2762 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

TABLE 358-2 DMARDs Used for the Treatment of Rheumatoid Arthritis

DRUG DOSAGE SERIOUS TOXICITIES

OTHER COMMON

SIDE EFFECTS

INITIAL

EVALUATION MONITORING

Hydroxychloroquine 200–400 mg/d orally (≤5 mg/kg) Irreversible retinal damage

Cardiotoxicity

Blood dyscrasia

Nausea

Diarrhea

Headache

Rash

Eye examination

if >40 years old

or prior ocular

disease

Optical coherence

tomography and visual

field testing every

12 months

Sulfasalazine Initial: 500 mg orally twice daily

Maintenance: 1000–1500 mg

twice daily

Granulocytopenia

Hemolytic anemia (with G6PD

deficiency)

Nausea

Diarrhea

Headache

CBC, LFTs

G6PD level

CBC every 2–4 weeks for

first 3 months, then every

3 months

Methotrexate 10–25 mg/week orally or SQ

Folic acid 1 mg/d to reduce toxicities

Hepatotoxicity

Myelosuppression

Infection

Interstitial pneumonitis

Pregnancy category X

Nausea

Diarrhea

Stomatitis/mouth

ulcers

Alopecia

Fatigue

CBC, LFTs

Viral hepatitis

panela

Chest x-ray

CBC, creatinine,

LFTs every 2–3 months

Leflunomide 10–20 mg/d Hepatotoxicity

Myelosuppression

Infection

Pregnancy category X

Alopecia

Diarrhea

CBC, LFTs

Viral hepatitis

panela

CBC, creatinine, LFTs

every 2–3 months

TNF-α inhibitors Infliximab: 3 mg/kg IV at weeks 0, 2,

6, then every 8 weeks. May increase

dose up to 10 mg/kg every 4 weeks

↑ Risk bacterial, fungal

infections

Reactivation of latent TB

↑ Lymphoma risk

(controversial)

Drug-induced lupus

Neurologic deficits

Infusion reaction

↑ LFTs

Tuberculosis

screeningb

LFTs periodically

Etanercept: 50 mg SQ weekly, or 25 mg

SQ biweekly

As above Injection site reaction Tuberculosis

screening

Monitor for injection site

reactions

Adalimumab: 40 mg SQ every other

week

As above Injection site reaction Tuberculosis

screening

Monitor for injection site

reactions

Golimumab: 50 mg SQ monthly As above Injection site reaction Tuberculosis

screening

Monitor for injection site

reactions

Certolizumab: 400 mg SQ weeks 0, 2, 4,

then 200 mg every other week

As above Injection site reaction Tuberculosis

screening

Monitor for injection site

reactions

Abatacept Weight based:

<60 kg: 500 mg

60–100 kg: 750 mg

>100 kg: 1000 mg

IV dose at weeks 0, 2, and 4, and then

every 4 weeks

OR

125 mg SQ weekly

↑ Risk bacterial, viral

infections

Headache

Nausea

Tuberculosis

screening

Monitor for infusion

reactions

Anakinra 100 mg SQ daily ↑ Risk bacterial, viral

infections

Reactivation of latent TB

Neutropenia

Injection site reaction

Headache

Tuberculosis

screening

CBC with

differential

CBC every month for

3 months, then every

4 months for 1 year

Monitor for injection site

reactions

Rituximab 1000 mg IV × 2, days 0 and 14

May repeat course every 24 weeks

or more

Premedicate with methylprednisolone 100 mg to decrease

infusion reaction

↑ Risk bacterial, viral

infections

Infusion reaction

Cytopenia

Hepatitis B reactivation

Rash

Fever

CBC

Viral hepatitis

panela

CBC at regular intervals

Interleukin-6

inhibitors

Tocilizumab:

4–8 mg/kg IV monthly

OR

162 mg SQ every other week (<100 kg

weight)

162 mg SQ every week (≥100 kg

weight)

Sarilumab:

200 mg SQ every other week

Risk of infection

Infusion reaction

LFT elevation

Dyslipidemia

Cytopenias

Tuberculosis

screening

CBC and LFTs at regular

intervals

(Continued)

Rheumatoid Arthritis

2763CHAPTER 358

maximal benefit in many cases, is often the next step for treatment

of patients with an inadequate response to methotrexate therapy.

Etanercept, adalimumab, certolizumab pegol, and golimumab have

also been approved for use as monotherapy.

Anti-TNF agents should be avoided in patients with active infection or a history of hypersensitivity to these agents and are contraindicated in patients with chronic hepatitis B infection or class III/IV

congestive heart failure. The major concern is the increased risk for

infection, including serious bacterial infections, opportunistic fungal infection, and reactivation of latent tuberculosis. For this reason,

all patients are screened for latent tuberculosis according to national

guidelines prior to starting anti-TNF therapy (Chap. 178). In the

United States, patients have historically been skin tested for tuberculosis using an intradermal injection of purified protein derivative

(PPD); individuals with skin reactions of >5 mm are presumed to

have had previous exposure to tuberculosis and are evaluated for

active disease and treated accordingly. Use of an IFN-γ release assay

may also be appropriate for screening as some data suggest a lower

rate of false-negative and false-positive tests with an IFN-γ release

assay compared with skin testing with PPD in patients treated with

corticosteroids. While a combination of PPD skin test and IFN-γ

release assay may offer the highest sensitivity for screening purposes, no consensus guidelines exist.

Anakinra Anakinra is the recombinant form of the naturally

occurring IL-1 receptor antagonist. Although anakinra has seen

limited use for the treatment of RA, it has enjoyed a resurgence of

late as an effective therapy of systemic juvenile-onset inflammatory

arthritis and adult Still’s disease and some rare inherited syndromes

dependent on IL-1 production, including neonatal-onset inflammatory disease, Muckle-Wells syndrome, familial cold urticaria, and

macrophage activation syndrome.

Abatacept Abatacept is a soluble fusion protein consisting of the

extracellular domain of human CTLA-4 linked to the modified

portion of human IgG. It inhibits the co-stimulation of T cells by

blocking CD28-CD80/86 interactions and may also inhibit the

function of antigen-presenting cells by reverse signaling through

CD80 and CD86. Abatacept has been shown in clinical trials to

reduce disease activity, slow radiographic progression of damage,

and improve functional disability. Many patients receive abatacept

in combination with a conventional DMARD. Abatacept therapy

has been associated with an increased risk of infection.

Rituximab Rituximab is a chimeric monoclonal antibody directed

against CD20, a cell-surface molecule expressed by most mature B

lymphocytes. It works by depleting B cells, which in turn, leads to a

reduction in the inflammatory response by unknown mechanisms.

These mechanisms may include a reduction in autoantibodies, inhibition of T-cell activation, and alteration of cytokine production.

Rituximab has been approved for the treatment of refractory RA

(failure of treatment with a TNF-α inhibitor) in combination with

methotrexate and has been shown to be more effective for patients

with seropositive than seronegative disease. Rituximab therapy has

been associated with mild to moderate infusion reactions as well as

an increased risk of infection. Notably, there have been rare isolated

reports of a potentially lethal brain disorder, progressive multifocal

leukoencephalopathy (PML), in association with rituximab therapy,

although the absolute risk of this complication appears to be very

low in patients with RA. Most of these cases have occurred on a

background of previous or current exposure to other potent immunosuppressive drugs.

Anti-IL-6 Agents IL-6 is a proinflammatory cytokine implicated

in the pathogenesis of RA, with effects on both joint inflammation

and damage. IL-6 binding to its receptor activates intracellular

signaling pathways that affect the acute-phase response, cytokine

production, and osteoclast activation. Tocilizumab and sarilumab

are both monoclonal antibodies directed against the membrane

and soluble forms of the IL-6 receptor. Clinical trials attest to the

clinical efficacy of these therapies for RA, both as monotherapy and

in combination with methotrexate and other DMARDs. Anti-IL-6

receptor agents have been associated with an increased risk of

infection, neutropenia, and thrombocytopenia; the hematologic

abnormalities appear to be reversible upon stopping the drug. In

addition, this agent has been shown to increase LDL cholesterol.

However, it is not known if this effect on lipid levels increases the

risk for development of atherosclerotic disease.

TARGETED SYNTHETIC DMARDs

Because some patients do not adequately respond to conventional

DMARDs or biologic therapy, other therapeutic targets have been

investigated to fill this gap. Recently, drug development in RA

has focused attention on the intracellular signaling pathways that

transduce the positive signals of cytokines and other inflammatory

mediators binding to their cell-surface receptors that create the

positive feedback loops in the immune response. These targeted

synthetic DMARDs aim to provide the same efficacy as biological

therapies in an oral formulation.

JAK Inhibitors Although several different kinases have been

evaluated as potential treatment targets in RA, only JAK inhibitors

have demonstrated safety and efficacy for the treatment of RA; they

are classified as targeted synthetic (ts) DMARDS. The JAK family

comprises four members (JAK1, JAK2, JAK3, and tyrosine kinase 2

[Tyk2]) that link extracellular cytokine receptors with intracellular

signaling domains. They mediate signaling of the receptors for the

common γ-chain-related cytokines IL-2, -4, -7, -9, -15, and -21, as

well as IFN-γ and IL-6. These cytokines all play roles in promoting

T- and B-cell activation as well as inflammation.

Tofacitinib is a selective JAK1 and JAK3 inhibitor with minor

inhibitory effects on JAK2 and Tyk2, whereas baricitinib is a selective JAK1 and JAK2 inhibitor with moderate inhibition of Tyk2

and minimal inhibition of JAK3. Upadacitinib is a predominately

TABLE 358-2 DMARDs Used for the Treatment of Rheumatoid Arthritis

DRUG DOSAGE SERIOUS TOXICITIES

OTHER COMMON

SIDE EFFECTS

INITIAL

EVALUATION MONITORING

JAK inhibitors Tofacitinib:

5 mg orally twice daily

OR

11 mg orally daily

Upadacitinib:

15 mg orally daily

Baricitinib:

2 mg orally daily

Risk of infection

LFT elevation

Dyslipidemia

Neutropenia

Thrombosis

Upper respiratory tract

infections

Diarrhea

Headache

Nasopharyngitis

Tuberculosis

screening

CBC, LFTs, and lipids at

regular intervals

a

Viral hepatitis panel: hepatitis B surface antigen, hepatitis C viral antibody. b

Tuberculosis screening can be performed using a Mantoux tuberculin skin test or blood

interferon-gamma release assay.

Abbreviations: CBC, complete blood count; DMARDs, disease-modifying antirheumatic drugs; G6PD, glucose-6-phosphate dehydrogenase; IV, intravenous; LFTs, liver

function tests; JAK, Janus kinase; SQ, subcutaneous; TB, tuberculosis.

 (Continued)

2764 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

TABLE 358-3 ACR/EULAR Provisional Definition of Remission in

Rheumatoid Arthritis

At any time point, patient must satisfy all of the following:

Tender joint count ≤1

Swollen joint count ≤1

C-reactive protein ≤1 mg/dL

Patient global assessment ≤1 (on a 0–10 scale)

OR

At any time point, patient must have a Simplified Disease Activity Index

score of ≤3.3

Abbreviations: ACR, American College of Rheumatology; EULAR, European League

Against Rheumatism.

Source: Reproduced with permission from DT Felson et al; American College of

Rheumatology/European League Against Rheumatism provisional definition of

remission in rheumatoid arthritis for clinical trials. Arthritis Rheum 63:573, 2011.

selective inhibitor of JAK1. It has been hypothesized that preferential inhibition of JAK1 might reduce dose-related toxicity, without

a significant detriment of its efficacy. JAK inhibitors can be used

as monotherapy or in combination with methotrexate. Possible

side effects of these agents include elevated serum transaminases

indicative of liver injury, neutropenia, increased cholesterol levels,

and elevation in serum creatinine. Recent studies have found an

increased risk of thrombosis, major adverse cardiovascular events

and malignancies in patients taking tofacitinib compared with TNF

inhibitors. Its use is also associated with an increased risk of infections, including bacterial infections and herpes zoster.

TREATMENT OF EXTRAARTICULAR MANIFESTATIONS

In general, treatment of the underlying RA favorably modifies

extraarticular manifestations, and it appears that aggressive management of early disease can potentially prevent their occurrence in

the first place. RA-ILD, however, can be particularly challenging to

treat because some of the DMARDs used for the treatment of RA

are associated with pulmonary toxicity, such as methotrexate and

leflunomide. High doses of corticosteroids and adjunctive immunosuppressive agents, such as azathioprine, mycophenolate mofetil,

and rituximab have been used for treatment of RA-ILD.

APPROACH TO THE PATIENT

Rheumatoid Arthritis

The treatment of RA adheres to the following principles and goals:

(1) early, aggressive therapy to prevent joint damage and disability;

(2) frequent modification of DMARD therapy to achieve treatment

goals with utilization of combination therapy where appropriate; (3)

individualization of DMARD therapy in an attempt to maximize

response and minimize side effects; (4) minimal use of long-term

glucocorticoid therapy; and (5) achieving, whenever possible, low

disease activity or clinical remission. A considerable amount of

evidence supports this intensive treatment approach.

As mentioned earlier, methotrexate is the DMARD of first

choice for initial treatment of moderate to severe RA. Failure to

achieve adequate improvement with methotrexate therapy calls for

a change in DMARD therapy, usually a transition to an effective

combination regimen. Effective combinations include methotrexate, sulfasalazine, and hydroxychloroquine (oral triple therapy);

methotrexate and leflunomide; and methotrexate plus a biological.

The combination of methotrexate and an anti-TNF agent, for example, has been shown in randomized controlled trials to be superior

to methotrexate alone, not only for reducing signs and symptoms

of disease but also for retarding the progression of structural joint

damage. Predicting which patients are at higher risk for developing

radiologic joint damage is imprecise at best, although some factors

such as an elevated serum level of acute-phase reactants, high burden of joint inflammation, and the presence of erosive disease are

associated with increased likelihood of developing structural injury.

In 2015, the ACR updated and published their guidelines for the

treatment of RA. They do make a distinction in the treatment of

patients with early (<6 months of disease duration) and established

disease and highlight the use of a treat-to-target approach and the

need to switch or add therapies for worsening or persistent moderate/high disease activity. For example, in patients with early RA

who have persistent moderate/high disease activity on DMARD

monotherapy, providers should consider escalation to combination

DMARD therapy or switching to an anti-TNF +/– methotrexate or

a non-TNF biologic +/– methotrexate. Since a more intensive initial

approach (e.g., combination DMARD therapy) has been shown

to produce superior long-term outcomes compared with starting

methotrexate alone, the usual approach is to begin with methotrexate and rapidly step up (e.g., after 3–6 months) to a combination

of DMARDs or an anti-TNF or non-TNF biological agent in the

absence of an adequate therapeutic response.

Some patients may not respond to an anti-TNF drug or may be

intolerant of its side effects. Initial responders to an anti-TNF agent

who later experience worsening of their condition may benefit from

switching to another anti-TNF agent or an alternative biological

with a different mechanism of action. Indeed, some studies suggest

that switching to an alternative biological such as abatacept is more

effective than switching to another anti-TNF drug. Unacceptable

toxicity from an anti-TNF agent may also call for switching to

another biological or tsDMARD with a different mechanism of

action or a conventional DMARD regimen.

Studies have also shown that oral triple therapy (hydroxychloroquine, methotrexate, and sulfasalazine) may be used effectively for

the treatment of early RA. Treatment may be initiated with methotrexate alone and, lacking an adequate treatment response, followed

within 6 months by a step-up to oral triple therapy.

A clinical state defined as low disease activity or remission is the

optimal goal of therapy, although most patients never achieve complete remission despite every effort to achieve it. Composite indices,

such as the Disease Activity Score-28 (DAS-28), are useful for classifying states of low disease activity and remission; however, they

are imperfect tools due to the limitations of the clinical joint examination in which low-grade synovitis may escape detection. Complete remission has been stringently defined as the total absence

of all articular and extraarticular inflammation and immunologic

activity related to RA. However, evidence for this state can be difficult to demonstrate in clinical practice. In an effort to standardize

and simplify the definition of remission for clinical trials, the ACR

and EULAR developed two provisional operational definitions of

remission in RA (Table 358-3). A patient may be considered in

remission if the patient (1) meets all the clinical and laboratory

criteria listed in Table 358-3 or (2) has a composite SDAI score of

<3.3. The SDAI is calculated by taking the sum of a tender joint

and swollen joint count (using 28 joints), patient global assessment

(0–10 scale), physician global assessment (0–10 scale), and CRP (in

mg/dL). This definition of remission does not take into account

the possibility of subclinical synovitis or that damage alone may

produce a tender or swollen joint. Ignoring the semantics of these

definitions, the aforementioned remission criteria are nonetheless

useful for setting a level of disease control that will likely result in

minimal or no progression of structural damage and disability.

PHYSICAL ACTIVITY AND ASSISTIVE DEVICES

In principle, all patients with RA should receive a prescription for

exercise and physical activity. Dynamic strength training, community-based comprehensive physical therapy, and physical-activity

coaching (emphasizing achieving 150 min of moderate-to-vigorous

physical activity per week) have all been shown to improve muscle

strength and perceived health status, as well as improve DAS-28

scores and inflammatory markers. Foot orthotics for painful valgus

deformity decrease foot pain and may reduce disability and functional limitations. Judicious use of wrist splints can also decrease

Rheumatoid Arthritis

2765CHAPTER 358

pain; however, their benefits may be offset by decreased dexterity

and variably curb grip strength.

SURGERY

Surgical procedures may improve pain and disability in RA with

varying degrees of reported long-term success—most notably the

hands, wrists, and feet. For large joints, such as the knee, hip, shoulder, or elbow, the preferred option for advanced joint disease may

be total joint arthroplasty. A few surgical options exist for dealing

with the smaller hand joints. Silicone implants are the most common prosthetic for MCP arthroplasty and are generally implanted

in patients with severe decreased arc of motion, marked flexion

contractures, MCP joint pain with radiographic abnormalities,

and severe ulnar drift. Arthrodesis and total wrist arthroplasty are

reserved for patients with severe disease who have substantial pain

and functional impairment. These two procedures appear to have

equal efficacy in terms of pain control and patient satisfaction.

Numerous surgical options exist for correction of hallux valgus in

the forefoot, including arthrodesis and arthroplasty, as well as primarily arthrodesis for refractory hindfoot pain.

OTHER MANAGEMENT CONSIDERATIONS

Pregnancy Up to 75% of female RA patients will note overall

improvement in symptoms during pregnancy but often will flare

after delivery. Flares during pregnancy are generally treated with

low doses of prednisone; hydroxychloroquine and sulfasalazine are

probably the safest DMARDs to use during pregnancy. Methotrexate and leflunomide therapy are contraindicated during pregnancy

due to their teratogenicity in animals and humans. The experience with biologic agents has been insufficient to make specific

recommendations for their use during pregnancy. Many patients

will discontinue biologic agents during pregnancy; however, active

inflammatory disease is associated with worse pregnancy outcomes,

and thus controlling disease activity may take precedence. In general, biologics are thought to be safe through the second trimester.

Elderly Patients RA presents in up to one-third of patients afterthe

age of 60; however, older individuals may receive less aggressive treatment due to concerns about increased risks of drug toxicity. Studies

suggest that conventional DMARDs and biological agents are equally

effective and safe in younger and older patients. Due to comorbidities, many elderly patients have an increased risk of infection. Aging

also leads to a gradual decline in renal function that may raise the risk

for side effects from NSAIDs and some DMARDS, such as methotrexate. Renal function must be taken into consideration before

prescribing methotrexate, which is mostly cleared by the kidneys. To

reduce the risks of side effects, methotrexate doses may need to be

adjusted downward for the drop in renal function that usually comes

with the seventh and eighth decades of life. Methotrexate is usually

not prescribed for patients with a serum creatinine >2 mg/dL.

GLOBAL CHALLENGES

Developing countries are finding an increase in the incidence of noncommunicable, chronic diseases such as diabetes, cardiovascular disease, and RA in the face of ongoing poverty, rampant infectious disease,

and poor access to modern health care facilities. In these areas, patients

tend to have a greater delay in diagnosis and limited access to specialists and, thus, greater disease activity and disability at presentation. In

addition, infection risk remains a significant issue for the treatment of

RA in developing countries because of the immunosuppression associated with the use of glucocorticoids and most DMARDs. For example,

in some developing countries, patients undergoing treatment for RA

have a substantial increase in the incidence of tuberculosis, which

demands the implementation of far more comprehensive screening

practices and liberal use of isoniazid prophylaxis than in developed

countries. The increased prevalence of hepatitis B and C, as well as

human immunodeficiency virus (HIV), in these developing countries

also poses challenges. Reactivation of viral hepatitis has been observed

in association with some of the DMARDs, such as rituximab. Also,

reduced access to antiretroviral therapy may limit the control of HIV

infection and therefore the choice of DMARD therapies.

Despite these challenges, one should attempt to initiate early

treatment of RA in the developing countries with the resources at

hand. Hydroxychloroquine, sulfasalazine, and methotrexate are all

reasonably accessible throughout the world where they can be used

as both monotherapy and in combination with other drugs. The use

of biological agents is increasing in the developed countries as well as

in other areas around the world, although their use is limited by high

cost; national protocols restrict their use, and concerns remain about

the risk for opportunistic infections.

SUMMARY

Improved understanding of the pathogenesis of RA and its treatment

has dramatically revolutionized the management of this disease.

The outcomes of patients with RA are vastly superior to those of the

prebiologic modifier era; more patients than in years past are able to

avoid significant disability and continue working, albeit with some

job modifications in many cases. The need for early and aggressive

treatment of RA as well as frequent follow-up visits for monitoring of

drug therapy has implications for our health care system. Primary care

physicians and rheumatologists must be prepared to work together as

a team to reach the ambitious goals of best practice. In many settings,

rheumatologists have reengineered their practice in a way that places

high priority on consultations for any new patient with early inflammatory arthritis.

The therapeutic regimens for RA are becoming increasingly complex with the rapidly expanding armamentarium. Patients receiving

these therapies must be carefully monitored by both the primary care

physician and the rheumatologist to minimize the risk of side effects

and identify quickly any complications of chronic immunosuppression.

Also, prevention and treatment of RA-associated conditions such as

ischemic heart disease and osteoporosis will likely benefit from a team

approach owing to the value of multidisciplinary care.

Research will continue to search for new therapies with superior

efficacy and safety profiles and investigate treatment strategies that can

bring the disease under control more rapidly and nearer to remission.

However, prevention and cure of RA will likely require new breakthroughs in our understanding of disease pathogenesis. Several prevention trials in RA are currently underway and focus on a variety of

prevention strategies in individuals who have serologic and/or clinical

features at higher risk than the general population for developing RA.

Equally important is the identification of predictive biomarkers that

enable a personalized approach to DMARD therapy for RA.

■ FURTHER READING

Aletaha D, Smolen JS: Diagnosis and management of rheumatoid

arthritis: A review. JAMA 320:1360, 2018.

Catrina AI et al: Lungs, joints and immunity against citrullinated

proteins in rheumatoid arthritis. Nat Rev Rheumatol 10:645, 2014.

Erickson AR et al: Clinical features of rheumatoid arthritis, in Kelley

and Firestein’s Textbook of Rheumatology, 10th ed, Firestein GS et al

(eds). Philadelphia, Elsevier, 2017, pp 1167–1186.

Karimi J et al: Genetic implications in the pathogenesis of rheumatoid

arthritis; an updated review. Gene 702:8, 2019.

McInnes IB, Schett G: The pathogenesis of rheumatoid arthritis.

N Engl J Med 365:2205, 2011.

Moreland LW et al: A randomized comparative effectiveness study

of oral triple therapy versus methotrexate plus etanercept in early

aggressive rheumatoid arthritis: The Treatment of Early Aggressive

Rheumatoid Arthritis Trial. Arthritis Rheum 64:2824, 2012.

Singh JA et al: 2015 American College of Rheumatology guideline

for the treatment of rheumatoid arthritis. Arthritis Rheumatol 68:1,

2016.

2766 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

Acute rheumatic fever (ARF) is a multisystem disease resulting from

an autoimmune reaction to infection with group A Streptococcus.

Although many parts of the body may be affected, almost all of the

manifestations resolve completely. The major exception is cardiac

valvular damage (rheumatic heart disease [RHD]), which may persist

after the other features have disappeared.

GLOBAL CONSIDERATIONS

ARF and RHD are diseases of poverty. They were common in all countries until the early twentieth century, when their incidence began to

decline in industrialized nations. This decline was largely attributable

to improved living conditions—particularly less crowded housing and

better hygiene—which resulted in reduced transmission of group A

streptococci. The introduction of antibiotics and improved systems of

medical care had a supplemental effect.

The virtual disappearance of ARF and reduction in the incidence

of RHD in industrialized countries during the first half of the twentieth century unfortunately was not replicated in developing countries,

where these diseases continue unabated. RHD is the most common

cause of acquired heart disease in children in developing countries

and is a major cause of mortality and morbidity in adults as well. It has

359 Acute Rheumatic Fever

Joseph Kado, Jonathan Carapetis

been estimated that between 29.7 and 43.1 million people worldwide

are affected by RHD, with >300,000 deaths occurring each year. Some

95% of ARF cases and RHD deaths now occur in developing countries,

with particularly high rates in sub-Saharan Africa, Pacific nations,

Australasia, and South and Central Asia. The pathogenetic pathway

from exposure to group A Streptococcus followed by pharyngeal or

superficial skin infection and subsequent development of ARF, ARF

recurrences, and development of RHD and its complications is associated with a range of risk factors and, therefore, potential interventions

at each point (Fig. 359-1). In affluent countries, many of these risk factors are well controlled, and where needed, interventions are in place.

Unfortunately, the greatest burden of disease is found in developing

countries, most of which do not have the resources, capacity, and/or

interest to tackle this multifaceted disease. In particular, few developing

countries have a coordinated, register-based RHD control program,

which is proven to be cost-effective in reducing the burden of RHD.

Enhancing awareness of RHD and mobilizing resources for its control

in developing countries are issues requiring international attention.

EPIDEMIOLOGY

ARF is mainly a disease of children age 5–14 years. Initial episodes

become less common in older adolescents and young adults and are

rare in persons aged >30 years. By contrast, recurrent episodes of

ARF remain relatively common in adolescents and young adults. This

pattern contrasts with the prevalence of RHD, which peaks between

25 and 40 years. There is no clear gender association for ARF, but RHD

more commonly affects females, sometimes up to twice as frequently

as males.

Risk

factors

Asymptomatic infection

Failure to seek health care

for sore throat

Inadequate diagnosis and

treatment of streptococcal

pharyngitis

Treatment failure

Inherited susceptibility

Female gender (chorea)

Poor access to health care

Poor access to health care

Poor delivery of secondary

prophylaxis

Asymptomatic or

undiagnosed acute

rheumatic fever

Poor access to health care

Lack of medication

Lack of cardiac surgical

facilities

Overcrowded living

conditions

Poverty

Rural residence

Urban slum residence

Good

evidence

base

Opportunities

for

Intervention

Unproven/

Hypothesized/

Future

Economic

development

Better living

conditions

Improved access

to health care

Secondary prophylaxis

Register-based programs

Integration of RHD control into

primary care, child health, and

noncommunicable disease

programs

Echocardiographic screening

(Immunotherapies)

Systematic sore throat

screening and treatment

programs

(Vaccine)

(Skin infection

control programs)

*Increasing evidence of the role of streptococcal skin infection

Exposure to

group A

streptococcus

Group A streptococcal

upper respiratory tract

infection*

Acute rheumatic

fever

Recurrent

acute rheumatic

fever

Rheumatic

heart

disease (RHD)

Heart

failure

Stroke

Endocarditis

Surgery

Disability

Death

Better diagnosis and

treatment of sore throat in

primary care

Better primary care

Register-based control programs

Specialist services

• Cardiology

• Cardiac surgery

FIGURE 359-1 Pathogenetic pathway for acute rheumatic fever and rheumatic heart disease (RHD), with associated risk factors and opportunities for intervention at each

step. Interventions in parentheses are either unproven or currently unavailable.

Acute Rheumatic Fever

2767CHAPTER 359

RV

LV

AV

MV

LA

FIGURE 359-2 Transthoracic echocardiographic image from a 5-year-old boy

with chronic rheumatic heart disease. This diastolic image demonstrates leaflet

thickening, restriction of the anterior mitral valve leaflet tip and doming of the body

of the leaflet toward the interventricular septum. This appearance (marked by the

arrowhead) is commonly described as a “hockey stick” or an “elbow” deformity.

AV, aortic valve; LA, left atrium; LV, left ventricle; MV, mitral valve; RV, right ventricle.

(Courtesy of Dr. Bo Remenyi, Department of Paediatric and Congenital Cardiac

Services, Starship Children’s Hospital, Auckland, New Zealand.)

PATHOGENESIS

■ ORGANISM FACTORS

Conventional teaching has it that ARF is exclusively caused by

infection of the upper respiratory tract with group A streptococci

(Chap. 148). Although classically, certain M-serotypes (particularly

types 1, 3, 5, 6, 14, 18, 19, 24, 27, and 29) were associated with ARF,

recent evidence demonstrates that many more M-serotypes are rheumatogenic and that so-called “rheumatogenic motifs” are found in

only a minority of serotypes associated with rheumatic fever. This epidemiologic evidence also points to a clear role of skin infection in the

pathogenesis of ARF. The potential role of groups C and G streptococci

is unclear at this time.

■ HOST FACTORS

Based on epidemiologic evidence, ~3–6% of any population may be susceptible toARF, and this proportion does not vary dramatically between

populations. Findings of familial clustering of cases and concordance

in monozygotic twins—particularly for chorea—confirm that susceptibility to ARF is an inherited characteristic, with 44% concordance in

monozygotic twins compared to 12% in dizygotic twins and heritability more recently estimated at 60%. Most evidence for host factors

focuses on immunologic determinants. Some human leukocyte antigen

(HLA) class II alleles, particularly HLA-DR7 and HLA-DR4, appear

to be associated with susceptibility, whereas other class II alleles have

been associated with protection (HLA-DR5, HLA-DR6, HLA-DR51,

HLA-DR52, and HLA-DQ). Associations have also been described

with polymorphisms at the tumor necrosis factor α locus (TNF-α308 and TNF-α-238), high levels of circulating mannose-binding

lectin, and Toll-like receptors. Recent genome-wide association studies

in different populations have identified connections at the HLA region,

particularly HLA-DQA1 to HLA-DQB1, and the immunoglobulin

heavy chain locus.

■ THE IMMUNE RESPONSE

The most widely accepted theory of rheumatic fever pathogenesis

is based on the concept of molecular mimicry, whereby an immune

response targeted at streptococcal antigens (mainly thought to be

on the M protein and the N-acetylglucosamine of group A streptococcal carbohydrate) also recognizes human tissues. In this model,

cross-reactive antibodies bind to endothelial cells on the heart valve,

leading to activation of the adhesion molecule VCAM-1, with resulting recruitment of activated lymphocytes and lysis of endothelial cells

in the presence of complement. The latter leads to release of peptides

including laminin, keratin, and tropomyosin, which, in turn, activates

cross-reactive T cells that invade the heart, amplifying the damage and

causing epitope spreading. An alternative hypothesis proposes that the

initial damage is due to streptococcal invasion of epithelial surfaces,

with binding of M protein to type IV collagen allowing it to become

immunogenic, but not through the mechanism of molecular mimicry.

CLINICAL FEATURES

There is a latent period of ~3 weeks (1–5 weeks) between the precipitating group A streptococcal infection and the appearance of the clinical

features of ARF. The exceptions are chorea and indolent carditis, which

may follow prolonged latent periods lasting up to 6 months. Although

many patients report a prior sore throat, the preceding group A streptococcal infection is commonly subclinical; in these cases, it can only

be confirmed using streptococcal antibody testing. The most common

clinical features are polyarthritis (present in 60–75% of cases) and carditis (50–75%). The prevalence of chorea in ARF varies substantially

between populations, ranging from <2 to 30%. Erythema marginatum

and subcutaneous nodules are now rare, being found in <5% of cases.

■ HEART INVOLVEMENT

Up to 75% of patients with ARF progress to RHD. The endocardium,

pericardium, or myocardium may be affected. Valvular damage is

the hallmark of rheumatic carditis. The mitral valve is almost always

affected, sometimes together with the aortic valve; isolated aortic valve

involvement is rare. Damage to the pulmonary or tricuspid valves is

usually secondary to increased pulmonary pressures resulting from

left-sided valvular disease. Early valvular damage leads to regurgitation. Over ensuing years, usually as a result of recurrent episodes,

leaflet thickening, scarring, calcification, and valvular stenosis may

develop (Fig. 359-2). See Videos 359-1 and 359-2. Therefore, the

characteristic manifestation of carditis in previously unaffected individuals is mitral regurgitation, sometimes accompanied by aortic

regurgitation. Myocardial inflammation may affect electrical conduction pathways, leading to P-R interval prolongation (first-degree atrioventricular block or rarely higher-level block) and softening of the

first heart sound.

People with RHD are often asymptomatic for many years before

their valvular disease progresses to cause cardiac failure. Moreover,

particularly in resource-poor settings, the diagnosis of ARF is often

not made, so children, adolescents, and young adults may have RHD

but not know it. These cases can be diagnosed using echocardiography; auscultation is poorly sensitive and specific for RHD diagnosis in

asymptomatic patients. Echocardiographic screening of school-aged

children in populations with high rates of RHD is becoming more

widespread and has been facilitated by improving technologies in portable echocardiography and the availability of consensus guidelines for

the diagnosis of RHD on echocardiography (Table 359-1). Although a

diagnosis of definite RHD on screening echocardiography should lead

to commencement of secondary prophylaxis, the clinical significance

of borderline RHD has yet to be determined.

■ JOINT INVOLVEMENT

The most common form of joint involvement in ARF is arthritis,

i.e., objective evidence of inflammation, with hot, swollen, red, and/

or tender joints, and involvement of more than one joint (i.e., polyarthritis). Polyarthritis is typically migratory, moving from one joint

to another over a period of hours. ARF almost always affects the large

joints—most commonly the knees, ankles, hips, and elbows—and is

asymmetric. The pain is severe and usually disabling until antiinflammatory medication is commenced.

Less severe joint involvement is also relatively common and has

been recognized as a potential major manifestation in high-risk

2768 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

populations in the most recent revision of the Jones criteria. Arthralgia

without objective joint inflammation usually affects large joints in the

same migratory pattern as polyarthritis. In some populations, aseptic

monoarthritis may be a presenting feature of ARF, which may, in turn,

result from early commencement of anti-inflammatory medication

before the typical migratory pattern is established.

The joint manifestations of ARF are highly responsive to salicylates

and other nonsteroidal anti-inflammatory drugs (NSAIDs). Indeed,

joint involvement that persists for more than 1 or 2 days after starting

salicylates is unlikely to be due to ARF.

■ CHOREA

Sydenham’s chorea commonly occurs in the absence of other manifestations, follows a prolonged latent period after group A streptococcal

infection, and is found mainly in females. The choreiform movements

affect particularly the head (causing characteristic darting movements

of the tongue) and the upper limbs (Chap. 436). They may be generalized or restricted to one side of the body (hemi-chorea). In mild

cases, chorea may be evident only on careful examination, whereas in

the most severe cases, the affected individuals are unable to perform

activities of daily living. There is often associated emotional lability

or obsessive-compulsive traits, which may last longer than the choreiform movements (which usually resolve within 6 weeks but sometimes

may take up to 6 months). More than 50% of patients presenting with

chorea will have carditis, for which reason echocardiography should be

part of the workup.

TABLE 359-1 World Heart Federation Criteria for Echocardiographic

Diagnosis of Rheumatic Heart Disease (RHD) in Individuals

<20 Years of Agea

Definite RHD (either A, B, C, or D)

(A) Pathologic MR and at least two morphologic features of RHD of the

mitral valve

(B) MS mean gradient ≥4 mmHg (note: congenital MV anomalies

must be excluded)

(C) Pathologic AR and at least two morphologic features of RHD of the AV

(note: bicuspid AV and dilated aortic root must be excluded)

(D) Borderline disease of both the MV and AV

Borderline RHD (either A, B, or C)

(A) At least two morphologic features of RHD of the MV without pathologic

MR or MS

(B) Pathologic MR

(C) Pathologic AR

Normal Echocardiographic Findings (all of A, B, C, and D)

(A) MR that does not meet all four Doppler criteria (physiologic MR)

(B) AR that does not meet all four Doppler criteria (physiologic AR)

(C) An isolated morphologic feature of RHD of the MV (e.g., valvular thickening),

without any associated pathologic stenosis or regurgitation

(D) Morphologic feature of RHD of the AV (e.g., valvular thickening), without any

associated pathologic stenosis or regurgitation

Definitions of Pathologic Regurgitation and Morphologic

Features of RHD

Pathologic MR: All of the following: seen in two views; in at least one view, jet

length 2 cm; peak velocity ≥3 m/s; pansystolic jet in at least one envelope

Pathologic AR: All of the following: seen in two views; in at least one view, jet

length ≥1 cm; peak velocity ≥3 m/s; pandiastolic jet in at least one envelope

Morphologic features of RHD in MV: anterior MV leaflet thickening ≥3 mm

(age specific); chordal thickening; restricted leaflet motion; excessive leaflet tip

motion during systole

Morphologic features of RHD in AV: irregular or focal thickening; coaptation

defect; restricted leaflet motion; prolapse

a

For criteria in individuals >20 years of age, see source document.

Abbreviations: AR, aortic regurgitation; AV, aortic valve; MR, mitral regurgitation;

MS, mitral stenosis; MV, mitral valve.

Source: Reproduced with permission from B Remenyi et al: World Heart Federation

criteria for echocardiographic diagnosis of rheumatic heart disease–an evidencebased guideline. Nat Rev Cardiol 9:297, 2012.

■ SKIN MANIFESTATIONS

The classic rash of ARF is erythema marginatum (Chap. 19), which

begins as pink macules that clear centrally, leaving a serpiginous,

spreading edge. The rash is evanescent, appearing and disappearing

before the examiner’s eyes. It occurs usually on the trunk, sometimes

on the limbs, but almost never on the face.

Subcutaneous nodules occur as painless,small(0.5–2 cm), mobile lumps

beneath the skin overlying bony prominences, particularly of the hands,

feet, elbows, occiput, and occasionally the vertebrae. They are a delayed

manifestation, appearing 2–3 weeks after the onset of disease, last for just

a few days up to 3 weeks, and are commonly associated with carditis.

■ OTHER FEATURES

Fever occurs in most cases of ARF, although rarely in cases of pure

chorea. Although high-grade fever (≥39°C) is the rule, lower grade

temperature elevations are not uncommon. Elevated acute-phase reactants are also present in most cases.

■ EVIDENCE OF A PRECEDING GROUP A

STREPTOCOCCAL INFECTION

With the exception of chorea and low-grade carditis, both of which

may become manifest many months later, evidence of a preceding

group A streptococcal infection is essential in making the diagnosis of

ARF. Because most cases do not have a positive throat swab culture or

rapid antigen test, serologic evidence is usually needed. The most common serologic tests are the anti-streptolysin O (ASO) and anti-DNase

B (ADB) titers. Where possible, age-specific reference ranges should

be determined in a local population of healthy people without a recent

group A streptococcal infection.

■ CONFIRMING THE DIAGNOSIS

Because there is no definitive test, the diagnosis of ARF relies on the

presence of a combination of typical clinical features together with

evidence of the precipitating group A streptococcal infection, and the

exclusion of other diagnoses. This uncertainty led Dr. T. Duckett Jones

in 1944 to develop a set of criteria (subsequently known as the Jones

criteria) to aid in the diagnosis. The most recent revision of the Jones

criteria (Table 359-2) requires the clinician to determine if the patient

is from a setting or population known to experience low rates of ARF.

For this group, there is a set of “low-risk” criteria; for all others, there is

a set of more sensitive criteria.

TREATMENT

Acute Rheumatic Fever

Patients with possible ARF should be followed closely to ensure

that the diagnosis is confirmed, treatment of heart failure and other

symptoms is undertaken, and preventive measures including commencement of secondary prophylaxis, inclusion on an ARF registry,

and health education are commenced. Echocardiography should be

performed on all possible cases to aid in making the diagnosis and

to determine the severity at baseline of any carditis. Other tests that

should be performed are listed in Table 359-3.

There is no treatment for ARF that has been proven to alter the

likelihood of developing, or the severity of, RHD. With the exception of treatment of heart failure, which may be life-saving in cases

of severe carditis, the treatment of ARF is symptomatic.

ANTIBIOTICS

All patients with ARF should receive antibiotics sufficient to treat

the precipitating group A streptococcal infection (Chap. 148).

Penicillin is the drug of choice and can be given orally (as phenoxymethyl penicillin, 500 mg [250 mg for children ≤27 kg] PO

twice daily, or amoxicillin, 50 mg/kg [maximum, 1 g] daily, for

10 days) or as a single dose of 1.2 million units (600,000 units for

children ≤27 kg) IM benzathine penicillin G.

SALICYLATES AND NSAIDS

These may be used for the treatment of arthritis, arthralgia, and

fever, once the diagnosis is confirmed. They are of no proven