Inflammatory Myopathies

2825CHAPTER 365

TABLE 365-2 Immunotherapies for Inflammatory Myopathies

THERAPY ROUTE DOSE SIDE EFFECTS MONITOR

Prednisone Oral 0.75–1.5 mg/kg per day to start Hypertension, fluid and weight gain,

hyperglycemia, hypokalemia, cataracts,

gastric irritation, osteoporosis, infection,

aseptic femoral necrosis

Weight, blood pressure, serum

glucose/potassium, cataract

formation

Methylprednisone Intravenous 1 g in 100 mL/normal saline over 1–2 h,

daily or every other day for 3–6 doses

Arrhythmia, flushing, dysgeusia,

anxiety, insomnia, fluid and weight gain,

hyperglycemia, hypokalemia, infection

Heart rate, blood pressure,

serum glucose/potassium

Azathioprine Oral 2–3 mg/kg per day; single a.m. dose Flu-like illness, hepatotoxicity, pancreatitis,

leukopenia, macrocytosis, neoplasia,

infection, teratogenicity

Blood count, liver enzymes

Methotrexate Oral 7.5–20 mg weekly, single or divided doses;

1 day a week dosing

Hepatotoxicity, pulmonary fibrosis, infection,

neoplasia, infertility, leukopenia, alopecia,

gastric irritation, stomatitis, teratogenicity

Liver enzymes, blood count

Subcutaneously 20–50 mg weekly; 1 day a week dosing Same as oral Same as oral

Cyclophosphamide Oral

Intravenous

1.5–2 mg/kg per day; single a.m. dose

0.5–1.0 g/m2

 per month × 6–12 months

Bone marrow suppression, infertility,

hemorrhagic cystitis, alopecia, infections,

neoplasia, teratogenicity

Blood count, urinalysis

Cyclosporine Oral 4–6 mg/kg per day, split into two daily

doses

Nephrotoxicity, hypertension, infection,

hepatotoxicity, hirsutism, tremor, gum

hyperplasia, teratogenicity

Blood pressure, creatinine/

BUN, liver enzymes,

cyclosporine levels

Tacrolimus Oral 0.1–0.2 mg/kg per day in two divided doses Nephrotoxicity, hypertension, infection,

hepatotoxicity, hirsutism, tremor, gum

hyperplasia, teratogenicity

Blood pressure, creatinine/

BUN, liver enzymes, tacrolimus

levels

Mycophenolate

mofetil

Oral Adults (1–1.5 g BID)

Children (600 mg/m2

 per dose BID)

(no >1 g/d in patients with renal failure)

Bone marrow suppression, hypertension,

tremor, diarrhea, nausea, vomiting,

headache, sinusitis, confusion, amblyopia,

cough, teratogenicity, infection, neoplasia

Blood count

Intravenous

immunoglobulin

Intravenous 2 g/kg over 2–5 days; then 1 g/kg every

4–8 weeks as needed

Hypotension, arrhythmia, diaphoresis,

flushing, nephrotoxicity, headache, aseptic

meningitis, anaphylaxis, stroke

Heart rate, blood pressure,

creatinine/BUN

Rituximab Intravenous A course is typically 750 mg/m2

 (up to 1 g)

and repeated in 2 weeks

Courses are then repeated usually every

6–18 months

Infusion reactions (as per IVIG), infection,

progressive multifocal leukoencephalopathy

Some check B-cell count prior

to subsequent courses (but this

may not be warranted)

Abbreviations: BUN, blood urea nitrogen; IVIG, intravenous immunoglobulin.

Source: From AA Amato, JA Russell (eds): Neuromuscular Disorders, 2nd ed. New York, McGraw-Hill Education; 2016, Table 33-8, p. 859, with permission.

agents. An oral dose of 5 or 7.5 mg/week is initiated and then gradually

increased as needed up to 25 mg/week. If there is no improvement after

1 month of 25 mg/week of oral methotrexate, a switch to weekly parenteral (usually subcutaneous) methotrexate is the next step, with dose

escalation by 5 mg weekly; only rarely is a dose >35 mg/week used. The

major side effects of methotrexate are alopecia, stomatitis, ILD, teratogenicity, oncogenicity, risk of infection, and pulmonary fibrosis, along

with bone marrow, renal, and liver toxicity. Patients are concomitantly

treated with folate or folinic acid.

Azathioprine A recommended initial dose is 50 mg/d in adults,

which can be increased by 50 mg every 2 weeks up to 2–3 mg/kg per

day. Approximately 12% of patients develop a systemic reaction characterized by fever, abdominal pain, nausea, vomiting, and anorexia that

requires discontinuation of the drug. The major practical limitation

of azathioprine is that 6–18 months of treatment are usually required

before benefit can be seen. Patients can be prescreened for thiopurine

methyltransferase (TPMT) deficiency that is associated with severe

bone marrow toxicity from this drug.

Mycophenolate Mofetil This drug inhibits the proliferation of T

and B lymphocytes by blocking purine synthesis. It appears to be effective in different forms of myositis and is the second-line treatment of

choice for myositis patients with ILD. The starting dose is 1.0 g twice

daily and can be increased to 3 g daily in divided doses, if necessary.

Mycophenolate is excreted through the kidneys; therefore, the dose

should be decreased (no >1 g/d total dose) in patients with renal insufficiency. An advantage of mycophenolate compared to other immunosuppressive agents is the lack of renal or hepatic toxicity.

Intravenous Immunoglobulin IVIG is used in patients refractory

to prednisone and at least one second-line immunosuppressive agent,

although recent reports suggest that it may be the treatment of choice

and effective as a monotherapy in anti-HMGCR myopathy. A dose of 2

g/kg is divided over 2–5 days, and repeat infusions are given at monthly

intervals for at least 3 months. Subsequently, intervals can be lengthened

or dosage decreased: 2 g/kg every 2 months or 1 g/kg per month.

Rituximab Rituximab is a monoclonal antibody directed against

CD20+ B cells. A large randomized controlled trial found no benefit,

but there were flaws in the study design. Most authorities feel that

rituximab can be beneficial in some patients who are refractory to

prednisone and at least one of the other second-line agents. The typical

dosage is 750 mg/m2 (up to 1 g) IV with a second infusion 2 weeks

later and with repeat courses (375 mg/m2 as a single infusion or with a

second infusion 2 weeks apart) every 6–18 months as needed.

MYOSITIS ASSOCIATED WITH

CHECKPOINT INHIBITORS

Autoimmune neurologic complications, including inflammatory neuropathy, myasthenia gravis, and myositis, can occur with use of immune

checkpoint inhibitors (anti-CTLA-4, anti-PD-1, and anti-PD-L1) to

treat various cancers (see Chaps. 447 and 448). Patients with myositis often develop muscle pain and weakness (axial musculature and

proximal limbs) after one or two cycles. Myocarditis can also develop.

Additionally, diplopia with extraocular weakness along with dysphagia

and dysarthria suggesting the co-occurrence of myasthenia gravis

(MG) may be present. In such cases, an elevated CK level helps support

the diagnosis of myositis, while acetylcholine receptor antibodies or

2826 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

Relapsing polychondritis is an uncommon disorder of unknown cause

characterized by inflammation of cartilage predominantly affecting

the ears, nose, and laryngotracheobronchial tree. Multisystem disease

occurs commonly and can also involve noncartilaginous tissues and

organs. Relapsing polychondritis has been estimated to have an annual

incidence of 3.5 per million. The peak age of onset is between 40 and

50 years, but the disease can be seen in all ages with both sexes being

equally affected. Approximately 30% of patients with relapsing polychondritis will have another rheumatologic disorder, most frequently

systemic vasculitis, rheumatoid arthritis, or systemic lupus erythematosus (SLE). Nonrheumatic disorders have also been associated with

relapsing polychondritis (Table 366-1). 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.

■ PATHOLOGY AND PATHOPHYSIOLOGY

The earliest abnormality of hyaline and elastic cartilage noted histologically is a focal or diffuse loss of basophilic staining indicating depletion of proteoglycan from the cartilage matrix. Inflammatory infiltrates

are found adjacent to involved cartilage and consist predominantly

of mononuclear cells and occasional plasma cells. In acute disease,

366 Relapsing Polychondritis

Carol A. Langford

TABLE 366-1 Disorders Associated with Relapsing Polychondritisa

Systemic vasculitis

Rheumatoid arthritis

Systemic lupus erythematosus

Overlapping connective tissue disease

Spondyloarthritides

Behçet’s disease

Polymyalgia rheumatica

Primary biliary cirrhosis

Pulmonary fibrosis

Hashimoto’s thyroiditis

Graves’ disease

Crohn’s disease

Ulcerative colitis

Myelodysplastic syndrome

a

Systemic 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.

decremental response on slow repetitive nerve stimulation can establish the diagnosis of MG. Endomysial inflammatory cell infiltrates

composed of macrophages expressing PD-L1 and CD8+ lymphocytes

expressing PD-1, overexpression of MHC-I on sarcolemma of muscle

fibers, and scattered necrotic and regenerating fibers can be found on

muscle biopsies.

The immune checkpoint inhibitor should be discontinued, but most

patients require concurrent treatment with glucocorticoids or IVIG.

Patients generally improve over several months, during which time

immunotherapy can be tapered. There are rare reports of patients

with mild myositis who were able to be successfully re-treated with an

immune checkpoint inhibitor.

MYOSITIS ASSOCIATED WITH COVID-19

INFECTION

Early series of patients hospitalized with COVID-19 report that as

many as 44% of patients experienced muscle pain or fatigue and 33%

have elevated CK levels. Rare cases are complicated by myoglobinuria.

Histopathology can demonstrate inflammatory cell infiltration and

necrotic muscle fibers. A major concern during this pandemic is

whether or not patients with inflammatory myopathies treated with

various immunotherapies are more susceptible to infection with

COVID-19 or at greater risk for severe complications. We strongly

encourage our patients to wear masks and maintain social distancing.

GLOBAL ISSUES

There is a lack of epidemiologic data with regard to the incidence and

prevalence of various subtypes of IM throughout the world. Complicating the issue is disease awareness and the inability to obtain and

process muscle biopsies and MSAs, particularly in less developed

countries. Nevertheless, each of these disorders occurs throughout the

world. The specific environmental triggers and genetic risk factors are

likely variable. Interestingly, a report from Japan found that 28% of

IBM patients had evidence of exposure to hepatitis C, which was much

higher than seen in the Western Hemisphere and also more common

than seen in PM and healthy population controls in Japan. HIVassociated PM and IBM are more commonly encountered in areas

endemic for HIV, and recent studies suggest most of these “PM”

patients turn out to have IBM and can develop symptoms at an earlier

age (e.g., in the 30s). Pyomyositis and parasitic myositis are clearly

more common in the tropics. The prevalence of different types of cancers varies in different parts of the world, an important consideration

with respect to paraneoplastic myositis seen in DM, PM, and IMNM.

For example, nasopharyngeal cancer is particularly common in Asia;

thus, assessment for this type of cancer should be considered in the

workup of patients from high-risk regions.

■ FURTHER READING

Amato AA, Russell JA (eds): Neuromuscular Disorders, 2nd ed.

New York, McGraw-Hill Education, 2016, pp. 827–871.

Aschman T et al: Association between SARS-CoV-2 infection and

immune-mediated myopathy in patients who have died. JAMA Neurol 78(8):948-960, 2021.

Beydon M et al: Myositis as a manifestation of SARS-CoV-2. Ann

Rheum Dis 2020.

Doughty CT, Amato AA: Toxic myopathies. Continuum (Minneap

Minn) 25:1712, 2019.

Greenberg SA: Inclusion body myositis: clinical features and pathogenesis. Nat Rev Rheumatol 15:257-272, 2019.

Huard C et al: Correlation of cutaneous disease activity with type 1

interferon gene signature and interferon beta in dermatomyositis. Br

J Dermatol 176:1224, 2017.

Larman HB et al: Cytosolic 5’-nucleotidase 1A autoimmunity in sporadic inclusion body myositis. Ann Neurol 73:408, 2013.

Lundberg IE et al: Diagnosis and classification of idiopathic inflammatory myopathies. J Intern Med 280:39, 2016.

Mammen AL et al: Autoantibodies against 3-hydroxy-3-

methylglutaryl-coenzyme A reductase in patients with statin-associated

autoimmune myopathy. Arthritis Rheum 63:713, 2011.

Pluk H et al: Autoantibodies to cytosolic 5’-nucleotidase 1A in inclusion body myositis. Ann Neurol 73:397, 2013.

Puwanant A et al: Clinical spectrum of neuromuscular complications

after immune checkpoint inhibition. Neuromuscul Disord 29:127,

2019.

Rose MR, Enmc IBM Working Group: 188th ENMC International

Workshop: Inclusion Body Myositis, 2–4 December 2011, Naarden,

The Netherlands. Neuromuscul Disord 23:1044, 2013.

Suh J et al: Skeletal muscle and peripheral nerve histopathology in

COVID-19. Neurology 97:e849-e885, 2021.

Watanabe Y et al: Clinical features and prognosis in anti-SRP and

anti-HMGCR necrotising myopathy. J Neurol Neurosurg Psychiatry

87:1038, 2016.

Relapsing Polychondritis

2827CHAPTER 366

which can impair hearing. Inflammation of the internal auditory artery

or its cochlear branch produces hearing loss, vertigo, ataxia, nausea,

and vomiting. Vertigo is almost always accompanied by hearing loss.

Approximately 61% of patients will develop nasal involvement, with

21% having this at the time of presentation. Patients may experience

nasal congestion, rhinorrhea, and epistaxis. The bridge of the nose and

surrounding tissue become red, swollen, and tender and may collapse,

producing a saddle nose deformity (Fig. 366-1). In some patients, nasal

deformity developsinsidiously without overt inflammation. Saddle nose

is observed more frequently in younger patients, especially in women.

Joint involvement is the presenting manifestation in relapsing polychondritis in approximately one-third of patients and may be present

for several months before other features appear. Eventually, more than

one-half of the patients will have arthralgias or arthritis. The arthritis

TABLE 366-2 Clinical Manifestations of Relapsing Polychondritis

CLINICAL FEATURE PRESENTING CUMULATIVE

Frequency, %

Auricular chondritis 43 89

Arthritis 32 72

Nasal chondritis 21 61

Ocular inflammation 18 59

Laryngotracheal symptoms 23 55

Reduced hearing 7 40

Saddle nose deformity 11 25

Cutaneous 4 25

Laryngotracheal stricture 15 23

Vasculitis 2 14

Elevated creatinine 7 13

Aortic or mitral regurgitation 0 12

Source: Reproduced with permission from PD Kent et al: Relapsing polychondritis.

Curr Opin Rheumatology 16:56, 2004. https://pubmed.ncbi.nlm.nih.gov/14673390/.

polymorphonuclear white cells may also be present. Destruction of

cartilage begins at the outer edges and advances centrally. There is

lacunar breakdown and loss of chondrocytes. Degenerating cartilage

is replaced by granulation tissue and later by fibrosis and focal areas

of calcification. Small loci of cartilage regeneration may be present.

Extracellular granular material observed in the degenerating cartilage

matrix by electron microscopy has been interpreted to be enzymes,

immunoglobulins, or proteoglycans.

The available data suggest that both humoral and cell-mediated

immunity play an important role in the pathogenesis of relapsing

polychondritis. Immunoglobulin and complement deposits are found

at sites of inflammation. In addition, antibodies to type II collagen and

to matrilin-1 and immune complexes are detected in the sera of some

patients. The possibility that an immune response to type II collagen

may be important in the pathogenesis is supported experimentally by

the occurrence of auricular chondritis in rats immunized with type II

collagen. Antibodies to type II collagen are found in the sera of these

animals, and immune deposits are detected at sites of ear inflammation. Humoral immune responses to type IX and type XI collagen,

matrilin-1, and cartilage oligomeric matrix protein have been demonstrated in some patients. Matrilin-1 is a noncollagenous protein present

in the extracellular matrix in cartilage. It is present in high concentrations in the trachea and is also present in the nasal septum but not in

articular cartilage. In one study, rats immunized with matrilin-1 were

found to develop severe inspiratory stridor and swelling of the nasal

septum but without involvement of the joint or ear cartilage. The

rats had severe inflammation with erosions of the involved cartilage,

which was characterized by increased numbers of CD4+ and CD8+ T

cells in the lesions, and all had IgG antibodies to matrilin-1. A subsequent study demonstrated serum anti-matrilin-1 antibodies in ~13%

of patients with relapsing polychondritis; ~70% of these patients had

respiratory symptoms. Cell-mediated immunity may also be operative in causing tissue injury, since lymphocyte transformation can be

demonstrated when lymphocytes of patients are exposed to cartilage

extracts. T cells specific for type II collagen have been found in some

patients, and CD4+ T cells have been observed at sites of cartilage

inflammation. Genetic background may also play a role in disease

development. A significantly higher frequency of HLA-DR4 has been

found in patients with relapsing polychondritis than in healthy individuals, although a predominant subtype allele(s) was not found.

■ CLINICAL MANIFESTATIONS

The onset of relapsing polychondritis is frequently abrupt, with the

appearance of one or two sites of cartilaginous inflammation. The pattern of cartilaginous involvement and the frequency of episodes vary

widely among patients. Noncartilaginous presentations may also occur.

Systemic inflammatory features such as fever, fatigue, and weight loss

commonly occur and may precede other clinical signs. Relapsing

polychondritis may go unrecognized for several months or even years

in patients who only initially manifest intermittent joint pain and/or

swelling or who have unexplained eye inflammation, hearing loss, valvular heart disease, or pulmonary symptoms. Recent studies have suggested that relapsing polychondritis may present in different subgroups

that vary in time to diagnosis, clinical and radiologic characteristics,

and disease-related complications. Although further investigation will

be necessary to determine how these subgroups may impact treatment

and outcome, recognition of disease patterns beyond cartilaginous

involvement may facilitate diagnosis.

Auricular chondritis is the most frequent presenting manifestation

of relapsing polychondritis, occurring in 40% of patients and eventually affecting ~85% of patients (Table 366-2). One or both ears are

involved, either sequentially or simultaneously. Patients experience

the sudden onset of pain, tenderness, and swelling of the cartilaginous

portion of the ear. This typically involves the pinna of the ears, sparing

the earlobes because they do not contain cartilage. The overlying skin

has a beefy red or violaceous color. Prolonged or recurrent episodes

lead to cartilage destruction and result in a droopy ear. Swelling may

close off the eustachian tube or the external auditory meatus, either of

FIGURE 366-1 Saddle nose resulting from destruction and collapse of the nasal

cartilage. (Image courtesy of Marcela Ferrada, MD)

2828 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

is usually asymmetric and oligo- or polyarticular, and it involves both

large and small peripheral joints. An episode of arthritis lasts from a

few days to several weeks and resolves spontaneously without joint

erosion or deformity. Attacks of arthritis may not be temporally related

to other manifestations of relapsing polychondritis. Joint fluid has

been reported to be noninflammatory. In addition to peripheral joints,

inflammation may involve the costochondral, sternomanubrial, and

sternoclavicular cartilages. Destruction of these cartilages may result in

a pectus excavatum deformity or even a flail anterior chest wall.

Eye manifestations occur in more than one-half of patients and

include conjunctivitis, episcleritis, scleritis, iritis, uveitis, and keratitis.

Ocular inflammation can be severe and visually threatening. Other manifestations include eyelid and periorbital edema, proptosis, optic neuritis,

extraocular muscle palsies, retinal vasculitis, and renal vein occlusion.

Laryngotracheobronchial involvement occurs in ~50% of patients

and is among the most serious manifestations of relapsing polychondritis (Fig. 366-2). Symptoms include hoarseness, a nonproductive

cough, and tenderness over the larynx and proximal trachea. Mucosal

edema, strictures, and/or collapse of laryngeal or tracheal cartilage

may cause stridor and life-threatening airway obstruction necessitating

tracheostomy. Involvement can extend into the lower airways resulting

in tracheobronchomalacia. Collapse of cartilage in bronchi leads to

pneumonia and, when extensive, to respiratory insufficiency.

Cardiac valvular regurgitation occurs in ~5–10% of patients and is

due to progressive dilation of the valvular ring or to destruction of the

valve cusps. Aortic regurgitation occurs in ~7% of patients, with the

mitral and other heart valves being affected less often. Other cardiac

manifestations include pericarditis, myocarditis, coronary vasculitis,

and conduction abnormalities. Aneurysms of the proximal, thoracic,

or abdominal aorta may occur even in the absence of active chondritis

and occasionally rupture.

Renal disease occurs in ~10% of patients. The most common renal

lesions include mesangial expansion or segmental necrotizing glomerulonephritis, which often have small amounts of electron-dense

deposits in the mesangium where there is also faint deposition of C3

and/or IgG or IgM. Tubulointerstitial disease and IgA nephropathy

have also been reported.

Approximately 25% of patients have skin lesions, which can include

purpura, erythema nodosum, erythema multiforme, angioedema/

urticaria, livedo reticularis, and panniculitis.

Features of vasculitis are seen in up to 25% of patients and can affect

any size vessel. Large vessel vasculitis may presentwith aortic aneurysms,

and medium vessel disease may affect the coronary, hepatic, mesenteric,

or renal arteries or vessel-supplying nerves. Cutaneous vasculitis can

also occur. A variety of primary vasculitides have also been reported

to occur in association with relapsing polychondritis (Chap. 363). One

specific overlap is the “MAGIC” syndrome (mouth and genital ulcers

with inflamed cartilage) in which patients present with features of both

relapsing polychondritis and Behçet’s disease (Chap. 364).

Relapsing polychondritis has also been found to be associated with

VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory,

somatic). VEXAS syndrome should be considered in male patients

with relapsing polychondritis who have hematologic abnormalities

often in the spectrum of myelodysplastic syndrome, fevers, venous

thrombotic events, pulmonary infiltrates, cutaneous lesions, or treatment resistant disease. VEXAS syndrome is strongly suggested by

its clinical features and the finding of vacuoles within bone marrow

precursor cells. It is proven by genetic testing for myeloid-restricted

somatic missense mutations in UBA1, the major E1 enzyme that initiates ubiquitylation.

■ LABORATORY FINDINGS AND

DIAGNOSTIC IMAGING

There are no laboratory features that are diagnostic for relapsing

polychondritis. Mild leukocytosis and normocytic, normochromic

anemia are often present. Eosinophilia is observed in 10% of patients.

The erythrocyte sedimentation rate and C-reactive protein are usually elevated. Rheumatoid factor and antinuclear antibody tests are

occasionally positive in low titers, and complement levels are normal.

Antibodies to type II collagen are present in fewer than one-half of

patients and are not specific. Circulating immune complexes may be

detected, especially in patients with early active disease. Elevated levels

of γ globulin may be present. Antineutrophil cytoplasmic antibodies

(ANCA), either cytoplasmic (cANCA) or perinuclear (pANCA),

are found in some patients with active disease. However, on target

antigen–specific testing, there are only occasional reports of positive

myeloperoxidase-ANCA, and proteinase 3-ANCA are very rarely

found in relapsing polychondritis.

The upper and lower airways can be evaluated by imaging techniques such as computed tomography (CT) and magnetic resonance

(MR). Dynamic inspiratory and expiratory CT imaging can be useful

in assessing airway involvement. Bronchoscopy provides direct visualization of the airways but can be a high-risk procedure in patients

with airway compromise. Pulmonary function testing with flowvolume loops can show inspiratory and/or expiratory obstruction.

Imaging can also be useful to detect extracartilaginous disease.

Arteriography by CT or MR should be pursued if features are present suggesting aortic or other large vessel involvement. Electrocardiography and echocardiography can be useful in further evaluating

for cardiac features of disease. A number of reports have described

the use of positron emission tomography in relapsing polychondritis, but it is currently unclear if this is useful and for what features.

■ DIAGNOSIS

Diagnosis is based on recognition of the typical clinical features. Biopsies of the involved cartilage from the ear, nose, or respiratory tract can

confirm the diagnosis but are only necessary when clinical features

are not typical and may be difficult to obtain. Diagnostic criteria were

suggested in 1976 by McAdam et al and included biopsy evidence

combined with three of the following: (1) recurrent chondritis of both

auricles; (2) nonerosive inflammatory arthritis; (3) chondritis of nasal

cartilage; (4) inflammation of ocular structures, including conjunctivitis, keratitis, scleritis/episcleritis, and/or uveitis; (5) chondritis of the

laryngeal and/or tracheal cartilages; and (6) cochlear and/or vestibular

damage manifested by neurosensory hearing loss, tinnitus, and/or vertigo. In 1979, Damiani and Levine suggested that the diagnosis could

be made when one or more of the above features and a positive biopsy

were present, when two or more separate sites of cartilage inflammation were present that responded to treatment, or when three or more

of the above features were present.

The differential diagnosis of relapsing polychondritis is centered

around its sites of clinical involvement. Patients with granulomatosis

with polyangiitis may have a saddle nose and tracheal involvement

but can be distinguished by the primary inflammation occurring

in the mucosa at these sites, the absence of auricular involvement,

and the presence of pulmonary parenchymal disease. Patients with

FIGURE 366-2 Narrowing of the subglottis occurring as a result of laryngotracheal

involvement in relapsing polychondritis. (Image courtesy of Marcela Ferrada, MD)

Sarcoidosis

2829CHAPTER 367

Cogan’s syndrome have interstitial keratitis and vestibular and

auditory abnormalities, but this syndrome does not involve the

respiratory tract or ears. Reactive arthritis may initially resemble

relapsing polychondritis because of oligoarticular arthritis and eye

involvement, but it is distinguished by the occurrence of urethritis

and typical mucocutaneous lesions and the absence of nose or ear

cartilage involvement. Rheumatoid arthritis may initially suggest

relapsing polychondritis because of arthritis and eye inflammation,

although the arthritis is erosive and symmetric. In addition, rheumatoid factor titers are usually high compared with those in relapsing

polychondritis, and anti-cyclic citrullinated peptide is usually not

seen. Bacterial infection of the pinna may be mistaken for relapsing

polychondritis but differs by usually involving only one ear, including

the earlobe. Auricular cartilage may also be damaged by trauma or

frostbite. Nasal destructive disease and auricular abnormalities can

also be seen in patients using cocaine adulterated with levamisole.

Ear involvement in this setting differs from relapsing polychondritis

by typically manifesting as purpuric plaques with necrosis extending

to the earlobe, which does not contain cartilage.

TREATMENT

Relapsing Polychondritis

In patients with active chondritis, prednisone, 40–60 mg/d, is often

effective in suppressing disease activity; it is tapered gradually once

disease is controlled. In some patients, prednisone can be stopped,

whereas in others, low doses in the range of 5–10 mg/d are required

for continued suppression of disease. Other immunosuppressive

drugs such as cyclophosphamide, methotrexate, azathioprine,

mycophenolate mofetil, or cyclosporine should be used in patients

who have severe organ-threatening disease, fail to respond to

prednisone, or require high doses to control disease activity. There

has been significant interest in the use of biologic agents to treat

relapsing polychondritis. Tumor necrosis factor inhibitors have

been the most widely examined therapies to date, and although

benefit has been suggested, this has come solely from retrospective

cases and series. Other agents with which there have been published

reports include anakinra, rituximab, tocilizumab, and abatacept, but

reports are too few in number to assess efficacy. Dapsone has also

been used in selected settings but has largely been supplanted by

other approaches and should not be used for severe disease. Heart

valve replacement or repair of an aortic aneurysm may be necessary.

When airway obstruction is severe, tracheostomy is required. Stents

may be necessary in patients with tracheobronchial collapse.

■ PATIENT OUTCOME, PROGNOSIS, AND SURVIVAL

The course of relapsing polychondritis is highly variable. Some patients

experience inflammatory episodes lasting from a few days to several

weeks that then subside spontaneously or with treatment. Attacks may

recur at intervals varying from weeks to months. In other patients,

the disease has a chronic, smoldering course that may be severe. In

one study, the 5-year estimated survival rate was 74%, and the 10-year

survival rate was 55%. About one-half of the deaths could be attributed

to relapsing polychondritis or complications of treatment. Airway

complications accounted for 10% of all fatalities, although higher rates

have been reported in other series. In general, patients with more widespread disease have a worse prognosis.

■ FURTHER READING

Beck DB et al: Somatic mutations in UBA1 and severe adult-onset

autoinflammatory disease. N Engl J Med 383:2628, 2020.

Chopra R et al: Relapsing polychondritis. Rheum Dis Clin North Am

39:263, 2013.

Ernst A et al: Relapsing polychondritis and airway involvement. Chest

135:1024, 2009.

Ferrada M et al: Defining clinical subgroups in relapsing polychondritis: A prospective observational cohort study. Arthritis Rheumatol

72:1396, 2020.

Moulis G et al: Efficacy and safety of biologics in relapsing polychondritis: A French national multicentre study. Ann Rheum Dis 77:1172,

2018.

Vitale A et al: Relapsing polychondritis: An update on pathogenesis,

clinical features, diagnostic tools, and therapeutic perspectives. Curr

Rheumatol Rep 18:3, 2016.

DEFINITION

Sarcoidosis is an inflammatory disease characterized by the presence

of noncaseating granulomas. The disease is often multisystemic and

requires the presence of involvement in two or more organs for a

specific diagnosis. The finding of granulomas is not specific for sarcoidosis, and other conditions known to cause granulomas must be ruled

out. These conditions include mycobacterial and fungal infections,

malignancy, and environmental agents such as beryllium. Although

sarcoidosis can affect virtually every organ of the body, the lung is

most commonly affected. Other organs commonly affected are the

liver, skin, and eye. The clinical outcome of sarcoidosis varies, with

remission occurring in over one-half of patients within a few years of

diagnosis; however, the remaining patients may develop chronic disease that lasts for decades.

ETIOLOGY

Despite multiple investigations, the cause of sarcoidosis remains

unknown. Currently, the most likely etiology is an infectious or noninfectious environmental agent that triggers an inflammatory response

in a genetically susceptible host. Among the possible infectious agents,

careful studies have shown a much higher incidence of Propionibacterium acnes in the lymph nodes of sarcoidosis patients compared

to controls. An animal model has shown that P. acnes can induce a

granulomatous response in mice similar to sarcoidosis. Others have

demonstrated the presence of a mycobacterial protein (Mycobacterium

tuberculosis catalase-peroxidase [mKatG]) in the granulomas of some

sarcoidosis patients. This protein is very resistant to degradation and

may represent the persistent antigen in sarcoidosis. Immune response

to this and other mycobacterial proteins has been documented by

another laboratory. These studies suggest that a Mycobacterium similar

to M. tuberculosis could be responsible for sarcoidosis. The mechanism exposure/infection with such agents has been the focus of other

studies. Environmental exposures to insecticides and mold have been

associated with an increased risk for disease. In addition, health care

workers appear to have an increased risk. Also, sarcoidosis in a donor

organ has occurred after transplantation into a sarcoidosis patient.

Some authors have suggested that sarcoidosis is not due to a single

agent but represents a particular host response to multiple agents.

Some studies have been able to correlate environmental exposures to

genetic markers. These studies have supported the hypothesis that a

genetically susceptible host is a key factor in the disease.

■ INCIDENCE, PREVALENCE, AND GLOBAL IMPACT

Sarcoidosis is seen worldwide, with the highest prevalence reported

in the Nordic population. In the United States, the disease has been

reported more commonly in African Americans than whites, with

the ratio of African Americans to whites ranging from 3:1 to 17:0.

In the United States, women are more susceptible than men. The

higher incidence in African Americans may have been influenced by

the fact that African Americans seem to develop more extensive and

chronic pulmonary disease. Because most sarcoidosis clinics are run

367 Sarcoidosis

Robert P. Baughman, Elyse E. Lower

2830 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

by pulmonologists, a selection bias may have occurred. Worldwide,

the prevalence of the disease varies from 20–60 per 100,000 for many

groups such as Japanese, Italians, and American whites. Higher rates

occur in Ireland and Nordic countries. In one closely observed community in Sweden, the lifetime risk for developing sarcoidosis was 3%.

Sarcoidosis often occurs in young, otherwise healthy adults. It is

uncommon to diagnose the disease in someone aged <18 years. However, it has become clear that a second peak in incidence develops

around age 60. In a study of nearly 30,000 sarcoidosis patients in the

United States, the median age at diagnosis was 55.

Although most cases of sarcoidosis are sporadic, a familial form of the

disease exists. At least 5% of patients with sarcoidosis will have a family

member with sarcoidosis. Sarcoidosis patients who are Irish or African

American seem to have a two to three times higherrate of familial disease.

■ PATHOPHYSIOLOGY AND

IMMUNOPATHOGENESIS

The granuloma is the pathologic hallmark of sarcoidosis. A distinct feature of sarcoidosis is the local accumulation of inflammatory cells. Extensive studies in the lung using bronchoalveolar lavage

(BAL) have demonstrated that the initial inflammatory response is an

influx of T helper cells. In addition, there is an accumulation of activated monocytes. Figure 367-1 is a proposed model for sarcoidosis.

Using the HLA-CD4 complex, antigen-presenting cells present an

unknown antigen to the helper T cell. Studies have clarified that specific

human leukocyte antigen (HLA) haplotypessuch as HLA-DRB1*

1101 are

associated with an increased risk for developing sarcoidosis. In addition,

different HLA haplotypes are associated with different clinical outcomes.

The macrophage/helper T-cell cluster leads to activation with the

increased release of several cytokines. These include interleukin (IL)

2 released from the T cell and interferon γ and tumor necrosis factor

(TNF) released by the macrophage. The T cell is a necessary part of the

initial inflammatory response. In advanced, untreated HIV infection,

patients who lack helper T cells rarely develop sarcoidosis. In contrast,

several reports confirm that sarcoidosis becomes unmasked as HIVinfected individuals receive antiretroviral therapy, with subsequent restoration of their immune system. In contrast, treatment of established

APC

HLA

Class II T cell antigen

receptor

CD-4

T cell

activation

CD-4 Ag peptide

TNF; IL-8, Endothelin

Fibrosis

IFN-γ; IL-12; IL-18; TNF IL-2; IFN-γ

IL-10

Resolution

FIGURE 367-1 Schematic representation of initial events of sarcoidosis. The

antigen-presenting cell and helper T-cell complex leads to the release of multiple

cytokines. This forms a granuloma. Over time, the granuloma may resolve or lead

to chronic disease, including fibrosis. APC, antigen-presenting cell; HLA, human

leukocyte antigen; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.

pulmonary sarcoidosis with cyclosporine, a drug that downregulates

helper T-cell responses, seems to have little impact on sarcoidosis.

The granulomatous response of sarcoidosis can resolve with or

without therapy. However, in at least 20% of patients with sarcoidosis, a

chronic form of the disease develops. This persistent form of the disease

is associated with increased levels in blood and/or BAL of IL-8, IL-17,

and CXCL9. Also, studies have reported that patients with this chronic

form of disease release excessive amounts of TNF in areas of inflammation. Specific gene signatures have been associated with more severe

disease, such as cardiac, neurologic, and fibrotic pulmonary disease.

At diagnosis, the natural history of the disease may be difficult to

predict. One form of the disease, Löfgren’s syndrome, consists of erythema

nodosum and hilar adenopathy on chest roentgenogram. In some cases,

periarticular arthritis may be identified without erythema nodosum.

Löfgren’s syndrome is associated with a good prognosis, with >90% of

patients experiencing disease resolution within 2 years. Recent studies

have demonstrated that the HLA-DRB1*

03 was found in two-thirds of

Scandinavian patients with Löfgren’s syndrome. More than 95% of those

patients who were HLA-DRB1*

03 positive had resolution of their disease

within 2 years, whereas nearly one-half of the remaining patients had disease for >2 years. It remains to be determined whether these observations

can be applied to a non-Scandinavian population.

■ CLINICAL MANIFESTATIONS

The presentation of sarcoidosis ranges from patients who are asymptomatic to those with organ failure. It is unclear how often sarcoidosis

is asymptomatic. In countries where routine chest roentgenogram

screening is performed, 20–30% of pulmonary cases are detected in

asymptomatic individuals. The inability to screen for other asymptomatic forms of the disease would suggest that as many as one-third of

sarcoidosis patients are asymptomatic.

Respiratory complaints including cough and dyspnea are the most

common presenting symptoms. In many cases, the patient presents

with a 2- to 4-week history of these symptoms. Unfortunately, due to

the nonspecific nature of pulmonary symptoms, the patient may see

physicians for up to a year before a diagnosis is confirmed. For these

patients, the diagnosis of sarcoidosis is usually only suggested when a

chest roentgenogram is performed.

Symptoms related to cutaneous and ocular disease are the next two

most common complaints. Skin lesions are often nonspecific. However,

because these lesions are readily observed, the patient and treating

physician are often led to a diagnosis. In contrast to patients with pulmonary disease, patients with cutaneous lesions are more likely to be

diagnosed within 6 months of symptoms.

Nonspecific constitutional symptoms include fatigue, fever, night

sweats, and weight loss. Fatigue is perhaps the most common constitutional symptom that affects these patients. Given its insidious nature,

patients are usually not aware of the association with their sarcoidosis

until their disease resolves.

The overall incidence of sarcoidosis at the time of diagnosis and

eventual common organ involvement are summarized in Table 367-1.

Over time, skin, eye, and neurologic involvement seem more apparent. In the United States, the frequency of specific organ involvement

appears to be affected by age, race, and gender. For example, eye disease

is more common among African Americans. Under the age of 40, it

occurs more frequently in women. However, in those diagnosed over

the age of 40, eye disease is more common in men.

■ LUNG

Lung involvement occurs in >90% of sarcoidosis patients. The most

commonly used method for detecting lung disease is still the chest

roentgenogram. Figure 367-2 illustrates the chest roentgenogram from

a sarcoidosis patient with bilateral hilar adenopathy. Although the CT

scan has changed the diagnostic approach to interstitial lung disease,

it is not usually considered a monitoring tool for patients with sarcoidosis except for those with pulmonary fibrosis. Figure 367-3 demonstrates some of the characteristic CT features, including peribronchial

thickening and reticular nodular changes, which are predominantly

Sarcoidosis

2831CHAPTER 367

subpleural. The peribronchial thickening seen on CT seems to explain

the high yield of granulomas from bronchial biopsies performed for

diagnosis.

Although the CT scan is more sensitive, the standard scoring system

described by Scadding in 1961 for chest roentgenograms remains the

preferred method of characterizing chest involvement. Stage 1 is hilar

adenopathy alone (Fig. 367-2), often with right paratracheal involvement. Stage 2 is a combination of adenopathy plus infiltrates, whereas

stage 3 reveals infiltrates alone. Stage 4 consists of fibrosis. Usually the

infiltrates in sarcoidosis are predominantly an upper lobe process. Only

in a few noninfectious diseases is an upper lobe predominance noted.

In addition to sarcoidosis, the differential diagnosis of upper lobe disease includes hypersensitivity pneumonitis, silicosis, and Langerhans

cell histiocytosis. For infectious diseases, tuberculosis and Pneumocystis pneumonia can often present as upper lobe diseases.

Lung volumes, mechanics, and diffusion are all useful in evaluating

interstitial lung diseases such as sarcoidosis. The diffusion of carbon

monoxide (DLCO) is the most sensitive test for interstitial lung disease.

Reduced lung volumes are a reflection of the restrictive lung disease

seen in sarcoidosis. However, a third of the patients presenting with

sarcoidosis still have lung volumes within the normal range, despite

abnormal chest roentgenograms and dyspnea.

Approximately one-half of sarcoidosis patients present with

obstructive disease, reflected by a reduced ratio of forced expiratory

volume in 1 s to forced vital capacity (FEV1

/FVC). Cough is a very

common symptom. Airway involvement causing varying degrees of

obstruction underlies the cough in most sarcoidosis patients. Airway

hyperreactivity, as determined by methacholine challenge, will be positive in some of these patients. A few patients with cough will respond

to traditional bronchodilators as the only form of treatment. In some

cases, high-dose inhaled glucocorticoids alone are useful. Airway

obstruction can be due to large airway stenosis, which can become

fibrotic and unresponsive to anti-inflammatory therapy.

Pulmonary arterial hypertension is reported in at least 5% of sarcoidosis patients. Either direct vascular involvement or the consequence of

fibrotic changes in the lung can lead to pulmonary arterial hypertension.

In sarcoidosis patients with end-stage fibrosis awaiting lung transplant,

70% will have pulmonary arterial hypertension. This is a much higher

incidence than that reported for other fibrotic lung diseases. In less

advanced but still symptomatic patients, pulmonary arterial hypertension has been noted in up to 50% of cases. Because sarcoidosis-associated

pulmonary arterial hypertension may respond to therapy, evaluation for

this should be considered in persistently dyspneic patients.

■ SKIN

Skin involvement is eventually identified in over a third of patients with

sarcoidosis. The classic cutaneous lesions include erythema nodosum,

maculopapular lesions, hyper- and hypopigmentation, keloid formation, and subcutaneous nodules. A specific complex of involvement

of the bridge of the nose, the area beneath the eyes, and the cheeks is

referred to as lupus pernio (Fig. 367-4) and is diagnostic for a chronic

form of sarcoidosis.

In contrast, erythema nodosum is a transient rash that can be seen

in association with hilar adenopathy and uveitis (Löfgren’s syndrome).

Erythema nodosum is more common in women and in certain selfdescribed demographic groups including whites and Puerto Ricans. In

the United States, the other manifestations of skin sarcoidosis, especially

lupus pernio, are more common in African Americans than whites.

The maculopapular lesions from sarcoidosis are the most common

chronic form of the disease (Fig. 367-5). These are often overlooked

by the patient and physician because they are chronic and not painful. Initially, these lesions are usually purplish papules and are often

indurated. They can become confluent and infiltrate large areas of

the skin. With treatment, the color and induration may fade. Because

these lesions are caused by noncaseating granulomas, the diagnosis of

sarcoidosis can be readily made by a skin biopsy.

■ EYE

The frequency of ocular manifestations for sarcoidosis varies depending on race. In Japan, >70% of sarcoidosis patients develop ocular

disease, whereas in the United States, only 30% have eye disease, with

FIGURE 367-2 Posterior-anterior chest roentgenogram demonstrating bilateral

hilar adenopathy, stage 1 disease.

FIGURE 367-3 High-resolution CT scan of the chest demonstrating patchy reticular

nodularity, including areas of confluence.

TABLE 367-1 Frequency of Common Organ Involvement and

Lifetime Riska

PRESENTATION, %b FOLLOW-UP, %c

Lung 95 94

Skin 24 43

Eye 12 29

Extrathoracic lymph node 15 16

Liver 12 14

Spleen 7 8

Neurologic 5 16

Cardiac 2 3

a

Patients could have more than one organ involved. b

From ACCESS study of 736

patients evaluated within 6 months of diagnosis. c

From follow-up of 1024 sarcoidosis

patients seen at the University of Cincinnati Interstitial Lung Disease and

Sarcoidosis Clinic from 2002 to 2006.

2832 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

problems more common in African Americans than whites. Although

the most common manifestation is anterior uveitis, over a quarter of

patients will have inflammation at the posterior of the eye, including

retinitis and pars planitis. Although symptoms such as photophobia,

blurred vision, and increased tearing can occur, some asymptomatic

patients still have active inflammation. Initially asymptomatic patients

with ocular sarcoidosis can eventually develop blindness. Therefore, it

is recommended that all patients with sarcoidosis receive a dedicated

ophthalmologic examination. Sicca is seen in over one-half of chronic

sarcoidosis patients. Dry eyes appear to be a reflection of prior lacrimal

gland disease. Although the patient may no longer have active inflammation, dry eyes may require natural tears or other lubricants.

■ LIVER

Using biopsies to detect granulomatous disease, liver involvement can

be identified in over one-half of sarcoidosis patients. However, using

liver function studies, only 20–30% of patients will have evidence of

liver involvement. The most common abnormality of liver function

is an elevation of the alkaline phosphatase level, consistent with an

obstructive pattern. In addition, elevated transaminase levels can

occur. An elevated bilirubin level is a marker for more advanced liver

disease. Overall, only 5% of sarcoidosis patients have sufficient symptoms from their liver disease to require specific therapy. Although

symptoms can be due to hepatomegaly, more frequently symptoms

result from extensive intrahepatic cholestasis leading to portal hypertension. In this case, ascites and esophageal varices can occur. It is rare

that a sarcoidosis patient will require a liver transplant because even

the patient with cirrhosis due to sarcoidosis can respond to systemic

therapy.

■ BONE MARROW AND SPLEEN

One or more bone marrow manifestations can be identified in many

sarcoidosis patients. The most common hematologic problem is lymphopenia, which is a reflection of sequestration of the lymphocytes

into the areas of inflammation. Anemia occurs in 20% of patients, and

leukopenia is less common. A bone marrow examination will reveal

granulomas in about a third of patients. Although splenomegaly can

be detected in 5–10% of patients, splenic biopsy reveals granulomas in

60% of patients. The CT scan can be relatively specific for sarcoidosis

involvement of the spleen (Fig. 367-6). Both bone marrow and spleen

involvement are more common in African Americans than whites.

Although these manifestations alone are rarely an indication for

therapy, on rare occasion, splenectomy may be indicated for massive

symptomatic splenomegaly or profound pancytopenia. Nonthoracic

lymphadenopathy can occur in up to 20% of patients.

■ CALCIUM METABOLISM

Hypercalcemia and/or hypercalciuria occur in ~10% of sarcoidosis

patients. It is more common in whites than African Americans and in

men. The mechanism of abnormal calcium metabolism is increased

production of 1,25-dihydroxyvitamin D by the granuloma itself. The

1,25-dihydroxyvitamin D causes increased intestinal absorption of

calcium, leading to hypercalcemia with a suppressed parathyroid

hormone (PTH) level (Chap. 410). Increased exogenous vitamin D

from diet or sunlight exposure may exacerbate this problem. Serum

calcium should be determined as part of the initial evaluation of all

sarcoidosis patients, and a repeat determination may be useful during

the summer months with increased sun exposure. In patients with a

history of renal calculi, a 24-h urine calcium measurement should be

obtained. If a sarcoidosis patient with a history of renal calculi is to be

placed on calcium supplements, a follow-up 24-h urine calcium level

should be measured.

FIGURE 367-5 Maculopapular lesions on the trunk of a sarcoidosis patient.

FIGURE 367-6 CT scan of the abdomen after oral and intravenous contrast. The

stomach is compressed by the enlarged spleen. Within the spleen, areas of hypoand hyperdensity are identified.

FIGURE 367-4 Chronic inflammatory lesions around the nose, eyes, and cheeks,

referred to as lupus pernio.

Sarcoidosis

2833CHAPTER 367

■ RENAL DISEASE

Direct kidney involvement occurs in <5% of sarcoidosis patients. It

is associated with granulomas in the kidney itself and can lead to

nephritis. However, hypercalcemia is the most likely cause of sarcoidosis-associated renal disease. In 1–2% of sarcoidosis patients, acute

renal failure may develop as a result of hypercalcemia. Successful treatment of hypercalcemia with glucocorticoids and other therapies often

improves but usually does not totally resolve renal dysfunction.

■ NERVOUS SYSTEM

Neurologic disease is reported in 5–10% of sarcoidosis patients and

appears to be of equal frequency across all ethnic groups. Any part of

the central or peripheral nervous system can be affected. The presence

of granulomatous inflammation is often visible on MRI studies. MRI

with gadolinium enhancement may demonstrate space-occupying

lesions, but the MRI can be negative due to small lesions or the effect

of systemic therapy in reducing the inflammation. Cerebral spinal fluid

(CSF) findings include lymphocytic meningitis with a mild increase in

protein. The CSF glucose level is usually normal but can be low. Certain

areas of the nervous system are more commonly affected in neurosarcoidosis. These include cranial nerve involvement, basilar meningitis,

myelopathy, and anterior hypothalamic disease with associated diabetes insipidus (Chap. 381). Seizures and cognitive changes also occur.

Of the cranial nerves, seventh nerve paralysis can be transient and

mistaken for Bell’s palsy (idiopathic seventh nerve paralysis). Because

this form of neurosarcoidosis often resolves within weeks and may not

recur, it may have occurred prior to a definitive diagnosis of sarcoidosis. Optic neuritis is another cranial nerve manifestation of sarcoidosis.

This manifestation is more chronic and usually requires long-term

systemic therapy. It can be associated with both anterior and posterior

uveitis. Differentiating between neurosarcoidosis and multiple sclerosis can be difficult at times. Optic neuritis can occur in both diseases.

In some patients with sarcoidosis, multiple enhancing white matter

abnormalities may be detected by MRI, suggesting multiple sclerosis.

In such cases, the presence of meningeal enhancement or hypothalamic involvement suggests neurosarcoidosis, as does evidence of

extraneurologic disease such as pulmonary or skin involvement, which

also suggests sarcoidosis. Because the response of neurosarcoidosis to

glucocorticoids and cytotoxic therapy is different from that of multiple

sclerosis, differentiating between these disease entities is important.

■ CARDIAC

The presence of cardiac involvement is influenced by race. Although

over a quarter of Japanese sarcoidosis patients develop cardiac disease,

only 5% of sarcoidosis patients in the United States and Europe develop

symptomatic cardiac disease. However, there is no apparent racial

predilection between whites and African Americans. Cardiac disease,

which usually presents as either congestive heart failure or cardiac

arrhythmias, results from infiltration of the heart muscle by granulomas. Diffuse granulomatous involvement of the heart muscle can

lead to profound dysfunction with left ventricular ejection fractions of

<10%. Even in this situation, improvement in the ejection fraction can

occur with systemic therapy. Arrhythmias can also occur with diffuse

infiltration or with more patchy cardiac involvement. If the atrioventricular (AV) node is infiltrated, heart block can occur, which can be

detected by routine electrocardiography. Ventricular arrhythmias and

ventricular tachycardia are common causes of death. Arrhythmias are

best detected using 24-h ambulatory monitoring, and electrophysiology studies may be negative. Other screening tests for cardiac disease

include routine electrocardiography and echocardiography. The confirmation of cardiac sarcoidosis is usually performed with either MRI

or positron emission tomography (PET) scanning. Because ventricular

arrhythmias are usually multifocal due to patchy multiple granulomas

in the heart, ablation therapy is not useful. Patients with significant

ventricular arrhythmias should be considered for an implanted defibrillator, which appears to have reduced the rate of death in cardiac

sarcoidosis. Although systemic therapy can be useful in treating

arrhythmias, patients may still have malignant arrhythmias up to

6 months after starting successful treatment, and the risk for recurrent

arrhythmias occurs whenever medications are tapered.

■ MUSCULOSKELETAL SYSTEM

Direct granulomatous involvement of bone and muscle can be documented by radiography (x-ray, MRI, PET scan [Fig. 367-7], or gallium

scan) or confirmed by biopsy in ~10% of sarcoidosis patients. However,

a larger percentage of sarcoidosis patients complain of myalgia and

arthralgia. These complaints are similar to those reported by patients

with other inflammatory diseases, including chronic infections such

as mononucleosis. Fatigue associated with sarcoidosis may be overwhelming for many patients. A link between fatigue and small peripheral nerve fiber disease in sarcoidosis has been described.

■ OTHER ORGAN INVOLVEMENT

Although sarcoidosis can affect any organ of the body, rarely does it

involve the breast, testes, ovary, or stomach. Because of the rarity of

involvement, a mass in one of these areas requires a biopsy to rule out

other diseases, including cancer. For example, in a study of breast problems in female sarcoidosis patients, a breast lesion was more likely to be a

granuloma from sarcoidosis than from breast cancer. However, findings

on the physical examination or mammogram cannotreliably differentiate

between these lesions. More importantly, as women with sarcoidosis age,

breast cancer becomes more common. Therefore, it is recommended that

routine screening including mammography be performed along with

other imaging studies (ultrasound, MRI) or biopsy as clinically indicated.

■ COMPLICATIONS

Sarcoidosis is usually a self-limited, non-life-threatening disease. However, organ-threatening disease can occur. These complications can

include blindness, paraplegia, or renal failure. Death from sarcoidosis

occurs in ~5% of patients seen in sarcoidosis referral clinics. The usual

causes of death related to sarcoidosis are from lung, cardiac, neurologic, or liver involvement. In respiratory failure, an elevation of the

right atrial pressure is a poor prognostic finding. Lung complications

can also include infections such as mycetoma, which can subsequently

lead to massive bleeding. In addition, the use of immunosuppressive

agents can increase the incidence of serious infections.

FIGURE 367-7 Positron emission tomography and CT scan merged, demonstrating

increased activity in the spleen, ribs, and spine of a patient with sarcoidosis.