Differential Diagnosis

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 [12]. 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 [13]. 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.

Clinical Presentation

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.

Hand deformities are common in patients with rheumatoid arthritis (Fig. 6.1). The most common ones are ulnar deviation with radial deviation of the wrist causing ulnar deviation of fingers; swan neck deformity with flexion of the MCP joint, hyperextension of PIP, flexion of DIP joint; boutonniere deformity with flexion of the PIP, hyperextension of the DIP joint; hitchhiker thumb with hyperextension of the IP joint, flexion of MCP, and adduction of first metacarpal.

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.

Rheumatoid nodules are present in 30% of patients with RF-positive RA and occur over pressure points typically extensor surface of the forearms, olecranon bursa, sacrum, occiput, heels, and fingers. Other common conditions to consider in a patient with arthritis and subcutaneous nodules include granuloma annulare, tophaceous gout, SLE, multicentric reticulohistiocytosis, calcinosis (as part of limited systemic sclerosis), and rheumatic fever. Rheumatoid nodules are composed of a central area of fibrinoid necrosis surrounded by histiocytes and connective tissue (Fig. 6.2). Small vessel vasculitis is to be the underlying culprit. Ten percent of patients treated with methotrexate can rapidly develop nodules often referred to as accelerated nodulosis. Discontinuing methotrexate often leads to nodule resolution.

Laboratory Tests

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.

Radiographic Features

The radiographic hallmarks of rheumatoid arthritis are soft tissue swelling, periarticular osteoporosis, joint space narrowing, marginal erosions with potentially subluxation of joints (Fig. 6.3). Soft tissue swelling can result from tenosynovitis and joint effusions. Common joints for early erosions include 2nd and 3rd MCPs and 1st and 5th MTP. Ultrasound and MRI may detect erosions not radiographically apparent in early RA. Four patients need to be screened with US in order to detect an additional patient with an erosion in comparison with conventional radiographs [15].

Therapeutic goals

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.

Treatment

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

The decision of which DMARD to initiate at the individual patient level is complex depends on the clinical situation. Starting with DMARD monotherapy is well substantiated by the TICORA, BeST, and TEAR trials [16, 17]; MTX is the initial DMARD prescribed for the majority of patients. It is inexpensive, well tolerated, and improves survival rates. MTX is usually administered orally at first or subcutaneously to improve bioavailability in sub-optimally treated patients at doses 20–25 mg weekly. Combination therapies at the onset result in earlier remission (e.g., within 6 months in TEAR trial) but at 2 years clinical and radiographic parameters are similar to the monotherapy. Long-term radiographic data beyond 2 years are needed to assess outcomes on combination regimens. It is key to note that patients who fail to achieve remission within 6 months of initial treatment (either combination or monotherapy) they require escalation. Based on the BeST trial switching between DMARDs is not effective compared to transitioning to combination regimens. Switching to biologics in patients with active disease who are receiving triple therapy provides additional benefit, as does switching to triple therapy in patients with active disease despite taking MTX and biologics. A cost-effective combo therapy (“triple therapy”) is methotrexate, hydroxychloroquine, and sulfasalazine at maximum tolerated doses (see Table 6.3).

Table 6.3

Therapeutic agents for treatment of rheumatoid arthritis

DMARD	Mechanism of action	Dose	Side effects
Conventional agents
Hydroxychloroquine	Increases lysosomal pH in antigen presenting cells and blocks TLR signaling	200–400 mg/day <5 mg/kg	Nausea, rash, retinopathy
Sulfasalazine	Converted into sulfapyridine and 5-ASA. Sulfapyridine has antinflammatory and immunomodulatory properties	1–3 grams/day	Nausea, rash, cytopenia
Methotrexate	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	Teratogenic
Leflunomide	Converted into teriflunomide, inhibits synthesis of pyrimidine-ribonucleotide uridine monophosphate pyrimidine (rUMP).	10–20 mg/day	Nausea, diarrhea, alopecia, elevated liver enzymes	Teratogenic
Biologic agents
TNF antagonist			Injection site/infusion reaction, latent TB reactivation, opportunistic infections	Increased risk malignancy, demyelinating disease, autoimmune phenomena, CHF
Etanercept	Dimeric, soluble, TNF receptor that binds TNF-a, TNF-b	50 mg/weekly SQ
Adalimumab	Fully human IgG monoclonal AB that binds soluble and transmembrane TNF-a.	40 mg SQ every other week
Infliximab	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
Certolizumab	Recombinant, humanized anti-TNF monoclonal AB	400 mg SQ at week 0,2,4 then 200 mg every 2 weeks
Golimumab	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
Costimulatory modulator
Abatacept	CTLA4 agonist	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
Tocilizumab	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, cytopenia, Lipid abnormalities	Increased risk for GI perforation
Small molecules
Tofacitinib	JAK 3/JAK1 inhibitor	5 mg bid PO	Nasopharyngitis, diarrhea, Headache, elevated liver enzymes, cytopenias	Increased risk for Herpes Zoster
Baricitinib	JAK 1/JAK2 inhibitor	2 mg daily PO	GI perforations, hematologic and hepatic toxicity, lipid abnormalities, thrombosis, latent TB reactivation
Anti CD-20
Rituximab	Monoclonal antibody against CD20 antigen	1000 mg IV repeated once 2 weeks later then every 6 months	Infusion reaction	Increased risk for viral infections, hypogammaglobulinemia, cytopenia
IL-1 inhibitors
Anakinra	IL-1 receptor antagonist	100 mg SQ daily	Injection site reaction, cytopenia

Abbreviations: TLR toll-like receptor, 5-ASA 5-aminosalicylic acid, PO per os, SQ subcutaneously, IM intramuscular, TNF tumor necrosis factor, AB antibody, CTLA4 Cytotoxic T-Lymphocyte Associated Protein 4, JAK Janus activation kinase

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