2010 ACR/EULAR classification criteria for RA
1 medium/large joint
2–10 medium joints
1–3 small joints
4–10 small joints
Negative RF and negative ACPA
Low positive RF or low positive ACPA
High positive RF or high positive ACPA
Acute phase reactants
Normal ESR and normal CRP
Abnormal ESR or abnormal CRP
Duration of symptoms
Rheumatoid arthritis must be differentiated from a number of other disorders. Many connective tissue diseases, seronegative spondyloarthropathies, infection-related reactive arthropathies, and endocrine related disorders may have symptoms in common with rheumatoid arthritis and thus should be part of the differential diagnosis when considering rheumatoid arthritis. Ten percent of RA patients may present in an asymmetric oligoarticular fashion. Inflammatory back pain affecting lumbarsacral spine and sacroiliac joints is not part of the clinical picture but cervical spine involvement is seen in up to 50% patients especially with advanced disease . Thirty percent of patients may present with palindromic symptoms defined as fleeting up to 72 hours of inflammatory arthropathy. Up to 50% of them are seropositive (either RF and/or CCP positive) and may progress to develop typical RA symptoms and signs . Palindromic rheumatism needs to be differentiated from crystal arthritis and viral syndromes. PMR usually affects proximal joints but it can affect peripheral joints in up to 50% of patients. Systemic symptoms to include fever, rash, lymphadenopathy should dictate work up for viral infections or Still’s disease. Fibromyalgia may present with diffuse pain affecting muscles and joints along with fatigue and sleep disturbances and may superimpose inflammatory symptoms in RA patients. Reaching an accurate diagnosis requires a careful examination focusing on identifying synovitis and enthesitis, along with directed imaging to unravel other common causes of regional pain syndromes or post-inflammatory osteoarthritis paired with labs such as ESR and CRP.
Patients with rheumatoid arthritis can present in several ways. The typical presentation, in about 50% of the patients, is the insidious onset of arthritis symptoms with number of joints increasing. However, patients can present in subacute, acute, and variant patterns. Palindromic symptoms affect joints in a migratory fashion with resolution of 72 hours, only for these to recur in random intervals either in the same or different joint. Arthritis robustus reflects an often relatively asymptomatic presentation usually in men causing bulky, erosive arthritis with deformities.
The joints most commonly affected in rheumatoid arthritis in decreasing frequency include metacarpophalangeals, proximal interphalangeal, wrists, knees, shoulders, metatarsophalangeals, ankles, cervical spine, elbows, hip, and temporomandibular joints. Smaller joints are usually symptomatic first. Involvement of the sacroiliac, thoracic, and lumbar spine is rare in rheumatoid arthritis.
Cervical spine involvement is seen in 30–50% of patients with C1–C2 the most commonly affected level. It can lead to instability and potential impingement of the spinal cord as a result of subluxation, compression, and subaxial involvement. C1–C2 anterior subluxation >3 mm can lead to spinal cord impingement or compression. In C1–C2 compression there is cephalad movement of odontoid into the foramen magnum potentially leading to impingement of brain stem. Subaxial involvement usually at C2–C4 levels occurs later than other forms of cervical involvement. Neurologic symptoms such as paresthesias, loss of bowel or bladder control, loss of fine motor skills and new onset neck stiffness and pain should prompt urgent work up.
Extra-articular manifestations of rheumatoid arthritis
Low grade fever, fatigue, weight loss
Pericarditis −50%, myocarditis, coronary vasculitis, atherosclerotic disease
Pleuritis (20%), nodules, pulmonary fibrosis, bronchiolitis obliterans (uncommon but poor prognosis), cryptogenic organizing pneumonia (COP formerly known as bronchiolitis obliterans with organizing pneumonia-BOOP), cricoarytenoid arthritis, ILD-UIP (Usual Interstitial Pneumonia most commonly, and NSIP (nonspecific interstitial pneumonitis less common)
Anemia, thrombocytosis, Lymphomas, Felty syndrome, large granular lymphocyte syndrome (LGL syndrome)
Reactive amyloid, membranous glomerular nephropathy
Entrapment neuropathy, peripheral neuropathy, mononeuritis multiplex, cervical myelopathy
Keratoconjunctivitis sicca, episcleritis, scleritis, uveitis, vasculitis
Leukocytoclastic vasculitis, small arteriolar vasculitis, medium vessel vasculitis, pyoderma gangrenosum
The typical laboratory findings present in RA include anemia and thrombocytosis, elevated ESR and CRP. However, these represent nonspecific markers of inflammation and can be elevated in the setting of infection, tissue injury, and malignancy. Rheumatoid factor (RF) is positive in 70–80% of patients. RF positivity is associated with severe disease, extra-articular manifestations, and increased mortality. RF titer does not correlate with disease activity. Elevated anti-CCP antibodies are present in 80–90% of patients highly specific for RA (95%) and are associated with severe, erosive disease. Nonspecific elevation of antinuclear antibodies (ANA) is observed in 30% of patients.
Synovial Fluid Analysis
Synovial fluid (SF) is inflammatory (WBC count >5000) predominantly composed of polymorphonuclear cells as opposed to synovial tissue where neutrophils are rare. SF is also comprised of T cells with CD8/CD4 at an inverse ratio compared to the pannus and peripheral blood.
The treatment of rheumatoid arthritis has evolved and changed dramatically during the past 20 years. Therapeutic goals include early diagnosis and treatment focusing on low disease activity or remission according to validated disease activity scores. Targeting low disease activity is accomplished by using disease modifying anti-rheumatic drugs (DMARDs)– both conventional and biologic. By definition, a DMARD has the ability to change the course of RA and retard radiographic progression.
Strategies to achieve remission vary from patient to patient depending on severity and presence of extra-articular manifestations, comorbidities, patient preferences, and cost. Clinically available validated instruments to monitor RA activity incorporate tender and swollen joint count, labs, and patient and physician assessment of disease activity. Examples include Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), and Routine Assessment Patient Index Data (RAPID) scores. No tool has advantage over the other and selection is influenced by resource setting and ease of application within the clinic.
There is an urgent need to identify predictors of response to treatment on individual patients as the known adverse prognostic factors for aggressive disease do not always inform about viable treatment options.
Treatment of DMARD-Naive Patients: Monotherapy Versus Combination Therapy
Therapeutic agents for treatment of rheumatoid arthritis
Mechanism of action
Increases lysosomal pH in antigen presenting cells and blocks TLR signaling
Nausea, rash, retinopathy
Converted into sulfapyridine and 5-ASA. Sulfapyridine has antinflammatory and immunomodulatory properties
Nausea, rash, cytopenia
Folic acid antagonist, decreases pyrimidine synthesis, increases release of adenosine, disrupts cellular functions by inhibiting transmethylating enzymes
7.5–25 mg/week PO, SQ, IM
Nausea, diarrhea, alopecia, elevated liver enzymes, myelosuppression, pneumonitis
Converted into teriflunomide, inhibits synthesis of pyrimidine-ribonucleotide uridine monophosphate pyrimidine (rUMP).
Nausea, diarrhea, alopecia, elevated liver enzymes
Injection site/infusion reaction, latent TB reactivation, opportunistic infections
Increased risk malignancy, demyelinating disease, autoimmune phenomena, CHF
Dimeric, soluble, TNF receptor that binds TNF-a, TNF-b
50 mg/weekly SQ
Fully human IgG monoclonal AB that binds soluble and transmembrane TNF-a.
40 mg SQ every other week
Chimeric mouse-human monoclonal AB that binds TNF-a
Loading dose 3 mg/kg IV at week 0,2,6 and then every 8 weeks
Dose can be increased to 5–10 mg/kg every 4 weeks
Recombinant, humanized anti-TNF monoclonal AB
400 mg SQ at week 0,2,4 then
200 mg every 2 weeks
Fully human IgG monoclonal AB that binds soluble and transmembrane TNF-a.
50 mg SQ every 4 weeks
2 mg/kg IV 0,4 weeks and then every 8 weeks
125 mg SQ weekly
<60 kg: 500 mg IV
60–100 kg: 750 mg IV
>100 kg: 1000 mg IV
Every 4 weeks
Infusion reaction, infection
Caution in COPD
IL-6 receptor antagonist
Monoclonal antibody against IL-6R
<100 kg: 162 mg SQ every other week
>100 kg: 162 mg SQ weekly
IV: 4 mg/kg every 4 weeks
Can be increased to 8 mg/kg every 4 weeks
Infusion reaction, elevated liver enzymes,
Increased risk for GI perforation
JAK 3/JAK1 inhibitor
5 mg bid PO
Nasopharyngitis, diarrhea, Headache, elevated liver enzymes, cytopenias
Increased risk for Herpes Zoster
JAK 1/JAK2 inhibitor
2 mg daily PO
GI perforations, hematologic and hepatic toxicity, lipid abnormalities, thrombosis, latent TB reactivation
Monoclonal antibody against CD20 antigen
1000 mg IV repeated once 2 weeks later then every 6 months
Increased risk for viral infections, hypogammaglobulinemia, cytopenia
IL-1 receptor antagonist
100 mg SQ daily
Injection site reaction, cytopenia