Rheumatoid Arthritis Drugs

• Drugs Used in Management of Rheumatoid Arthritis provided by Patson Kalunga (Dr. Kaluson)

Clinical Sense

• A Rheumatoid arthritis patient experiences worsening of symptoms and progressive destruction in the joints of several fingers.
• The patient is on methotrexate and another second-line agent for rheumatoid arthritis was considered.
• Etanercept is a parenterally administered DMARD whose mechanism of anti-inflammatory action is antagonism of tumor necrosis factor.

Pathophysiology

• Rheumatoid arthritis is an autoimmune condition causing inflammation of the synovial joint, synovial proliferation, and articular cartilage destruction.
• Untreated, it causes disability and loss of function.
• Chronic inflammation can lead to higher risk of CVS disease, osteoporosis and certain cancers (e.g., lymphoma).
• TNFa and IL-1 have a major role in the disease process.

Drug Classes Used

• Disease Modifying Antirheumatic Drugs (DMARDs) retard the disease process and can bring about remission and can take up to 6 months to bring about an effect.
• DMARDs can be conventional (nonbiological) or biological.
• Conventional DMARDs: Immunosuppressants like Methotrexate, Azathioprine, Cyclosporine, Sulfasalazine, Chloroquine or Hydroxychloroquine and Leflunomide.
• Biological DMARDs: TNFa inhibitors like Etanercept and Infliximab.
• IL-1 antagonists include Anakinra.
• IL-6 receptor antagonists: tocilizumab, sarilumab.
• T-cell costimulation blocker: abatacept.
• B cell deplete monoclonal antibody: Rituximab.
• JAX inhibitors: Tofacitinib.
• Adjuvant drugs do not modify the disease process but provide supportive treatment like NSAIDs (Nonsteroidal anti-inflammatory drugs) and Glucocorticoids.

Approach in Management

• The 2022 recommendations of the European Alliance of Associations for Rheumatology recommend an early start of a DMARD or combination of DMARD.
• Methotrexate is the drug of choice as first line of treatment.
• Second line includes the other conventional DMARDs (Sulfasalazine etc.) or a TNFa inhibitor.
• NSAIDs and glucocorticoids are mostly used in the initiate stages for symptomatic relief as DMARD is taking effect. Never use as primary treatment drugs.

Methotrexate

• Methotrexate is a dihydrofolate reductase inhibitor, having immunosuppressant and anti-inflammatory properties, reducing cytokine production, chemotaxis, and cell-mediated response.
• Methotrexate is the first-line drug in RA management, and it takes 4-6 weeks to work.
• Side effects include Oral ulceration, GI upset, Liver damage and cirrhosis (long term) and increased incidence of infection (especially chest).
• Contraindications: Pregnancy, breastfeeding mothers, liver disease, active infection, peptic ulcers, leucopeci.
• Azathioprine works as a purine synthase inhibitor, selectively suppressing T-cells and NK cells, reducing inflammation.

Other Conventional DMARDs

• Sulfasalazine: Sulfapyridine (active metabolite) decreases B-cell functions; 5-ASA possibly inhibits COX.
• Side effects: Hemolysis in G6PD deficiency, rash, gastrointestinal disturbance, dizziness, headache, leukopenia.
• Chloroquine and hydroxychloroquine (antimalarial drugs): MOA: Monocyte IL-1 inhibiting B-lymphocytes.
• Side effects: accumulation in melanin containing tissue like the retina leading to retinal damage and corneal ulceration.
• Other side effects: rashes, graying of hair, irritable bowel syndrome, myopathy, and neuropathy.
• Leflunomide decreases proliferation of stimulated lymphocytes.
• ADRs: leflunomide includes diarrhoea, headache, nausea, rashes, loss of hair, thrombocytopenia, leucopenia, increased chances of chest infection, and raised hepatic transaminases
• Contraindications: in pregnancy.

Gold

• Sodium aurothiomalate (gold salts thiomalic acid).
• MOA is not well known but can arrest progression of RA.
• Now obsolete due to high toxicity: (hypertension, dermatitis, stomatitis, kidney/ liver/bone marrow damage).

TNFa Inhibitors

• Can either be soluble TNFa or TNF antibodies which can bind TNF.
• They work mainly by suppression of macrophages and reduction of T cell function and inflammation.
• They have quicker response than conventional DMARDs.
• Etanercept: TNF receptor + Fc portion of IgG.
• Infliximab: monoclonal TNF antibody.
• Adalimumab: anti-TNF antibody.
• Side effects include increased infection risk, malignancy and hepatotoxicity.