Rheumatoid Arthritis (RA)

Definition, Etiology, PathogenesisTop

Rheumatoid arthritis (RA) is a chronic systemic autoimmune connective tissue disease of unknown etiology characterized by symmetric polyarthritis and associated extra-articular and systemic manifestations. RA leads to impairment, disability, and premature death if treated inadequately. The onset and progression of the disease is considered to be related to the response of CD45RO+ T cells (memory cells) to an unknown antigen or antigens, exogenous or endogenous, in a genetically predisposed individual. Based on the presence or absence of autoantibodies (IgM rheumatoid factor [RF] and/or anti-citrullinated protein antibodies [ACPAs; also termed antibodies to cyclic citrullinated peptides]), the disease can be divided into seropositive RA and seronegative RA, respectively.

Clinical Features and Natural HistoryTop

RA affects women 3 times as often as men, with the peak age of onset occurring between 30 and 50 years. In ~70% of patients with RA, relapses and partial remissions are observed, leading to progressive joint destruction. In ~15% of patients the course of RA is mild, with moderate disease activity, involvement of a few joints, and slowly progressive joint destruction. In ~10% of patients remissions are prolonged, lasting up to several years. Very rarely, the course of the disease is episodic (so-called palindromic rheumatism) or self-limiting. Up to 25% of these seropositive patients will go on to develop RA in subsequent years. Usually the disease onset is insidious, over a few weeks to months; however, in 10% to 15% of patients signs and symptoms develop rapidly over a few days (in these cases joint involvement may be asymmetric). In 75% of pregnant patients, symptoms improve in the first trimester and worsen after delivery. RA itself does not increase the risk of maternal or fetal complications.

1. Typical signs and symptoms: Symmetric pain and swelling of the joints of hands and feet, less frequently also of larger joints (eg, knee or shoulder). Morning joint stiffness of variable duration, usually lasting >1 hour.

2. Systemic manifestations: Low-grade fever, myalgia, fatigue, anorexia, and weight loss can occur. These usually precede the diagnosis.

3. Musculoskeletal manifestations: Early RA usually presents with a symmetric polyarthritis particularly affecting wrists, hands (metacarpophalangeal [MCP] and proximal interphalangeal [PIP] joints), and feet (metatarsophalangeal [MTP] joints), although the disease can present with large joint polyarthritis. The lumbar spine, distal interphalangeal (DIP) joints, and hip joints are unlikely to be involved in the inflammatory arthritis process. Joints of the upper extremities (particularly wrist joints) are affected more frequently than those of the lower extremities, although MTP joint involvement may be the first sign of RA. The onset of RA may be atypical, manifesting as monoarthritis or as palindromic rheumatism (pain and/or swelling in various joints lasting from a few hours to a few days and remitting spontaneously). Features occurring in the early stages of RA include heat (without erythema of the overlying skin), tenderness and swelling of joints and tendons, and joint effusions.

1) Joints of the hand (see Fingers in Rheumatic Diseases): In patients with early RA, fusiform swelling of PIP and MCP joints and palmar erythema located on the thenar and hypothenar eminences may be observed. Deformities develop in patients with more advanced RA. Atrophy of the interosseous and lumbrical muscles may occur due to disuse or neuropathy. Ulnar deviation of digits is the most frequent deformity. In later stages patients may develop volar subluxation of the phalanges at the level of the MCP joints, hyperextension of the PIP joint with flexion of the DIP joint (“swan-neck deformity”), or flexion of the PIP joint with hyperextension of the DIP joint (“boutonnière deformity,” caused by involvement of ligaments and tendons and muscle contractures), which lead to a significant impairment of finger movement. Wrist involvement includes dorsal or palmar swelling at the radiocarpal and carpal joints, swelling around the extensor carpi ulnaris tendon, and erosion of the ulnar styloid with interruption of the supporting ligaments, resulting in the “piano key” sign. The expanding synovium may compress the median nerve under the flexor retinaculum at the wrist, leading to carpal tunnel syndrome.

2) Elbow: Pain, swelling, and limited extension. Some patients may develop permanent flexion contractures.

3) Shoulder: Synovitis of the glenohumeral joint, subacromial-subdeltoid bursitis, rotator cuff tendonitis (causing subluxation), and atrophy of adjacent muscles. The acromioclavicular joint is rarely involved in RA (usually due to degenerative arthritis).

4) MTP joints are very frequently involved from the onset of the disease, causing toe deformities similar to those of the fingers.

5) Ankle and midfoot joints may be involved in progressive RA, often resulting in instability.

6) Hip involvement is uncommon in RA and is more commonly found in osteoarthritis. Hip synovitis presents with pain in the groin and progressive difficulty in walking.

7) Knees are frequently involved in patients with RA. Suprapatellar joint effusion results in a positive patellar tap test or swelling of the medial and/or lateral aspects of the joint, which increases upon compression of the suprapatellar region. A Baker cyst may develop (causing a palpable popliteal protrusion); increasing pressure of the accumulating effusion may lead to a rupture of the Baker cyst, leakage of the synovial fluid into tissues of the lower leg, significant lower leg edema, and worsening of knee pain with concomitant contracture of the knee (this needs to be differentiated from deep vein thrombosis of the lower leg). When this is accompanied by blood tracking down to the ankle, a crescent sign may be seen (discoloration around the lateral malleolus).

8) Spine: The cervical spine can be affected, leading to subluxation, destruction of the cartilage of the intervertebral disk, and disk prolapse. Atlantoaxial subluxation is potentially dangerous and presents with pain referred to the occipital area, paresthesias within the shoulder girdle and the upper extremity, and spastic paraplegia in the case of spinal cord compression.

9) Other joints: Involvement of the temporomandibular joint (pain in the temporomandibular area, difficulty opening the mouth and eating), cricoarytenoid joint (hoarseness), and less commonly the sternoclavicular joint.

4. Extra-articular manifestations occur particularly in patients with severe, long-standing seropositive RA and include:

1) Painless subcutaneous nodules on extensor surfaces, in particular of the forearm but also in pressure areas (eg, buttocks), within tendons, and over the joints. Nodules may also develop within internal organs.

2) Cardiovascular manifestations: Atherosclerosis and thromboembolic events (cardiovascular events are a common cause of death in patients with RA), pericarditis (in advanced RA), pericardial effusion that can be clinically asymptomatic, myocardial and valvular lesions (nodules, cardiomyopathy), pulmonary hypertension.

3) Pulmonary manifestations: Pleuritis (effusion is often clinically asymptomatic), nodules in the lungs (which may undergo fibrosis, calcification, or infection, and may be mistaken for neoplastic lesions), obliterative bronchiolitis, pulmonary fibrosis.

4) Ocular manifestations: Dry conjunctiva in the course of secondary Sjögren syndrome, episcleritis, and rarely scleritis (“corneal melt”).

5) Renal manifestations (mainly due to adverse effects of drugs used in RA treatment): Interstitial nephritis, pyelonephritis, secondary amyloidosis (complication of chronic active inflammation).

6) Other: Small- and medium-vessel vasculitis (this may lead to necrosis of distal digits, skin, and internal organs); involvement of the nervous system: carpal tunnel syndrome, polyneuropathy (particularly in the course of vasculitis), mononeuritis multiplex related to vasculitis, spinal nerve root compression due to destruction of cervical spine joints; submaxillary, cervical, axillary, and cubital lymphadenopathy; splenomegaly (with leukopenia [neutropenia] as part of Felty syndrome).

DiagnosisTop

Diagnostic Tests

1. Laboratory tests: Elevated erythrocyte sedimentation rate (ESR) (>30 mm/h) and/or elevated C-reactive protein (CRP) levels, anemia (may be normocytic normochromic in anemia of chronic disease, microcytic hypochromic in iron deficiency anemia secondary to gastrointestinal blood loss, or macrocytic related to folate deficiency [methotrexate—MTX—use] or B12 deficiency [pernicious anemia can be associated with RA]), minor elevations in the white blood cell count with a normal differential count or leukopenia associated with disease-modifying antirheumatic drug (DMARD) use, thrombocytosis (in patients with highly active disease) or thrombocytopenia (adverse effect of drugs), elevated plasma alpha1-globulin and alpha2-globulin levels, positive serum IgM RF in ~75% of patients (high titers correlate with rapid joint destruction and presence of extra-articular features), ACPAs (sensitivity >50% and specificity >98% in patients with RA; ~40% of patients with negative IgM RF have positive ACPAs, which are an adverse prognostic factor [similar to RF] and predict rapid joint destruction). A new test, 14-3-3eta, is used in conjunction with the other autoantibodies and confers greater specificity and sensitivity. A triple antibody test is available commercially as “JOINTstat” (RF, ACPA, 14-3-3eta).

2. Synovial fluid analysis: Features of inflammation. Other than when excluding infection, synovial fluid is not routinely examined in RA. If done, some clinicians consider testing for RF, which may be detected earlier than plasma RF. In some patients ragocytes may be observed (neutrophils, macrophages, monocytes, or synoviocytes with cytoplasmic inclusions of phagocytosed immune complexes).

3. Imaging studies: Radiographs of the affected joints reveal lesions that correlate with stage of the disease and may show 4 typical features: soft tissue swelling, joint space narrowing, periarticular osteopenia, and/or marginal erosions. Ultrasonography reveals synovial thickening, increased synovial vascularity, and effusions and erosions in small and large joints; joint erosions may be detected earlier by ultrasonography than by radiography. Magnetic resonance imaging (MRI) allows for early detection of synovitis, joint erosions, and bone marrow edema, which may precede synovitis. Computed tomography (CT) detects joint destruction earlier than radiographs and is the best method for visualizing bone cysts in patients with preserved or only slightly altered continuity of the bone cortex (in such cases the MRI signal of the cysts is normal and they may not be visualized); it is particularly useful in evaluating lesions in the cervical spine.

Diagnostic Workup

Basic laboratory investigations that should be undertaken include the ESR, CRP, IgM RF, ACPAs, complete blood count with a differential count, serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), uric acid (if gout is suspected in the differential diagnosis), creatinine and electrolyte levels, urinalysis, synovial fluid analysis (to exclude other joint pathologies in patients with joint effusion [specifically infections or crystal arthropathies]), and radiographs of the hands, feet, or other affected joints. In patients with normal radiographs, ultrasonography with power Doppler and/or MRI could be performed to assess for early disease activity. Antinuclear antibody (ANA) levels are not useful in the clinical setting of probable RA but could be considered if a connective tissue disease such as lupus is in the differential diagnosis.

The diagnosis should also take into account disease activity (Table 1) and functional capacity (assessed, eg, with the Health Assessment Questionnaire score or EuroQol tools).

Diagnostic Criteria

The American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria are used: Table 2.

Differential Diagnosis

The most likely alternative diagnosis is crystalline arthritis with “pseudo-RA.” Other conditions that can mimic the joint pain of RA include spondyloarthritides encompassing psoriatic arthritis, and infective arthritis. Less commonly any of connective tissue diseases can present with arthritis; patients with connective tissue diseases develop arthralgia (pain but no inflammation in the joints) more frequently.

TreatmentTop

Treat-to-Target Approach

The treatment target is clinical remission according to one of several criteria. The ACR/EULAR criteria (Table 2) are frequently used. The target should be attained within 6 months; however, treatment should be modified if no improvement is observed after 3 months. The 2016 EULAR treatment algorithm: Figure 1.

Pharmacotherapy

1. DMARDs are the mainstay of therapy in RA, as they prevent or delay joint damage. They should be introduced promptly after the diagnosis of RA is established.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Gaujoux-Viala C, Nam J, Ramiro S, et al. Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature review informing the2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2014 Mar;73(3):510-5. doi: 10.1136/annrheumdis-2013-204588. Epub 2014 Jan 6. Review. PubMed PMID: 24395555; PubMed Central PMCID: PMC3932966. Nam JL, Ramiro S, Gaujoux-Viala C, et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2014 Mar;73(3):516-28. doi: 10.1136/annrheumdis-2013-204577. Epub 2014 Jan 7. Review. Erratum in: Ann Rheum Dis. 2015 Jan;74(1):320. PubMed PMID: 24399231. Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016 Jan;75(1):3-15. doi: 10.1136/annrheumdis-2015-207524. Epub 2015 May 12. Review. PubMed PMID: 25969430; PubMed Central PMCID: PMC4717393. DMARDs are classified as follows:

1) Synthetic DMARDs:

a) Conventional DMARDs: MTX, leflunomide, sulfasalazine, gold salts, hydroxychloroquine.

b) Targeted DMARDs: Tofacitinib (Janus kinase [JAK] 3 and 1 inhibitor), baricitinib (JAK 1 and 2 inhibitor), upadacitinib (JAK 1 inhibitor).

2) Biologic agents (biologics; biologic DMARDs):

a) Innovator biologics, including anticytokine agents targeting tumor necrosis factor (TNF)-alpha (etanercept, adalimumab, infliximab, certolizumab, golimumab), interleukin 6 (IL-6) (tocilizumab), interleukin 1 (IL-1) (anakinra), and other biologic drugs targeting noncytokine pathways (abatacept, rituximab).

b) Biosimilar agents: For instance, biosimilar infliximab.

The choice of individual agents depends on disease activity and duration, prior treatment, prognostic factors (adverse prognostic factors include positive autoantibodies [RF and/or ACPAs, particularly in high titers], very high disease activity, early development of erosions), and comorbidities, as well as adverse effects and availability of the drugs (agents, dosage, contraindications, and treatment monitoring: Table 3).

In patients with active RA, start with MTX 15 mg once weekly, titrate up to the optimal dose (usually 20-25 mg/wk, with 25 mg/wk being the maximum; in the East Asian population, because of a lower body weight and possibly different pharmacogenetics, the maximum dose should be lower; Table 3) over 4 to 6 weeks (target dose might be a little lower in patients with adverse effects of MTX), and continue for ≥8 weeks in combination with folic acid 5 mg 24 hours after MTX. Folic acid counteracts some of the adverse effects (such as aphthous ulceration, nausea, hair loss) of the antimetabolite, MTX. In the case of contraindications to or intolerance of MTX, use oral leflunomide (10-20 mg daily) or oral sulfasalazine (up to 1.5 g bid); consider hydroxychloroquine in patients with low disease activity. In the initial treatment strategy, consider adding glucocorticoids for the shortest period possible (<3 months); the ACR suggests initiation of a conventional synthetic DMARD without short-term glucocorticoid use in DMARD-naive patients. Ensure prevention/treatment of osteoporosis (see Osteoporosis).

In the event that little improvement is observed within 3 months or the goals of treatment are not achieved within 6 months despite the use of optimal doses of a conventional synthetic DMARD or drug adverse effects develop (in the case of MTX intolerance start by changing the route of administration from oral to IM or subcutaneous), consider the following (see Figure):

1) In patients with poor prognostic factors (RF/ACPAs [especially in high titers], high disease activity, high swollen joint count, early joint damage, failure of ≥2 conventional synthetic DMARDs), add a biologic DMARD (TNF inhibitor [adalimumab, certolizumab, etanercept, golimumab, infliximab, or respective well-studied biosimilars], abatacept, IL-6 inhibitor [tocilizumab], or rituximab), or JAK inhibitor (tofacitinib, baricitinib, filgotinib, upadacitinib).Evidence 3Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Nam JL, Ramiro S, Gaujoux-Viala C, et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2014 Mar;73(3):516-28. doi: 10.1136/annrheumdis-2013-204577. Epub 2014 Jan 7. Review. Erratum in: Ann Rheum Dis. 2015 Jan;74(1):320. PubMed PMID: 24399231.

2) In patients without poor prognostic factors change to or add a second conventional synthetic DMARD, optimally in combination with short-term glucocorticoids.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Gaujoux-Viala C, Nam J, Ramiro S, et al. Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature review informing the2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2014 Mar;73(3):510-5. doi: 10.1136/annrheumdis-2013-204588. Epub 2014 Jan 6. Review. PubMed PMID: 24395555; PubMed Central PMCID: PMC3932966.

Use all biologic DMARDs in combination with MTX (~10 mg/wk) or other conventional synthetic DMARDs. If a patient does not tolerate conventional synthetic DMARDs in combination therapy, IL-6 inhibitors or targeted synthetic DMARDs may be preferred. If the treatment target of low disease activity or remission has not been achieved within 3 to 6 months, consider switching to another biologic DMARD combined with a conventional synthetic DMARD. In rare cases (severe treatment-resistant RA or contraindications to conventional and/or biologic DMARDs) you may consider using azathioprine or cyclosporine (INN ciclosporin) (or, exceptionally, cyclophosphamide).

If a patient is in persistent (≥6 months) remission after having tapered glucocorticoids, you could discuss with the patient a careful reduction of the doses or increase of the use interval of a biologic DMARD, especially when a patient continues conventional DMARDs. Discontinuation of conventional DMARDs in patients in remission may also be considered but often results in a flare or exacerbation of RA and achieving a second remission is much more difficult.

2. Oral nonsteroidal anti-inflammatory drugs (NSAIDs) could be used for acute control of signs and symptoms of inflammation. In patients with contraindications to or intolerance of NSAIDs, use acetaminophen (INN paracetamol) and/or weak opioids (eg, tramadol).

3. Intra-articular glucocorticoids may be considered when the disease (or its exacerbation) involves only one or a few joints (injections to a single joint can be repeated not more often than every 3 months). Before injection exclude any other reasons for the exacerbation of joint manifestations, such as infection or crystal-associated arthropathy. Doses depend on the size of the joint: methylprednisolone, 40 to 80 mg; betamethasone, 0.8 to 4 mg; dexamethasone, 0.2 to 6 mg.

Rehabilitation

Rehabilitation should be part of treatment in every phase of the disease:

1) Physiotherapy increases muscle strength, improves physical functioning, prevents contractures and deformities, and prevents disability. There is no clear evidence for beneficial effects of other therapies, including electrotherapy, laser therapy, thermotherapy, cryotherapy, massage, and balneotherapy.

2) Psychological counseling.

Surgical Treatment

Consider surgical treatment in the case of:

1) Severe pain and inflammation despite maximal intensity of medical treatment.

2) Joint destruction that limits the range of movement to an extent that causes significant disability.

Types of surgical interventions: synovectomy, reconstructive and corrective procedures, arthrodesis, and arthroplasty.

Synthetic DMARDs need not be stopped in the perioperative period; targeted DMARD tofacitinib should be stopped 7 days before surgeryEvidence 4Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and imprecision. Goodman SM, Springer B, Guyatt G, et al. 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty. Arthritis Rheumatol. 2017 Aug;69(8):1538-1551. doi: 10.1002/art.40149. Epub 2017 Jun 16. PubMed PMID: 28620948. It is recommended that biologic DMARDs are stopped within 2 half-lives prior to surgery and restarted after the surgical wound has healed with exact timing depending on the severity of underlying rheumatologic condition and probability of its deterioration.Evidence 5Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and indirectness. Goodman SM, Springer B, Guyatt G, et al. 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty. Arthritis Rheumatol. 2017 Aug;69(8):1538-1551. doi: 10.1002/art.40149. Epub 2017 Jun 16. PubMed PMID: 28620948.

Biologics should be stopped if the patient has an intercurrent infection.

Tables and FiguresTop

Figure 18.21-1. Management algorithm for rheumatoid arthritis. Based on Ann Rheum Dis. 2020;79:685-699.