Rheumatology

Rheumatoid Arthritis

Does this patient have rheumatoid arthritis?

The typical clinical features of RA include pain and swelling of at least three or more joints, and typically will involve the wrist, metacarpophalangeal (MCP), proximal interphalangeal (PIP), and/or metatarsophalangeal (MTP) joints. Knees, elbows and ankles are also commonly involved, and morning stiffness often lasts for at least one hour. RA may also present atypically with monoarticular pain and swelling.

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 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.

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 permit 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. The 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. Radiographic features were not included in the algorithm, but if the presence of typical changes are seen in a target joint of RA, the need for the diagnostic algorithm is obviated. Note, however, that the classification criteria for RA are just that, and do not supplant the diagnostic role of the physician. Diagnosis and classification are not synonymous.

The presence of other diseases, including acute viral polyarthritis, Lyme disease, crystalline arthritis (i.e. gout 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 Sjögren syndrome preclude the diagnosis of RA.

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 involvement commonly presents as symmetric swelling and tenderness of the MCPs, PIPs, and wrists. DIP arthritis should prompt consideration of other diagnoses such as osteoarthritis or psoriatic arthritis.

    • 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 most often occur later in disease. The earliest symptom of hip involvement is pain with, or loss of, internal rotation. Thus, the presence of hip arthritis is assessed by flexing the hip to 90 degrees with the patient supine; internal and external rotation typically elicit pain.

    • Knee and elbow involvement is common, often with effusion in the knee.

  • 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 (hyperflexion at PIP joints) deformities 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 signs include hyperreflexia, and muscle weakness may be present. Not all patients with severe cervical spine involvement have symptoms, however, so the index of suspicion for cervical spine instability should be high, especially in patients who have longstanding, erosive disease.

  • Cricoarytenoid arthritis is rare, but should be considered in patients with upper airway signs or symptoms.

Extra-articular manifestations

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

  • Rheumatoid nodules. These are subcutaneous nodes that typically occur on the extensor surface of the forearm or on the fingers. Episcleritis, scleritis, keratitis, or uveitis.

  • Interstitial pulmonary fibrosis, pleural effusions, pulmonary nodules.

  • Anemia of chronic disease. It is not always straightforward to separate this from iron deficiency anemia because serum ferritin is an acute phase reactant in addition to a marker of iron stores. Thus, a normal or high level serum ferritin level does not preclude the presence of iron deficiency anemia.

  • Tendinitis or bursa contiguous to affected joints.

Less common extra-articular features include:

  • Systemic involvement such as fever, fatigue, weight loss.

  • Vasculitis with skin ulceration or internal organ involvement.

  • Pericarditis, myocarditis.

  • Felty’s syndrome (splenomegaly with neutropenia and large granular lymphocytes). Interestingly, there is anecdotal evidence to suggest that fewer patients are developing this condition in the era of biologic drugs for treatment of RA.

  • Cervical myelopathy. This is related to cervical spine involvement and may result from subluxation and instability or basilar invagination.

Comorbid conditions often seen with RA include:

  • Coronary artery disease. Careful screening for hyperlipidemia, diabetes, and other risk factors should be performed. Consider risk adjustment by a factor of around 1.5 when including the presence of RA as an independent contributor to vascular risk (see EULAR Guidelines).Entrapment neuropathies. The most commonly seen is carpal tunnel syndrome (median nerve), but tarsal tunnel syndrome (posterior tibial nerve), or ulnar nerve involvement may occur as well.

  • Other autoimmune conditions including secondary Sjögren 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 have been reported to be associated with 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 clinical test is the anti-cyclic citrullinated peptide (anti-CCP) antibody. 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 more rapid, or severe 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 are often 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). High resolution small coil magnetic resonance imaging (MRI) and color Doppler ultrasonography (US) are sensitive techniques for identifying bone erosions and synovitis, especially in early disease.

    Plain film radiographs of a patient with RF, CCP positive RA. There are erosions within the left fifth metacarpal base, right triquetrum, bilateral distal radii as well as diffuse peri-articular osteopenia.

  • 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.

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 radiographs should also be performed. Plain films 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 by expert panels to maximize the likelihood of achieving and maintaining optimal disease control. A strategy of treating to a target of low disease activity or disease remission (treat to target; T2T) is the best approach for optimal long-term outcomes. Screening should also be performed for conditions RA patients are at high risk for, such as coronary artery disease, which is associated with sustained inflammation, and osteopenia/osteoporosis. Management recommendations are discussed with regard to both initial assessment and subsequent evaluation.

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 at least one of several validated, quantitative instruments. These tools generate a composite score, typically consisting of patient and clinician assessment of overall disease activity, patient reported assessment of functional disability, a physical exam including enumeration of tender and swollen joints, and laboratory markers of inflammation. Patients may report pain and fatigue in visual analog scales.

Physical assessment includes a joint examination for the number of tenderness and swelling. 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 (https://www.rheumatology.org/practice-quality/clinical-support/quality-measurement/disease-activity-functional-status-assessments).

The Clinical Disease Activity Index (CDAI) and Disease Activity Score-28 (DAS-28) are the most commonly used validated measures. The CDAI score is the sum of the values for tender joint score, swollen joint score, patient global score, and provider global score. The joints scored for tenderness and swelling are the bilateral PIPs, MCPs, wrists, elbows, shoulders, and knees. Categories of disease activity include remission, low activity, moderate activity, and high activity. The DAS28 provides a score based on a more complex formula, for which there are many calculators on line or available for download at no cost. The DAS28 score is calculated from counts of the tender and swollen joints (the same as the 28 joints in the CDAI), as well as patient and/or provider assessment of the disease status, plus a measure of systemic inflammation such as the ESR or CRP.

There are additional versions of the DAS that include larger numbers of joints for more detail analyses and other validated disease activity indices that can be used (see link to ACR website above). The degree of functional impairment is typically reported via a health assessment questionnaire such as the Health Assessment Questionnaire Disability Index (HAQ-DI). The HAQ-DI assesses the ability to perform activities of daily living. The value of performing one or more of these indices at the initial assessment is to provide a baseline for subsequent longitudinal measurements that can be used to track the efficacy of a treatment regimen, facilitate the T2T approach, and assess functional decline.

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 and other factors. Interval monitoring is similar to the baseline assessment and includes history and physical exam, and repeated measures of disease activity (e.g., CDAI or DAS28) and functional disability (e.g., HAQ).

Patients should be questioned about symptoms that would suggest toxicity of medications, and there should be vigilance for the development of co-morbid conditions such as cardiovascular disease, osteoporosis, etc. Laboratory monitoring should include ESR or CRP measurements, which are useful for assessing disease activity and response to therapy. Periodic CBC, comprehensive metabolic profile (including blood glucose, serum liver function tests, and creatinine) should also be checked to monitor for drug toxicity or development of other medical conditions. Serum lipid profiles should be checked periodically to assess risk of cardiovascular disease.

Radiographs of the hands/wrists and feet may be repeated every 1-2 years to monitor disease progression on therapy. Radiographs of other joints should be performed based on patient symptoms and findings on physical exam. Of note, there is not complete concordance of disease activity scores with development of joint damage. If there is radiographic evidence of disease progression (i.e. worsening or new joint space narrowing or bone erosions), it may be appropriate to adjust therapy even if there is consistent low clinical disease activity. In addition to conventional radiographs, other imaging (MRI or CT) may be indicated. Power Doppler ultrasound may 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 with active RA 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 pharmacologic therapies below are commonly utilized. For more detailed information on use of nbDMARDs and biologic DMARDs, see the recent ACR/EULAR Guidelines for the Treatment of RA.

Nonsteroidal anti-inflammatory drugs (NSAIDS): NSAIDs are typically used on an as needed basis to control joint pain and inflammation. 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 (often as bridge therapy while awaiting the efficacy of DMARDs or biologic agents) or for disease flares. They typically provide short-term anti-inflammatory benefit, but due to potential toxicities with long-term use (osteopenia, cataracts, increased susceptibility to infections, etc.) GCs should generally be tapered as quickly as possible. For one or two affected joints, intra-articular injections of GC may alleviate pain and swelling.

Conventional 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, and presence of high titer RF and/or anti-CCP antibodies.

Summary of conventional synthetic disease modifying anti-rheumatic drugs (csDMARD)

  • Methotrexate (MTX): MTX is generally recommended as first-line therapy for active RA. It may be used as monotherapy or in combination with other csDMARDs or biologic DMARDs, depending on patient prognostic factors, cost, comorbidities, toxicity, and patient preference. Weekly 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 radiographs), 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 is strongly advised, as it has been shown to reduce toxicities such as oral ulcers and nausea without abrogating the therapeutic effect. Folinic acid may be used, but is typically much more expensive. 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, elevated LFTs, or neutropenia, additional csDMARDs or biological DMARDs may be substituted. Patients for whom oral weekly therapy is ineffective at the highest recommended and/or tolerable dose, or who have toxicities such as oral ulcers or nausea, may be switched to a parenteral (subcutaneous or intramuscular) route of administration.

  • Hydroxychloroquine (HCQ) and sulfasalazine (SSZ): HCQ or SSZ may be used singly or in combination for treatment of mild to moderate RA. They may also be used with MTX (triple DMARD) therapy for patients not responsive to a single csDMARD. The most common toxicities of SSZ include gastrointestinal upset and rash. HCQ is generally well-tolerated but requires a yearly ophthalmologic exam to monitor for retinal toxicity.

  • Leflunomide (LEF): LEF may be used in patients who are unable to tolerate MTX. LEF may be used as monotherapy or in combination with other csDMARDs or biologic DMARDs. Common side effects include gastrointestinal upset and elevated liver function tests. Some clinicians screen for G6PD deficiency to identify patients at risk for hemolytic anemia associated with SSZ. Periodic liver enzyme monitoring is required with LEF therapy, and LEF is contraindicated in pregnancy.

In patients with an insufficient response to csDMARDs, changes in medication are warranted. Incomplete response is typically defined as failure to achieve disease remission or low disease activity as quantitated by disease activity scores within 3 months of starting therapy. csDMARDs may be combined or an addition of a biologic DMARDs should considered, especially if the patient has poor prognostic factors as mentioned above. Biologic DMARDs may be used as monotherapy in patients who are unable to tolerate csDMARDs.

Summary of biologic disease modifying anti-rheumatic drugs

  • Anti-tumor necrosis factors (TNF) inhibitors: Etanercept, adalimumab, infliximab, golimumab and certolizumab are TNF inhibitors that are FDA approved for treatment of RA. These medications improve the signs and symptoms of RA and slow radiographic progression of joint damage. The TNF inhibitors are administered subcutaneously except for infliximab which is an intravenous infusion. Typically, TNF alpha inhibitors are used in combination with MTX. Side effects include injection site reactions or infusion reactions. TNF 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 antagonists: Tocilizumab is a humanized anti IL6 receptor antibody. Tocilizumab is administered intravenously every four weeks. There is an increased frequency of hyperlipidemia, elevated liver function tests, neutropenia, and thrombocytopenia with this drug. The most recent FDA-approved drug, sarilumab is an interleukin-6 (IL-6) receptor antagonist. It is administered subcutaneously every two weeks, and there is an increased risk for neutropenia, thrombocytopenia, elevated liver function tests, and lipid abnormalities. Similar infection risk profiling done prior to initiation of biologic DMARDs apply to sarilumab.

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

  • CTLA4-Ig: Abatacept blocks T cell co-stimulation and may be administered subcutaneously or intravenously. Abatacept should be used in caution in patients with chronic obstructive pulmonary disease (COPD).

  • Jak kinase inhibitor: Tofacitinib inhibits janus kinases (Jak) that are intracellular enzymes important in immune cell functions. It is a small molecule given orally, but it is frequently classified as a biologic agent. Tofactinib is administered as a 5 mg tablet taken orally twice daily; an extended release 11 mg tablet is administered once daily. It should not be taken in combination with biologic agents. Similar infection risk profiling done prior to initiation of biologic DMARDs apply to tofacitinib. This class of agents is termed targeted synthetic DMARD (tsDMARD).

  • Biosimilars: An important issue facing clinicians treating RA is the rise of biosimilars, which the US Food and Drug Administration defines as a biological product that is highly similar to an approved biologic product (the “originator” product) and that has no clinically meaningful differences in safety or effectiveness. The number of biosimilars in development has burgeoned since the Biologics Price Competition and Innovation (BPCI) Act of 2009 was passed by the US Congress with the intent of reducing costs and thereby increasing patients’ access to biologics. As of May 2017, the FDA had approved five biosimilars, four of which are TNF inhibitors, for rheumatologic and other inflammatory diseases: infliximab-dyyb (Inflectra/Remsima) and infliximab-abda (Renflexis) (biosimilars of infliximab-hjmt [Remicade]); etanercept-szzs (Elrezi) (biosimilar of Enbrel); and adalimumab-atto (Amjevita) (biosimilar of adalimumab). For more information, see recent review.

Baseline infection screening, as is recommended before starting TNF inhibitors, should also take place prior to starting any biological DMARD. Furthermore, patients should preferably receive killed, recombinant, and live attenuated vaccinations prior to starting any biologic DMARD. In patients who do not respond to MTX or other csDMARDs, a suggested next therapeutic step is to add a TNF inhibitor, although there are an increasing number of other biologics that may be used. Triple therapy, which is a combination of HCQ, MTX, and SSZ, is another therapeutic option, and is often efficacious.

Reassessment should take place 1-3 months after starting a biologic DMARD. Sufficient time for response should be allowed (typically ~ 3 months) to avoid exhausting all therapeutic options quickly. If treatment goals are not achieved in 3 months, therapy should be changed. If a patient responded to the initial TNF inhibitor but lost the effect (secondary non-responder), there are several therapeutic options, including switching to another TNF inhibitor or use of a biologic with a different mechanism of action. If there was an incomplete response to the initial TNF inhibitor (primary non-responder), the patient can be switched to a non-TNF inhibitor biologic agent (i.e., tociluzumab, rituximab, abatacept). The decision to switching to a different DMARD (either biologic or nonbiologic) depends on many factors, such as patient prognostic factors, cost/insurance status, comorbidities, and patient preference.

Ultimately, the treatment plan for an RA patient should be a shared decision between the patient and her/his clinician. Frequent, close monitoring and open communication between patient and health care provider are required for optimal outcomes. 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, health insurance status, and other factors.

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 therapies (e.g., osteoporosis with prolonged glucocorticoid use, etc.).

Despite the variety of treatment options, as many as 30% of patients are refractory to therapy and develop progressive worsening and in many cases, joint destruction. Synovectomy or other surgical approaches may be considered, particularly if a small number of joints remain active. Total joint arthroplasty may be required for severely damaged joints, particularly the knee, hip, or shoulder. Length of stay for procedures such as total hip replacement or total knee replacement may be longer for RA patients than for osteoarthritis patients. Many joints are not amenable to replacement (e.g., wrist) and arthrodesis may be an alternative to alleviate pain. Recommendations for joint replacement should be carefully considered in the context of symptom management (oral analgesics, etc.) perioperative risk factors, and goals and expectations of the patient.

RA is associated with an increased risk of coronary artery disease, and medications such as glucocorticoids and NSAIDs may increase this risk. Aggressively treating RA with DMARDs, screening for hyperlipidemia and diabetes, and smoking cessation have 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 as clinically indicated, with appropriate follow up management.

How to utilize team care?

Coordination between the patient’s rheumatologist, primary care provider, and other specialists is required for optimal outcomes. Frequently, patients have cardiovascular, ophthalmologic, pulmonary comorbidities, or toxicities from medications and require referrals to specialists. Consultations 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 to improve pain and function 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 multiple documents that include recommendations on the management of patients with RA.

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