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InternalMed_Harrison. Acute mortality directly from cryoglobulinemic vasculitis is uncommon, but the presence of glomerulonephritis is a poor prognostic sign for overall outcome. In such patients, 15% progress to end-stage renal disease, with 40% later experiencing fatal cardiovascular disease, infection, or liver failure. As indicated above, the majority of cases are associated with hepatitis C infection. In such patients, treatment with antiviral therapy (Chap. 360) can prove beneficial and should be considered first-line therapy for hepatitis C–associated cryoglobulinemic vasculitis. Clinical improvement with antiviral therapy is dependent on the virologic response. Patients who clear hepatitis C from the blood have objective improvement in their vasculitis along with significant reductions in levels of circulating cryoglobulins, IgM, and rheumatoid factor. However, substantial portions of patients with hepatitis C do not have a sustained virologic response to such therapy, and the vasculitis typically


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InternalMed_Harrison. cryoglobulins, IgM, and rheumatoid factor. However, substantial portions of patients with hepatitis C do not have a sustained virologic response to such therapy, and the vasculitis typically relapses with the return of viremia. While transient improvement can be observed with glucocorticoids, a complete response is seen in only 7% of patients. Plasmapheresis and cytotoxic agents have been used in anecdotal reports. These observations have not been confirmed, and such therapies carry significant risks. Randomized trials with rituximab (anti-CD20) in hepatitis C–associated cryoglobulinemic vasculitis have provided evidence of benefit such that this agent should be considered in patients with active vasculitis either in combination with antiviral therapy or alone in patients who have relapsed through, are intolerant to, or have con-2191 traindications to antiviral agents.


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InternalMed_Harrison. The potential for vasculitis to affect single organs has become increasingly recognized.This has beendefinedasvasculitisin arteriesorveins of any size in a single organ that has no features that indicate that it is a limited expression of a systemic vasculitis. Examples include isolated aortitis, testicular vasculitis, vasculitis of the breast, isolated cutaneous vasculitis, and primary CNS vasculitis. In some instances, this may be discovered at the time of surgery such as orchiectomy for a testicular mass where there is concern for neoplasm that is found instead to be vasculitis. Some patients originally diagnosed with single-organ vasculitis may later develop additional manifestations of a more systemic disease. In instances where there is no evidence of systemic vasculitis and the affected organ has been removed in its entirety, the patient may be followed closely without immunosuppressive therapy. In other instances, such as primary CNS vasculitis or some patients with isolated


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InternalMed_Harrison. organ has been removed in its entirety, the patient may be followed closely without immunosuppressive therapy. In other instances, such as primary CNS vasculitis or some patients with isolated cutaneous vasculitis, medical intervention is warranted.


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InternalMed_Harrison. Theterm cutaneous vasculitis isdefinedbroadlyasinflammationofthe blood vessels of the dermis. Due to its heterogeneity, cutaneous vasculitis has been described by a variety of terms including hypersensitivity vasculitis and cutaneous leukocytoclastic angiitis. However, cutaneous vasculitis is not one specific disease but a manifestation that can be seen in a variety of settings. In >70% of cases, cutaneous vasculitis occurs either as part of a primary systemic vasculitis or as a secondary vasculitis related to an inciting agent or an underlying disease (see “Secondary Vasculitis,” below). In the remaining 30% of cases, cutaneous vasculitis occurs idiopathically. Cutaneous vasculitis represents the most commonly encountered vasculitis in clinical practice. The exact incidence of idiopathic cutaneous vasculitis has not been determined due to the predilection for cutaneous vasculitis to be associated with an underlying process and the variability of its clinical course.


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InternalMed_Harrison. The typical histopathologic feature of cutaneous vasculitis is the presence of vasculitis of small vessels. Postcapillary venules are the most commonly involved vessels; capillaries and arterioles may be involved less frequently. This vasculitis is characterized by a leukocytoclasis,a term that refers to the nuclear debris remaining from the neutrophils that have infiltrated in and around the vessels during the acute stages. In the subacute or chronic stages, mononuclear cells predominate; in certain subgroups, eosinophilic infiltration is seen. Erythrocytes often extravasate from the involved vessels, leading to palpable purpura. Cutaneous arteritis can also occur, which involves slightly larger-sized vessels within the dermis.


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InternalMed_Harrison. The hallmark of idiopathic cutaneous vasculitis is the predominance of skin involvement. Skin lesions may appear typically as palpable purpura; however, other cutaneous manifestations of the vasculitis may occur, including macules, papules, vesicles, bullae, subcutaneous nodules, ulcers, and recurrent or chronic urticaria. The skin lesions may be pruritic or even quite painful, with a burning or stinging sensation. Lesions most commonly occur in the lower extremities in ambulatory patients or in the sacral area in bedridden patients due to the effects of hydrostatic forces on the postcapillary venules. Edema may accompany certain lesions, and hyperpigmentation often occurs in areas of recurrent or chronic lesions. There are no specific laboratory tests diagnostic of idiopathic cutaneous vasculitis. A mild leukocytosis with or without eosinophilia is characteristic, as is an elevated ESR. Laboratory studies should be


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InternalMed_Harrison. The Vasculitis Syndromes 2192 aimed toward ruling out features to suggest an underlying disease or a systemic vasculitis. The diagnosis of cutaneous vasculitis is made by the demonstration of vasculitis on biopsy. An important diagnostic principle in patients with cutaneous vasculitis is to search for an etiology of the vasculitis—be it an exogenous agent, such as a drug or an infection, or an endogenous condition, such as an underlying disease (Fig. 385-1). In addition, a careful physical and laboratory examination should be performed to rule out the possibility of systemic vasculitis. This should start with the least invasive diagnostic approach and proceed to the more invasive only if clinically indicated.


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InternalMed_Harrison. When an antigenic stimulus is recognized as the precipitating factor in the cutaneous vasculitis, it should be removed; if this is a microbe, appropriate antimicrobial therapy should be instituted. If the vasculitis is associated with another underlying disease, treatment of the latter often results in resolution of the former. In situations where disease is apparently self-limited, no therapy, except possibly symptomatic therapy, is indicated. When cutaneous vasculitis persists and when there is no evidence of an inciting agent, an associated disease, or an underlying systemic vasculitis, the decision to treat should be based on weighing the balance between the degree of symptoms and the risk of treatment. Some cases of idiopathic cutaneous vasculitis resolve spontaneously, whereas others remit and relapse. In patients with persistent vasculitis, a variety of therapeutic regimens have been tried with variable results. In general, the treatment of idiopathic cutaneous vasculitis has


InternalMed_Harrison

InternalMed_Harrison. remit and relapse. In patients with persistent vasculitis, a variety of therapeutic regimens have been tried with variable results. In general, the treatment of idiopathic cutaneous vasculitis has not been satisfactory. Fortunately, since the disease is generally limited to the skin, this lack of consistent response to therapy usually does not lead to a life-threatening situation. Agents with which there have been anecdotal reports of success include dapsone, colchicine, hydroxychloroquine, and nonsteroidal anti-inflammatory agents. Glucocorticoids are often used in the treatment of idiopathic cutaneous vasculitis. Therapy is usually instituted as prednisone, 1 mg/kg per day, with rapid tapering where possible, either directly to discontinuation or by conversion to an alternate-day regimen followed by ultimate discontinuation. In cases that prove refractory to glucocorticoids, a trial of a cytotoxic agent may be indicated. Patients with chronic vasculitis isolated to cutaneous venules


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InternalMed_Harrison. followed by ultimate discontinuation. In cases that prove refractory to glucocorticoids, a trial of a cytotoxic agent may be indicated. Patients with chronic vasculitis isolated to cutaneous venules rarely respond dramatically to any therapeutic regimen, and cytotoxic agents should be used only as a last resort in these patients. Methotrexate and azathioprine have been used in such situations in anecdotal reports. Although cyclophosphamide is the most effective therapy for the systemic vasculitides, it should almost never be used for idiopathic cutaneous vasculitis because of the potential toxicity.


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InternalMed_Harrison. Primary CNS vasculitis is an uncommon clinicopathologic entity characterized by vasculitis restricted to the vessels of the CNS without otherapparentsystemicvasculitis.Theinflammatoryprocessisusually composed of mononuclear cell infiltrates with or without granuloma formation.


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InternalMed_Harrison. Patients may present with headaches, altered mental function, and focal neurologic defects. Systemic symptoms are generally absent. Devastating neurologic abnormalities may occur depending on the extent of vessel involvement. The diagnosis can be suggested by abnormal magnetic resonance imaging of the brain, an abnormal lumbar puncture, and/or demonstration of characteristic vessel abnormalities on arteriography (Fig. 385-4), but it is confirmed by biopsy of the brainparenchymaandleptomeninges.Intheabsenceofabrainbiopsy, care should be taken not to misinterpret as true primary vasculitis arteriographic abnormalities that might actually be related to another cause. An important entity in the differential diagnosis is reversible cerebral vasoconstrictive syndrome, which typically presents with “thunderclap” headache and is associated with arteriographic abnormalities that mimic primary CNS vasculitis that are reversible. Other diagnostic considerations include infection,


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InternalMed_Harrison. presents with “thunderclap” headache and is associated with arteriographic abnormalities that mimic primary CNS vasculitis that are reversible. Other diagnostic considerations include infection, atherosclerosis, emboli, connective tissuedisease,sarcoidosis,malignancy,anddrug-associated causes. The prognosis of granulomatous primary CNS vasculitis is poor; however, some reports indicate that glucocorticoid therapy, alone or together with cyclophosphamide administered as described above, has induced clinical remissions.


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InternalMed_Harrison. FIGUrE 385-4 Cerebral arteriogram from a 32-year-old male with primary central nervous system vasculitis. Dramaticbeading(arrow)typicalofvasculitisisseen. Behçet’s disease is a clinicopathologic entity characterized by recurrent episodes of oral and genital ulcers, iritis, and cutaneous lesions. The underlying pathologic process is a leukocytoclastic venulitis, although vessels of any size and in any organ can be involved. This disorder is described in detail in Chap. 387. Cogan’s syndrome is characterized by interstitial keratitis together with vestibuloauditory symptoms. It may be associated with a systemic vasculitis, particularly aortitis with involvement of the aortic valve. Glucocorticoids are the mainstay of treatment. Initiation of treatment as early as possible after the onset of hearing loss improves the likelihood of a favorable outcome.


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InternalMed_Harrison. Kawasaki disease is an acute, febrile, multisystem disease of children. Some 80% of cases occur prior to the age of 5, with the peak incidence occurring at ≤2 years. It is characterized by nonsuppurative cervical adenitis and changes in the skin and mucous membranes such as edema; congested conjunctivae; erythema of the oral cavity, lips, and palms; and desquamation of the skin of the fingertips. Although the disease is generally benign and self-limited, it is associated with coronary artery aneurysms in ∼25% of cases, with an overall case fatality rate of 0.5–2.8%. These complications usually occur between the third and fourth weeks of illness during the convalescent stage. Vasculitis of the coronary arteries is seen in almost all the fatal cases that have been autopsied. There is typical intimal proliferation and infiltration of the vesselwallwithmononuclearcells.Beadlikeaneurysmsandthromboses may be seen along the artery. Other manifestations include pericarditis, myocarditis,


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InternalMed_Harrison. intimal proliferation and infiltration of the vesselwallwithmononuclearcells.Beadlikeaneurysmsandthromboses may be seen along the artery. Other manifestations include pericarditis, myocarditis, myocardial ischemia and infarction, and cardiomegaly.


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InternalMed_Harrison. Apart from the up to 2.8% of patients who develop fatal complications, the prognosis of this disease for uneventful recovery is excellent. High-dose IV γ-globulin (2 g/kg as a single infusion over 10 h) together with aspirin (100 mg/kg per day for 14 days followed by 3–5 mg/kg per day for several weeks) have been shown to be effective in reducingtheprevalenceofcoronaryarteryabnormalitieswhenadministered early in the course of the disease. Surgery may be necessary for Kawasaki disease patients who have giant coronary artery aneurysms or other coronary complications. Surgical treatment most commonly includes thromboendarterectomy, thrombus clearing, aneurysmal reconstruction, and coronary artery bypass grafting.


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InternalMed_Harrison. Somepatientswithsystemicvasculitismanifestclinicopathologiccharacteristics that do not fit precisely into any specific disease but have overlappingfeaturesofdifferentvasculitides.Activesystemicvasculitis in such settings has the same potential for causing irreversible organ system damage as when it occurs in one of the defined syndromes listed in Table 385-1. The diagnostic and therapeutic considerations as well as the prognosis for these patients depend on the sites and severity of active vasculitis. Patients with vasculitis that could potentially cause irreversible damage to a major organ system should be treated as described under “Granulomatosis with Polyangiitis (Wegener’s).”


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InternalMed_Harrison. Vasculitis associated with drug reactions usually presents as palpable purpura that may be generalized or limited to the lower extremities or other dependent areas; however, urticarial lesions, ulcers, and hemorrhagic blisters may also occur (Chap. 74). Signs and symptoms may be limited to the skin, although systemic manifestations such as fever, malaise, and polyarthralgias may occur. Although the skin is the predominant organ involved, systemic vasculitis may result from drug reactions. Drugs that have been implicated in vasculitis include allopurinol, thiazides, gold, sulfonamides, phenytoin, and penicillin (Chap. 74).


InternalMed_Harrison

InternalMed_Harrison. An increasing number of drugs have been reported to cause vasculitis associated with antimyeloperoxidase ANCA. Of these, the best evidenceof causality existsforhydralazineand propylthiouracil.Theclinical manifestations in ANCA-positive drug-induced vasculitis can range from cutaneous lesions to glomerulonephritis and pulmonary hemorrhage. Outside of drug discontinuation, treatment should be based on the severity of the vasculitis. Patients with immediately life-threatening small-vessel vasculitis should initially be treated with glucocorticoids and cyclophosphamide as described for granulomatosis with polyangiitis(Wegener’s).Followingclinicalimprovement,considerationmaybe given for tapering such agents along a more rapid schedule.


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InternalMed_Harrison. These reactions are characterized by the occurrence of fever, urticaria, polyarthralgias, and lymphadenopathy 7–10 days after primary exposure and 2–4 days after secondary exposure to a heterologous protein (classicserumsickness)oranonproteindrugsuchaspenicillinorsulfa (serum sickness–like reaction). Most of the manifestations are not due to a vasculitis; however, occasional patients will have typical cutaneous venulitis that may progress rarely to a systemic vasculitis. Certain infections may directly trigger an inflammatory vasculitic process. For example, rickettsias can invade and proliferate in the endothelial cells of small blood vessels causing a vasculitis (Chap. 211). In addition, the inflammatory response around blood vessels associated 21 with certain systemic fungal diseases such as histoplasmosis (Chap.


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InternalMed_Harrison. 236) may mimic a primary vasculitic process. A leukocytoclastic vasculitis predominantly involving the skin with occasional involvement of other organ systems may be a minor component of many other infections. These include subacute bacterial endocarditis, Epstein-Barr virus infection, HIV infection, and a number of other infections. Vasculitis can be associated with certain malignancies, particularly lymphoid or reticuloendothelial neoplasms. Leukocytoclastic venulitis confinedtotheskinisthemostcommonfinding;however,widespread systemic vasculitis may occur. Of particular note is the association of hairy cell leukemia (Chap. 134) with polyarteritis nodosa.


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InternalMed_Harrison. A number of connective tissue diseases have vasculitis as a secondary manifestation of the underlying primary process. Foremost among these are systemic lupus erythematosus (Chap. 378), rheumatoid arthritis (Chap. 380), inflammatory myositis (Chap. 388), relapsing polychondritis (Chap. 389), and Sjren’s syndrome (Chap. 383). The most common form of vasculitis in these conditions is the small-vessel venulitis isolated to the skin. However, certain patients may develop a fulminant systemic necrotizing vasculitis. Secondary vasculitis has also been observed in association with ulcerative colitis, congenital deficiencies of various complement components, sarcoidosis, primary biliary cirrhosis, ≥1-antitrypsin deficiency, and intestinal bypass surgery. The Vasculitis Syndromes


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InternalMed_Harrison. The Vasculitis Syndromes Atlas of the Vasculitic Syndromes Carol A. Langford, Anthony S. Fauci Diagnosis of the vasculitic syndromes is usually based on characteristic histologic or arteriographic findings in a patient who has clinically 386e compatible features. The images provided in this atlas highlight some of the characteristic histologic and radiographic findings that may be seen in the vasculitic diseases. These images demonstrate the importance that tissue histology may have in securing the diagnosis of vasculitis, the utility of diagnostic imaging in the vasculitic diseases, and the improvements in the care of vasculitis patients that have resulted from radiologic innovations.


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InternalMed_Harrison. Tissue biopsies represent vital information in many patients with a suspected vasculitic syndrome, not only in confirming the presence of vasculitis and other characteristic histologic features, but also in ruling out other diseases that can have similar clinical presentations. The determination of where biopsies should be performed is based on the presence of clinical disease in an affected organ, the likelihood of a positive diagnostic yield from data contained in the published literature, and the risk of performing a biopsy in an affected site. Common sites where biopsies may be performed include the lung, kidney, and skin. Other sites such as sural nerve, brain, testicle, and gastrointestinal tissues may also demonstrate features of vasculitis and be appropriate locations for biopsy when clinically affected.


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InternalMed_Harrison. Surgical biopsies of radiographically abnormal pulmonary parenchyma have a diagnostic yield of 90% in patients with granulomatosis with polyangiitis (Wegener’s) and play an important role in ruling out infection or malignancy. The yield of lung biopsies is highly associated with amount of tissue that can be obtained, and transbronchial biopsies, while less invasive, have a yield of only 7%. Lung biopsies also play an important role in microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), and any vasculitic disease where an immunosuppressed patient has pulmonary disease that is suspected to be an infection.


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InternalMed_Harrison. Kidney biopsy findings of a focal, segmental, crescentic, necrotizing glomerulonephritis with few to no immune complexes (pauci-immune glomerulonephritis) are characteristic in patients with granulomatosis with polyangiitis (Wegener’s), microscopic polyangiitis, or eosinophilic granulomatosis with polyangiitis (Churg-Strauss), who have active renal disease. These findings not only distinguish these entities from other causes of glomerulonephritis, but can also confirm the presence of active glomerulonephritis that requires treatment. As a result, renal biopsies can also be helpful to guide management decisions in these diseases when an established patient has worsening renal function and an inactive or equivocal urine sediment. Cryoglobulinemic vasculitis and IgA vasculitis (Henoch-Schlein) are other vasculitides 386e-1 where renal involvement may occur and where biopsy may be important in diagnosis or prognosis.


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InternalMed_Harrison. Biopsies of the skin are commonly performed and are well tolerated. Because not all purpuric or ulcerative lesions are due to vasculitis, skin biopsy plays an important role to confirm the presence of vasculitis as the cause of the manifestation. Cutaneous vasculitis represents the most common vasculitic feature that affects people and can be seen in a broad spectrum of settings including infections, medications, malignancies, and connective tissue diseases. As a result, for systemic vasculitides that will require aggressive immunosuppressive treatment, a skin biopsy may not represent sufficient evidence to secure the diagnosis.


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InternalMed_Harrison. Diagnostic imaging represents a critical assessment tool in patients who are known or suspected to have a systemic vasculitic disease. Imaging contributes unique information about the patient that, when taken together with the history, physical examination, and laboratory determinations, can guide the differential diagnosis and the subsequent assessment or treatment plan. A diverse range of imaging techniques is used in the assessment of vasculitis including plain radiography, ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography, and catheter-directed dye arteriography. These procedures have specific utilities that can allow differing perspectives on the spectrum and severity of vasculitis.


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InternalMed_Harrison. For vasculitic diseases that involve the largeor medium-sized blood vessels, arteriography provides information regarding blood vessel stenoses or aneurysms that can support the diagnosis. Catheter-directed dye arteriography provides information on central blood pressure and offers the most precise detail regarding vessel lumen dimensions but carries risks related to dye exposure and the invasive nature of the procedure. Advancements in magnetic resonance (MR) and CT arteriography have brought about noninvasive options to view the lumen and vessel wall, thus enhancing the ability to perform serial studies for patient monitoring in large-vessel vasculitis. However, in patients suspected to have a medium-vessel vasculitis such as polyarteritis nodosa, catheter-directed dye arteriography should still be performed because MR and CT arteriograms do not currently have sufficient resolution to visualize arteries of this size.


InternalMed_Harrison

InternalMed_Harrison. Although vasculitis involving the small blood vessels cannot be directly visualized, diagnostic imaging plays an essential role in detecting tissue injury that occurs as result of blood vessel and tissue inflammation. In granulomatosis with polyangiitis (Wegener’s), 80% of patients may have pulmonary involvement during their disease course. Chest imaging should be obtained whenever active disease is suspected, because up to one-third of patients with radiographic abnormalities are asymptomatic. Pulmonary imaging is also important to detect complications of vasculitis therapy such as opportunistic pneumonias and medication-related pneumonitis. CHAPTER 386e Atlas of the Vasculitic Syndromes Figure 386e-1 Bilateral nodular infiltrates seen on computed tomography of the chest in a 40-year-old woman with granulomatosis with polyangiitis (Wegener’s).


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InternalMed_Harrison. Figure 386e-1 Bilateral nodular infiltrates seen on computed tomography of the chest in a 40-year-old woman with granulomatosis with polyangiitis (Wegener’s). Figure 386e-2 Computed tomography of the chest in two patients with granulomatosis with polyangiitis (Wegener’s) demonstrating (A) single and (B) multiple cavitary lung lesions. Figure 386e-3 Bilateral ground-glass infiltrates due to alveolar hemorrhage from pulmonary capillaritis as seen in the same patient by (A) chest radiograph and (B) computed tomography. This manifestation can occur in granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis. Figure 386e-5 Computed tomography of the orbits in a patient with granulomatosis with polyangiitis (Wegener’s) who presented with right-eye proptosis. The image demonstrates inflammatory tissue extending from the ethmoid sinus through the lamina papyracea and filling the orbital space.


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InternalMed_Harrison. the right upper lobe due to bacterial pneumonia in an immunosuppressed patient with granulomatosis with polyangiitis (Wegener’s). Collapse of the left upper lobe secondary to endobronchial stenosis from granulomatosis with polyangiitis (Wegener’s) also is seen on this image. Figure 386e-6 Computed tomography of the sinuses in two patients with granulomatosis with polyangiitis (Wegener’s). (A) Mucosal thickening of the bilateral maxillary sinuses and a perforation of the nasal septum. (B) Osteitis with obliteration of the left maxillary sinus in a patient with long-standing sinus disease. Figure 386e-7 Computed tomography of the chest demonstrat-ing a large pericardial effusion in a patient with eosinophilic granulo-matosis with polyangiitis (Churg-Strauss). Cardiac involvement is an important cause of morbidity and mortality in eosinophilic granulo-matosis with polyangiitis and can include myocarditis, endocarditis, and pericarditis. CHAPTER 386e Atlas of the Vasculitic Syndromes


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InternalMed_Harrison. CHAPTER 386e Atlas of the Vasculitic Syndromes Figure 386e-8 Arteriogram of a 40-year-old man with polyarteri-tis nodosa demonstrating microaneurysms in the hepatic circulation. Figure 386e-9 Arteriogram of a 19-year-old man with polyarteri-tis nodosa demonstrating multiple microaneurysms in the renal cir-culation. The patient presented with headache and severe hyperten-sion that was due to medium-vessel vasculitis affecting the kidney. Figure 386e-11 Upper-extremity arteriogram demonstrating a long stenotic lesion of the axillary artery in a 75-year-old female with giant cell arteritis. Figure 386e-10 Cerebral arteriogram demonstrating beading along branches of the internal carotid artery in a patient with primary central nervous system vasculitis.


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InternalMed_Harrison. Figure 386e-10 Cerebral arteriogram demonstrating beading along branches of the internal carotid artery in a patient with primary central nervous system vasculitis. Figure 386e-12 Magnetic resonance imaging demonstrating extensive aneurysmal disease of the thoracic aorta in an 80-year-old female. The patient had been diagnosed with biopsy-proven giant cell arteritis 10 years prior to presenting with this aneurysm. Figure 386e-13 Arteriogram of the aortic arch demonstrating complete occlusion of the left common carotid artery just after its origin from the aorta. This 20-year-old female presented with syncope and was subsequently diagnosed with Takayasu arteritis. Figure 386e-14 Arteriogram demonstrating stenosis of the abdominal aorta in a 25-year-old female with Takayasu arteritis. Figure 386e-15 Arteriogram of the hand demonstrating arterial skip lesions and vessel cutoffs in a patient with cryoglobulinemic vas-culitis due to multiple myeloma.


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InternalMed_Harrison. Figure 386e-15 Arteriogram of the hand demonstrating arterial skip lesions and vessel cutoffs in a patient with cryoglobulinemic vas-culitis due to multiple myeloma. Figure 386e-16 Lung histology in granulomatosis with polyangi-itis (Wegener’s). This lung biopsy shows areas of geographic necrosis with a border of histiocytes and giant cells. There is also vasculitis with neutrophils, lymphocytes, and giant cells infiltrating the wall of an artery. CHAPTER 386e Atlas of the Vasculitic Syndromes Figure 386e-17 Lung histology in microscopic polyangiitis. This lung biopsy demonstrates hemorrhage in the alveolar spaces due to capillaritis in a patient with microscopic polyangiitis. Similar find-ings can also be seen in granulomatosis with polyangiitis (Wegener’s) and less commonly in eosinophilic granulomatosis with polyangiitis (Churg-Strauss).


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InternalMed_Harrison. Figure 386e-18 Kidney biopsy in granulomatosis with polyangiitis (Wegener’s). This renal biopsy shows a crescentic and necrotizing glomerulonephritis. These findings were focal and segmental with normal and scarred glomeruli also being found in the biopsy. By immunofluorescence and electron microscopy, no immune deposits were present, indicative of a pauci-immune glomerulonephritis. Similar findings can also be seen in microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Figure 386e-19 Sural nerve biopsy in polyarteritis nodosa. This sural nerve biopsy was performed in a patient with polyarteritis nodo-sa, who had presented with a mononeuritis multiplex. Neutrophils are seen infiltrating all layers of this medium-sized vessel, which resulted in vessel occlusion and nerve infraction.


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InternalMed_Harrison. Figure 386e-20 Temporal artery biopsy in giant cell arteritis. This temporal artery biopsy demonstrates a panmural infiltration of mono-nuclear cells and lymphocytes that are particularly seen in the media and adventitia. Scattered giant cells are also present. Figure 386e-21 Cutaneous vasculitis. This skin biopsy reveals two arterioles beneath the dermis with a neutrophilic inflammatory infiltrate in and around the vessel wall with leukocytoclasis (nuclear debris). While such features are diagnostic of vasculitis, they can be seen in a variety of settings and are not specific for any single disease.


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InternalMed_Harrison. Figure 386e-22 Granulomatous primary central nervous system vasculitis. This brain biopsy demonstrates a medium-sized artery with granulomatous inflammation present within the vessel wall indicative of a granulomatous vasculitis. This patient presented with progressive headache, clinical and radiographic features of a stroke, and had arteriographic features consistent with vasculitis. Because no evidence of vasculitis could be found outside of the brain, this was consistent with granulomatous primary central nervous system vasculitis. Haralampos M. Moutsopoulos DEFINITION, INCIDENCE, aND PrEVaLENCE Behçet’s syndrome is a multisystem disorder presenting with recurrent oral and genital ulcerations as well as ocular involvement. The diagnosis is clinical and based on internationally agreed diagnostic criteria (Table 387-1).


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InternalMed_Harrison. ThesyndromeaffectsyoungmalesandfemalesfromtheMediterranean region, the Middle East, and the Far East, suggesting a link with the ancient Silk Route. Males and females are affected equally, but males often have more severe disease. Blacks are very infrequently affected.


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InternalMed_Harrison. The etiology and pathogenesis of this syndrome remain obscure. The disease appears to be in the crossroads of autoinflammatory and autoimmune disorders. The main pathologic lesion is systemic perivasculitis with early neutrophil infiltration and endothelial swelling. In some patients, diffuse inflammatory disease, involving all layers of large vesselsandresultingtoformationofpseudoaneurysms,suggestsvasculitis of vasa vasorum. Apart from activated neutrophils, increased numbers of infiltrating TH1, TH17, cytotoxic CD8+, and γδ T cells are observed, suggesting a link between innate and adaptive autoreactive immune response. Circulating autoantibodies against α-enolase of endothelial cells, selenium binding protein, and anti-Saccharomyces cerevisiae antibodies have been observed, but their pathogenic role remains unclear. A recent genome-wide association study confirmed the known association of Behçet’s syndrome with HLA-B*51 and identified a second, independent association within the


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InternalMed_Harrison. pathogenic role remains unclear. A recent genome-wide association study confirmed the known association of Behçet’s syndrome with HLA-B*51 and identified a second, independent association within the major histocompatibility complex (MHC) class I region. In addition, an association with interleukin (IL) 10 and the IL-23R–IL-12RB2 locus was also observed. Interestingly, the disease-associated IL-10 variant was correlated with diminished mRNA expression and low protein production.


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InternalMed_Harrison. The recurrent aphthous ulcerations are a sine qua non for the diagnosis. The ulcers are usually painful, are shallow or deep with a central yellowish necrotic base, appear singly or in crops, and are located anywhere in the oral cavity. Small ulcers, less than 10 mm in diameter, are seen in 85% of patients, whereas large or herpetiform lesions are less frequent. The ulcers persist for 1–2 weeks and subside without leaving scars. The genital ulcers are less common but more specific, are painful, do not affect the glans penis or urethra, and produce scrotal scars. Skin involvement is observed in 80% of patients and includes folliculitis, erythema nodosum,an acne-like exanthem,and, infrequently, vasculitis, Sweet syndrome, and pyoderma gangrenosum. Nonspecific skin inflammatory reactivity to any scratches or intradermal saline injection (pathergy test) is a common and specific manifestation.


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InternalMed_Harrison. Eye involvement with scarring and bilateral panuveitis is the most dreadedcomplication,sinceitoccasionallyprogressesrapidlytoblindness. Theeyedisease,occurring in50% ofpatients,is usuallypresentat the onsetbut may alsodevelop within thefirst few years. Inaddition to iritis, posterior uveitis, retinal vessel occlusions, and optic neuritis can be seen in some patients with the syndrome. Nondeforming arthritis or arthralgias are seen in 50% of patients and affect the knees and ankles. Recurrent oral ulceration plus two of the following:


InternalMed_Harrison

InternalMed_Harrison. Nondeforming arthritis or arthralgias are seen in 50% of patients and affect the knees and ankles. Recurrent oral ulceration plus two of the following: Superficial or deep peripheral vein thrombosis is seen in 30% of patients. Pulmonary emboli are a rare complication. The superior vena cava is obstructed occasionally, producing a dramatic clinical picture. Arterial involvement occurs in less than 5% of patients and presents with aortitis or peripheral arterial aneurysm and arterial thrombosis. Pulmonary artery vasculitis presenting with dyspnea, cough,chestpain,hemoptysis,andinfiltratesonchestroentgenograms has been reported in 5% of patients and should be differentiated from thromboembolic disease since it warrants anti-inflammatory and not thrombolytic therapy.


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InternalMed_Harrison. Neurologic involvement (5–10%) appears mainly in the parenchymal form (80%); it is associated with brainstem involvement and has a serious prognosis (central nervous system [CNS]-Behçet’s syndrome). IL-6 is persistently raised in cerebrospinal fluid of these patients. Cerebral venous thrombosis is most frequently observed in the superiorsagittalandtransversesinusesandisassociatedwithheadacheand increased intracranial pressure. Magnetic resonance imaging (MRI) and/or proton magnetic resonance spectroscopy (MRS) are very sensitive and should be employed if CNS-Behçet’s syndrome is suspected. Gastrointestinal involvement is seen more frequently in patients from Japan and consists of mucosal ulcerations of the gut, resembling Crohn’s disease. Epididymitis is seen in 5% of patients, whereas amyloidosis of AA type and glomerulonephritis are uncommon.


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InternalMed_Harrison. Epididymitis is seen in 5% of patients, whereas amyloidosis of AA type and glomerulonephritis are uncommon. Laboratory findings are mainly nonspecific indices of inflammation, such as leukocytosis and elevated erythrocyte sedimentation rate, as well as C-reactive protein levels. The severity of the syndrome usually abates with time. Apart from the patients with CNS-Behçet’s syndrome and major vessel disease, the life expectancy seems to be normal and the only serious complication is blindness.


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InternalMed_Harrison. Mucous membrane involvement may respond to topical glucocorticoids in the form of mouthwash or paste. In more serious cases, thalidomide (100 mg/d) is effective. Thrombophlebitis is treated with aspirin, 325 mg/d. Colchicine can be beneficial for the mucocutaneous manifestations and arthritis. Uveitis and CNS-Behçet’s syndrome require systemic glucocorticoid therapy (prednisone, 1 mg/kg per day) and azathioprine (2–3 mg/kg per day). Cyclosporine (5 mg/kg) has been used for sight-threatening uveitis, alone or in combination with azathioprine. Pulse doses of cyclophosphamide are useful early in the course of the disease for pulmonary or peripheral arterial aneurysms. Anti–tumor necrosis factor therapy is recommended in panuveitis refractory to immunosuppressives. Administration of this therapy improves visual acuity in more than two-thirds of patients. polymyositis, Dermatomyositis, 388 and Inclusion Body Myositis Marinos C. Dalakas


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InternalMed_Harrison. polymyositis, Dermatomyositis, 388 and Inclusion Body Myositis Marinos C. Dalakas The inflammatory myopathies represent the largest group of acquired and potentially treatable causes of skeletal muscle weakness. They are classified into three major groups: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). The prevalence of the inflammatory myopathies is estimated at 1 in 100,000. PM as a stand-alone entity is a rare disease. DM affects both children and adults and women more often than men. IBM is three times more frequent in men than in women, more common in whites than blacks, and is most likely to affect persons age >50 years.


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InternalMed_Harrison. Thesedisorderspresentas progressiveandsymmetricmuscleweakness except for IBM, which can have an asymmetric pattern. Patients usually report increasing difficulty with everyday tasks requiring the use of proximal muscles, such as getting up from a chair, climbing steps, stepping onto a curb, lifting objects, or combing hair. Fine-motor movements that depend on the strength of distal muscles, such as buttoning a shirt, sewing, knitting, or writing, are affected only late in the course of PM and DM, but fairly early in IBM. Falling is common in IBM because of early involvement of the quadriceps muscle, with buckling of the knees. Ocular muscles are spared, even in advanced, untreated cases; if these muscles are affected, the diagnosis of inflammatory myopathy should be questioned. Facial muscles are unaffectedinPMandDM,butmildfacialmuscleweaknessiscommon in patients with IBM. In all forms of inflammatory myopathy, pharyngeal and neck-flexor muscles are often involved, causing dysphagia


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InternalMed_Harrison. are unaffectedinPMandDM,butmildfacialmuscleweaknessiscommon in patients with IBM. In all forms of inflammatory myopathy, pharyngeal and neck-flexor muscles are often involved, causing dysphagia or difficulty in holding up the head (head drop). In advanced and rarely in acute cases, respiratory muscles may also be affected. Severe weakness, if untreated, is almost always associated with muscle wasting. Sensation remains normal. The tendon reflexes are preserved but may be absent in severely weakened or atrophied muscles, especially in IBM, where atrophy of the quadriceps and the distal muscles is common. Myalgia and muscle tenderness may occur in a small number of patients, usually early in the disease, and particularly in DM associated with connective tissue disorders. Weakness in PM and DM progresses subacutely over a period of weeks or months and rarely acutely; by contrast, IBM progresses very slowly, over years, simulating a late-life muscular dystrophy (Chap. 462e) or slowly


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InternalMed_Harrison. and DM progresses subacutely over a period of weeks or months and rarely acutely; by contrast, IBM progresses very slowly, over years, simulating a late-life muscular dystrophy (Chap. 462e) or slowly progressive motor neuron disorder (Chap. 452).


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InternalMed_Harrison. aSystemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, systemic sclerosis, mixed connective tissue disease. bCrohn’s disease, vasculitis, sarcoidosis, primary biliary cirrhosis, adult celiac disease, chronic graft-versus-host disease, discoid lupus, ankylosing spondylitis, Behçet’s syndrome, myasthenia gravis, acne fulminans, dermatitis herpetiformis, psoriasis, Hashimoto’s disease, granulomatous diseases, agammaglobulinemia, monoclonal gammopathy, hypereosinophilic syndrome, Lyme disease, Kawasaki disease, autoimmune thrombocytopenia, hypergammaglobulinemic purpura, hereditary complement deficiency, IgA deficiency. cHIV (human immunodeficiency virus) and HTLV-1 (human T cell lymphotropic virus type 1). dDrugs include penicillamine (dermatomyositis and polymyositis), zidovudine (polymyositis), statins (necrotizing, toxic, or autoimmune myositis), and contaminated tryptophan (dermatomyositis-like illness). Other myotoxic drugs may cause myopathy but not an


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InternalMed_Harrison. zidovudine (polymyositis), statins (necrotizing, toxic, or autoimmune myositis), and contaminated tryptophan (dermatomyositis-like illness). Other myotoxic drugs may cause myopathy but not an inflammatory myopathy (see text for details). eParasites (protozoa, cestodes, nematodes), tropical and bacterial myositis (pyomyositis).


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InternalMed_Harrison. Polymyositis The actual onset of PM is often not easily determined, 2195 and patients typically delay seeking medical advice for several weeks or even months. This is in contrast to DM, in which the rash facilitates early recognition (see below). PM mimics many other myopathies and is a diagnosis of exclusion. It is a subacute inflammatory myopathy affecting adults, and rarely children, who do not have any of the following: rash, involvement of the extraocular and facial muscles, family history of a neuromuscular disease, history of exposure to myotoxic drugs or toxins, endocrinopathy, neurogenic disease, muscular dystrophy, biochemical muscle disorder (deficiency of a muscle enzyme), or IBM as excluded by muscle biopsy analysis (see below). As an isolated entity, PM is a rare (and overdiagnosed) disorder; more commonly, PM occurs in association with a systemic autoimmune or connective tissue disease or with a known viral or bacterial infection. Drugs, especially D-penicillamine,


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InternalMed_Harrison. disorder; more commonly, PM occurs in association with a systemic autoimmune or connective tissue disease or with a known viral or bacterial infection. Drugs, especially D-penicillamine, statins, or zidovudine (AZT), may also trigger an inflammatory myopathy similar to PM.


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InternalMed_Harrison. Dermatomyositis DM is a distinctive entity identified by a character istic rash accompanying, or more often preceding, muscle weakness. The rash may consist of a blue-purple discoloration on the upper eyelids with edema (heliotrope rash; see Fig. 73-3), a flat red rash on the face and upper trunk, and erythema of the knuckles with a raised violaceous scaly eruption (Gottron’s sign; see Fig. 73-4). The erythematous rash can also occur on other body surfaces, including the knees, elbows, malleoli, neck and anterior chest (often in a V sign), or back and shoulders (shawl sign), and may worsen after sun exposure. In some patients, the rash is pruritic, especially on the scalp, chest, and back. Dilated capillary loops at the base of the fingernails are also characteristic. The cuticles may be irregular, thickened, and distorted, and the lateral and palmar areas of the fingers may become rough and cracked, with irregular, “dirty” horizontal lines, resembling mechanic’s hands. The weakness


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InternalMed_Harrison. irregular, thickened, and distorted, and the lateral and palmar areas of the fingers may become rough and cracked, with irregular, “dirty” horizontal lines, resembling mechanic’s hands. The weakness can be mild, moderate, or severe enough to lead to quadriparesis. At times, the muscle strength appears normal, hence the term dermatomyositis sine myositis. When muscle biopsy is performed in such cases, however, significant perivascular and perimysial inflammation is often seen.


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InternalMed_Harrison. DM usually occurs alone but may overlap with scleroderma and mixed connective tissue disease. Fasciitis and thickening of the skin, similar to that seen in chronic cases of DM, have occurred in patients with the eosinophilia-myalgia syndrome associated with the ingestion of contaminated l-tryptophan.


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InternalMed_Harrison. Inclusion Body Myositis In patients ≥50 years of age, IBM is the most common of the inflammatory myopathies. It is often misdiagnosed as PM and is suspected only later when a patient with presumed PM does not respond to therapy. Weakness and atrophy of the distal muscles, especially foot extensors and deep finger flexors, occur in almost all cases of IBM and may be a clue to early diagnosis. Some patients present with falls because their knees collapse due to early quadriceps weakness. Others present with weakness in the small muscles of the hands, especially finger flexors, and complain of inability to hold objectssuchasgolfclubsorperformtaskssuchasturningkeysortying knots. On occasion, the weakness and accompanying atrophy can be asymmetric and selectively involve the quadriceps, iliopsoas, triceps, biceps, and finger flexors, resembling a lower motor neuron disease. Dysphagia is common, occurring in up to 60% of IBM patients, and may lead to episodes of choking. Sensory examination


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InternalMed_Harrison. triceps, biceps, and finger flexors, resembling a lower motor neuron disease. Dysphagia is common, occurring in up to 60% of IBM patients, and may lead to episodes of choking. Sensory examination is generally normal; some patients have mildly diminished vibratory sensation at the ankles that presumably is age-related. The pattern of distal weakness, which superficially resembles motor neuron or peripheral nerve disease, results from the myopathic process affecting distal muscles selectively. Disease progression is slow but steady, and most patients require an assistive device such as cane, walker, or wheelchair within several years of onset.


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InternalMed_Harrison. In at least 20% of cases, IBM is associated with systemic autoimmune or connective tissue diseases. Familial aggregation of typical IBM may occur; such cases have been designated as familial inflammatory IBM. This disorder is distinct from hereditary inclusion body myopathy (h-IBM), which describes a heterogeneous group of recessive, Polymyositis, Dermatomyositis, and Inclusion Body Myositis 2196 and less frequently dominant, inherited syndromes; the h-IBMs are noninflammatory myopathies. A subset of h-IBM that spares the quadriceps muscles has emerged as a distinct entity. This disorder, originally described in Iranian Jews and now seen in many ethnic groups,islinkedtochromosome9p1andresultsfrommutationsinthe UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. aSSOCIaTED CLINICaL FINDINGS Extramuscular Manifestations These may be present to a varying degree in patients with PM or DM, and include: 1.


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InternalMed_Harrison. aSSOCIaTED CLINICaL FINDINGS Extramuscular Manifestations These may be present to a varying degree in patients with PM or DM, and include: 1. Systemic symptoms, such as fever, malaise, weight loss, arthralgia, and Raynaud’s phenomenon, especially when inflammatory myopathy is associated with a connective tissue disorder. 2. Joint contractures, mostly in DM and especially in children. 3. Dysphagia and gastrointestinal symptoms, due to involvement of oropharyngeal striated muscles and upper esophagus, especially in DM and IBM. 4. Cardiac disturbances, including atrioventricular conduction defects, tachyarrhythmias, dilated cardiomyopathy, a low ejection fraction,andcongestiveheartfailure,whichmayrarelyoccureither from the disease itself or from hypertension associated with longterm use of glucocorticoids. 5.


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InternalMed_Harrison. 5. Pulmonary dysfunction, due to weakness of the thoracic muscles, interstitial lung disease, or drug-induced pneumonitis (e.g., from methotrexate), which may cause dyspnea, nonproductive cough, and aspiration pneumonia. Interstitial lung disease may precede myopathyoroccurearlyinthediseaseanddevelopsinupto10%of patients with PM or DM, most of whom have antibodies to t-RNA synthetases, as described below. 6. Subcutaneous calcifications, in DM, sometimes extruding on the skin and causing ulcerations and infections. 7. Arthralgias, synovitis, or deforming arthropathy with subluxation intheinterphalangealjoints,whichcan occurinsome patientswith DM and PM who have Jo-1 antibodies (see below).


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InternalMed_Harrison. association with Malignancies Although all the inflammatory myopathies can have a chance association with malignant lesions, especially in older age groups, the incidence of malignant conditions appears to be specifically increased only in patients with DM and not in those with PM or IBM. The most common tumors associated with DM are ovarian cancer, breast cancer, melanoma, colon cancer, and non-Hodgkin’s lymphoma. The extent of the search that should be conducted for an occult neoplasm in adults with DM depends on the clinical circumstances. Tumors in these patients are usually uncovered by abnormal findings in the medical history and physical examination and not through an extensive blind search. The weight of evidence argues against performing expensive, invasive, and nondirected tumor searches. A complete annual physical examination with pelvic, breast (mammogram, if indicated), and rectal examinations (with colonoscopy according to age and family history); urinalysis; complete


InternalMed_Harrison

InternalMed_Harrison. searches. A complete annual physical examination with pelvic, breast (mammogram, if indicated), and rectal examinations (with colonoscopy according to age and family history); urinalysis; complete blood count; blood chemistry tests; and a chest film should suffice in most cases. In Asians, nasopharyngeal cancer is common, and a careful examination of ears, nose, and throat is indicated. If malignancy is clinically suspected, screening with a whole-body positron emission tomography (PET) scan should be considered.


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InternalMed_Harrison. Overlap Syndromes These describe the association of inflammatory myopathies with connective tissue diseases. A well-characterized overlap syndrome occurs in patients with DM who also have manifestations of systemic sclerosis or mixed connective tissue disease, such as sclerotic thickening of the dermis, contractures, esophageal hypo-motility, microangiopathy, and calcium deposits (Table 388-1). By contrast, signs of rheumatoid arthritis, systemic lupus erythematosus, or Sjögren’s syndrome are very rare in patients with DM. Patients with theoverlapsyndromeofDMandsystemicsclerosismayhaveaspecific antinuclear antibody, the anti-PM/Scl, directed against a nucleolarprotein complex.


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InternalMed_Harrison. An autoimmune etiology of the inflammatory myopathies is indirectly supported by an association with other autoimmune or connective tissue diseases; the presence of various autoantibodies; an association with specific major histocompatibility complex (MHC) genes; demonstration of T cell–mediated myocytotoxicity or complement-mediated microangiopathy; and a response to immunotherapy.


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InternalMed_Harrison. autoantibodies and Immunogenetics Various autoantibodies against nuclear antigens (antinuclear antibodies) and cytoplasmic antigens are found in up to 30% of patients with inflammatory myopathies. The antibodies to cytoplasmic antigens are directed against ribonucleoproteins involved in protein synthesis (antisynthetases) or translational transport (anti-signal-recognition particles). The antibody directed against the histidyl-transfer RNA synthetase, called anti-Jo-1, accounts for 75% of all the antisynthetases and is clinically useful because up to 80% of patients with anti-Jo-1 antibodies have interstitial lung disease. Some patients with the anti-Jo-1 antibody also have Raynaud’s phenomenon, nonerosive arthritis, and the MHC molecules DR3 and DRw52. DR3 haplotypes (molecular designation DRB1*0301, DQB1*0201) occur in up to 75% of patients with PM and IBM, whereas in juvenile DM, there is an increased frequency of DQA1*0501 (Chap. 373e). Antibodies against the cytosolic


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InternalMed_Harrison. designation DRB1*0301, DQB1*0201) occur in up to 75% of patients with PM and IBM, whereas in juvenile DM, there is an increased frequency of DQA1*0501 (Chap. 373e). Antibodies against the cytosolic 5′-nucleotidase 1A, an enzyme abundantly expressed in muscle and thought to be involved in DNA degradation and repair, have been detected in one-third of IBM patients. Although the pathogenic significance of these antibodies is still unknown, they highlight the presence of an immune response, as discussed below.


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InternalMed_Harrison. Immunopathologic Mechanisms In DM, humoral immune mechanisms are implicated, resulting in a microangiopathy and muscle ischemia (Fig. 388-1). Endomysial inflammatory infiltrates are composed of B cells located in proximity to CD4 T cells, plasmacytoid dendritic cells, and macrophages; there is a relative absence of lymphocytic invasion of nonnecrotic muscle fibers. Activation of the complement C5b-9 membranolytic attack complex is thought to be a critical early event that triggers release of proinflammatory cytokines and chemokines, induces expression of vascular cell adhesion molecule (VCAM) 1 and intercellular adhesion molecule (ICAM) 1 on endothelial cells, and facilitates migration of activated lymphoid cells to the perimysial and endomysial spaces. Necrosis of the endothelial cells, reduced numbers of endomysial capillaries, ischemia, and muscle-fiber destruction resembling microinfarcts occur. The remaining capillaries often have dilated lumens in response to the ischemic


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InternalMed_Harrison. reduced numbers of endomysial capillaries, ischemia, and muscle-fiber destruction resembling microinfarcts occur. The remaining capillaries often have dilated lumens in response to the ischemic process. Larger intramuscular blood vessels may also be affected in the same pattern. Residual perifascicular atrophy reflects the endofascicular hypoperfusion that is prominent in the periphery of muscle fascicles. Increased expression of type I interferon–inducible proteins is also noted in these regions.


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InternalMed_Harrison. By contrast, in PM and IBM, a mechanism of T cell–mediated cytotoxicity is likely. CD8 T cells, along with macrophages, initially surround and eventually invade and destroy healthy, nonnecrotic muscle fibers that aberrantly express class I MHC molecules. MHC-I expression, absent from the sarcolemma of normal muscle fibers, is probably induced by cytokines secreted by activated T cells and macrophages. The CD8/MHC-I complex is characteristic of PM and IBM; its detection can aid in confirming the histologic diagnosis of PM, as discussed below. The cytotoxic CD8 T cells contain perforin and granzymegranulesdirectedtowardthesurfaceofthemusclefibersand capable of inducing myonecrosis. Analysis of T cell receptor molecules expressed by the infiltrating CD8 cells has revealed clonal expansion and conserved sequences in the antigen-binding region, both suggesting an antigen-driven T cell response. Whether the putative antigens are endogenous (e.g., muscle) or exogenous (e.g., viral) sequences


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InternalMed_Harrison. conserved sequences in the antigen-binding region, both suggesting an antigen-driven T cell response. Whether the putative antigens are endogenous (e.g., muscle) or exogenous (e.g., viral) sequences is unknown. Viruses have not been identified within the muscle fibers. Co-stimulatory molecules and their counterreceptors, which are fundamental for T cell activation and antigen recognition, are strongly upregulated in PM and IBM. As noted above, the possibility that B cells and the humoral immune system might also play a role in IBM is suggested by the identification of anti-cytosolic 5′-nucleotidase


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InternalMed_Harrison. Molecular mimicry, tumors, viruses? NO, TNF-° STAT-1, Chemokines, Cathepsin, TGF-˜


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InternalMed_Harrison. FIGUrE 388-1 Immunopathogenesis of dermatomyositis. Activation of complement, possibly by autoantibodies (Y), against endothelial cells and formation of C3 via the classic or alternative pathway. Activated C3 leads to formation of C3b, C3bNEO, and membrane attack complexes (MAC), which are deposited in and around the endothelial cell wall of the endomysial capillaries. Deposition of MAC leads to destruction of capillaries, ischemia, or microinfarcts, most prominent in the periphery of the fascicles, and perifascicular atrophy. B cells, plasmacytoid dendritic cells, CD4 T cells, and macrophages traffic from the circulation to the muscle. Endothelial expression of vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) is induced by cytokines released by the mononuclear cells. Integrins, specifically very late activation antigen (VLA)-4 and lymphocyte function–associated antigen (LFA)-1, bind VCAM and ICAM and promote T cell and macrophage infiltration of


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InternalMed_Harrison. cells. Integrins, specifically very late activation antigen (VLA)-4 and lymphocyte function–associated antigen (LFA)-1, bind VCAM and ICAM and promote T cell and macrophage infiltration of muscle through the endothelial cell wall.


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InternalMed_Harrison. Polymyositis, Dermatomyositis, and Inclusion Body Myositis 1A antibodies in some patients. Key molecules involved in T cell– mediated cytotoxicity are depicted in Fig. 388-2.


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InternalMed_Harrison. The role of Nonimmune Factors in IBM In IBM, the presence of Congo red–positive amyloid deposits within some vacuolated muscle fibers and abnormal mitochondria with cytochrome oxidase–negative fibers suggest that, in addition to the autoimmune component, there is also a degenerative process. Similar to Alzheimer’s disease, the intracellular amyloiddepositsinIBMareimmunoreactiveagainstamyloidprecursor protein (APP), β-amyloid, chymotrypsin, apolipoprotein E, presenilin, ubiquitin, and phosphorylated tau, but it is unclear whether these deposits, which are also seen in other vacuolar myopathies, are directly pathogenic orrepresentsecondary phenomena. The sameis true for the mitochondrialabnormalities,whichmayalsobesecondarytotheeffects of aging or a bystander effect of upregulated cytokines. Expression of cytokines and upregulation of MHC class I by the muscle fibers may cause an endoplasmic reticulum stress response resulting in intracellular accumulation of stressor molecules or


InternalMed_Harrison

InternalMed_Harrison. Expression of cytokines and upregulation of MHC class I by the muscle fibers may cause an endoplasmic reticulum stress response resulting in intracellular accumulation of stressor molecules or misfolded glycoproteins and activation of nuclear factor κB (NF-κB), leading to further cytokine activation.


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InternalMed_Harrison. association with Viral Infections and the role of retroviruses Several viruses, including coxsackieviruses, influenza, paramyxoviruses, mumps, cytomegalovirus, and Epstein-Barr virus, have been indirectly associated with myositis. For the coxsackieviruses, an autoimmune myositis triggered by molecular mimicry has been 2197 proposed because of structural homology between histidyl-transfer RNA synthetase that is the target of the Jo-1 antibody (see above) and genomic RNA of an animal picornavirus, the encephalomyocarditisvirus.Sensitivepolymerasechainreaction(PCR) studies, however, have repeatedly failed to confirm the presence of such viruses in muscle biopsies.


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InternalMed_Harrison. The best evidence of a viral connection in PM and IBM is with the retroviruses. Some individuals infected with HIV or with human T cell lympho-tropicvirus1(HTLV-1)developPMorIBM;asimilar disorder has been described in nonhuman primates infected with the simian immunodeficiency virus. The inflammatory myopathy may occur as the initial manifestation of a retroviral infection, or myositis may develop later in the disease course. Retroviralantigenshavebeendetectedonlyinoccasional endomysial macrophages and not within the muscle fibers themselves, suggesting that persistent infection and viral replication within the muscle does not occur. Histologic findings are identical to retroviral-negative PM or IBM. The infiltrating T cells in the muscle have a clonal bias and a number ofthemareretroviral-specific.Thisdisordershould be distinguished from a toxic myopathy related to long-term therapy with AZT, characterized by fatigue, myalgia, mild muscle weakness, and mild elevation of creatine


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InternalMed_Harrison. be distinguished from a toxic myopathy related to long-term therapy with AZT, characterized by fatigue, myalgia, mild muscle weakness, and mild elevation of creatine kinase (CK). AZT-induced myopathy, which generally improves when the drug is discontinued, is a mitochondrial disorder characterized histologically by “ragged-red” fibers. AZTinhibitsγ-DNApolymerase, anenzymefound solely in the mitochondrial matrix.


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InternalMed_Harrison. Inadequate data exist with respect to pos sible differences in the prevalence of the inflammatory myopathies in various parts of the world. PM appears to be reported more often in Asia and southern Europe, whereas IBM seems tobemorefrequentlyrecognizedinNorthAmerica, northern Europe, and Australia. Whether this represents differences in diagnostic methods and dis easeawarenessortruediseaseprevalenceremainsunclear.Pyomyositis andparasiticmyositisareclearlymorecommoninthetropics,whereas HIV-associated PM and IBM are more commonly encountered in areas endemic for HIV. In patients from Asia, nasopharyngeal cancer appears to be a malignancy more commonly associated with DM, necessitating the need to specifically search for these tumors in this population. The clinical picture of the typical skin rash and proximal or diffuse muscle weakness has few causes other than DM. However, proximal muscle weakness without skin involvement can be due to many conditions other than PM or IBM.


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InternalMed_Harrison. Subacute or Chronic Progressive Muscle Weakness This may be due to denervating conditions such as the spinal muscular atrophies or amyotrophic lateral sclerosis (Chap. 452). In addition to the muscle weakness, upper motor neuron signs in the latter and signs of denervation detected by electromyography (EMG) aid in the diagnosis. The muscular dystrophies (Chap. 462e) may be additional considerations; however, these disorders usually develop over years rather than weeks or months and rarely present after the age of 30 years. It may be difficult, even with a muscle biopsy, to distinguish chronic PM from a rapidly advancing muscular dystrophy. This is particularly true of facioscapulohumeral muscular dystrophy, dysferlin myopathy, and


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InternalMed_Harrison. VCAM-1 TCR CD28 CTLA-4 LFA-1 Chemokines (MCP-1, Mig, IP-10) Infection? Co-stimulation Clonal expansion Cytokines Systemic immune compartment MHC TCR Macrophage Antigen Integrins LFA-4 CD8 CD8CD8 ICAM-1 MHC-I MMP-9 MMP-9 MMP-2 IFN-˜IFN-˜TFN-°TNF-°IL-1, 2 IL-1, 2 MMPs Perforin Necrosis Endoplasmic reticulum BB1 ˛2m Calnexin MHC-I TAP Ag (virus, muscle peptide) CD8 2198 with very high levels of serum CK (often in the thousands), painful muscle cramps, rhabdomyolysis, and myoglobinuria, it may be due to a necrotizing autoimmunemyositis,asdiscussedbelow,aviralinfection or a metabolic disorder such as myophosphorylase deficiency, or carnitine palmitoyltransferase deficiency (Chap. 462e).Several animal parasites,including protozoa (Toxoplasma, Trypanosoma), cestodes (cysticerci), and nematodes (trichinae), may produce a focal or diffuse inflammatory myopathy known as parasitic polymyositis.Staphylococcus aureus,Yersinia, Streptococcus, or anaerobic bacteria may produce a suppurative


InternalMed_Harrison

InternalMed_Harrison. (trichinae), may produce a focal or diffuse inflammatory myopathy known as parasitic polymyositis.Staphylococcus aureus,Yersinia, Streptococcus, or anaerobic bacteria may produce a suppurative myositis, known as tropical polymyositis, or pyomyositis. Pyomyositis, previously rare in the west,isnowoccasionallyseeninAIDSpatients.Other bacteria, such as Borrelia burgdorferi (Lyme disease) and Legionella pneumophila (Legionnaire’s disease), may infrequently cause myositis. Patients with periodic paralysis experience recurrent episodes of acute muscle weakness without pain, always beginning in childhood. Chronic alcoholics may develop painful myopathy with myoglobinuria after a bout of heavy drinking. Acute painless muscle weakness with myoglobinuria may occur with prolonged hypokalemia, or hypophosphatemia and hypomagnesemia, usually in chronic alcoholics or in patients on nasogastric suction receiving parenteral hyperalimentation.


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InternalMed_Harrison. Myofasciitis This distinctive inflammatory disor-FIGUrE 388-2 Cell-mediated mechanisms of muscle damage in polymyositis (PM) der affecting muscle and fascia presents as diffuse and inclusion body myositis (IBM). Antigen-specific CD8 cells are expanded in the myalgias, skin induration, fatigue, and mild muscle periphery, cross the endothelial barrier, and bind directly to muscle fibers via T cell recep-weakness; mild elevations of serum CK are usually tor (TCR) molecules that recognize aberrantly expressed major histocompatibility com-present. The most common form is eosinophilic plex (MHC)-I. Engagement of co-stimulatory molecules (BB1 and ICOSL) with their ligands myofasciitischaracterizedbyperipheralbloodeosin(CD28, CTLA-4, and ICOS), along with ICAM-1/LFA-1, stabilize the CD8–muscle fiber inter-ophiliaandeosinophilicinfiltratesinthe endomysial action. Metalloproteinases (MMPs) facilitate the migration of T cells and their attachment tissue. In some patients, the eosinophilic


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InternalMed_Harrison. fiber inter-ophiliaandeosinophilicinfiltratesinthe endomysial action. Metalloproteinases (MMPs) facilitate the migration of T cells and their attachment tissue. In some patients, the eosinophilic myositis/ to the muscle surface. Muscle fiber necrosis occurs via perforin granules released by the fasciitis occurs in the context of parasitic infections, autoaggressive T cells. A direct myocytotoxic effect exerted by the cytokines interferon vasculitis, mixed connective tissue disease, hypereo(IFN) γ, interleukin (IL) 1, or tumor necrosis factor (TNF) α may also play a role. Death of sinophilic syndrome, or toxic exposures (e.g., toxic the muscle fiber is mediated by necrosis. MHC class I molecules consist of a heavy chain oil syndrome, contaminated l-tryptophan) or with and a light chain (β2 microglobulin [β2m]) complexed with an antigenic peptide that is mutations in the calpain gene. A distinct subset of transported into the endoplasmic reticulum by TAP proteins (Chap. 373e).


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InternalMed_Harrison. chain (β2 microglobulin [β2m]) complexed with an antigenic peptide that is mutations in the calpain gene. A distinct subset of transported into the endoplasmic reticulum by TAP proteins (Chap. 373e). myofasciitis is characterized by pronounced infiltra tion of the connective tissue around the muscle by sheets of periodic acid–Schiff-positive macrophages the dystrophinopathies where inflammatory cell infiltration is often and occasional CD8 T cells (macrophagic myofasciitis or inflammatory found early in the disease. Such doubtful cases should always be given myositis with abundant macrophages [IMAM]). A focal form of this anadequatetrialofglucocorticoidtherapyandundergogenetictesting disorder,limitedtositesofpreviousvaccinations,administeredmonths to exclude muscular dystrophy. Identification of the MHC/CD8 lesion or years earlier, has been linked to an aluminum-containing substrate by muscle biopsy is helpful to identify cases of PM. Some metabolic in vaccines. This disorder, which


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InternalMed_Harrison. of the MHC/CD8 lesion or years earlier, has been linked to an aluminum-containing substrate by muscle biopsy is helpful to identify cases of PM. Some metabolic in vaccines. This disorder, which to date has not been observed outside myopathies,including glycogenstoragedisease dueto myophosphory-of France, responds to glucocorticoid therapy, and the overall prognosis lase or acid maltase deficiency, lipid storage myopathies due to carni-seems favorable. tine deficiency, and mitochondrial diseases produce weakness that is often associated with other characteristic clinical signs; diagnosis rests


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InternalMed_Harrison. Necrotizing autoimmune Myositis This is an increasingly recognized upon histochemical and biochemical studies of the muscle biopsy. entitythathasdistinctfeatures,eventhoughitisoftenlabeledasPM.It The endocrine myopathies such as those due to hypercorticosteroidpresents as an acute or subacute onset of symmetric muscle weakness; ism, hyper-and hypothyroidism, and hyper-and hypoparathyroidism CK is typically extremely high. The weakness can be severe. Coexisting require the appropriate laboratory investigations for diagnosis. Muscle interstitial lung disease and cardiomyopathy may be present. The dis-wasting in patients with an underlying neoplasm may be due to disuse, order may develop after a viral infection, in association with cancer, cachexia, or rarely a paraneoplastic neuromyopathy (Chap. 122).


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InternalMed_Harrison. or in patients taking statins when the myopathy continues to worsenDiseases of the neuromuscular junction, including myasthenia after statin withdrawal. Some patients have antibodies against signal gravis or the Lambert-Eaton myasthenic syndrome, cause fatiguing recognition particle (SRP) or against the 3-hydroxy-3-methylglutarylweakness that also affects ocular and other cranial muscles (Chap. coenzyme A reductase (HMGCR), a 100-kDa protein considered the 461). Repetitive nerve stimulation and single-fiber EMG studies aid pharmacologic target of statins. The muscle biopsy demonstratesin diagnosis.


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InternalMed_Harrison. necrotic fibers infiltrated by macrophages but only rare, if any, T cell acute Muscle Weakness Thismaybecausedbyanacuteneuropathysuch infiltrates.MuscleMHC-IexpressionisonlyslightlyandfocallyupregasGuillain-Barrésyndrome (Chap. 460),transversemyelitis (Chap. 456), ulated. The capillaries may be swollen with hyalinization, thickening a neurotoxin (Chap. 462e), or a neurotropic viral infection such as polio-of the capillary wall, and deposition of complement. Most patients myelitisorWestNilevirus(Chap. 164).Whenacuteweaknessisassociated respondtoimmunotherapy,butsomeareresistant.


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InternalMed_Harrison. Hyperacute Necrotizing Fasciitis/Myositis (Flesh-Eating Disease) This a fulminant infectious disease, seen most often in the tropics or in conditions with poor hygiene, characterized by widespread necrosis of the superficial fascia and muscle of a limb; if the scrotum, perineum, and abdominal wall are affected, the condition is referred to as Fournier’s gangrene. It may be caused by group A β-hemolytic Streptococcus, methicillin-sensitive S. aureus, Pseudomonas aeruginosa, Vibrio vulnificus, clostridial species (gas gangrene; Chap. 179), or polymicrobial infection with anaerobes and facultative bacteria (Chap. 201); toxins from these bacteria may act as superantigens (Chap. 372e). The port of bacterial entry is usually a trivial cut or skin abrasion, and the source is contactwithcarriersoftheorganism.Individualswithdiabetesmellitus, immunodeficiency states, or systemic illnesses such as liver failure are most susceptible. Systemic varicella is a predisposing factor in children.


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InternalMed_Harrison. Thediseasepresentswithswelling,pain,andrednessintheinvolved area followed by a rapid tissue necrosis of fascia and muscle that progresses at an estimated rate of 3 cm/h. Emergency debridement, antibiotics, IV immunoglobulin (IVIg), and even hyperbaric oxygen have been recommended. In progressive or advanced cases, amputation of the affected limb may be necessary to avoid a fatal outcome.


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InternalMed_Harrison. Drug-Induced Myopathies d-Penicillamine, procainamide, and statins may produce a true myositis resembling PM or necrotizing myositis. A DM-like illness has been associated with the contaminated preparations of l-tryptophan. As noted above, AZT causes a mitochondrial myopathy. Other drugs may elicit a toxic noninflammatory myopathy that is histologically different from DM, PM, or IBM. These include cholesterol-lowering agents such as clofibrate, lovastatin, simvastatin, or pravastatin, especially when combined with cyclosporine, amiodarone, or gemfibrozil. Mild statin-induced myopathic symptoms (such as myalgia, fatigue, or asymptomatic elevations of CK) are self-limited and usually improve after discontinuation of the drug. In rare patients, however, muscle weakness continues to progress even after the statin is withdrawn; in these cases, a diagnostic muscle biopsy is indicated and search for antibodies to HMGCR is suggested; if histologic evidence of PM or necrotizing myositis is


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InternalMed_Harrison. even after the statin is withdrawn; in these cases, a diagnostic muscle biopsy is indicated and search for antibodies to HMGCR is suggested; if histologic evidence of PM or necrotizing myositis is present, immunotherapy should be initiated. Rhabdomyolysis and myoglobinuria have been rarely associated with amphotericin B, ε-aminocaproic acid, fenfluramine, heroin, and phencyclidine. The use of amiodarone, chloroquine, colchicine, carbimazole, emetine, etretinate, and ipecac syrup; chronic laxative or licoriceuseresultinginhypokalemia;andglucocorticoidorgrowthhormone administration have also been associated with myopathic muscle weakness. Some neuromuscular blocking agents such as pancuronium, in combination with glucocorticoids, may cause an acute critical illness myopathy. A careful drug history is essential for diagnosis of these drug-induced myopathies, which do not require immunosuppressive therapy except when an autoimmune myopathy has been triggered, as 2199 noted above.


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InternalMed_Harrison. “Weakness” due to Muscle Pain and Muscle Tenderness A number of conditions including polymyalgia rheumatica (Chap. 385) and arthritic disorders of adjacent joints may enter into the differential diagnosis of inflammatory myopathy, even though they do not cause myositis. The muscle biopsy is either normal or discloses type II muscle fiber atrophy. Patients with fibrositis and fibromyalgia (Chap. 396) complain of focal or diffuse muscle tenderness, fatigue, and aching, which is sometimes poorly differentiated from joint pain. Some patients, however, have muscle tenderness, painful muscles on movement, and signs suggestive of a collagen vascular disorder, such as an increased erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, or rheumatoid factor, along with modest elevation of the serum CK and aldolase. They demonstrate a “break-away” pattern of weaknesswithdifficultysustainingeffortbutnottruemuscleweakness.


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InternalMed_Harrison. antibody, or rheumatoid factor, along with modest elevation of the serum CK and aldolase. They demonstrate a “break-away” pattern of weaknesswithdifficultysustainingeffortbutnottruemuscleweakness. Themusclebiopsyisusuallynormalornonspecific.Manysuchpatients show some response to nonsteroidal anti-inflammatory agents or glucocorticoids, although most continue to have indolent complaints. An indolent fasciitis in the setting of an ill-defined connective tissue disorder may be at times present, and these patients should not be labeled as having a psychosomatic disorder. Chronic fatigue syndrome, which may follow a viral infection, can present with debilitating fatigue, sore throat, painful lymphadenopathy, myalgia, arthralgia, sleep disorder, and headache (Chap. 464e). These patients do not have muscle weakness, and the muscle biopsy is normal.


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InternalMed_Harrison. The clinically suspected diagnosis of PM, DM, IBM, or necrotizing myositis is confirmed by analysis of serum muscle enzymes, EMG findings, and muscle biopsy (Table 388-2). The most sensitive enzyme is CK, which in active disease can be elevated as much as 50-fold. Although the CK level usually parallels disease activity, it can be normal in some patients with active IBM or DM, especially when associated with a connective tissue disease. The CK is always elevated in patients with active PM. Along with the CK, the serum glutamic-oxaloacetic and glutamate pyruvate transaminases, lactate dehydrogenase, and aldolase may be elevated.


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InternalMed_Harrison. Needle EMG shows myopathic potentials characterized by short-duration, low-amplitude polyphasic units on voluntary activation and increased spontaneous activity with fibrillations, complex repetitive discharges, and positive sharp waves. Mixed potentials (polyphasic units of short and long duration) indicating a chronic process and muscle fiber regeneration are often present in IBM. These EMG findings are not diagnostic of an inflammatory myopathy but are useful


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InternalMed_Harrison. Polymyositis, Dermatomyositis, and Inclusion Body Myositis aMyopathic muscle weakness, affecting proximal muscles more than distal ones and sparing eye and facial muscles, is characterized by a subacute onset (weeks to months) and rapid progression in patients who have no family history of neuromuscular disease, no endocrinopathy, no exposure to myotoxic drugs or toxins, and no biochemical muscle disease (excluded on the basis of muscle biopsy findings). bIn some cases with the typical rash, the muscle strength is seemingly normal (dermatomyositis sine myositis); these patients often have new onset of easy fatigue and reduced endurance. Careful muscle testing may reveal mild muscle weakness. cSee text for details. dAn adequate trial of prednisone or other immunosuppressive drugs is warranted in probable cases. If, in retrospect, the disease is unresponsive to therapy, another muscle biopsy should be considered to exclude other diseases or possible evolution in inclusion body myositis.


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InternalMed_Harrison. in probable cases. If, in retrospect, the disease is unresponsive to therapy, another muscle biopsy should be considered to exclude other diseases or possible evolution in inclusion body myositis. eIf the muscle biopsy does not contain vacuolated fibers but shows chronic myopathy with hypertrophic fibers, primary inflammation with the CD8/MHC-I complex, and cytochrome oxygenase–negative fibers, the diagnosis is probable inclusion body myositis. fIf rash is absent but muscle biopsy findings are characteristic of dermatomyositis, the diagnosis is probable dermatomyositis.


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InternalMed_Harrison. FIGUrE 388-3 Cross-section of a muscle biopsy from a patient with polymyositis demonstrates scattered inflammatory foci with lymphocytes invading or surrounding muscle fibers. Note lack of chronic myopathic features (increased connective tissue, atrophic or hypertrophic fibers) as seen in inclusion body myositis. to identify the presence of active or chronic myopathy and to exclude neurogenic disorders. Magnetic resonance imaging (MRI) is not routinely used for the diagnosis of PM, DM, or IBM. However, it may provide information or guide the location of the muscle biopsy in certain clinical settings.


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InternalMed_Harrison. Muscle biopsy—despite occasional variability in demonstrating all of the typical pathologic findings—is the most sensitive and specific test for establishing the diagnosis of inflammatory myopathy and for excluding other neuromuscular diseases. Inflammation is the histologic hallmark for these diseases; however, additional features are characteristic of each subtype (Figs. 388-3, 388-4, and 388-5).


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InternalMed_Harrison. In PM the inflammation is primary, a term used to indicate that the inflammation is not reactive and the T cell infiltrates, located primarily withinthemusclefascicles(endomysially),surroundindividual,healthy muscle fibers and result in phagocytosis and necrosis (Fig. 388-3). The MHC-I molecule is ubiquitously expressed on the sarcolemma, even in fibers not invaded by CD8+ cells. The CD8/MHC-I lesion is characteristic and useful to confirm or establish the diagnosis and to exclude disorders with secondary, nonspecific, inflammation, such as insomemusculardystrophies.Whenthediseaseischronic,connective tissue is increased and may react positively with alkaline phosphatase. In necrotizing myositis, there are abundant necrotic fibers invaded or surrounded by macrophages, but no lymphocytic infiltrates or MHC-I expression beyond the necrotic fibers.


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InternalMed_Harrison. FIGUrE 388-4 Cross-section of a muscle biopsy from a patient with dermatomyositis demonstratesatrophyofthefibersattheperipheryofthefascicle(perifascicularatrophy). In DM the endomysial inflammation is predominantly perivascular or in the interfascicular septae and around—rather than within—the muscle fascicles (Fig. 388-4). The intramuscular blood vessels show endothelial hyperplasia with tubuloreticular profiles, fibrin thrombi, and obliteration of capillaries. The muscle fibers undergo necrosis, degeneration, and phagocytosis, often in groups involving a portion of a muscle fasciculus in a wedge-like shape or at the periphery of the fascicle, due to microinfarcts within the muscle. This results in perifascicular atrophy, characterized by 2–10 layers of atrophic fibers at the periphery of the fascicles. The presence of perifascicular atrophy is diagnostic of DM, even in the absence of inflammation.


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InternalMed_Harrison. In IBM (Fig. 388-5), there is endomysial inflammation with T cells invading MHC-I-expressing nonvacuolated muscle fibers; basophilic granular deposits distributed around the edge of slit-like vacuoles (rimmed vacuoles); loss of fibers, replaced by fat and connective tissue, hypertrophic fibers, and angulated or round fibers; rare eosinophilic cytoplasmic inclusions; abnormal mitochondria characterized by the presence of ragged-red fibers or cytochrome oxidase–negative fibers; andamyloiddepositswithinornexttothevacuolesbestvisualizedwith crystal violet or Congo-red staining viewed with fluorescent optics. Electron microscopy demonstrates filamentous inclusions in the vicinity of the rimmed vacuoles. In at least 15% of patients with the typical clinical phenotype of IBM, there is brisk inflammation in the muscle biopsy but no vacuoles or amyloid deposits, leading to an erroneous diagnosis of PM. Such patients are often referred to as having “clinical IBM.” Close clinicopathologic


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InternalMed_Harrison. inflammation in the muscle biopsy but no vacuoles or amyloid deposits, leading to an erroneous diagnosis of PM. Such patients are often referred to as having “clinical IBM.” Close clinicopathologic correlations are therefore essential; if uncertain, a repeat muscle biopsy from another site is often helpful.


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InternalMed_Harrison. The goal of therapy is to improve muscle strength, thereby improving function in activities of daily living, and ameliorate the extra-muscular manifestations (rash, dysphagia, dyspnea, fever). When strength improves, the serum CK falls concurrently; however, the reverse is not always true. Unfortunately, there is a common tendency to “chase” or treat the CK level instead of the muscle weakness, a practice that has led to prolonged and unnecessary use of immunosuppressive drugs and erroneous assessment of their efficacy. It is prudent to discontinue these drugs if, after an adequate trial, there is no objective improvement in muscle strength whether or not CK levels are reduced. Agents used in the treatment of PM and DM include the following: 1. Glucocorticoids. Oral prednisone is the initial treatment of choice; the effectiveness and side effects of this therapy determine the future need for stronger immunosuppressive drugs. High-dose prednisone, at least 1 mg/kg per day, is initiated


InternalMed_Harrison

InternalMed_Harrison. treatment of choice; the effectiveness and side effects of this therapy determine the future need for stronger immunosuppressive drugs. High-dose prednisone, at least 1 mg/kg per day, is initiated as early in the disease as possible. After 3–4 weeks, prednisone is tapered slowly over a period of 10 weeks to 1 mg/kg every other day. If there is evidence of efficacy and no serious side effects, the dosage is then further reduced by 5 or 10 mg every 3–4 weeks until the lowest possible dose that controls the disease is reached. The efficacy of prednisone is determined by an objective increase in muscle strength and activities of daily living, which almost always occurs by the third month of therapy. A feeling of increased energy or a reduction of the CK level without a concomitant increase in muscle strength is not a reliable sign of improvement. If prednisone provides no objective benefit after ~3 months of high-dose therapy, the disease is probably unresponsive to the drug and tapering


InternalMed_Harrison

InternalMed_Harrison. muscle strength is not a reliable sign of improvement. If prednisone provides no objective benefit after ~3 months of high-dose therapy, the disease is probably unresponsive to the drug and tapering should be accelerated while the next-in-line immunosuppressive drug is started. Although controlled trials have not been performed, almost all patients with true PM or DM respond to glucocorticoids to some degree and for some period of time; in general, DM responds better than PM.


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InternalMed_Harrison. The long-term use of prednisone may cause increased weakness associated with a normal or unchanged CK level; this effect is referred to as steroid myopathy. In a patient who previously FIGUrE 388-5 Cross-sections of a muscle biopsy from a patient with inclusion body myositis demonstratethetypicalfeaturesofvacuoleswithlymphocyticinfiltratessurroundingnonvacuolatedornecroticfibers(A),tinyendomysialdepositsofamyloidvisualizedwithcrystalviolet(B),cytochromeoxidase–negativefibers,indicativeofmitochondrialdysfunction(C),andubiquitousmajorhistocompatibilitycomplexclassIexpressionattheperipheryofallfibers(D).


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InternalMed_Harrison. Polymyositis, Dermatomyositis, and Inclusion Body Myositis responded to high doses of prednisone, the development of new weakness may be related to steroid myopathy or to disease activity that either will respond to a higher dose of glucocorticoids or has become glucocorticoid-resistant. In uncertain cases, the prednisone dosage can be steadily increased or decreased as desired: the cause of the weakness is usually evident in 2–8 weeks. 2. Other immunosuppressive drugs. Approximately 75% of patients ultimately require additional treatment. This occurs when a patient fails to respond adequately to glucocorticoids after a 3-month trial, the patient becomes glucocorticoid-resistant, glucocorticoid-related side effects appear, attempts to lower the prednisone dose repeatedly result in a new relapse, or rapidly progressive disease with evolving severe weakness and respiratory failure develops.


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InternalMed_Harrison. The following drugs are commonly used but have never been tested in controlled studies: (1) Azathioprine is well tolerated, has few side effects, and appears to be as effective for longterm therapy as other drugs. The dose is up to 3 mg/kg daily. (2) Methotrexate has a faster onset of action than azathioprine. It is given orally starting at 7.5 mg weekly for the first 3 weeks (2.5 mg every 12 h for 3 doses), with gradual dose escalation by 2.5 mg per week to a total of 25 mg weekly. A rare side effect is methotrexate pneumonitis, which can be difficult to distinguish from the interstitial lung disease of the primary myopathy associated with Jo-1 antibodies (described above). (3) Mycophenolate mofetil also has a faster onset of action than azathioprine. At doses up to 2.5 or 3 g/d in two divided doses, it is well tolerated for long-term use. (4) Monoclonal anti-CD20 antibody (rituximab) has been shown in a small uncontrolled series to benefit patients with DM and PM, but a controlled


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InternalMed_Harrison. divided doses, it is well tolerated for long-term use. (4) Monoclonal anti-CD20 antibody (rituximab) has been shown in a small uncontrolled series to benefit patients with DM and PM, but a controlled study did not show differences between patients randomized 8 weeks apart. (5) Cyclosporine has inconsistent and mild benefit. (6) Cyclophosphamide (0.5–1 g/m2 IV monthly for 6 months) has limited success and significant toxicity.


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InternalMed_Harrison. (7) Tacrolimus (formerly known as Fk506) has been effective in some difficult cases of PM especially with interstitial lung disease. 3. Immunomodulation. In a controlled trial of patients with refractory DM, IVIg improved not only strength and rash but also the underlying immunopathology. The benefit is often short-lived (≤8 weeks), and repeated infusions every 6–8 weeks are generally required to maintain improvement. A dose of 2 g/kg divided over 2–5 days per course is recommended. Uncontrolled observations suggest that IVIg may also be beneficial for patients with PM. Neither plasmapheresis nor leukapheresis appears to be effective in PM and DM.


InternalMed_Harrison

InternalMed_Harrison. The following sequential empirical approach to the treatment of PM and DM is suggested: Step 1: high-dose prednisone; Step 2: azathioprine, mycophenolate, or methotrexate for steroid-sparing effect; Step 3: IVIg; Step 4: a trial, with guarded optimism, of one of the following agents, chosen according to the patient’s age, degree of disability, tolerance, experience with the drug, and general health: rituximab, cyclosporine, cyclophosphamide, or tacrolimus. Patients with interstitial lung disease may benefit from aggressive treatment with cyclophosphamide or tacrolimus.


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InternalMed_Harrison. Immune-Mediated, Inflammatory, and Rheumatologic Disorders relapsing polychondritis Carol A. Langford Relapsingpolychondritisisanuncommondisorderofunknowncausecharacterizedbyinflammationofcartilagepredominantlyaffectingtheears,nose,andlaryngotracheobronchialtree.Othermanifesta-tionsincludescleritis,neurosensoryhearingloss,polyarthritis,cardiac389 2202 A patient with presumed PM who has not responded to any form of immunotherapy most likely has IBM or another disease, usually a metabolic myopathy, a muscular dystrophy, a drug-induced myopathy, or an endocrinopathy. In these cases, a repeat muscle biopsy and a renewed search for another cause of the myopathy is indicated. Calcinosis, a manifestation of DM, is difficult to treat; however, new calcium deposits may be prevented if the primary disease responds to the available therapies. Bisphosphonates, aluminum hydroxide, probenecid, colchicine, low doses of warfarin, calcium blockers, and surgical excision have all been tried without


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InternalMed_Harrison. disease responds to the available therapies. Bisphosphonates, aluminum hydroxide, probenecid, colchicine, low doses of warfarin, calcium blockers, and surgical excision have all been tried without success. IBM is generally resistant to immunosuppressive therapies. Prednisone together with azathioprine or methotrexate is often tried for a few months in newly diagnosed patients, although results are generally disappointing. Because occasional patients may feel subjectively weaker after these drugs are discontinued, some clinicians prefer to maintain these patients on low-dose, every-otherday prednisone along with mycophenolate in an effort to slow disease progression, even though there is no objective evidence or controlled study to support this practice. In two controlled studies of IVIg in IBM, minimal benefit in up to 30% of patients was found; the strength gains, however, were not of sufficient magnitude to justify its routine use. Another trial of IVIg combined with prednisone was


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InternalMed_Harrison. IBM, minimal benefit in up to 30% of patients was found; the strength gains, however, were not of sufficient magnitude to justify its routine use. Another trial of IVIg combined with prednisone was ineffective. Nonetheless, some experts believe that a 2to 3-month trial with IVIg may be reasonable for selected patients with IBM who experience rapid progression of muscle weakness or choking episodes due to worsening dysphagia.


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InternalMed_Harrison. The 5-year survival rate for treated patients with PM and DM is ~95%, and the 10-yearsurvivalrateis 84%; deathisusuallyduetopulmonary, cardiac, or other systemic complications. The prognosis is worse for patients who are severely affected at presentation, when initial treatment is delayed, and in cases with severe dysphagia or respiratory difficulties. Older patients and those with associated cancer also have a worse prognosis. DM responds more favorably to therapy than PM and thus has a better prognosis. Most patients improve with therapy, and many make a full functional recovery, which is often sustained with maintenance therapy. Up to 30% may be left with some residual muscle weakness. Relapses may occur at any time.


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InternalMed_Harrison. IBM has the least favorable prognosis of the inflammatory myopathies. Most patients will require the use of an assistive device such as a cane, walker, or wheelchair within 5–10 years of onset. In general, the oldertheageofonsetinIBM,themorerapidlyprogressiveisthecourse.


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InternalMed_Harrison. abnormalities, skin lesions, and glomerulonephritis. Relapsing polychondritis has been estimated to have an incidence of 3.5 per million population per year. The peak age of onset is between the ages of 40 and 50 years, but relapsing polychondritis may affect children and the elderly. It is found in all races, and both sexes are equally affected. No familial tendency is apparent. A significantly higher frequency of HLA-DR4 has been found in patients with relapsing polychondritis than in healthy individuals. A predominant subtype allele(s) of HLA-DR4 was not found. Approximately 30% of patients with relapsing polychondritis will have another rheumatologic disorder, the most frequent being systemic vasculitis, followed by rheumatoid arthritis, and systemic lupus erythematosus (SLE). Nonrheumatic aSystemic vasculitis is the most common association, followed by rheumatoid arthritis and systemic lupus erythematosus. Source: Modified from CJ Michet et al: Ann Intern Med 104:74, 1986.


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InternalMed_Harrison. Source: Modified from CJ Michet et al: Ann Intern Med 104:74, 1986. disorders associated with relapsing polychondritis include Hashimoto’s thyroiditis, primary biliary cirrhosis, and myelodysplastic syndrome (Table 389-1). In most cases, these disorders antedate the appearance of relapsing polychondritis, usually by months or years; however, in other instances, the onset of relapsing polychondritis can accompany disease presentation.