Part one of a clinical approach to rheumatoid arthritis.

1. Week
3
Rheumatoid Arthritis
Part I
Anas Bahnassi PhD CDM CDE

2. Criteria for diagnosis of rheumatoid arthritis
1. Morning stiffness in and around joints lasting ≥1 hr before
maximal involvement
2. Soft tissue swelling (arthritis) of ≥3 joint areas observed by a
physician
3. Swelling (arthritis) of the proximal interphalangeal,
metacarpophalangeal, or wrist joints
4. Symmetric arthritis
5. Subcutaneous nodules
6. Positive test for RF
Criteria 1-4 must be present for ≥ 6 weeks
≥ 4 criteria must be present

3. Prevalence
Arthritis is the most common chronic condition in persons older than 15 years of
age.
Individuals who are overweight or inactive, and those without a high school
education.
The prevalence rate is higher in women (25.4%) than men (17.6%), and in the
elderly (50.0% of those ≥65 years of age versus 29.3% of those between 45 and
64 years of age).

4. Course of rheumatoid arthritis
Polycyclic
Monocyclic
70% of people
10% of people
20% of people
Mild symptoms
over several
weeks or months
Symptoms free
for several weeks
or months
Experience more
sever symptoms
Progressive
Sudden onset of
symptoms
Prolonged clinical
remission of
disease progress
Progressive
uninterrupted
disease
Evolves over few
months
Evolves over few
months
Doesn’t responds to
aggressive therapy
Responds to
aggressive therapy

5. Criteria for complete clinical remission in RA
A minimum of five of the following requirements must be fulfilled
for at least 2 consecutive months in a patient with RA:
Morning stiffness not >15 minutes
No fatigue
No joint pain
No joint tenderness or pain on motion
No soft tissue swelling in joints or tendon sheaths
ESR (Westergren's) <30 mm/hour(females) or 20 mm/hr (males)

6. Pathophysiology
Begins with inflammation of the
synovial lining
The pannus, a highly erosive enzyme-laden
inflammatory exudate, invades articular
cartilage (leading to narrowing of joint spaces),
erodes bone (resulting in osteoporosis), and
destroys periarticular structures resulting in
joint deformities

7. Molecular pathophysiology of
rheumatoid arthritis
Some immune sell develop to be self-targeting escaping destruction.
Activation of these cells can be activated by a bacteria or virus.
When activation source reaches the joint, complex cell-to-cell interactions take place
leading to the pathology associated with RA.
Autoimmune response takes place between AntigenPresenting-Cells (APC) and CD4 T-cells.
B-cells are activated  antibody formation (RF) +
proinflammatory cytokines + accumulation of
polymorphonuclear leukocytes
All are destructive to the synovium and joint structure.
B cells also act as APCs, leading to T-cell activation and
acceleration of the inflammatory process

8. Molecular pathophysiology of
rheumatoid arthritis
T-cell activation requires two signals:
(a) an antigen-specific signal occurring when an MHC class II antigen molecule on an
APC binds to a T-cell receptor; and
(b) binding of CD39 on the T-cell to either CD80 or CD86 on the APC. T-cell activation
leads to activation of macrophages and secretion of cytotoxins and cytokines.
In healthy individuals, the inflammatory process is
regulated by balancing the ratios of proinflammatory
cytokines (e.g., IL-1, IL-6, TNF-α) with anti-inflammatory
cytokines—for example, IL-1 receptor antagonist (IL1Ra), IL-4, IL-10, and IL-11. In the synovium of RA
patients, however, this balance is heavily weighted
toward the proinflammatory cytokines, which results in
sustained inflammation and tissue destruction.

9. Goals of therapy
• To relieve pain, stiffness, swelling, fatigue
• To prevent joint damage/disability
• To improve quality of life/achieve disease remission

10. Treatment pyramid approach to RA
This model is based on the assumption
that RA is a slowly progressing, benign
disease that is not life threatening

11. Current treatment guidelines
Still support the use of NSAIDs to provide rapid
anti-inflammatory and analgesic effects
DMARD therapy should be initiated within the first 3 months of RA
diagnosis to slow down the process:
hydroxychloroquine [HCQ], sulfasalazine [SSZ], MTX, leflunomide [LEF],
gold, azathioprine [AZA], or D-penicillamine [DPEN]
The newest class of DMARDs( anticytokines, biologicals, biological
modifiers, or biological response modifiers), etanercept (Enbrel),
infliximab (Remicade), anakinra (Kineret), adalimumab (Humira), abatacept
(Orencia), and rituximab (Rituxan).
These agents target the physiological proinflammatory and jointdamaging effects of TNF-α, IL-1, T-cell activation, or B cells.

12. Current treatment guidelines
MTX is the initial treatment of choice because of its efficacy and safety
profile.
TNF-α are recommended when MTX alone or MTX + traditional DMARDs
fail to respond. or for patients intolerant to MTX.
TNF-α worsen heart failure in patients with preexisting condition.
Newer biologicals, abatacept and rituximab, are effective when TNF-α fail
and seem to be free of cardiovascular adverse effects.
Abatacept and rituximab are expensive, and associated with serious
side effects.
Glucocorticoids are potent anti-inflammatory agents
they slow the progression of joint damage in RA
They generally are reserved for brief periods of active disease (low-dose oral
therapy), or for isolated joints experiencing disease flare ups.
Alkylating cytotoxic drugs, although effective, are also toxic and are
normally reserved for severe disease uncontrolled by other drug therapies.

13. Nonsteroidal Anti-Inflammatory Drugs
Although NSAIDs differ in chemical structure, they generally have similar pharmacologic
properties, MoA, and PK properties.
NSAIDs are better tolerated than Aspirin.
Selection of NSAIDs depends on:
1. Cost.
2. Duration of action.
3. Patient preference.
COX-1 is expressed in most tissues of the body while COX-2 is expressed throughout the
body in low concentrations.
Inflammatory mediators such as cytokines, however, upregulate COX-2 expression,
resulting in high levels of COX-2 in inflamed tissues.
Selective inhibition of COX-2, therefore, could be expected to produce anti-inflammatory
activity with minimal adverse effects on GI mucosa

14. Traditional Disease-Modifying Antirheumatic Drugs
DMARD therapy should be considered for all RA within 3 months of diagnosis
Although DMARDs 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.
Onset of action of most DMARDs is slow (about 3–6 months)
SSZ, MTX, LEF, and cyclosporine can be beneficial within 1 to 2
months and biological agents can be beneficial within days to weeks.

15. Traditional Disease-Modifying Antirheumatic Drugs
MTX is heavily favored because of its relatively rapid onset, high rate of response, mild side
effect profile, relatively low cost, and long sustained efficacy.
MTX therapy is associated with a reduction in cardiovascular morbidity and mortality in
patients with RA, which is important because of the strong association between RA and
cardiovascular disease.
HCQ and SSZ are relatively safe, convenient, and inexpensive.
They can be selected as initial therapy .
HCQ is used more often than SSZ, even though it is less potent.
LEF is an attractive option for severe RA because its onset of effect (4
weeks) and efficacy similar to MTX.
Injectable gold is effective, but can be inconvenient and causes
numerous intolerable adverse effects.
Parenteral gold, MTX, SSZ, and penicillamine are the most effective
of the traditional DMARD therapies.

16. Biological Agents
TNF-α exerts its physiological effects by binding to two different cell-surface receptors known
as p55 and p75 on inflammatory cells.
These receptors, with portions extending from within the cell cytoplasm to the cell exterior,
are capable of binding TNF 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:
(a) the use of soluble TNF receptors with high TNF
binding affinity (e.g., etanercept)
(b) antibodies against TNF-α (e.g., infliximab,
adalimumab).

17. Role of TNF in RA

18. Biological Agents
Etanercept (Enbrel) is a recombinant TNF-receptor Fc fusion protein with the extracellular
portion of two p75 receptors fused to the Fc portion of human immunoglobulin (Ig)-G1.
Infliximab (Remicade) is a chimeric IgG antibody directed against TNF-α
Adalimumab is a genetically engineered human IgG1 monoclonal antibody.
All three TNF-α inhibitors (Enbrel, Remicade, and
Humira) render TNF biologically unavailable and are
highly effective in reducing RA disease activity.
It is not clear whether one agent is superior to the
other.
Anti-infliximab antibodies can develop with the longterm use of infliximab, but these can be prevented by
concomitant immunosuppression with MTX.

19. Biological Agents
IL-1 overexpression is prevented by naturally occurring IL-1Ra.
IL-1 augments cartilage damage and inhibits bone formation.
Although TNF-α seems to be key in RA inflammation regulation and symptomatology, IL-1 may
be largely responsible for bony erosion and periarticular osteoporosis.
TNF-α and IL-1 serve important physiological functions
(e.g., protection against infections).
Hospitalizations and deaths secondary to major
infections have developed in patients treated with
biological agents.
Increased serum levels of TNF-α seem to be associated
with worsening of heart failure

20. Corticosteroids
Relieve symptoms and slow progression rate when administered orally at low dosages (i.e., the
equivalent of 10 mg of daily prednisone or less) or through local injection.
Long-term use of corticosteroids is associated with many serious adverse effects (e.g.,
osteoporosis, weight gain, diabetes, cataract formation, adrenal suppression, hypertension,
infections, impaired wound healing).
Oral corticosteroid dosing should be limited to daily doses of 7.5 to 10 mg of prednisone (or
equivalent) and should be administered for as short a time as possible.
Oral corticosteroids are particularly useful when patients are waiting the onset of DMARD
action or during brief flares of active RA involving multiple joints.
Local corticosteroid injections are useful when flares involve only a few joints. Frequent
corticosteroid injections over an extended period have the potential to accelerate bone and
cartilage deterioration; therefore, the same joint should not be injected more than once every
3 months.

21. Other therapies
Minocycline
Apheresis with with the Prosorba column.
The Prosorba column contains highly purified staphylococcal protein A bound to a silica
matrix that has a high affinity for IgG and complexes of IgG and IgM, including RF and
circulating immune complexes.
Cyclosporin
Thalidomide

22. Dosing and Administration of Biological DiseaseModifying Antirheumatic Drugs
Biological DMARD
Abatacept (Orencia)
Route of
Dosing Interval
Administration
IV
Every 2 weeks ×3
doses, then every
4 weeks
Any Infusion
Fatal Infusion
Can Be SelfReaction Reported? Reactions Reported? Administered?
Yes
No
No
No
No
No
Every 1–2 weeks
Adalimumab (Humira)
SC
Anakinra (Kineret)
SC
Daily
No
No
No
Etanercept (Enbrel)
SC
1–2 times per
week
No
No
No
Infliximab (Remicade)
IV
Every 8 weeks
Yes
Yes
No
IV
Variable (usually
every 24 weeks)
Yes
Yes
Yes
Rituximab (Rituxan)

23. A case approach to rheumatoid arthritis
T.W., a previously healthy 42-year-old, 60-kg woman, has been suffering from morning
stiffness that persists for several hours, anorexia, fatigue, and generalized muscle and joint
pain over the past 4 months.
In addition, she reports that her eyes seem red most of the time and are unusually dry.
Her symptoms have been much worse during the past month and a half, and she
has limited her physical activities.
She also can no longer wear her wedding ring because of swelling of her hand.

24. A case approach to rheumatoid arthritis
Physical examination
Bilaterally symmetrical swelling, tenderness, and warmth of the metacarpophalangeal (MCP)
and proximal interphalangeal (PIP) joints of the hands and the metatarsophalangeal (MTP) joints
of the feet.
A subcutaneous nodule is evident on the extensor surface of the left forearm.

25. A case approach to rheumatoid arthritis
Laboratory findings
ESR by the Westergren method, 52 mm/hour (normal for women, <20 mm/hour )
Hgb, 10.6 g/dL (normal, 12–16 g/dL)
Hct, 33% (normal, 36%–47%)
Platelets, 480,000/mm3 (normal, 140,000–400,000/mm3)
Albumin, 3.8 g/dL (normal, 4.3–5.6 g/dL)
Serum uric acid, 3.0 µg/dL (normal, 2–8 mg/dL)
Serum iron, 40 µg/dL (normal, 60–180 mg/dL)
TIBC, 275 mg/dL (normal, 200–400 mg/dL)
Positive anti-cyclic citrullinated peptide (anti-CCP) at 82 U
(normal, <20 U; weak positive, 20–39 U; moderate positive, 40–59 U; strong
positive, >60 U)
Positive RF.
Tests for antinuclear antibodies (ANA) and tuberculin sensitivity are negative.
Radiographic films of the hands and feet show soft tissue swelling, narrowing of
joint spaces, and marginal erosions of the second and third MCP and PIP
joints bilaterally with no evidence of tophi or calcification

26. What signs and symptoms of RA are manifested by T.W.?
Fatigue and morning stiffness are prominent features of RA in T.W
Musculoskeletal pain localizes to the joints bilaterally. Bilaterally symmetrical joint swelling and
pain, involving the MCP and PIP joints of the hands and MTP joints of the feet.
Joint involvement is characterized by soft tissue swelling and warmth, decreased
range of motion (ROM), and sometimes muscle atrophy around affected joints.
Progressive disease is characterized by irreversible joint deformities

27. Parameters Used to Assess Disease Activity and
Drug Response in RA
Duration and intensity of morning stiffness
Number of painful or tender joints
Number of swollen joints; severity of joint swelling
Range of joint motion
Time to onset of fatigue
ESR or CRP
Anti-CCP
Radiographic changes: osteopenia, joint space
narrowing, bony erosions
Hgb/Hct
Subcutaneous nodules, pleuritis, pneumonitis,
myocarditis, vasculitis
AIMS: arthritis impact measure scale;
AIMS
Anti-CCP: anti-cyclic citrullinated peptide
HAQ
CRP: C-reactive protein
Validated clinical assessment tools
ESR: erythrocyte sedimentation rate
HAQ: health assessment questionnaire

28. What abnormal laboratory values in T.W. could be used to
monitor the efficacy of drug therapy or disease progression?
No test is specific for RA.
Elevated ESR is a nonspecific indication of inflammation.
CRP can be tested instead of ESR.
Levels of CRP correlate with RA disease activity better than ESR still not disease specific.
T.W.'s hematologic findings are consistent with a mild anemia of chronic
inflammation. Although her serum iron concentration is decreased, her normal
iron-binding capacity makes a diagnosis of iron-deficiency anemia unlikely. Her
anemia probably results from a failure of iron release from the reticuloendothelial
tissues and would not be expected to respond to iron therapy.
Mild thrombocytosis is additional evidence of a systemic inflammatory response.
low serum albumin concentration in RA patients can result in higher free drug
serum concentrations
RF is not in the serum of all patients with RA. It also can be present in 3%
to 5% of healthy individuals and in patients with diseases other than RA

29. What nondrug therapy should be included in the management of
T.W.'s RA?
Exercise
Joint protection and energy preservation
Emotional support

30. RA drug therapy
Treatment of choice: DMARD within 3 months of diagnosis.
Severe RA: MTX or MTX + traditional DMARD
Mild RA: Hydroxychloroquin or Sulfasalazine
Treatment consideration: NSAIDs or Corticosteroids.
Non drug intervention: Patient education, physical therapy,
occupational therapy
Reassess
Periodically
Satisfactory response
Modify DMARD therapy:
1. Substitute or add MTX.
2. Substitute with different DMARD.
3. Combination treatment with traditional DMARD.
4. Biological agent +/- MTX

31. Pharmacottherapy
Anas Bahnassi PhD CDM CDE
abahnassi@gmail.com
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