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Chapter 4: Rheumatoid Arthritis

INTRODUCTION
Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease that primarily affects joints and the synovium but with possible systemic
effects.

CLINICAL PRESENTATION
Nonspecific prodromal symptoms developing over weeks to months include fatigue, weakness, low­grade fever, anorexia, and joint pain. Stiffness
and myalgias may precede synovitis.

Joint involvement is typically symmetric, affecting small joints of the hands, feet, wrists, and ankles; elbows, knees, shoulders, hips, cervical spine,
and temporomandibular joints may also be involved.

Morning stiffness usually lasts over 30 minutes and can persist all day.

On examination, joint swelling may be visible or detectable by palpation. Affected tissue is soft, spongy, warm, and possibly erythematous.
Untreated, chronic inflammation may lead to bony erosions and subluxations of wrists, metacarpophalangeal joints, and proximal interphalangeal
joints (swan neck deformity, boutonnière deformity, and ulnar deviation).

Extra­articular manifestations may include rheumatoid nodules, interstitial lung disease, pleural effusions, vasculitis, ocular issues, pericarditis,
cardiac conduction abnormalities, bone marrow suppression, and lymphadenopathy.

Rheumatoid factor (RF) is found in 70%–80% of patients; higher titers often indicate more severe disease. Anti‐citrullinated protein antibodies
(ACPAs) are more specific, may appear early, and predict a more aggressive course. Antinuclear antibody is positive in 25% of patients. Elevated
erythrocyte sedimentation rate and C­reactive protein reflect nonspecific inflammation. Normocytic anemia, thrombocytosis or thrombocytopenia,
and leukopenia may occur. Synovial fluid analysis typically shows a high white blood cell count without crystals or infection.

Early radiologic findings include soft tissue swelling and periarticular osteoporosis. As the disease progresses, joint space narrowing, erosions,
subluxations, and deformities may develop.

DIAGNOSIS
The 2010 diagnostic criteria for RA, revised by the American College of Rheumatology (ACR) and the European League Against Rheumatism, aim to
identify early disease and enable prompt treatment to prevent joint damage. Patients with synovitis in at least one joint, with no other explanation,
are eligible for evaluation. A scoring system is used, and a total score of 6 or more out of 10 indicates definite RA.

TREATMENT
Goals of Treatment: The primary goal is to achieve complete remission or low disease activity (“treat to target”). Additional goals include reducing
inflammation and symptoms, preserving daily function, slowing joint damage, and delaying disability.

NONPHARMACOLOGIC THERAPY

Patient education on the disease and medications (eg, side effects, self­injection techniques) is essential.

Physical therapy helps reduce pain and inflammation while maintaining joint function. Regular physical activity—including aerobic and strength
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Assistive devices and orthoses (eg, braces, splints, compression, and taping) can relieve pain and enhance function. Occupational therapy offers
additional support, such as footwear recommendations and splinting.
 inflammation and symptoms, preserving daily function, slowing joint damage, and delaying disability.
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Patient education on the disease and medications (eg, side effects, self­injection techniques) is essential.

Physical therapy helps reduce pain and inflammation while maintaining joint function. Regular physical activity—including aerobic and strength
training—can improve outcomes.

Assistive devices and orthoses (eg, braces, splints, compression, and taping) can relieve pain and enhance function. Occupational therapy offers
additional support, such as footwear recommendations and splinting.

Weight loss reduces joint stress.

Surgical options, like joint replacement, are reserved for advanced cases with significant cartilage loss.

Alternative therapies, including acupuncture, massage, and thermal modalities (eg, heat, cryotherapy), may also relieve pain and improve function.

PHARMACOLOGIC THERAPY

General Approach

Therapies to treat RA and slow disease progression include disease­modifying antirheumatic drugs (DMARDs) which is categorized into
conventional synthetic, targeted synthetic, and biologic DMARDs.

✓ Conventional synthetic disease­modifying antirheumatic drugs (csDMARDs) include methotrexate, leflunomide, sulfasalazine, and
hydroxychloroquine.

✓ Biologic disease­modifying antirheumatic drugs (bDMARDs) include tumor necrosis factor (TNF) inhibitors (adalimumab, certolizumab
pegol, etanercept, golimumab, and infliximab) and non­TNF inhibitor biologics (abatacept, sarilumab, tocilizumab, and rituximab).

✓ Tofacitinib, baricitinib, and upadacitinib are oral targeted synthetic disease­modifying antirheumatic drugs (tsDMARDs) that are also
janus kinase (JAK) inhibitors.

DMARD therapy should begin promptly after RA diagnosis. The 2021 ACR guidelines outline treatment based on disease activity, safety,
comorbidities, and structural damage progression (Fig. 4­1).

According to the guidelines, DMARD choice in treatment­naïve patients depends on disease activity. For moderate­to­high activity, methotrexate
monotherapy is strongly recommended as first­line. For low disease activity, hydroxychloroquine is preferred over other csDMARDs.

Systematic glucocorticoid prescribing at csDMARD initiation is not recommended. However, short­term use may be needed for symptom control, as
DMARDs can take weeks to months to work. If used, prescribe the lowest effective dose for the shortest time. Nonsteroidal anti‐inflammatory drugs
(NSAIDs) or acetaminophen can also relieve symptoms but carry potential side effects.

For patients treated with csDMARDs but methotrexate­naïve and with moderate­to­high disease activity, methotrexate monotherapy is preferred
over combining it with a bDMARD or tsDMARD. If methotrexate fails to achieve the target, adding a bDMARD or tsDMARD is recommended over triple
csDMARD therapy. For patients on a bDMARD or tsDMARD who are not at target, consider switching to a different class.

For patients in remission or with low disease activity for at least 6 months, continuing all DMARDs is recommended over dose reduction or
discontinuation. If discontinuation is the goal, taper gradually. In those not meeting treatment targets, poor prognostic factors may guide next
steps. These include moderate­to­high disease activity despite csDMARDs, elevated acute phase reactants, high swollen joint count, rheumatoid
factor and/or ACPA positivity, early erosions, and failure of two or more csDMARDs.

In the absence of poor prognostic factors, other csDMARDs may be used. If poor prognostic factors are present, add a bDMARD to the csDMARD. JAK
inhibitors may be considered, factoring in cardiovascular and malignancy risks. If both bDMARDs and tsDMARDs have failed, switching to another
agent from either class is an option.

Monitor patients with active disease every 1 to 3 months. If there is no improvement by 3 months or the treatment target is not met by 6 months,
adjust therapy. In patients off glucocorticoids and in sustained remission, DMARD dose reduction may be considered.

See Tables 4­1 and 4­2 for usual dosages, adverse reactions, and monitoring parameters for medications used to treat RA.

TABLE 4­1
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Usual Doses
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4: Rheumatoid Arthritis, Antirheumatic Drugs Page 2 / 10
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Drugs Brand Routes of Starting Dose Usual Ranges or Comments

 Monitor patients with active disease every 1 to 3 months. If there is no improvement by 3 months or the treatmentUniversity
target is not met by
of New 6 months,
England ­ Maine
adjust therapy. In patients off glucocorticoids and in sustained remission, DMARD dose reduction may be considered.
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See Tables 4­1 and 4­2 for usual dosages, adverse reactions, and monitoring parameters for medications used to treat RA.

TABLE 4­1
Usual Doses for Disease­Modifying Antirheumatic Drugs

Drugs Brand Routes of Starting Dose Usual Ranges or Comments

Names Administration Maintenance Dose

Conventional DMARDs

Methotrexate Rasuvo Oral, SC, IM Oral: 7.5–15 mg once 7.5–25 mg once Give with folic acid 1–5 mg/day to reduce
Trexall weekly weekly adverse reactions
Otrexup SC/IM: 7.5–15 mg once
(SC) weekly

Leflunomide Arava Oral Loading dose: 100 mg 10–20 mg daily Not recommended in liver disease (ALT >3
daily for 3 days, then 20 times ULN)
mg daily or 10–20 mg
daily without loading
dose

Hydroxychloroquine Plaquenil Oral 200 mg twice daily or 400 200 mg twice daily or Take with food or milk; use with caution in
mg daily 400 mg daily renal or hepatic impairment

Sulfasalazine Azulfidine Oral 500 mg once or twice 1000 mg twice daily Not recommended in renal or hepatic
daily (maximum 3000 impairment
mg/day if inadequate
response after 12
weeks of 2000 mg/day)

Tumor Necrosis Factor Inhibitors

Adalimumab Humira SC 40 mg every 2 weeks 40 mg every 2 weeks

(may increase to 40
mg once weekly or 80
mg every other week
in select patients)

Certolizumab pegol Cimzia SC 400 mg at 0, 2, and 4 200 mg every other

weeks week or 400 mg every
4 weeks

Etanercept Enbrel SC 50 mg once weekly or 25 Same as starting dose

mg twice weekly

Golimumab Simponi SC 50 mg once monthly Same as starting dose

Infliximab Remicade IV 3 mg/kg at 0, 2, and 6 3–10 mg/kg every 4–8 Give in combination with methotrexate;
weeks, and then every 8 weeks pretreat with methylprednisolone,
weeks acetaminophen, and antihistamine

Costimulation Modulator

Abatacept
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SC: 125 mg weekly
initial IV dose followed by
125 mg SC within 24
 weeks, and then every 8 weeks pretreat with methylprednisolone,
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Costimulation Modulator

Abatacept Orencia IV, SC IV: <60 kg: 500 mg, 60–100 IV: dose based on
kg: 750 mg, >100 kg: 1000 weight every 4 weeks
mg at 0, 2, and 4 weeks or SC: 125 mg weekly
initial IV dose followed by
125 mg SC within 24
hours
SC: 125 mg weekly

IL­6 Receptor Antagonists

Sarilumab Kevzara SC 200 mg every 2 weeks Same as starting dose

Tocilizumab Actemra IV, SC IV: 4 mg/kg every 4 IV: 4–8 mg/kg every 4 Can increase the metabolism of CYP3A4
weeks, SC: <100 kg: 162 weeks (maximum 800 substrates
mg every other week, mg per infusion)
>100 kg: 162 mg weekly SC: <100 kg: 162 mg
every other week,
followed by an
increase to weekly
injections if needed;
>100 kg: 162 mg
weekly

Janus Kinase Inhibitors

Baricitinib Olumiant Oral IR 2 mg once daily Same as starting dose 1 mg once daily in patients taking strong
OAT3 inhibitors eGFR 30–60 mL/min/1.73

m2: 1 mg daily; use is contraindicated with

eGFR <30 mL/min/1.73 m2; use is not
recommended in severe hepatic
impairment

Tofacitinib Xeljanz Oral IR: 5 mg twice daily Same as starting dose 5 mg once daily in moderate­to­severe
ER: 11 mg daily renal insufficiency, moderate hepatic
impairment, or concomitant CYP3A4 or
CYP2C19 inhibitors; not recommended in
severe hepatic impairment

Upadacitinib Rinvoq Oral ER 15 mg once daily Same as starting dose Use with caution with strong CYP3A4
inhibitors; coadministration with strong
CYP3A4 inducers is not recommended; use
is not recommended in severe hepatic
impairment

Anti­CD20 Monoclonal Antibody

Rituximab Rituxan IV 1000 mg in 2 doses given Initial dose may be Pretreat with methylprednisolone,
2 weeks apart repeated every 16–24 acetaminophen, and antihistamine
weeks based on
response

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ALT, alanine Arthritis,
transaminase; Page
CYP, cytochrome P; ER, extended release; IM, intramuscular; IR, immediate release; IV, intravenous; SC, subcutaneous; ULN, upper limit4of/ 10
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normal.

TABLE 4­2
 Rituximab Rituxan IV 1000 mg in 2 doses given Initial dose may be Pretreat with methylprednisolone,
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weeks based on
response

ALT, alanine transaminase; CYP, cytochrome P; ER, extended release; IM, intramuscular; IR, immediate release; IV, intravenous; SC, subcutaneous; ULN, upper limit of
normal.

TABLE 4­2
Adverse Drug Reactions and Monitoring Recommended for Medications Used in RA Treatment

Drugs Adverse Drug Reactions Initial Monitoring Maintenance Monitoring

Conventional Synthetic Disease­Modifying Antirheumatic Drugs

Methotrexate Infection, hepatotoxicity, hepatic fibrosis, cirrhosis, SCr, CBC with differential, SCr, CBC with differential, LFTs every 2–4
elevated liver enzymes, interstitial pneumonitis, LFTs, hepatitis B and C weeks for 3 months after starting or
oral mucosal ulcers, rash, photosensitivity, GI screening, tuberculosis following a dose increase, then every 8–12
perforation, diarrhea, nausea, vomiting, screening Consider chest x­ weeks during 3–6 months of therapy, and
thrombocytopenia, leukopenia, anemia, ray in patients with every 12 weeks after 6 months of therapy
neutropenia, cough underlying lung disease

Leflunomide Elevated liver enzymes, diarrhea, nausea, alopecia, CBC with differential, SCr, CBC with differential, SCr, ALT, AST every 2–4
elevated blood pressure, rash ALT, AST, blood pressure, weeks for 3 months after starting or
tuberculosis screening following a dose increase, then every 8–12
weeks during 3–6 months of therapy, and
every 12 weeks after 6 months of therapy;
blood pressure periodically, signs of infection

Sulfasalazine Rash, delayed severe hypersensitivity reactions, CBC with differential, SCr, CBC with differential, SCr, LFTs every 2–4
nausea, vomiting, diarrhea, photosensitivity, LFTs, G6PD weeks for 3 months after starting or
alopecia, leukopenia, anemia, thrombocytopenia, following a dose increase, then every 8–12
elevated liver enzymes, headache weeks during 3–6 months of therapy, and
every 12 weeks after 6 months of therapy,
signs of infection, dermatologic toxicity,
hypersensitivity reactions

Hydroxychloroquine Retinal damage, rash, diarrhea, nausea, vomiting Ophthalmologic exam Ophthalmologic exam annually if risk factors
(fundus examination plus for retinal damage present or annually
visual fields and spectral­ beginning after 5 years of use if no risk factors
domain optical coherence
tomography if
maculopathy present)
within 5 years of starting
therapy

Biologic Disease­Modifying Antirheumatic Drugs

Etanercept, Local injection­site reactions, infection, malignancy, Tuberculosis screening, Periodic skin examination, signs/symptoms
Adalimumab, hepatotoxicity, rash, new or worsening heart failure, hepatitis B and C screening, of infection and malignancy, CBC with
golimumab, new or worsening demyelinating disease CBC with differential, CMP differential, and LFTs at 4 and 12 months,
certolizumab pegol then every 3–6 months, neurological
symptoms, heart failure symptoms

Infliximab Infusion­related reactions, infection, malignancy, Tuberculosis screening, CBC with differential, LFTs, signs/symptoms
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Chapter 4: Rheumatoid Arthritis,
new or worsening heart failure, new or worsening CBC with differential, LFTs, symptoms, heart failure symptoms
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demyelinating disease CMP
 Adalimumab, hepatotoxicity, rash, new or worsening heart failure, hepatitis B and C screening, of infection and malignancy, CBC with
golimumab, new or worsening demyelinating disease CBC with differential, CMP University
differential, and LFTs at 4ofand
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12 months,
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certolizumab pegol then every 3–6 months, neurological
symptoms, heart failure symptoms

Infliximab Infusion­related reactions, infection, malignancy, Tuberculosis screening, CBC with differential, LFTs, signs/symptoms
headache, hepatotoxicity, rash, abdominal pain, hepatitis B and C screening, of infection and malignancy, neurological
new or worsening heart failure, new or worsening CBC with differential, LFTs, symptoms, heart failure symptoms
demyelinating disease CMP

Abatacept Headache, nausea, infusion reactions, infection, Tuberculosis screening, Signs/symptoms of infection, hypersensitivity
malignancy, rash hepatitis B and C screening reaction, and malignancy

Tocilizumab Local injection­site reactions, hypersensitivity Tuberculosis screening, LFTs, CBC with differential every 4–8 weeks
reactions, infection, malignancy, GI perforation, hepatitis B and C screening, after starting then every 3 months; FLP after
neutropenia, thrombocytopenia, headache, CBC with differential, LFTs, 4–8 weeks of starting, then every 6 months,
hypertension, increased liver enzymes, infusion FLP signs/symptoms of infection; CNS
reactions, increased cholesterol demyelinating disorders, new onset
abdominal symptoms

Sarilumab Local injection­site reactions, infection, malignancy, Tuberculosis screening, CBC with differential and LFTs 4–8 weeks
neutropenia, thrombocytopenia, increased liver hepatitis B screening, CBC after starting and then every 3 months, FLP
enzymes, GI perforation, increased cholesterol, with differential, LFTs, FLP 4–8 weeks after starting and every 6 months
hypersensitivity reactions during therapy, signs/symptoms of infection,
hypersensitivity reaction, and GI perforation

Rituximab Serious, including fatal, infusion reactions, infection, Tuberculosis screening, CBC with differential before each treatment
malignancy, hepatitis B reactivation, hepatitis B and C screening, course and at 2­ to 4­month intervals,
mucocutaneous reactions, progressive multifocal CBC with differential signs/symptoms of infection
leukoencephalopathy, bowel obstruction and
perforation, CV events, blood cell disorders

Targeted Synthetic Disease­Modifying Antirheumatic Drugs

Tofacitinib Infection, malignancy, GI perforations, upper Tuberculosis screening, CBC with differential after 4–8 weeks and
respiratory tract and other infections, headache, hepatitis B and C screening, every 3 months, FLP after 4–8 weeks and
diarrhea, nasopharyngitis, CV events, thrombosis, CBC with differential, LFTs, periodically, LFTs periodically, periodic skin
ILD, blood cell disorders, hyperlipidemia, FLP, HR, and blood examinations, HR and blood pressure,
hypertension pressure signs/symptoms of infection and malignancy

Upadacitinib Malignancy, GI perforations, upper respiratory tract Tuberculosis screening, CBC with differential, and LFTs periodically,
and other infections, neutropenia, hepatitis B and C screening, FLP 12 weeks after therapy initiation and
lymphocytopenia, nausea, hepatotoxicity, increased CBC with differential, LFTs, periodically thereafter, symptoms of
liver enzymes, CV events, thrombosis, increased FLP thrombosis and malignancy
cholesterol

Baricitinib Malignancy, upper respiratory tract herpes zoster CBC with differential, LFTs, CBC with differential, LFTs periodically, FLP
and other infections, hepatotoxicity, increased liver FLP, tuberculosis, and 12 weeks after therapy initiation and
enzymes, anemia, gastrointestinal perforations, hepatitis B and C screening periodically thereafter, abdominal
thrombosis, lymphocytopenia, neutropenia, CV symptoms, of thrombosis and malignancy
events, increase in SCr and CK

Other Medications

NSAIDs GI ulceration, bleeding, and perforation, renal SCr, CBC every 2–4 weeks Same as initial plus stool guaiac every 6–12
damage after starting therapy months

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behavioral and mood changes, increased appetite, blood pressure every 3–6
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weight gain, electrolyte imbalances, impaired months
healing, hirsutism, Cushing syndrome, HPA axis
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NSAIDs GI ulceration, bleeding, and perforation, renal SCr, CBC every 2–4 weeks Same as initial plus stool guaiac every 6–12
damage after starting therapy months

Corticosteroids Fluid retention, hyperglycemia, hypertension, Glucose, CBC periodically, Same as initial
behavioral and mood changes, increased appetite, blood pressure every 3–6
weight gain, electrolyte imbalances, impaired months
healing, hirsutism, Cushing syndrome, HPA axis
suppression, osteonecrosis of femoral and humeral
heads, osteoporosis and fractures, myopathy,
glaucoma, cataracts

ALT, alanine aminotransferase; AST, aspartate transaminase; BP, blood pressure; CBC, complete blood count; CK, creatine kinase; CMP, comprehensive metabolic
panel; CNS, central nervous system; CV, cardiovascular; FLP, fasting lipid panel; GI, gastrointestinal; Hgb, hemoglobin; HPA, hypothalamic–pituitary–adrenal; HR, heart
rate; ILD, interstitial lung disease; LFTs, liver function tests; NSAIDs, nonsteroidal anti‐inflammatory drugs; SCr, serum creatinine.

FIGURE 4­1

Treatment algorithm for rheumatoid arthritis. (bDMARD, biologic disease­modifying antirheumatic drug; csDMARD, conventional synthetic
disease­modifying antirheumatic drug; MTX, methotrexate; tsDMARD, targeted synthetic disease­modifying antirheumatic drug.)

Conventional Synthetic Disease­Modifying Antirheumatic Drugs (DMARDs)

Methotrexate inhibits dihydrofolate reductase, blocking DNA synthesis, repair, and cell replication. It is the DMARD of choice for most patients
unless contraindicated. It can be used alone or with other DMARDs and has a glucocorticoid­sparing effect.

✓ Methotrexate is taken once weekly, usually as an oral tablet or subcutaneous (SC) injection. Oral tablets are preferred initially due to ease of
use. An intramuscular (IM) form is also available but rarely used.

✓ Methotrexate should be given with folic acid 1 to 5 mg daily to reduce the incidence of methotrexate toxicities.

✓ Injectable methotrexate has greater bioavailability and superior clinical efficacy compared to oral forms, with fewer GI side effects. Patients
who do not tolerate oral methotrexate may try a split oral dose over 24 hours, switch to SC injections, or increase folic acid before considering
another DMARD. RA treatment doses typically range from 7.5 to 25 mg weekly. ACR guidelines recommend starting or titrating to at least 15 mg
weekly within 4 to 6 weeks.

✓ Clinical benefit typically appears 3 to 6 weeks after starting methotrexate. Adverse effects are common (Table 4­2).

✓ Methotrexate is teratogenic—patients should use contraception and stop the drug if planning pregnancy. Methotrexate is contraindicated in
pregnancy, breastfeeding, alcoholism, chronic liver disease, immunodeficiency, and hematologic disorders (eg, leukopenia,
thrombocytopenia). Reduced renal function can impair excretion, requiring dose adjustment or discontinuation.

Leflunomide inhibits pyrimidine synthesis; it reduces signs and symptoms of RA, inhibits structural damage, and improves physical function. It can
be used as monotherapy or in combination with other DMARDs.

✓ The typical maintenance dose is 20 mg daily; reduce to 10 mg daily if higher doses aren’t tolerated. A 100­mg daily loading dose for 3 days
may speed up steady state but can increase toxicity risk.

✓ Adverse effects are shown in Table 4­2. Leflunomide is teratogenic and should not be used in patients with severe hepatic impairment.

Sulfasalazine has immunomodulatory and anti​­inflammatory effects. It can be used alone or with other DMARDs.

✓ The usual starting dose is 500 mg daily or 1 g daily in two divided doses, increased by 500 mg weekly to a maintenance dose of 2 g daily in two
doses to reduce adverse events.

✓ Clinical
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✓ Use with caution in renal impairment; contraindicated in sulfonamide or salicylate allergy. GI side effects (eg, diarrhea, nausea, vomiting) are
common. It may also cause urine or skin discoloration.
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Sulfasalazine has immunomodulatory and anti​­inflammatory effects. It can be used alone or with other DMARDs.
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✓ The usual starting dose is 500 mg daily or 1 g daily in two divided doses, increased by 500 mg weekly to a maintenance dose of 2 g daily in two
doses to reduce adverse events.

✓ Clinical benefit typically appears within 4 weeks, though some may need up to 12 weeks. If the response is inadequate at 12 weeks, the dose
may be increased to 3 g/day in divided doses.

✓ Use with caution in renal impairment; contraindicated in sulfonamide or salicylate allergy. GI side effects (eg, diarrhea, nausea, vomiting) are
common. It may also cause urine or skin discoloration.

Hydroxychloroquine can be used in combination with other DMARDs or as monotherapy in mild cases.

✓ The typical dose is 400 mg daily either as one dose or as two divided doses. Clinical benefit is delayed and may take several weeks.

✓ Its main advantage is that it does not require frequent lab monitoring, because it’s not typically linked to infection risk or hepatic, renal, or
hematologic issues. GI side effects may be reduced by taking it with food or splitting the dose.

✓ Irreversible retinal damage can occur. Patients with risk factors—such as low body weight, renal, or hepatic impairment—should have a
baseline eye exam, followed by annual screening after 5 years, or sooner if risk factors are present. For high­risk patients, annual exams may be
started earlier without waiting 5 years (Table 4­2).

Biologic DMARDs

Biologic agents are genetically engineered proteins that reduce inflammation through various mechanisms and are classified as either TNF
inhibitors or non­TNF biologics.

Biologic DMARDs increase infection risk due to immunosuppression. A tuberculin skin test or interferon­gamma release assay should be done
before identifying and treating latent or active TB. Patients should also be screened for hepatitis B due to reactivation risk, and hepatitis C screening
is recommended.

Biologics may be combined with conventional DMARDs, but multiple biologics should not be used together due to additive immunosuppression.
When switching biologics, the new agent should be started when the next dose of the prior one is due to reduce adverse effects. Due to
immunosuppressive risks, patients should inform providers if they are being treated for an infection or planning major surgery. Treatment may
need to be paused until the infection resolves or healing occurs. Live vaccines should not be given during biologic therapy.

Biosimilars are biologic products shown to have no clinically meaningful differences from the Food and Drug Administration ()­approved reference
biologics. They help improve access to RA treatment by offering lower­cost alternatives to originator products. Biologics with FDA­approved
biosimilars include adalimumab, infliximab, and rituximab.

TNF­α Inhibitor Biologics

TNF inhibitors block the proinflammatory cytokine TNF­α. Clinical benefit may take several weeks, with full effect in up to 3 months. They are
typically used when disease activity remains moderate to high despite csDMARDs and are more expensive.

Selection of a TNF inhibitor depends on cost and patient preference for route and dosing frequency. These agents are contraindicated in moderate­
to­severe heart failure (New York Heart Association [NYHA] class III/IV) due to reports of new or worsening symptoms. They also raise the risk of
serious infections, malignancies (eg, lymphoma, skin cancers), and may trigger or worsen demyelinating disorders like multiple sclerosis.

See Tables 4­1 and 4­2 for dosing and monitoring information.

✓ Adalimumab (Humira) binds TNF­α and blocks its interaction with p55 and p75 TNF receptors. It is available as a prefilled syringe or pen for
SC injection.

✓ Certolizumab pegol (Cimzia) is a pegylated humanized Fab fragment of a TNF­α monoclonal antibody. Lacking the Fc region, it does not
trigger complement activation, antibody­dependent cell­mediated cytotoxicity, or apoptosis. Pegylation delays elimination and extends half­
life. Available as a prefilled syringe for SC injection.

✓ Etanercept (Enbrel) is a recombinant TNF receptor linked to the Fc fragment of human IgG1. It is available as a prefilled syringe or pen for
SC injection.
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✓ Golimumab (Simponi) is a human monoclonal antibody targeting human TNF­α. Available as a prefilled syringe or pen for SC use and8as an
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IV product.
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✓ Infliximab (Remicade) is a chimeric monoclonal antibody against TNF­α, given by IV infusion. To prevent antibody formation, methotrexate
 trigger complement activation, antibody­dependent cell­mediated cytotoxicity, or apoptosis. Pegylation delays elimination and extends half­
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life. Available as a prefilled syringe for SC injection.
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✓ Etanercept (Enbrel) is a recombinant TNF receptor linked to the Fc fragment of human IgG1. It is available as a prefilled syringe or pen for
SC injection.

✓ Golimumab (Simponi) is a human monoclonal antibody targeting human TNF­α. Available as a prefilled syringe or pen for SC use and as an
IV product.

✓ Infliximab (Remicade) is a chimeric monoclonal antibody against TNF­α, given by IV infusion. To prevent antibody formation, methotrexate
should be coadministered at RA treatment doses. Premedication with an antihistamine, acetaminophen, and/or glucocorticoid can reduce
infusion reactions. Infliximab plus methotrexate improves clinical response compared to methotrexate alone.

Non­TNF Inhibitor Biologics

Abatacept (Orencia) inhibits T­cell activation by binding to CD80 and CD86, which blocks the interaction between T cells CD28, thus inhibiting the
activation of T cells. Abatacept can be used as an alternative to methotrexate in DMARD­naïve patients with moderate to high disease activity or as
adjunctive therapy in patients who have not met treatment goals despite methotrexate therapy.

✓ Abatacept plus methotrexate has been shown to have similar efficacy and incidence of adverse events compared to adalimumab plus
methotrexate in biologic­naïve patients who had an incomplete response to methotrexate.

✓ Abatacept is available in a prefilled syringe or auto­injector for SC injection and as an IV infusion.

Tocilizumab(Actemra) is a monoclonal antibody that blocks IL­6 from binding to its receptor. It is used for moderate­to­severe RA with csDMARDs
or as monotherapy if other options are not tolerated. Available as prefilled SC syringes and IV infusion.

Sarilumab (Kevzara) is an IL­6 receptor antagonist for moderate­to­severe RA in patients with inadequate response to one or more DMARDs. It can
be used alone or with csDMARDs and is given as a 200 mg SC injection every 2 weeks.

Rituximab (Rituxan) is a monoclonal antibody that binds the CD20 antigen on the surface of B cells. It can be used alone or with methotrexate in
patients with moderate­to­severe RA who have not responded to TNF inhibitors or have a history of lymphoproliferative disorders. Patients who
failed one TNF inhibitor showed greater disease activity score reductions with rituximab than with a second TNF inhibitor.

✓ Rituximab is given as an IV infusion—two 1000 mg doses, 2 weeks apart. B­cell recovery may take months, allowing dosing every 24 weeks.
Some patients may go longer between doses, based on symptom recurrence. It should not be given more often than every 16 weeks.

✓ Serious, sometimes fatal, infusion reactions can occur. Premedication with IV methylprednisolone 100 mg, plus acetaminophen and an
antihistamine, is recommended 30 minutes before each infusion. Hepatitis B reactivation, mucocutaneous reactions, and progressive
multifocal leukoencephalopathy have been reported.

Anakinra (Kineret) is an IL­1 receptor antagonist that is less effective than other biologics and is used infrequently. It is not included in current ACR
treatment recommendations but may be used in moderate­to­severe RA after failure of one or more DMARDs. It can be given alone or with DMARDs
other than TNF­α inhibitors.

Targeted Synthetic DMARDs: Janus­Kinase Inhibitors

Baricitinib (Olumiant), tofacitinib (Xeljanz), and upadacitinib (Rinvoq) are oral, small­molecule, nonbiologic JAK inhibitors. Baricitinib is FDA­
approved for adults with moderately to severely active RA who have not responded to one or more TNF inhibitors and may be used alone or with
methotrexate or other csDMARDs. Tofacitinib and upadacitinib are approved for adults with moderately to severely active RA who have had an
inadequate response or intolerance to methotrexate. They can be used as monotherapy or with methotrexate or other nonbiologic DMARDs. JAK
inhibitors should not be combined with biologic DMARDs or other JAK inhibitors.

All JAK inhibitors carry black­box warnings for serious infections, malignancies (eg, lymphoma), and thrombosis (eg, deep vein thrombosis [DVT],
pulmonary embolism [PE]). Live vaccines should be avoided, and patients must be screened and treated for latent tuberculosis before starting
therapy.

Nonsteroidal Anti­inflammatory Drugs

NSAIDs inhibit prostaglandin synthesis, targeting only a small part of the inflammatory cascade. They possess both analgesic and anti­inflammatory
properties
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Glucocorticoids
 pulmonary embolism [PE]). Live vaccines should be avoided, and patients must be screened and treated for latent tuberculosis before starting
therapy. University of New England ­ Maine
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Nonsteroidal Anti­inflammatory Drugs

NSAIDs inhibit prostaglandin synthesis, targeting only a small part of the inflammatory cascade. They possess both analgesic and anti­inflammatory
properties and reduce stiffness, but they do not slow disease progression or prevent joint damage. They should not be used as monotherapy but
have a more rapid onset of action than DMARDs and may be beneficial to “bridge” patients while DMARDs take effect. For more details on NSAIDs,
see Chapter 115, “Osteoarthritis.”

Glucocorticoids

Glucocorticoids have anti­inflammatory and immune­modulating properties and can slow RA progression. However, due to the risk of serious, long­
term adverse effects, they should not be used as monotherapy (Table 4­2). Use the lowest effective dose for the shortest duration. Per ACR and
European Alliance of Associations for Rheumatology (EULAR), short­term use is <3 months, and low­dose is defined as prednisone ≤7.5 mg/day (or
equivalent).

Like NSAIDs, oral glucocorticoids (eg, prednisone, methylprednisolone) can be used to “bridge” patients while DMARDs take effect. They may also
serve as low­dose DMARD adjuncts in refractory cases. For acute RA flares, high­dose short­term bursts can be used, followed by tapering to the
lowest effective dose or discontinuing over several days.

Long­term glucocorticoid use is limited by adverse effects, including fluid retention, hyperglycemia, hypertension, mood changes, increased
appetite, weight gain, electrolyte imbalances, poor wound healing, hirsutism, Cushing syndrome, hypothalamic–pituitary–adrenal (HPA) axis
suppression, osteonecrosis (femoral/humeral heads), osteoporosis, fractures, myopathy, glaucoma, and cataracts.

To prevent withdrawal from HPA axis suppression, glucocorticoids should be tapered—especially after prolonged or high­dose use—rather than
stopped abruptly.

The IM route may benefit nonadherent patients. Depot forms (triamcinolone acetonide, triamcinolone hexacetonide, methylprednisolone acetate)
offer 2 to 6 weeks of symptom control, though onset may be delayed for several days. The depot effect provides a physiologic taper, reducing risk of
HPA axis suppression.

Intra­articular injections are useful when few joints are affected but should not be repeated frequently due to the risk of accelerated cartilage loss.

EVALUATION OF THERAPEUTIC OUTCOMES

Assess disease activity at baseline and each follow­up to monitor disease control and treatment response. Signs of improvement include reduced
joint pain, swelling, and tenderness; less morning stiffness and fatigue; and better function in daily activities.

Perform a physical exam every visit to evaluate the number of swollen and tender joints, mobility, and deformity.

Use validated assessment tools to measure RA disease activity, such as the Clinical Disease Activity Index, Disease Activity Score, Patient Activity
Scale, Routine Assessment of Patient Index Data 3, and Simplified Disease Activity Index.

Monitor erythrocyte sedimentation rate and C­reactive protein to assess inflammation.

Obtain baseline radiographs of hands, wrists, and forefeet, and repeat every 2 years in patients with low disease activity or remission. Imaging may
be needed more often in moderate to high disease activity. If radiographic signs of progression are present (eg, osteopenia, erosions, joint space
narrowing), adjust drug therapy accordingly.

It is important to monitor and assess for clinical and laboratory adverse effects of RA medications (Table 4­2).

See Chapter 116, Rheumatoid Arthritis, authored by Stephanie Gruber, Bianca Harris, and Susan Hylland, for a detailed discussion of this topic.

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