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Label
Rheumatoid Arthritis (RA)

DefinitionEtiologyEpidemiologyPathophysiologyClinical Presentation
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Definition:

A chronic systemic inflammatory autoimmune disease of unknown cause, involving synovial joints, resulting in joint deformities and functional limitations if not adequately controlled. The disease can also produce systemic inflammation and involve extra-articular structures and organs (e.g. skin, lungs, heart and eyes).

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Etiology:

The precise cause is unknown. Various factors can contribute and include:

  1. Environmental: Smoking induces formation of citrullinated peptides in susceptible individuals leading to formation of antibodies to Cyclic Citrullinated Peptides (anti-CCP) and Rheumatoid Factors (RF) triggering auto-immunity which underlies Rheumatoid Arthritis (RA)
  2. Infection: Various pathogens (e.g. viruses and mycoplasma) induce inflammation and triggers autoimmunity in a susceptible host leading to RA. None of the potential pathogens appear to be RA specific, and no specific pathogen is definitely linked to RA
  3. Hormonal: Female predominance, ~3 fold >males. Estrogen may play a role in RA development by facilitating immune system activation
  4. Genes: Play role in susceptibility
    • May account for ~50% risk of developing RA
    • May impact disease severity
    • Class II MHC genes (containing a specific 5-amino acid sequence in the hyper variable region of HLA-DR4, called the SHARED EPITOPE), have been implicated
  5. Immunologic Factors:
    • Complex process involving T and B lymphocytes, antigen presenting cells (macrophages and dendritic cells) and cytokines. The latter may have pleiotropic actions and multiple targets and may exhibit both pro-inflammatory and anti-inflammatory actions. Controlling the balance between competing cytokines is considered as an important therapeutic goal. Key pro-inflammatory cytokines are TNF, IL-1, and IL-6
    • T cells activates macrophages/synovial fibroblasts which produces proinflammatory cytokines leading to initiation of RA
    • B cells produce autoantibodies/cytokines eventually contributing to pathological injury
  6. The synovial membrane is ultimately transformed into pannus tissue with activated synovial cells and osteoclasts eroding cartilage and bone
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Epidemiology:
  • Rheumatoid arthritis (RA) affects about 1% of the population
  • Women are affected ~3 times more than men
  • Onset may be at any age, most often appears between the ages of 35 and 50
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Pathophysiology:

Pathogenesis is not completely understood, but may include:

  • Autoimmune reaction triggered by infection/trauma → synovial hypertrophy → joint inflammation (synovitis)
  • Subsequent uncontrolled inflammation → cartilage and bone destruction
  • Increased immune activity in genetically susceptible individuals, facilitate the disease
  • Immune activity involves:
    • T cells, phagocytes, fibroblasts, osteoclasts, and neutrophils
    • B cells produce characteristic autoantibodies (i.e. rheumatoid factors [RFs] and anti-CCP)
    • Aberrant production of numerous cytokines, inflammatory mediators (e.g. TNF & IL-1), and growth factors ensues
  • Inflammation, excessive proliferation of synovium, formation of granulation tissue (i.e. pannus) promotes tissue destruction
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Clinical Presentation:
  • Some experience a gradual onset, with slow progression of signs and symptoms, however many patients may present with progressive joint pain and stiffness, functional limitation and radiographic damage
  • RA is also associated with significant morbidity and increased mortality, primarily related to cardiovascular disease and infections
  • RA has been redefined as of 2010 by ACR/EULAR, based on the following criteria

Signs and symptoms include:

  • Gradual onset, slowly progressive joint pain
  • Morning stiffness ( may last 45 minutes or longer)
  • Functional limitation
  • Constitutional symptoms
    • Fatigue/malaise
    • Anorexia
    • Generalized weakness
    • Low grade fever
  • Boutonniere deformity: PIP joint is flexed and DIP joint hyperextended
  • Swan-neck deformity: DIP joint is flexed and the PIP joint is hyperextended
  • Baker's cyst: The synovial sac of knee joint produces a bulge into the popliteal space and forms a cystic swelling, which can rupture and cause pain

Extra-articular manifestations:

  • Less common with better therapy
  • Subcutaneous rheumatoid nodules at sites of pressure and chronic irritation
  • Damage to the ligaments and tendons
  • Vasculitis causing leg ulcers
  • Lymphadenopathy
  • Felty's syndrome (splenomegaly and leukopenia)
  • Sjögren's syndrome (dry eyes, mouth, skin etc.)
  • Scleromalacia
  • Episcleritis
  • Involvement of the cervical spine can cause atlantoaxial subluxation and spinal cord compression
  • Cardiac: Pericarditis, valvular disease, pericardial effusion (usually asymptomatic)
  • Lung: Pleural effusion with very low glucose level, pulmonary nodules, infiltrates and fibrosis
  • Blood: Anemia with normal MCV
  • Nerve: Mononeuritis multiplex
  • Skin: Nodules at pressure points
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Investigation and Workup:

History:

Detailed history should include:

  • History of joint pain
    • Duration
    • Number of joints involved
    • Frequency
  • History of stiffness/swelling over the joints
  • History of constitutional symptoms e.g. fatigue, malaise, weakness
  • Inquiries about quality of life
  • Inquiries if disease interferes with daily activities
  • Family history of RA

Physical Examination:

Is required for assessment of joint inflammation and structural deformity, by the clients care giver and should include:

  • Assessment of symmetric joint swelling is characteristic of RA
  • Palpation of joint can distinguishes swelling from bony enlargement
  • Pain occurring with both active and passive movement is a hallmark of joint inflammation should be reported
  • Persistent inflammation of tendons and muscles of the joints

Laboratory Tests:

The presence of prognostic features should be assessed at baseline and considered when making treatment decisions; they are also used to monitor the disease activity and medication effects:

Pretreatment or baseline investigations include:

  • CBC, LFTs, urea, creatinine
  • ESR-usually elevated as is CRP paralleling the disease activity
  • CRP (C reactive protein)
  • RF (rheumatoid factor); an immunoglobulin antibody
    • Present in ~75% of patients
    • Reflects disease activity to some extent, but not usually measured serially
  • ANTI-CCP (anti-cyclic citrullinated peptide antibodies) highly specific in early disease

Screening before starting biologic therapy:

  • Hepatitis B and C (and HIV in high-risk patients)
  • Screening for latent tuberculosis is recommended prior to anti-TNF, abatacept, and tocilizumab
  • Baseline antinuclear antibody (ANA) may be considered

Imaging:

X-rays:

  • First choice for screening of affected joints

MRI:

  • Expensive but may provide more detail of erosions, synovitis and bone edema

Ultrasound:

  • May help in visualizing effusions, erosions and synovitis by Grey scale and power Doppler assessments
  • Helpful in assessing some joints (e.g. hip joints) in obese patients

Bone scan:

  • Radionuclide scans distinguish between inflammatory and non-inflammatory processes
  • Bone densitometry (DEXA) provides info regarding osteoporosis

Diagnostic procedures:

  • Arthrocentesis: To diagnose superimposed septic arthritis

Diagnostic criteria:

  • Early intervention improves disease outcome and decreases joint damage
  • The criteria are aimed at assessing those with clinical synovitis or with synovitis not explained by any other cause. The number and types of joints (large and/or small) involved, serology for (rheumatoid factor) RF and/or (anti-citrullinated protein antibody) ACPA, acute phase reactants (CRP and ESR) and duration of symptoms are all taken into account when making the diagnosis of RA. Patients presenting with new symptoms as well as those with existing erosive disease should be reassessed to determine if they fulfill the 2010 criteria for RA
  • RA has been redefined as of 2010 by ACR/EULAR, based on the following criteria
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Treatment Goals:
  • Inhibit disease progression by early diagnosis and intervention
  • Achieve remission or at least Low Disease Activity
  • Relieve the signs and symptoms
  • Improve quality of life
  • Reduce joint pain and limit functional disability
  • Reduction of inflammation
  • Protection of articular structures
  • Maintain and improve joint function and mobility
  • Control of systemic involvement
  • Emphasize weight reduction to overweight
  • Educate about self-management skills
  • Identify and treat any associated comorbidities
  • Minimal or no adverse effects from medications
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Therapeutic Choices:
  • Pharmacological Interventions
  • Non-pharmacological Interventions
  • Surgical Interventions

PHARMACOLOGICAL INTERVENTIONS:

  • Patients are symptomatically treated as they present to the clinic. Previously undiagnosed patients with possible RA diagnosis should be given an urgent referral to the rheumatologist for definitive diagnosis and treatment
  • Treatment approach has undergone major changes over the years:
    • NSAIDs are beneficial only for relief of symptoms
    • NSAIDs have no effect on disease retardation
    • Irreversible joint damage may occur in early disease

1. NSAIDs:

  • Recommended for the relief of symptomatic pain and inflammation (if present)
  • No longer used as the sole first-line agent for RA

2. Disease modifying antirheumatic drugs (DMARDs):

Start DMARDs immediately if patient has active disease.

  • Active RA patients: Require frequent monitoring (every 1-3months)
  • Patients with well controlled disease: May be monitored less frequently
  • DMARD: Should be adjusted every 3-6 months, to achieve treatment goals

REF: Bykerk V P et al. J Rheumatol 2011; 38:11

Types of DMARDs:

  • Nonbiologic
  • Biologic

A. Nonbiologic DMARDs:

Includes and are usually chosen to initiate therapy, due to fast onset of action and less toxicity

  • Methotrexate (MTX): Most preferred of all the DMARDs
    • 7.5-25 mg per week PO, plus folic acid 5 mg PO daily to prevent from toxicity
    • Although unlabeled route; SC route may be more effective and better tolerated, especially at doses greater than 15 mg/week. Dose should be escalated quickly to at least 15-20 mg/week in most patients
    • Monitor CBC, renal, and liver function every 8-12 weeks
    • Contraindicated in renal disease
    • Most patients treated with MTX exhibit clinical and radiological improvement, a change in therapy should be considered in patients with radiographic progression despite adequate clinical response
  • Sulfasalazine: 500 mg/day; max: 2-3 g/day; 3-month trial. Monitor CBC, liver enzymes every 8-12 weeks. Screen for G6PD deficiency
  • Hydroxychloroquine: Dose is based on body weight not to exceed 400 mg/day; or 6.5 mg/kg/day in general. Used in milder forms or in combination with other DMARDs. Yearly ophthalmologic exam. Adjust dose in renal insufficiency
  • Minocycline /Cyclosporin/Azathioprine: Can be considered as alternative options
  • Leflunomide: 10-20 mg/day. Modifies T-cell function to decrease autoimmune activity and reduce structural damage. Side effects: GI disturbances, hair loss, hypertension, liver and lung toxicity; also potentially teratogenic
  • Intramuscular gold /D-penicillamine: Rarely induce sustained remission. Have been largely replaced by more effective agents

Note: Glucocorticoids may be used for flare-ups while initiating or waiting for DMARDs to take affect. Lowest possible effective dose for short time period is suggested

  • Prednisone: 5-10mg/day is commonly used in patients to bridge the therapy in early RA. Once the disease is controlled; it should be weaned to the lowest possible dose, and then stopped to avoid adverse effects
  • Combination therapy with DMARDs indicated if:
    • Poor prognostic features
    • Moderate to high disease activity in newly diagnosed patients
    • Poor response to monotherapy
  • MTX is used as an anchor agent

 

B. Biologic DMARDs:

  • Switch to biological agents if:
    • At least 2 nonbiologic DMARDs (including MTX), have failed to control disease activity with mono or combination therapy after 3 months of targeted dose
  • Agents include:
    • Tumor necrosis factor inhibitors
      • Infliximab
      • Adalimumab
      • Etanercept
      • Golimumab
      • Certolizumab pegol
    • T cell costimulatory inhibitors
      • Abatacept (ABAT)
    • B lymphocyte depleting agent
      • Rituximab (RTX)
    • Interleukin 6 (IL-6) antagonist
      • Tocilizumab (TCZ)
    • IL-1receptor antagonist
      • Anakinra

No evidence to suggest that one is superior to the other, though anakinra appears to be least effective agent, except for Adult Still's disease variant of RA. Combination with MTX appears to be the most effective regimen for most biologics.

If a patient achieves sustained remission after discontinuation of NSAID and glucocorticoids, a reduction in traditional and biologic DMARD can be attempted.

 

NON-PHARMACOLOGICAL INTERVENTIONS:

Supportive measures

  • Nutrition
  • Rest
  • Physical measures
    • Joint splinting
    • Orthopedic or athletic shoes
    • Exercises
    • Heat and cold therapy
    • Paraffin baths
    • Massage

Surgical Interventions:

  • Tendon reconstruction, joint fusion, and joint replacement are potential treatment modalities to prevent disability in advanced RA

Follow-up Recommendations

  • Monitor patient regularly
  • Address risk factors and evaluate for osteoporosis, a major comorbidity that can result from the disease itself or corticosteroid use
  • Cardiovascular disease is the number one cause of death. Evaluate and manage CV risk factors; low dose aspirin may be used as prophylactic therapy

Prognosis

  • Poor prognostic findings:
    • Persistent moderate to severe disease
    • Positive anti-CCP antibody
    • Inheritance of shared epitope
    • Early or advanced age at disease onset
  • 50% cannot function in primary job within 10 years of onset

 

MEDICATIONS:

NSAIDs-Analgesic

TYPES

  • Salicylates
  • Acetic acid derivatives
    • Diclofenac
    • Etodolac
    • Indomethacin
    • Sulindac
  • Enolic acid (Oxicam) derivatives
    • Meloxicam
    • Piroxicam
    • Tenoxicam
  • Napthylkanone derivatives
    • Nabumetone
  • Propionic acid derivatives (profens)
    • Fenoprofen
    • Flurbiprofen
    • Ibuprofen
    • Ketoprofen
    • Naproxen
    • Oxaprozin
  • COX-2 inhibitors
    • Celecoxib

NSAIDs Mechanism(s):

  • Prostaglandins are common locally produced chemicals mediating pain, fever, and inflammation
  • These drugs reversibly inhibit cyclooxygenase-1 and 2 (COX-1 and 2) enzymes
  • This results in decreased formation of prostaglandin precursors

Acetylsalicylic acid: (additional MODE OF ACTION)

  • Irreversibly interferes with the production of thromboxane A2 within the platelet, thus inhibiting platelet aggregation

NSAIDs Doses:

Salicylates: (rarely used for RA therapy at present)

Aspirin

  • 325-650 mg PO daily, every 4-6 hrs; Max. 4 g/day

Diflunisal

  • 500-1000 mg/day PO in 2 divided doses

Renal impairment:

  • ClCr<50 mL/minute: Decrease by 50% of normal dose

 

Acetic Acid Derivatives:

Diclofenac

  • Immediate-release: 50 mg PO BID or TID; Max. 150 mg/day
  • Slow-release: 75-100 mg PO once a day; Max. 150 mg/day
  • Rectal suppository: 50-100 mg/day; Max. 100 mg/day or combined dose(rectal+oral) is 150 mg/day

Diclofenac/Misoprostol

  • 50 mg/200 mcg and 75 mg/200 mcg tablets; Max. 150 mg Diclofenac/day

Etodolac

  • Immediate-release: 200-300 mg PO BID or TID; Max. 1000 mg/day

Indomethacin

  • 25-50 mg PO BID or TID; Max. 200 mg/day
  • Extended-release: 75 mg PO BID or TID; Max. 150 mg/day

Sulindac

  • 150-200 mg PO BID; Max.400 mg/day

 

Enolic Acid (Oxicam) Derivatives:

Meloxicam

  • 7.5 mg PO once daily; may increase to 15 mg daily; Max. 15 mg/day

Piroxicam

  • 10-20 mg PO once daily; Max. 20 mg/day

Tenoxicam

  • 10-20 mg PO once daily; usual dose 20 mg PO once daily

 

Napthylkanone Derivative:

Nabumetone

  • 1000 mg PO once daily; may increase upto 2000 mg/day in 2 divided doses

Renal impairment:

  • ClCr 30-49 mL/minute: 750 mg/day may increase upto 1500 mg/day

 

Propionic Acid Derivatives (profens):

Fenoprofen

  • 300-600 mg PO TID or QID; Max. 3.2 g/day

Flurbiprofen

  • 200-300 mg PO daily in 2,3 or 4 divided doses
    Note: Do not administer more than 100 mg per single dose; Max 300 mg/day

Ibuprofen

  • 200-800 mg PO TID or QID; Max. 3.2 g/day

Ketoprofen

  • Regular release: 150-200 mg PO TID or QID; Max. 300 mg/day
  • Extended release: 200 mg PO daily
  • Renal impairment:
  • Mild: 150 mg/day
  • Severe (Clcr <25mL/min): 100 mg/day

Naproxen

  • Regular release: 250-500 mg PO BID; may increase to 1.5 g/day
  • Extended release: 750-1000 mg PO BID or once daily
  • EC-Naproxen + IR-Esomeprazole: 375/20 mg or 500/20 mg PO BID

Oxaprozin

  • 600-1200 mg PO daily; Max. 1800 mg or 26 mg/kg, whichever is less

 

COX-2 inhibitors:

Celecoxib

  • Initial 100 mg PO BID may increase to 200 mg/day PO BID; Max. 200 mg/day

 

Analgesic, Non-NSAID

  • Acetaminophen

Mechanism:

  • Analgesic action: Inhibits the synthesis of prostaglandins in the central nervous system
  • Antipyretic action: Inhibits the hypothalamic heat-regulating center

Dose:

Acetaminophen

  • 325-650 mg PO every 4-6 hrs or 1000 mg PO TID or BID; Max. of 4 g/day and 1 gm/dose

 

Corticosteroid

  • Betamethasone
  • Methylprednisolone acetate (most commonly used)
  • Triamcinolone acetonide
  • Triamcinolone hexacetonide

Mechanism:

  • Decreases inflammation and the normal immune response through multiple mechanisms, also suppresses adrenal function at high dose, also has mineralocorticoid activity.

Doses:

Betamethasone (Intra-articular):

  • Hip: 1-2 ml
  • Knee, ankle, shoulder: 1 ml
  • Elbow, wrist: 0.5-1 ml
  • Metacarpophalangeal, sternoclavicular: 0.25-0.5 ml

Methylprednisolone (Intra-articular):

  • Ankle, shoulder: 40 mg dose
  • Hip: 80-160 mg
  • Knee: 40-80 mg
  • Elbow, wrist: 20-40 mg
  • Small joint like MCP, PIP, DIP, SC joint: 10 mg

Triamcinolone acetonide (Intra-articular):

  • Large joints: 5-40 mg
  • Small joints: 2.5-10 mg

Triamcinolone hexacetonide (Intra-articular):

  • Large joints: 10-20 mg
  • Small joints: 2-6 mg

 

NONBIOLOGIC DMARDs

Antimetabolite/Antirheumatic Agent

  • Methotrexate

Mechanism:

  • It is a folate antagonist that inhibits DNA synthesis and cell reproduction
  • Inhibits purine and thymidylic acid synthesis
  • It also has immune modulator and anti-inflammatory actions

Dose:

Methotrexate

  • Oral: Initiate at 7.5-15 mg/week PO given as a single dose or divided in 3 equal doses at 12 hour intervals for 3 doses along with folic acid; Max. 25 mg/week
  • Subcutaneous: 7.5-25 mg once weekly

 

Anti-inflammatory (5-Aminosalicylic Acid Derivative)

  • Sulfasalazine

Mechanism:

  • Actual mechanism not determined
  • Interferes with secretion by prostaglandin synthesis inhibition

Dose:

Sulfasalazine

Slow release formulation prescribed as follows:

  • Week 1 = 500 g/day PO at bed time daily
  • Week 2 = 500 g/day PO BID
  • Week 3 = 500 g/day PO in the morning and 1000 g PO at bedtime
  • Week 4 and onwards: 1000 g/day PO BID
  • Note: May increase to maximum 3 g/day, if response to 2 g/day is inadequate after 2 months of use

 

Antirheumatic Agent, Gold Compound

  • Sodium Aurothiomalate (rarely used in current management of RA)

Mechanism:

  • Unknown, may decrease prostaglandin synthesis or may alter cellular mechanisms by inhibiting sulfhydryl systems
  • It exhibits anti-inflammatory, antiarthritic and immunomodulating effects

Dose:

Sodium Aurothiomalate

  • Intramuscular Injections: 1st week: 10 mg IM, 2nd week: 25 mg IM, then 25 to 50 mg IM weekly for the next 20 weeks or until toxicity occur
  • Maintenance: 50 mg IM tapered progressively to every 2 to 4 weeks according to clinical response and tolerance, and maintained indefinitely

 

Antirheumatic-Immunomodulator Agent

  • Leflunomide

Mechanism:

  • Inhibits pyrimidine synthesis via dihydroorotate dehydrogenase, resulting in antiproliferative and anti-inflammatory effects

Dose:

Leflunomide

  • 20 mg PO daily; may decrease dose to 10 mg PO daily if 20 mg PO is not tolerated well

 

Anti-inflammatory-Antimalarial

  • Hydroxychloroquine

Mechanism:

  • Exact mode of action in controlling these diseases is unknown
  • Antirheumatic/immunosuppressive effects: Inhibits rheumatoid factor, acute phase reactants, and many enzymes

Dose:

Hydroxychloroquine (rarely used now)

  • Start 200-400 mg/day PO; do not exceed 6.5 mg/kg dose
  • Note: Eye checkups for retinal toxicity required on an annual basis

 

Immunosuppressant Agent

  • Azathioprine

Mechanism:

  • Complete mechanism of immunosuppression is not fully known
  • It antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins
  • May also interfere with cellular metabolism and inhibit mitosis

Dose:

Azathioprine

  • Start 1 mg/kg/day PO daily or in 2 divided doses for 6-8 weeks; may increase by 0.5 mg/kg every 4 weeks, up to 2.5 mg/kg/day; for minimum of 12 weeks
  • Maintenance dose: Reduce dose by 0.5 mg/kg (~25 mg daily) every 4 weeks until lowest effective dose is reached

 

BIOLOGIC DMARDs

Tumor necrosis factor (TNF) Inhibitors

  • Infliximab
  • Adalimumab
  • Etanercept
  • Certolizumab pegol
  • Golimumab

Mechanism:

  • Neutralizes the biological activity of TNFα by
    • Binding with high affinity to the soluble and transmembrane forms of TNFα
    • Inhibits binding of TNFα with its receptors
  • Leads to an overall reduction in inflammation

Note: Etanercept also neutralize TNFβ (lymphotoxin α)

Dose:

Infliximab

  • In combination with methotrexate: 3 mg/kg IV at 0, 2, and 6 weeks, then 3 mg/kg IV every 8 weeks thereafter; may increase dose to 10 mg/kg or decrease dosing interval to as often as every 4 weeks if needed

Adalimumab

  • 40 g SC every other week; may increase dose to 40 mg SC every week

Etanercept

  • 50 mg SC once weekly; may be given as 25 mg SC twice weekly (individual doses should be at 3 or 4 days apart)

Certolizumab pegol

  • 400 mg SC at 0, 2 and 4 weeks; then 200 mg every other week; may consider maintenance dose of 400 mg every 4 weeks

Golimumab

  • In combination with methotrexate: 50 mg SC once per month

 

Antirheumatic, Disease Modifying; Interleukin-1 Receptor Antagonist

  • Anakinra (used only for adult Still's disease variant of RA)

Mechanism:

  • Antagonist of the interleukin-1 (IL-1) receptor
  • Endogenous IL-1 is induced by inflammatory stimuli and mediates a variety of immunological responses, including degradation of cartilage (loss of proteoglycans) and stimulation of bone resorption

Dose:

Anakinra

  • 100 mg SC once daily. Administer at approximately the same time each day

Renal impairment

  • ClCr <30 mL/min or End Stage Renal Disease: 100 mg SC every other day

 

Antirheumatic, Disease Modifying; Interleukin-6 Receptor Antagonist

  • Tocilizumab

Mechanism:

  • Antagonist of the interleukin-6 (IL-6) receptor
  • Endogenous IL-6 is induced by inflammatory stimuli and mediates a variety of immunological responses
  • Inhibition of IL-6 leads to a reduction in cytokine and acute phase reactant production

Dose:

Tocilizumab

  • 4 mg/kg IV infusion over 1 hour every 4 weeks; may be increased to 8 mg/kg based on clinical response. Maximum 800 mg/infusion

 

Antirheumatic, Disease Modifying; Selective T-Cell Costimulation Blocker

  • Abatacept

Mechanism:

  • Selective costimulation modulator
  • Inhibits T-cell (T-lymphocyte) activation by binding to CD80 and CD86 on antigen presenting cells (APC), thus blocking the required CD28 interaction between APCs and T cells

Dose:

Abatacept

Note: Administered as a 30-minute intravenous infusion utilizing weight based dosing and following the initial IV infusion, repeat IV dose (using the same weight-based dosing) at 2 weeks and 4 weeks after the initial infusion, and every 4 weeks thereafter.

  • Weight
  • <60 kg: 500 mg
  • 60-100 kg: 750 mg
  • >100 kg: 1000 mg

 

Biologic-Selective B cell Depleter

  • Rituximab

Mechanism:

  • Binds specifically to the antigen CD20 (human B-lymphocyte-restricted differentiation antigen, Bp35) on the cell surface
  • Activate complement-dependent B-cell cytotoxicity; and to human Fc receptors, mediating cell killing through an antibody-dependent cellular toxicity

Dose:

Rituximab (IV infusion)

  • Initial 1000 mg followed two weeks later by the second 1000 dose; subsequent courses may be administered every 24 weeks (based on clinical evaluation), if necessary may be repeated no sooner than 16 weeks following the previous course

Note: Infusions should be administered in a setting where full resuscitation facilities are available, and under the close supervision. Also administer 100 mg IV methylprednisolone 30 minutes prior to both Rituximab infusions. Acetaminophen and diphenhydramine may also be given prior to rituximab.

 

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Clinical Trials:
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Pipeline Agents:
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Pharmacist Resources:

a) Tips for patient care

Encourage

  • Participation in activities of daily living
  • Emphasize appropriate exercise, reduction of joint stress and strengthening of muscles supporting the joint
  • Weight lose to decrease stress on weight-bearing joints and frequent rest periods between activities
  • Use of appropriate adaptive devices for the performance of activities of daily living
  • Use appropriate footwear and any assistive devices, if required
  • Teach self-management and provide resources
  • Consider consultation for occupational therapy

Drugs

  • Evaluate risks and benefits of pharmacological therapy
  • DMARDs are recommended as soon as possible in patients with active disease
  • Consider concurrent comorbidities while choosing the therapy/in therapeutic decision
  • Advise to take one NSAID at a time (with the exception of low-dose ASA for cardiac and stroke prophylaxis)
  • Misoprostol or proton pump inhibitors are recommended in patients who are taking NSAIDs and are at increased risk for upper gastrointestinal adverse events
  • Evaluate cost, affordability and insurance coverage for patients

Unlabeled/Alternate uses

Include but not limited to:

  • Acetylsalicylic acid
    • Pre-eclampsia
    • Antiphospholipid syndrome
  • Methotrexate
    • Ectopic pregnancy
    • Systemic lupus erythematosus
  • Minocycline
    • Rheumatoid arthritis

Counseling

  • Patients with RA are prone to fatigue and muscle weakness, advise rest when tired
  • Avoid exercising tender, injured or severely inflamed joints
  • Educate about the importance of regular rheumatologist visits for monitoring the course of the disease and medication side effects
  • Gentle exercise can help strengthen the muscles around joints
  • Emphasize adapting correct posture and body mechanics
  • Inform patients that NSAIDs can cause GI bleeds that can occur with or without warning
  • Counsel women of child bearing age regarding potential teratogenicity of DMARDs

Alerts

  • Septic arthritis should be suspected for a single joint flare-up in patient with established diagnosis of RA
  • Long-term use of corticosteroids increase the risk of osteoporosis
  • Women of child bearing age taking DMARDs should use effective contraception
  • Discontinue NSAIDs (except ASA) in patients presenting with acute coronary syndromes
    • If required, an opioid analgesic (e.g. morphine) may be used as an alternative for pain control in this setting
  • NSAIDs may cause GI ulceration/bleeding, exacerbation of CHF, as well as renal dysfunction and HTN
  • COX-2 inhibitors may have a reduced risk of GI problems

Tips

  • Early referral to a rheumatologist is recommended
  • Combination DMARDs may be more effective than individual drugs
  • Evaluate joint and extra-articular involvement
  • Pregnancy is associated with clinical improvement in at least 50% of patients
    • May be related to elevated blood levels of free cortisol or to enhanced phagocytosis of immune complexes
  • Early aggressive treatment for RA can delay joint destruction
  • Joint protection techniques, heat and cold treatments, and splints or orthotic devices to support and align joints may be very helpful
    • Avoid cold treatments if patient has poor circulation or numbness
  • Periodic evaluation for disease activity or disease progression is recommended
  • RA is associated with many complications such as:
    • Pleuritis, Pericarditis, Eye inflammation, Osteoporosis, Heart disease
  • Occasionally surgery is needed to correct severely damaged joints. Surgery may include:
    • Synovectomy (Removal of the joint lining)
    • Arthroplasty (joint replacement)

Expected outcome

  • There is no cure for rheumatoid arthritis
  • Prognosis depends on the severity of symptoms
  • Individuals who develop RA at young age usually get worse quickly
  • Early treatment of patients with the medications reduces joint pain and damage

 

b) Scales and Tables

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References:

Core Resources:

  • Aletaha D, Neogi T, Silman AJ et al.2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis & Rheumatism 2010, 69; 1580-1588
  • Bykerk V P, Akhavan P, Hazelwood GS, et al. Canadian Rheumatology Association Recommendations for Pharmacological Management of Rheumatoid Arthritis with Traditional and Biologic Disease-modifying Antirheumatic Drugs. J Rheumatol 2011; 38:11; doi:10.3899/jrheum.110207
  • Compendium of Pharmaceuticals and Specialties (CPS). Canadian Pharmacist association. Toronto: Webcom Inc. 2012
  • Day RA, Paul P, Williams B, et al (eds). Brunner & Suddarth's Textbook of Canadian Medical-Surgical Nursing. 2nd ed. Philadelphia: Lippincott Williams and Wilkins; 2010
  • Foster C, Mistry NF, Peddi PF, Sharma S, eds. The Washington Manual of Medical Therapeutics. 33rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010
  • Gray J, ed. Therapeutic Choices. Canadian Pharmacists Association. 6th ed. Toronto: Webcom Inc. 2011
  • Katzung BG, Masters SB, Trevor AJ, eds. Basic and Clinical Pharmacology. 11th ed. New York: McGraw-Hill; 2009
  • Longo D, Fauci A, Kasper D, et al (eds). Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2011
  • McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment. 49th ed. New York: McGraw-Hill; 2010
  • Pagana KD, Pagana TJ eds. Mosby's Diagnostic and Laboratory Test Reference. 9th ed. St. Louis: Elsevier-Mosby; 2009
  • Skidmore-Roth L. ed. Mosby's drug guide for nurses. 9th ed. St. Louis: Elsevier-Mosby; 2011
  • Skidmore-Roth L, ed. Mosby's nursing drug reference. 24th ed. St. Louis: Elsevier-Mosby; 2011
  • Online resource/weblinks:
    • The Merck Manuals
    • RheumInfo
    • The Arthritis Society, Canada
    • Canadian Agency for Drugs and Technologies in Health

 

Online Pharmacological Resources:

  • e-therapeutics
  • Lexicomp
  • Rxlist
  • Epocrates Online

 

Journals/Clinical Trials:

  • Aletaha D, Ward MM, Machold KP et al. Remission and active disease in rheumatoid arthritis: defining criteria for disease activity states. 2005 Sep;52(9):2625-36
  • Breedveld FC, Weisman MH, Kavanaugh AF et al. A Multicenter, Randomized, Double-Blind Clinical Trial of Combination Therapy With Adalimumab Plus Methotrexate Versus Methotrexate Alone or Adalimumab Alone in Patients With Early, Aggressive Rheumatoid Arthritis Who Had Not Had Previous Methotrexate Treatment(PREMIER) Arthritis & Rheumatism Vol. 54, No. 1, January 2006, pp 26-37
  • Grigor C; Capell H; Stirling A; et al. Effect of a treatment strategy of tight control for rheumatoid arthritis- the TICORA Study. The Lancet; Jul 17-Jul 23, 2004; 364, 9430
  • Issues in Emerging Health Technologies: Rituximab for Rheumatoid Arthritis. Retrieved from Canadian Agency for Drugs and Technologies in Health. 2006; 89 www.cadth.ca
  • Klarenbeek NB, Güler-Yüksel M, van der Kooij SM et al. The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study. Ann Rheum Dis. 2011 Jun; 70(6):1039-46
  • Klareskog L; Heijde DVD; P de Jager J; Gough A; et al. Therapeutic effect of the combination of etanercept and MTX compared with each treatment alone in patient with rheumatoid arthritis(TEMPO) The Lancet; Feb 28, 2004; 363, 9410
  • Lipsky PE, Desiree, Heijde VD et al. Infliximab and Methotrexate in the Treatment of Rheumatoid Arthritis (ATTRACT). N Engl J Med 2000;343: 1594-602
  • Moreland, L W., O'Dell,J R., et al. Treatment of Early Aggressive RA: A Randomized, Double-Blind, 2-Year Trial Comparing Immediate Triple DMARD Versus MTX Plus Etanercept to Step-up From Initial MTX Monotherapy(TEAR). Arthritis & Rheumatism, Volume 60, October 2009 Abstract Supplement.10:1895. DOI: 10.1002/art.26968
  • Rantalaiho V, Korpela M, Laasonen L, et al. Early combination disease-modifying antirheumatic drug therapy and tight disease control improve long-term radiologic outcome in patients with early rheumatoid arthritis: the 11-year results of the Finnish Rheumatoid Arthritis Combination Therapy trial(FINRACO) Arthritis Research & Therapy 2010, 12:R122
  • http://arthritis-research.com/content/12/3/R122
  • R F van Vollenhoven, S Ernestam, P Geborek et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial.Lancet 2009; 374: 459-66
  • Schnitzer TJ, Hochberg MC, Marrero CE et al. 2011, 285-297

 

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EXPERT REVIEWER:
Philip A. Baer, MDCM, FRCPC, Internal medicine (Rheumatology), Chair, OMA Section on Rheumatology, VP, Ontario Rheumatology Association, ON Canada
.......................................... PHARMACY REVIEWER:
Cathy Sochasky, B.Sc.(Pharm), FCSHP, Drug Information Pharmacist, Health Sciences Centre, Winnipeg, MB Canada

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