Keywords

FormalPara Goals and Objectives

  • Goal: To introduce the reader to the key risk factors and concepts related to diagnosis and management of rheumatoid arthritis

  • Objectives: On completion of this unit, the learner should be able to describe and define the:

    1. 1.

      Risk factors for development of rheumatoid arthritis (RA)

    2. 2.

      Pathophysiology and clinical presentation of RA

    3. 3.

      Approach to diagnostic laboratory and imaging studies

    4. 4.

      Principles of medical management in RA

    5. 5.

      Role of surgical treatment

1 Risk Factors

RA affects from 0.5 to 1% of the population worldwide, although it is reported to have a prevalence rate of 5% in some native American populations [1]. Risk factors for the disease include female gender, genetics, and certain environmental factors. Women are 2–3 times more likely to develop RA than men, and the reasons for this are not established. RA can occur at any age and the peak incidence is in the 60s.

Concordance for RA among monozygotic twins is reported to be about 10–15%. Genetic factors may be responsible for up to 60% of the risk for RA in patients who are ACPA positive [2]. HLA DRB1 is strongly implicated in both the onset of seropositive RA and the severity of the disease [3]. Disease-associated HLA DR alleles contain a common amino acid sequence in the binding groove of the molecule, the so-called shared epitope. This finding implicates an important role for peptide binding in the onset of the disease. Numerous other genes encoding immune and inflammatory pathways have also been associated with the development of RA, but these have a weaker association. It is likely that multiple risk alleles in association with environmental factors are important in the development of RA.

Among environmental factors, cigarette smoking is the most important. Smoking increases the risk of RA in a dose-dependent fashion, and it is most striking in RA patients who are positive for the CCP antibody or who have the shared epitope [4]. Current smoking is accompanied by increased levels of inflammatory mediators and increased disease activity. In addition, some studies have shown that smokers respond less well to disease-modifying therapy [5].

The microbiome has been implicated in the development of RA. Periodontal disease is associated with an increased risk of RA [6], and this is thought to be related to two oral pathogens, Porphyromonas gingivalis [7] and Aggregatibacter actinomycetemcomitans. The intestinal microbiota is also thought to possibly play a role in the development of RA [8].

2 Pathophysiology

The synovium plays a central role in the pathogenesis of RA. In its normal state, the synovium plays two important roles: to produce the lubricants necessary for the cartilage surfaces to effortlessly glide and to provide nutrients for the cartilage, which lacks its own blood supply. The hallmark of rheumatoid arthritis is synovial inflammation characterized by an expansion of synoviocytes which produce pro-inflammatory cytokines such as TNF-alpha, IL-6, and GM-CSF. In addition, there is infiltration of the synovium with mononuclear cells, predominantly CD4+ lymphocytes and macrophages. The synovial compartment becomes the nidus of inflammation with a complex interplay of cytokines, chemokines, matrix metalloproteinases, activated T and B cells, fibroblasts, and osteoclasts. Local inflammation in the synovium leads to the development of a pannus, a local tumor, mediating the destruction of cartilage and bone.

3 Clinical Presentation

3.1 Articular Features

RA is a symmetric inflammatory polyarthritis that can involve almost any joint. In early disease, the predominant joints are the small joints of the hands and feet, and over time other joints may become involved. Pain and swelling of the joints are the earliest sign of disease. This is often associated with morning stiffness or stiffness after any period of prolonged inactivity lasting several hours. Most patients describe improvement in stiffness and sometimes pain with activity. The joint swelling associated with RA is usually soft or boggy which can be differentiated from the joint swelling in osteoarthritis which tends to be more boney.

In the hands, the wrists, MCPs, and PIPs are typically involved with sparing of the DIPs. In the feet, involvement of the MTPs predominates. After the hands and feet, the most common joints involved are the elbows, shoulders, ankles, knees, and hip. As in the hands and feet, these joints become painful, stiff, and swollen.

On physical examination inflamed joints are tender, are swollen, and often have a reduced range of motion. When the hand joints are inflamed, the grip strength is diminished. A new diagnosis of carpal tunnel syndrome, particularly when bilateral, should raise the suspicion for RA since wrist synovitis can be a cause of a compressive median neuropathy. In the spine, RA is generally confined to the cervical region. Among the cervical spine joints the atlantoaxial (C1–2) joint is most prone to subluxation and may lead to a cervical myelopathy.

Over time, if the disease is not adequately treated, swelling and tenderness progress to articular damage with malalignment, subluxation, and dysfunction of the joints. In the hands this may manifest as ulnar deviation of the fingers at the MCP joints, swan neck deformities (extension of the PIPs with flexion of the DIPs), or boutonniere deformity (flexion of the PIP and extension of the DIPs). In the feet, erosive damage in the MTPs leads to lateral drift of the toes and plantar subluxation of the metatarsal heads leading to “cock-up” toes. Involvement of the midfoot is common and can lead to collapse with chronic tarsal malalignment and pain.

3.2 Extra-Articular Features

RA is a multisystem disease, and extra-articular features are a sign of more advanced disease and a poorer prognosis. The skin and eye are the most common organs involved aside from the joints. Subcutaneous nodules typically are found on the extensor surfaces of the forearm just distal to the elbow joint, but they can occur in many other locations including the dorsum of the hands and over the Achilles tendons. They can also be found in internal organs such as the lung, heart, and meninges. Rheumatoid nodules have a classical histology with a central area of necrosis surrounded by palisading macrophages and lymphocytes [9]. Up to one third of patients with RA have sicca or secondary Sjögren syndrome characterized by keratoconjunctivitis and/or xerostomia. Rarely, some patients may develop episcleritis or scleritis, the latter of which can be sight limiting.

Other organs that may be involved include the lungs (pleurisy and interstitial lung disease), the heart (pericarditis, premature atherosclerotic disease), the vasculature (small vessel vasculitis), and the nervous system (compressive neuropathies and mononeuritis due to vasculitis). Hematologic abnormalities are common including anemia of chronic inflammation and thrombocytosis. Patients with RA have an increased risk of hematologic malignancy compared to age- and gender-matched controls.

Patients with RA have a 1.5–2.0 times higher risk for cardiovascular disease when compared to the general population, and this risk is attributed to the role of chronic systemic inflammation [10]. While it is not clear whether control of inflammation can ameliorate this risk, strategies to control the known risk factors for cardiovascular disease as well as appropriate management of inflammation are recommended [11].

4 Laboratory Studies

Rheumatoid factor (RF) is present in about 75% of patients with RA, but in only about one half of patients with early disease. It is not specific for RA; it is seen in patients with mixed cryoglobulinemia, systemic lupus, and many viral illnesses. High-titer rheumatoid factor has a higher specificity for RA than a low titer, and higher titers are associated with a poorer prognosis. Antibodies to cyclic citrullinated peptides (CCP) are similarly insensitive for RA, but have a higher rate of specificity compared to RF [12]. The absence of a RF and/or CCP does not rule out the diagnosis of RA.

Synovial fluid evaluation shows an inflammatory joint fluid (>5000 cell/mm3) with a predominance in polymorphonuclear leukocytes. Higher cell counts (>25,000 cells/mm3) may occur and when they do should raise the suspicion of a joint infection. In that case, a synovial fluid culture should be obtained.

Markers of acute inflammation including the Westergren sedimentation rate and C-reactive protein are useful markers of disease activity in RA and can be used both to aid in diagnosis and to follow disease activity in patients undergoing RA therapy. While markers of inflammation are typically elevated, the absence of this should not rule out the diagnosis of RA in the appropriate clinical setting.

Patients with active RA may have a mild to moderate normochromic normocytic anemia related to systemic inflammation. In addition, the platelet count may be mildly elevated. These values tend to normalize with effective treatment of the disease.

5 Imaging

5.1 Plain Radiographs

Plain radiographs of the hands and feet are recommended at baseline to assess any joint damage, although radiographs are frequently normal in early disease. Nonspecific signs of early inflammatory arthritis may include periarticular osteopenia and soft tissue swelling at this stage. As the disease progresses, there is loss of joint width signaling the loss of articular cartilage. Periarticular erosions occur later and can be seen at the ulnar styloid, base of the fifth metacarpal, and at the MCP and PIP joints. Later, ulnar deviation, subluxation, and other chronic deformities may become evident (Fig. 8.1). Routine periodic radiographic assessment is recommended to assure stability in patients undergoing therapy for RA. If radiographs show progression of disease despite therapy, this indicates a need for intensification of therapy.

Fig. 8.1
figure 1

Hand radiograph rheumatoid arthritis. There are diffuse osteopenia and soft tissue swelling noted around the MCP joints. There is joint space narrowing involving predominantly the MCP joints, radiocarpal joints, and scattered PIP joints with ulnar subluxation in the right hand. Numerous erosions involving the multiple bilateral MCP heads, left second proximal phalangeal base

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5.2 Ultrasound

Ultrasonography is increasingly used in rheumatology practices to assess the degree of joint inflammation, the volume of synovitis, and the presence of boney erosions. While plain radiography has been the standard imaging modality in RA, ultrasound has been shown to be more sensitive to change in boney erosion than plain radiography [13]. Ultrasonography may also be more sensitive than physical examination to assess subtle synovitis. Power Doppler ultrasound can be used to demonstrate active inflammation and can be used to monitor clinical response to DMARD therapy in patients with RA [14].

5.3 MRI

MRI is more sensitive in the detection of erosions than both plain radiography and ultrasound, but the clinical significance and natural history of these lesions are not known. Like ultrasound, MRI can also more accurately assess the volume of synovitis and intra-articular fluid than plain radiography [15]. In general, MRI is not regularly used to assess RA due to the need for MRI scanners appropriate for imaging the extremity, the uncertain clinical significance of the findings, and the cost of the procedure.

6 Diagnostic Approach

There are no diagnostic criteria for RA. The diagnosis of rheumatoid arthritis relies on a careful medical history and comprehensive physical examination with attention to the duration of symptoms, pattern of joint involvement, and complete assessment of other organ systems. Signs and symptoms of other autoimmune diseases should be queried including rash, oral ulcers, Raynaud phenomenon, infectious symptoms, alopecia, muscle weakness with elevated muscle enzymes, and antinuclear antibodies as these may indicate an alternative diagnosis.

The differential diagnosis is broad and includes other early autoimmune diseases such as systemic lupus, osteoarthritis, psoriatic arthritis, crystal-induced arthritis, and numerous viral diseases that can present with a symmetric polyarthritis. A symmetric polyarthritis may also be the initial presentation of a systemic vasculitis.

In the correct clinical setting, a positive RF and/or CCP can be used to support the diagnosis of RA. Marginal erosive disease on plain radiographs of the hands and/or feet is also highly suggestive of RA in the appropriate clinical setting.

In many cases, a definitive diagnosis cannot be made on the first evaluation, and a provisional diagnosis of undifferentiated inflammatory arthritis may be made. It is best to leave the diagnosis open and assess the future evolution of the disease process before moving to a definitive diagnosis. In either the case of RA or an undifferentiated inflammatory arthritis, disease-modifying therapy will be indicated.

New classification criteria for rheumatoid arthritis were developed in 2010 by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) in collaboration [16] (Table 8.1). While these criteria can be used to support the diagnosis of RA, their primary goal is to define a homogeneous population for the purpose of clinical studies.

Table 8.1 ACR/EULAR classification criteria for rheumatoid arthritis
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7 Treatment

7.1 Non-pharmacologic Management

The importance of lifestyle modification cannot be overemphasized. Smoking cessation is strongly encouraged. Efforts to attain and maintain a healthy body weight are essential and should be supported with counseling on nutrition and appropriate exercise individualized to each patient. Physical activity has numerous positive effects in patients with RA including decreased disease activity, decreased pain and fatigue, improved quality of life, improved sleep, and lower rates of depression [17].

7.2 Pharmacologic Therapy

Once the diagnosis is established, disease-modifying therapy should be rapidly instituted (Table 8.2). Since therapeutic onset may take from weeks to months for DMARD therapy to become effective, initial treatment with either nonsteroidal anti-inflammatory medications or low-dose prednisone is recommended as a bridge. Low-dose 7.5–10 mg prednisone daily is generally adequate for most patients. Higher doses, while effective, will have a greater toxicity and may make tapering more difficult. NSAIDs should be avoided in patients with renal insufficiency, peptic ulcer disease, or other contraindications.

Table 8.2 Disease-modifying antirheumatic drugs for RA
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Weekly low-dose oral or SQ methotrexate (MTX) is the first-line drug of choice for patients with RA [18] due to its high rate of efficacy and good long-term tolerability profile. Leflunomide is a good option as monotherapy for patients who are not able to tolerate methotrexate. Efficacy of therapy should be assessed at 8–12 weeks, and if it is not adequate to control the disease, therapy should be escalated. Combination therapy with an additional DMARD (hydroxychloroquine, sulfasalazine, leflunomide) or biologic, usually a TNF inhibitor, is recommended. Triple therapy with MTX, SSZ, and HCQ can be very effective in some patient populations who do not have an adequate response to MTX monotherapy [19].

When therapeutic changes are made, reassessment at around 12 weeks is important to make sure that treatment goals are being met. Tight control of disease is essential to prevent joint damage and maintain function [20]. Patients with the most severe disease will certainly require combination therapy and often frequent changes in biologic therapy to attain the optimal treatment response. Combinations of nonbiologic DMARDs and biologic DMARDs are more effective than monotherapy with either a nonbiologic or biologic DMARD [21]. Numerous biologic DMARDs with different mechanisms of action are available. In general, the efficacy of the biologic DMARDs is similar, and excellent treatment responses can be achieved with a wide variety of biologic DMARDs. Combinations of multiple biologic DMARDs are not recommended due to increase in toxicity.

Once a stable effective regimen of DMARDs is established, every effort should be made to taper off steroids and then decrease the NSAIDs to just prn use. Inability to withdraw steroids or NSAIDs indicates that the background DMARD therapy is not adequate and further adjustments to therapy are recommended.

7.3 Surgical Management

In general, surgical therapy is indicated only for disease that is resistant to medical therapy. The goal of surgery is to relieve pain and restore joint function [22]. Numerous surgical procedures are available to treat the manifestation of RA including tenosynovectomy for inflamed tendon sheaths or to repair tendon ruptures, synovectomy to remove inflamed synovium that is resistant to medical therapy, metatarsal head arthroplasties to relieve forefoot pain and improve walking, and joint fusion to stabilize painful destroyed joints. Total joint arthroplasty is reserved for patients with end-stage disease. The most common procedures include hip and knee arthroplasty, and in most cases the outcomes are very good. Other joints that may undergo total joint arthroplasty include the shoulder, elbow, and ankle.