Passive ROM exercises should be prescribed for T.W. because they minimize

muscle atrophy and flexion contractures and maintain joint function without

increasing inflammation or radiographic progression of disease.

29,30 Regular aerobic

exercises, such as cycling, swimming, or walking, enhance muscle function and joint

function as well.

31 Overall, physical and occupational therapies can provide valuable

assistance to patients with compromised activities of daily living to maximize the

potential for self-sufficiency. Some orthoses––medical devices secured to any part of

a patient’s body designed to support, immobilize, align, correct, or prevent

deformity, or improve functioning––can reduce pain and inflammation or improve

joint function in targeted joints for RA patients.

32

Finally, emotional support should be provided to all patients including T.W. As

with all chronic debilitating diseases, the potential loss of independence, selfesteem, and employment, as well as altered interpersonal relationships with friends

and family, can result in a twofold to threefold increase in depression.

33,34

The expertise of different health care disciplines (e.g., physical therapists, social

workers, health educators, psychiatrists, clinical psychologists, podiatrists,

vocational rehabilitation therapists, and pharmacists) should be consulted depending

on T.W.’s needs. Pharmacists in outpatient clinical practices can monitor RA drug

therapy for therapeutic and adverse effects under collaborative practice agreements

with other practitioners and can counsel patients on proper medication use and

clarify expectations.

35

Insufficient literature evidence is available to support the use of spa therapy and

thermotherapies such as ultrasound, electrotherapies (e.g., transcutaneous nerve

stimulation and electrostimulation of muscles), and laser therapy in the treatment of

RA. Heat treatments in general should be avoided during periods of active joint

inflammation because heat can further exacerbate pain and swelling.

36

While symptoms of RA may be controlled by conservative management, more

aggressive therapy is needed to prevent disease progression and disability.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often used to provide rapid antiinflammatory and analgesic effects. However, they do not prevent or slow joint

destruction as compared to the disease-modifying antirheumatic drugs (DMARDs)

and should be reserved for rapid symptomatic relief while awaiting DMARD onset

of action. DMARDs do alter long-term disease course. As such they are the mainstay

of pharmacologic care and should be initiated in all patients as soon as they are

diagnosed with RA.

26–28 Specific choice of treatment is individualized based on joint

function, degree of disease activity, patient age, sex, occupation, family

responsibilities, drug costs, and results of previous therapy. The two classes of

DMARDs are synthetic chemical compounds (sDMARDs) and biologic agents

(bDMARDs). With the recent advent of tofacitinib, EULAR has further subdivided

sDMARDs into the conventional sDMARDs (csDMARDs) and targeted sDMARD

(tsDMARD).

26,27

csDMARDs (e.g., hydroxychloroquine [HCQ], sulfasalazine [SSZ], methotrexate

[MTX], and leflunomide [LEF]) have demonstrated the ability to slow disease

progression. These agents, alone or in combination, are considered as initial therapy

for most patients and in the absence of contraindication, MTX is the treatment of

choice because of its strong efficacy and favorable safety profile. Other csDMARDs

such as azathioprine [AZA], gold, and D-penicillamine are rarely used because of

slow onset of action and toxicity profile.

26,27 The first and only tsDMARD,

tofacitinib, is considered in those with moderate-to-severe disease who have failed

treatment with or are intolerant to methotrexate.

37

The bDMARDs, also referred to as anticytokines, biologics, biologic modifiers,

or biologic response modifiers, target the physiologic proinflammatory and jointdamaging effects of inflammatory mediators, including TNF-α, IL-1, IL-6, T cell, and

B cells. Agents in this class include the TNF-α inhibitors (adalimumab [ADA],

certolizumab pegol [CZP], etanercept [ETA], golimumab [GLM], and infliximab

[IFX]), anti-IL-1 receptor antagonist (anakinra), anti-B cell therapy (rituximab

[RXB]), IL-6 receptor antagonist (tocilizumab [TCZ]), and the T cell modulator

(abatacept [ABT]). The bDMARDs are typically reserved for patients who fail to

achieve an adequate response with csDMARD monotherapy.

28

Corticosteroids are also potent anti-inflammatory agents that slow the progression

of joint damage in RA. However, long-term systemic use should be avoided because

of serious adverse effects associated with chronic therapy. Short-term oral therapy

may be reserved as bridge therapy in early RA with moderate-to-high disease

activity while awaiting onset of DMARD activity, brief periods of active disease, or

with therapy failure.

28 Local intra-articular injections may be used for isolated joints

experiencing disease flares.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

NSAIDs have a long history of use in RA treatment. They are effective for providing

short-term pain and inflammation control but do not alter disease course.

38

In

addition, NSAIDs are associated with side effects related to COX inhibition such as

GI intolerance, nephrotoxicity, and increased risk of bleeding and cardiovascular

events. The cardiovascular risk associated with some agents is particularly

concerning since RA patients are at higher cardiovascular mortality risk. Therefore,

given both the safety profile and the lack of long-term disease-modifying efficacy,

NSAID use should be judicious and reserved only as an adjunct to DMARD

therapy.

38,39

Although NSAIDs differ in chemical structure, they generally have similar

pharmacologic properties (e.g., antipyresis, analgesia, anti-inflammatory activity,

and inhibition of prostaglandin synthesis), mechanisms of action (i.e., inhibition of

COX activity), pharmacokinetic properties (e.g., highly protein bound and

extensively metabolized to renally cleared inactive metabolites), and side effect

profile.

40 Aspirin, an acetylated salicylate, is the standard against which the

effectiveness of all other NSAIDs are measured. Other NSAIDs are available,

including nonacetylated salicylates

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(e.g., salsalate, choline salicylate, and magnesium salicylate) and nonsalicylate or

nonaspirin NSAIDs (e.g., ibuprofen, naproxen, and cyclo-oxygenase [COX]

inhibitors). (Note: For simplicity and clarity, the term NSAID is used henceforth to

describe NSAIDs other than acetylated [i.e., aspirin] and nonacetylated

salicylates.)

38–40 Choice of particular NSAID has traditionally been based on cost,

duration of action, and patient preference because of interpatient variability in

response. Courses of several different NSAIDs, even those within the same chemical

class, may be necessary to determine the best choice for an individual patient.

CONVENTIONAL SYNTHETIC DISEASE-MODIFYING ANTIRHEUMATIC

DRUGS (csDMARDs)

With rare exception, every patient should receive csDMARD therapy soon after

diagnosis to minimize loss of joint integrity, function, and risk of cardiovascular

disease related to RA.

26,28 Although csDMARDs have the potential to cause serious

toxicity, they can substantially reduce joint inflammation, reduce or prevent joint

damage, maintain joint function and integrity, and ultimately reduce health care costs

and allow patients to remain productive.

26,27 The onset of action of most csDMARDs

is slow over 3 to 6 months; however, SSZ, MTX, and LEF can be beneficial within 1

to 2 months.

38 Several factors must be considered when selecting a csDMARD,

including convenience of administration, monitoring requirements, medication and

monitoring costs, time to therapeutic onset, and frequency and severity of adverse

reactions.

MTX, a folate antimetabolite with immunosuppressive and anti-inflammatory

properties, remains the mainstay first-line DMARD because of its relatively rapid

onset of action and excellent history of efficacy and safety.

26,28 LEF and SSZ are

recommended if a contraindication to MTX is present, or if intolerance to MTX

occurs. The primary metabolite of LEF, A77 1726 (M1), is responsible for nearly all

of its pharmacologic activity. Although the exact mechanism of M1 is not completely

understood, it is known that M1 inhibits dihydro-orotate dehydrogenase, an enzyme in

cell mitochondria responsible for catalyzing an important step in de novo pyrimidine

synthesis; this is believed to be its main mechanism of action. SSZ appears to induce

anti-inflammatory effects through one of its active metabolites, mesalamine, which is

believed to inhibit both COX and lipooxygenase. HCQ as monotherapy or in

combination may be used for relatively mild cases of RA.

26 The mechanism of antiinflammatory effect of HCQ may be attributable to inhibition of migration of

neutrophils and eosinophils, histamine and serotonin blockade, or inhibition of

prostaglandin synthesis. Older csDMARDs such as azathioprine, cyclosporine,

minocycline, and gold are no longer recommended because of the superior risk–

benefit ratio of other csDMARDs, bDMARDs, and tofacitinib.

28

TARGETED SYNTHETIC DMARD (tsDMARD)

Tofacitinib was recently placed in its own medication subcategory by ACR and

EULAR since the janus kinase (JAK) inhibitor, a targeted molecule involved with

inhibition of signal transduction pathways, is mechanistically different from the

csDMARDs. Tofacitinib inhibits JAKs, enzymes that stimulate inflammatory

cytokines; therefore, inhibition modulates leukocyte function and immune response. It

is indicated for individuals with moderate-to-high disease activity who have failed

csDMARD monotherapy.

26,28

BIOLOGIC DMARDs (bDMARDs)

In general, the bDMARDs are reserved for patients who have failed to respond to

one or more csDMARDs alone or in combination. The ACR and EULAR guidelines

recommend the use of bDMARDs in patients with established RA who experience

moderate or high disease activity despite csDMARD monotherapy.

26,28 The ACR

guidelines also recommend the use of bDMARDs in early RA (<6 months) in patients

with moderate-to-high disease activity despite csDMARD monotherapy.

28 Since the

late 1990s a total of nine biologic agents have been approved for RA treatment. The

earliest biologic agents targeted proinflammatory cytokines, such as TNF-α and IL-1,

which play key roles in the immunopathogenesis of RA.

41 These cytokines are

abundant in rheumatoid synovial tissues and fluid. Most cytokines can independently

induce expression of the others, and IL-1 is capable of upregulating its own

expression.

42 Excessive macrophage-produced cytokines (e.g., TNF-α, IL-1, IL-6,

and IL-8) correlate closely with RA disease activity and severity. Most importantly,

RA improves when the physiologic action of TNF-α or several different ILs are

suppressed. In more recent years, new agents have been developed to target

additional key processes in RA, including T cell costimulation, the depletion of

CD20+ B cells, and the inhibition of IL-6.

39

The proinflammatory cytokine TNF-α is produced by activated macrophages and T

cells in RA-affected joints. It also plays a role in keeping infections localized by

increasing platelet activation and adhesion, resulting in local blood vessel occlusion

and containment of infection. This action of TNF-α is responsible for its tumor

necrosis properties, thus leading to the name. TNF-α exerts its physiologic effects by

binding to two different cell-surface receptors known as p55 (i.e., 55 kDa) and p75

(i.e., 75 kDa) on inflammatory cells.

41 These receptors, with portions extending from

within the cell cytoplasm to the cell exterior, are capable of binding TNF-α to the

domains extending above the cell surface. Soluble forms of these receptors can be

found in the serum and synovial fluid and seem to play a role in regulating TNF-α.

Two approaches have targeted the action of TNF-α: (1) the use of soluble TNF

receptors with high TNF-binding affinity (i.e., etanercept) and (2) antibodies against

TNF-α (i.e., infliximab, adalimumab, golimumab, and certolizumab pegol).

39

Etanercept is a recombinant TNF-receptor Fc fusion protein with the extracellular

portion of two p75 receptors fused to the Fc portion of human immunoglobulin G1

(IgG1).

43,44

Infliximab is a chimeric IgG monoclonal antibody directed against

TNF-α, and adalimumab is a genetically engineered human IgG1 monoclonal

antibody.

45,46 Certolizumab pegol is a polyethylene glycolated (PEG) Fab fragment of

a humanized anti-TNF monoclonal antibody. Golimumab is a fully human anti-TNF-α

IgG1 monoclonal antibody that targets and neutralizes both soluble and membranebound forms of TNF-α.

48,49 All five TNF-α inhibitors render TNF biologically

unavailable and are highly effective in reducing RA disease activity. Currently, there

is no conclusive evidence from well-controlled comparative trials that any one

TNF-α inhibitor is superior to another with regard to efficacy and safety.

50

Comparative efficacy and safety will be discussed further in the section

“Pharmacologic Treatment.” TNF-α inhibitor selection may be driven by cost,

insurance coverage, provider preference, and patient-specific factors.

There are also three non-TNF biologic agents recommended for RA patients who

have not responded to at least one csDMARD, which include abatacept, rituximab,

and tocilizumab.

28 Each of these agents possesses a novel mechanism of action

targeting either T cells, B cells, or IL-6. Abatacept and tocilizumab may be

considered as first-line biologic DMARDs along with the TNF-α inhibitors.

However, rituximab should only be considered as a first-line bDMARD in the

presence of certain contraindications (i.e., recent history of lymphoma, latent TB

with contraindications to treatment, or history of demyelinating disease) to the other

bDMARDs.

26 There is also one final bDMARD, anakinra, which is seldom used

because of lack of comparative efficacy. Anakinra

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is a recombinant human interleukin-1 (IL-1) receptor antagonist, which inhibits the

binding of cytokines IL-1a and IL-1b to their receptor.

39

In healthy individuals, IL-1

overexpression is prevented by naturally occurring IL-1Ra.

41,51 Consequently,

inadequate production of IL-1Ra, relative to IL-1, is hypothesized to be an important

contributor to active RA. In addition to proinflammatory properties, IL-1 augments

cartilage damage and inhibits bone formation. Anakinra has not shown comparable

efficacy against other bDMARDs in meta-analyses and is infrequently used, although

some individuals may still respond to this agent.

26,27 Anakinra was not included in the

most recent ACR 2015 guidelines owing to lack of any new data since 2012 and

infrequent use in RA.

28

Abatacept is a selective costimulation modulator that inhibits T cell activation.

52

For T cells to be fully activated, a CD80/CD86:CD28 costimulatory signal is

required.

53 This costimulation is blocked by cytotoxic T-lymphocyte–associated

antigen 4. Abatacept, a soluble fusion protein consisting of extracellular cytotoxic Tlymphocyte–associated antigen 4 attached to the Fc portion of IgG1, which inhibits T

cell activation by preventing the binding of CD80 and CD86 ligands on the surface of

APCs to the CD28 receptor on the T cell.

53

Rituximab, is a chimeric monoclonal antibody, binds to the CD20 antigen on the

surface of pre-B cells and mature B cells, resulting in the depletion of B cells from

peripheral blood, lymph nodes, and bone marrow.

54 Stem cells, pro-B cells, and

antibody-producing plasma cells do not express CD20 and are not affected by RXB.

The exact role of B cells in RA pathogenesis is not known. However, studies have

shown that B cells may contribute to the autoimmune and inflammatory processes by

producing RF, acting as APCs, activating T cells, and producing proinflammatory

cytokines.

54 Owing to its chimeric composition, RXB must be administered with

MTX to reduce the risk of human antichimeric antibody (HACA) formation.

55,56

Inhibition of T cell activation and depletion of proinflammatory B cells result in

significant reductions in RA-related inflammation and joint destruction.

Tocilizumab is a humanized anti–IL-6 receptor antibody. The pleiotropic

proinflammatory cytokine IL-6 is produced by a variety of cell types including

lymphocytes, monocytes, and fibroblasts and is involved in multiple immunologic

processes, including T cell activation and B-cell proliferation.

57 When bound to the

soluble IL-6 receptor, IL-6 activates chemokine production and upregulates

expression of adhesion molecules. This leads to the recruitment of leukocytes at

inflammatory sites, thus implicating IL-6 as an important factor in RA.

58,59 High

levels of IL-6 have been found in the serum and joints of patients with RA.

Additionally, IL-6 has been shown to induce proliferation of osteoclasts, which may

be a component of the bone degradation seen in RA.

58,59 TCZ is a humanized,

monoclonal antibody that can bind to both membranous and soluble IL-6 receptors.

This blockade prevents the interaction of IL-6 with the IL-6 receptor, thus

interrupting the inflammatory pathways that contribute to the disease processes in

RA.

58,59

Owing to their immunosuppressive nature, all bDMARDs should be avoided in

patients with serious infections until the infection has been controlled. All five of the

TNF-α inhibitors as well as tocilizumab carry boxed warnings for serious infections.

Although these infections occurred primarily among patients with significant risk

factors for infection (e.g., poorly controlled diabetes, concurrent corticosteroid use,

or concomitant csDMARD therapy), biologic agents should not be given to patients

with active infection, history of recurring infections, or medical conditions

predisposing them to infection. There has been some debate regarding whether or not

bDMARDs are associated with an increased risk of serious infections when

compared to csDMARDs. A recent meta-analysis including all currently available

bDMARDs concluded that standard and high-dose biologic DMARDs are associated

with an increase in risk of serious infections compared to csDMARDs. Risk was

increased whether or not the patient was using csDMARDs concomitantly. However,

low-dose bDMARDs were not associated with increased risk.

60