Rheumatoid arthritis 1
Definition Rheumatoid arthritis is one of the most common inflammatory disorders affecting the population worldwide. It is a systemic inflammatory disease which affects not only the joints but a wide range of extra-articular organs. Women before the menopause are affected three times more often than men. After the menopause the frequency of onset is similar between the genders. 2
Etiology and pathophysiology The cause of rheumatoid arthritis remains unclear with hormonal, genetic and environmental factors playing a key role. Genetic factors contribute 53 65% of the risk of developing this disease. Cigarette smoking is a strong risk factor for developing rheumatoid arthritis. 3
Chronic inflammation of the synovial tissue lining the joint capsule results in the proliferation of this tissue. The inflamed, proliferating synovium characteristic of rheumatoid arthritis is called pannus. This pannus invades the cartilage and eventually the bone surface, producing erosions of bone and cartilage and leading to destruction of the joint. 4
The inflammatory cells involved in rheumatoid arthritis include T-cells (predominantly CD4 helper cells), B-cells, macrophages and plasma cells. Cytokines are released by these cells which cause the synovium to release proteolytic enzymes, resulting in the destruction of bone and cartilage. cytokines involved in rheumatoid arthritis include tumour necrosis factor (TNF)-α, interleukin-1, interleukin- 6. 5
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Clinical manifestations The disease may present as a polyarticular arthritis with a gradual onset, intermittent or migratory joint involvement, or a monoarticular onset. In addition, Extra articular features occur are associated with a poor prognosis. The predominant symptoms of rheumatoid arthritis including pain, stiffness and swelling of the joints. Typically, the metacarpophalangeal and proximal interphalangeal joints of the fingers, interphalangeal joints of the thumbs, the wrists, and metatarsophalangeal joints of the toes are affected during the early stages of the disease. 7
Other joints of the upper and lower limbs, are also affected. Morning stiffness may last for 30 min to several hours, and usually reflects the severity of joint inflammation. Patients also suffer from prominent myalgia, fatigue, low-grade fever, weight loss and depression at disease onset. 8
Criteria for the diagnosis of rheumatoid arthritis Morning stiffness > 1 hour at least 6 weeks. Swelling of three or more joints for at least 6 weeks Swelling of the wrist, metacarpophalangeal or proximal interphalangeal joints for at least 6 weeks Symmetric joint swelling for at least 6 weeks Hand X-ray changes typical of rheumatoid arthritis that must include erosions or periarticular osteopenia. Rheumatoid subcutaneous nodules Positive rheumatoid factor The presence of at least 4 of these indicates a diagnosis of rheumatoid arthritis. 9
Investigations Inflammatory markers, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) Immunoglobulin Rheumatoid factor (IgMRF) which is present in 75 80% of patients with rheumatoid arthritis (termed seropositive disease). Anti-cyclic citrullinated peptide antibodies (anti- CCP antibody) are a more specific test for rheumatoid arthritis with a specificity of 90 96% compared with the specificity of IgM RF. 10
Antinuclear antibodies (ANA) and extractable nuclear antigens (ENA). Other abnormal laboratory tests include an elevated alkaline phosphatase, an elevated platelet count, a decreased serum albumin. White cell count, particularly neutrophils, is elevated in patients with infected joints. 11
Drug treatment There are four primary goals in the treatment of rheumatoid arthritis: Symptom relief including pain control Slowing or prevention of joint damage Preserving and improving functional ability Achieving and maintaining disease remission 12
There are four main categories of drugs used in the treatment of rheumatoid arthritis: Non selective NSAIDs or COX-2 inhibitor drugs Glucocorticoids DMARDs Biological therapies. 13
Non drug treatment The most useful types of nonpharmacological therapy used in patient with rheumatoid arthritis include: Rest Physical therapy Use of assistive devices such as canes, walkers, and splints. Weight reduction Surgical techniques like synovectomy and joint replacement. 14
Drug treatment Non selective NSAIDs or COX-2 inhibitor drugs The analgesic and anti-inflammatory properties of NSAIDs are used to reduce joint pain and swelling. NSAIDs are categorized as either non-selective NSAIDs or selective COX-2 inhibitors. NSAIDs and/ or corticosteriods may be used for symptomatic relief if needed. They provide relatively rapid improvement in symptoms compared with DMAIDs. 15
Disease-modifying anti-rheumatic drugs (DMARDs) The DMARDs that are commonly used for rheumatoid arthritis are methotrexate, sulphasalazine, leflunomide and intramuscular gold. Hydroxychloroquine, d-penicillamine, oral gold, ciclosporin and azathioprine are less used. 16
Patients with a new diagnosis of rheumatoid arthritis should be offered combination DMARD therapy as first-line therapy early (within 3 months ideally).the combination therapy should include methotrexate and at least one other DMARD, usually sulphasalazine and/or hydroxychloroquine. In patients where combination therapy is not appropriate, for example where there are contraindications to a drug due to existing comorbidities, DMARD monotherapy should be started 17
Methotrexate Methotrexate is recognized as the gold standard DMARD in the management of rheumatoid arthritis. It is given as a once weekly dose and can be given orally or parenterally via the intramuscular or subcutaneous routes. Methotrexate is primarily excreted unchanged by the kidneys and so elderly patients or those with renal impairment may require lower doses. Urea and electrolyte should be monitored during treatment. 18
Methotrexate is a folic acid antagonist, so it should be used with oral folic acid to reduce adverse effects of methotrexate. It is causes hepatotoxicity, myelosuppression, thrombocytopenia, leukopenia, pulmonary fibrosis, pneumonitis, stomatitis, nausea, and vomiting. Liver function test, full blood count, chest X ray should be monitored during treatment. 19
Sulphasalazine Sulphasalazine has been shown to slow joint erosions and suppress inflammatory activity in rheumatoid arthritis. Sulphasalazine causes GI disturbance, rash, alopecia, hepatotoxicity and myelosuppression. Liver function test and full blood count should be monitored during treatment. 20
Hydroxychloroquine Hydroxychloroquine is significantly less effective than other DMARDs. It has also been used relatively safely in pregnancy. Hydroxychloroquine causes rash, alopecia ocular toxicity, GI and visual disturbance, so Regular visual assessment for retinopathy is recommended. 21
Leflunomide Leflunomide has a long half- life of approximately 2 weeks. Leflunomide causes GI disturbance, hepatotoxicity, myelosuppression hypertension and weight loss. Liver function test, full blood count, blood pressure and weight should be monitored during treatment. 22
Gold Gold can be given via intramuscular injection as sodium aurothiomalate, or orally as auranofin. Intramuscular gold is more effective than oral. Gold causes myelosuppression, proteinuria, rash, stomatitis. 23
Other DMARDs D-Penicillamine is less commonly used and side effects such as rashes, taste loss, myelosuppression and vomiting. Azathioprine and ciclosporin can be used in refractory rheumatoid arthritis, but use is limited due to high incidence of side effects. Azathioprine causes myelosuppression and hepatic impairment. Ciclosporin causes hypertension, renal dysfunction, gingival hyperplasia, electrolyte imbalance and hyperlipidaemia. 24
Glucocorticoids Steroids can be given via the oral, intramuscular or intraarticular routes. Prednisolone is the most commonly used oral steroid. Intra-articular injections, such as triamcinolone or methylprednisolone, are administered into inflamed joints for local anti-inflammatory action, pain relief and to reduce deformity. 25
Intramuscular and, less commonly intravenous, injections are used as high-dose pulse therapy to control aggressive disease flares. Steroids are also used as a bridging therapy and are particularly useful when introducing DMARDs which may take several months to take effect. 26
Steroids can induce osteoporosis, which is a known complication associated with rheumatoid arthritis itself. Prophylactic therapy, such as calcium and vitamin D supplementation and bisphosphonates, should be considered in patients on steroids at a high dose or for an extended period of time. Gastroprotection may also be necessary in the form of H2 antagonists or proton pump inhibitors. Other adverse effects associated with steroids are diabetes, increased risk of infection, hypertension and weight gain. 27
Biological therapies Anti-TNF agents There are five anti-tnf agents available: adalimumab, etanercept, golimumab, infliximab and certolizumab pegol. All inhibit TNF-α which is an inflammatory cytokine found in high concentrations within the joint synovium of rheumatoid arthritis patients. Optimum clinical benefit is achieved when these drugs are used in combination with methotrexate. However, adalimumab, etanercept and certolizumab pegol can be used alone as monotherapy in patients for whom methotrexate is not appropriate or not tolerated. 28
The anti-tnf agents are generally well tolerated, with the main side effects being injection site reactions with the subcutaneous agents, and infusion-related reactions with infliximab. Patients using anti-tnf agents are more susceptible to serious infections such as sepsis, and opportunistic infections. Patients should not start anti-tnf therapy in the presence of infection. Those who develop infection whilst receiving treatment should stop and wait until the infection is controlled. 29
Rituximab Rituximab in combination with methotrexate is licensed for the treatment of severe active rheumatoid arthritis in patients who have had an inadequate response or intolerance to other DMARDs including one or more anti-tnf agent. the most common adverse effects are infusion-related reactions including fever, changes in blood pressure and rash. The incidence of adverse effects is minimized by pre-medicating with methylprednisolone, paracetamol and an anti-histamine 1 h prior to the infusion. Hypersensitivity reactions and anaphylaxis are rare but serious side effects. 30
Rituximab increases the risk of infections and should not be used in the presence of active or severe infections. It may also exacerbate existing cardiac conditions such as angina pectoris and atrial fibrillation. Patients with a known history of cardiac disease should be closely monitored during treatment administration for changes in blood pressure and pulse. 31
Abatacept It is licensed for use in combination with methotrexate in the treatment of moderate to severe active rheumatoid arthritis in adults who have had an insufficient response or intolerance to other DMARDs including at least one anti-tnf agent and who cannot receive rituximab because they have a contraindication to rituximab, or when rituximab is withdrawn due to an adverse event. 32
Anakinra It is less effective at relieving the clinical signs and symptoms of rheumatoid arthritis than anti-tnf agents in combination with methotrexate. 33
Tocilizumab Tocilizumab is licensed for use in combination with methotrexate in the treatment of moderate to severe active rheumatoid arthritis in adults who have had an insufficient response or intolerance to other DMARDs including at least one anti-tnf agent, or cannot receive rituximab. It is requires regular monitoring of liver function tests and full blood count. 34