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Rheumatoid Arthritis
CHAPTER 152
Rheumatoid Arthritis Kevin Byram, MD Sallaya Chinratanalab, MD John Sergent, MD
Synonyms None
ICD-10 Codes M05 M06.9
Rheumatoid arthritis
Definition Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory arthritis that usually affects the small joints of the hands and feet in a symmetric distribution. Without treatment, RA can cause erosive joint damage and deformity that leads to significant morbidity and disability. In addition to the arthritis, RA is a systemic disease that can involve multiple organ systems, including the skin, lungs, and cardiovascular system.1 RA affects about 1% of the adults in the United States and Europe, but rates vary in other populations. For example, Nigerian adults have some of the lowest prevalent RA rates (0.1%), while Pima and Chippewa indigenous populations in the US have among the highest rates (5%).2 The prevalence of RA in any population increases with age. RA occurs more frequently in women and cigarette smokers.3 The American College of Rheumatology has developed a set of criteria to classify patients as having RA, most recently revised in 2010 (Table 152.1).4 These criteria were validated to appropriately classify patients with RA for clinical study, and serve to update the previous 1987 criteria in an attempt to appropriately classify patients with early RA.5
Symptoms Patients with RA generally present with arthralgias and joint swelling of the small joints of the hands, wrists, and feet in a symmetric pattern. Loss of function is a common complaint among patients with RA, particularly activities requiring fine motor movements (e.g., fastening buttons) or grip strength (e.g., opening jars). 876
Warmth and redness around a joint can occur, but these are more common in other arthritis syndromes, such as gout. Morning stiffness is also a common complaint by patients with RA, typically lasting more than one hour. In addition, since RA is a systemic disease, it is common for patients to have extra-articular features associated with their presentation.6
Systemic Patients with RA can present with nonspecific features of malaise and fatigue. Fevers are uncommon but can occur.
Cutaneous The most common extra-articular feature of RA is the development of subcutaneous nodules, known as rheumatoid nodules, on the extensor surfaces of joints. Rheumatoid vasculitis is a particularly rare, but potentially devastating cutaneous feature of RA. Rheumatoid vasculitis presents with typical vasculitic eruptions, ranging from purpura to ulceration and infarct.
Ophthalmologic Patients with RA frequently complain of dry eye and dry mouth, known as keratoconjunctivitis sicca. Episcleritis and scleritis also can in occur with patients with RA, which manifests as red, painful eyes.
Pulmonary Pleuritis and pleural effusions occur in as many as 20% of RA patients, and may occur early in the course of the disease. Interstitial inflammation and fibrosis usually present with cough and dyspnea and can be life-threatening.
Neurologic Nerve entrapment secondary to inflammation or deformity is common in RA. Carpal tunnel syndrome (median nerve entrapment) is the most common of these, and presents with sensory loss or paresthesias in the median nerve distribution. A potentially devastating neurologic complication in
CHAPTER 152 Rheumatoid Arthritis
877
Table 152.1 2010 ACR/EULAR Rheumatoid Arthritis Classification Criteria Criterion
Points
Arthritis Joint Distribution 1 large joint
0
2–10 large joints
1
1–3 small joints (large joints not counted)
2
4–10 small joints (large joints not counted)
3
>10 joints (at least one small joint)
5
Serology Negative RF AND negative ACPA
0
Low positive RF OR low positive ACPA
2
High positive RF OR high positive ACPA
3
Symptom Duration <6 weeks
0
>6 weeks
1
Acute Phase Reactants Normal CRP AND normal ESR
0
Abnormal CRP OR abnormal ESR
1
FIG. 152.1 Boutonnière deformity in rheumatoid arthritis. This deformity occurs with hyperextension of the distal interphalangeal joint and flexion of the proximal interphalangeal joint. (From Concannon MJ. Common Hand Problems in Primary Care. Philadelphia: Hanley & Belfus; 1999.)
The appropriate population to apply these criteria to are those with at least one joint with definite clinical synovitis that is not better explained by another disease. A patient is said to have definite RA if they score 6 or more points or if they have characteristic radiographic erosions of rheumatoid arthritis. ACPA, Anti-citrullinated protein antibody; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RF, rheumatoid factor.
advanced RA is atlanto-occipital instability or subluxation, which can cause symptoms ranging from radicular pain and paresthesias to myelopathy and death. Mononeuritis multiplex can occur in the setting of rheumatoid vasculitis and causes weakness or paresthesias in single or multiple single nerves (e.g., footdrop or wrist drop).
Cardiac RA is associated with an increased rate of cardiovascular mortality, secondary to coronary artery disease. Thus, patients with RA should be monitored for symptoms that could be consistent with coronary artery disease, such as substernal chest pain, dyspnea, and diaphoresis. Less commonly, myocarditis, pericarditis, and subsequent arrhythmia can occur in RA.7,8 Rarely, RA can cause inflammation along valve rings, causing valvular inflammation, and along the conduction system, resulting in heart block or arrhythmia. Conduction abnormalities can present variably, including dyspnea, chest pain, or syncope.
Physical Examination The clinician will examine all joints for evidence of synovitis, including swelling, tenderness, warmth, or effusion. The metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, wrists, knees, and ankles are most commonly involved. Importantly, the distal interphalangeal joints are usually not involved in RA. Rarely, patients will present with a monoarticular arthritis.
FIG. 152.2 Swan neck deformity in rheumatoid arthritis. This deformity occurs with hyperextension of the proximal interphalangeal joint and flexion of the distal interphalangeal joint. (From Concannon MJ. Common Hand Problems in Primary Care. Philadelphia: Hanley & Belfus; 1999.)
Early RA generally presents with swelling and tenderness about the involved joints that is synonymous with activity of the disease. More chronic disease might reveal physical exam signs that correlate with damage from the disease. Early involvement in the fingers will present with fusiform swelling in the wrists, MCPs, and PIPs. Joint involvement is usually symmetric. Chronic inflammation in the hands or wrists may lead to subluxation of the MCP joints or carpal bones. Wrist subluxation is suggested by a prominent ulnar styloid. Ulnar deviation of the fingers is common in advanced disease. Ligamentous damage at the PIPs can cause the classic boutonnière and swan neck deformities. A boutonnière deformity describes PIP joint flexion and DIP joint hyperextension, while a swan neck deformity describes PIP joint hyperextension and DIP joint flexion (Figs. 152.1 and 152.2). The tendon sheaths of the fingers are also common sites of inflammation in RA. If tenosynovitis is present, then crepitus can be felt by the examiner when the fingers of the patient are slowly flexed and extended. Stenosing tenosynovitis (trigger finger) can occur with more prolonged inflammatory involvement of the tendon sheaths. The elbow can also be involved in RA. Early disease will cause effusion in the elbow joint, which can be palpated by the clinician in the para-olecranon groove, and is usually accompanied by decreased range of motion. Advanced RA
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will cause inability to fully extend or flex the elbow, even in passive motion. The shoulders are also possible sites of inflammation in RA. Active RA is suggested by shoulder effusions, which, if present, are usually visible on the anterior aspect of the joint below the acromion. The rotator cuff and biceps tendon are also important for the clinician to evaluate, since tear or rupture might occur as a result of the chronic inflammation. The knee is commonly affected in RA and should be evaluated for effusions and Baker’s cysts. Large knee effusions are detectable by ballottement of the patella against the femur. Smaller effusions can be detected by evaluation for the “bulge sign.” With the patient comfortably lying down, the clinician “milks” fluid from the medial patellar pouch superiorly, then subsequently “milks” fluid in the lateral pouch inferiorly. The sign is positive (and thus a small effusion is suggested) if a bulge appears in the medial pouch with the lateral downward stroke. A Baker’s cyst is a cyst in the popliteal fossa that communicates with the joint cavity. If present, a fullness can be palpated in the popliteal fossa. Involvement of the ankle and subtalar joints may reveal decreased range of motion with dorsi- and plantar-flexion or inversion and eversion. Metatarsophalangeal (MTP) joints may be inflamed, in which case compressing the MTP row may reveal tenderness (a positive “MTP squeeze” sign). Baker’s cysts can rupture, causing swelling in the calf and the ecchymotic “crescent” sign around the medial malleoli of the ankle. More advanced disease might cause hallux valgus deformity or claw and hammer toe deformity. Hindfoot valgus deformity and resultant flatfoot deformity can occur with longstanding disease. The cervical spine should be examined for decreased range of motion, pain with motion, and impingement phenomenon. Patients with advanced and deforming arthritis elsewhere should have a thorough neurologic examination to evaluate for cervical or atlanto-occipital instability, suggested by paresthesias, weakness, occipital pain, or hyperactive reflexes. Systemic involvement should also be evaluated during the physical exam. The eyes should be assessed for conjunctival or scleral involvement. The lungs should be auscultated for the fine crackles of interstitial lung disease. A thorough skin exam might reveal rheumatoid nodules on the extensor surfaces of joints or bony prominences or other areas of friction such as the Achilles tendon. These are sometimes difficult to distinguish from the tophi of gouty arthritis.
Functional Limitations Functional limitation in patients with RA stems from the location and severity of articular involvement or systemic involvement of the disease. For instance, patients with deformed or severely eroded lower extremity joints might have issues with mobility, whereas a patient with advanced small joint hand deformity might have issues with self-care or other activities of daily living. Functional limitation related to systemic disease depends on the organ involved. For example, patients with RA-related interstitial lung disease could have functional limitations related to hypoxia, including decreased exertional capacity. Fortunately, early, aggressive treatment of RA can mitigate the progression of disease, and thus decrease the functional limitations that accompany advanced disease.9
FIG. 152.3 Radiograph demonstrating advanced rheumatoid arthritis. Features include metacarpophalangeal (MCP) subluxation, marginal erosions, and ulnar deviation of the fingers of the left hand. In addition, implanted prostheses can be visualized at the MCP joints on the right hand. (From Weinzweig J. Plastic Surgery Secrets. Philadelphia: Hanley & Belfus; 1999.)
Diagnostic Studies While the suspicion for diagnosis of RA is raised during the patient interview and physical examination, laboratory testing and imaging can aid in the diagnosis. Importantly, no test is diagnostic of the disease in and of itself.
Laboratory Evaluation Rheumatoid factor (RF), which is an antibody against the Fc portion of IgG, can be found in the serum in about 85% of patients with RA. Anti-cyclic citrullinated protein antibodies (ACPAs) can also be demonstrated in the serum in patients with RA. While RF and ACPA have similar sensitivity (around 67%), ACPA is more specific (95% vs. 85%). Up to 20% of patients with RA have negative RF and ACPA evaluations, with these patients being referred to as having “seronegative” RA.10 Elevations of C-reactive protein and erythrocyte sedimentation rate can occur in patients with RA. A normocytic or mildly microcytic anemia can occur that is consistent with anemia of chronic disease. Mild thrombocytosis can occur in patients with active disease. While these tests are not specific for the inflammation that occurs in RA, they can be a clue to systemic involvement. Analysis of synovial fluid will demonstrate an inflammatory cell count (over 2000 white blood cells). Joints with damage for any reason are at an increased risk of septic arthritis, and so joint cultures should be obtained in the appropriate clinical context. Pleural fluid, if sampled, will characteristically demonstrate an extremely low glucose concentration.
Imaging Traditionally, plain radiography is used as a first-line radiographic evaluation of the joints of a patient with RA. Erosions on the margins of the joint space, periarticular osteopenia, and ulnar deviation of the phalanges are classic features on joint radiographs of more advanced RA (Fig. 152.3). Importantly, plain radiography of patients with early RA can be
CHAPTER 152 Rheumatoid Arthritis
normal and does not rule out disease. Flexion and extension views of the cervical spine should be considered in patients with more advanced disease to screen for atlantoaxial subluxation. Other imaging modalities are increasingly being used by clinicians in the management of patients with RA. Magnetic resonance imaging can determine tendon sheath or synovial inflammation, though this modality can be quite expensive and exposes the patient to gadolinium if contrast is used.11 Ultrasound imaging can demonstrate active synovial inflammation if hypertrophied synovium, hypoechoic effusion, and power Doppler signal are present in the examined joint.12 Differential Diagnoses CRYSTALLINE ARTHRITIS Gout Calcium pyrophosphate deposition disease SPONDYLOARTHROPATHY Psoriatic arthritis Ankylosing spondylitis Enteropathic arthritis Reactive arthritis (formerly Reiter syndrome) INFECTION-RELATED ARTHRITIS Viral polyarthritis Septic arthritis OSTEOARTHRITIS CONNECTIVE TISSUE DISEASE Systemic lupus erythematosus (particularly Jaccoud arthropathy) Sjogren syndrome
Treatment Treatment in RA is aimed at relieving symptoms but also at quelling the inflammatory response, and thus stopping the damage and deformity the disease is known to cause. Studies have shown that early initiation of disease-modifying antirheumatic drugs (DMARDs) can relieve symptoms and slow the progression of RA.9 Given the wide variety of available disease-modifying agents available today, rheumatologists can now “treat to target.” In the “treat to target” approach, the rheumatologist and patient set a goal of treatment, usually complete remission. The provider then continuously adjusts treatment until that goal is reached. The “treat to target” approach has been associated with improved outcomes.9,13 Many disease activity measures have been developed and validated to aid clinicians in their assessment of the patient. Various combinations of physician and patient global assessments, pain scores, functional scores, tender and swollen joint counts, as well as serum inflammatory markers have been validated to measure the activity of RA in patients.14 Nonsteroidal anti-inflammatory drugs and prednisone were early mainstays of treatment decades ago, and continue to be important adjunct medications to alleviate the symptoms of patients with RA. These drugs have not been shown to modify the disease and thus are not commonly used as monotherapy in patients with RA. Methotrexate is the most commonly prescribed DMARD for RA and has been shown to improve symptoms and
879
decrease the clinical and radiographic progression of RA. For RA treatment, methotrexate is prescribed either orally or subcutaneously, and is dosed usually once weekly, although various dosing schedules exist. The dose of methotrexate used for RA is much lower than the dose for malignancy treatment. Leflunomide, sulfasalazine, and hydroxychloroquine are also commonly used DMARDs. When methotrexate, sulfasalazine, and hydroxychloroquine are used together, the patient is said to be on “triple therapy,” which has been shown to be as effective as some of the more advanced biologic therapies in many patients.15 The past two decades have shown an immense leap in the number of available medications used to treat RA. Biologic therapies have proven very effective in treating the symptoms of RA and stopping disease progression. Tumor necrosis factor inhibitors were the first biologic therapies available for the treatment of RA.16 Abatacept, a T-cell costimulatory inhibitor, is also available to treat RA.17 Tocilizumab is an interleukin-6 antagonist used in the treatment of RA.18 Rituximab can be useful in refractory cases of RA.19 Most recently, tofacitinib, a Janus kinase inhibitor, became the first oral targeted therapy for the treatment of RA.20 Biologic and biosimilar therapies are rapidly expanding as options for treatment in patients with RA.21 Sometimes a rheumatologist will use several medications in combination to achieve remission in RA.22 For more severe manifestations of disease such as ulcerating scleritis or vasculitis, rheumatologists will use cyclophosphamide.
Rehabilitation The goals of physical therapy in RA involve relief from pain and preservation of function, particularly activities of daily living and vocational actions. In early disease, a supervised graded physical therapy program can be a helpful adjunct therapy to return function and decrease fatigue in a patient with RA.23 The physical therapist should have experience in treating this specific patient population.24 Range of motion exercises can help to preserve joint function. Orthotic devices can be used in acute synovitis to help alleviate pain, but should be not be used chronically to avoid loss of function. In end-stage disease complicated by loss of joint function and stability, evaluation by an experienced occupational therapist can be very beneficial to the patient with RA. Adaptive devices for mobility and self-care exist that can help the patient with RA maintain independence. If contracture develops at a joint, periodic splinting with range of motion and strengthening exercises can be employed to prevent further contracture.25 Throughout the disease course, maintaining strength is important to help preserve function. Aerobic and weightbearing strengthening exercises can safely be used in this patient population.23 Cardiopulmonary rehabilitation can be effective in maintaining function in patients with interstitial lung disease related to RA.26
Procedures For monoarticular or oligoarticular synovitis or tenosynovitis, local corticosteroid injection can be a helpful adjunct
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treatment to alleviate pain and restore function. Carpal tunnel injections or surgical decompression can be pursued if patients develop evidence of carpal tunnel syndrome.27 Ultrasound guidance of an injection can be utilized to increase the accuracy of the treatment.12
Technology
Table 152.2 Side Effects and Adverse Reactions Associated With Medications Used to Treat Rheumatoid Arthritis Medication
Side Effect or Adverse Reactions
Glucocorticoids
Weight gain Anxiety, depression Exacerbation of hypertension Glucose intolerance or diabetes mellitus Acne vulgaris Glaucoma, cataracts Osteoporosis Avascular necrosis Impaired wound healing Serious infection
Nonsteroidal anti-inflammatory drugs
Dyspepsia, peptic ulcers Renal insufficiency Hepatotoxicity Platelet inhibition
Methotrexate
Hepatic fibrosis Myelosuppression Mucositis Pneumonitis Dyspepsia Alopecia Exacerbation of rheumatoid nodules Spontaneous abortion
Leflunomide
Dyspepsia, diarrhea Myelosuppression Hepatic fibrosis Alopecia Teratogenicity
Antimalarials
Dyspepsia Rash Hemolysis (in glucose-6 phosphate dehydrogenase-deficient patients) Deposition retinopathy (rare) Neuromyopathy (including cardiomyopathy) (rare)
Sulfasalazine
Myelosuppression Hepatotoxicity Hemolysis (in glucose-6 phosphate dehydrogenase-deficient patients) Rash Dyspepsia, diarrhea Headaches
Tumor necrosis factor inhibitors • Etanercept • Adalimumab • Infliximab • Certolizumab pegol • Golimumab
Injection site reaction Serious infection Reactivation of tuberculosis Non-melanoma skin cancer
Abatacept
Injection site reaction Serious infection
There is no specific technology for the treatment or rehabilitation of this condition.
Surgery Orthopedic consultation for consideration of arthrodesis or arthroplasty could be considered for patients with advanced RA. Goals of therapy should be to preserve and restore function, as well as reduce pain. Larger joints, such as hips and knees, are frequently replaced, and many patients have improved outcomes after such procedures.28 Replacement or reconstruction of the small joints of the hands and feet are also possible and should be considered in the context of goals of therapy (see Fig. 152.3).29,30 Consultation with a neurosurgical team will be required for patients that develop myelopathy or atlanto-occipital instability.31 Troublesome rheumatoid nodules can be excised, but are at risk of recurring.
Potential Disease Complications Tendon rupture can occur at sites of chronic inflammation and deformity, most commonly the extensor tendons of the fourth and fifth fingers. In addition to the deformity noted above that can occur with longstanding, uncontrolled disease, RA can also cause systemic complications. Rheumatoid vasculitis is a particularly devastating complication that can cause rapidly ulcerating skin lesions and vasculitic neuropathy.32 Felty syndrome can occur and is the triad of RA, neutropenia, and splenomegaly. The presentation of large granulocyte lymphocytic leukemia can appear similar to that of Felty syndrome and can be diagnosed by peripheral blood flow cytometry.33 Amyloid A (AA) amyloidosis can occur with longstanding, chronic inflammation of any cause, including RA. AA amyloidosis frequently involves the kidney, liver, and spleen. AA amyloidosis may present with nephrotic syndrome in a patient with advanced RA.34 Patients with RA are at increased risk of coronary atherosclerosis and subsequent death due to cardiovascular disease. Clinicians should screen for modifiable risk factors, such as hyperlipidemia and tobacco use, at each encounter. Practitioners should also screen patients with RA for atlanto-occipital subluxation prior to surgical procedures requiring anesthesia.
Potential Treatment Complications Many of the medications used to treat RA require close clinical and laboratory monitoring on the part of the clinician to prevent complications. Table 152.2 details possible side effects and adverse reactions of medications that are used to treat RA.
CHAPTER 152 Rheumatoid Arthritis
Table 152.2 Side Effects and Adverse Reactions Associated With Medications Used to Treat Rheumatoid Arthritis—cont’d Medication
Side Effect or Adverse Reactions
Tocilizumab
Injection site reaction Serious infection Neutropenia, thrombocytopenia Lipid abnormalities Hepatotoxicity Diverticulitis, bowel perforation
Janus kinase inhibitors Tofacitinib Baricitinib
Serious infection Myelosuppression Hepatoxicity Lipid abnormalities Diverticulitis, bowel perforation
Rituximab
Infusion hypersensitivity reaction Neutropenia Serious infection Hypogammaglobulinemia Mucocutaneous reactions Reactivation of hepatitis B virus Progressive multifocal encephalopathy (rare)
Cyclophosphamide
Dyspepsia, diarrhea Myelosuppression Alopecia Hemorrhagic cystitis Ovarian and testicular failure Teratogenicity Malignancy Serious infection
References 1. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356–361. 2. Spector TD. Rheumatoid arthritis. Rheum Dis Clin North Am. 1990;16:513–537. 3. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205–2219. 4. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69:1580–1588. 5. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–324. 6. Fuchs HA, Sergent JS. Rheumatoid arthritis: the clinical picture. In: Koopman WJ, ed. Arthritis and Allied Conditions: A Textbook of Rheumatology, 13th ed. Baltimore: Williams & Wilkins; 1997:1041–1070. 7. Chung CP, Avalos I, Raggi P, et al. Atherosclerosis and inflammation: insights from rheumatoid arthritis. Clin Rheumatol. 2007;26:1228–1233. 8. Friedewald VE, Ganz P, Kremer JM, et al. AJC editor’s consensus: rheumatoid arthritis and atherosclerotic cardiovascular disease. Am J Cardiol. 2010;106:442–447. 9. van den Broek M, Lems WF, Allaart C. BeSt practice: the success of early-targeted treatment in rheumatoid arthritis. Clin Exp Rheumatol. 2012;30:S35–38. 10. Pincus T, Sokka T. Laboratory tests to assess patients with rheumatoid arthritis: advantages and limitations. Rheum Dis Clin N Am. 2009;35:731–734.
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11. Troum OM, Pimienta O, Olech E. Magnetic resonance imaging applications in early rheumatoid arthritis diagnosis and management. Rheum Dis Clin N Am. 2012;38:277–297. 12. Thiele RG. Ultrasonography applications in diagnosis and management of early rheumatoid arthritis. Rheum Dis Clin N Am. 2012;38:259–275. 13. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a singleblind randomised controlled trial. Lancet. 2004;364:263–269. 14. Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res. 2012;64:640–647. 15. Moreland LW, O’Dell JR, Paulus HE, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012;64:2824–2835. 16. Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68:1–26. 17. Genovese MC, Becker J, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005;353:1114–1123. 18. Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67:1516–1523. 19. Cohen SB, Emery P, Grenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006;54:2793–2806. 20. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370:2377–2386. 21. Rein P, Mueller RB. Treatment with biologicals in rheumatoid arthritis: an overview. Rheumatol Ther. 2017;4(2):247–261. 22. Singh JA, Hossain A, Tanjong-Ghogomu E, et al. Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2016;(5):CD012183. 23. Metsios GS, Stavropoulos-Kalinoglous A, Kitas GD. The role of exercise in the management of rheumatoid arthritis. Expert Rev Clin Immunol. 2015;11:1121–1130. 24. Briggs AM, Fary RE, Slater H, et al. Disease-specific knowledge and clinical skills required by community-based physiotherapists to co-manage patients with rheumatoid arthritis. Arthritis Care Res. 2012;64:1514–1526. 25. Ekelman BA, Hooker L, Davis A, et al. Occupational therapy interventions for adults with rheumatoid arthritis: an appraisal of the evidence. Occup Ther Health Care. 2014;28:347–361. 26. Lee JS, Fischer A. Current and emerging treatment options for interstitial lung disease in patients with rheumatic disease. Expert Rev Clin Immunol. 2016;12:509–520. 27. Muramatsu K, Tanaka H, Taguchi T. Peripheral neuropathies of the forearm and hand in rheumatoid arthritis: diagnosis and options for treatment. Rheumatol Int. 2008;28:951–957. 28. Dunbar RP, Alexiades MM. Decision making in rheumatoid arthritis. determining surgical priorities. Rheum Dis Clin North Am. 1998;24:35–54. 29. Chim HW, Reese SK, Toomey SN, et al. Update on the surgical treatment for rheumatoid arthritis of the wrist and hand. J Hand Ther. 2014;27:134–141. 30. Moran SL, Bishop AT. Clinical update: surgical management of rheumatoid hand. Lancet. 2007;370:372–374. 31. Wolfs JFC, Kloppenburg M, Fehlings MG, et al. Neurologic outcome of surgical and conservative treatment of rheumatoid cervical spine subluxation: a systematic review. Arthritis Rheum. 2009;61:1743–1752. 32. Makol A, Matteson EL, Warrington KJ. Rheumatoid vasculitis: an update. Curr Opin Rheumatol. 2015;27:63–70. 33. Liu X, Loughran TP. The spectrum of large granular lymphocyte leukemia and Felty’s syndrome. Curr Opin Hematol. 2011;18:254–259. 34. Nakamura T. Amyloid A amyloidosis secondary to rheumatoid arthritis: pathophysiology and treatments. Clin Exp Rheumatol. 2011;29:850–857.
Rheumatoid Arthritis Kevin Byram, MD Sallaya Chinratanalab, MD John Sergent, MD
Synonyms None
ICD-10 Codes M05 M06.9
Rheumatoid arthritis
Definition Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory arthritis that usually affects the small joints of the hands and feet in a symmetric distribution. Without treatment, RA can cause erosive joint damage and deformity that leads to significant morbidity and disability. In addition to the arthritis, RA is a systemic disease that can involve multiple organ systems, including the skin, lungs, and cardiovascular system.1 RA affects about 1% of the adults in the United States and Europe, but rates vary in other populations. For example, Nigerian adults have some of the lowest prevalent RA rates (0.1%), while Pima and Chippewa indigenous populations in the US have among the highest rates (5%).2 The prevalence of RA in any population increases with age. RA occurs more frequently in women and cigarette smokers.3 The American College of Rheumatology has developed a set of criteria to classify patients as having RA, most recently revised in 2010 (Table 152.1).4 These criteria were validated to appropriately classify patients with RA for clinical study, and serve to update the previous 1987 criteria in an attempt to appropriately classify patients with early RA.5
Symptoms Patients with RA generally present with arthralgias and joint swelling of the small joints of the hands, wrists, and feet in a symmetric pattern. Loss of function is a common complaint among patients with RA, particularly activities requiring fine motor movements (e.g., fastening buttons) or grip strength (e.g., opening jars). 876
Warmth and redness around a joint can occur, but these are more common in other arthritis syndromes, such as gout. Morning stiffness is also a common complaint by patients with RA, typically lasting more than one hour. In addition, since RA is a systemic disease, it is common for patients to have extra-articular features associated with their presentation.6
Systemic Patients with RA can present with nonspecific features of malaise and fatigue. Fevers are uncommon but can occur.
Cutaneous The most common extra-articular feature of RA is the development of subcutaneous nodules, known as rheumatoid nodules, on the extensor surfaces of joints. Rheumatoid vasculitis is a particularly rare, but potentially devastating cutaneous feature of RA. Rheumatoid vasculitis presents with typical vasculitic eruptions, ranging from purpura to ulceration and infarct.
Ophthalmologic Patients with RA frequently complain of dry eye and dry mouth, known as keratoconjunctivitis sicca. Episcleritis and scleritis also can in occur with patients with RA, which manifests as red, painful eyes.
Pulmonary Pleuritis and pleural effusions occur in as many as 20% of RA patients, and may occur early in the course of the disease. Interstitial inflammation and fibrosis usually present with cough and dyspnea and can be life-threatening.
Neurologic Nerve entrapment secondary to inflammation or deformity is common in RA. Carpal tunnel syndrome (median nerve entrapment) is the most common of these, and presents with sensory loss or paresthesias in the median nerve distribution. A potentially devastating neurologic complication in
CHAPTER 152 Rheumatoid Arthritis
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Table 152.1 2010 ACR/EULAR Rheumatoid Arthritis Classification Criteria Criterion
Points
Arthritis Joint Distribution 1 large joint
0
2–10 large joints
1
1–3 small joints (large joints not counted)
2
4–10 small joints (large joints not counted)
3
>10 joints (at least one small joint)
5
Serology Negative RF AND negative ACPA
0
Low positive RF OR low positive ACPA
2
High positive RF OR high positive ACPA
3
Symptom Duration <6 weeks
0
>6 weeks
1
Acute Phase Reactants Normal CRP AND normal ESR
0
Abnormal CRP OR abnormal ESR
1
FIG. 152.1 Boutonnière deformity in rheumatoid arthritis. This deformity occurs with hyperextension of the distal interphalangeal joint and flexion of the proximal interphalangeal joint. (From Concannon MJ. Common Hand Problems in Primary Care. Philadelphia: Hanley & Belfus; 1999.)
The appropriate population to apply these criteria to are those with at least one joint with definite clinical synovitis that is not better explained by another disease. A patient is said to have definite RA if they score 6 or more points or if they have characteristic radiographic erosions of rheumatoid arthritis. ACPA, Anti-citrullinated protein antibody; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RF, rheumatoid factor.
advanced RA is atlanto-occipital instability or subluxation, which can cause symptoms ranging from radicular pain and paresthesias to myelopathy and death. Mononeuritis multiplex can occur in the setting of rheumatoid vasculitis and causes weakness or paresthesias in single or multiple single nerves (e.g., footdrop or wrist drop).
Cardiac RA is associated with an increased rate of cardiovascular mortality, secondary to coronary artery disease. Thus, patients with RA should be monitored for symptoms that could be consistent with coronary artery disease, such as substernal chest pain, dyspnea, and diaphoresis. Less commonly, myocarditis, pericarditis, and subsequent arrhythmia can occur in RA.7,8 Rarely, RA can cause inflammation along valve rings, causing valvular inflammation, and along the conduction system, resulting in heart block or arrhythmia. Conduction abnormalities can present variably, including dyspnea, chest pain, or syncope.
Physical Examination The clinician will examine all joints for evidence of synovitis, including swelling, tenderness, warmth, or effusion. The metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, wrists, knees, and ankles are most commonly involved. Importantly, the distal interphalangeal joints are usually not involved in RA. Rarely, patients will present with a monoarticular arthritis.
FIG. 152.2 Swan neck deformity in rheumatoid arthritis. This deformity occurs with hyperextension of the proximal interphalangeal joint and flexion of the distal interphalangeal joint. (From Concannon MJ. Common Hand Problems in Primary Care. Philadelphia: Hanley & Belfus; 1999.)
Early RA generally presents with swelling and tenderness about the involved joints that is synonymous with activity of the disease. More chronic disease might reveal physical exam signs that correlate with damage from the disease. Early involvement in the fingers will present with fusiform swelling in the wrists, MCPs, and PIPs. Joint involvement is usually symmetric. Chronic inflammation in the hands or wrists may lead to subluxation of the MCP joints or carpal bones. Wrist subluxation is suggested by a prominent ulnar styloid. Ulnar deviation of the fingers is common in advanced disease. Ligamentous damage at the PIPs can cause the classic boutonnière and swan neck deformities. A boutonnière deformity describes PIP joint flexion and DIP joint hyperextension, while a swan neck deformity describes PIP joint hyperextension and DIP joint flexion (Figs. 152.1 and 152.2). The tendon sheaths of the fingers are also common sites of inflammation in RA. If tenosynovitis is present, then crepitus can be felt by the examiner when the fingers of the patient are slowly flexed and extended. Stenosing tenosynovitis (trigger finger) can occur with more prolonged inflammatory involvement of the tendon sheaths. The elbow can also be involved in RA. Early disease will cause effusion in the elbow joint, which can be palpated by the clinician in the para-olecranon groove, and is usually accompanied by decreased range of motion. Advanced RA
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will cause inability to fully extend or flex the elbow, even in passive motion. The shoulders are also possible sites of inflammation in RA. Active RA is suggested by shoulder effusions, which, if present, are usually visible on the anterior aspect of the joint below the acromion. The rotator cuff and biceps tendon are also important for the clinician to evaluate, since tear or rupture might occur as a result of the chronic inflammation. The knee is commonly affected in RA and should be evaluated for effusions and Baker’s cysts. Large knee effusions are detectable by ballottement of the patella against the femur. Smaller effusions can be detected by evaluation for the “bulge sign.” With the patient comfortably lying down, the clinician “milks” fluid from the medial patellar pouch superiorly, then subsequently “milks” fluid in the lateral pouch inferiorly. The sign is positive (and thus a small effusion is suggested) if a bulge appears in the medial pouch with the lateral downward stroke. A Baker’s cyst is a cyst in the popliteal fossa that communicates with the joint cavity. If present, a fullness can be palpated in the popliteal fossa. Involvement of the ankle and subtalar joints may reveal decreased range of motion with dorsi- and plantar-flexion or inversion and eversion. Metatarsophalangeal (MTP) joints may be inflamed, in which case compressing the MTP row may reveal tenderness (a positive “MTP squeeze” sign). Baker’s cysts can rupture, causing swelling in the calf and the ecchymotic “crescent” sign around the medial malleoli of the ankle. More advanced disease might cause hallux valgus deformity or claw and hammer toe deformity. Hindfoot valgus deformity and resultant flatfoot deformity can occur with longstanding disease. The cervical spine should be examined for decreased range of motion, pain with motion, and impingement phenomenon. Patients with advanced and deforming arthritis elsewhere should have a thorough neurologic examination to evaluate for cervical or atlanto-occipital instability, suggested by paresthesias, weakness, occipital pain, or hyperactive reflexes. Systemic involvement should also be evaluated during the physical exam. The eyes should be assessed for conjunctival or scleral involvement. The lungs should be auscultated for the fine crackles of interstitial lung disease. A thorough skin exam might reveal rheumatoid nodules on the extensor surfaces of joints or bony prominences or other areas of friction such as the Achilles tendon. These are sometimes difficult to distinguish from the tophi of gouty arthritis.
Functional Limitations Functional limitation in patients with RA stems from the location and severity of articular involvement or systemic involvement of the disease. For instance, patients with deformed or severely eroded lower extremity joints might have issues with mobility, whereas a patient with advanced small joint hand deformity might have issues with self-care or other activities of daily living. Functional limitation related to systemic disease depends on the organ involved. For example, patients with RA-related interstitial lung disease could have functional limitations related to hypoxia, including decreased exertional capacity. Fortunately, early, aggressive treatment of RA can mitigate the progression of disease, and thus decrease the functional limitations that accompany advanced disease.9
FIG. 152.3 Radiograph demonstrating advanced rheumatoid arthritis. Features include metacarpophalangeal (MCP) subluxation, marginal erosions, and ulnar deviation of the fingers of the left hand. In addition, implanted prostheses can be visualized at the MCP joints on the right hand. (From Weinzweig J. Plastic Surgery Secrets. Philadelphia: Hanley & Belfus; 1999.)
Diagnostic Studies While the suspicion for diagnosis of RA is raised during the patient interview and physical examination, laboratory testing and imaging can aid in the diagnosis. Importantly, no test is diagnostic of the disease in and of itself.
Laboratory Evaluation Rheumatoid factor (RF), which is an antibody against the Fc portion of IgG, can be found in the serum in about 85% of patients with RA. Anti-cyclic citrullinated protein antibodies (ACPAs) can also be demonstrated in the serum in patients with RA. While RF and ACPA have similar sensitivity (around 67%), ACPA is more specific (95% vs. 85%). Up to 20% of patients with RA have negative RF and ACPA evaluations, with these patients being referred to as having “seronegative” RA.10 Elevations of C-reactive protein and erythrocyte sedimentation rate can occur in patients with RA. A normocytic or mildly microcytic anemia can occur that is consistent with anemia of chronic disease. Mild thrombocytosis can occur in patients with active disease. While these tests are not specific for the inflammation that occurs in RA, they can be a clue to systemic involvement. Analysis of synovial fluid will demonstrate an inflammatory cell count (over 2000 white blood cells). Joints with damage for any reason are at an increased risk of septic arthritis, and so joint cultures should be obtained in the appropriate clinical context. Pleural fluid, if sampled, will characteristically demonstrate an extremely low glucose concentration.
Imaging Traditionally, plain radiography is used as a first-line radiographic evaluation of the joints of a patient with RA. Erosions on the margins of the joint space, periarticular osteopenia, and ulnar deviation of the phalanges are classic features on joint radiographs of more advanced RA (Fig. 152.3). Importantly, plain radiography of patients with early RA can be
CHAPTER 152 Rheumatoid Arthritis
normal and does not rule out disease. Flexion and extension views of the cervical spine should be considered in patients with more advanced disease to screen for atlantoaxial subluxation. Other imaging modalities are increasingly being used by clinicians in the management of patients with RA. Magnetic resonance imaging can determine tendon sheath or synovial inflammation, though this modality can be quite expensive and exposes the patient to gadolinium if contrast is used.11 Ultrasound imaging can demonstrate active synovial inflammation if hypertrophied synovium, hypoechoic effusion, and power Doppler signal are present in the examined joint.12 Differential Diagnoses CRYSTALLINE ARTHRITIS Gout Calcium pyrophosphate deposition disease SPONDYLOARTHROPATHY Psoriatic arthritis Ankylosing spondylitis Enteropathic arthritis Reactive arthritis (formerly Reiter syndrome) INFECTION-RELATED ARTHRITIS Viral polyarthritis Septic arthritis OSTEOARTHRITIS CONNECTIVE TISSUE DISEASE Systemic lupus erythematosus (particularly Jaccoud arthropathy) Sjogren syndrome
Treatment Treatment in RA is aimed at relieving symptoms but also at quelling the inflammatory response, and thus stopping the damage and deformity the disease is known to cause. Studies have shown that early initiation of disease-modifying antirheumatic drugs (DMARDs) can relieve symptoms and slow the progression of RA.9 Given the wide variety of available disease-modifying agents available today, rheumatologists can now “treat to target.” In the “treat to target” approach, the rheumatologist and patient set a goal of treatment, usually complete remission. The provider then continuously adjusts treatment until that goal is reached. The “treat to target” approach has been associated with improved outcomes.9,13 Many disease activity measures have been developed and validated to aid clinicians in their assessment of the patient. Various combinations of physician and patient global assessments, pain scores, functional scores, tender and swollen joint counts, as well as serum inflammatory markers have been validated to measure the activity of RA in patients.14 Nonsteroidal anti-inflammatory drugs and prednisone were early mainstays of treatment decades ago, and continue to be important adjunct medications to alleviate the symptoms of patients with RA. These drugs have not been shown to modify the disease and thus are not commonly used as monotherapy in patients with RA. Methotrexate is the most commonly prescribed DMARD for RA and has been shown to improve symptoms and
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decrease the clinical and radiographic progression of RA. For RA treatment, methotrexate is prescribed either orally or subcutaneously, and is dosed usually once weekly, although various dosing schedules exist. The dose of methotrexate used for RA is much lower than the dose for malignancy treatment. Leflunomide, sulfasalazine, and hydroxychloroquine are also commonly used DMARDs. When methotrexate, sulfasalazine, and hydroxychloroquine are used together, the patient is said to be on “triple therapy,” which has been shown to be as effective as some of the more advanced biologic therapies in many patients.15 The past two decades have shown an immense leap in the number of available medications used to treat RA. Biologic therapies have proven very effective in treating the symptoms of RA and stopping disease progression. Tumor necrosis factor inhibitors were the first biologic therapies available for the treatment of RA.16 Abatacept, a T-cell costimulatory inhibitor, is also available to treat RA.17 Tocilizumab is an interleukin-6 antagonist used in the treatment of RA.18 Rituximab can be useful in refractory cases of RA.19 Most recently, tofacitinib, a Janus kinase inhibitor, became the first oral targeted therapy for the treatment of RA.20 Biologic and biosimilar therapies are rapidly expanding as options for treatment in patients with RA.21 Sometimes a rheumatologist will use several medications in combination to achieve remission in RA.22 For more severe manifestations of disease such as ulcerating scleritis or vasculitis, rheumatologists will use cyclophosphamide.
Rehabilitation The goals of physical therapy in RA involve relief from pain and preservation of function, particularly activities of daily living and vocational actions. In early disease, a supervised graded physical therapy program can be a helpful adjunct therapy to return function and decrease fatigue in a patient with RA.23 The physical therapist should have experience in treating this specific patient population.24 Range of motion exercises can help to preserve joint function. Orthotic devices can be used in acute synovitis to help alleviate pain, but should be not be used chronically to avoid loss of function. In end-stage disease complicated by loss of joint function and stability, evaluation by an experienced occupational therapist can be very beneficial to the patient with RA. Adaptive devices for mobility and self-care exist that can help the patient with RA maintain independence. If contracture develops at a joint, periodic splinting with range of motion and strengthening exercises can be employed to prevent further contracture.25 Throughout the disease course, maintaining strength is important to help preserve function. Aerobic and weightbearing strengthening exercises can safely be used in this patient population.23 Cardiopulmonary rehabilitation can be effective in maintaining function in patients with interstitial lung disease related to RA.26
Procedures For monoarticular or oligoarticular synovitis or tenosynovitis, local corticosteroid injection can be a helpful adjunct
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treatment to alleviate pain and restore function. Carpal tunnel injections or surgical decompression can be pursued if patients develop evidence of carpal tunnel syndrome.27 Ultrasound guidance of an injection can be utilized to increase the accuracy of the treatment.12
Technology
Table 152.2 Side Effects and Adverse Reactions Associated With Medications Used to Treat Rheumatoid Arthritis Medication
Side Effect or Adverse Reactions
Glucocorticoids
Weight gain Anxiety, depression Exacerbation of hypertension Glucose intolerance or diabetes mellitus Acne vulgaris Glaucoma, cataracts Osteoporosis Avascular necrosis Impaired wound healing Serious infection
Nonsteroidal anti-inflammatory drugs
Dyspepsia, peptic ulcers Renal insufficiency Hepatotoxicity Platelet inhibition
Methotrexate
Hepatic fibrosis Myelosuppression Mucositis Pneumonitis Dyspepsia Alopecia Exacerbation of rheumatoid nodules Spontaneous abortion
Leflunomide
Dyspepsia, diarrhea Myelosuppression Hepatic fibrosis Alopecia Teratogenicity
Antimalarials
Dyspepsia Rash Hemolysis (in glucose-6 phosphate dehydrogenase-deficient patients) Deposition retinopathy (rare) Neuromyopathy (including cardiomyopathy) (rare)
Sulfasalazine
Myelosuppression Hepatotoxicity Hemolysis (in glucose-6 phosphate dehydrogenase-deficient patients) Rash Dyspepsia, diarrhea Headaches
Tumor necrosis factor inhibitors • Etanercept • Adalimumab • Infliximab • Certolizumab pegol • Golimumab
Injection site reaction Serious infection Reactivation of tuberculosis Non-melanoma skin cancer
Abatacept
Injection site reaction Serious infection
There is no specific technology for the treatment or rehabilitation of this condition.
Surgery Orthopedic consultation for consideration of arthrodesis or arthroplasty could be considered for patients with advanced RA. Goals of therapy should be to preserve and restore function, as well as reduce pain. Larger joints, such as hips and knees, are frequently replaced, and many patients have improved outcomes after such procedures.28 Replacement or reconstruction of the small joints of the hands and feet are also possible and should be considered in the context of goals of therapy (see Fig. 152.3).29,30 Consultation with a neurosurgical team will be required for patients that develop myelopathy or atlanto-occipital instability.31 Troublesome rheumatoid nodules can be excised, but are at risk of recurring.
Potential Disease Complications Tendon rupture can occur at sites of chronic inflammation and deformity, most commonly the extensor tendons of the fourth and fifth fingers. In addition to the deformity noted above that can occur with longstanding, uncontrolled disease, RA can also cause systemic complications. Rheumatoid vasculitis is a particularly devastating complication that can cause rapidly ulcerating skin lesions and vasculitic neuropathy.32 Felty syndrome can occur and is the triad of RA, neutropenia, and splenomegaly. The presentation of large granulocyte lymphocytic leukemia can appear similar to that of Felty syndrome and can be diagnosed by peripheral blood flow cytometry.33 Amyloid A (AA) amyloidosis can occur with longstanding, chronic inflammation of any cause, including RA. AA amyloidosis frequently involves the kidney, liver, and spleen. AA amyloidosis may present with nephrotic syndrome in a patient with advanced RA.34 Patients with RA are at increased risk of coronary atherosclerosis and subsequent death due to cardiovascular disease. Clinicians should screen for modifiable risk factors, such as hyperlipidemia and tobacco use, at each encounter. Practitioners should also screen patients with RA for atlanto-occipital subluxation prior to surgical procedures requiring anesthesia.
Potential Treatment Complications Many of the medications used to treat RA require close clinical and laboratory monitoring on the part of the clinician to prevent complications. Table 152.2 details possible side effects and adverse reactions of medications that are used to treat RA.
CHAPTER 152 Rheumatoid Arthritis
Table 152.2 Side Effects and Adverse Reactions Associated With Medications Used to Treat Rheumatoid Arthritis—cont’d Medication
Side Effect or Adverse Reactions
Tocilizumab
Injection site reaction Serious infection Neutropenia, thrombocytopenia Lipid abnormalities Hepatotoxicity Diverticulitis, bowel perforation
Janus kinase inhibitors Tofacitinib Baricitinib
Serious infection Myelosuppression Hepatoxicity Lipid abnormalities Diverticulitis, bowel perforation
Rituximab
Infusion hypersensitivity reaction Neutropenia Serious infection Hypogammaglobulinemia Mucocutaneous reactions Reactivation of hepatitis B virus Progressive multifocal encephalopathy (rare)
Cyclophosphamide
Dyspepsia, diarrhea Myelosuppression Alopecia Hemorrhagic cystitis Ovarian and testicular failure Teratogenicity Malignancy Serious infection
References 1. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356–361. 2. Spector TD. Rheumatoid arthritis. Rheum Dis Clin North Am. 1990;16:513–537. 3. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205–2219. 4. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69:1580–1588. 5. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–324. 6. Fuchs HA, Sergent JS. Rheumatoid arthritis: the clinical picture. In: Koopman WJ, ed. Arthritis and Allied Conditions: A Textbook of Rheumatology, 13th ed. Baltimore: Williams & Wilkins; 1997:1041–1070. 7. Chung CP, Avalos I, Raggi P, et al. Atherosclerosis and inflammation: insights from rheumatoid arthritis. Clin Rheumatol. 2007;26:1228–1233. 8. Friedewald VE, Ganz P, Kremer JM, et al. AJC editor’s consensus: rheumatoid arthritis and atherosclerotic cardiovascular disease. Am J Cardiol. 2010;106:442–447. 9. van den Broek M, Lems WF, Allaart C. BeSt practice: the success of early-targeted treatment in rheumatoid arthritis. Clin Exp Rheumatol. 2012;30:S35–38. 10. Pincus T, Sokka T. Laboratory tests to assess patients with rheumatoid arthritis: advantages and limitations. Rheum Dis Clin N Am. 2009;35:731–734.
881
11. Troum OM, Pimienta O, Olech E. Magnetic resonance imaging applications in early rheumatoid arthritis diagnosis and management. Rheum Dis Clin N Am. 2012;38:277–297. 12. Thiele RG. Ultrasonography applications in diagnosis and management of early rheumatoid arthritis. Rheum Dis Clin N Am. 2012;38:259–275. 13. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a singleblind randomised controlled trial. Lancet. 2004;364:263–269. 14. Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res. 2012;64:640–647. 15. Moreland LW, O’Dell JR, Paulus HE, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012;64:2824–2835. 16. Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68:1–26. 17. Genovese MC, Becker J, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005;353:1114–1123. 18. Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67:1516–1523. 19. Cohen SB, Emery P, Grenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006;54:2793–2806. 20. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370:2377–2386. 21. Rein P, Mueller RB. Treatment with biologicals in rheumatoid arthritis: an overview. Rheumatol Ther. 2017;4(2):247–261. 22. Singh JA, Hossain A, Tanjong-Ghogomu E, et al. Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2016;(5):CD012183. 23. Metsios GS, Stavropoulos-Kalinoglous A, Kitas GD. The role of exercise in the management of rheumatoid arthritis. Expert Rev Clin Immunol. 2015;11:1121–1130. 24. Briggs AM, Fary RE, Slater H, et al. Disease-specific knowledge and clinical skills required by community-based physiotherapists to co-manage patients with rheumatoid arthritis. Arthritis Care Res. 2012;64:1514–1526. 25. Ekelman BA, Hooker L, Davis A, et al. Occupational therapy interventions for adults with rheumatoid arthritis: an appraisal of the evidence. Occup Ther Health Care. 2014;28:347–361. 26. Lee JS, Fischer A. Current and emerging treatment options for interstitial lung disease in patients with rheumatic disease. Expert Rev Clin Immunol. 2016;12:509–520. 27. Muramatsu K, Tanaka H, Taguchi T. Peripheral neuropathies of the forearm and hand in rheumatoid arthritis: diagnosis and options for treatment. Rheumatol Int. 2008;28:951–957. 28. Dunbar RP, Alexiades MM. Decision making in rheumatoid arthritis. determining surgical priorities. Rheum Dis Clin North Am. 1998;24:35–54. 29. Chim HW, Reese SK, Toomey SN, et al. Update on the surgical treatment for rheumatoid arthritis of the wrist and hand. J Hand Ther. 2014;27:134–141. 30. Moran SL, Bishop AT. Clinical update: surgical management of rheumatoid hand. Lancet. 2007;370:372–374. 31. Wolfs JFC, Kloppenburg M, Fehlings MG, et al. Neurologic outcome of surgical and conservative treatment of rheumatoid cervical spine subluxation: a systematic review. Arthritis Rheum. 2009;61:1743–1752. 32. Makol A, Matteson EL, Warrington KJ. Rheumatoid vasculitis: an update. Curr Opin Rheumatol. 2015;27:63–70. 33. Liu X, Loughran TP. The spectrum of large granular lymphocyte leukemia and Felty’s syndrome. Curr Opin Hematol. 2011;18:254–259. 34. Nakamura T. Amyloid A amyloidosis secondary to rheumatoid arthritis: pathophysiology and treatments. Clin Exp Rheumatol. 2011;29:850–857.