Rheumatoid Arthritis Part I

Anas Bahnassi PhD CDM CDE

3 Week

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

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).

Course of rheumatoid arthritis

Polycyclic Monocyclic Progressive

70% of people

Mild symptoms over several

weeks or months

Symptoms free for several weeks

or months

Experience more sever symptoms

20% of people

Sudden onset of symptoms

Prolonged clinical remission of

disease progress

10% of people

Progressive uninterrupted

disease

Evolves over few months

Evolves over few months

Responds to aggressive therapy

Doesn’t responds to aggressive therapy

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)

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

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 Antigen-Presenting-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

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 (IL-1Ra), 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.

Goals of therapy

• To relieve pain, stiffness, swelling, fatigue

• To prevent joint damage/disability

• To improve quality of life /achieve disease remission

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

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 joint-damaging effects of TNF-α, IL-1, T-cell activation, or B cells.

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.

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

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.

Traditional Disease-Modifying Antirheumatic Drugs

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.

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.

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).

Role of TNF in RA

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 long-term use of infliximab, but these can be prevented by concomitant immunosuppression with MTX.

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

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.

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

Dosing and Administration of Biological Disease-Modifying Antirheumatic Drugs

Biological DMARD

Route of Administration

Dosing Interval

Any Infusion Reaction Reported?

Fatal Infusion Reactions Reported?

Can Be Self-Administered?

Abatacept (Orencia)

IV

Every 2 weeks ×3 doses, then every 4 weeks

Yes

No

No

Adalimumab (Humira)

SC

Every 1–2 weeks No

No

No

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

Rituximab (Rituxan)

IV

Variable (usually every 24 weeks)

Yes

Yes

Yes

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.

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.

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

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

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 HAQ Validated clinical assessment tools

AIMS: arthritis impact measure scale; Anti-CCP: anti-cyclic citrullinated peptide CRP: C-reactive protein ESR: erythrocyte sedimentation rate HAQ: health assessment questionnaire

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

What nondrug therapy should be included in the management of T.W.'s RA?

Exercise Joint protection and energy preservation Emotional support

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

Modify DMARD therapy: 1. Substitute or add MTX. 2. Substitute with different DMARD. 3. Combination treatment with traditional DMARD. 4. Biological agent +/- MTX

Satisfactory response

Reassess Periodically

Pharmacottherapy Anas Bahnassi PhD CDM CDE

abahnassi@gmail.com

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