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C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M

Rheumatoid Arthritis Rheumatoid Arthritis (RA) is a chronic, autoimmune, inflammatory systemic disease. While the exact cause is not known, it is considered to be an autoimmune disease. The primary target of the autoimmune inflammatory process in RA is the synovium — the membrane that lines the joints. The hallmark of RA is synovitis with joint inflammation and damage. RA’s impact, however, is not limited to joints, and it may affect other organs as well. Patients often progress to potentially debilitating joint damage due to persistent joint inflammation.

of tendons and ligaments. In patients, these are manifested by the deformities and disability that are the clinical picture of RA.

Streptococcus, Mycoplasma, Escherichia coli, or Helicobacter pylori; viruses that might include rubella, Epstein-Barr or parvovirus), and many others.

It is apparent that genetics play a role in determining both risk and severity of disease. However, genetics is not the only factor. In twin studies, if one of two monozygotic twins had RA, the other twin was affected only 15-20% of the time. The incidence is approximately 5% for dizygotic twins. RA is likely due to a complex interaction of genetic and environmental factors.

Once RA is initiated, the synovial tissue proliferates. The resulting synovitis leads to excess synovial fluid production and infiltration of pannus (extra tissue) into adjacent bone and cartilage. The synovitis causes destruction of cartilage and bone and the stretching or rupture

Triggers for RA have long been the target of active research with no specific cause yet isolated. It is widely believed, however, that infectious or other environmental agents are the catalyst. Ostensible triggers have included bacteria such as Myobacteria,

Both cellular and humoral immune system activity also appears to be important. Activated T-cells secrete cytokines, cells of the immune system that are potent pro-inflammatory mediators, including interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-α), that contribute to synovial proliferation. Significant amounts of IL-1 and TNF-α are present in the synovial lining of the joint and, in fact, the level of disease activity in RA and progression of joint destruction correlate with the plasma and synovial levels of IL-1. IL-1 stimulates the production of prostaglandin E@, nitric oxide and metalloproteases — all of which promote joint degradation, suppresses joint repair by inhibiting the synthesis of collagen and stimulates the osteoclasts to resorb bone. Rheumatoid factor is a serologic marker of RA and also correlates with more severe disease.

System Musculoskeletal

Skin

Lungs Peripheral Nervous System Eyes

Potential Manifestations ƒƒ Muscular atrophy, especially in the hands ƒƒ Deformities 2° bone and tendon damage ƒƒ Osteoporosis ƒƒ Carpal tunnel syndrome ƒƒ Small nodules under the skin ƒƒ Vasculitis induced purpura ƒƒ Skin ulcers ƒƒ Pleuritis ƒƒ Fibrosis (less common) ƒƒ Nerve entrapment ƒƒ Sjögren (SHOW-grin) syndrome

Incidence and Risk Factors The incidence of RA in women increases with age until about age 45 when it tends to plateau. In men younger than 45 the incidence is much lower, about 1/3 of that of women, but increases steadily with age and approaches that of women in the over-65 age group.

Table 1

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Other potential risk factors include estrogen use, smoking (significant risk) and coffee consumption, although some investigators have suggested that this risk may be limited to decaffeinated coffee. More research is needed.

Clinical Manifestations The hallmark symptoms of RA are inflammation and deformity of the smaller joints. However, a review of systems may also indicate systemic involvement. See Table 1. Joints are always involved. RA usually affects the joints of the hands, wrists, elbows, knees, ankles and/or feet. Larger joints such as of the shoulders, hip and jaw may also be affected. The vertebrae may be involved in patients who have had the disease for a long time. At least two or three joints are generally involved on both sides of the body and the sides tend to mirror each other. A patient who presents with wrist inflammation, for example, will have wrist involvement on both sides. Patients present with signs of inflammation and swelling around the joint as well as joint stiffness, pain and decreased range of motion. Nodules may be present on or near the joint, particularly when the elbows are involved. These symptoms often prevent patients from being able to carry out their normal activities. Generalized symptoms such as malaise, fever, myalgias and fatigue typically develop gradually, often before the joint symptoms present. As with most autoimmune diseases, the symptoms of RA tend to fluctuate. Most patients experience periods of active disease or flares separated by periods during which symptoms are improved. In some cases, the RA may become inactive and the patient goes into remission.

abnormal white blood cell count (WBC) or platelet counts. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are markers of inflammation and are usually elevated in RA, indicating the extent of disease activity at any given time. Assessment of electrolytes and chemistries may indicate systemic involvement. Serum immunological tests such as Rheumatoid factor (RF) and antinuclear antibodies (ANA) will be drawn. Most patients will have a positive serum Rheumatoid Factor (RF) during periods of active disease. Antinuclear antibodies (ANA) are found in about 40% of patients, indicating an unusually active immune system. However, in the

Stage 1

2

A sample of synovial fluid is withdrawn from a joint via arthrocentesis to evaluate for signs of inflammation such as elevated WBCs in the fluid. Early in the disease process an X-ray of an affected joint usually appears normal or may show only soft-tissue swelling, but damage is still occurring. Over time, an x-ray will show erosion of the bony part of the joint. The erosion of RA is distinguishable from the bone changes seen with osteoarthritis or other types of arthritis. An MRI may allow for earlier detection of the bony erosion.

Stage 3

Stage 4

Stage Clinical Manifestations 1

ƒƒ No damage seen on x-ray ƒƒ May be signs of bone thinning ƒƒ Evidence of bone thinning around a joint on x-ray, with or without slight bone damage

2

3

4

Diagnosis No single test can confirm a diagnosis of RA. A CBC can determine anemia,

Stage 2

first few months of disease RF and ANA may be negative and in some patients remain negative.

ƒƒ Slight cartilage damage ƒƒ Limited joint mobility without deformity ƒƒ Atrophy of adjacent muscle ƒƒ Soft tissue abnormalities around the joint ƒƒ Cartilage and bone damage on x-ray ƒƒ Evidence of bone thinning ƒƒ Joint deformity without permanent stiffness or fixation ƒƒ Extensive muscle atrophy ƒƒ Soft tissue abnormalities around the joint ƒƒ Cartilage and bone damage on x-ray ƒƒ Evidence osteoporosis ƒƒ Joint deformity with permanent ankylosis ƒƒ Extensive muscle atrophy ƒƒ Soft tissue abnormalities around the joint

Table 2

VOLUME 2

Class Functional Status 1 2 3 4

ƒƒ Completely able to perform activities of daily living ƒƒ Able to perform usual self-care and work activities ƒƒ Limited in activities outside of work ƒƒ Able to perform usual self-care activities ƒƒ Limited in work and other activities ƒƒ Limited in ability to perform usual self-care, work and other activities

Table 3 A joint effusion may be seen on ultrasound and diseased or damaged bone on a bone scan. An arthroscopy is not always necessary, but may be used to look for signs of RA or other joint disease.

Classification The American College of Rheumatology classifies severity of RA in stages. See Table 2. RA can also be classified in terms of functional status. See Table 3.

ƒƒ Physical therapy to help preserve and improve range of motion, increase muscle strength and decrease pain

ƒƒ Occupational therapy to teach

effective ways to use the body and reduce the stress on joints Assistive devices and environmental adaptations can be designed to support activity, ADLs, etc.

ƒƒ Hydrotherapy which involves

exercising or relaxing in warm water. Water reduces the weight on joints and warmth helps muscles relax

ƒƒ Both heat and cold treatments to relieve pain and reduce inflammation

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It may take 2 or 3 months for DMARDs to reach their full effect. In the meantime patients may also need antiinflammatory or analgesic agents as a bridging therapy to reduce pain and swelling.

ƒƒ A prosorba column to filter

The next step in pharmacologic treatment is the use of injectable Biologic Response Modifiers (BRMs) which work to inhibit either TNF, interleukins, or T or B cells. See Table 5.

ƒƒ Surgical interventions that may

Site-of-therapy options should be considered for BRM administration. Cost-effective options often include Ambulatory Infusion Centers and home.

antibodies linked to RA from the blood. This is available only in some medical centers and is typically used only in severe cases include removing damaged synovium, repairing damaged tendons or replacing damaged joints (especially knees and hips), or spinal fusion. Joint reconstructive or replacement surgery often provides the best outcome

Pharmacologic Non-pharmacologic Therapy The goals of pharmaceutical therapy Treatments are to eliminate evidence of disease A number of interventions can be applied to support patient function. These might include:

to 12 months after symptoms begin. DMARDs are central to RA treatment to stop or slow progression and bring about remission. Types of DMARDs works uniquely to modify the immune system, but they ultimately all work to help stop joint damage. See Table 4.

and support symptom management. Most patients require a combination of drugs, especially as the disease progresses. Historically, RA was treated with a stepwise approach, beginning with the “least invasive” drugs and progressing to disease modifying drugs only when patients presented with joint damage. Today, however, we recognize that patients treated early with disease modifying anti-rheumatic drugs (DMARDs) have better long-term outcomes. Early treatment controls inflammation better than the less potent drugs. These drugs support greater preservation of joint function, less work disability and a smaller risk of premature death. The current treatment approach is aggressive use of DMARDs within 3

Steroids, while well-known for their anti-inflammatory properties, are given for only short periods of time because of their serious potential side effects. Non-steroidal anti-inflammatories (NSAIDs) or other analgesics effectively reduce swelling and pain, but they do not stop joint damage and are therefore not used as monotherapy.

DMARDs ƒƒ methotrexate

(Rheumatrex®, Folex PFS)

ƒƒ sulfasalazine (Azulfadine®) ƒƒ leflunomide (Arava®) ƒƒ gold salts – aurothiolalate, auranofin (Ridaura®)

ƒƒ D-penicillamine ƒƒ hydroxychloroquine (Plaquenil®) ƒƒ azathioprine (Imuran®) ƒƒ cyclosporine (Neoral®) Table 4

Biologic Administration Response Modifier

Comments

Anti-TNF agents

ƒƒ SQ 2xweek ƒƒ etanercept (Enbril®) ƒƒ IV q 3-8 weeks ƒƒ infliximab (Remicade®) ƒƒ SQ q 2 weeks ƒƒ adalimumab (Humira®)

IL-1 blocker

ƒƒ anakinra (Kineret®) T-cell inhibitor

ƒƒ abatacept (Orencia®)

B-cell inhibitor

ƒƒ 4ituximab (Rituxin®)

ƒƒ SQ daily

Reserved for patients who have not responded to DMARDs

ƒƒ IV (over 30 mins) at 2 and 4

For patients who do not respond to DMARDs. Anti-TNF agents or methotrexate

weeks, then q week

ƒƒ IV (over 4-5 hours) twice, two weeks apart, then q 4-10 mos.

IL-6 antagonist

ƒƒ toclizumab (Actemra®)

In combination with methotrexate, indicated for the treatment of adult with moderate to severe active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies. Potential for serious side effects that can lead to death, including: infusion reactions, tumor lysis syndrome, severe skin and mouth reactions, and progressive multifocal leukoencephalopathy (PML; a rare, serious brain infection). An option when at least one other TNF antagonist has proven ineffective

Table 5 Opioids may be used for moderate to severe pain that is not relieved by other drugs.

Prognosis As mentioned, periods of disease activity are interspersed with periods of little or no activity as symptoms improve. In some cases, the disease will go away entirely. The duration of these cycles and the severity varies widely between individuals with RA. Some patients have a relatively mild condition with little disability or loss of function, others experience severe disability. Disease that remains persistently active for more than a year is likely to lead to joint deformities and disability. In fact, about 40% of patients will have some degree of disability 10 years after diagnosis. For most, RA is a chronic, progressive disease. But interestingly, about 5-10% of the patients will have a spontaneous remission, without treatment. Spontaneous remission is unlikely if it has not occurred within the first few months. Over time, the

disease becomes less aggressive and symptoms may even improve. Unfortunately, any joint damage that has already developed is permanent. RA is not fatal, but complications of the disease may shorten a person’s life span by a few years. The most common causes of premature death are infection, vasculitis and poor nutrition. Patients have a greater risk of infection, in part because of the autoimmune process, as well as a result of the immunosuppressant medications. Similarly, the risk of lymphoma or certain other cancers (including prostate and lung) are higher, again because of the abnormal immune system and immunosuppression.

References

ƒƒ Alonso-Ruiz, A; Pijoan, JI; Ansuategui, E; Urkaregi, A; Calabozo, M; Quintana, A. (2008). Tumor Necrosis Factor Alpha Drugs in Rheumatoid Arthritis: Systematic Review and Metaanalysis of Efficacy and Safety. BMC Musculoskeletal Disorders © 2008 Alonso-Ruiz et al; licensee BioMed Central Ltd.

ƒƒ Castro-Rueda, H and Kavanaugh, A (2008).

Biologic Therapy for Early Rheumatoid Arthritis. Curr Opin Rheum 2008; 20(3), 314-319.

ƒƒ Systemic DAS-Driven Therapy May Improve Outcomes in Rheumatoid Arthritis.

ƒƒ www.medscape.com/viewarticle/714546. Retrieved May 10, 2010.

ƒƒ www.arthritis.org/disease-center ƒƒ www.webmed/rheumatoid-arthritis/default.htm

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C O N T I N U I N G E D U C A T I O N 4

Healthline Self-Assessment Quiz Rheumatoid Arthritis LEARNING OBJECTIVES

LEARNING GOAL

Have a general understanding of the immune processes involved in RA, the resulting clinical manifestations and related treatment options.

At the end of this program, the reader will be able to: 1. Describe the impact of autoimmune activity specific to rheumatoid arthritis 2. Describe the characteristic clinical impact on joints 3. List additional systems potentially involved 4. Describe treatment options

SELF-ASSESSMENT QUESTIONS In the Quiz Answers section on the next page, circle the correct answer for each question. To obtain two (2.0) contact hours toward CE credit, the passing score is 100%. Return your SelfAssesment Quiz to Coram via email, fax or mail. See the next page for details on how to return to your quiz. Please allow approximately seven days to process your test and receive your certificate upon achieving a passing score. 1. R A is an autoimmune process that results in the following EXCEPT: a. Diminished amounts of synovial fluid around the joints b. Joint inflammation and damage

6. BRMs a. Are injectables b. Work to modify various components of immune system

c. Bone thinning

c. Are prescribed in combination with long-term steroids

d. Decreased range of motion

d. Should be considered for alternate-site delivery

2. Joints are not always affected in RA. a. True b. False 3. The current treatment approach for RA is earlier treatment with disease-modifying anti-rheumatic drugs (DMARDs): a. True b. False 4. DMARDs a. All work similarly to decrease joint inflammation and resulting damage b. Should be ordered early in the RA process c. May require concomitant anti-inflammatories or analgesics after initiation d. All of the above e. A, C f. B, C 5. Early use of DMARDs is more effective at controlling inflammation than steroids or NSAIDs

e. All of the above f. A, B and D 7. C orticosteroids or NSAIDs are effective monotherapies for the treatment of early RA. a. True b. False 8. Which of the following is NOT true about RA? a. Is a chronic, progressive disease b. Ultimately leads to joint deformity in more than 75% of patients c. May become less aggressive over time d. May present with multisystemic manifestations 9. Joint involvement in RA a. Typically affects at least two joints b. Joint involvement is mirrored on both sides of the body c. Affects larger joints more commonly than smaller joints d. All of the above

a. True

e. A and B

b. False

f. B and C 10. Early diagnosis of RA is best supported by x-ray. a. True

5

b. False

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