Pharmacotherapy of _Rheumatoid Arthritis
Pharmacotherapy of _Rheumatoid Arthritis_____________________________
Amol Joshi, PharmD Candidate 2007
|Epidemiology[1] |Worldwide distribution. |
| |Estimated prevalence of 1 to 2%. |
| |Prevalence increases with age, approaching 5% in women over age 55. |
| |The average annual incidence in the United States is about 70 per 100,000 annually. |
| |Incidence and prevalence of rheumatoid arthritis are two to three times greater in women than in men. |
| |Rheumatoid arthritis may present at any age, patients most commonly are first affected in the third to sixth decades. |
|Disease State Definition[2]|Rheumatoid arthritis is a type of chronic arthritis that occurs in joints on both sides of the body (such as hands, wrists or knees). |
| |This symmetry as well as inflammation and soft-tissue swelling of many joints at the same time distinguish rheumatoid arthritis from |
| |other types of arthritis. |
| |In addition to affecting the joints, rheumatoid arthritis may occasionally affect the skin, eyes, lungs, heart, blood, nerves or |
| |kidneys. |
|Patho-physiology[1] |The cause of RA is still unknown to this day, but has long been suspected to be infectious. It has also been theorized that RA is |
| |caused by could be due to food allergies or external organisms. The predominant theory is that people are born with a genetic |
| |susceptibility to RA and later on there is a triggering factor such as stress and/or infection which spurs the onset of RA. |
| |It known that RA has an autoimmune basis. Once triggered, the immune response causes inflammation of the synovium. Early and |
| |intermediate molecular mediators of inflammation include tumor necrosis factor alpha (TNF-α), interleukins IL-1, IL-6, IL-8 among |
| |others. The inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate |
| |and evidence of joint destruction increases. |
| |Two theories on the pathogenesis of rheumatoid arthritis (RA): |
| |1) T cell, through interaction with an unknown antigen, is the primary cell responsible for initiating the disease inaddition to |
| |driving the chronic inflammatory process. This theory is based upon the large number of CD4+ T cells and skewed T cell receptor gene |
| |usage in the RA synovium. |
| |2) T cells may be important in initiating the disease, chronic inflammation however, is self-perpetuated by macrophages and fibroblasts|
| |in a T-cell independent manner. This theory is based upon the relative absence of activated T cells phenotypes in chronic RA and the |
| |preponderance of activated macrophage and fibroblast phenotypes. |
| |In RA there are many changes that occur in the body, the histopathological are described below: |
| |Histopathological changes can be divided into changes in the Synovium, Cartilage, Bone, Synovial Cavity. |
| |Synovium: This is a thin delicate lining that serves several important functions. The synovium serves as an important source of |
| |nutrients for cartilage. As well as synthesizing joint lubricants such as hyaluronic acid, in addition to collagens and fibronectin |
| |which make up the structural framework of the synovial interstitium. In normal adult the synovial lining is only 2-3 cell layers thick.|
| |In adults with RA this lining undergoes hypertrophy (8-10 cells thick). Primary cell populations in this layer are fibroblasts and |
| |macrophages. In the Subintimal area of synovium synovial blood vessels are located. This area normally has very few cells. In RA, |
| |however, the subintimal area is heavily infiltrated with inflammatory cells, including T and B lymphocytes, macrophages and mast cells.|
| |The intense cellular infiltrate is accompanied by new blood vessel growth (angiogenesis). |
| |Cartilage: Is typically composed primarily of type II collagen and proteoglycans. Cartilage is normally a very resilient tissue that |
| |absorbs considerable impact and stress. However in RA, its integrity, resilience and water content are all impaired. This seems to be |
| |caused by increased secretion of proteolytic enzymes (collagenase, stromelysin) by synovial lining cells and by chondrocytes |
| |themselves. |
| |Bone: Is composed primarily of type I collagen, The inflammed synovium causes erosion of bone by increased release of prostaglandins |
| |and proteases. This can also occur possibly via osteoclasts. |
| |Synovial Cavity: This space is normally only filled with 1-2ml of highly viscous fluid with few cells. In RA, large collections of |
| |fluid occur which have high protein content. This synovial fluid is highly inflammatory. The predominant cell in the synovial fluid is |
| |the neutrophil. |
| |The propagation of the disease: CD4+ T cells, B cells and monocytes-macrophages migrate into, and remain in the synovial interstitium.|
| |Neutrophils, in contrast, are found almost exclusively in the synovial cavity (fluid) and only rarely in the synovial tissue. |
| |Macrophages and fibroblasts produce cytokines. |
| |The activated macrophage continuously secretes IL-1 and TNF which maintain the synovial fibroblast in an activated state. |
| |The fibroblast then secrete large amounts of: a) cytokines - IL6, IL8 and GM-CSF; b) prostaglandins; and c) protease enzymes. GM-CSF |
| |feeds back to promote the maturation of newly recruited monocytes to macrophages. IL-8 and IL-6 contribute to the recruitment and/or |
| |activation of yet other cell populations, while the prostaglandins and proteases act directly to erode and destroy nearby connective |
| |tissues such as bone and cartilage. |
| |IL-6: (secreted by fibroblasts) |
| |-Is a potent stimulus for maturation of B cells to plasma cells which secrete rheumatoid factor. |
| |-Suppresses albumin synthesis by the liver and stimulates acute phase protein synthesis. |
| | |
| |Il-8: (secreted by fibroblasts) |
| |-Chemotactic stimulus for neutrophils |
| |-Synovial fibroblasts line the joint cavity, this explains the selective recruitment of neutrophils to the synovial |
| |cavity. |
| |-Neutrophils in the synovial fluid release oxygen-derived free radicals that depolymerize hyaluronic acid and inactivate endogenous |
| |inhibitors of proteases, promoting damage to the joint. |
| |Prostaglandins: (secreted by fibroblasts) |
| |-PGE2 resorbs bone and contributes to the erosions at the site of synovial-bone attachment. |
| | |
| |Proteases: (collagenase, stromelysin and gelatinase) (secreted by fibroblasts) |
| |-Act enzymatically to degrade the collagen and proteoglycan matrix of bone and cartilage. |
| |Other contributing substances: |
| |Kinins: Cause release of prostaglandins from synovial fibroblasts, and are also potent algesic (pain-producing) agents. |
| |Chondrocytes: like synovial fibroblasts, are activated by IL1 and TNF to secrete proteolytic enzymes. They may, contribute to the |
| |dissolution of their own cartilage matrix |
| |Substance P: Is a potent vasoactive, proinflammatory peptide that is likely to contribute to joint destruction. |
|Clinical Presentation[1] |Usually RA begins with the slow development of signs and symptoms over weeks to months. Often the patient first notices stiffness in |
| |one or more joints, usually accompanied by pain on movement and by tenderness in the joint. The number of joints involved is highly |
| |variable, but almost always the process is eventually polyarticular, involving five or more joints. Atypical presentations include |
| |intermittent joint inflammation that can be confused with gout or pseudogout, proximal muscle pain and tenderness mimicking polymyalgia|
| |rheumatica or diffuse musculoskeletal pain seen in fibromyalgia. |
| |The joints most often involved: |
| |Proximal interphalangeal (PIP) |
| |Metacarpophalangeal (MCP) |
| |The wrists |
| |Shoulders, elbows, knees, ankles, |
| |Metatarsophalangeal (MTP) |
| | |
| |The joints usually spared are: |
| |The distal interphalangeal (DIP) joints are generally spared. |
| |The spine except the atlanto-axial articulation in late disease is never affected. |
| | |
| |Morning stiffness: > 1 hour (often lasting several hours), may be a feature of any inflammatory arthritis but is especially |
| |characteristic of rheumatoid arthritis. Its duration is a useful gauge of the inflammatory activity of the disease. Stiffness can also |
| |occur after long periods of sitting or inactivity. |
| | |
| |Nonspecific systemic symptoms: |
| |Fatigue ( Patients complain of severe fatigue 4 to 6 hours after wakening. |
| |Malaise |
| |Depression |
| |Fever ( Occasionally occurs and is almost always low grade (37° to 38°C; 99° to 100°F). |
| | |
| | |
| |Physical Examination: |
| |Careful palpation of the joints can help to distinguish the swelling of joint inflammation from the bony enlargement seen in |
| |osteoarthritis. |
| |Fusiform swelling of the PIP joints of the hands is a common early finding. |
| |In contrast to gout or septic arthritis, redness of affected joints is not a prominent feature of rheumatoid arthritis. |
| |Pain on passive motion is the most sensitive test for joint inflammation. |
| |Occasionally inflamed joints will feel warm to the touch. |
| |Inflammation, structural deformity, or both may limit the range of motion of the joint. |
| |Eventual formation of synovial cysts and displaced or ruptured tendons. |
| |Bony erosions seen at the margins of the joint, at the attachment of the synovium, are the hallmark of rheumatoid arthritis. |
| |Erosions, are clearly seen in an x-ray occur rapidly within the first 2 years of the disease. Erosions result in limitations in range |
| |of motion, flexion contractures, and incomplete dislocation of articulating bones. |
| | |
| |Lab Tests: |
| |Chemistries: |
| |Normal in rheumatoid arthritis |
| |Slight decrease in albumin and increase in total protein reflecting the chronic inflammatory process. |
| | |
| |Hematology: |
| |A mild anemia with hematocrit values in the range of 30-34% occurs in approximately 25- 35% of patients. Usually a |
| |normocytic-normochromic. Low concentration of serum iron, a low serum iron-binding capacity, and a normal or increased serum ferritin |
| |concentration. |
| |White cell count can be mildly elevated due to inflammation. |
| | |
| |Serology: |
| |70-90% of patients with RA are positive for rheumatoid factor. However a positive test is not a definite indication of RA. |
| |The titer of the disease does not necessarily correlate with the activity of the disease however patients with a higher titer are more |
| |likely to have erosive joint disease, extra-articular manifestations and greater functional disabilities. |
| |Rheumatoid negative patients generally exhibit a milder course of the disease. |
| |Erythrocyte sedimentation rate is usually elevated |
| | |
| |Radiology: |
| |Early on only soft tissue swelling is seen. |
| |After some time periarticular osteopenia may develop. Narrowing of joint space caused by loss of cartilage and erosions appear at the |
| |point of attachment. |
| |At the later stages of disease large cystic erosions can be seen as well as possible bony proliferation. |
| | |
| | |
| | |
| | |
| |Extra Articular Disease: |
| |Rheumatoid Nodules: Most characteristic manifestation. (20-30%) Almost exclusively in seropositve patients. Usually on extensors of |
| |arms or on pressure points of feet and knees. |
| |Cardiopulmonary Disease: |
| |Pleurisy, nodules, fibrosis, pneumothroax, reduced lung volumes, decreased diffusing capacity for carbon monoxide. |
| |Pericarditis |
| |*Pleurisy is a painful inflammation of membranes surrounding lungs |
| |*Pneumothorax is a collection of air or gas in the space surrounding the lungs. |
| |*Pericarditis: Inflamation of the pericardium |
| | |
| |Ocular Disease: |
| |Keratoconjunctivitis: Inflammation of cornea and conjunctiva |
| |Sicca: Dry eyes |
| |Episcleritis: Red eyes, mild pain |
| | |
| |Neurological Disease: |
| |Mild sensory peripheral neuropathy (usually lower extremities) |
| |Carpal tunnel syndrome, and tarsal tunnel syndrome |
| |Cervical myelopathy (injury to spinal chord) |
| | |
| |Felty’s Syndrome: |
| |Rare |
| |Splenomegaly and leukopenia |
| |Recurrent bacterial infections and chronic refractory leg ulcers are major complications |
| | |
| |Sjourney’s syndrome: |
| |A chronic inflammatory disorder characterized by lymphocyte infiltration of the lacrimal and salivary glands occurs in 10-15% of |
| |patients |
| |Leads to impaired secretion of tears and saliva |
| |Dry skin, dry membranes, and non productive cough. |
| | |
| |Rheumatoid vasculitis: |
| |Small infarcts on digits along nail beds. |
| |Normally occurs after years of being seropositive |
|Risk Factors | |
|[1,4] |Prevalence increases with age |
| |Women 2-3 times more likely to develop RA |
| |Family History (Not a strong correlation) |
| |Higher intake of protein??? |
| | |
| | |
| | |
| | |
|Diagnosis[1,2] |The diagnosis of rheumatoid arthritis is based on a combination of factors, including: |
| |The specific location and symmetry of painful joints. |
| |The presence of joint stiffness in the morning. |
| |Presence of bumps and nodules under the skin (rheumatoid nodules). |
| |Results of X-ray tests that suggest rheumatoid arthritis. |
| |Positive results of a blood test called the rheumatoid factor. [2] |
| | |
| | |
| |Four of the following must be present with 1 through 4 present a minimum of 6 weeks: |
| | |
| |1. Morning stiffness for > 1 hour |
| |2. Arthritis of 3 or more of the following joints: Right or left PIP, MCP, wrist elbow, knee, ankle and MTP. |
| |3. Arthritis of the wrist, MCP, or PIP joint |
| |4. Symmetric involvement of the joints |
| |5. Rheumatoid nodules over bony prominence, or extensor surfaces, or in juxaarticular regions |
| |6. Positive serum rheumatoid factor |
| |7. Radiographic changes including erosions or bony decalcification localized in or adjacent to involved joints.[1] |
| |*PIP: Proximal interphalangeal |
| |*MCP: Metacarpophalangeal |
| |*MTP: Metatarsophalangeal |
|Desired Therapeutic | |
|Outcomes* |1) Prevent or control joint damage |
|[3] |2) Prevent loss of function |
| |3) Decrease/alleviate pain. |
|*Reference of |4) Induced/maintain remission |
|Guidelines Used | |
|Treatment Options** |Selection of the treatment regimen requires an assessment of prognosis. |
| |Poor prognosis is suggested by: |
|(Non-drug and Drug Therapy)|Earlier age at disease onset |
|[4,3] |High titer of RF |
| |Elevated ESR |
| |Swelling of > 20 joints |
| |Extra articular manifestations of RA |
|– include all therapeutic |Active polyarticular, RF-positive RA have a >70% probability of developing joint damage or erosions within 2 years of the onset of |
|classes/agents available |disease. |
|and preferences per |*Patients with poorer prognosis should be given a more aggressive treatment initially.[3] |
|treatment guidelines) | |
| |Non Drug Therapy: |
| |Rest: relieves stress on inflamed joints and prevents further joint destruction. Also helps alleviate pain. Too much rest can lead to |
| |decreased range of motion and muscle atrophy. |
| |Occupational therapy & Physical therapy: Helps patient with skill and strength to increase or maintain mobility |
| |Use of assistive devices (canes, walkers etc.) |
| |Weight reduction: alleviate stress on inflamed joints |
|**See Treatment Options |Surgery: Reserved for patients with severe disease.[4] |
|Table | |
| | |
| | |
| |Pharmacological Options[3]: |
| |NSAIDs: |
| |Initial drug treatment of RA usually involves the use of salicylates, NSAIDs, or a selective cyclooxygenase 2 (COX-2) inhibitors. |
| |Reduce joint pain and swelling and to improve joint function. Do not alter the course of the disease or prevent joint destruction. |
| |Should not be used as the sole treatment for RA. |
| |Must be vigilant for GI side effects |
| | |
| |DMARDs: |
| |May reduce or prevent joint damage, preserve joint integrity and function. |
| |The initiation of DMARD therapy should not be delayed beyond 3 months for any patient with an established diagnosis who, despite |
| |adequate treatment with NSAIDs, has ongoing joint pain, significant morning stiffness or fatigue, active synovitis, persistent |
| |elevation of the ESR or CRP level, or radiographic joint damage. |
| |For any untreated patient with persistent synovitis and joint damage, DMARD treatment should be started promptly to prevent or slow |
| |further damage. |
| |Can have toxic side effects |
| | |
| |Glucocorticiods: |
| |Effective for relieving symptoms in patients with active RA. |
| |Patient may experience marked and rapid improvement in functional status within a matter of days following initiation of low-dose |
| |glucocorticoids. |
| |Disabling synovitis can recur when glucocorticoids are discontinued, even in patients who are receiving combination therapy with one or|
| |more DMARDs. |
| |Many patients with RA are functionally dependent on glucocorticoids and continue them long-term. |
| |Recent evidence suggests that low-dose glucocorticoids slow the rate of joint damage and, therefore, appear to have disease-modifying |
| |potential. |
| |Must weigh risk/benefit of steroid use. |
|Monitoring | |
| | |
|**See treatment options | |
|table for efficacy and | |
|toxicity of drugs | |
| | |
|(Efficacy and Toxicity | |
|Parameters) | |
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References:
1)
2)
3) American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines, guidelines for the Management of Rheumatoid Arthritis, 2002 Update ARTHRITIS & RHEUMATISM
Vol. 46, No. 2, February 2002, pp 328–346.
4) Dipiro et al. “Pharmacotherapy: A Pathophysiologic Approach” 6th edition, McGraw Hill Medical Publishing Division, 2005 New York.
5) Ellsworth et al. Mosby’s Medical Drug Reference 2006, Mosby Inc, Philadelphia, PA.
6) Lexicomp Online:
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