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Increased contribution of age-related comorbidities
Decreased medication tolerance; increased incidence of hydroxychloroquine-associated maculopathy and sulfasalazine-induced nausea/vomiting, NSAID-induced gastric ulcers, and corticosteroid induced diabetes
Pregnancy Considerations
Use effective contraception in patients taking disease-modifying antirheumatic drugs (DMARDs).
Methotrexate and other DMARDS such as Arava, cyclophosphamide, and cyclosporine are teratogenic. Appropriate medication regimens for pregnant or breastfeeding patients is important.
50-80% of patients improve during pregnancy because of immunologic tolerance. Most relapse in 6 months. First episode may occur in pregnancy or postpartum.
EPIDEMIOLOGY
Incidence
- 25 to 30/100,000 cases for males
- 50 to 60/100,000 cases for females
- Peak age is 35 to 50 years.
Prevalence
General population: 0.3-1%
ETIOLOGY AND PATHOPHYSIOLOGY
- An insult (e.g., infection, smoking, trauma) precipitates an initial autoimmune reaction where antibody-complement complex activation ultimately results in endothelial activation, synovial hypertrophy, and joint inflammation. RA is a systemic disorder. Pathogenesis is mediated by abnormal B- and T-cell interactions and overproduction of cytokines such as TNF and IL-6.
- Multifactorial disease with genetic, host (hormonal, immunologic), and environmental (socioeconomic, smoking) factors
Genetics
- RA is 50% attributable to genetic causes. HLA-DR4 is a shared epitope in over 50% of cases.
- Monozygotic twin concordance 15-20%, suggesting that nongenetic roles also contribute to development of RA
- HLA DR4 and DRB1, STAT4, and CD40+ persons have increased relative risk.
RISK FACTORS
- Family history: First-degree relatives have 2- to 3-fold increased risk.
- Smokers have elevated relative risk of 1.4-2.2%
- Pregnancy and breastfeeding for 24 months lowers risk.
- Women affected 3:1, difference diminishes with age.
COMMONLY ASSOCIATED CONDITIONS
Accelerated atherosclerosis, pericarditis, amyloidosis, Felty syndrome (RA, splenomegaly, neutropenia), interstitial lung disease, pulmonary nodules, rheumatoid nodules, vasculitis, lymphomas, and carpal tunnel syndrome
DIAGNOSIS
HISTORY
- Symmetric polyarthritis most commonly affecting the hands and feet
- Constitutional symptoms: fatigue, malaise, weight loss, low-grade fevers (1,2)[A],(3)[C]
- Articular symptoms: tender/swollen joints, early morning stiffness (at least 60 minutes), and difficulty with activities of daily living (ADL) (1,2)[A],(3)[C]
- Extra-articular involvement: skin, pulmonary, cardiovascular, and ocular symptoms; Onset is typically insidious. Patients rarely present with abrupt onset of symptoms and extra-articular manifestations (1,2)[A],(3)[C].
PHYSICAL EXAM
- Evaluate for swollen, boggy, or tender joints:
- Small joints: metacarpophalangeal (MCP), proximal intraphalangeal (PIP) leading to Boutonni ¨re and swan-neck deformities, wrist, 2nd to 5th metatarsophalangeal (MTP), and thumb interphalangeal (IP) joints. Pain and decreased ROM; usually symmetric and affected first
- Large joints: shoulders, elbows (rheumatoid nodules), hips, knees, and ankles will show evidence of effusions.
- Joint deformity, nodules, and fusion are late findings.
- Extra-articular findings associated with RA:
- Splenomegaly, lymphadenopathy, subcutaneous nodules, peripheral neuropathy, and atlantoaxial joint instability. Axial migration of dens into foramen magnum may contribute to occipital headaches.
- Cardiovascular mortality increased with RA-evaluate rhythm, presence of murmurs (valvular dysfunction), and for effusion
- Pulmonary disease typically manifests as effusion and fibrosis (dullness, rales).
DIFFERENTIAL DIAGNOSIS
Sj ¶gren syndrome, systemic lupus erythematosus (SLE), systemic sclerosis, adult Still disease, psoriatic arthritis, polymyalgia rheumatica (older), seronegative polyarthritis, erosive osteoarthritis, crystal arthropathy, septic arthritis, chronic Lyme disease, viral-induced arthritis (parvovirus B19, hepatitis C [with cryoglobulinemia]), occult malignancy, vasculitis (Beh §et syndrome), inflammatory bowel disease, RS3PE hemochromatosis, sarcoidosis (3)[B]
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- CBC: Mild anemia and thrombocytosis are common and relate to disease activity (3)[C].
- ESR and C-reactive protein (CRP) are nonspecific markers used to assess disease activity (1)[A].
- Rheumatoid factor (RF): >1:80 in 70-80% of patients with RA (most commonly IgM Ab) (1)[A]
- Anticyclic citrullinated peptide antibodies (anti-CCP antibodies); Specificity >90% (1)[A]
- Antinuclear antibody: present in 20-30%
- Electrolytes, creatinine, liver function, and urinalysis to assess comorbid states, establish baseline, and to assist with medication management (4)[C]
- Radiographic findings help establish diagnosis and monitor treatment (2)[C].
- MRI of hands and wrists looking for erosions, pannus, synovitis
- Diagnostic ultrasound: to assess for synovial thickening/erosions.
- Plain film radiographs are preferred for RA:
- Initial radiographs of the hands, wrists, and feet
- Hallmark is a lack of bony remodeling and symmetric joint space narrowing.
- Earliest pattern of erosions is loss of cortical distinctness, followed by dot-dash pattern of cortical bone loss. Marginal erosions at cortical bone within joint capsule not covered by cartilage result in "mouse-ear"ť erosions.
Follow-Up Tests & Special Considerations
- 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria
- Patients with symptoms in at least one joint and definite clinical synovitis not explained by another disease
- A score of ≥6 is needed for to classify as definite RA
- Joint score
- 1 large joint: 0
- 2 to 10 large joints: 1
- 1 to 3 small joints (with or without large joints; distal interphalangeal [DIP], 1st MCP, and 1st MTP joints are excluded from assessment.): 2
- 4 to 10 small joints (with/without large joints): 3
- >10 joints (at least 1 small joint): 5
- Serology score: At least one test is needed: negative RF (rheumatoid factor) and negative ACPA (anticitrullinated protein antibody): 0; low positive RF or low positive ACPA: 2; high positive RF or high positive ACPA: 3
- Acute-phase reactants score: At least one result is needed. Normal CRP and normal ESR: 0; abnormal CRP or ESR: 1
- Self-reported symptom duration score: <6 weeks: 0; ≥6 weeks: 1
- Patients with a score of <6/10 do not meet RA criteria, and reevaluation is likely necessary over time (3)[C].
Diagnostic Procedures/Other
- Joint aspiration can exclude crystal arthropathy and septic arthritis.
- Synovial fluid
- Gram stain, cell count, culture, crystal analysis, and overall appearance
- Yellowish-white, turbid, poor viscosity in RA
- WBC increased (3,500 to 50,000 cells/mm3)
- Protein: ~4.2 g/dL (42 g/L)
- Serum-synovial glucose difference ≥30 mg/dL (≥1.67 mmol/L)
TREATMENT
Goals: Control disease activity and progression, relieve pain, maintain or improve function, and promote self-management to maximize activities of daily living.
GENERAL MEASURES
- Target treatment to achieve remission or minimize disease activity, prevent structural damage and disability (5)[A].
- Early, aggressive treatment prevents structural damage and disability (1)[A],(2,3 and 4)[C].
- Periodic evaluation of disease activity and extent of synovitis is important (1)[A].
- Arthritis self-management education (1)[A]
MEDICATION
- Early DMARD therapy to slow disease progression and induce remission is standard of care (1)[A].
- Symptomatic therapy in addition to DMARDs:
- NSAIDs:naproxen (500 mg BID) or ibuprofen (800 mg TID) for symptomatic relief. If poor response to initial NSAID after 2 weeks, try alternative NSAID (1)[A].
- If still poor response, prednisone (5 to 30 mg/day); taper off NSAID or prednisone as soon as effective control of disease activity with DMARD is achieved (1)[A].
- Notes on DMARD therapy
- History of hepatitis, malignancy, and heart failure (HF) may alter first-line therapy (4)[C].
- Nonbiologic DMARDs
- Should be started within 3 months of making the diagnosis of RA (1)[A].
- Due to greater convenience, lower toxicity profiles and quicker onset of action, initial therapy is a nonbiologic DMARD: methotrexate, sulfasalazine, and leflunomide have comparable efficacy (1)[A].
- Methotrexate is the first-line DMARD in patients with active RA; the optimal dosage should be reached within no more than 4 to 8 weeks (5)[A].
- Methotrexate (MTX) (Rheumatrex): 7.5 to 25 mg/week PO. DMARD with the most predictable benefit; many significant side effects, but the addition of folate reduces toxicity. Monitor CBC and renal and liver function every month — 3 months. Give with folic acid 1 mg PO daily. Contraindicated in renal and hepatic diseases, pregnancy, and breastfeeding (1)[A].
- Sulfasalazine (SSZ): 500 mg/day, increase to 2 g/day over 1 month; max: 2 to 3 g/day; 6-month trial. Monotherapy for low disease activity. Monitor CBC, liver enzymes every 2 weeks — 3 months, then every month — 3 months, then every 3 months. Screen for G6PD deficiency.
- Leflunomide (Arava): loading dose 100 mg/day — 3 days, then 10 to 20 mg/day. GI side effects and potentially teratogenic; contraindicated in pregnancy. Monitor CBC, LFTs, and phosphate monthly for the first 6 months. Stop use if ALT >3 — upper limit normal.
- Antimalarials: hydroxychloroquine (HCQ) (Plaquenil) 400 mg QHS for 2 to 3 months, then 200 mg at bedtime; 6-month trial is usual. Usually used to treat milder forms or in combination with other DMARDs. Ophthalmologic exam every 6 to 12 months due to potential maculopathy. Adjust dose in renal insufficiency.
- Minocycline (100 mg BID)
- Biologic DMARDs:
- TNF inhibitors: IV infliximab (Remicade), SC adalimumab (Humira), and SC etanercept (Enbrel). No evidence that one is superior. Certolizumab pegol (Cimzia) and golimumab (Simponi), approved in moderate to severe disease.
- Janus kinase (JAK) inhibitor: Xeljanz, Interleukin-6 (IL-6) receptor antagonist: Actemra is approved to treat moderate to severe active rheumatoid arthritis in which methotrexate did not work well.
- Abatacept (Orencia) and Anakinra (Kineret) no longer considered cost-effective or efficacious treatment for RA (1)[A].
- Rituximab (Rituxan) is recommended with or without MTX for active moderate to severe RA with inadequate response to other DMARDs or failed anti-TNF agent (1)[A].
- All biologics are best used in combination with methotrexate. (5)[A].
- Optimal dosage and duration of treatment unclear. Check purified protein derivative (PPD or QuantiFERON gold) prior to treatment and periodic CBC. Risk of lymphoma and CHF (1)[A].
- Ensure vaccinations are up-to-date prior to starting biologic agents. Recommended vaccinations: Pneumococcal, HPV, hepatitis B, influenza, varicella zoster (4)[C]
- Flare-ups
- Intra-articular steroids: If disease is well-controlled after ruling out intra-articular infection (1)[A]. Can also use Acthar, a repository corticotropin injection. (5)[A].
ADDITIONAL THERAPIES
- Capsaicin cream: Apply 3 to 4 times per day. Best results are seen after 2 to 4 weeks of continuous use.
- Interdisciplinary care and management including physical therapy to minimize the consequences of loss of function, joint damage, maladaptive coping, and social isolation (1,4,6)[A]
SURGERY/OTHER PROCEDURES
- Surgical treatment including synovectomy, tendon reconstruction, joint fusion, and joint replacement may be considered to prevent disability in RA unresponsive to therapy or in advanced RA (1)[A].
- Important to get flexion/extension films of cervical spine prior to any surgery due to high risk of atlantoaxial joint instability and subluxation
ONGOING CARE
The goals of comprehensive, interdisciplinary care are to inhibit the disease process, reduce pain, optimize symptom management (fatigue and stiffness), preserve joint integrity and joint function, maintain social and occupational roles, and maximize quality of life.
FOLLOW-UP RECOMMENDATIONS
- Encourage full activity as tolerated. Avoid heavy work or exercise during active (flare) phases. Emphasize exercise, mobility, and reduction of joint stress.
- Promote general health and psychosocial well-being.
Patient Monitoring
Address risk factors and evaluate for cardiovascular disease and osteoporosis. Disease Activity Score (DAS28) questionnaire for disease activity periodically and Health Assessment Questionnaire (HAQ) for functional status yearly.
DIET
Most beneficial diets for symptom control are gluten-free and vegetarian. Some benefits have been noted for "allergen-free,"ť elemental, and Mediterranean diets.
PROGNOSIS
- Poor prognostic findings
- Persistent moderate to severe disease; early or advanced age at disease onset
- Many affected joints; swelling and pain in affected joints, positive MCP squeeze test, and PIP and MCP symmetric involvement
- 50% cannot function in their primary jobs within 10 years of onset.
REFERENCES
11 National Collaborating Centre for Chronic Conditions (UK). Rheumatoid Arthritis: National Clinical Guideline for Management and Treatment in Adults (NICE Clinical Guidelines, No. 79.). London, United Kingdom: Royal College of Physicians; 2009.22 Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-2581.33 Wasserman AM. Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 2011;84(11):1245-1252.44 Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(5):625-639.55 Gaujoux-Viala C, Gossec L, Cantagrel A, et al. Recommendations of the French Society for Rheumatology for managing rheumatoid arthritis. Joint Bone Spine. 2014;81(4):287-297.66 Richards BL, Whittle SL, Buchbinder R. Neuromodulators for pain management in rheumatoid arthritis. Cochrane Database Syst Rev. 2012;(1):CD008921.
CODES
ICD10
- M06.9 Rheumatoid arthritis, unspecified
- M05.60 Rheu arthritis of unsp site w involv of organs and systems
- M05.30 Rheumatoid heart disease w rheumatoid arthritis of unsp site
- M05.70 Rheu arthritis w rheu factor of unsp site w/o org/sys involv
ICD9
- 714.0 Rheumatoid arthritis
- 714.2 Other rheumatoid arthritis with visceral or systemic involvement
SNOMED
- 69896004 Rheumatoid arthritis (disorder)
- 239793008 Rheumatoid arthritis with organ / system involvement
- 28880005 Rheumatoid carditis
- 239795001 Rheumatoid arthritis with multisystem involvement (disorder)
CLINICAL PEARLS
- RA is an idiopathic, chronic, and systemic inflammatory disease characterized by symmetric polyarthritis and synovitis.
- Rheumatoid arthritis occurs in 1% of the U.S. population.
- Females have more articular disease; males have more systemic manifestations.
- Plain films are the imaging modality of choice in RA.
- Treatment with DMARDs within 3 months of diagnosis slows disease progression and improves chance for remission.
- Methotrexate is the first-line DMARD in patients with active RA.
- Atlantoaxial joint involvement leads to instability; avoid unnecessary manipulation of the cervical spine.