Overview of rheumatoid arthritis

ESSENTIALS OF DIAGNOSIS ㅡ Usually insidious onset with morning stiffness and joint pain. Symmetric polyarthritis with predilection for small joints of the hands and feet; deformities common with progressive disease and extra-articular manifestations. Rheumatoid factor and antibodies to cyclic citrullinated peptides (anti-CCP) are present in 70–80%.. Radiographic findings include: (1) Juxta-articular osteoporosis. (2) Joint erosions. (3) Joint space narrowing. 

           General Considerations: (1) Cause is unknown. (2) Multiple genes contribute to susceptibility; best characterized genetic risk factor is inheritance of HLA DRB1 alleles encoding a distinctive five-amino-acid sequence known as the "shared epitope". (3) The pathologic findings in the joint include chronic synovitis with formation of a pannus, which erodes cartilage, bone, ligaments, and tendons. Effusion and other manifestations of inflammation are common. In the late stage, organization may result in fibrous ankylosis; true bony ankylosis is rare.

Demographics: (1) Prevalence is 1%. (2) More common in women than men (female:male ratio of 3:1). (3) Can begin at any age, but the peak onset is in the fourth or fifth decade for women and the sixth to eighth decades for men

ASSESSMENT

Joint involvement tends to be symmetric and affects small joints of the hands, feet, wrists, and ankles; elbows, knees, shoulders, hips, cervical spine, and temporomandibular joints may also be affected. Joint stiffness is typically worse in the morning, usually exceeds 30 minutes, and may persist all day.

          On examination, joint swelling may be visible or apparent only by palpation. Tissue is soft, spongy, warm, and may be erythematous. If left untreated, long-term joint inflammation may lead to bony erosions and subluxations of wrists, metacarpophalangeal joints, and proximal interphalangeal joints (swan neck deformity, boutonnière deformity, and ulnar deviation).

Extra-articular involvement may include rheumatoid nodules, interstitial lung disease, pleural effusions, vasculitis, ocular manifestations, pericarditis, cardiac conduction abnormalities, bone marrow suppression, and lymphadenopathy. RF is detected in 70%–80% of patients; higher titers generally reflect a more severe disease course. ACPA antibodies are more specific for RA and may be detectable very early in the disease; they generally predict a more aggressive disease course. Antinuclear antibodies (ANAs) are detected in 25% of patients with RA. Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) indicate the presence of a nonspecific inflammatory process. Normocytic anemia, thrombocytosis or thrombocytopenia, and leukopenia may also be present. Analysis of aspirated synovial fluid typically demonstrates a high white blood cell count without crystals or infection.

Early radiologic findings include soft tissue swelling and periarticular osteoporosis. With disease progression, joint space narrowing, bony erosions, and joint subluxations and deviations may occur.

DIAGNOSIS

The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) revised criteria for diagnosis of RA in 2010. These criteria are intended for patients early in their disease to allow for earlier treatment targeted toward preventing structural joint damage. Patients with synovitis of at least one joint and no other explanation for the finding are candidates for assessment. The criteria use a scoring system with a combined score of 6 or more out of 10 indicating that the patient has definite RA.

MANAGEMENT

• Medications include (Corticosteroids, Synthetic and Biological DMARDs).
  

CORTICOSTEROIDS. Low-dose corticosteroids (e.g., oral prednisone 5–10 mg daily). Often used as a "bridge" to reduce disease activity until the disease modifying antirheumatic drugs (DMARDs) take effect or as adjunctive therapy for active disease that persists despite treatment with DMARDs. No more than 10 mg of prednisone or equivalent per day is appropriate for articular disease. Higher doses are used to manage serious extra-articular manifestations (e.g., pericarditis, necrotizing scleritis).

          Intra-articular corticosteroids ㅡ May be helpful if one or two joints are the chief source of difficulty. Intra-articular triamcinolone, 10–40 mg depending on the size of the joint to be injected, may be given for symptomatic relief but not more than four times a year.

SYNTHETIC DMARDs. DMARDs should be started as soon as the diagnosis is certain and then adjusted with the aim of suppressing disease activity

1. Methotrexate: initial synthetic DMARD of choice. Generally well tolerated. Often produces a beneficial effect in 2–6 weeks. Initial dose, 7.5 or 10 mg of methotrexate orally once weekly and can be increased to 15 mg orally once weekly if the patient has tolerated initial dose but has not responded in 1 month (Maximal oral dose: 20 mg/wk). Liver biochemical tests and a complete blood count should be monitored at least every 12 weeks. Daily folate (1 mg orally) or weekly leucovorin calcium (2.5–5 mg taken orally 24 hours after the dose of methotrexate) should be prescribed to all patients to reduce: gastric irritation, stomatitis, cytopenias and hepatotoxicity. Contraindications include any form of chronic hepatitis, pregnancy or any patient with significant kidney dysfunction (estimated glomerular filtration rate < 30 mL/min). For further information, see note on "How to manage methotrexate in patients with rheumatoid arthritis (RA)?".
2. Sulfasalazine: second-line agent, start with 500 mg orally twice daily and then increased each week by 500 mg until the patient improves or the daily dose reaches 3000 mg. Complete blood counts should be monitored every 2–4 weeks for the first 3 months, then every 3 months. Side effects include particularly neutropenia and thrombocytopenia, occur in 10–25% and are serious in 2–5%. Also causes hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, so a G6PD level should be checked before initiating sulfasalazine. Patients with aspirin sensitivity should not be given sulfasalazine.
3. Leflunomide: given orally as single daily dose of 20 mg. Most frequent side effects are diarrhea, rash, reversible alopecia, and hepatotoxicity. Contraindicated in premenopausal women who wish to bear children.
4. Hydroxychloroquine sulfate: monotherapy should be reserved for patients with very mild disease because only a small percentage will respond and in some of those cases only after 3–6 months of therapy. Often used in combination with other conventional DMARDs, particularly methotrexate and sulfasalazine. Start with 200–400 mg/day orally (not to exceed 5 mg/kg/day). Side effects include retinal toxicity causing visual loss, neuropathies and myopathies of both skeletal and cardiac muscle.
5. Tofacitinib, an inhibitor of Janus kinase: used to manage severe disease that is refractory to methotrexate. Start with 5 mg or 10 mg orally twice daily. Tofacitinib can be used either as monotherapy or in combination with methotrexate. Patients should be screened and treated for latent tuberculosis prior to receiving the drug. Vaccination against varicella is also recommended.
6. Baricitinib (Olumiant), an inhibitor of Janus kinase: approved for disease that has failed to respond to inhibitors of tumor necrosis factor (TNF). Dose, 2 mg orally once daily. Baricitinib can be used either as monotherapy or in combination with methotrexate. Patients should be screened and treated for latent tuberculosis prior to receiving the drug. Vaccination against varicella is also recommended.

BIOLOGICAL DMARDS. TNF inhibitors are frequently added to the treatment of patients who have not responded adequately to methotrexate and can be used as initial therapy in combination with methotrexate for patients with poor prognostic factors

          Five TNF inhibitors are in use (1) Etanercept: 50 mg subcutaneously once per week. (2) Infliximab: 3–10 mg/kg intravenously; infusions are repeated after 2, 6, 10, and 14 weeks and then are administered every 8 weeks. (3) Adalimumab: 40 mg subcutaneously every other week. (4) Golimumab: 50 mg subcutaneously once monthly. (5) Certolizumab pegol: 200–400 mg subcutaneously every 2–4 weeks.

Abatacept produces clinically meaningful responses in approximately 50% of individuals whose disease did not respond to the combination of methotrexate and a TNF inhibitor. Rituximab can be used in combination with methotrexate for patients whose disease has been refractory to treatment with a TNF inhibitor. Tocilizumab and sarilumab are used most often in combination with methotrexate for patients whose disease has been refractory to treatment with a TNF inhibitor.

REFERENCES

• Goodman, S.M., Springer, and others. 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients with Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty. Arthritis & Rheumatology, 69(8), pp.1538–1551. Available at: https://onlinelibrary.wiley.com/doi/full/10.1002/art.40149

  Van der Woude, D. and van der Helm-van Mil, A.H.M. (2018). Update on the epidemiology, risk factors, and disease outcomes of rheumatoid arthritis. Best Practice & Research Clinical Rheumatology, 32(2), pp.174–187. Available at: https://pubmed.ncbi.nlm.nih.gov/30527425

  Boleto, G., Kanagaratnam, L., Dramé, M. and Salmon, J.-H. (2019). Safety of combination therapy with two bDMARDs in patients with rheumatoid arthritis: A systematic review and meta-analysis. Seminars in Arthritis and Rheumatism, 49(1), pp.35–42. Available at: https://pubmed.ncbi.nlm.nih.gov/30638975