2834 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

LABORATORY FINDINGS

The chest roentgenogram remains the most commonly used tool

to assess lung involvement in sarcoidosis. As noted above, the chest

roentgenogram classifies involvement into four stages, with stages 1

and 2 having hilar and paratracheal adenopathy. The CT scan has been

used increasingly in evaluating interstitial lung disease. In sarcoidosis,

the presence of adenopathy and a nodular infiltrate is not specific for

sarcoidosis. Adenopathy up to 2 cm can be seen in other inflammatory

lung diseases such as idiopathic pulmonary fibrosis. However, adenopathy >2 cm in the short axis supports the diagnosis of sarcoidosis over

other interstitial lung diseases.

The PET scan has increasingly replaced gallium-67 scanning to identify areas of granulomatous disease in the chest and other parts of the

body (Fig. 367-7). Both tests can be used to identify potential areas for

biopsy. Cardiac PET scanning has also proved useful in assessing cardiac

sarcoidosis. The identification of hypermetabolic activity may be due to

the granulomas from sarcoidosis and not to disseminated malignancy.

MRI has also proved useful in the assessment of extrapulmonary

sarcoidosis. Gadolinium enhancement has been demonstrated in areas

of inflammation in the brain, heart, and bone. MRI scans may detect

asymptomatic lesions. Like the PET scan, MRI changes appear similar

to those seen with malignancy and infection. In some cases, biopsy

may be necessary to determine the cause of the radiologic abnormality.

Serum levels of angiotensin-converting enzyme (ACE) can be helpful in the diagnosis of sarcoidosis. However, the test has somewhat low

sensitivity and specificity. Elevated levels of ACE are reported in 60%

of patients with acute disease and only 20% of patients with chronic

disease. Although there are several causes for mild elevation of ACE,

including diabetes, elevations of >50% of the upper limit of normal are

seen in only a few conditions including sarcoidosis, leprosy, Gaucher’s

disease, hyperthyroidism, and disseminated granulomatous infections

such as miliary tuberculosis. Because the ACE level is determined by a

biologic assay, the concurrent use of an ACE inhibitor such as lisinopril

will lead to a very low ACE level.

DIAGNOSIS

The diagnosis of sarcoidosis requires both compatible clinical features

and pathologic findings. Because the cause of sarcoidosis remains elusive, the diagnosis cannot be made with 100% certainty. Nevertheless,

the diagnosis can be made with reasonable certainty based on history

and physical features along with laboratory and pathologic findings.

Patients are usually evaluated for possible sarcoidosis based on two

scenarios (Fig. 367-8). In the first scenario, a patient may undergo a

biopsy revealing a noncaseating granuloma in either a pulmonary or

an extrapulmonary organ. If the clinical presentation is consistent with

sarcoidosis and there is no alternative cause for the granulomas identified, the patient is felt to have sarcoidosis.

In the second scenario, signs or symptoms suggesting sarcoidosis

such as the presence of bilateral adenopathy may be present in an

otherwise asymptomatic patient or a patient with uveitis or a rash consistent with sarcoidosis. At this point, a diagnostic procedure should be

performed. For the patient with a compatible skin lesion, a skin biopsy

should be considered. Other biopsies to consider could include liver,

extrathoracic lymph node, or muscle. In some cases, a biopsy of the

affected organ may not be easy to perform (such as a brain or spinal

cord lesion). In other cases, such as an endomyocardial biopsy, the

likelihood of a positive biopsy is low. Because of the high rate of pulmonary involvement in these cases, the lung may be easier to approach

by bronchoscopy. During the bronchoscopy, a transbronchial biopsy,

bronchial biopsy, or transbronchial needle aspirate can be performed.

The endobronchial ultrasonography-guided (EBUS) transbronchial

needle aspirate can assist in diagnosing sarcoidosis in patients with

mediastinal adenopathy (stage 1 or 2 radiographic pulmonary disease),

whereas transbronchial biopsy has a higher diagnostic yield for those

with only parenchymal lung disease (stage 3). These tests are complementary and may be performed together.

If the biopsy reveals granulomas, an alternative diagnosis such as

infection or malignancy must be excluded. Bronchoscopic washings

can be sent for cultures for fungi and tuberculosis. For the pathologist,

Patient referred for possible sarcoidosis

Biopsy showing

granuloma:

no alternative

diagnosis

Clinically

consistent with

sarcoidosis

Features suggesting sarcoidosis:

Consistent chest roentgenogram (adenopathy)

Consistent skin lesions: lupus pernio, erythema nodosum,

maculopapular lesions

Uveitis, optic neuritis, hypercalcemia, hypercalciuria,

seventh nerve paralysis

Biopsy affected organ if possible

Bronchoscopy: biopsy with granuloma

Needle aspirate: granulomas

Negative but no evidence

of alternative diagnosis

Yes and no alternative

diagnosis

Features highly consistent with sarcoidosis:

Serum ACE level >2 times upper limit of normal

BAL lymphocytosis >2 times upper limit of normal

Panda/lambda sign on gallium scan

Possible sarcoidosis; seek other diagnosis

Sarcoidosis

Sarcoidosis

No Yes

Yes No

FIGURE 367-8 Proposed approach to management of a patient with possible sarcoidosis. Presence of one or more of the following features supports the diagnosis of

sarcoidosis: uveitis, optic neuritis, hypercalcemia, hypercalciuria, seventh cranial nerve paralysis, and/or diabetes insipidus. ACE, angiotensin-converting enzyme; BAL,

bronchoalveolar lavage.

Sarcoidosis

2835CHAPTER 367

the more tissue that is provided, the more comfortable is the diagnosis of sarcoidosis. A needle aspirate may be adequate in an otherwise

classic case of sarcoidosis but may be insufficient in a patient in whom

lymphoma or fungal infection is a likely alternative diagnosis. Because

granulomas can be seen on the edge of a lymphoma, the presence of a

few granulomas from a needle aspirate may not be sufficient to clarify

the diagnosis. Mediastinoscopy provides a larger sample to confirm the

presence or absence of lymphoma in the mediastinum. Alternatively,

for most patients, evidence of extrathoracic disease (e.g., eye involvement) may further support the diagnosis of sarcoidosis.

For patients with negative pathology, positive supportive tests may

increase the likelihood of the diagnosis of sarcoidosis. These tests

include an elevated ACE level, which can also be elevated in other

granulomatous diseases but not in malignancy. A positive PET scan

can support the diagnosis if multiple organs are affected. BAL is often

performed during the bronchoscopy. An increase in the percentage of

lymphocytes supports the diagnosis of sarcoidosis. The lymphocyte

markers CD4 and CD8 can be used to determine the CD4/CD8 ratio of

these increased lymphocytes in the BAL fluid. A ratio of >3.5 is strongly

supportive of sarcoidosis but is less sensitive than an increase in lymphocytes alone. Although in general an increase in BAL lymphocytes

is supportive of the diagnosis, other conditions must be considered.

Supportive findings, when combined with commonly associated but

nondiagnostic clinical features of the disease, improve the diagnostic

probability of sarcoidosis. These clinical features include uveitis, renal

stones, hypercalcemia, seventh cranial nerve paralysis, and erythema

nodosum. A sarcoidosis diagnostic score has been developed that

incorporates the cumulative information from multiorgan involvement

and allows one to quantitate the likelihood of sarcoidosis.

Because the diagnosis of sarcoidosis can never be certain, over time,

other features may arise that lead to an alternative diagnosis. Conversely, evidence for new organ involvement may eventually confirm

the diagnosis of sarcoidosis.

PROGNOSIS

The risk of death or loss of organ function remains low in sarcoidosis.

Poor outcomes usually occur in patients who present with advanced

disease in whom treatment seems to have little impact. In these cases,

irreversible fibrotic changes have frequently occurred. The overall

mortality of sarcoidosis is approximately 5%. Mortality is associated

with advanced pulmonary fibrosis (>20% fibrosis on chest CT scan

and/or DLCO <50%) and pulmonary hypertension. Over the past

20 years, the reported mortality from sarcoidosis has increased in

the United States and England. Whether this is due to heightened

awareness of the chronic nature of this disease or to other factors

such as more widespread immunosuppressive therapy usage remains

unclear.

For the majority of patients, initial presentation occurs during the

granulomatous phase of the disease, as depicted in Fig. 367-1. It is

clear that many patients resolve their disease within 2–5 years. These

patients are felt to have acute, self-limiting sarcoidosis. However, there

is a form of the disease that does not resolve within the first 2–5 years.

These chronic patients can be identified at presentation by certain

risk factors at presentation such as fibrosis on chest roentgenogram,

presence of lupus pernio, bone cysts, cardiac or neurologic disease

(except isolated seventh nerve paralysis), and presence of renal calculi

due to hypercalciuria. In several studies, patients who required glucocorticoids for any manifestation of their disease in the first 6 months

of presentation had a >50% chance of having chronic disease. In contrast, <10% of patients who required no systemic therapy in the first

6 months required chronic therapy.

TREATMENT

Sarcoidosis

The decision to treat sarcoidosis is based on two indications: to

avoid danger or improve quality of life. A dangerous outcome from

sarcoidosis is the possibility of organ- or life-threatening disease,

including disease involving the eye, heart, or nervous system.

The patient with asymptomatic elevated liver function tests or an

abnormal chest roentgenogram probably does not benefit from

treatment. However, these patients should be monitored for evidence of progressive, symptomatic disease. Improvement of quality

of life is an important indication to treat; however, one must be

careful to avoid toxicity from therapy that is more problematic than

the disease itself.

One approach to therapy issummarized in Figs. 367-9 and 367-10.

We have divided the approach into treating acute versus chronic

disease. For acute disease, no therapy remains a viable option for

patients with no or mild symptoms. For symptoms confined to only

one organ, topical therapy is preferable. For multiorgan disease or

disease too extensive for topical therapy, an approach to systemic

therapy is outlined. Glucocorticoids remain the drugs of choice

for this disease. However, the decision to continue to treat with

glucocorticoids or to add steroid-sparing agents depends on the tolerability, duration, and dosage of glucocorticoids. Table 367-2 summarizesthe dosage and monitoring ofseveral commonly used drugs.

According to the available trials, evidence-based recommendations

Acute disease

Minimal to no symptoms Single organ disease Symptomatic multiple organs

Abnormalities of

neurologic, cardiac,

ocular, calcium

Affecting only:

anterior eye, localized

skin, cough

Systemic therapy:

glucocorticoids (e.g.,

prednisone)

Yes: consider

systemic therapy

No: no therapy

and observe

Yes: try topical

steroids

No: systemic

therapy

Taper to <10 mg in less than

6 months: continue prednisone

Cannot taper to <10 mg in 6

months or glucocorticoid toxicity

Consider methotrexate, hydroxychloroquine, azathioprine

FIGURE 367-9 The management of acute sarcoidosis is based on level of symptoms and extent of organ involvement. In patients with mild symptoms, no therapy may be

needed unless specified manifestations are noted.

2836 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

are made. Most of these recommendations are for pulmonary disease because most of the trials were performed only in pulmonary

disease. Treatment recommendations for extrapulmonary disease

are usually similar with a few modifications. For example, the dosage of glucocorticoids is usually higher for neurosarcoidosis and

lower for cutaneous disease. There was some suggestion that higher

doses would be beneficial for cardiac sarcoidosis, but one study

found that initial prednisone doses >40 mg/d were associated with

a worse outcome because of toxicity.

Systemic therapies for sarcoidosis are usually immunosuppressive, including glucocorticoids, cytotoxics, or biologics. Although

most patients receive glucocorticoids as their initial systemic

therapy, toxicity associated with prolonged therapy often leads

to steroid-sparing alternatives. The antimalarial drugs, such as

hydroxychloroquine, are more effective for skin than pulmonary

disease. Minocycline may also be useful for cutaneous sarcoidosis.

For pulmonary and other extrapulmonary disease, cytotoxic agents

that include methotrexate, azathioprine, leflunomide, mycophenolate, and cyclophosphamide are often used. The most widely

studied cytotoxic agent has been methotrexate. This agent works

in approximately two-thirds of sarcoidosis patients, regardless of

the disease manifestation. In one retrospective study comparing

methotrexate with azathioprine, both drugs were equally effective.

However, methotrexate was associated with significantly less toxicity. As noted in Table 367-2, specific guidelines for monitoring

therapy have been recommended. Cytokine modulators such as

thalidomide and pentoxifylline have also been used in a limited

number of cases.

The biologic anti-TNF agents have recently been studied in sarcoidosis, with prospective randomized trials completed for etanercept, golimumab, and infliximab. Etanercept has a limited role as a

steroid-sparing agent. Golimumab was not significantly different

than placebo in treating chronic pulmonary disease. However, this

may have been due to the relatively low dose of golimumab studied.

Infliximab significantly improved lung function when administered

to glucocorticoid and cytotoxic pretreated patients with chronic

disease. The difference in response between etanercept and infliximab is similar to that observed in Crohn’s disease, where infliximab

is effective and etanercept is not. However, there is a higher risk for

reactivation of tuberculosis with infliximab compared with etanercept. The differential response rate could be explained by differences in mechanism of action because etanercept is a TNF receptor

antagonist and infliximab is a monoclonal antibody against TNF. In

contrast to etanercept, infliximab also binds to TNF on the surface

Chronic disease

Glucocorticoids

tolerated

Glucocorticoids

not tolerated

Glucocorticoids

not effective

Dose <10 mg/d

Continue therapy

Seek alternative agents

Alternative agents

Methotrexate

Hydroxychloroquine

Azathioprine

Leflunomide

Mycophenolate

Minocycline

Try alternative agents

If effective, taper off

glucocorticoids

If not effective,

consider:

multiple agents

Infliximab

Cyclophosphamide

Thalidomide

No

Yes

FIGURE 367-10 Approach to chronic disease is based on whether glucocorticoid therapy is tolerated or not.

TABLE 367-2 Commonly Used Drugs to Treat Sarcoidosis

DRUG INITIAL DOSE MAINTENANCE DOSE MONITORING TOXICITY SUPPORT THERAPYa

SUPPORT

MONITORINGa

Prednisone 20–40 mg qd Taper to 5–10 mg Glucose, blood

pressure, bone

density

Diabetes,

osteoporosis

A: Acute pulmonary

D: Extrapulmonary

Hydroxychloroquine 200–400 mg qd 400 mg qd Eye examination

q6–12 mo

Ocular B: Some forms of

disease

D: Routine eye

examination

Methotrexate 10 mg qwk 2.5–15 mg qwk CBC, renal, hepatic

q2mo

Hematologic, nausea,

hepatic, pulmonary

B: Steroid sparing

C: Some forms

chronic disease

D: Routine hematologic,

renal, and hepatic

monitoring

Azathioprine 50–150 mg qd 50–200 mg qd CBC, renal q2mo Hematologic, nausea C: Some forms

chronic disease

D: Routine hematologic

monitoring

Infliximab 3–5 mg/kg q2wk for

2 doses

3–10 mg/kg q4–8 wk Initial PPD Infections, allergic

reaction, carcinogen

A: Chronic pulmonary

disease

B: Caution in patients

with latent tuberculosis

or advanced congestive

heart failure

a

Grade A: supported by at least two double-blind randomized control trials; grade B: supported by prospective cohort studies; grade C: supported primarily by two or more

retrospective studies; grade D: only one retrospective study or based on experience in other diseases.

Abbreviations: CBC, complete blood count; PPD, purified protein derivative test for tuberculosis.

Source: Reproduced with permission from RP Baughman, O Selroos: Evidence-based approach to treatment of sarcoidosis in PG Gibson et al (eds): Evidence-based

respiratory medicine. Oxford, BMJ Books Blackwell, 2005.

IgG4-Related Disease

2837CHAPTER 368

of some cells that release TNF, which leads to cell lysis. This effect

has been documented in Crohn’s disease. Adalimumab is a humanized monoclonal anti-TNF antibody that also appears effective for

sarcoidosis when dosed at higher strengths, as recommended for

the treatment of Crohn’s disease. The role of the newer therapeutic agents for sarcoidosis is still evolving. However, these targeted

therapies confirm that TNF may be an important target, especially

in the treatment of chronic disease. However, these agents are not

a panacea because sarcoidosis-like disease has occurred in patients

treated with anti-TNF agents for nonsarcoidosis indications.

■ FURTHER READING

Baughman RP et al: Sarcoidosis in America. Analysis based on health

care use. Ann Am Thorac Soc 13:1244, 2016.

Bickett AN et al: Sarcoidosis diagnostic score: A systematic evaluation to enhance the diagnosis of sarcoidosis. Chest 154:1052, 2018.

Broos CE et al: Granuloma formation in pulmonary sarcoidosis. Front

Immunol 4:437, 2013.

James WE, Baughman R: Treatment of sarcoidosis: Grading the evidence. Expert Rev Clin Pharmacol 11:677, 2018.

Spagnolo P et al: Pulmonary sarcoidosis. Lancet Respir Med 6:389,

2018.

IgG4-related disease (IgG4-RD) is a fibroinflammatory condition

characterized by a tendency to form tumefactive lesions. The clinical

manifestations of this disease, however, are protean, as IgG4-RD can

affect virtually any organ system. Commonly affected organs are the

pancreas, biliary tree, major salivary glands (submandibular, parotid),

periorbital tissues, kidneys, lungs, lymph nodes, and retroperitoneum.

In addition, IgG4-RD involvement of the meninges, aorta, prostate,

thyroid, pericardium, skin, and other organs is well described. The

disease affects the brain parenchyma, the joints, the bone marrow, and

the bowel mucosa only rarely.

The pathologic findings are consistent across all affected organs.

These findings include a lymphoplasmacytic infiltrate with a high

percentage of IgG4-positive plasma cells; a characteristic pattern of

fibrosis termed “storiform” (from the Latin storea, for “woven mat”);

a tendency to target blood vessels, particularly veins, through an

obliterative process (“obliterative phlebitis”); and a mild to moderate

tissue eosinophilia. Although the pathology is consistent from organ

to organ, it is essentially never diagnostic in and of itself. Classification

criteria emphasize the importance of careful correlation among clinical, serologic, radiologic, and pathologic findings in deciding whether

a patient should be classified as having IgG4-RD. Biopsy is not required

in order to establish the diagnosis in classic cases, but most patients

undergo a biopsy at some point in the evaluation in order to exclude

malignancy.

IgG4-RD encompasses a number of conditions previously regarded

as separate, organ-specific entities. A condition once known as “lymphoplasmacytic sclerosing pancreatitis” became the paradigm of

IgG4-RD in 2000, when Japanese investigators recognized that these

patients had elevated serum concentrations of IgG4. This form of sclerosing pancreatitis is now termed type 1 (IgG4-related) autoimmune

pancreatitis (AIP). By 2003, extrapancreatic disease manifestations

had been identified in patients with type 1 AIP, and descriptions of

IgG4-RD in other organs followed. Mikulicz’s disease, once considered

to be a subset of Sjögren’s syndrome that affected the lacrimal, parotid,

368 IgG4-Related Disease

John H. Stone

and submandibular glands, is one of the most common presentations

of IgG4-RD.

■ CLINICAL FEATURES

The major organ lesions are summarized in Table 368-1. IgG4-RD

usually presents subacutely, and even in the setting of multiorgan disease, most patients do not have fevers or high elevations of C-reactive

protein levels. Some patients, however, experience substantial weight

loss over periods of months, largely because of exocrine pancreatic

failure. Failure of the endocrine pancreas, leading to diabetes mellitus,

is also common. Clinically apparent disease can evolve over months,

years, or even decades before the manifestations within a given organ

become sufficiently severe to bring the patient to medical attention.

Some patients have disease that is marked by the appearance and

then resolution or temporary improvement in symptoms within a

particular organ. Other patients accumulate new organ involvement as

their disease persists in previously affected organs. Many patients with

IgG4-RD are misdiagnosed as having other conditions, particularly

malignancies, or their findings are attributed initially to nonspecific

inflammation. The disorder is often identified incidentally through

radiologic findings or unexpectedly in pathology specimens.

Multiorgan disease may be evident at diagnosis but can also evolve

over months to years. Some patients have disease confined to a single

organ for many years. Others have either known or subclinical organ

involvement at the same time as the major clinical feature. Patients

with type 1 AIP may have their major disease focus in the pancreas;

however, thorough evaluations by history, physical examination, blood

tests, and cross-sectional imaging may demonstrate lacrimal gland

enlargement, sialoadenitis, lymphadenopathy, a variety of pulmonary

findings, tubulointerstitial nephritis, hepatobiliary disease, aortitis,

retroperitoneal fibrosis, or other organ involvement.

Two common characteristics of IgG4-RD are allergic disease and

the tendency to form tumefactive lesions that mimic malignancies

(Fig. 368-1). Many IgG4-RD patients have allergic features such as

atopy, eczema, asthma, nasal polyps, sinusitis, and modest peripheral

eosinophilia. IgG4-RD also appears to account for a significant proportion of tumorous swellings—pseudotumors—in many organ systems

(Fig. 368-2). Some patients undergo major surgeries (e.g., modified

Whipple procedures or thyroidectomy) for the purpose of resecting

malignancies before the correct diagnosis is identified.

IgG4-RD often causes major morbidity and can lead to organ failure;

however, its general pattern is to cause damage in a subacute manner.

Destructive bone lesions in the sinuses, head, and middle ear spaces

that mimic granulomatosis with polyangiitis occur occasionally in

IgG4-RD, but less aggressive lesions are the rule in most organs. In

regions such as the retroperitoneum, substantial fibrosis often occurs

before the diagnosis is established, leading to ureteral entrapment,

hydronephrosis, postobstructive uropathy, and renal atrophy. Undiagnosed or undertreated IgG4-related sclerosing cholangitis can lead to

hepatic failure within months. Similarly, IgG4-related aortitis can cause

aneurysms and dissections. Substantial renal dysfunction and even

renal failure can ensue from IgG4-related tubulointerstitial nephritis,

and renal atrophy is a frequent sequel to this disease complication even

following apparently effective immunosuppressive therapy. IgG4-related

membranous glomerulonephropathy, a less common renal manifestation than tubulointerstitial nephritis, must be distinguished from

idiopathic membranous glomerulonephropathy.

■ SEROLOGIC FINDINGS

The majority of patients with IgG4-RD have elevated serum IgG4 concentrations; however, the range of elevation varies widely. Serum concentrations of IgG4 as high as 30 or 40 times the upper limit of normal

sometimes occur, usually in patients with disease that affects multiple

organ systems simultaneously. Approximately 30% of patients have normalserum IgG4 concentrations despite classic histopathologic and immunohistochemical findings. Such patients tend to have disease that affects

fewer organs. Patients with IgG4-related retroperitoneal fibrosis often

have normal serum IgG4 concentrations, perhaps because the process has

advanced to a fibrotic stage by the time the diagnosis is considered.

2838 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

FIGURE 368-1 A major clinical feature of IgG4-related disease is its tendency to form tumefactive lesions. Shown here are mass lesions of the lacrimal glands (A) and the

submandibular glands (B).

A B

TABLE 368-1 Organ Manifestations of IgG4-Related Disease

ORGAN MAJOR CLINICAL FEATURES

Orbits and periorbital tissues Painless eyelid or periocular tissue swelling; orbital pseudotumor; dacryoadenitis; dacryocystitis; orbital myositis; and mass lesions

extending into the pterygopalatine fossa and infiltrating along the trigeminal nerve

Ears, nose, and sinuses Allergic phenomena (nasal polyps, asthma, allergic rhinitis, peripheral eosinophilia); nasal obstruction, rhinorrhea, anosmia, chronic

sinusitis; occasional bone-destructive lesions

Salivary glands Submandibular and/or parotid gland enlargement (isolated bilateral submandibular gland involvement more common); minor salivary

glands sometimes involved

Meninges Headache, radiculopathy, cranial nerve palsies, or other symptoms resulting from spinal cord compression; tendency to form mass

lesions; MRI shows marked thickening and enhancement of dura

Hypothalamus and pituitary Clinical syndromes resulting from involvement of the hypothalamus and pituitary, e.g., anterior pituitary hormone deficiency, central

diabetes insipidus, or both; imaging reveals thickened pituitary stalk or mass formation on the stalk, swelling of the pituitary gland, or

mass formation within the pituitary

Lymph nodes Generalized lymphadenopathy or localized disease adjacent to a specific affected organ; the lymph nodes involved are generally

1–2 cm in diameter and nontender

Thyroid gland Riedel’s thyroiditis; fibrosing variant of Hashimoto’s thyroiditis

Lungs Asymptomatic finding on lung imaging; cough, hemoptysis, dyspnea, pleural effusion, or chest discomfort; associated with

parenchymal lung involvement, pleural disease, or both; four main clinical lung syndromes: inflammatory pseudotumor, paravertebral

mass often extending over several vertebrae, central airway disease, localized or diffuse interstitial pneumonia; pleural lesions have

severe, nodular thickening of the visceral or parietal pleura with diffuse sclerosing inflammation, sometimes associated with pleural

effusion

Aorta Asymptomatic finding on radiologic studies; surprise finding at elective aortic surgery; aortic dissection; clinicopathologic syndromes

described include lymphoplasmacytic aortitis of thoracic or abdominal aorta, aortic dissection, periaortitis and periarteritis, and

inflammatory abdominal aneurysm

Retroperitoneum Backache, lower abdominal pain, lower extremity edema, hydronephrosis from ureteral involvement, asymptomatic finding on

radiologic studies. Classic radiologic appearance is periaortic inflammation extending caudally to involve the iliac vessels.

Kidneys Tubulointerstitial nephritis; membranous glomerulonephritis in a small minority; asymptomatic tumoral lesions, typically multiple and

bilateral, are sometimes detected on radiologic studies; renal involvement strongly associated with hypocomplementemia

Pancreas Type 1 autoimmune pancreatitis, presenting as mild abdominal pain; weight loss; acute, obstructive jaundice, mimicking

adenocarcinoma of the pancreas (including a pancreatic mass); between 20 and 50% of patients present with acute glucose

intolerance; imaging shows diffuse (termed “sausage-shaped pancreas”) or segmental pancreatic enlargement, with loss of normal

lobularity; a mass often raises the suspicion of malignancy

Biliary tree and liver Obstructive jaundice associated with autoimmunity in most cases; weight loss; steatorrhea; abdominal pain; and new-onset diabetes

mellitus; mimicker of primary sclerosing cholangitis and cholangiocarcinoma

Other organs involved Gallbladder, liver (mass), breast (pseudotumor), prostate (prostatism), pericardium (constrictive pericarditis), mesentery (sclerosing

mesenteritis), mediastinum (fibrosing mediastinitis), skin (erythematous or flesh-colored papules), peripheral nerve (perineural

inflammation)

Correlations between serum IgG4 concentrations, disease activity,

and the need for treatment are imperfect. Serum IgG4 concentrations

typically decline swiftly with the institution of therapy but often do

not normalize completely. Patients can achieve clinical remissions

yet have persistently elevated serum IgG4 concentrations. Following

treatment and a disease response, however, steadily rising serum IgG4

concentrations are useful in identifying patients atrisk for clinical flares

who should be considered for re-treatment. Clinical relapses occur in

some patients despite persistently normal IgG4 concentrations.

IgG4 concentrations in serum are usually measured by nephelometry assays. In the setting of extremely high serum IgG4 concentrations,

these assays can generate spuriously low IgG4 values because of the

IgG4-Related Disease

2839CHAPTER 368

FIGURE 368-2 Thickening of extraocular muscles and meninges. A. Computed

tomography scan of the orbits, showing enlargement of extraocular muscles in

a patient with IgG4-related orbital disease. B. Computed tomography scan of the

brain, showing thickening of the pachymeninges.

A

B

prozone effect. Failure to identify dramatic serum IgG4 elevations can

have a substantial impact on patients because that subset of patients is

at greatest risk for multiorgan disease and substantial end-organ injury.

The prozone effect should be considered when the results of serologic

testing for IgG4 concentrations are normal despite the presence of clinical features that strongly suggest IgG4-RD. This effect can be corrected

by dilution of the serum sample in the laboratory.

■ EPIDEMIOLOGY

The typical patient with IgG4-RD is a middle-aged to elderly man. This

epidemiology stands in stark contrast to that of many classic autoimmune conditions, which tend to affect young women. Studies of AIP

patients in Japan indicate that the male-to-female ratio in that disease

subset is on the order of 3:1. A striking male predominance has also

been reported in IgG4-related tubulointerstitial nephritis and IgG4-

related retroperitoneal fibrosis, but among IgG4-RD manifestations

that involve organs of the head and neck—the orbits, lacrimal glands,

and major salivary glands—the sex ratio may be closer to 1:1.

■ PATHOLOGY

The key histopathology characteristics of IgG4-RD are a dense lymphoplasmacytic infiltrate (Fig. 368-3) that is organized in a storiform

FIGURE 368-3 Hallmark histopathology characteristics of IgG4-related disease

(IgG4-RD) are a dense lymphoplasmacytic infiltrate and a mild to moderate

eosinophilic infiltrate. The cellular inflammation is often encased in a distinctive

type of fibrosis termed “storiform,” which often has a basket weave pattern.

Abundant fibroblasts and strands of fibrosis accompany the lymphoplasmacytic

infiltrate in this figure. This biopsy is from a patient with IgG4-related hypertrophic

pachymeningitis. However, the findings are identical to the pathology found in the

pancreas, kidneys, lungs, salivary glands, and other organs affected by IgG4-RD.

pattern, obliterative phlebitis, and a mild to moderate eosinophilic

infiltrate. Lymphoid follicles and germinal centers are frequently

observed. The infiltrate tends to aggregate around ductal structures

when it affects glands. The inflammatory lesion often aggregates into

tumefactive masses that destroy the involved tissue.

Obliterative arteritis is observed in some organs, particularly the

lung; however, venous involvement is more common (and is indeed a

hallmark of IgG4-RD). Several histopathology features are uncommon

in IgG4-RD and, when detected, mitigate against the diagnosis of

IgG4-RD. These include intense neutrophilic infiltration, leukocytoclasis, granulomatous inflammation, multinucleated giant cells, and

fibrinoid necrosis.

The inflammatory infiltrate is composed of an admixture of B and T

lymphocytes. B cells are typically organized in germinal centers. Plasma

cells staining for CD19, CD138, and IgG4 appear to radiate from the

germinal centers. In contrast, the T cells, usually CD4+, are distributed

more diffusely throughout the lesion and generally represent the most

abundant cell type. Fibroblasts, histiocytes, and eosinophils can all be

observed in moderate numbers. Some biopsy samples are particularly

enriched with eosinophils. In other samples, particularly from longstanding cases, fibrosis predominates.

The histologic appearance of IgG4-RD, although highly characteristic, requires immunohistochemical confirmation of the diagnosis with

IgG4 immunostaining. IgG4-positive plasma cells predominate within

the lesion, but plasma cells containing immunoglobulins from each

subclass can be found. The number of IgG4-positive plasma cells can

be quantified by either counting the number of cells per high-power

field (HPF) or by calculating the ratio of IgG4- to IgG-bearing plasma

cells. Tissue fibrosis predominates in the latter phases of organ involvement, and in this relatively acellular phase of inflammation, both the

IgG4:total IgG ratio and the pattern of tissue fibrosis are more important than the number of IgG4-positive cells per HPF in establishing

the diagnosis.

■ PATHOPHYSIOLOGY

Despite the emphasis of IgG4 in the name of this disease, the IgG4

molecule is not believed to play a direct role in the pathophysiology

of disease within most organs. The IgG4 molecule can undergo Fab

exchange, a phenomenon in which the two halves of the molecule

dissociate from each other and reassociate with hemi-molecules of

different antigen specificity that have originated from other dissociated

2840 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

IgG4 molecules. Partly as a result of this Fab exchange, IgG4 antibodies

do not bind antigen tightly. Moreover, the molecules have low affinities

for Fc receptors and C1q and are regarded generally as noninflammatory immunoglobulins. The low affinities for Fc receptors and C1q

impair the ability of IgG4 antibodies to induce phagocyte activation,

antibody-dependent cellular cytotoxicity, and complement-mediated

damage. It is possible, therefore, that the role of IgG4 in this disease

is actually as a counterregulatory mechanism rather than part of the

primary inflammatory process.

Next-generation sequencing studies of CD4+ effector T cells have

demonstrated a unique CD4+ cytotoxic T cell. This cell, also found in

abundance at tissue sites of disease, makes interferon γ, T-cell growth

factor-β, and interleukin-1, all of which may contribute to the storiform fibrosis found in this condition. The cells also elaborate perforin,

granzyme A and B, and granulysin, products capable of inducing cytotoxicity. The pronounced oligoclonal expansion of this CD4+ cytotoxic

T cell at tissue sites suggests that this cell is a major disease driver.

Oligoclonal expansions of plasmablasts are also present within the

blood of patients with IgG4-RD. Continuous antigen presentation by

B cells and plasmablasts may support this cell, which in turn produces

profibrotic cytokines and other molecules, thereby directly mediating

tissue injury.

■ TREATMENT

Vital organ involvement must be treated aggressively because IgG4-RD

can lead to serious organ dysfunction and failure. Aggressive disease

can lead quickly to end-stage liver disease, permanent impairment of

pancreatic function, renal atrophy, aortic dissection or aneurysms, and

destructive lesions in the sinuses and nasopharynx. Not every disease

manifestation of IgG4-RD requires immediate treatment, however,

because the disease may take an indolent form in some patients.

IgG4-related lymphadenopathy, for example, can be asymptomatic

for years, without evolution to other disease manifestations. Thus,

watchful waiting is prudent in some cases, but monitoring is essential

because serious organ involvement may evolve over time.

Glucocorticoids are the first line of therapy. Treatment regimens,

extrapolated from experience with the management of type 1 AIP,

generally begin with 40 mg/d of prednisone, with tapering to discontinuation or maintenance doses of 5 mg/d within 2 or 3 months.

Although the clinical response to glucocorticoids is usually swift and

striking, prolonged steroid-free remissions are uncommon and the risk

of steroid-induced morbidity in this middle-aged to elderly patient

population is high, particularly in those with baseline comorbidities

and pancreatic involvement by IgG4-RD. Few data exist to support the

utility of conventional steroid-sparing agents in this disease.

For patients with relapsing or glucocorticoid-resistant disease,

B-cell depletion with rituximab is an excellent second-line therapy.

Rituximab treatment (two doses of 1 g IV, separated by approximately

15 days) leads to a swift decline in serum IgG4 concentrations, suggesting thatrituximab achievesits effectsin part by preventing the repletion

of short-lived plasma cells that produce IgG4. More important than its

effects on IgG4 concentrations, however, may be the effect of B-cell

depletion on T-cell function. Specific effects of rituximab on the CD4+

cytotoxic T cell described above have been documented in IgG4-RD.

Rituximab may be an appropriate first-line therapy for some patients,

particularly those at high risk for glucocorticoid toxicity and patients

with immediately organ-threatening disease. The rapidly evolving

understanding of the pathophysiology of IgG4-RD suggests several

novel targeted approaches to treating the disease, some of which are

in clinical trials. These novel strategies include inhibition of Bruton’s

tyrosine kinase, the depletion of CD19+ cells of the B lymphocyte

lineage, and targeting of SLAM-F7, the molecule found on the surfaces

of both B lymphocytes and the CD4+ cytotoxic T lymphocyte. Both of

these cell types have been implicated in disease pathophysiology.

■ FURTHER READING

Perugino CA, Stone JH: IgG4-related disease: An update on pathophysiology and implications for clinical care. Nat Rev Rheumatol

16:702, 2020.

Perugino CA et al: CD4+ and CD8+ cytotoxic T lymphocytes may

induce mesenchymal cell apoptosis in IgG4

-related disease. J Allergy

Clin Immunol 147:368, 2021.

Wallace ZS et al: The 2019 American College of Rheumatology/

European League Against Rheumatism classification criteria for

IgG4-related disease. Arthritis Rheumatol 72:7, 2020.

Wallace ZS et al: The 2019 American College of Rheumatology/

European League Against Rheumatism classification criteria for

IgG4-related disease. Ann Rheum Dis 79:77, 2020.

Wallwork R et al: Rituximab for idiopathic and IgG4-related retroperitoneal fibrosis. Medicine (Baltimore) 97:e12631, 2018.

Zhang W, Stone JH: Management of IgG4-RD. Lancet Rheumatol

1:e55, 2019.

Familial Mediterranean fever (FMF) is the prototype of a group of

inherited diseases (Table 369-1) that are characterized by recurrent

episodes of fever with serosal, synovial, or cutaneous inflammation

and, in some individuals, the eventual development of systemic AA

amyloidosis (Chap. 112). Because of the relative infrequency of hightiter autoantibodies or antigen-specific T cells, the term autoinflammatory has been proposed to describe these disorders, rather than

autoimmune. The innate immune system, with its myeloid effector

cells and germline receptors for pathogen-associated molecular patterns and endogenous danger signals, plays a predominant role in the

pathogenesis of the autoinflammatory diseases. Although the hereditary recurrent fevers comprise a major category of the autoinflammatory diseases, other inherited disorders of inflammation in which

recurrent fever plays a less prominent role are now also considered to

be autoinflammatory.

BACKGROUND AND PATHOPHYSIOLOGY

FMF was first recognized among Armenians, Arabs, Turks, and

non-Ashkenazi (primarily North African and Iraqi) Jews. With the

advent of genetic testing, FMF has been documented with increasing

frequency among Ashkenazi Jews, Italians, and other Mediterranean

populations, and occasional cases have been confirmed even in the

absence of known Mediterranean ancestry. FMF is generally regarded

as recessively inherited, but there is an increasing awareness of clearcut clinical cases with only a single demonstrable genetic mutation,

and for certain relatively rare FMF mutations, there is strong evidence

for dominant inheritance. Particularly in countries where families are

small, a positive family history can only be elicited in ~50% of cases.

DNA testing demonstrates carrier frequencies as high as 1:10 among

affected populations, most likely due to some selective advantage.

The FMF gene encodes a 781-amino-acid, ~95-kDa protein denoted

pyrin that is expressed in granulocytes, eosinophils, monocytes, dendritic cells, and synovial and peritoneal fibroblasts. The N-terminal 92

amino acids of pyrin define a motif, the PYRIN domain, that mediates

homotypic protein-protein interactions and has been found in several

other proteins, including cryopyrin (NLRP3), which is mutated in

three other recurrent fever syndromes. Through the interaction of its

PYRIN domain with an intermediary adaptor protein, pyrin nucleates

the formation of a macromolecular pyrin inflammasome to activate

caspase-1 (interleukin [IL] 1β–converting enzyme) and thereby IL-1β

369 Familial Mediterranean

Fever and Other

Hereditary Autoinflammatory

Diseases

Daniel L. Kastner

Familial Mediterranean Fever and Other Hereditary Autoinflammatory Diseases

2841CHAPTER 369

TABLE 369-1 The Hereditary Recurrent Fever Syndromes

FMF TRAPS HIDS/MKD MWS FCAS NOMID

Ethnicity Jewish, Arab, Turkish,

Armenian, Italian

Any ethnic group Predominantly Dutch,

northern European

Any ethnic group Any ethnic group Any ethnic group

Inheritance Recessive or

dominanta

Dominant Recessive Dominant Dominant Most commonly de

novo mutations; somatic

mosaicism in a significant

minority

Gene/chromosome MEFV/16p13.3 TNFRSF1A/12p13 MVK/12q24 NLRP3/1q44 NLRP3/1q44 NLRP3/1q44

Protein Pyrin p55 TNF receptor Mevalonate kinase NLRP3 (cryopyrin) NLRP3 (cryopyrin) NLRP3 (cryopyrin)

Attack length 1–3 days Often >7 days 3–7 days 1–2 days Minutes–3 days Continuous, with flares

Serosa Pleurisy, peritonitis;

asymptomatic

pericardial effusions

Pleurisy, peritonitis,

pericarditis

Abdominal pain, but

seldom peritonitis;

pleurisy, pericarditis

uncommon

Abdominal pain;

pleurisy, pericarditis

rare

Rare Rare

Skin Erysipeloid erythema Centrifugally

migrating erythema

Diffuse

maculopapular rash;

oral ulcers

Diffuse urticaria-like

rash

Cold-induced

urticaria-like rash

Diffuse urticaria-like rash

Joints Acute monoarthritis;

chronic hip arthritis

(rare)

Acute monoarthritis,

arthralgia

Arthralgia,

oligoarthritis

Arthralgia, large joint

oligoarthritis

Polyarthralgia Epiphyseal, patellar

overgrowth, clubbing

Muscle Exercise-induced

myalgia common;

protracted febrile

myalgia rare

Migratory myalgia Uncommon Myalgia common Sometimes

myalgia

Sometimes myalgia

Eyes, ears Uncommon Periorbital edema,

conjunctivitis, rarely

uveitis

Uncommon Conjunctivitis,

episcleritis, optic disc

edema; sensorineural

hearing loss

Conjunctivitis Conjunctivitis, uveitis,

optic disc edema,

blindness, sensorineural

hearing loss

CNS Aseptic meningitis

rare

Headache Headache Headache Headache Aseptic meningitis,

seizures

Amyloidosis Most common in

M694V homozygotes

~15% of cases,

most often cysteine

mutations, T50M

Sometimes

associated with

V377I/I268T MVK

genotype

~25% of cases Uncommon Late complication

Treatment Oral colchicine

prophylaxis, IL-1

inhibitors for

refractory cases

Glucocorticoids, IL-1

inhibitors, etanercept

NSAIDs for fever; IL-1

inhibitors

Canakinumab,

rilonacept, anakinra

Canakinumab,

rilonacept,

anakinra

Anakinra

a

A substantial percentage of patients with clinical FMF have only a single demonstrable MEFV mutation on DNA sequencing.

Abbreviations: CNS, central nervous system; FCAS, familial cold autoinflammatory syndrome; FMF, familial Mediterranean fever; HIDS/MKD, hyperimmunoglobulinemia

D with periodic fever syndrome, also known as mevalonate kinase deficiency; IL, interleukin; MWS, Muckle-Wells syndrome; NOMID, neonatal-onset multisystem

inflammatory disease; NSAIDs, nonsteroidal anti-inflammatory drugs; TNF, tumor necrosis factor; TRAPS, TNF receptor-associated periodic syndrome.

and IL-18 secretion and gasdermin d-mediated cell death (pyroptosis).

Certain bacterial toxins that block leukocyte cytoskeletal assembly by

inactivating RhoA GTPase trigger pyrin inflammasome activation as

a part of the normal host defense; in FMF patients, the threshold for

pyrin inflammasome activation is reduced. Population genetic and

immune functional studies support a role for bubonic plague pandemics in selecting for FMF founder mutations that had arisen in Biblical

times in the Middle East.

ACUTE ATTACKS

Febrile episodes in FMF may begin even in early infancy; 90% of

patients have had their first attack by age 20. Typical FMF episodes

generally last 24–72 h, with arthritic attacks tending to last somewhat

longer. In some patients, the episodes occur with great regularity, but

more often, the frequency of attacks varies over time, ranging from as

often as once every few days to remissions lasting several years. Attacks

are often unpredictable, although some patients relate them to physical

exertion, emotional stress, or menses; pregnancy may be associated

with remission.

If measured, fever is nearly always present throughout FMF attacks.

Severe hyperpyrexia and even febrile seizures may be seen in infants,

and feverissometimesthe only manifestation of FMF in young children.

Over 90% of FMF patients experience abdominal attacks at some

time. Episodes range in severity from dull, aching pain and distention with mild tenderness on direct palpation to severe generalized

pain with absent bowel sounds, rigidity, rebound tenderness, and

air-fluid levels on upright radiographs. Computed tomography (CT)

scanning may demonstrate a small amount of fluid in the abdominal

cavity. If such patients undergo exploratory laparotomy, a sterile, neutrophil-rich peritoneal exudate is present, sometimes with adhesions

from previous episodes. Ascites is rare.

Pleural attacks are usually manifested by unilateral, sharp, stabbing

chest pain. Radiographs may show atelectasis and sometimes an effusion. If performed, thoracentesis demonstrates an exudative fluid rich

in neutrophils. After repeated attacks, pleural thickening may develop.

FMF arthritisis most frequent among individuals homozygousforthe

M694V mutation, which is especially common in the non-Ashkenazi Jewish population. Acute arthritis in FMF is usually monoarticular, affecting the knee, ankle, or hip, although other patterns can be seen. Large

sterile effusions rich in neutrophils are frequent, without commensurate

erythema or warmth. Even after repeated arthritic attacks, radiographic

changes are rare. Before the advent of colchicine prophylaxis, chronic

arthritis of the knee or hip was seen in ~5% of FMF patients with arthritis. Chronic sacroiliitis can occur in FMF irrespective of the HLA-B27

antigen, even in the face of colchicine therapy. In the United States, FMF

patients are much more likely to have arthralgia than arthritis.

The most characteristic cutaneous manifestation of FMF is erysipelaslike erythema, a raised erythematous rash that most commonly occurs on

the dorsum of the foot, ankle, or lower leg alone or in combination with

abdominal pain, pleurisy, or arthritis. Biopsy demonstrates perivascular

2842 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

infiltrates of granulocytes and monocytes. This rash is seen most often in

M694V homozygotes and is relatively rare in the United States.

Exercise-induced (nonfebrile) myalgia is common in FMF, and

a small percentage of patients develop a protracted febrile myalgia

that can last several weeks. Symptomatic pericardial disease is rare,

although small pericardial effusions may be noted on echocardiography. Unilateral acute scrotal inflammation may occur in prepubertal

boys. Aseptic meningitis has been reported in FMF, but the causal connection is controversial. Vasculitis, including Henoch-Schönlein purpura and polyarteritis nodosa (Chap. 363), may be seen at increased

frequency in FMF. The M694V FMF mutation has been shown to be a

risk factor for Behçet’s disease and ankylosing spondylitis.

Laboratory features of FMF attacks are consistent with acute

inflammation and include an elevated erythrocyte sedimentation rate,

leukocytosis, thrombocytosis (in children), and elevations in C-reactive

protein, fibrinogen, haptoglobin, and serum immunoglobulins. Transient

albuminuria and hematuria may also be seen.

AMYLOIDOSIS

Before the advent of colchicine prophylaxis, systemic amyloidosis was a

common complication of FMF. It is caused by deposition of a fragment

of serum amyloid A, an acute-phase reactant, in the kidneys, adrenals,

intestine, spleen, lung, and testes (Chap. 112). Amyloidosis should be

suspected in patients who have proteinuria between attacks; renal or

rectal biopsy is used most often to establish the diagnosis. Risk factors

include the M694V homozygous genotype, positive family history

(independent of FMF mutational status), the SAA1 genotype, male

gender, noncompliance with colchicine or IL-1 inhibitory therapy, and

having grown up in the Middle East.

DIAGNOSIS

For typical cases, physicians experienced with FMF can often make

the diagnosis on clinical grounds alone. Clinical criteria sets for FMF

have been shown to have high sensitivity and specificity in parts of the

world where the pretest probability of FMF is high. Genetic testing

can provide a useful adjunct in ambiguous cases or for physicians not

experienced in FMF. Most of the more severe disease-associated FMF

mutations are in exon 10 of the gene. An updated list of mutations

for FMF and other hereditary recurrent fevers can be found online at

http://fmf.igh.cnrs.fr/infevers/.

Genetic testing has permitted a broadening of the clinical spectrum

and geographic distribution of FMF and may be of prognostic value.

Most studies indicate that M694V homozygotes have an earlier age

of onset and a higher frequency of arthritis, rash, and amyloidosis. In

contrast, the E148Q variant in exon 2 is quite common in certain Asian

populations and is more likely to affect overall levels of inflammation

than to cause clinical FMF. E148Q is sometimes found in cis with exon

10 mutations, which may complicate the interpretation of genetic test

results. Only ~70% of patients with clinically typical FMF have two identifiable mutations in trans, consistent with the concept that FMF mutations are gain-of-function with regard to inflammasome activation, with

a dosage effect. In those cases in which only a single mutation is identified, clinical judgment is very important, and sometimes a therapeutic

trial of colchicine or an IL-1 inhibitor may help to confirm the diagnosis.

If a patient is seen during his or her first attack, the differential diagnosis may be broad, although delimited by the specific organ involvement. After several attacks, the differential diagnosis may include the

other hereditary recurrent fever syndromes (Table 362-1); the syndrome of periodic fever with aphthous ulcers, pharyngitis, and cervical

adenopathy (PFAPA); systemic-onset juvenile rheumatoid arthritis or

adult Still’s disease; porphyria; hereditary angioedema; inflammatory

bowel disease; and, in women, gynecologic disorders.

TREATMENT

Familial Mediterranean Fever

The initial treatment of choice for FMF is daily oral colchicine,

which decreases the frequency and intensity of attacks and prevents

the development of amyloidosis in compliant patients. Intermittent

dosing at the onset of attacks is not as effective as daily prophylaxis

and is of unproven value in preventing amyloidosis. The usual adult

dose of colchicine is 1.2–1.8 mg/d, which causes substantial reduction in symptoms in two-thirds of patients and some improvement

in >90%. Children may require lower doses, although not proportionately to body weight.

Common side effects of colchicine include bloating, abdominal

cramps, lactose intolerance, and diarrhea. They can be minimized

by starting at a low dose and gradually advancing as tolerated,

splitting the dose, use of simethicone for flatulence, and avoidance

of dairy products. If taken by either parent at the time of conception, colchicine may cause a small increase in the risk of trisomy

21 (Down’s syndrome). Colchicine is usually continued during

pregnancy, because the risk of miscarriage due to FMF attacks

is thought to outweigh any effect of colchicine on fetal development. In elderly patients with renal insufficiency, colchicine can

cause a myoneuropathy characterized by proximal muscle weakness

and elevation of the creatine kinase. Cyclosporine inhibits hepatic

excretion of colchicine by its effects on the multidrug resistance 1

(MDR1) transport system, sometimes leading to colchicine toxicity

in patients who have undergone renal transplantation for amyloidosis. Intravenous colchicine should generally not be administered to

patients already taking oral colchicine, because severe, sometimes

fatal, toxicity has been observed in this setting.

For FMF patients who do not respond to colchicine or cannot tolerate therapeutic doses, injectable IL-1 inhibitors may be

used. Based on a randomized placebo-controlled phase 3 trial, the

monoclonal anti-IL-1β antibody canakinumab received U.S. Food

and Drug Administration (FDA) approval for this indication. In a

small randomized placebo-controlled trial, weekly subcutaneous

rilonacept, a recombinant IL-1 receptor fusion protein, significantly

reduced the frequency of attacks. There is also substantial anecdotal

experience with daily subcutaneous anakinra, a recombinant IL-1

receptor antagonist, in preventing the acute attacks of FMF and, in

some cases, reducing established amyloid deposits. Bone marrow

transplantation has been suggested for refractory FMF, but the

risk-benefit ratio is currently regarded as unacceptable.

OTHER HEREDITARY RECURRENT FEVERS

■ TNF RECEPTOR–ASSOCIATED

PERIODIC SYNDROME

Tumor necrosis factor (TNF) receptor–associated periodic syndrome

(TRAPS) is caused by dominantly inherited mutations in the extracellular domains of the 55-kDa TNF receptor (TNFR1, p55). Although

originally described in a large Irish family (and hence the name familial

Hibernian fever), TRAPS has a broad ethnic distribution. TRAPS episodes often begin in childhood. The duration of attacks ranges from

1 to 2 days to as long as several weeks, and in severe cases, symptoms

may be nearly continuous. In addition to peritoneal, pleural, and synovial attacks similar to FMF, TRAPS patients frequently have ocular

inflammation (most often conjunctivitis and/or periorbital edema),

and a distinctive migratory myalgia with overlying painful erythema

may be present. TRAPS patients generally respond better to glucocorticoids than to prophylactic colchicine. Untreated, ~15% develop

amyloidosis. The diagnosis of TRAPS is based on the demonstration

of a TNFRSF1A mutation in the presence of characteristic symptoms.

Two particular variants, R92Q and P46L, are common in certain populations and may act more as functional polymorphisms than as disease-causing mutations. In contrast, pathogenic TNFRSF1A mutations,

including a number of substitutions at highly conserved cysteine residues, are associated with intracellular TNFR1 misfolding, aggregation,

and retention, with consequent ligand-independent kinase activation,

mitochondrial reactive oxygen species production, and proinflammatory cytokine release. Etanercept, a TNF inhibitor, ameliorates TRAPS

attacks, but the long-term experience with this agent has been less

favorable. IL-1 inhibition has been beneficial in a large percentage

of the patients in whom it has been used, and canakinumab recently

Familial Mediterranean Fever and Other Hereditary Autoinflammatory Diseases

2843CHAPTER 369

received FDA approval for the treatment of TRAPS. Monoclonal

anti-TNF antibodies should be avoided, because they may exacerbate

TRAPS attacks.

■ HYPERIMMUNOGLOBULINEMIA D WITH

PERIODIC FEVER SYNDROME (ALSO KNOWN AS

MEVALONATE KINASE DEFICIENCY)

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)

is a recessively inherited recurrent fever syndrome found primarily in

individuals of northern European ancestry. It is caused by mutations in

mevalonate kinase (MVK), encoding an enzyme involved in the synthesis of cholesterol and nonsterol isoprenoids, including geranylgeranyl

pyrophosphate. The latter compound is essential for proper localization

of RhoA GTPase to the cell membrane, and the mislocalization of RhoA

leads to its inactivation and the consequent activation of the pyrin

inflammasome. HIDS attacks usually begin in infancy and last 3–5 days.

Clinically distinctive features include painful cervical adenopathy, a diffuse maculopapular rash sometimes affecting the palms and soles, and

aphthous ulcers; pleurisy is rare. Amyloidosis has been observed associated with the V377I/I268T MVK genotype. Although originally defined

by the persistent elevation of serum IgD, disease activity is not related to

IgD levels, and some patients with FMF or TRAPS may have modestly

increased serum IgD. Moreover, occasional patients with MVK mutations and recurrent fever have normal IgD levels, while all patients with

mutations have markedly elevated urinary mevalonate levels during

their attacks. For these reasons, some have proposed renaming this disorder mevalonate kinase deficiency (MKD). Canakinumab was recently

approved by the FDA for the treatment of HIDS/MKD.

■ NLRP3-ASSOCIATED AUTOINFLAMMATORY

DISEASE (ALSO KNOWN AS THE

CRYOPYRINOPATHIES OR CRYOPYRIN-ASSOCIATED

PERIODIC SYNDROMES)

Three hereditary febrile syndromes, familial cold autoinflammatory

syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatalonset multisystem inflammatory disease (NOMID), are all caused by

mutations in NLRP3 (formerly known as CIAS1), the gene encoding

cryopyrin (or NLRP3), and represent a clinical spectrum of disease.

FCAS patients develop chills, fever, headache, arthralgia, conjunctivitis,

and an urticaria-like rash in response to generalized cold exposure. In

MWS, an urticarial rash is noted, but it is not usually induced by cold;

MWS patients also develop fevers, abdominal pain, limb pain, arthritis,

conjunctivitis, and, over time, sensorineural hearing loss. NOMID is

the most severe of the three disorders, with chronic aseptic meningitis,

a characteristic arthropathy, and rash. Like the FMF protein pyrin,

cryopyrin has an N-terminal PYRIN domain, allowing the formation

of an NLRP3 inflammasome that mediates caspase-1 activation, IL-1β

and IL-18 release, and pyroptosis. Peripheral blood leukocytes from

patients with FCAS, MWS, and NOMID release increased amounts of

IL-1β upon in vitro stimulation, relative to healthy controls. Macrophages from cryopyrin-deficient mice exhibit decreased IL-1β production in response to certain gram-positive bacteria, bacterial RNA, and

monosodium urate crystals. Patients with all three cryopyrinopathies

or cryopyrin-associated periodic syndromes (CAPS) show a dramatic

response to injections of IL-1 inhibitors. Canakinumab and rilonacept

are approved by the FDA for the treatment of FCAS and MWS, whereas

anakinra is approved for the treatment of NOMID.

Approximately one-third of patients with clinical manifestations of

NOMID do not have germline mutations in NLRP3, but they have been

found to be mosaic for somatic NLRP3 mutations. Such patients also

respond dramatically to IL-1 inhibition. Somatic mosaicism in NLRP3

has been reported rarely in Schnitzler’s syndrome, which presents in

middle age with recurrent fever, urticarial rash, elevated acute-phase

reactants, monoclonal IgM gammopathy, and abnormal bone remodeling. IL-1 inhibition is the treatment of choice for Schnitzler’s syndrome.

■ PERIODIC FEVER WITH APHTHOUS STOMATITIS,

PHARYNGITIS, AND CERVICAL ADENITIS

Periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever syndrome in children,

notable for the almost clock-like regularity of episodes and the tendency for resolution of attacks by early adulthood. PFAPA tends to run

in families, but not in a Mendelian fashion. Recent studies indicate that

common shared variants in the IL12A, IL10, STAT4, and CCR1-CCR3

loci confer susceptibility for a spectrum of phenotypes ranging from

common aphthous ulcers to PFAPA to Behçet’s disease. Therapeutic

options for PFAPA include intermittent glucocorticoids; daily oral

colchicine, cimetidine, or apremilast; or tonsillectomy/adenoidectomy.

OTHER INHERITED AUTOINFLAMMATORY

DISEASES

There are a number of other Mendelian autoinflammatory diseases

in which recurrent fevers are not a prominent clinical sign but that

involve abnormalities of innate immunity. The syndrome of pyogenic arthritis with pyoderma gangrenosum and acne (PAPA) is a

dominantly inherited disorder that presents with episodes of sterile

pyogenic monoarthritis often induced by trauma, severe pyoderma

gangrenosum, and severe cystic acne usually beginning in puberty. It is

caused by mutations in PSTPIP1, which encodes a pyrin-binding protein, and the arthritic manifestations often respond to IL-1 inhibition.

Dominantly inherited gain-of-function mutations in NLRC4 lead to

increased IL-1 and IL-18 production and potentially life-threatening

recurrent macrophage activation syndrome.

Whereas the aforementioned disorders all involve mutations in

IL-1-related molecules, other autoinflammatory diseases are caused by

mutations in other components of innate immunity. Blau’s syndrome

is caused by mutations in CARD15 (also known as NOD2), which

regulates nuclear factor κB activation. Blau’s syndrome is characterized

by granulomatous dermatitis, uveitis, and arthritis; distinct CARD15

variants predispose to Crohn’s disease. Recessive mutations in one

or more components of the proteasome lead to excessive interferon

signaling and a severe form of generalized panniculitis. De novo

gain-of-function mutations in TMEM173, encoding the stimulator of

interferon genes (STING), cause severe vasculopathy and pulmonary

fibrosis. Recessive loss-of-function mutations in the gene encoding

adenosine deaminase 2 (ADA2) cause a vasculopathy that can manifest

as livedoid rash, early-onset lacunar strokes, or polyarteritis nodosa,

often responsive to TNF inhibition. Mutations in the gene encoding

the A20 ubiquitin-modifying enzyme cause a Behçet’s-like monogenic

illness (“HA20”), whereas mutations in a different deubiquitinase

(OTULIN) cause a form of panniculitis (“otulipenia”). Mutations at the

site where RIPK1 is inactivated by caspase-8 cause a condition manifesting recurrent fevers, painful lymphadenopathy, and organomegaly,

denoted CRIA (cleavage-resistant RIPK1-induced autoinflammatory)

syndrome, that may respond to IL-6 inhibition.

Finally, it should be noted that a number of common, genetically

complex disorders are now sometimes considered autoinflammatory,

because of evidence that components of the innate immune system,

such as the inflammasome, may play a role in the pathogenesis. Two

prominent examples are gout and atherosclerosis. Myeloid-restricted

somatic mutations in an essential ubiquitylation enzyme have recently

been implicated in a severe adult-onset autoinflammatory disease

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

somatic) syndrome, which can present as relapsing polychondritis,

vasculitis, or myelodysplastic syndrome.

■ GLOBAL CONSIDERATIONS

All the disorders discussed in this chapter have been observed in multiple populations. However, as noted herein, FMF is most frequently

observed in Mediterranean and Middle Eastern populations and HIDS

in northern European populations, particularly the Dutch. A recessive

founder mutation in ADA2 is particularly common in the Georgian

Jewish population and is associated with polyarteritis nodosa.

■ FURTHER READING

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

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

De Benedetti F et al: Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 378:1908, 2018.