The Vasculitis Syndromes

2813CHAPTER 363

TAKAYASU ARTERITIS

■ DEFINITION

Takayasu arteritis is an inflammatory and stenotic disease of mediumand large-sized arteries characterized by a strong predilection for the

aortic arch and its branches.

■ INCIDENCE AND PREVALENCE

Takayasu arteritis is an uncommon disease with an estimated annual

incidence rate of 1.2–2.6 cases per million. It is most prevalent in adolescent girls and young women. Although it is more common in Asia,

it is neither racially nor geographically restricted.

■ PATHOLOGY AND PATHOGENESIS

The disease involves medium- and large-sized arteries, with a strong

predilection for the aortic arch and its branches; the pulmonary artery

may also be involved. The most commonly affected arteries seen by

arteriography are listed in Table 363-7. The involvement of the major

branches of the aorta is much more marked at their origin than distally. The disease is a panarteritis with inflammatory mononuclear

cell infiltrates and occasionally giant cells. There are marked intimal

proliferation and fibrosis, scarring and vascularization of the media,

and disruption and degeneration of the elastic lamina. Narrowing of

the lumen occurs with or without thrombosis. The vasa vasorum are

frequently involved. Pathologic changes in various organs reflect the

compromise of blood flow through the involved vessels.

Immunopathogenic mechanisms, the precise nature of which is

uncertain, are suspected in this disease. As with several of the vasculitis

syndromes, circulating immune complexes have been demonstrated,

but their pathogenic significance is unclear.

■ CLINICAL AND LABORATORY MANIFESTATIONS

Takayasu arteritis is a systemic disease with generalized as well as vascular symptoms. The generalized symptoms include malaise, fever, night

sweats, arthralgias, anorexia, and weight loss, which may occur months

before vessel involvement is apparent. These symptoms may merge into

those related to vascular compromise and organ ischemia. Pulses are

commonly absent in the involved vessels, particularly the subclavian

artery. The frequency of arteriographic abnormalities and the potentially

associated clinical manifestations are listed in Table 363-7. Hypertension

occurs in 32–93% of patients and contributes to renal, cardiac, and cerebral injury.

Characteristic laboratory findings include an elevated ESR and/or

CRP, mild anemia, and elevated immunoglobulin levels.

TABLE 363-7 Frequency of Arteriographic Abnormalities and Potential

Clinical Manifestations of Arterial Involvement in Takayasu Arteritis

ARTERY

PERCENTAGE OF

ARTERIOGRAPHIC

ABNORMALITIES

POTENTIAL CLINICAL

MANIFESTATIONS

Subclavian 93 Arm claudication, Raynaud’s

phenomenon

Common carotid 58 Visual changes, syncope, transient

ischemic attacks, stroke

Abdominal aortaa 47 Abdominal pain, nausea, vomiting

Renal 38 Hypertension, renal failure

Aortic arch or root 35 Aortic insufficiency, congestive heart

failure

Vertebral 35 Visual changes, dizziness

Coeliac axisa 18 Abdominal pain, nausea, vomiting

Superior

mesenterica

18 Abdominal pain, nausea, vomiting

Iliac 17 Leg claudication

Pulmonary 10–40 Atypical chest pain, dyspnea

Coronary <10 Chest pain, myocardial infarction

a

Arteriographic lesions at these locations are usually asymptomatic but may

potentially cause these symptoms.

Source: G Kerr et al: Ann Intern Med 120:919, 1994.

■ DIAGNOSIS

The diagnosis of Takayasu arteritis should be suspected strongly in a

young woman who develops a decrease or absence of peripheral pulses,

discrepancies in blood pressure, and arterial bruits. The diagnosis

is confirmed by the characteristic pattern on arteriography, which

includes irregular vessel walls, stenosis, poststenotic dilation, aneurysm

formation, occlusion, and evidence of increased collateral circulation.

Complete imaging of the aorta and its major branches by magnetic resonance or computed tomography arteriography should be obtained to

fully delineate the distribution and degree of arterial disease. Because

of the involvement of the large vessels, tissue is rarely available as a

means of diagnosis and obtained only if vascular surgery is necessary.

IgG4-related disease (Chap. 368) is a potential cause of aortitis and

periaortitis that is histologically differentiated from Takayasu arteritis

by a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma

cells, a storiform pattern of fibrosis, and obliterative phlebitis.

TREATMENT

Takayasu Arteritis

The long-term outcome of patients with Takayasu arteritis has varied widely between studies. Although two North American reports

found overall survival to be ≥94%, the 5-year mortality rate from

other studies has ranged from 0 to 35%. Disease-related mortality

most often occurs from congestive heart failure, cerebrovascular

events, myocardial infarction, aneurysm rupture, or renal failure.

Even in the absence of life-threatening disease, Takayasu arteritis

can be associated with significant morbidity. The course of the disease is variable, and although spontaneous remissions may occur,

Takayasu arteritis is most often chronic and relapsing. Although

glucocorticoid therapy in doses of 40–60 mg prednisone per day

alleviates symptoms, there are no convincing studies that indicate that it increases survival. The combination of glucocorticoid

therapy for acute signs and symptoms and an aggressive surgical

and/or arterioplastic approach to stenosed vessels has markedly

improved outcome and decreased morbidity by lessening the risk

of stroke, correcting hypertension due to renal artery stenosis, and

improving blood flow to ischemic viscera and limbs. Unless it is

urgently required, surgical correction of stenosed arteries should

be undertaken only when the vascular inflammatory process is well

controlled with medical therapy.

In individuals who are refractory to or unable to taper glucocorticoids, methotrexate in doses up to 25 mg per week has yielded

encouraging results. Results from retrospective series with antiTNF therapies have been encouraging, but these agents have not

been studied through randomized trials to determine efficacy.

Abatacept was examined in the first randomized trial to be

conducted in Takayasu arteritis but did not demonstrate efficacy

beyond glucocorticoids alone. Tocilizumab has been investigated

in a randomized trial where it did not reach its primary efficacy

endpoint. In this study, it was found to have secondary benefits and

encouraging results have also been seen in retrospective studies

such that the utility of this agent remains an active question.

IgA VASCULITIS (HENOCH-SCHÖNLEIN)

■ DEFINITION

IgA vasculitis (Henoch-Schönlein) is a small-vessel vasculitis characterized by palpable purpura (most commonly distributed over the

buttocks and lower extremities), arthralgias, gastrointestinal signs and

symptoms, and glomerulonephritis.

■ INCIDENCE AND PREVALENCE

IgA vasculitis (Henoch-Schönlein) is usually seen in children ages 4–7

years; however, the disease may also be seen in infants and adults. It is

not a rare disease; in one series, it accounted for between 5 and 24 admissions per year at a pediatric hospital. The male-to-female ratio is 1.5:1. A

seasonal variation with a peak incidence in spring has been noted.

2814 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

■ PATHOLOGY AND PATHOGENESIS

The presumptive pathogenic mechanism for IgA (Henoch-Schönlein)

vasculitis is immune-complex deposition. A number of inciting antigens have been suggested including upper respiratory tract infections,

various drugs, foods, insect bites, and immunizations. IgA is the antibody class most often seen in the immune complexes and has been

demonstrated in the renal biopsies of these patients.

■ CLINICAL AND LABORATORY MANIFESTATIONS

In pediatric patients, palpable purpura is seen in virtually all patients;

most patients develop polyarthralgias in the absence of frank arthritis.

Gastrointestinal involvement, which is seen in almost 70% of pediatric

patients, is characterized by colicky abdominal pain usually associated

with nausea, vomiting, diarrhea, or constipation, and is frequently

accompanied by the passage of blood and mucus per rectum; bowel

intussusception may occur. Renal involvement occurs in 10–50%

of patients and is usually characterized by mild glomerulonephritis

leading to proteinuria and microscopic hematuria, with red blood

cell casts in the majority of patients; it usually resolves spontaneously

without therapy. Rarely, a progressive glomerulonephritis will develop.

In adults, presenting symptoms are most frequently related to the skin

and joints, while initial complaints related to the gut are less common.

Although certain studies have found that renal disease is more frequent

and more severe in adults, this has not been a consistent finding. However, the course of renal disease in adults may be more insidious and

thus requires close follow-up. Myocardial involvement can occur in

adults but is rare in children.

Laboratory studies generally show a mild leukocytosis, a normal

platelet count, and occasionally eosinophilia. Serum complement

components are normal, and IgA levels are elevated in about one-half

of patients.

■ DIAGNOSIS

The diagnosis of IgA vasculitis (Henoch-Schönlein) is based on clinical

signs and symptoms. Skin biopsy specimen can be useful in confirming

leukocytoclastic vasculitis with IgA and C3 deposition by immunofluorescence. Renal biopsy is rarely needed for diagnosis but may provide

prognostic information in some patients.

TREATMENT

IgA Vasculitis (Henoch-Schönlein)

The prognosis of IgA vasculitis (Henoch-Schönlein) is excellent.

Mortality is exceedingly rare, and 1–5% of children progress to

end-stage renal disease. Most patients recover completely, and some

do not require therapy. When glucocorticoids are required, prednisone, 1 mg/kg per day and tapered according to clinical response,

has been shown to be useful in decreasing tissue edema, arthralgias,

and abdominal discomfort; however, it has not proved beneficial

in the treatment of skin or renal disease and does not appear to

shorten the duration of active disease or lessen the chance of recurrence. Patients with rapidly progressive glomerulonephritis have

been anecdotally reported to benefit from glucocorticoids used

in combination with another immunosuppressive agent. Disease

recurrences have been reported in 10–40% of patients.

CRYOGLOBULINEMIC VASCULITIS

■ DEFINITION

Cryoglobulins are cold-precipitable monoclonal or polyclonal immunoglobulins. Cryoglobulinemia may be associated with a systemic

vasculitis characterized by palpable purpura, arthralgias, weakness,

neuropathy, and glomerulonephritis. The most common association

has been with hepatitis C, although cryoglobulinemia can be observed

in association with a variety of underlying disorders including multiple

myeloma, lymphoproliferative disorders, connective tissue diseases,

infection, and liver disease and can be idiopathic.

■ INCIDENCE AND PREVALENCE

The incidence of cryoglobulinemic vasculitis has not been established.

It has been estimated that 5% of patients with chronic hepatitis C will

develop cryoglobulinemic vasculitis.

■ PATHOLOGY AND PATHOGENESIS

Skin biopsies in cryoglobulinemic vasculitis reveal an inflammatory

infiltrate surrounding and involving blood vessel walls, with fibrinoid

necrosis, endothelial cell hyperplasia, and hemorrhage. Deposition of

immunoglobulin and complement is common. Abnormalities of uninvolved skin including basement membrane alterations and deposits in

vessel walls may be found. Membranoproliferative glomerulonephritis

is responsible for 80% of allrenal lesions in cryoglobulinemic vasculitis.

The association between hepatitis C and cryoglobulinemic vasculitis

has been supported by the high frequency of documented hepatitis C

infection, the presence of hepatitis C RNA and anti–hepatitis C antibodies in serum cryoprecipitates, evidence of hepatitis C antigens in

vasculitic skin lesions, and the effectiveness of antiviral therapy. Current evidence suggests that in the majority of cases, cryoglobulinemic

vasculitis occurs when an aberrant immune response to hepatitis C

infection leads to the formation of immune complexes consisting of

hepatitis C antigens, polyclonal hepatitis C–specific IgG, and monoclonal IgM rheumatoid factor. The deposition of these immune complexes

in blood vessel walls triggers an inflammatory cascade that results in

cryoglobulinemic vasculitis.

■ CLINICAL AND LABORATORY MANIFESTATIONS

The most common clinical manifestations of cryoglobulinemic vasculitis are cutaneous vasculitis, arthritis, peripheral neuropathy, and

glomerulonephritis. Renal disease develops in 10–30% of patients.

Life-threatening rapidly progressive glomerulonephritis or vasculitis of

the CNS, gastrointestinal tract, or heart occurs infrequently.

The presence of circulating cryoprecipitates is the fundamental

finding in cryoglobulinemic vasculitis. Rheumatoid factor is almost

always found and may be a useful clue to the disease when cryoglobulins are not detected. Hypocomplementemia occurs in 90% of patients.

An elevated ESR and/or CRP and anemia occur frequently. Evidence

for hepatitis C infection must be sought in all patients by testing for

hepatitis C antibodies and hepatitis C RNA.

TREATMENT

Cryoglobulinemic Vasculitis

Acute mortality directly from cryoglobulinemic vasculitisis uncommon, but the presence of glomerulonephritis is a poor prognostic

sign for overall outcome. In such patients, 15% progress to endstage 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. 341) is first-line

therapy for hepatitis C–associated cryoglobulinemic vasculitis,

particularly given the efficacy of current hepatitis C therapies.

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. 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 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 contraindications to antiviral

agents.

The Vasculitis Syndromes

2815CHAPTER 363

SINGLE-ORGAN VASCULITIS

Single-organ vasculitis has been defined as vasculitis in arteries or veins

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 cutaneous vasculitis, medical intervention is warranted.

IDIOPATHIC CUTANEOUS VASCULITIS

■ DEFINITION

The term cutaneous vasculitis is defined broadly as inflammation of

the blood vessels of the dermis. Because of 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.

■ INCIDENCE AND PREVALENCE

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.

■ PATHOLOGY AND PATHOGENESIS

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.

■ CLINICAL AND LABORATORY MANIFESTATIONS

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 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 and/or CRP. Laboratory studies

should be aimed toward ruling out features to suggest an underlying

disease or a systemic vasculitis.

■ DIAGNOSIS

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. 363-1). 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.

TREATMENT

Idiopathic Cutaneous Vasculitis

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 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 another immunosuppressive 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.

PRIMARY CENTRAL NERVOUS SYSTEM

VASCULITIS

Primary CNS vasculitis is an uncommon clinicopathologic entity

characterized by vasculitis restricted to the vessels of the CNS without

other apparent systemic vasculitis. The inflammatory process is usually

composed of mononuclear cell infiltrates with or without granuloma

formation.

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. 363-4), but it is confirmed by biopsy of the brain

parenchyma and leptomeninges. In the absence of a brain biopsy, 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

2816 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

considerations include infection, atherosclerosis, emboli, connective

tissue disease, sarcoidosis, malignancy, and drug-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. Following disease remission, cyclophosphamide is switched to azathioprine or mycophenolate mofetil as these

have good penetration into the CNS.

BEHÇET’S DISEASE

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. 364.

COGAN’S SYNDROME

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.

KAWASAKI’S DISEASE

Kawasaki’s 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 and can cause complications into adulthood. There is typical

intimal proliferation and infiltration of the vessel wall with mononuclear cells. Beadlike aneurysms and thromboses may be seen along the

FIGURE 363-4 Cerebral arteriogram from a 32-year-old man with primary central

nervous system vasculitis. Dramatic beading (arrow) typical of vasculitis is seen.

artery. Other manifestations include pericarditis, myocarditis, myocardial ischemia and infarction, and cardiomegaly.

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/d for 14 days followed by 3–5 mg/kg per day

for several weeks) has been shown to be effective in reducing the prevalence of coronary artery abnormalities when administered 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.

Multisystem inflammatory syndrome (MIS-C), a serious condition that may resemble Kawasaki’s disease, has been observed with

infections due to the novel coronavirus, SARS-CoV-2 (Chap. 199).

Although clinical features consistent with Kawasaki’s disease have

been observed, these patients can also have manifestations atypical for

Kawasaki’s disease, including gastrointestinal symptoms, myocarditis,

neurocognitive symptoms, and shock. Any patient who presents with

a clinical picture suggestive of Kawasaki’s disease should be tested for

SARS-CoV-2 to guide care and management.

POLYANGIITIS OVERLAP SYNDROMES

Some patients with systemic vasculitis manifest clinicopathologic

characteristics that do not fit precisely into any specific disease but

have overlapping features of different vasculitides. 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.”

SECONDARY VASCULITIS

■ DRUG-INDUCED VASCULITIS

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. 60). 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. 60).

An increasing number of drugs have been reported to cause vasculitis associated with ANCA. Of these, the best evidence of causality

exists for hydralazine and propylthiouracil. The clinical 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. Following

clinical improvement, consideration may be given for tapering such

agents along a more rapid schedule.

■ SERUM SICKNESS AND SERUM SICKNESS–LIKE

REACTIONS

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

(classic serum sickness) or a nonprotein drug such as penicillin or sulfa

(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.

Behçet Syndrome

2817CHAPTER 364

■ VASCULITIS ASSOCIATED WITH OTHER

UNDERLYING DISEASES

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. 187). In

addition, the inflammatory response around blood vessels associated

with certain systemic fungal diseases such as histoplasmosis (Chap. 212)

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

confined to the skin is the most common finding; however, widespread

systemic vasculitis may occur. Of particular note is the association of

hairy cell leukemia (Chap. 110) with polyarteritis nodosa.

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. 356), rheumatoid

arthritis (Chap. 358), inflammatory myositis (Chap. 365), relapsing

polychondritis (Chap. 366), and Sjögren’s syndrome (Chap. 361). 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, α1

-antitrypsin deficiency,

and intestinal bypass surgery.

■ FURTHER READING

Buttgereit F et al: Polymyalgia rheumatica and giant cell arteritis:

A systematic review. JAMA 315:2442, 2016.

Fauci AS et al: Wegener’s granulomatosis: Prospective clinical and

therapeutic experience with 85 patients for 21 years. Ann Intern Med

98:76, 1983.

Finkielman JD et al: Antiproteinase 3 antineutrophil cytoplasmic

antibodies and disease activity in Wegener granulomatosis. Ann

Intern Med 147:611, 2007.

Guillevin L et al: Churg-Strauss syndrome. Clinical study and longterm follow-up of 96 patients. Medicine (Baltimore) 78:26, 1999.

Hoffman GS et al: Wegener granulomatosis: An analysis of 158

patients. Ann Intern Med 16:488, 1992.

Jayne D et al: A randomized trial of maintenance therapy for vasculitis

associated with antineutrophil cytoplasmic autoantibodies. N Engl J

Med 349:36, 2003.

Jayne DRW et al: Avacopan for the treatment of ANCA-associated

vasculitis. N Engl J Med 18:599, 2021.

Jennette JC et al: 2012 revised International Chapel Hill Consensus

Conference Nomenclature of Vasculitides. Arthritis Rheum 65:1, 2013.

Kerr GS et al: Takayasu arteritis. Ann Intern Med 120:919, 1994.

Langford CA et al: A randomized, double-blind trial of abatacept

(CTLA-4Ig) for the treatment of giant cell arteritis. Arthritis Rheumatol

69:837, 2017.

Pagnoux C et al: Clinical features and outcomes in 348 patients with

polyarteritis nodosa: A systematic retrospective study of patients

diagnosed between 1963 and 2005 and entered into the French Vasculitis Study Group Database. Arthritis Rheum 62:616, 2010.

Stone JH et al: Rituximab versus cyclophosphamide for ANCAassociated vasculitis. N Engl J Med 363:221, 2010.

Stone JH et al: Trial of tocilizumab in giant-cell arteritis. N Engl J Med

377:317, 2017.

Walsh M et al: Plasma exchange and glucocorticoids in severe

ANCA-associated vasculitis. N Engl J Med 382:622, 2020.

Wechsler ME et al: Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med 376:1921, 2017.

Weyand CM, Goronzy JJ: Clinical practice. Giant-cell arteritis and

polymyalgia rheumatica. N Engl J Med 371:50, 2014.

Behçet syndrome is a systemic vasculitis, first described by Hulusi

Behçet, a Turkish dermatologist. It can present with skin and mucosal

lesions, uveitis, arthritis, major arterial and venous vessel disease, and

gastrointestinal and neurologic manifestations. These manifestations

can be present in various combinations and sequences over time.

Patients are most commonly from the Middle East, the Mediterranean

region, and the Far East; it is most prevalent in Turkey, with a prevalence of 1 in 250 adults. It is relatively rare before the late teens and

after age 50. Males and females are equally affected; however, males

frequently have more severe disease and poorer outcomes. Some manifestations may show regional differences; for example, gastrointestinal

involvement, rare in Turkey, is more common in Japan and is seen in

~30% of patients in the United States.

■ DIAGNOSIS

Behçet syndrome is diagnosed clinically. There are no specific laboratory, imaging, or histologic features that can help in the diagnosis of a

patient with suggestive symptoms, and the diagnosis is based on a combination of clinical features in the setting of ruling out other potential

causes. In this regard, some patients may require months to years to

develop the array of symptoms that would lead to a definitive diagnosis,

although a tentative diagnosis may be made well before. The most commonly used and best performing diagnostic criteria are the International Study Group (ISG) criteria (sensitivity ~95%, specificity ~96%);

patients need to have recurrent oral ulcers plus two of the following

four clinical manifestations: recurrent genital ulcers, skin lesions, eye

lesions, or a positive pathergy test (Table 364-1). Additional clinical

manifestations may involve various organ systems, including the gastrointestinal, vascular, pulmonary, and central nervous systems. Up to

50–60% of patients, depending on where they are from, can be positive

for HLA B*

51; however, it is not used as a diagnostic test because it is

also found in up to 20% of the normal population.

■ PATHOGENESIS

The pathogenesis and etiology of Behçet syndrome are unknown.

Family studies show a possible genetic predisposition, and increased

inflammation and immunologic mechanisms play a role. Both innate

and adaptive immune systems may be involved. Unlike other autoimmune diseases, however, Behçet syndrome is not typically associated

with autoantibodies, Raynaud’s phenomenon, Sjögren’s syndrome,

thrombocytopenia, hemolytic anemia, sun hypersensitivity, serosal

involvement, or an increased risk for other autoimmune diseases.

On the other hand, features that separate it from autoinflammatory

364 Behçet Syndrome

Yusuf Yazici

TABLE 364-1 International Study Group Criteria for the Diagnosis of

Behçet Syndrome

CRITERIA FREQUENCY COMMENTS

Oral ulcers ~98% 3 times in a 12-month period

Plus 2 out of 4 from below:

Recurrent genital ulcers ~80% Usually scarring

Skin lesions ~80% Erythema nodosum,

pseudofolliculitis,

papulopastular or acneiform

nodules (postadolescent, not

receiving corticosteroids)

Eye lesions ~50% Anterior/posterior uveitis cells

in vitreous or retinal vasculitis

Pathergy ~50% 24–48 h, after dermal insertion

of a 20-gauge needle

2818 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

conditions include tendency to abate with time, absence of mutations

associated with autoinflammatory diseases, and higher prevalence

than typical autoinflammatory diseases such as familial Mediterranean

fever (Chap. 369). There is neutrophil hyperreactivity; however, it is

not clear whether this is primary or secondary to cytokine-directed

activation. There is also evidence from retrospective patient cohort

analyses that there may be different clusters of disease presentation;

for example, acne lesions are more commonly seen with arthritis and

associated with enthesitis, and each of these clusters may have a different pathogenesis.

■ CLINICAL PRESENTATION

The most common symptoms are associated with mucocutaneous

tissues. Oral ulcers are seen in virtually all patients and are commonly

the first manifestation. Commonly, like ordinary cancer sores, they are

usually multiple. They last around 10 days but recur unless treated.

Only the uncommon, major ulcers tend to scar. Beneficial effects of

dental and periodontal therapies suggest that decreased oral health is

associated with disease severity.

Genital ulcers are the most specific lesions, most commonly occurring on the scrotum or labia. They are larger and deeper and take

longer to heal than oral ulcers and tend to form scars.

Acne-like or papulopustular lesions are indistinguishable from acne

vulgaris in appearance and pathology. They are seen both at the usual

acne sites as well as at uncommon sites such as lower extremities. Other

skin findings are the nodular lesions, which are of two types: erythema

nodosum lesions due to panniculitis and superficial vein thromboses.

Superficial thrombophlebitis often occurs in men and is associated

with deep-vein thrombosis; it should trigger workup for other vascular

involvement, including pulmonary artery aneurysms.

Pathergy reaction is a nonspecific hyperreactivity of the skin to

trauma. Typically, a papule or pustule forms in 24–48 h after a needle

prick. It is rather unique for Behçet syndrome and is part of the ISG

diagnostic criteria.

Arthralgia or arthritis is seen in about half of patients; it is usually

a mono- or oligoarthritis in the lower extremities and does not usually

cause deformity or erosions.

Eye involvement is seen in half of all patients and in ~70% of males.

It is most commonly a bilateral panuveitis. A hypopyon, seen in ~10%

of patients with eye disease, is an intense inflammation in the anterior

chamber and is quite specific for Behçet syndrome. Ocular involvement develops usually in the first 2 years after fulfillment of diagnostic

criteria and is most severe during the first few years and then tends to

abate. Male gender, posterior involvement, frequent attacks (>3 per

year), strong vitreous opacity, and macular edema are poor prognostic

factors.

Vascular disease is seen in up to 40% of patients. It is associated with

intensive thrombosis and runs a relapsing course. Several well-defined

venous vascular associations are seen, and superficial and deep-vein

thrombosis, Budd-Chiari syndrome, inferior vena cava syndrome,

pulmonary artery involvement, intracardiac thrombosis, and cerebral

venous sinus thrombosis frequently cluster in various combinations.

Pulmonary artery aneurysms carry a 5-year mortality rate of 20–25%.

Prevalence of neurologic involvement is ~5%, with about threequarters of patients presenting with parenchymal involvement, while

the remaining cases present with cerebral venous sinus thrombosis.

These two forms only rarely occur together. Parenchymal involvement

usually affects the telencephalic-diencephalic junction, brainstem, and

spinal cord. Patients may present with a subacute onset of severe headache, cranial nerve palsy, dysarthria, ataxia, and hemiparesis.

Prevalence of gastrointestinal involvement changes significantly

across different populations (up to 50% in the Far East but rare in the

Middle East). Clinical and endoscopic appearance of intestinal involvement can be similar to, and thus cannot easily be differentiated from,

Crohn’s disease. Ulcers tend to be single or less than five, are usually

confined to the ileocecal area, are more likely to be deep and round,

and are prone to perforate; perianal and rectal area involvement is rare.

In practice, it is difficult to distinguish Behçet syndrome from Crohn’s

disease unless extraintestinal lesions are present.

TREATMENT

Behçet Syndrome

Treatment is guided by type and severity of involvement, with the

goal of preventing long-term damage. Most new manifestations

present within the first 5 years, and for most patients, the natural

course is one of diminishing symptoms culminating in potential

remission, frequently not requiring ongoing treatment with medications. Patient characteristics, such as being young and male, need

to be kept in mind as these patients tend to have a worse prognosis.

For most patients, tapering and/or stopping their medications in

2–3 years after the symptoms have improved should be attempted.

Oral ulcers can be managed with topical glucocorticoids and on

an as-needed basis if mild. Lesions resistant to local measures may

require systemic treatment with colchicine, oral glucocorticoids,

immunosuppressants such as apremilast, azathioprine, or a tumor

necrosis factor-α inhibitor such as infliximab. Apremilast has now

been approved in the United States and Japan for the treatment of

oral ulcers of Behçet syndrome. A similar treatment approach can

be used for genital ulcers and other mucocutaneous manifestations.

Patients may need a combination of medications, at least initially,

to control disease activity.

Eye involvement, given its frequency and potential morbidity, requires early and aggressive treatment with brief courses of

glucocorticoids and longer-term treatment with an immunosuppressant. Azathioprine is usually the preferred agent. Infliximab,

adalimumab, or cyclosporine can also be used, in combination with

systemic glucocorticoids and azathioprine, for control of disease

activity. Monotherapy with interferon is another option. Glucocorticoids can be tapered in many patients after active disease has been

controlled, whereas immunosuppressants are generally continued

for at least 2 years.

Gastrointestinal involvement is treated with a glucocorticoid

plus an immunosuppressant such as azathioprine alone or in combination with infliximab.

Venous thrombotic events are treated by controlling systemic

inflammation with immunosuppressive medications (usually azathioprine or, for more severe cases, cyclophosphamide), rather than

using anticoagulants. However, if venous thrombotic events occur,

standard anticoagulation treatment can be given, provided there is

a low risk of bleeding and there are no coexistent pulmonary artery

aneurysms. For central nervous system involvement, the combination of azathioprine and a tumor necrosis factor inhibitor is usually

the first choice.

■ FURTHER READING

Hatemi G et al: 2018 update of the EULAR recommendations for the

management of Behçet’s syndrome. Ann Rheum Dis 77:808, 2018.

Kural-Seyahi E et al: The long-term mortality and morbidity of

Behçet syndrome: A 2-decade outcome survey of 387 patients followed at a dedicated center. Medicine (Baltimore) 82:60, 2003.

Yazici H et al: Behçet syndrome: A contemporary view. Nat Rev Rheumatol 14:107, 2018.

Inflammatory Myopathies

2819CHAPTER 365

This chapter focuses on the major types of inflammatory myopathies

(IMs), including dermatomyositis (DM), polymyositis (PM), immunemediated necrotizing myopathy (IMNM), antisynthetase syndrome

(AS), and inclusion body myositis (IBM) (Table 365-1). Other IMs

include those caused by infection, eosinophilic myositis, granulomatous myositis, and myositis triggered by checkpoint inhibitors. Of note,

inflammatory cell infiltrates can also be occasionally seen in muscle

biopsies in hereditary (e.g., muscular dystrophies, metabolic myopathies) and toxic myopathies.

Epidemiologic studies suggest that the incidence of IM grouped

together is >4 cases per 100,000 with prevalence in the range of 14–32

per 100,000. Defining the actual incidence and prevalence of the

individual myositides is limited, however, by the different diagnostic

365 Inflammatory

Myopathies

Steven A. Greenberg, Anthony A. Amato

criteria employed in various epidemiologic studies, increasing recognition of AS, and frequent misdiagnosis of IBM and IMNM. Idiopathic

PM without signs of an overlap syndrome is quite rare, while DM,

IBM, and IMNM occur in roughly similar frequencies. DM can occur

in children (juvenile DM), while IBM always occurs in adults and is

the most common cause of myopathy in those aged >50. DM, PM, and

AS are more common in women, while IBM is more common in men.

DIAGNOSTIC APPROACH AND

DIFFERENTIAL DIAGNOSIS

The approach to patients with suspected myopathy is detailed in

Chap. 449. In any patient presenting with weakness, the first step is to

localize the site of the lesion by history and clinical findings (Chap. 24).

Weakness could be caused by a process in the cerebral hemispheres, spinal cord (Chap. 442), anterior horn cell (Chap. 437), peripheral nerve

(Chaps. 446-447), neuromuscular junction (Chap. 448), or muscle

(Chap. 449). Past medical history, medication use, and family history,

combined with a detailed clinical examination and an appreciation for

the pattern of muscle involvement (e.g., what muscles are weak and

atrophic or hypertrophic as well as the presence of scapular winging,

early contractures, sensory abnormalities, fasciculations, or rash), help

TABLE 365-1 Inflammatory Myopathies: Clinical and Laboratory Features

DISORDER SEX

AGE OF

ONSET RASH

PATTERN OF

WEAKNESS

LABORATORY

FEATURES MUSCLE BIOPSY

CELLULAR

INFILTRATE

RESPONSE

TO IS

THERAPY

COMMON

ASSOCIATED

CONDITIONS

DM F > M Childhood and

adult

Yes Proximal >

distal

Normal or increased

CK (up to 50× normal

or higher); various

MSAs (anti-MDA5,

anti-TIF1, anti-Mi-2,

anti-NXP2)

Perimysial and

perivascular

inflammation; IFN-1

regulated proteins

(MHC-1, MxA),

MAC deposition on

capillaries

CD4+ dendritic

cells; B cells;

macrophages

Yes Myocarditis,

ILD, malignancy,

vasculitis, other

CTDs

PM F > M Adult No Proximal >

distal

Increased CK (up to

50× normal or higher)

Endomysial and

perivascular

inflammation;

ubiquitous

expression of

MHC-1

CD8+ T cells;

macrophages;

plasma cells

Yes Myocarditis,

ILD, other CTDs

NM M = F Children and

adults

No Proximal >

distal

Elevated CK (>10×

normal or higher);

anti-HMGCR or antiSRP antibodies

Necrotic muscle

fibers; minimal

inflammatory

infiltrate

Macrophages

in necrotic

fibers

undergoing

phagocytosis

Yes Malignancy,

CTD, HMGCR

antibody cases

can be triggered

by statin use

AS F > M Children and

adults

Sometimes Proximal >

distal

Elevated CK (>10×

normal or higher);

antisynthetase

antibodies

Perimysial and

perivascular

inflammation;

perimysial

fragmentation

with alkaline

phosphatase

staining; perimysial

muscle damage

with necrosis

CD4+ dendritic

cells; B cells;

macrophages

Yes Nonerosive

arthritis, ILD,

Raynaud’s

phenomenon,

mechanic

hands, and

fever

IBM M > F Older adults

(>50 years)

No Proximal

and distal;

predilection

for: finger/

wrist

flexors, knee

extensors

Normal or mildly

increased CK

(usually <10×

normal); anticN-1A antibodies;

large granular

lymphocytes on

flow cytometry and

reduced CD4/CD8

ratio with increased

CD8 count

Endomysial and

perivascular

inflammation;

ubiquitous

expression of

MHC-1; rimmed

vacuoles; p62, LC3,

TDP-43 aggregates;

EM: 15–18 nm

tubulofilaments;

ragged red and

COX-negative fibers

CD8+ T cells;

macrophages;

plasma cells;

myeloid

dendritic cells;

large granular

lymphocytes

None or

minimal

Granular

lymphocytic

leukemia/

lymphocytosis,

sarcoidosis,

sicca or

Sjögren’s

syndrome

Abbreviations: CK, creatine kinase; cN-1A, cytosolic 5′-nucleotidase 1A; CTDs, connective tissue diseases; COX, cytochrome oxidase; DM, dermatomyositis; F, female; g,

immunoglobulin; IBM, inclusion body myositis; IFN-1, type 1 interferon; ILD, interstitial lung disease; IS, immunosuppressive; M, male; MAC, membrane attack complex;

MDA5, melanoma differentiation antigen; MHC-1, major histocompatibility antigen 1; MSA, myositis-specific autoantibodies; NCP2, nuclear matrix protein 2 (NXP2); NM,

necrotizing myopathy; PM, polymyositis; TIF1, transcriptional intermediary factor 1.

Source: From AA Amato, JA Russell (eds): Neuromuscular Disorders, 2nd ed. New York, McGraw-Hill Education; 2016, Table 33-1, p. 824, with permission.

2820 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

A

B

C

D

E

FIGURE 365-1 Cutaneous manifestations of dermatomyositis. A. Macular erythema plaques (Gottron sign) and

erythematous papules (Gottron papules) on extensor surface of fingers and B. elbow. C. Macular erythema plaques

over anterior neck and chest (V-sign) and D. the posterior neck, shoulder, and upper back (Shawl sign). E. Nail bed

changes with dilated capillaries.

differentiate myopathies from other neuromuscular disorders and the

different types of myopathies from each other (see Chap. 449). For

example, atrophy with fasciculations suggests a neurogenic process

such as amyotrophic lateral sclerosis, fatigable weakness on examination points to a neuromuscular junction defect such as myasthenia

gravis, and concomitant sensory symptoms suggest a central process

such as a spinal cord disorder or a polyneuropathy. Scapular winging,

calf hypertrophy or atrophy, and early contractures before significant

weakness develops would strongly suggest a muscular dystrophy,

particularly if there is a positive family history. A heliotrope rash combined with Gottron papules and dilated nailfold capillaries is diagnostic

for DM. The presence of atrophy and weakness of the flexor forearm

muscles and quadriceps in a person aged >50 years is most likely IBM.

When the site of the lesion cannot be localized based on history

and clinical examination alone, laboratory testing is required. Serum

creatine kinase (CK) is the most sensitive laboratory marker of muscle

destruction. Not all myopathies are associated with elevated CK levels,

but a markedly elevated CK (e.g., >2000 U/L) is almost always due

to a myopathy. A slightly elevated CK can also be seen in neurogenic

disorders, however. Myositis-associated and myositis-specific antibodies (MSAs) help to distinguish subtypes of IM, as discussed below.

Electromyography (EMG) and nerve conductions studies (NCS) are

useful in localizing the site of the lesion but are less specific in helping

to determine the actual cause of a myopathy. EMG can be useful at

times in guiding what muscle to biopsy, especially if muscles typically

biopsied are normal on clinical examination. Imaging skeletal muscle

can be helpful in assessing muscle involvement and revealing fatty

replacement, atrophy, or edema within muscle or surrounding fascia.

A muscle biopsy is usually required to definitively distinguish one

myopathy from another. The different forms of IM can have distinctive

histopathologic abnormalities as discussed below. In a patient with a

classic DM rash, a muscle or skin biopsy can be performed, but an

argument can also be made that biopsy is unnecessary—particularly if

the patient also has an MSA specific for DM. However, a muscle biopsy

should be performed in every case of suspected PM to exclude IBM

(if not clinically apparent) and other causes of myopathy. Diagnosis of

IMNM is by definition based upon histologic findings. It is important

to biopsy a muscle that is clinically affected but not too weak (e.g.,

Medical Research Council grade 4 out of 5 in strength); otherwise, one

may just see end-stage muscle. A biopsy should always be coordinated

with an experienced muscle histopathology laboratory.

Patients with severe muscle pain, subjective weakness, and fatigue

with normal strength and function on examination are not likely to

have an IM. Polymyalgia rheumatica should be considered in older

individuals with an elevated erythrocyte sedimentation rate (ESR) or

C-reactive protein (CRP) but normal CK and EMG. Fibromyalgia is

likely in patients with a normal laboratory workup. In general, a muscle

biopsy is not indicated unless there is objective weakness, an abnormal

EMG, or elevated CK.

SPECIFIC DISORDERS

■ DERMATOMYOSITIS

Clinical Features DM manifests with symmetric, proximal greater

than distal weakness along with a characteristic rash that includes the

heliotrope rash (erythematous discoloration of eyelids with periorbital

edema), Gottron sign (erythematous rash over the extensor surfaces

of joints such as the knuckles, elbows, knees, and ankles), Gottron

papules (raised erythematous rash over knuckles) (Fig. 365-1), V-sign

(rash on the sun-exposed anterior neck and chest), shawl sign over

the back of the neck and shoulders, nail bed telangiectasias, and subcutaneous calcium deposits. The weakness and rash usually accompany one another but can be separated by

several months. Furthermore, there is a

spectrum of involvement such that some

patients continue to manifest only with

a rash (amyopathic DM), while others

may present mainly with weakness and

little or no visible skin changes. Patients

can also complain of myalgias, arthralgias, dysphagia, and dysarthria. Cutaneous disease activity is highly relevant in

DM; in comparison to other debilitating

skin diseases including cutaneous lupus

erythematosus, psoriasis, and atopic dermatitis, skin symptoms in DM patients

are associated with an overall reduction

in life quality. Pruritus can be especially

debilitating. Dyspnea can occur from

ventilatory muscle weakness or intrinsic

pulmonary problems including interstitial

lung disease (ILD), bronchopneumonia,

and alveolitis. Pulmonary manifestations

are often associated with antisynthetase

antibodies; myositis associated with the

AS can be considered a distinct disorder

(discussed below). DM can present in children (juvenile DM) or in adults. There is a

higher risk for malignancy in adult-onset

cases, ~15% within the first 2–3 years.

Laboratory Features Serum CK levels are elevated in 70–80% of patients;

in 10% of those with normal CK, serum

aldolase may be increased. Antinuclear

antibodies can be positive but are a nonspecific finding. DM is associated with

several MSA targeting melanoma differentiation antigen 5 (MDA5), transcriptional

intermediary factor 1 (TIF1), Mi-2, and

Inflammatory Myopathies

2821CHAPTER 365

A B

FIGURE 365-2 Perifascicular atrophy and myxovirus resistance protein A (MxA) expression in dermatomyositis.

A. Perifascicular myofibers (black arrows) bordering on disrupted perimysial connective tissue are atrophic and

basophilic on hematoxylin and eosin (H&E) stains. B. Perifascicular myofibers (white arrows) show intense staining for

MxA protein along a gradient from superficial to deep; all capillaries show intense MxA expression (white arrowheads).

FIGURE 365-3 Skeletal muscle MRI with short T1 inversion recovery (STIR) imaging in polymyositis. MRI of the thigh

demonstrates bright signal indicative of edema/inflammation, particularly in the rectus femoris muscle. This contrasts

with MRI in IBM in which there is more selective involvement of the vastus lateralis and medialis with relative sparing

of the rectus femoris (see Fig. 365-7F and G).

nuclear matrix protein 2 (NXP2). These antibodies are usually associated with characteristic clinical features. For example, anti-MDA5

antibodies are associated with amyopathic DM with severe palmar

rash, digital ulcers, and rapidly progressive ILD. Anti-TIF1 (or p155)

antibodies and anti-NXP2 antibodies are associated with an increased

risk of cancer, while anti-Mi-2 antibodies are often associated with

more benign DM and a favorable response to treatment.

EMG of weak muscles shows increased insertional and spontaneous

activity in the form of positive sharp waves and fibrillation potentials,

or complex repetitive discharges along with early recruitment of small

amplitude, short duration, polyphasic motor units. These findings

are nonspecific and can be seen in other myopathies. Skeletal muscle

magnetic resonance imaging (MRI muscle) reveals edema in affected

muscles and sometimes more specific findings of abnormalities of

fascia suggesting fasciitis.

Histopathology and Pathogenesis The characteristic histopathologic abnormality on muscle biopsy is perifascicular atrophy

(Fig. 365-2A); however, this is present in perhaps only 50% of patients.

Immunohistochemical staining for myxovirus resistance protein A

(MxA) is diagnostically more sensitive and highly specific (Fig. 365-2B).

The inflammatory cell infiltrate is predominantly perivascular and

located in the perimysium and is composed primarily of macrophages,

B cells, and plasmacytoid dendritic cells (PDCs). Skin biopsies reveal

cell-poor interface dermatitis, which is analogous to the perifascicular

atrophy in that the basal layer of keratinocytes is most damaged; the

inflammatory infiltrate is typically absent or minimal and, when present, is located mainly at the border zone of the dermis and epidermis.

The pathogenesis of DM was traditionally attributed to an antibody-mediated attack on endothelial

cells, followed by complement-mediated

destruction of capillaries and watershed

ischemia of muscle fibers. However,

recent studies suggest that this is not

likely the case. Immunoglobulin deposition is largely absent on endothelial

cells, and complement deposition may

be a secondary phenomenon. There is

increasing evidence that the microvasculopathy and skin and muscle damage

associated with DM are primarily due

to toxicity from type I interferon (IFN)–

mediated pathways, most likely IFN-β.

Prognosis In the absence of malignancy, prognosis is generally favorable

in patients with DM, with 5-year survival rates ranging from 70 to 93%. Poor

prognostic features are increased age,

associated ILD, cardiac disease, and late

or previous inadequate treatment.

■ POLYMYOSITIS

Clinical Features PM is a heterogenous group of disorders that usually

presents with symmetric and proximal

weakness that worsens over several

weeks to months. As with DM, there

can be associated heart, lung, and joint

involvement as well as an increased risk

of cancer. Some epidemiologic studies

suggest that the risk of cancer in PM

is less than that in DM, but these older

series likely included patients with IBM

and dystrophies with inflammation who

were misdiagnosed as having PM.

Laboratory Features CK levels are

always elevated in uncontrolled PM. A

normal CK should alert clinicians to the

possibility of IBM. As in DM, EMG and skeletal muscle imaging can be

abnormal, but the findings are not specific (Fig. 365-3).

Histopathology and Pathogenesis Because PM is a heterogeneous category, muscle pathology varies substantially. Most often,

patients with nonspecific inflammatory cells present in perimysial

more often than endomysial locations have been categorized as PM.

A small minority of patients have mononuclear inflammatory infiltrate that surrounds fibers with sarcolemmal major histocompatibility

(MHC-I) expression (Fig. 365-4). There is debate as to whether true

invasion of myofibers occurs in PM, or rather always indicates IBM.

The inflammatory infiltrate predominantly consists of CD8+ T cells

and macrophages located in the endomysial, perimysial, and perivascular regions. As PM is heterogeneous, its varied forms of pathogenesis

are poorly understood.

Prognosis Most patients with PM improve with immunotherapies

but usually require lifelong treatment. Some retrospective studies suggest that PM does not respond as well as DM to these therapies. However, many of these older series of “PM” likely included patients who

actually had IMNM, IBM, or other myopathies (including muscular

dystrophies) that do not respond to immunotherapies. As in DM, poor

prognostic features are cancer, increased age, lung or cardiac involvement, and late or previously inadequate treatment.

■ OVERLAP SYNDROMES

The term overlap syndrome is applied when DM or PM is associated

with other well-defined connective tissue diseases (CTDs) such as

scleroderma, mixed connective tissue disease (MCTD), Sjögren’s syndrome, systemic lupus erythematosus (SLE), or rheumatoid arthritis.

2822 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

As in DM and PM, the myositis associated with these overlap syndromes is usually responsive to immunotherapies.

■ IMMUNE-MEDIATED NECROTIZING MYOPATHY

Clinical Features IMNM, or autoimmune necrotizing myopathy,

is characterized by the acute or insidious onset of symmetric, proximal

more than distal weakness. Dysphagia, dysarthria, or myalgia may

occur. Patients may have an underlying CTD (usually scleroderma

or MCTD) or cancer (paraneoplastic necrotizing myopathy), or the

condition may be idiopathic. There are at least two distinct forms of

IMNM associated with specific autoantibodies (anti-3-hydroxy-3-

methyl-glutaryl-coenzyme reductase [HMGCR] and anti-signal recognition particle [SRP]). Anti-HMGCR myopathy can be seen in patients

receiving statins, inhibitors of HMGCR, particularly in patients aged

>50 years. However, anti-HMGCR myopathy can develop in children

and young adults without a history of statin use and can mimic a limb

girdle muscular dystrophy. Unlike the more common “toxic” myopathy

associated with statin use, anti-HMGCR myopathy does not improve

when statins are discontinued. Anti-SRP myopathies are notable for the

presence of anti-SRP antibodies and a typically subacute, aggressive,

and relatively refractory course.

Laboratory Features CK levels are markedly elevated (usually

>10 × normal) in IMNM. As mentioned, IMNM can be associated

with anti-HMGCR or anti-SRP antibodies. EMG often shows increased

insertional and spontaneous activity, including myotonic discharges.

Skeletal muscle imaging findings are nonspecifically abnormal.

Histopathology and Pathogenesis Muscle biopsies reveal multifocal necrotic and regenerating muscle fibers with a paucity of inflammatory cells (Fig. 365-5). However, some patients with anti-HMGCR

myopathy have endomysial, macrophage-predominant infiltrates similar to what is seen in PM. Overexpression of MHC-I and membrane

attack complex (MAC) may be evident on sarcolemma of nonnecrotic

fibers and MAC deposition on capillaries. The pathogenesis of IMNM

is not completely understood but may be complement mediated.

Prognosis IMNM is generally much more difficult to treat than

either DM or PM, and aggressive immunotherapy is usually required.

The progressive course despite immunotherapy and marked weakness

with atrophy can lead to a misdiagnosis of a limb girdle muscular dystrophy. There may be an increased incidence of cancer in patients with

anti-HMGCR myopathy; thus, patients should undergo a malignancy

workup.

■ ANTISYNTHETASE SYNDROME

Clinical Features The presence of myositis, nonerosive arthritis,

ILD, Raynaud’s phenomenon, mechanic hands, and fever associated

with antibodies against aminoacyl-tRNA synthetase constitute the AS.

Some patients have an erythematous rash, and muscle biopsies share

histopathologic features of DM, which likely accounts for many of

these patients being classified as having DM.

Laboratory Features Antibodies against aminoacyl-tRNA synthetases are the most common MSA, present in 25–35% of patients

with myositis. The most common aminoacyl-tRNA synthetase antibody is anti-Jo-1. CK is usually elevated in patients with AS and myositis. Those with ILD demonstrate reduced forced vital capacity and

diffusion capacity on pulmonary function tests. Spiral chest CT scans

are best at demonstrating the honeycomb pattern of ILD. Skeletal muscle MRI and EMG show abnormalities similar to DM, PM, and IMNM.

Histopathology and Pathogenesis Muscle biopsies demonstrate

a predilection for perimysial damage including perimysial fragmentation and staining with alkaline phosphatase (Fig. 365-6), PDCs and

macrophages in the perimysium and around blood vessels, and MAC

deposition on capillaries. Also similar to DM, there is perifascicular

muscle fiber damage, but with AS, there is more perifascicular muscle

fiber necrosis compared to DM, in which perifascicular atrophy is

more prominent. MHC-I and MAC deposits on muscle fibers may be

seen on sarcolemma of perifascicular muscle fibers.

Prognosis Most patients respond to treatment, although responses

are less complete than for DM and PM; ILD can be particularly refractory to treatment. Unlike DM, PM, and IMNM, there does not appear

to be an increased risk of malignancy.

■ INCLUSION BODY MYOSITIS

Clinical Features IBM usually manifests in patients over the age of

50 years and is slightly more common in men than women. It is associated with slowly progressive weakness and muscle atrophy that has a

predilection for early involvement of the wrist and finger flexors in the

arms and quadriceps in the legs (Fig. 365-7). Weakness is often asymmetric. Dysphagia is common and rarely can be the presenting feature.

These clinical features can help distinguish IBM from PM and other

forms of myopathy. The mean duration from onset of symptoms to use

of wheelchair or scooter is ~15 years. There is no known increased risk

of malignancy.

Laboratory Features CK levels can be normal or only slightly

elevated (usually <10 times normal). Antibodies targeting cytosolic

5′-nucleotidase 1A (cN-1A) are detected in the blood in a third to

more than two-thirds of IBM patients and are a highly specific diagnostic biomarker for IBM among patients with myopathy. Other blood

biomarkers for IBM include the presence of an abnormal population

of large granular lymphocytes on flow cytometry and a reduced CD4/

CD8 ratio with an increased CD8 count. Needle EMG may demonstrate large-amplitude, long-duration motor unit potentials that can be

FIGURE 365-4 Pathology of polymyositis. Muscle biopsy demonstrates endomysial

infiltrates surrounding nonnecrotic muscle fibers.

FIGURE 365-5 Pathology of immune-mediated necrotizing myopathy. Muscle

biopsy demonstrates scattered necrotic fibers with inflammatory infiltrate confined

to those fibers undergoing myophagocytosis along with a few regenerating fibers.

Inflammatory Myopathies

2823CHAPTER 365

A

B C

100.00 µm

FIGURE 365-6 Pathology of myositis with anti-Jo-1 antibodies (antisynthetase syndrome). A. Perifascicular/perimysial

muscle fiber atrophy and necrosis (thin arrow) associated with perimysial connective tissue is edematous and

fragmented in appearance (thick arrow), hematoxylin and eosin stain. B. The perimysial connective tissue intensely

stains red with alkaline phosphatase stain (arrowhead). C. Immunostaining demonstrates deposition of membrane

attack complex (MAC) deposits on the sarcolemma of nonnecrotic perifascicular muscle fibers (open arrow).

A B

D E F

G

C

FIGURE 365-7 Muscle manifestations of inclusion body myositis (IBM; A–C). Finger flexor weakness can be (A) subtle and multifocal (black arrows), (B) moderate, or (C)

severe. Note that even with complete paralysis of deep and superficial finger flexors, metacarpophalangeal joint flexion (arrows) is often maintained due to preservation of

lumbricals. D. Ventral forearm atrophy (arrows). E. Atrophy of medial thighs due to loss of vastus medialis (arrows). F. Early IBM, with relatively preserved vastus medialis

(arrows), in contrast to (G) advanced IBM with marked fibrous replacement of vastus medialis (arrows).

misinterpreted as neurogenic but reflect the chronicity of the myopathy. Muscle MRI may show a predilection for involvement of the flexor

digitorum profundus in the arms and the vastus medialis and lateralis

muscles with sparing of the rectus femoris muscle.

Histopathology and Pathogenesis Muscle biopsies demonstrate endomysial inflammatory infiltrates predominantly composed

of CD8+ T cells and macrophages surrounding and invading nonnecrotic muscle fibers, MHC-1 expression on the sarcolemma, fibers

with rimmed vacuoles, cytochrome oxidase (COX)–negative fibers, and inclusions on light or electron microscopy

(Fig. 365-8). The inclusions contain

beta-sheet misfolded proteins (amyloid)

but are difficult to appreciate with routine Congo red stain (they are seen

on frozen but not paraffin sections).

Immunostaining for p62 appears to

be the most sensitive stain for detection of these inclusions. Importantly,

rimmed vacuoles may not be seen in

as many as 20–30% of muscle biopsies.

In such cases, the presence of mitochondrial abnormalities (ragged red and

COX-negative fibers) and immunostaining demonstrating p62 inclusions are

helpful in distinguishing IBM from PM

(aside from the clinical pattern of muscle

weakness).

The pathogenesis of IBM is poorly

understood. The marked adaptive

immune system abnormalities related to

T-cell inflammation and the presence of

a relatively specific autoantibody against

a muscle protein indicate an autoimmune attack on muscle. The chronic

and highly inflammatory environment

within muscles in IBM may alter protein

synthesis and degradation pathways in

part via aberrant immunoproteasome

expression. Additional histologic features, typically referred to as “degenerative,” include aggregation of various

proteins including markers of endoplasmic reticulum (ER) stress and

autophagy (e.g., p62 and LC3). Involvement of ER stress and autophagy

has also been observed in other autoimmune diseases, such as primary

biliary cholangitis (PBC), inflammatory bowel disease, and ankylosing

spondylitis, some of which can be highly refractory to immunotherapy.

Prognosis The myopathy is slowly progressive and is not typically

responsive to immunotherapies. Most patients require a scooter or

wheelchair within 10–15 years of onset of symptoms.

2824 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

A

C D

B

FIGURE 365-8 Pathology of inclusion body myositis. A. Scattered muscle fibers with rimmed vacuoles and rare fibers with eosinophilic inclusions (arrow), hematoxylin and

eosin stain. B. Cytochrome oxidase stain demonstrates an increased number of pale-staining or COX-negative muscle fibers. C. Cytoplasmic inclusions stain positive with

p62 within a muscle fiber (thick arrow). D. Electromicroscopy reveals 15- to 21-nm tubulofilamentous inclusions within a myonucleus.

TREATMENT OF THE IM (TABLE 365-2)

DM, PM, AS, and IMNM are typically responsive to immunotherapy.

High-dose glucocorticoids (i.e., starting dose of prednisone 0.75–1.0 mg/

kg per day) are considered the first-line treatment. There is uncertainty regarding when to start second-line agents (e.g., methotrexate,

azathioprine, mycophenolate, immunoglobulin, or rituximab). The

clinician must weigh with the patient the increased risks of immunosuppression versus possible benefits (e.g., faster improvement,

steroid-sparing effect, and/or avoidance of the morbidities associated

with long-term glucocorticoid use). We usually start a second-line

agent (typically methotrexate) with glucocorticoids in patients with

severe weakness or other organ system involvement (e.g., myocarditis, ILD), those with increased risk of steroid complications (e.g.,

diabetics, osteoporosis, or postmenopausal women), and patients with

IMNM who are known to have difficult-to-treat myositis. In those

in whom we initiate treatment with prednisone alone, a second-line

agent is added in patients who fail to significantly improve after 2–4

months of treatment or in those who cannot be tapered to a low dose

of prednisone.

Most patients with IMNM do not respond to prednisone alone

or even prednisone plus a second-line agent in combination. Many

require triple therapy with prednisone, methotrexate, and intravenous

immunoglobulin (IVIG) and, if this fails, rituximab. Recent reports

suggest that anti-HMGCR myopathy may respond to monotherapy

with IVIG, and a large multicenter clinical trial to test this approach

is underway. Additionally, muscle biopsies demonstrate deposition of

membrane attack complexes on sarcolemma of nonnecrotic fibers in

IMNM, suggesting that muscle destruction is complement mediated.

In this regard, there is an ongoing international trial investigating the

safety and efficacy of a complement inhibitor in anti-HMGCR and

anti-SRP myopathies.

Unfortunately, IBM does not typically respond to any known

immunotherapies. The mainstay of treatment is physical and occupational therapy to improve function and swallowing therapy (and

sometimes esophageal dilation or cricopharyngeal myotomy) in those

with dysphagia.

■ GENERAL GUIDELINES FOR USE OF

SPECIFIC IMMUNOTHERAPIES

Glucocorticoids Treatment is initiated with prednisone (0.75–1.5

mg/kg up to 100 mg) administered as a daily morning single dose (the

most common dose used in adults is 60 mg daily). In patients with

severe weakness or comorbidities (e.g., ILD, myocarditis), treatment

with a short course of intravenous methylprednisolone (1 g daily for

3 days) is recommended prior to starting oral glucocorticoids. Patients

are generally maintained on high-dose prednisone until strength

normalizes or until improvement in strength has reached a plateau

(usually 3–6 months). Subsequently, prednisone can be tapered by

5 mg every 2–4 weeks. Once the dose is reduced to 20 mg every day

or every other day, the taper is slowed to 2.5 mg every 2–4 weeks. The

goal is to taper prednisone to ≤10 mg daily. Although most patients

improve, the response may not be complete and many will require

at least a small dose of prednisone or a second-line agent to have a

sustained remission. Serum CK levels are monitored; however, dose

adjustments of prednisone and other immunotherapies are primarily

based on the objective clinical examination and not the CK levels or

the patients’ subjective response. When no response is noted after an

adequate trial of high-dose prednisone, alternative diagnoses (e.g., IBM

or an inflammatory muscular dystrophy) and a repeat muscle biopsy

should be considered.

Relapse of the myositis needs to be distinguished from steroid

myopathy. Features suggesting a steroid myopathy include weakness

developing while on high dosage, a normal serum CK, clinical features

of steroid excess such as ecchymoses and “moon facies,” and absence

of muscle membrane irritability on EMG. By contrast, patients experiencing relapse of myositis may become weaker during the prednisone

taper, have increasing serum CK levels, and display abnormal spontaneous activity on EMG.

■ SECOND-LINE THERAPIES

Methotrexate Methotrexate is usually the second-line treatment

of choice because most authorities believe it works faster than other