash is a key investigation in all patients. \200 In patients suspecte d of having a medium vessel vasculitis, the most valuable investigation is often angiograph y of the affected region (e.g., renal, mesenteric, or extremity). Conventional angiography and CT-angiography are both acceptable; MR-angiography may not have CHAPTER 4 The spectrum of presentation 208 adequate resolution to exclude the presence of a medium vessel vasculitis. In patients suspected of having a large vessel vasculitis, MR-angiography is preferred, sin ce MR may demonstrate vessel wall characteristics (e.g., edema, thickening, enhancement) th at may not be visualized with other modalities. This page intentionally left blank CHAPTER 4 The spectrum of presentation 210 Cardiac manifestations Subclinical cardiac involvement is found in many of the rheumatic di s- eases, and it is not uncommon for a cardiac abnormality to be discov- ered incidentally. As our ability to treat the underlying rheumatic diseases improves, our ability to identif y and to treat the cardiac complications of these diseases becomes increasingly important. Pericardium \200 Pericardial effusions are not uncommon, and have been reported in associ ation with a large number of rheumatic diseases, including scleroderma, Sj gren \200\231 s, polymyositis, mixed connective tissue disease, the spondyloarthropathies, and the system ic vasculitides. In the majority of cases, these effusions are discovered incidentally. These effusions are often small, clinically asymptomatic, and require no speci \201 c ther apy. Pericardial effusions can also occur in the setting of nonrheumatic illness. When a patient with a known rheumatic disease presents with a symptomatic effusion , it is important to consider other possible explanations, such as infection (e.g., tubercu losis, viral, Whipple \200\231s disease), malignancy, and other unrelated conditions (uremi a, hypothyroidism, cardiac amyloid). Pericardial effusions are a common manifestation of systemic lupus erythematosus (SLE), largely due to immune complex deposition into the pericardium. These e ffusions can be serous, serosanguinous, or hemorrhagic. Analysis of the pericardial \202 uid generally demonstrates evidence of complement, immune complexes, and leukocytes, consis tent with an active in \202 ammatory state. Although pericardial effusions are common with SLE, they are generally trivial. Cardiac tamponade is found in less than 1% of patients with SLE. Since t he effusion tends to re \202 ect the overall disease state, generally treatment of the und erlying disease is adequate to resolve the effusion. Rarely, therapeutic pericardiocentesis may be required. Pericardial effusions are found in up to 30% of patients with rheumatoid arthritis, although only a small number of these patients will present with peri carditis or evidence of tamponade. Pericardial effusions are more common in RF-positive pat ients with a history of rheumatoid nodules. Chronic pericardial effusions can become superi nfected, and in rare cases lead to a constrictive pericarditis. \200 For both groups of p atients, the presence of a symptomatic pericardial effusion is associated with increased mo rtality. In one study of patients with SLE who presented with cardiac tamponade, the 5-year survival was only 46%. Myocardium \200 Myocarditis is a relatively uncommon manifestation of rheumatic disease. Myocarditis can be found among patients with active SLE and RA, although it generally does not lead to clinically signi \201 cant dysfunction. CARDIAC MANIFESTATIONS 211 Cardiomyopathy among patients with RA and SLE is more likely to be due to premature coronar y artery disease, followed by the development of ischemic heart disease. Although uncommon, the possibility of hydroxychloroquine-induced cardiomyopathy should be c onsidered in a patient who develops congestive heart failure in the absence of coronary art ery disease. This diagnosis can be con \201 rmed with myocardial biopsy, and often respond s to drug cessation. Eosinophilic granulomatosis with polyangiitis (the Churg-Strauss syndrome) can lead to an acute eosinophilic myocarditis that can be life-threatening if not treated promptly. One-third of patients with granulomatosis with polyangiitis (Wegener \200\231s granulomatos is) may have cardiac dysfunction as a consequence of the underlying vasculitis. The majorit y of these patients will have wall motion abnormalities on echocardiography, but valvulitis and ventricular aneurysm have also been reported. The majority of these lesions will be as ymptomatic, but the 5-year survival rate for patients with cardiac lesions attributable to Wegener \200\231s granulomatosis is 57%. Valvular disease \200 Aortic regurgitation is an important potential consequence of aorti tis, which can occur with any of diseases associated with large-vessel vasculitis (includin g Takayasu \200\231s arteritis, giant cell arteritis, Cogan \200\231s syndrome, and Beh et \200\231s disease). In these cases, aortitis leads to aneurysm formation, which creates valvular incompetence. Aortic regurgitation can also occur as a consequence of ankylosing spondylitis. Unlike the vasculitides, ankylosing spondylitis causes in \202 ammation at the aortic root, which lea ds to dense scarring of the aortic valves. Although the mechanism is unique to this disease , it should be monitored and treated like any form of aortic insuf \201 ciency. \200 Mit ral regurgitation and mitral prolapse are common manifestations of SLE, particularly among patients who have antiphospholipid antibodies. A more serious valvulitis can occur in association with SLE. In the process of healing, the valves become scarred and calci \201 ed, a process that can eventu ally lead to clinically signi \201 cant valvular disease. \200 Libman-Sacks endocarditis is a classic manifestation of SLE. In this disease, vegetations form from immune complexes, mononuclear cells, and \201 brin, which attach to the valves. Although not infectious, these vegetations can embolize Hemodynamically insigni \201 cant valve lesions have also been reported in association with RA, MCTD, scleroderma, and Sj gren \200\231s. Coronary artery disease \200 Surprisingly, the primary vasculitides rarely lead to corona ry artery in \202 ammation, although coronary artery vasculitis has been reported in assoc iation with polyarteritis nodosa and the ANCA-associated vasculitides. The antiphospholipid syndrome is associated with a substantial increased risk of myocardial infarction, even in the absence of true coronary artery diseas e. CHAPTER 4 The spectrum of presentation 212 Both RA and SLE are strongly associated with coronary artery disease. This may be the resul t of systemic in \202 ammation or a response to chronic immunosuppression. Regardless, pat ients with these diagnoses should undergo early cardiac evaluation to address modi \201 ab le risk factors for coronary artery disease. Accelerated atherosclerosis may be an important consequence of glucocorticoid exposure. Even chronic low dose prednisone may place some patients at increa sed risk of cardiovascular disease. Conduction abnormalities \200 Clinically insigni \201 cant arrhythmias and conduction de fects are common among patients with in \202 ammatory myopathies (dermatomyositis, polymyositis) and sclero derma. Clinically signi \201 cant arrhythmias (including heart block) can be seen in patients with spondyloarthropathies as a result of the same scaring process that leads t o the valvular abnormalities noted in the preceding section, Coronary Artery Disease. This page intentionally left blank CHAPTER 4 The spectrum of presentation 214 Pulmonary manifestations Pleura \200 Pleural effusion is found in up to 50% of patients w ith SLE. These effusions can be unilateral or bilateral, and frequently are found in associ ation with a pericardial effusion. Pleural disease is also a common manifestation of rheumatoid arthritis, which is associated with both pleural effusions and pleural thickening. These effusions are generally asymptom atic, and are found in the setting of active disease. Asymptomatic pleural effusions can also be found in 10 \200\22330% of patients with ANCA-associated vasculitis. Pulmonary nodules/masses \200 Both granulomatosis with polyangiitis (Wegener \200\231s gr anulomatosis) and sarcoidosis are often diagnosed incidentally, after the discovery of lung masses. Sarcoidosis is associated with hilar lymphadenopathy, while granulomatosis with po lyangiitis (Wegener \200\231s granulomatosis) generally presents with multiple peripheral p ulmonary nodules that can be mistaken for lung cancer or fungal infection. In a patient with a known rheumatic disease who presents with a lung mass, it is always imp ortant to consider the possibility of malignancy. Lung cancer risk is increased among patie nts with rheumatoid arthritis and scleroderma, and many rheumatic diseases are associated w ith an increased risk of lymphoma Granulomatosis with polyangiitis (Wegener \200\231s granulomatosis) \200\223 and less comm only, ankylosing spondylitis and rheumatoid arthritis \200\223 can lead to cavitating apic al lesions that can be mistaken for tuberculosis. Interstitial lung disease \200 Pulmonary \201 brosis (with a predilection for the lung bases and periphery) is a common feature of both scleroderma and the in \202 ammatory myop athies (also known as the antisynthetase syndromes). Pulmonary \201 brosis is found in 20% \200\22365% of patients with scleroderma. Radiograp hically, the lesions take on the appearance of ground glass in \201 ltrates that gradually lead to honeycombing and \201 brosis. Pulmonary \201 brosis may be the initial manifestation of an in \202 ammatory myopathy, and pulmonary symptoms may precede clinical evidence of muscle involvement. Rheumatoid arthritis is also associated with an interstitial lung disease, although this has become increasingly rare. Apical \201 brosis can be found in 1% of patients with ankylosing spondylitis. Apical \201 brosis is also an uncommon feature of rheumatoid lung. Pulmonary \201 brosis can also occur as the long-term sequelae of pulmonary capillaritis, which may occur in patients with granulomatosis with polyangiitis ( Wegener \200\231s granulomatosis) and microscopic polyangiitis. PULMONARY MANIFESTATIONS 215 Vasculature \200 Hemoptysis can be the result of pulmonary capillaritis, which can be fou nd in association with the so-called \200\234pulmonary renal syndromes \200\235: SLE, ANCA -associated vasculitis (predominantly microscopic polyangiitis), and antiglomerular basemen t membrane (GBM) syndrome. Cryoglobulinemic vasculitis can also cause pulmonary capillaritis, although this is not one of its more common manifestations. Pulmonary artery hypertension (PAH) is most commonly associated with limited cutaneous scle roderma. Isolated PAH can also be seen with diffuse cutaneous scleroderma, although it gene rally appears as a consequence of pulmonary \201 brosis. Scleroderma causes PAH by narrowing of the small arteries and arterioles that gradually leads to obliteration of the pulmonary vascular bed. RA, SLE, in \202 ammatory myopathy, mixed connective tissue disease, and Sj gren \200 \231s syndrome can also be associated with PAH, but it is considered an uncommon feature of these diseases. Airways \200 RA can lead to laryngeal obstruction when it affects the cricoarytenoid join ts. Such patients will present with hoarseness or odynophagia. \200 Hoarseness and non-pr oductive cough may also be an uncommon manifestation of giant cell arteritis, due to in \202 ammation of the recurrent laryngeal nerve by the aortitis. Subglottic stenosis is a common feature of granulomatosis with polyangiitis (Wegener \200\231s granulomatosis), which can lead to signi \201 cant stridor. \200 Unco ntrolled relapsing polychondritis can cause tracheomalacia or tracheal stenosis, which is a signi \201 cant cause of morbidity and mortality for this di sease. CHAPTER 4 The spectrum of presentation 216 Renal manifestations Evaluation of renal failure: overview \200 The kidneys are a key com ponent to the evaluation and management of the rheumatic diseases. Many conditions affect the kidneys directly, and a careful examination may yield important clues to the correct diagnosis. For other patients, the kidneys must be considered because many treatments have renal toxicity or are renally cleared. In terms of time course, renal failure is frequently divided into \200\234acute kidney inj ury \200\235 and \200\234chronic kidney disease. \200\235 Acute kidney injury describes th e rapid loss of renal function, which might be reversible if the underlying cause is addres sed; chronic kidney disease is the result of an irreversible loss of nephrons. Acute kidney injury (AKI) is often divided by the source of the injury. Acute renal failure due to renal hypoperfusion is called \200\234prerenal \200\235; acute renal failure due t o urinary tract obstruction is called \200\234post- renal. \200\235 Intrinsic renal failure (i.e., renal failure due to direct involvement of the renal parench yma) should be evaluated with a careful examination of the urine. The presence of red blood cells and protein, or red blood cell casts (i.e., an \200\234active sediment \200\235) im plies glomerulonephritis, which can occur with vasculitis and SLE. Prerenal azotemia \200 Hypovolemia is an important cause of prerenal AKI. Dehydration and anemia can both lead to prerenal azotemia. Renal hypoperfusion can also be caused by diminished blood \202 ow to the kidneys. Diseas es involving the renal artery (such as renal artery stenosis, polyarteritis nodosa affectin g the renal artery, or renal artery thrombosis) may cause prerenal azotemia. If long-standi ng, this leads to intrinsic renal failure. Conditions associated with low cardiac output (including shock, congestive heart failure, m yocarditis, tamponade, and pulmonary arterial hypertension) may all predispose the patient to prerenal AKI. Hyperviscosity, which is seen with type I (monoclonal) cryoglobulinemia, is a rare cause of prerenal azotemia. All of these conditions may be exacerbated by drugs that decrease renal perfusion, including NSAIDs and ACE-inhibitors. \200 With prerenal azotemia, the fr actional excretion of sodium \200 (FENa=(UNa x PCr)/(PNa x UCr)) is less than 1.0; this t est is not reliable in patients treated with diuretics. Postrenal azotemia \200 Nephrolithiasis is not a common cause of postrenal azotemia, but should be considered in a patient with gout. 5 \200\22310% of renal calculi in the United S tates are caused by uric acid; this is particularly common among patients with gout who hav e been treated with uricosuric agents (e.g., probenecid). RENAL MANIFESTATIONS 217 Sarcoidosis can cause hypercalcemia and hypercalcuria, which in turn can lead to nephrolith iasis and nephrocalcinosis, both of which can rarely cause postrenal azotemia. Methotrexate and trimethoprim/sulfamethoxazole can cause crystalluria and renal obstruction. Ultrasound is a useful modality to evaluate both for the presence of obstruction leading to hydronephrosis and renal calculi. Intrinsic renal failure \200\224 \200\234active sediment \200\235 \200 The nephritic synd romes are an important cause of rapidly progressive renal failure among patients with rheum atic diseases, particularly small vessel vasculitis and SLE. The presence of hematuria, proteinuria, and red blood cell casts strongly suggests the pres ence of glomerulonephritis, but a renal biopsy is crucial to determining the underlying dia gnosis and the severity/chronicity of the disease. Nephritic syndromes can be divided into \200\234focal proliferative \200\235 and \200\234diffuse proliferative \200\235 based on histology. Causes of focal proliferative glomerulonephritis include SLE, Henoch- Sch nlein purpura, and other forms of small vessel vasculitis. Diffuse proliferative glomerulonephritis is caused by cryoglobulinemia, SLE, anti-glomerular basement membrane (GBM) disease (Goodpasture \200\231s syndrome), and ANCA-associated vasculitis. Direct immuno \202 uorescence can also provide valuable information regarding the correct diagnosis. SLE is associated with multiple immunoreactants ( \200\234full house \200\235 st aining pattern). IgA deposition implies Henoch-Sch nlein purpura. Cryoglobulinemic vascu litis leads to IgG and C3 deposition. Sparse or absent immunoreactants on biopsy is sometim es called \200\234pauci-immune, \200\235 and implies an ANCA-associated vasculitis. Intrinsic renal failure \200\224 \200\234bland sediment \200\235 \200 A bland sediment re fers to a urine sample that is acellular; transparent hyaline casts may be seen. Remember t hat a bland sediment is also seen in prerenal and postrenal azotemia. Acute tubular necrosis (ATN) is used to describe causes of acute, intrinsic renal failure associated with a urine sediment that has muddy brown casts and tub ular epithelial cells. Nephrotoxic tubular injury from drugs is a common cause of ATN in patients with rheumatic disease. Prolonged prerenal azotemia can lead to permanent kidney damage; therefore, diseases of the renal artery (including polyarteritis nodosa and renal artery thrombosis from antiphosphol ipid antibody syndrome) should be considered. Interstitial nephritis is most commonly seen as a drug reaction (e.g., NSAIDs, azathioprine, allopurinol) Interstitial nephritis can also be seen as a manifestation of several rheumatic diseases, i ncluding Sj gren \200\231s, SLE, sarcoidosis, and eosinophilic granulomatosis with polya ngiitis (the Churg-Strauss syndrome). CHAPTER 4 The spectrum of presentation 218 NSAIDs cause renal vasoconstriction and interstitial nephritis, both of which can eventually lead to a chronic analgesic nephropathy. Unlike the other forms of ANCA-associated vasculitis, the mechanism of renal failure among patients with eosinophilic granulomatosis with polyangiitis (Churg-S trauss syndrome) is an interstitial nephritis; glomerulonephritis is relatively rare with t his diagnosis. The most common causes of secondary renal amyloidosis are rheumatoid arthritis and familial Mediterranean fever. Glomerular deposits of amyloid lead to proteinuria (which can be nephrotic range) and progressive renal failure. Scleroderma renal crisis \200 Scleroderma renal crisis is a rheumatologic emergency chara cterized by acute renal failure and malignant hypertension. Patients with diffuse cutaneous scleroderma are at greatest risk; scleroderma renal crisis generally occurs within the \201 rst 4 years after diagnosis, bu t it can occur at any time. Patients who are treated with corticosteroids may be at the hig hest risk. Urinalysis generally demonstrates a bland sediment. Kidney biopsy demonstrates evidence of a thrombotic microangiopathy that histologically cannot be distinguished from malignant hyp ertensive nephrosclerosis, hemolytic-uremic syndrome, SLE, or the antiphospholipid antibody syndrome. The cornerstone of therapy is gradually escalating doses of ACE- inhibitors, followed by an giotensin II receptor blockers (ARB) and calcium channel blockers if adequate blood pressur e control is not achieved. Renal tubular acidosis \200 Renal tubular acidosis (RTA) causes a nonanion gap metabolic acidosis caused by a failure of the renal tubules to maintain acid-base status. Type I RTA, caused by an inability to excrete acid, is found with Sj gren \200\231s syndrome and SLE. Type IV RTA is most commonly caused by hyporeninemic hypoaldosteronism, can occur as a result of treatment with NSAIDs, ACE-inhibitors, and ARBs . This is commonly associated with hyperkalemia. This page intentionally left blank CHAPTER 4 The spectrum of presentation 220 Endocrine manifestations Well-characterized musculoskeletal conditions occur in many endocr ine disorders. Some are speci \201 c for certain disorders; others are nonspeci \201 c, b ut occur with greater frequency among patients with endocrine disease. Musculoskeletal mani festations occur either as a result of metabolic dis- turbances or are in \202 uenced by a common link through their autoimmune pathophysiology. Diabetes \200 Dupuytren \200\231s contracture, trigger \201 nger, carpal tunnel syndrom e, diffuse idiopathic skeletal hyperostosis (DISH), and adhesive capsulitis all occur with greater fre quency among patients with diabetes. Some form of tissue or joint hypomobility/stiffness is common among patients with diabetes (see Table 4.5); in some cases, this can appear similar to scleroderma. These scleroderma-l ike skin changes are more prevalent among patients with type I diabetes. Table 4.5 Patterns of joint and tissue hypomobility or stiffness in diabetes by reported se ries. Tissue changes are thought to occur from excessive hydration (a consequence of an exc essive local production of sugar alcohols) Patient series Major abnormalities Associations Occasional lung \201 brosis. Microvascular diabetic complications Diabetics overall In about 30 \200\22340% mainly in long-standing disease: slow decrease in hand mobility; wa xy skin thickening ( \200\230scleroderma-like \200\231) Adults 55 \200\22376% prevalence of joint hypomobility in type 1/type 2 diabetes, respectively Not associated with diabetic complications Mature onset diabetes (mean 61 years) Stiffening of connective tissue (assessed in hands) Diabetic nephropathy Children with type 1 diabetes 31% have limited joint mobility None with glycemic control, retinopathy, or proteinuria Juvenile and young adult onset (age 1 \200\22324 years) diabetes 34% had skin thickening. Changes rarely proximal to MCPs and never proximal to wrists. Join t contractures in >50%, often third or fourth \201 ngers No \202 exor tendon rubs (as seen in scleroderma) ENDOCRINE MANIFESTATIONS 221 Hand weakness may be due to diabetic neuropathy and may be mistaken for carpal tunnel syndrome. Nerve conduction studies help discriminate between the se two diagnoses. Calci \201 cation of soft tissues around the shoulder occurs in approximately 20% of diabetics, and is associated with variable symptoms and disability.