Rheumatoid ARHTRITIS Therapeutics 4th stage

Rheumatoid arthritis Rheumatoid arthritis (RA) is chronic progressive systemic inflammatory condition manifesting initially as symmetric swollen and tender joints of the hands and/or feet. RA prevalence 1 – 2%. It is more common in Females.

Risk factors Etiology still unknown , but there are many possible risk factors: 1.Genetic Factors. 2.Current tobacco smoking 3.Female gender 4.Increasing age (peak onset 35 to 50 years of age) 5.Stress

PATHOPHYSIOLOGY The characteristics of a synovium affected by RA are: (a) The presence of a thickened, inflamed membrane lining called Pannus. (b) The development of new blood vessels; and (c) An influx of inflammatory cells in the synovial fluid, predominantly T lymphocytes.

PATHOPHYSIOLOGY The pathogenesis of RA is driven by T lymphocytes, but the initial catalyst causing this response is unknown. The components of most significance are T lymphocytes Cytokines, and B lymphocytes.

PATHOPHYSIOLOGY Once a T cell successfully passes through all stages, the inflammatory cascade is activated. Activation of T lymphocytes: (a) Stimulates the release of macrophages, which subsequently causes the release of inflammatory cytokines; (b) Activates osteoclasts; (c) Activates the release of matrix metalloproteinases or enzymes responsible for the degradation of connective tissue; and (d) Stimulates B lymphocytes and the production of antibodies.

PATHOPHYSIOLOGY 2. Cytokines Cytokines are proteins secreted by cells that serve as intercellular mediators. An imbalance of Proinflammatory and anti-inflammatory cytokines in the synovium leads to inflammation and joint destruction.

PATHOPHYSIOLOGY 2. Cytokines The Pro-inflammatory cytokines interleukin 1 (IL-1), tumor necrosis factor-α(TNF-α), IL-6, and IL-17 are found in high concentrations in synovial fluid. These Pro-inflammatory cytokines cause the activation of other cytokines and adhesion molecules responsible for the recruitment of lymphocytes to the site of inflammation.

PATHOPHYSIOLOGY 2. Cytokines Anti-inflammatory cytokines and mediators (IL-4, IL-10, and IL-1 receptor antagonist) are present in the synovium, although concentrations are not high enough to overcome the effects of the Proinflammatory cytokines.

PATHOPHYSIOLOGY 3. B Lymphocytes B lymphocytes may produce Proinflammatory cytokines and antibodies. Antibodies of significance in RA are rheumatoid factors and antibodies against cyclic citrullinated peptide (CCP). RF are not present in all patients with RA, but their presence is indicative of disease severity, likelihood of extra-articular manifestations, and increased mortality.

PATHOPHYSIOLOGY Anti-Cyclic Citrullinated Antibody (anti-CCPs) are produced early in the course of disease. High levels of anti-CCP antibodies are indicative of aggressive disease and a greater likelihood of poor outcomes. Monitoring anti-CCP antibodies may be useful to predict the severity of disease and match aggressive treatment appropriately.

Comorbidities Associated with RA The comorbidities with the greatest impact on morbidity and mortality associated with RA are: (a) cardiovascular disease, Half of all deaths in RA patients are cardiovascular related. (b) infections, (c) malignancy,(e.g., lymphoma, leukemia, and multiple myeloma) and (d) osteoporosis.

Clinical Presentation and Diagnosis General About 60% of patients develop symptoms gradually over several weeks to months. Patients may present with systemic findings, joint findings, or both. Nonspecific systemic symptoms may include: Fatigue Weakness Anorexia, Diffuse musculoskeletal pain and morning joint stiffness.

Signs The metacarpophalangeal (MCP), proximal interphalangeal (PIP), metatarsophalangeal (MTP), and wrist joints are involved frequently. Joint involvement is usually symmetric. There is often limited joint function.

Signs Signs of joint inflammation are present (tenderness, warmth, swelling, and erythema). Low-grade fever may be present.

Laboratory dignosis Positive rheumatoid factor (the test is negative in up to 30% of patients). Elevated ESR (Westergren ESR: greater than 20 mm/h in men; greater than 30 mm/h in women). Elevated C-reactive protein (CRP) (greater than 0.7 mg/dL or 7 mg/L). 4.Complete blood count: Slight elevation in WBC count with a normal differential; slight anemia; thrombocytosis 5.Positive anti-CCP antibodies

Laboratory dignosis

DAS28 score DAS28 score is a valid and sensitive tool to evaluate RA disease activity. The DAS28 score is widely used to assess; Disease activity The response to treatment and The need for biological therapy.

HOW TO CALCULATE DAS 28 1. Count the number of tender joints 2. Count the number of swollen joints 3. Measure the ESR or CRP 4. Ask the patient to rate global activity of arthritis during the past week from 0 (no symptoms) to 100 (very severe) Enter data into an online calculator 1 or work out using a formula

HOW TO CALCULATE DAS 28 DAS28 scores representing 1.Remission (<2.6) disease activity 2.Mild or low (2.6 to 3.2) disease activity 3.Moderate (>3.2 and <5.1) disease activity or 4.Severe (>5.1) disease activity,

Features of poor prognosis Features of poor prognosis include: Functional limitation Extra-articular disease (eg, rheumatoid nodules, vasculitis). Positive rheumatoid factor or high ACPA, and Bone erosions.

Treatment The goals of treatment in RA are to: (a) induce complete remission or low disease activity (b) Eliminate pain and protect articular structures, (c) Control systemic complications, (d) Prevent loss of joint function,and (e) Improve or maintain quality of life.

Non-Pharmacologic Therapy Adequate rest weight reduction Surgical procedures Patient education

Pharmacological Treatment NSAIDs. Corticosteroids. DMARDs. Non-biological DMARDs Biological DMARDs

1.NSAIDs. NSAIDs inhibit prostaglandin synthesis, which is only a small portion of the inflammatory cascade. They possess both analgesic and anti-inflammatory properties and reduce stiffness, but they do not slow disease progression or prevent bony erosions or joint deformity.

2.Glucocorticoids Low-dose glucocorticoid treatment (equivalent to prednisone 10 mg/day or less) effectively reduces inflammation through inhibition of cytokines and inflammatory mediators and prevents disease progression.

2.Glucocorticoids Patients may receive glucocorticoids for a brief time as “bridge therapy” following DMARD initiation or via intra-articular injections to relieve symptoms of active disease.

3.DMARDs. Start (DMARDs) as soon as possible after disease onset because early treatment results in more favorable outcomes. DMARDs slow RA disease progression.

3.DMARDs. Common non-biologic DMARDs include: Methotrexate (MTX), Hydroxychloroquine, Sulfasalazine Leflunomide

Biologic DMARDs A. Anti-TNF agents: Etanercept, Infliximab, Adalimumab, Certolizumab, And Golimumab. B. Co-stimulation modulator : Abatacept C. IL-6 receptor antagonist: Tocilizumab; and D. peripheral Bcell Inhibitors: Rituximab Biologic DMARDs have proven effective for patients failing treatment with non-biologic DMARDs.

3.DMARDs. The order of selection is not clearly defined, but MTX is often chosen initially because long-term data suggest superior outcomes compared with other DMARDs and lower cost than biologic agents. Combination therapy with two or more non-biologic DMARDs may be effective when single-DMARD treatment is unsuccessful.

MTX plus hydroxychloroquine MTX plus leflunomide MTX plus sulfasalazine,and MTX plus hydroxychloroquine plus sulfasalazine Relatively rapid onset , High response rate, Low cost and Long sustained efficacy

1.Methotrexate

1.Methotrexate Methotrexate (MTX) inhibits cytokine production and purine biosynthesis, and may stimulate adenosine release, all of which may lead to anti-inflammatory properties. Onset is as early as 2 to 3 weeks, and 45% to 67% of patients remained on it in studies ranging from 5 to 7 years.

1.Methotrexate Concomitant folic acid may reduce some adverse effects without loss of efficacy. Monitor liver injury tests periodically. MTX is teratogenic, and patients should use contraception and discontinue the drug if conception is planned before three months.

1.Methotrexate MTX is contraindicated in pregnant and nursing women, chronic liver disease, immunodeficiency, pleural or peritoneal effusions, leukopenia, thrombocytopenia, preexisting blood disorders, and creatinine clearance of less than 40 mL/min. CBC, creatinine, LFTs every 4–8 weeks; monitor for signs of infection should be monitored

2.Leflunomide (Arava)

2.Leflunomide (Arava) Leflunomide inhibits pyrimidine synthesis, which reduces lymphocyte proliferation and modulation of inflammation. Efficacy for RA is similar to that of MTX. A loading dose of 100 mg/day for 3 days may result in therapeutic response within the first month.

2.Leflunomide (Arava) The usual maintenance dose of 20 mg/day may be lowered to 10 mg/day in cases of GI intolerance, alopecia, or other dose-related toxicity. Leflunomide is contraindicated in patients with preexisting liver disease. It is teratogenic and must be avoided during pregnancy

Monitoring parameters 2.Leflunomide (Arava) Monitoring parameters CBC, creatinine, LFTs every months for 6 months; then every 4–8 weeks, Monitor for signs of infection

3.Hydroxychloroquine(plaquenil)

3.Hydroxychloroquine(plaquenil) Hydroxychloroquine is often used in mild RA or as an adjuvant in combination DMARD therapy. It lacks the myelo-suppressive, hepatic, and renal toxicities seen with some other DMARDs, which simplifies monitoring.

3.Hydroxychloroquine(plaquenil) Onset may be delayed for up to 6weeks, but the drug should not be considered a therapeutic failure until after 6 months of therapy with no response. Periodic ophthalmologic examinations are necessary for early detection of reversible retinal toxicity.

4.Sulfasalazine

4.Sulfasalazine Sulfasalazine use is often limited by adverse effects. Antirheumatic effects should be seen within 2 months. GI symptoms may be minimized by starting with low doses, dividing the dose evenly throughout the day, and taking it with food. Monitoring parameters CBC every 2–4 weeks for 3 months, then every 3 month

Biologic DMARDs Biologic DMARDs carry a small increased risk for infection, tuberculosis. Tuberculin skin testing should be performed before treatment to detect latent tuberculosis. Biologic agents should be at least temporarily discontinued in patients who develop infections while on therapy until the infection is cured.

Biologic DMARDs Live vaccines should not be given to patients taking biologic agents. Combination biologic DMARD therapy is not recommended because of increased infection risk.

1.TNF inhibitors heart failure (HF) is a relative contraindication for anti-TNF agents due to reports of increased cardiac mortality and HF exacerbations. Patients with New York Heart Association class III or IV and an ejection fraction of 50% or less should not use anti-TNF therapy. Discontinue the drugs if HF worsens during treatment.

1. TNF inhibitors TNF inhibitors are associated with increased risk of cancer, especially lympho-proliferative cancers. Anti-TNF biologics may also be used in patients with early disease of high activity and poor prognostic factors, regardless of previous DMARD use.

1. Etanercept (ENBREL) Etanercept provides a therapeutic effect by binding to soluble TNF and preventing its binding with TNF receptors. It is administered subcutaneously once or twice weekly; noticeable symptomatic improvement is seen in 1 to 4 weeks.

1.Etanercept Etanercept is very effective as monotherapy or in combination with other Non-biologic DMARDs. The most common adverse reactions with etanercept are injection-site reactions. If such reactions are bothersome, patients should be advised to place ice on the injection site before and after administration or apply a topical anesthetic or corticosteroid to the affected area.

2.Infliximab Is a chimeric IgGl monoclonal antibody that binds to soluble and bound TNF-α. Methotrexate typically is given with it to suppress antibody production against the mouse-derived portion of the molecule. Infliximab is delivered via IV infusion every 4 to 8 weeks; however, patients may notice benefit within 1 to 4 weeks of receiving the first infusion.

2.Infliximab (Remicade) Infusion-related reactions including rash, urticaria, flushing, headache, fever, chills, nausea, tachycardia, and dyspnea may occur during treatment. Qualified healthcare personnel must be present during the infusion to respond to the infusion-related reactions, if they occur.

2.Infliximab (Remicade) Clinicians may prescribe pretreatment regimens with corticosteroids or antihistamines if the patient continues to experience infusion reactions.

1. TNF inhibitors Adalimumab (Humira) , Golimumab (Simponi) , Certolizumab (Cimzia) , they have response rates similar to other TNF inhibitors.

2.Peripheral B cell Inhibitors: Rituximab is useful in patients failing MTX or TNF inhibitors. Give methylprednisolone 100mg, 30 minutes prior to rituximab to reduce incidence and severity of infusion reactions.

Rituximab Acetaminophen and antihistamines may also benefit patients who have a history of reactions. MTX should be given concurrently in the usual doses for RA to achieve optimal therapeutic outcomes.

RA DURING PREGNANCY Immunological changes in pregnancy: most patients with RA go into remission during pregnancy. Conception: methotrexate and leflunomide should be discontinued for at least 3 months before trying to conceive. Paracetamol: the oral analgesic of choice during pregnancy.

RA DURING PREGNANCY Oral NSAIDs and selective COX-2 inhibitors: can be used after implantation up until the last trimester. Corticosteroids: may be used to control disease flares; the main maternal risks are hypertension, glucose intolerance and osteoporosis.

RA DURING PREGNANCY DMARDs that may be used: sulfasalazine, hydroxychloroquine, if required to control inflammation. DMARDs that must be avoided: methotrexate and leflunomide. Biological therapies: safety during pregnancy is currently unclear.