Acute Rheumatic Fever

2769CHAPTER 359

value in the treatment of carditis or chorea. Aspirin is a common

first-line choice, delivered at a dose of 50–60 mg/kg per day, up to

a maximum of 80–100 mg/kg per day (4–8 g/d in adults) in 4–5

divided doses. At higher doses, the patient should be monitored

for symptoms of salicylate toxicity such as nausea, vomiting, or

tinnitus; if symptoms appear, lower doses should be used. When

the acute symptoms are substantially resolved, usually within the

first 2 weeks, patients on higher doses can have the dose reduced to

50–60 mg/kg per day for a further 2–4 weeks. Fever, joint manifestations, and elevated acute-phase reactants sometimes recur up to

3 weeks after the medication is discontinued. This does not indicate

a recurrence and can be managed by recommencing salicylates for

a brief period. Many clinicians prefer to use naproxen at a dose of

10–20 mg/kg per day, because it may be safer than aspirin and has

the advantage of twice-daily dosing.

CONGESTIVE HEART FAILURE

Glucocorticoids The use of glucocorticoids in ARF remains controversial. Two meta-analyses have failed to demonstrate a benefit

of glucocorticoids compared to placebo or salicylates in improving

the short- or longer-term outcome of carditis. However, the studies

included in these meta-analyses all took place >40 years ago and did

not use medications in common usage today. Many clinicians treat

cases of severe carditis (causing heart failure) with glucocorticoids

TABLE 359-2 Jones Criteria

A. For All Patient Populations with Evidence of Preceding Group A

Streptococcal Infection

Diagnosis: initial ARF 2 major manifestations or 1 major plus

2 minor manifestations

Diagnosis: recurrent ARF 2 major or 1 major and 2 minor or

3 minor

B. Major Criteria

Low-risk populationsa Moderate- and high-risk populations

Carditisb Carditis

• Clinical and/or subclinical • Clinical and/or subclinical

Arthritis Arthritis

• Polyarthritis only • Monoarthritis or polyarthritis

• Polyarthralgiac

Chorea Chorea

Erythema marginatum Erythema marginatum

SC nodules SC nodules

C. Minor Criteria

Low-risk populationsa Moderate- and high-risk populations

Polyarthralgia Monoarthralgia

Fever (≥38.5°C) Fever (≥38°C)

 ESR ≥60 mm in the first hour and/or

CRP ≥3.0 mg/dLd

 ESR ≥30 mm/h and/or CRP ≥3.0 mg/

dLd

 Prolonged PR intervale

, after

accounting for age variability (unless

carditis is a major criterion)

 Prolonged PR intervale

, after

accounting for age variability (unless

carditis is a major criterion)

a

Low-risk populations are those with ARF incidence ≤2 per 100,000 school-age

children or all-age rheumatic heart disease prevalence of ≤1 per 1000 population

per year. b

Subclinical carditis indicates echocardiographic valvulitis. (See source

document.) c

Polyarthralgia should only be considered as a major manifestation

in moderate- to high-risk populations after exclusion of other causes. As in past

versions of the criteria, erythema marginatum and SC nodules are rarely “standalone” major criteria. Additionally, joint manifestations can only be considered in

either the major or minor categories but not both in the same patient. (See source

document for more information.) d

CRP value must be greater than upper limit of

normal for laboratory. Also, because ESR may evolve during the course of ARF, peak

ESR values should be used. e

Prolonged PR interval can only be considered in the

absence of carditis as a major criterion.

Abbreviations: ARF, acute rheumatic fever; CRP, C-reactive protein; ESR, erythrocyte

sedimentation rate.

Source: Reproduced with permission from MH Gewitz et al: Revision of the Jones criteria

for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: A

scientific statement from the American Heart Association. Circulation 131(20):1806, 2015.

https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000205.

TABLE 359-3 Testing and Monitoring of ARF in the Acute Setting

Investigations

Always request:

• Electrocardiogram (ECG)

• Echocardiogram

• Complete blood count (CBC)

• C-reactive protein (CRP)

• Streptococcal serology (antistreptolysin and anti-DNase B)

In relevant situations:

• Throat swab

• Skin sore swab

• Blood cultures

• Synovial fluid aspirate

• Ensure sample does not clot by using correct tubes that have been well

mixed and transported promptly to the laboratory

• Include request for cell count, microscopy, culture, and gonococcal

polymerase chain reaction (PCR)

• Pregnancy test

• Creatinine test (UEC [urea, electrolytes, creatinine]) since nonsteroidal

anti-inflammatory drugs can affect renal function

Tests to exclude alternative diagnoses, depending on clinical presentation and

locally endemic infections:

• Autoantibodies, double-stranded DNA, anti–cyclic citrullinated peptide

(anti-CCP) antibodies

• Urine for Neisseria gonorrhoeae molecular test

• Urine for Chlamydia trachomatis molecular test

• Serologic or other testing for viral hepatitis, Yersinia spp., cytomegalovirus

(CMV), parvovirus B19, respiratory viruses, Ross River virus, Barmah

Forest virus

Source: Reproduced with permission from RDHAustralia, Menzies School of Health

Research. RHDAustralia (ARF/RHD writing group). The 2020 Australian guideline

for prevention, diagnosis and management of acute rheumatic fever and rheumatic

heart disease (3rd edition); 2020. Available at https://www.rhdaustralia.org.au/

arf-rhd-guideline.

in the belief that they may reduce the acute inflammation and result

in more rapid resolution of failure. However, the potential benefits

of this treatment should be balanced against the possible adverse

effects. If used, prednisone or prednisolone is recommended at a

dose of 1–2 mg/kg per day (maximum, 80 mg), usually for a few

days or up to a maximum of 3 weeks.

MANAGEMENT OF HEART FAILURE

See Chap. 258.

BED REST

Traditional recommendations for long-term bed rest, once the cornerstone of management, are no longer widely practiced. Instead,

bed rest should be prescribed as needed while arthritis and arthralgia are present and for patients with heart failure. Once symptoms

are well controlled, gradual mobilization can commence as tolerated.

CHOREA

Medications to control the abnormal movements do not alter the

duration or outcome of chorea. Milder cases can usually be managed by providing a calm environment. In patients with severe chorea, carbamazepine or sodium valproate is preferred to haloperidol.

A response may not be seen for 1–2 weeks, and medication should

be continued for 1–2 weeks after symptoms subside. There is recent

evidence that corticosteroids are effective and lead to more rapid

symptom reduction in chorea. They should be considered in severe

or refractory cases. Prednisone or prednisolone may be commenced

at 0.5 mg/kg daily, with weaning as early as possible, preferably

after 1 week if symptoms are reduced, although slower weaning or

temporary dose escalation may be required if symptoms worsen.

INTRAVENOUS IMMUNOGLOBULIN (IVIG)

Small studies have suggested that IVIg may lead to more rapid

resolution of chorea but have shown no benefit on the short- or

2770 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

long-term outcome of carditisinARFwithout chorea.In the absence

of better data, IVIg is not recommended except in cases of severe

chorea refractory to other treatments.

PROGNOSIS

Untreated, ARF lasts on average 12 weeks. With treatment, patients

are usually discharged from hospital within 1–2 weeks. Inflammatory

markers should be monitored every 1–2 weeks until they have normalized (usually within 4–6 weeks), and an echocardiogram should be

performed after 1 month to determine if there has been progression of

carditis. Cases with more severe carditis need close clinical and echocardiographic monitoring in the longer term.

Once the acute episode has resolved, the priority in management is

to ensure long-term clinical follow-up and adherence to a regimen of

secondary prophylaxis. Patients should be entered onto the local ARF

registry (if present) and contact made with primary care practitioners

to ensure a plan for follow-up and administration of secondary prophylaxis before the patient is discharged. Patients and their families should

also be educated about their disease, emphasizing the importance of

adherence to secondary prophylaxis.

PREVENTION

■ PRIMARY PREVENTION

Ideally, primary prevention would entail elimination of the major risk

factors for streptococcal infection, particularly overcrowded housing.

This is difficult to achieve in most places where ARF is common.

Concerted international efforts are underway to develop a vaccine

against group A Streptococcus that would prevent infection of the throat

or skin and consequently prevent ARF in the absence of a suitable vaccine; however, the mainstay of primary prevention for ARF remains

primary prophylaxis (i.e., the timely and complete treatment of group

A streptococcal sore throat with antibiotics). If commenced within

9 days of sore throat onset, a course of penicillin (as outlined above for

treatment of ARF) will prevent almost all cases of ARF that would otherwise have developed. In settings where ARF and RHD are common

but microbiologic diagnosis of group A streptococcal pharyngitis is not

available, such as in resource-poor countries, primary care guidelines

often recommend that all patients with sore throat be treated with

penicillin or, alternatively, that a clinical algorithm be used to identify

patients with a higher likelihood of group A streptococcal pharyngitis.

Although imperfect, such approaches recognize the importance of ARF

prevention at the expense of overtreating many cases of sore throat that

are not caused by group A Streptococcus. Although there is no proof

that antibiotic treatment of group A streptococcal skin infections can

prevent ARF, the increasing evidence that impetigo is strongly associated with ARF in some populations argues for a focus on treatment

and prevention of group A streptococcal skin infections as part of a

comprehensive ARF control strategy in regions with endemic impetigo.

■ SECONDARY PREVENTION

The mainstay of controlling ARF and RHD is secondary prevention.

Because patients with ARF are at dramatically higher risk than the general population of developing a further episode of ARF after a group

A streptococcal infection, they should receive long-term penicillin

prophylaxis to prevent recurrences. The best antibiotic for secondary

prophylaxis is benzathine penicillin G (1.2 million units, or 600,000

units if ≤27 kg) delivered every 4 weeks. It can be given every 3 weeks,

or even every 2 weeks, to persons considered to be at particularly

high risk, although in settings where good compliance with an every4-week dosing schedule can be achieved, more frequent dosing is rarely

needed. Oral penicillin V (250 mg) can be given twice daily instead but

is less effective than benzathine penicillin G. Penicillin-allergic patients

can receive erythromycin (250 mg) twice daily.

The duration of secondary prophylaxis is determined by

many factors, in particular the duration since the last episode of

ARF (recurrences become less likely with increasing time), age (recurrences are less likely with increasing age), and the severity of RHD (if

severe, it may be prudent to avoid even a very small risk of recurrence

because of the potentially serious consequences) (Table 359-4). Secondary prophylaxis is best delivered as part of a coordinated RHD control program, based around a registry of patients. Registries improve

the ability to follow patients and identify those who default from prophylaxis and to institute strategies to improve adherence.

■ FURTHER READING

Carapetis JR et al: Acute rheumatic fever and rheumatic heart disease.

Nat Rev Dis Primers 14:15084, 2016.

Gewitz MH et al: Revision of the Jones Criteria for the diagnosis of

acute rheumatic fever in the era of Doppler echocardiography: A scientific statement from the American Heart Association. Circulation

131:1806, 2015.

RHD Australia (ARF/RHD Writing Group): The 2020 Australian

guideline for prevention, diagnosis and management of acute rheumatic fever and rheumatic heart disease (3rd edition); 2020. Available

at https://www.rhdaustralia.org.au/arf-rhd-guideline.

Vekemans J et al: The path to group A Streptococcus vaccines: World

Health Organization research and development technology roadmap

and preferred product characteristics. Clin Infect Dis 69:5, 2019.

Zühlke L et al: Clinical outcomes in 3343 children and adults with

rheumatic heart disease from 14 low- and middle-income countries:

Two-year follow-up of the Global Rheumatic Heart Disease Registry

(the REMEDY Study). Circulation 134:1456, 2016.

TABLE 359-4 American Heart Association Recommendations for

Duration of Secondary Prophylaxisa

CATEGORY OF PATIENT DURATION OF PROPHYLAXIS

Rheumatic fever without carditis For 5 years after the last attack or

21 years of age (whichever is longer)

Rheumatic fever with carditis but no

residual valvular disease

For 10 years after the last attack, or

21 years of age (whichever is longer)

Rheumatic fever with persistent

valvular disease, evident clinically or

on echocardiography

For 10 years after the last attack, or

40 years of age (whichever is longer);

sometimes lifelong prophylaxis

a

These are only recommendations and must be modified by individual

circumstances as warranted. Note that some organizations recommend a minimum

of 10 years of prophylaxis after the most recent episode, or until 21 years of age

(whichever is longer), regardless of the presence of carditis with the initial episode.

Source: Reproduced with permission from MA Gerber et al: Prevention

of rheumatic fever and diagnosis and treatment of acute streptococcal

pharyngitis. Circulation 119:1541, 2009. https://www.ahajournals.org/doi/10.1161/

CIRCULATIONAHA.109.191959?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.

org&rfr_dat=cr_pub%20%200pubmed.

VIDEO 359-1B Transthoracic echocardiographic images of a 9-year-old girl

with first episode of acute rheumatic fever. Images demonstrate the typical

echocardiographic findings of acute rheumatic carditis. The valve leaflets are

relatively thin and highly mobile. The failure of coaptation of the mitral valve

leaflets is the result of chordal elongation and annular dilatation. The mitral valve

regurgitation is moderate with a typical posterolaterally directed regurgitant jet of

rheumatic carditis. B. Acute rheumatic carditis (apical four-chamber view color

Doppler echocardiogram).

VIDEO 359-1A Transthoracic echocardiographic images of a 9-year-old girl

with first episode of acute rheumatic fever. Images demonstrate the typical

echocardiographic findings of acute rheumatic carditis. The valve leaflets are

relatively thin and highly mobile. The failure of coaptation of the mitral valve

leaflets is the result of chordal elongation and annular dilatation. The mitral valve

regurgitation is moderate with a typical posterolaterally directed regurgitant jet

of rheumatic carditis. A. Acute rheumatic carditis (apical four-chamber view

echocardiogram).

VIDEO 359-1C Transthoracic echocardiographic images of a 9-year-old girl

with first episode of acute rheumatic fever. Images demonstrate the typical

echocardiographic findings of acute rheumatic carditis. The valve leaflets are

relatively thin and highly mobile. The failure of coaptation of the mitral valve

leaflets is the result of chordal elongation and annular dilatation. The mitral valve

regurgitation is moderate with a typical posterolaterally directed regurgitant jet

of rheumatic carditis. C. Acute rheumatic carditis (parasternal long-axis view

echocardiogram).

Systemic Sclerosis (Scleroderma) and Related Disorders

2771CHAPTER 360

VIDEO 359-1D Transthoracic echocardiographic images of a 9-year-old girl

with first episode of acute rheumatic fever. Images demonstrate the typical

echocardiographic findings of acute rheumatic carditis. The valve leaflets are

relatively thin and highly mobile. The failure of coaptation of the mitral valve

leaflets is the result of chordal elongation and annular dilatation. The mitral valve

regurgitation is moderate with a typical posterolaterally directed regurgitant jet of

rheumatic carditis. D. Acute rheumatic carditis (parasternal long-axis view color

Doppler echocardiogram).

VIDEO 359-2A Transthoracic echocardiographic images are from a 5-year-old boy

with chronic rheumatic heart disease with severe mitral valve regurgitation and

moderate mitral valve stenosis. Images demonstrate the typical echocardiographic

findings in advanced chronic rheumatic heart disease. Both the anterior and

posterior mitral valve leaflets are markedly thickened. During diastole, the motion

of the anterior mitral valve leaflet tip is restricted with doming of the body of the

leaflet toward the interventricular septum. This appearance is commonly described

as a “hockey stick” or an “elbow” deformity. A. Chronic rheumatic heart disease

(parasternal long-axis view).

VIDEO 359-2B Transthoracic echocardiographic images are from a 5-year-old boy

with chronic rheumatic heart disease with severe mitral valve regurgitation and

moderate mitral valve stenosis. Images demonstrate the typical echocardiographic

findings in advanced chronic rheumatic heart disease. Both the anterior and

posterior mitral valve leaflets are markedly thickened. During diastole, the motion of

the anterior mitral valve leaflet tip is restricted with doming of the body of the leaflet

toward the interventricular septum. This appearance is commonly described as a

“hockey stick” or an “elbow” deformity. B. Chronic rheumatic heart disease (apical

two-chamber view echocardiogram).

DEFINITION AND CLASSIFICATION

Systemic sclerosis (SSc) is an orphan disease of unknown etiology, complex pathogenesis, and variable clinical presentations. SSc frequently

follows a progressive course and is associated with significant disability

and mortality. Virtually every organ can be affected (Fig. 360-1).

There is marked variability among SSc patients in patterns of skin

involvement and organ complications, rates of disease progression,

response to treatment, disease severity, and survival. The early stages

of SSc are associated with prominent inflammatory features, but over

time, structural alterations in multiple vascular beds and visceral organ

dysfunction due to fibrosis and atrophy progressively dominate the

clinical picture. Recently developed classification criteria for the diagnosis of SSc (shown in Table 360-1) are >90% specific and selective.

Although thickened and indurated skin (scleroderma) is the distinguishing hallmark of SSc, similar skin changes can also be seen in localized forms of scleroderma, along with a variety of metabolic, inherited,

autoimmune, and iatrogenic conditions (Table 360-2). Patients with

SSc can be broadly segregated into two major subsets defined by the

pattern of skin involvement and associated with characteristic clinical

and serologic features and natural history (Table 360-3). Patients with

diffuse cutaneous SSc (dcSSc) have extensive skin induration, starting

in the fingers (sclerodactyly) and ascending from distal to proximal

limbs and the trunk. In these patients, progressive skin disease, interstitial lung disease (ILD), and less commonly acute renal involvement

may develop relatively early. In contrast, in patients with limited cutaneous SSc (lcSSc), Raynaud’s phenomenon generally precedes sclerodactyly and other disease manifestations, sometimes by years. In these

patients, skin involvement remains confined to the fingers, distal limbs,

and face, while the trunk is spared. A subset of patients with lcSSc

360 Systemic Sclerosis

(Scleroderma) and

Related Disorders

John Varga

display the characteristic constellation of clinical findings (calcinosis

cutis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly,

and telangiectasia), historically termed the CREST syndrome. In lcSSc,

visceral organ involvement tends to follow an insidious and often

benign course, while digital ischemic ulcers, pulmonary arterial hypertension (PAH), hypothyroidism, Sjogren’s symptoms, and primary

biliary cirrhosis may occur as late complications. In some patients,

Raynaud’s phenomenon and characteristic clinical and laboratory features of SSc occurs in the absence of detectable skin thickening. This

relatively benign disease subset has been termed SSc sine scleroderma.

INCIDENCE AND PREVALENCE

SSc is an acquired sporadic disease with a worldwide distribution and

affecting all races. In the United States, the incidence is 9–46 cases per

million per year. There are an estimated 100,000 U.S. cases, although

this number may be significantly higher if patients who do not fulfill

classification criteria are also included. There are large regional variations in incidence rates of SSc, potentially reflecting differences in case

definition, environmental exposures, or genetic susceptibility genes

in populations with different ancestries. Prevalence rates in England,

northern Europe, and Japan appear to be lower than in North America

and Australia. Age, sex, and ethnicity influence disease susceptibility,

and blacks have higher age-specific incidence rates and mortality. In

common with other connective tissue diseases, SSc shows a strong

female predominance (4.6:1), which is most pronounced in the

childbearing years and declines after menopause. An additional risk

factor for SSc is having an affected first-degree family member, which

increases disease risk 13-fold. Although SSc can present at any age, the

peak age of onset in women with both limited and diffuse cutaneous

forms is 65–74 years, although in blacks, disease onset occurs at an

earlier age. Furthermore, blacks with SSc are more likely to have diffuse

cutaneous disease, ILD, and a worse prognosis.

GENETIC CONTRIBUTION TO DISEASE

PATHOGENESIS

In general, the genetic associations of SSc identified to date make

only a relatively modest contribution to disease susceptibility.

Twin studies showed low disease concordance rates (4.7%) in

monozygotic twins, a rate much lower than in other autoimmune diseases such as rheumatoid arthritis (12.3%). On the other hand, supporting the genetic contribution to disease susceptibility is the

observation that 1.6% of SSc patients have a first-degree relative with

SSc, a prevalence rate that is markedly increased compared to the general population. Moreover, the risk of Raynaud’s phenomenon, ILD,

and other autoimmune diseases, including systemic lupus erythematosus (SLE) (Chap. 356), rheumatoid arthritis (Chap. 358), and autoimmune thyroiditis (Chap. 383), is also increased in first-degree relatives

of patients with SSc. Current approaches to uncover the genetic factors

that contribute to SSc include DNA sequencing and single nucleotide

polymorphism (SNP) analysis of candidate genes and SNP analysis of

the entire genome in a hypothesis-free manner. Genome-wide association studies (GWAS) involve large multicenter and multinational

cohorts. A majority of the robustly validated genetic susceptibility loci

for SSc are genes at the highly polymorphic human leukocyte antigen

(HLA) region and other genes involved in innate and adaptive immunity and interferon responses, highlighting the importance of autoimmunity as the initial trigger for the disease. Genetic studies have shown

associations with common (small effect size) variants related to B and

T lymphocyte activation (BANK1, BLK, CD247, STAT4, IL2RA, CCR6,

IDO1, TNFSF4/OX40L, PTPN22, and TNIP1). In addition, candidate

gene studies and GWAS identified a strong and consistent association

with HLA class II haplotypes on chromosome 6, including HLADRB1*

11:04, DQA1*

05:01, and DQB1*

03:01, and the non-HLA histocompatibility complex (MHC) genes NOTCH4 and PSORSC1. Other

genetic variants associated with SSc are involved in innate immunity

and type 1 interferon signaling (IRF5, IRF7, STAT4, TNFAIP3, and

TLR2). Additional associations with IL12RB2, IL-21, the autophagy

and apoptosis-related genes DNASE1L3 and SOX5, and the

2772 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

Pulmonary:

Interstitial lung disease

Pulmonary artery

hypertension

Cardiac:

Pericarditis

Diastolic dysfunction

Cardiomyopathy

Arrhythmia

Skin:

Induration

Calcinosis cutis

Telangiectasia

Hyperpigmentation

Xerosis

Muscloskeletal:

Joint contractures

Tendon friction rubs

Myositis

Upper GI:

GERD

GAVE

Barrett’s

Gastroparesis

Oral:

Xerostomia

Reduced aperture

Mucocutaneous

telangiectasia

Lower GI:

Hypomotility

Bacterial overgrowth

Pseudo-obstruction

Vasular:

Raynaud’s

Digital ischemic ulcers

Renal:

Scleroderma

renal crisis

FIGURE 360-1 Multiorgan involvement in systemic sclerosis (SSc). Prominent complications of SSc: red, those more common in diffuse cutaneous SSc; black, those

more common in limited cutaneous SSc; blue, complications common in both SSc subsets. GAVE, gastric antral vascular ectasia; GERD, gastroesophageal reflux disease;

GI, gastrointestinal.

TABLE 360-1 Classification Criteria for Diagnosis of Systemic Sclerosis

ITEM SUBITEM WEIGHT/SCORE

Skin thickening

(bilateral); fingers

extending proximal to

MCP joints

9

Skin thickening of

fingers only

Puffy fingers

Sclerodactyly (skin

thickened distal to MCP

joints)

2

4

Fingertip lesions Digital tip ulcer

Fingertip pitting scars

2

3

Mucocutaneous

telangiectasia

2

Abnormal nailfold

capillary pattern

2

Lung involvement PAH

Interstitial lung disease

2

2

Raynaud’s phenomenon 3

SSc-specific

autoantibodies

ACA

Scl-70

RNA polymerase III

3

Abbreviations: ACA, anticentromere antibodies; MCP, metacarpophalangeal joint;

PAH, pulmonary arterial hypertension.

TABLE 360-2 Conditions Associated with Skin Induration

Systemic sclerosis (SSc)

Limited cutaneous SSc

Diffuse cutaneous SSc

Localized scleroderma

Guttate (plaque) morphea, diffuse (pansclerotic) morphea, bullous morphea

Linear scleroderma, coup de sabre, hemifacial atrophy

Pansclerotic morphea

Overlap syndromes

Mixed connective tissue disease

SSc/polymyositis

Diabetic scleredema and scleredema of Buschke

Scleromyxedema (papular mucinosis)

Chronic graft-versus-host disease

Diffuse fasciitis with eosinophilia (Shulman’s disease, eosinophilic fasciitis)

Stiff skin syndrome

Pachydermoperiostosis (primary hypertrophic osteoarthropathy)

Chemically induced and drug-associated scleroderma-like conditions

Vinyl chloride–induced disease

 Eosinophilia-myalgia syndrome (associated with L-tryptophan contaminant

exposure)

Nephrogenic systemic fibrosis (associated with gadolinium exposure)

Paraneoplastic syndrome

Systemic Sclerosis (Scleroderma) and Related Disorders

2773CHAPTER 360

TABLE 360-3 Subsets of Systemic Sclerosis (SSc): Features of Limited

Cutaneous Versus Diffuse Cutaneous Disease

CHARACTERISTIC

FEATURE

LIMITED CUTANEOUS

SSc

DIFFUSE CUTANEOUS

SSc

Skin involvement Indolent onset. Limited to

fingers, distal to elbows,

face; slow progression

Rapid onset. Diffuse:

fingers, extremities, face,

trunk; rapid progression

Raynaud’s phenomenon Antedates skin

involvement, sometimes

by years; may be

associated with critical

ischemia in the digits

Onset coincident with

skin involvement; critical

ischemia less common

Musculoskeletal Mild arthralgia Severe arthralgia, carpal

tunnel syndrome, tendon

friction rubs

Interstitial lung disease Slowly progressive,

generally mild

Frequent, early onset

and progression, can be

severe

Pulmonary arterial

hypertension

Frequent, late, may

occur as an isolated

complication

Often occurs in

association with

interstitial lung disease

Scleroderma renal crisis Very rare Occurs in 15%; generally

early (<4 years from

disease onset)

Calcinosis cutis Frequent, prominent Less common, mild

Characteristic

autoantibodies

Anti-centromere Anti–topoisomerase I

(Scl-70), anti-RNA

polymerase III

extracellular matrix–related genes CSK, CAV1, PPARG, and GRB10

have been reported. In addition to SSc susceptibility, some of these

genetic loci are associated with particular disease manifestations or

serologic subsets, including ILD (CTGF, CD226), PAH (TNIP1), scleroderma renal crisis (HLA-DRB1*

), and anticentromere antibodies

(HLA-DPB1*

05:01). While the functional consequences of these gene

variants and their potential roles in pathogenesis are not well understood, it seems likely that in combination they cause a state of altered

immune regulation, leading to increased susceptibility to autoimmunity and persistent inflammation. Of note, several of the SSc genetic

variants are also implicated in other autoimmune disorders, including

SLE, Sjögren’s syndrome, rheumatoid arthritis, multiple sclerosis, and

psoriasis, suggesting common pathogenic pathways shared among

these phenotypically dissimilar conditions. Notably, the genetic associations identified to date only explain a fraction of the heritability of SSc

and focus on common variants. By contrast, next-generation sequencing, such as whole exome sequencing, may help identify additional

genetic susceptibility factors in SSc, particularly rare (and potentially

causal) coding variants and their association with specific

phenotypes.

ENVIRONMENTAL AND OCCUPATIONAL

EXPOSURES

The etiology of SSc is unknown. Given the relatively modest genetic

contribution to susceptibility in SSc, environmental factors, such as

infectious agents, microbiome, and occupational, dietary, lifestyle, and

drug exposures, are likely to play a major role. Evidence suggests potential pathogenic roles for viruses, including parvovirus B19, EpsteinBarr virus (EBV), and cytomegalovirus (CMV), and Rhodotorula

glutinis. Toxic oil syndrome, a novel disease with features suggestive

of SSc, occurred as an epidemic outbreak in Spain in the 1980s and

was linked to contaminated rapeseed oil used for cooking. Another

epidemic outbreak, termed eosinophilia-myalgia syndrome (EMS),

occurred in the United States in the 1990s and was linked to consumption of L-tryptophan-containing dietary supplements. Exposure to

gadolinium contrast material in individuals with compromised renal

function undergoing magnetic resonance scanning has been associated

with nephrogenic systemic fibrosis. While each of these novel toxic-epidemic syndromes was characterized by chronic indurative skin changes

and variable visceral organ involvement, the constellation of associated

clinical, pathologic, and laboratory features distinguishes them from

SSc. Occupational exposures tentatively linked with SSc include particulate silica (quartz), polyvinyl chloride, epoxy resins, welding fumes,

and organic solvents and aromatic hydrocarbons including paint thinners, toluene, xylene, and trichloroethylene. These exposures can elicit

cell type–specific stable and heritable epigenetic modifications such as

DNA methylation and histone modification that could drive pathogenic alterations in cellular gene expression. Several of these epigenetic

modifications are reversible and represent potential targets for therapy.

Drugs implicated in SSc-like illnesses include bleomycin, pentazocine,

cocaine, and appetite suppressants linked with PAH. Most recently,

immune checkpoint inhibitors such as PD-1 blockers used in cancer

therapy have been implicated as triggers for SSc-like illnesses. Radiation therapy for cancer has been linked with de novo onset of SSc as

well as with exacerbation of preexisting SSc. In contrast to rheumatoid

arthritis, cigarette smoking does not increase the risk of SSc. Although

case reports and series describing the occurrence of SSc in women with

silicone breast implants had raised concern regarding a putative pathogenic role of silicone in SSc, large-scale epidemiologic investigations

found no evidence of increased prevalence of SSc.

PATHOGENESIS

The pathogenesis of SSc involves putative environmental insults that

trigger epigenetic modifications in a genetically predisposed host,

causing alterations in gene expression underlying durable changes in

the behavior of multiple cell types (Fig. 360-2).

Three cardinal pathomechanistic processes underlie the protean

clinical manifestations and pathologic changes of SSc: (1) diffuse

microangiopathy, (2) inflammation and autoimmunity, and (3) visceral

and vascular fibrosis affecting multiple organs (Fig. 360-3). While each

of these distinct processes may be synchronously active in a given SSc

patient, their relative severity, progression, and contribution to the

overall clinical picture vary among individual patients and over time.

In general, autoimmunity and reversible vascular reactivity are early

features of SSc, whereas fibrosis and atrophy occur later in the disease.

Drugs

Silica

Solvents

Viral Agents

Environmental

factors

HLA genes

Non-HLA genes

Genetic

susceptibility

DNA methylation

Histone modifications

Noncoding RNA

Epigenetic

dysregulation

Systemic sclerosis

FIGURE 360-2 The interplay of genetic risk factors and environmental exposure–

induced epigenetic modifications underlying the complex pathogenesis of systemic

sclerosis. HLA, human leukocyte antigen. (Reproduced with permission from Amr

Sawalha and Pei-Suen Tsou, University of Pittsburgh and University of Michigan.)