By

Terry L. New

Advisor: Dr. Gurwell

Date: 3-21-2008

 

• Rheumatoid arthritis develops worldwide in approximately one percent of the population, regardless of race or country of origin.

• The effects of rheumatoid arthritis occurs in women two to three times more often than men, with the manifestation of rheumatoid arthritis appearing between twenty-five and fifty years of age

• The proposed etiology of rheumatoid arthritis ranges from a genetic predisposition, environmental factors, to possible hormonal influences playing a key role in the development of rheumatoid arthritis.

• Joint damage from rheumatoid arthritis usually starts with proliferation of synovial macrophages and fibroblasts, often triggered by possibly autoimmune or infectious infiltrations.

• It is hypothesized that lymphocytes are activated and infiltrate perivascular regions, which results in endothelial cell proliferation and neovascularization. Specific B and T lymphocytes, macrophages, monocytes, endothelial cells, and fibroblasts play putative roles in the joint destructive process

• the synovial tissue grows irregularly, forming pannus tissue that invades and causes destruction of cartilage and bone.

• Morning stiffness that lasts longer than 45 minutes

• Painful joints often occurring with any activity or movement

• Rheumatoid arthritis involves symmetrically three or more joints being filled with fluid or with soft tissue swelling

• Rheumatoid nodules occur under the skin, especially over areas subject to pressure

• Inflammation of blood vessels (vasculitis) rarely occurs, causing ulcers of the skin and paralysis of the nerves

• Rheumatoid factor, which is a distinctive antibody in approximately seventy percent of individuals with rheumatoid arthritis

• Anticyclic citrullinated peptide antibody tends to correlate well with disease progression, which increases the sensitivity of this test when used in combination with rheumatoid factor and is more specific than rheumatoid factor (90 versus 80 percent)

• C-reactive protein (CRP) shows an increase to >0.7 picograms per ml and demonstrates the presence of inflammation

• Nonsteroidal anti-inflammatory drugs (NSAIDS) inhibit cyclooxygenase (COX)

• Through inhibition of COX-1, unwanted side effects occur in the form of undesired gastrointestinal dysfunction, renal failure, and inhibited platelet aggregation, whereas COX-2 inhibition results in an anti-inflammatory effect with associated side effects of cardiovascular effects in patients with cardiovascular disease

• Prostaglandin E2 is important in the contribution of rheumatoid arthritis signs and symptoms of bone destruction, inflammation and pain

• COX-1 and COX-2 inhibitors lead to suppression of the formation of PGE2 and a decrease in bone destruction, pain and inflammation

• The American College of Rheumatology Subcommittee on Rheumatoid Arthritis (ACRSRA) recommends a baseline liver function testing, complete blood count, erythrocyte sedimentation rate, C-reactive protein and renal function testing to monitor disease progression and examining side effect of medications

• DMARDS inhibit the production of TNF and reduce joint destruction and possible synovial inflammation

• Methrotrexate inhibits the enzyme involved in the metabolism of folic acid and dihyrofolate reductase thru affecting the TNF pathways

• Leflunomide is a nontraditional disease modifying antirheumatic drug that targets lymphocyte activation, cell migration and activation of transcription factor NF-KB

• Methotrexate followed by leflunomide was most optimal with decreasing the effects of systemic inflammation caused by rheumatoid arthritis

• Etanercept--binding and reducing TNFα activity in circulation Anakinra--IL-1 receptor antagonist

• Showed no improvement with these drugs given in combination

• Combination, increased adverse effects of neutropenia, injection site allergic reactions.

• Adalimumab is an anti-TNFα monoclonal antibody with high affinity for TNF

• Adverse effects of serious infections occurred in 3.1% of participants, demyelinating disease occurred in 0.06% and systemic lupus erythematosus occurred in 0.03%

• Treatment with adalimumab in combination with methrotrexate has an increased prevalence in regressing the effects of rheumatoid arthritis in joint destruction, pain, inflammation and possible increase in activities of daily living.

• Infliximab is often used in combination with methrotrexate, because infliximab used as an monotherapy often can result in the production of anti-infliximab antibodies and less effective treatment for rheumatoid arthritis

• tumor necrosis factor α (TNFα) blocking agent may be an effective strategy for suppressing joint inflammation, slow radiographic progression of joint damage and improve physical function with less possible deformities

• most common corticosteroids used as an adjunctive therapy for rheumatoid arthritis is prednisone, or methylprednisolone.

• Prednisone is usually started at low doses of five to ten milligrams daily, but can be started at higher doses (15 to 20mg daily). However, attempts should be made to taper the dose to ten milligrams over the next few weeks.

• Many adverse effects are associated with administrated prednisone, which include weight gain, cushingoid appearance, hypertension, hyperglycemia, avascular necrosis of bones and osteoporosis

• Rituximab is a monoclonal antibody that binds to the B cell and decreases interactions between T and B cells reducing autoantibodies and joint pain and swelling

• all patients received methrotrexate and were treated with either a placebo, 500mg rituximab or 1000mg rituximab plus a placebo glucocorticoid, parentally given methyprednisolone premedication, or parentally methylprednisolone premedication plus oral prednisone for two weeks.

• Rituximab showed improvements in rheumatoid arthritis and can be used as an alternative treatment in patients who have an inadequate response to anti tumor necrosis factor α receptor therapies, or DMARDS

• Overall, combination therapy for rheumatoid arthritis continues to be effective in treating the signs and symptoms of rheumatoid arthritis. However, combination therapy does show an overall increase in adverse effects, the most commonly seen adverse effect being increased infections.

• The development of therapies targeting COX-1 and COX-2 receptors, tumor necrosis factor and interleukin-1, has caused improvement in the outcomes of reducing the progression of rheumatoid arthritis seen radiographically.

• Aletaha D, Stamm T, Ebrel G, Grisar J, Machold KP, Smolen JS. Survival and effectiveness of leflunomide compared with methotrexate and sulfasalazine in rheumatoid arthritis: a matched observational study. Ann Rheum Dis. 2003; 62: 944-51. PMID: 12972472.

• Burmester GR, Mariette X, Montecucco C, Monteagudo-Saez I, Malaise M, Tzioufas AG, et al. Adalimumab alone and in combination with disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial. Ann Rheum Dis. 2007; 66: 732-9. Epub 2007 Feb 28. PMID: 17329305.

• Cohen SB, Emery P, Greenwald MW, Dougados M, Furis RA, Genovese MC, et al.Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis & Rheumatism. 2006; 54: 2793-806. PMID: 16947627.

• Dutmer-Knijff EAJ, Martens A, Laar-Fjvd AFM. Effects of nabutemone compared with naproxen on platelet aggregation in patients with rheumatoid arthritis. Ann Rheum Dis. 1999;58: 257-259. PMID: 10364907.

• Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis & Rheumatism. 2006; 54: 1390-400. PMID: 16649186.

• Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, Bekker P, 20000223 Study Group. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis & Rheumatism. 2004; 50: 1412-9. PMID: 15146410.

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• Matsumoto AK M.D., Bathon J M.D., III Bingham CO M.D. Rheumatoid Arthritis Treatments. The John Hopkins University on Behalf of its Division of Rjeumatology 1998-2007: www.hopkins-arthritis.org/arthritis-info/rheumatoid-arthritis/rheum_treat.html Assessed on 11/2/2007 

• Price-Forbes AN, Callagham R, Allen ME, Rowe IF, on behalf of the West Midlands Rheumatology Services and Training Committee. A regional audit of the use of COX-2 selective non-steroidal anti-inflammatory drugs (NSAIDS) in rheumatology clinics in the West Midlands, in relation to NICE guidelines. Rheumatology 2005; 44: 921-924.

• Rheumatoid Arthritis. Mayo Clinic 2006: www.mayoclinic.com/health/rheumatoid-arthritis/DS00020/DSECTION=8. Accessed 10/31/07. 

• Rheumatoid Arthritis (RA), Merck manual online medical library home edition 2003. www.merck.com/mmhe/sec05/cho67/cho67bhtm. Accessed 10/20/07. 

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• Smolen JS, Han C, Bala M, Maini RN, Kalden JR, Breedveld FC, et al. Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis & Rheumatism. 2005; 52: 1020-30. PMID: 15818697.

• St. Clair EW, Van der Heijde DM, Smolen,JS, Maini RN, Bathon JM, Keystone EP, et al.Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis & Rheumatism. 2004 Nov;50(11):3432-43. PMID: 15529377.

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