Rheumatoid Arthritis

Does this patient have rheumatoid arthritis?

Early recognition of rheumatoid arthritis (RA) has become increasingly important, as early use of disease-modifying therapy has a long-term impact on the ultimate course of the disease. With the explicit aim of facilitating early use of methotrexate, new classification criteria have supplanted the classic 1987 criteria (Table I) for RA, which depended on features of RA present for greater than 6 weeks, and features more typical of longstanding disease such as rheumatoid nodules and radiographic erosions.

Table I.

The typical clinical features of RA include pain and swelling of at least three or more joints of the wrist, metacarpophalangeal (MCP), proximal interphalangeal (PIP), and metatarsophalangeal (MTP) joints although knees, elbows and ankles may also commonly be involved, and morning stiffness for at least one hour. RA may also present atypically with monoarticular pain or as episodes of arthritis followed by symptom-free periods lasting weeks to months – a condition known as palindromic rheumatism.

While the initial diagnosis of RA was traditionally suspected in a patient with more than a six-week duration of inflammatory symmetric polyarthritis, the new criteria (Table II) permits inclusion of patients with symptoms of shorter duration. Furthermore, application of the new criteria permits consideration of the diagnosis of RA whenever a patient presents with inflammation manifest by swelling of even a single joint if not explained by another disease. The diagnostic algorithm can then be applied. Number of swollen joints, presence of elevated inflammatory markers such as c-reactive protein (CRP), the erythrocyte sedimentation rate (ESR), antibodies to anti-citrullinated protein antibodies (ACPA), and rheumatoid factor (RF) all contribute to confirm the diagnosis.

Table II.

Other diseases, including acute viral polyarthritis, lyme disease, crystalline arthritis (i.e. monosodium urate disease or calcium pyrophosphate deposition disease), septic arthritis, reactive arthritis, osteoarthritis, psoriatic arthritis, or arthritis seen in setting of connective tissue diseases such as systemic lupus erythematosus or Sjogrens syndrome should be excluded as appropriate.

Musculoskeletal manifestations

  • Joint pain and swelling preferentially affecting the small joints in a symmetric fashion is the cardinal musculoskeletal manifestation of RA. An examination for joint swelling, tenderness and active and passive range of motion is essential.

    • Hand and wrist – RA commonly leads to symmetric swelling and tenderness of the MCPs, PIPs, and wrists. DIP involvement is uncommon but may be involved later in the disease.

    • Foot and ankle involvement is common in early disease and may include tenderness of the MTP joints, elicited by squeezing the forefoot, referred to as the “MTP squeeze test”, and swelling of the ankle.

    • Shoulder and hip involvement are less common and occur later in disease.

    • Hip arthritis is elicited by examining the supine patient, flexing the hip to 90 degrees, and evaluating internal and external rotation, as the earliest sign of hip involvement is pain with, or loss of, internal rotation.

    • Knee and elbow involvement is common with joint effusion.

  • Joint deformities, resulting from destruction, typically occur in late disease and manifest as restricted range of motion.

    • Common destructive features of the hands in RA include ulnar deviation, swan neck (hyperextension of PIP joints) or boutonniere deformities (hyperflexion at PIP joints) of the fingers.

    • Fixed flexion contractures of the elbows may limit the ability to reach the mouth or perform personal hygiene.

    • Flexion deformities of the knees can be extremely limiting to normal gait.

  • Symptoms of cervical spine instability include localized or radicular pain, sensory loss, or neck stiffness, and on exam hyperreflexia, muscle atrophy, or weakness may be present. Many patients with severe cervical spine involvement have no symptoms, however, so the index of suspicion for cervical spine instability should be high especially in patients who have longstanding, erosive disease.

Nonmusculoskeletal manifestations

RA is a systemic inflammatory disease. Extra-articular manifestations may affect up to 50% of patients. Common extra-articular manifestations include:

  • Occasionally systemic signs of fever, fatigue, weight loss

  • Rheumatoid nodules which are subcutaneous nodes that typically occur on the extensor surface of the elbow or within the tendon sheaths of the fingers

  • Vasculitis with skin ulceration or internal organ involvement

  • Episcleritis, scleritis, keratitis, or uveitis

  • Interstitial fibrosis, pleural effusions, pulmonary nodules

  • Upper airway involvement through cricoarytenoid arthritis or formation of vocal cord nodules

  • Pericarditis, myocarditis

  • Coronary artery disease at similar risk as diabetes requiring careful screening for risk reduction

  • Anemia either due to iron deficiency or anemia of chronic disease

  • Felty’s syndrome (splenomegaly with neutropenia and large granular lymphocytes) is rare

  • Entrapment neuropathies commonly affecting the ulnar, median, or posterior tibial nerve

  • Cervical myleopathy if the cervical spine is affected via basilar invagination or subluxation and instability

  • Other autoimmune conditions including secondary Sjogren’s syndrome

  • Osteopenia or osteoporosis

What tests to perform?

Laboratory studies are necessary to support the diagnosis, exclude other conditions, screen for potential contraindications to starting certain therapeutic agents, and assess the degree of inflammation.

  • Rheumatoid factor: Rheumatoid factor (RF) is commonly an IgM antibody directed against the Fc portion of IgG. RF is detectable in approximately 75-85% of patients with RA. Higher titers of RF suggest more severe disease manifested as radiographic joint damage, poorer functional status, and extra-articular manifestations. The sensitivity and specificity of RF in diagnosing RA is about 66% and 82% respectively.

  • Anti-citrullinated peptide/protein antibodies (ACPA): The most commonly available is the anti-cyclic citrullinated peptide (anti-ccp). The sensitivity of anti-ccp antibody for RA is approximately 50-75% and specificity is close to 90%-95%. Notably, RF and anti-ccp may be present before clinical disease and 35% of patients with a negative RF may test positive for anti ccp antibody. Presence of anti-ccp antibody early in disease may be predictive of development of joint damage.

  • C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR): ESR and CRP are acute phase reactants which may correlate with disease activity and response to therapy. An elevated ESR or CRP in early RA may be predictive of greater radiographic joint damage and poorer functional status.

  • Synovial fluid analysis: Synovial fluid in active RA demonstrates an inflammatory process with a predominant polymorphonuclear leukocytosis above 2,000/mm3. Concomitant infections and crystalline arthritis should always be ruled out via gram stain, culture and crystal analysis.

  • Radiographic imaging: Plain films of hands, wrists and feet should be obtained on all patients at baseline and repeated at 1-2 year intervals on therapy. In early disease, radiographs are typically normal. However, if abnormal, they may indicate an aggressive course. Radiographic changes suggestive of RA include soft tissue swelling, periarticular osteopenia, erosions and symmetric joint space narrowing (Figure 1). Magnetic resonance imaging (MRI) and color Doppler ultrasonography (US) are sensitive techniques for identifying bone erosions and synovitis, especially in early disease.

  • Infectious panel: As some of the therapeutic agents for RA may increase the risk of infections or reactivation of tuberculosis or hepatitis B, generally it is recommended to screen for tuberculosis, hepatitis B and C, and HIV prior to starting therapy or at the baseline visit if possible.

Figure 1.

For the initial work-up for suspected RA, we generally recommend checking a complete blood count (CBC) with differential, comprehensive metabolic panel (CMP) to include liver enzymes (LFTs), ESR, CRP, RF, and anti ccp antibody. Prior to initiation of pharmacologic agents, testing for latent tuberculosis, serological testing for hepatitis, and baseline chest X-ray should also be performed. Plain film radiographs of hands, wrists, and feet should also be obtained. Plain film radiographs of the cervical spine – anterior-posterior, lateral, and flexion/extension views - should be obtained if there are any cervical spine symptoms, or prior to surgery.

How should patients be managed?

The goals in treating RA are to minimize inflammation which causes pain and swelling and slow the development of erosions and joint destruction. Early diagnosis and therapeutic intervention along with frequent and regular monitoring are recommended strategies from expert panels to achieve and maintain disease control. A strategy of treating to a target of low disease activity or disease remission is the best approach to management. Screening should also be performed for conditions RA patients are at higher risk for, such as coronary artery disease, which is associated with sustained inflammation, and osteopenia, and osteoporosis.

Management recommendations here are divided by initial assessment and subsequent assessment.

Initial evaluation

After establishing the diagnosis of RA, the initial evaluation should start with an assessment of disease activity. Disease activity is typically measured by a validated, quantitative instrument. A composite score consists of patient and clinician assessment of overall disease severity, patient reported assessment of functional disability, a physical exam including tender and swollen joint count, and laboratory markers of inflammation. Patients may report pain and fatigue in visual analog scales, and degree of functional impairment is typically reported via a health assessment questionnaire such as the Health Assessment Questionnaire Disability Index (HAQ-DI).

Physical exam includes a joint examination for tenderness and swelling as well as screening for extra-articular disease. Elevated acute phase reactants such as ESR and CRP are useful measures of active disease. The composite score will then help to differentiate remission, mild/low, moderate, or severe/high disease activity. Therapy is then decided based on level of disease activity, patient preference, cost, and medical comorbidities. Several commonly utilized instruments to measure RA disease activity can be reviewed in the American College of Rheumatology (ACR) guidelines and via the ACR website.

The Composite Disease Activity Index (CDAI) and Disease Activity Score-28 (DAS-28) which are calculated from counts of the tender and swollen joints, as well as global assessment of the disease status, plus a measure of systemic inflammation such as the erythrocyte sedimintation rate (ESR) or c-reactive protein (CRP) are the most commonly performed assessments. These are used to track the success of the treatment regimen and treatment target.

Subsequent evaluations

The major treatment goal of RA is to quickly achieve “tight control” of disease by minimizing disease activity. After the initial evaluation, patients should be seen frequently and regularly (usually every 1-3 months) depending on disease activity. Components of interval monitoring are similar to the baseline assessment and include patient and clinician assessment of pain and fatigue, patient assessment of functional disability, physical exam, and laboratory monitoring. Ongoing assessment is necessary to monitor disease activity as well as to monitor for therapeutic toxicities.

Serial ESR or CRP measurements are useful for assessing disease activity and response to therapy. Periodic CBC and CMP should also be checked to monitor for drug toxicity. Serial radiographs may be repeated every 1-2 years to monitor disease progression on therapy. Notably, if there is radiographic evidence of disease progression (i.e. worsening or new joint space narrowing, periarticular osteopenia, or bone erosions) despite low clinical disease activity, it may be appropriate to adjust therapy. Power Doppler ultrasound may also be used as a sensitive tool to assess for synovitis and subtle erosions.

Therapeutic options

Early intervention with disease modifying antirheumatic drugs (DMARDs) helps to achieve and maintain low disease activity or disease remission. DMARDs can reduce or prevent joint damage. Hence, all patients should be started on DMARDs as soon as possible after confirming the diagnosis. If patients do not achieve low disease activity or remission after three months, therapy should be modified.

The following pharmacologic therapies are commonly utilized:

  • Nonsteroidal anti-inflammatory drugs (NSAIDS): NSAIDs are anti-inflammatory medications and are typically used on an as needed basis to control symptomatic pain and inflammation in RA exacerbations. Monitoring of renal and hepatic function and hemoglobin/hematocrit at baseline and at regular intervals is necessary to screen for NSAID toxicity. Consideration of comorbidities such as hypertension, coronary artery disease, as well as the risk of gastrointestinal effects including gastritis and peptic ulcer disease should also be considered.

  • Systemic and intra-articular glucocorticoids (GCs): Systemic GCs may be utilized in early disease or for disease flares. They typically provide short-term anti-inflammatory benefit, but due to potential toxicities with long-term use, GCs should be tapered as quickly as possible. For one or two affected joints, intra-articular injections of GC may alleviate pain and swelling.

  • Nonbiologic disease modifying anti-rheumatic drugs (nbDMARDS): These may be used initially as monotherapy or in combination depending on "poor prognostic factors" or preference. “Poor prognostic factors” which warrant consideration for more aggressive therapy, (i.e. combination nbDMARDs or biologic DMARDs) include poor functional status, high disease activity, extra-articular involvement, early erosive disease, smoking, male sex, and presence of high titer RF and/or anti ccp antibodies.

Summary of nonbiologic disease modifying anti-rheumatic drugs

  • Methotrexate (MTX): Methotrexate is generally recommended as first-line therapy for active RA. It may be used as monotherapy or in combination with other nbDMARDs or biologic DMARDs, depending on patient prognostic factors, cost, comorbidities, toxicity, and patient preference. MTX has been shown to reduce signs and symptoms of RA and slow radiographic progression. Prior to starting MTX, a laboratory and radiographic assessment (CBC, CMP including LFTs, hepatitis screening, and chest radiograph), comorbidity and vaccination screening should be completed. CBC and CMP should also be monitored at regular intervals to monitor for drug toxicities. Concomitant folic acid or folinic acid must be administered. If MTX is contraindicated due to either pregnancy or significant renal or liver disease, or not tolerated due to side effects such as gastrointestinal upset, mucositis, transaminitis, or neutropenia, additional nbDMARDs or biological DMARDs may be substituted.

  • Hydroxychloroquine (HCQ) and sulfasalazine (SSZ): HCQ or SSZ are typically used in combination for treatment of milder RA. Most common toxicities of HCQ and SSZ include gastrointestinal upset and rash. HCQ requires a yearly ophthalmologic exam.

  • Leflunomide (LEF): LEF may be used in patients who are unable to tolerate MTX or a biologic DMARD for initial therapy. LEF may be used as monotherapy or in combination with other nbDMARDs. Common side effects include gastrointestinal upset and transaminitis. Periodic liver enzyme monitoring is required with LEF therapy, and LEF is contraindicated in pregnancy.

In patients with an insufficient response to nbDMARDs within 3 months of starting therapy (i.e. failure to achieve disease remission or low disease activity), nbDMARDs may be combined or the addition of biologic DMARDs should be considered, especially if the patient has “poor prognostic factors” as mentioned above. Furthermore, biologic DMARDs may be the initial therapy in patients who are unable to take nbDMARDs.

Summary of biologic disease modifying anti-rheumatic drugs

  • Anti-tumor necrosis factors (TNF) alpha inhibitors: Etanercept, adalimumab, infliximab, golimumab and certolizumab are TNF alpha inhibitors approved for treatment of RA. These medications improve the signs and symptoms of RA and slow radiographic progression of joint damage. The TNF alpha inhibitors are administered subcutaneously except for infliximab which is an intravenous infusion. Typically, TNF alpha inhibitors are used in combination with MTX. Common side effects include either injection site reactions or infusion reactions. TNF alpha inhibitor use may increase the risk of reactivation of TB or hepatitis B, as well as the development of lymphoproliferative conditions, solid tumors, demyelinating disorders, drug induced lupus reactions, or exacerbation of pre-existing heart failure. Patients should be screened for prior TB exposure, hepatitis B and C, and HIV prior to starting a TNF alpha inhibitor.

  • Anti IL-6 receptor antagonist: Tocilizumab is a non TNF alpha inhibitor biologic agent used to treat RA. It is a humanized anti IL6 receptor antibody. Tocilizumab is administered intravenously every four weeks. There is an increased risk of hyperlipidemia, transaminitis, neutropenia, and thrombocytopenia with tocilizumab.

  • Monoclonal antibody to CD20: Rituximab is infused as one dose repeated two weeks later. Common side effects are infusion reactions, which are minimized with an intravenous methylprednisolone infusion administered prior to the rituximab infusion. Rituximab has an increased risk of reactivation of hepatitis B and screening should take place prior to starting rituximab.

  • CTLA-4 antagonist to block T cell co-stimulation: Abatacept is a non TNF alpha inhibitor biologic agent and may be administered as a subcutaneous injection or as an intravenous infusion. Abatacept should also be used in caution in patients with chronic obstructive pulmonary disease (COPD).

  • Baseline infection screening, as is recommended before starting TNF alpha inhibitors, should also take place prior to starting any biological DMARD. Furthermore, patients should receive killed, recombinant, and particularly live attenuated vaccinations prior to starting any biologic DMARD.

A newer non-biologic but nonsynthetic DMARD which recently became available is tofacitinib. Tofacitinib is an oral medication which inhibits janus kinase (JAK) enzymes. JAKs are intracellular enzymes involved in immune cell function. Tofactinib is administered as a 5mg tablet taken twice daily. It may be used as monotherapy or in addition to other nbDMARDs in patients who did not respond to MTX alone. It should not be taken in combination with biologic agents. Similar infection risk profiling done prior to initiation of biologic DMARDs apply to tofacitinib.

In patients who do not respond to MTX or nbDMARDs, a suggested next therapeutic step is to add a TNF alpha inhibitor to MTX. Triple therapy, which is a combination of HCQ, MTX, and SSZ, has been suggested as a therapeutic option, and is efficacious, but many patients have difficulty with the number of pills required on this regimen. If treatment goals are not achieved in 3 months, therapy should be changed. If a patient responded to the initial TNF alpha inhibitor but lost the effect (secondary non-responder), he/she should be switched to another TNF alpha inhibitor. If there was no response to the initial TNF alpha inhibitor (primary non-responder), the patient can be switched to a non-TNF alpha inhibitor biologic agent (i.e., tociluzumab, rituximab, abatacept). Reassessment should take place 1-3 months after starting a biologic DMARD. Despite various treatment options, as many as 30% of patients are refractory to therapy and develop progressive worsening of disease. Arthroplasty may then be required for destroyed joints.

Ultimately, treatment of RA is a decision between the patient and their clinician and requires frequent, close monitoring. If patients are intolerant or resistant to initial nbDMARD therapy, starting additional nbDMARDs or switching to a different DMARD (either biologic or nonbiologic depending on patient prognostic factors, cost, comorbidities, and patient preference) is recommended. Active inflammation and pain can be treated with short courses of NSAIDs and intra-articular or systemic glucocorticoids as needed. Treatment should be adjusted every 3-6 months to achieve “treatment target” which is disease remission or low disease activity. In addition to disease activity, treatment modification should account for comorbidities, radiographic progression, and safety/toxicity of medications.

What happens to patients with rheumatoid arthritis?

RA is a chronic, progressive disease. If not optimally treated, RA can lead to significant pain and disability. Clinical and radiographic outcomes have improved with aggressive, early initiation of treatment, establishing target goals, and frequent and regular monitoring. Patients with RA are at increased risk of infections, lymphoproliferative conditions, pulmonary disease, cardiovascular disease, and osteoporosis. These increased risks may be attributed to the chronicity of active disease, but may also be complicated by the therapies.

RA is particularly associated with an increased risk of coronary artery disease, and medications such as glucocorticoids and NSAIDs may also increase this risk. Aggressively treating RA with DMARDs and screening for hyperlipidemia, smoking, and diabetes, has been shown to reduce the risk of coronary artery disease. Osteoporosis is another major comorbidity in RA. Patients should take adequate calcium and vitamin D and have bone mineral density testing to further guide osteoporosis management.

How to utilize team care?

Coordination is required between the patient’s rheumatologist and primary care physician. Frequently, patients have cardiovascular, ophthalmologic, pulmonary comorbidities, or toxicities from medications and require referrals to specialists. Coordination with an orthopedic surgeon for damaged joints or a neurosurgeon for suspected cervical subluxation may also be necessary. Physical therapy, occupational therapy and psychosocial support are adjunctive therapeutic options for RA patients.

Are there clinical practice guidelines to inform decision making?

The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have developed recommendations on the management of patients with RA.

Other considerations

  • ICD-9 code: 714.0

  • Length of stay for common procedures such as total hip replacement or total knee replacement are longer than for comparable osteoarthritis patients by 12-24 hours.

What is the evidence?

Arnett, F, Edworthy, S, Bloch, D. "The American Rheumatism Association 1987 Revised Criteria for the classification of rheumatoid arthritis". Arthritis and Rheumatism. vol. 31. 1998. pp. 315-324..

Lee, DM, Weinblatt, ME. "Rheumatoid arthritis". Lancet. vol. 358. 2011. pp. 903-11..

Jacoby, R, Cosh, J, Jayson, M. "Onset, early stages, and prognosis of rheumatoid arthritis: a clinical study with 100 patients with 11 years of follow-up". Br Med J. vol. 2. 1973. pp. 96-100..

Aletaha, D, Neogi, T, Silman, A. "2010 Rheumatoid Arthritis Classification Criteria. An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative". Arthritis & Rheumatism. vol. 62. 2010. pp. 2569-2581..

Turesson, C, O’Fallon, WM, Crowson, CS. "Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years". Ann Rheum Dis. vol. 62. 2003. pp. 722-7.

Van der Heijde, DM, van Riel, PL, van Rijswijk, MH. "Influence of prognostic features on the final outcome in rheumatoid arthritis: a review of the literature". Semin Arthritis Rheum. vol. 17. 1988. pp. 284-92.

Nishimura, K, Sugiyama, D, Kogata, Y. "Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis". Ann Intern Med. vol. 146. 2007. pp. 797-808..

Nielen, M, van Schaardenburg, D, Reesink, H. "Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors". Arthritis Rheum. vol. 50. 2004. pp. 380-386.

Schellekens, G, Visser, H, de Jong, B. "The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide". Arthritis Rheum. vol. 43. 2000. pp. 155-163..

Lindqvist, E, Eberhardt, K, Bendtzen, K. "Prognostic laboratory markers of joint damage in rheumatoid arthritis". Ann Rheum Dis. vol. 64. 2005. pp. 196-201.

Singh, J, Furst, D, Bharat, A. "2012 Update of the 2008 American College of Rheumatology Recommendation for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis". Arthritis Care & Research. vol. 64. 2012. pp. 625-39..

Smolen, JD, Landewe, R, Breedveld, FC. "EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update". Ann Rheum Dis. 2013 Oct 25.

Anderson, J, Caplan, L, Yazdany, J. "Rheumatoid Arthritis Disease Activity Measures: American College of Rheumatology Recommendations for Use in Clinical Practice". Arthritis Care & Research. vol. 64. 2012. pp. 640-647..


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