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Arthritic disease is known as one of the most common chronic diseases and rheumatoid arthritis causes most of the disability cases around the world1. Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease which has a prevalence/morbidity of 1-3% of the population of Europe and North America2. One out of three patients suffering from this disease is likely to become severely disabled1. RA is a non-fatal disease but it may dramatically decrease quality and length of life. The range of 1.13-2.98 standardized mortality ratios was obtained from various studies. It is found that the life spans of RA patients were shortened by 5-10 years. The complication of RA and also non-specific death causes for example renal disease and bacterial infection may increase the mortality rate6, 7, 8.
Rheumatoid arthritis may occur at all ages and the prevalence increases with age until the age of 703. Women before menopause is more likely to suffer from this disease compared to men3. This disease affects the proximal interphalangeal and metacarpophalangeal joints, elbows, knees, ankles and spine. Normally, the joints are often affected at the same time and in a symmetric pattern3. The whole process consists of repeating remission and exacerbation.
RA is an autoimmune disease where the body's immune system starts to attack healthy joints instead of defending the body from infections. The cause of RA is unknown but there are a number of factors that have been involved. The first is genetic factor where an important genetic locus is found in HLA II genes which predispose to RA and a specific set of HLA-DR (DR1, DR4, DR10, DR14) alleles is increased in RA patients3. Immunological mechanisms play an important part in RA where the lymphocytes and plasma cells builds up in the synovium and generate immunoglobin causing rising serum levels of IgM, IgA and IgG3. 80% of normal RA patients are tested positive for rheumatoid factor which is mainly IgM. Cellular immunity may contribute to RA due to the interaction of T-cells with macrophages by producing cytokines. Studies show that joint destruction in RA express local production of cytokines, mainly tumour necrosis factor (TNF) and interleukin-1 (IL-1)3.
In summary, an unknown agent infects the join resulting in antibodies production in genetically susceptible patients. These immunoglobins operate as antigens thus trigger the formation of rheumatoid factor. Immune complexes are then distributed in the synovium causing increased vascular permeability and uptake of immune complex by leukocytes due to activation of complement cascade3. The activated macrophages in the synovium are unknown antigens to T cells in the body, therefore causes stimulation of cytokines which enhances inflammation, tissue injury along with synovial cells proliferation3. The synovium will eventually becomes locally invasive (pannus) and this inflammatory process will finally result in irreversible destruction of cartilage as well as erosion of periarticular bone4.
Sign and Symptoms
The symptoms of RA often emerge slowly. While RA is a chronic disease, patient may not experience any symptoms for many years5. During remission, the symptoms disappear and patients will often feel well. The symptoms return when the disease relapse and this is called a flare5. The joints that have been affected are warm, swollen and painful4. In the morning, the stiffness of the joint, due to the increase in extracellular fluid in as well as around the joint may cause many troubles4. In RA patients, the lining of joint is inflamed, causing excessive synovium fluid production. Systemic disturbance for example fatique and malaise is also common in RA patients4. In long term, the erosion of cartilage as well as bones and muscles will cause deformity and also destruction in joints. In the end, this causes functional loss of joint5.
The diagnosis of RA is to examine the symptoms pattern as well as distribution of inflamed joints. Blood test and X-ray are also done. In RA patients, the small joints of hand, feet, knee and wrist are commonly inflamed symmetrically. The degree of inflammation in the body can be tested by erythrocytes sedimentation rate and C-reactive protein5. These blood tests are done to measure joints inflammation. The rate is normally faster during flare and slower during remission. In unexplained joint inflammation, antibody called rheumatoid factor may be used for RA diagnosis. X-rays can be used to show bone erosion in the joints and also to monitor disease progress over time5.
Patients of RA are classified as below:
completely able to perform usual activities of daily living
able to perform usual self-care and work activities but limited in activities outside of work (such as playing sports, household chores)
able to perform usual self-care activities but limited in work and other activities
limited in ability to perform usual self-care, work, and other activities
Table 1: Classification of RA patients.5
The most effective way to treat RA is via early treatment, multidisciplinary drug approach, appropriate counseling, joint protection and also exercise5. Drug treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is used to relieve pain, inflammation and muscle stiffness but do not change the long-term progression of joint destruction. Disease-modifying antirheumatic drugs (DMARDs), also known as second-line drugs are used to modify the disease progress or induce remission. DMARDs normally improves symptoms and produce long-term inflammatory depression. DMARDs may be initiated when definite diagnosis has been done but the onset of these drugs is slow, with little improvement in symptoms until around 3 months after treatment. Hence, NSAIDs is used to provide 'cover' during this induction period1, 2, 3, 4.
NSAIDs act by inhibiting the cyclooxygenase (Cox) pathway9. In RA patients, the preferred target is Cox 2 because this pathway produces prostagladins which determine pain as well as inflammation9. Evidence showed that NSAIDs are effective in providing relief in pain and stiffness without influencing disease progress11.
The adverse effects of NSAIDs are gastrointestinal intolerance and peptic ulceration2. When the disease is mild, ibuprofen or diclofenac (75-150mg daily) is used. Paracetamol may also be used. When the inflammation becomes severe, aspirin (2-6g daily), indomethacin (50-200mg daily) or piroxicam (30mg daily) are used2, 10. The advantages of NSAIDs are fewer side effects and effective management of pain12.
Sulphasalazine is a first choice DMARD used in the United Kingdom (UK)1. Radiographic evidence shows that this drug slows down active RA progression but its mode of action is poorly understood2. Toxic oxygen metabolites generated by neutrophils may be scavenged by this drug1. Sulphasalazine is hydrolysed by the colon's bacteria to form 5-aminosalicylic acid which is known as a radical scavenger and also sulfapyridine1, 4. The latter component may decrease the antigens absorption from the colon which encourages inflammation of joints4. Besides that, sulphasalazine can alter various signal transduction pathways which are responsible in the pro-inflammatory cytokines production for example gene transcription mediated by NF-κB4. Evidence showed that sulphasalazine had a statistically significant improvement in tender, swollen joint scores, ESR and pain when compared to placebo13.
The common adverse effects are gastrointestinal disturbance, malaise, headache, mouth ulcer and rash1. Soft contact lenses may be stained and urine may be coloured orange10. Besides that, reversible oligospermia, a decrease in sperm count has been reported4. In some patients, blood dyscrasias as well as anaphylactic-type reactions may occur1. The advantages of sulphasalazine is the rapid onset of action which is within 8-12 weeks, can be used during diagnosis uncertainty and it is safe in thrombocytopenia9. The monitoring requirements are full blood count, renal and liver function as well as urinalysis9.
Hydroxychloroquine and chloroquine are known as 4-aminoquinoline drugs which are used in the prophylaxis and treatment of malaria1. They are also used as DMARDs due to the reduction in T-lymphocyte transformation as well as chemotaxis4. These drugs function as anti-inflammatory and have immunomodulating effects which are useful in RA2. Antimalarials increase the pH of macrophage lysosomes, thus reducing the interaction between T-helper cells and antigen-presenting macrophage. It also helps reduce the generation of several inflammatory cytokines4. Evidence showed that hydroxychloroquine is statistically significant in RA treatment compared to placebo by improving joint count, pain and ESR14.
Antimalarials build up in many organs including the eyes thus the major side effect of these drugs is on the retina but this is rare and safe and low doses that are recommended. Other side effects include nausea and headaches4. The advantages of these drugs are no blood monitoring required, can be used in diagnosis uncertainty and safe in thrombocytopenia and leucopenia9. Eye check should be done before starting and every 6 months during therapy2.
Methotrexate is a folate antagonism which has immunosuppressive, cytotoxic properties and antirheumatoid activity1. Methotrexate or sulphasalazine is usually first choice DMARDs due to better tolerability10. This drug may cause adenosine accumulation, which is a potent anti-inflammatory mediator that affects neutrophil adhesion, cytokine production along with macrophage function4. A 5 years study showed that there is significant improvement (p=0.0001) in ESR, joint pain and tenderness index and joint swelling index15.
The common adverse effects are nausea, diarrhoea, mouth ulcer and rash9. In long term, it may cause chronic liver disease, pneumonitis, blood dyscrasias and opportunistic infection2. Hence, the usage of this drug should be closely monitored and it is contra-indicated in liver and renal impairment patients because it is excreted renally1. The advantages are rapid onset of action compared to others DMARDs (6-10weeks), can be used in diagnosis uncertainty and available orally, intravenous and subcutaneous9. It is also administered weekly which may increase compliance9.
Sodium aurothiomalate by intramascular injection and auranofin by mouth are commonly used2. Mononuclear cells takes up gold compounds resulting in phagocytic inhibition. This will cause reduction in inflammatory mediators release such as TNF-α and IL-1 and also cause inflammatory cells proliferation inhibition1, 4. It also inhibits NF-κB which is involved in inflammation4. A trial showed that gold compounds are statistically significant in improving grip strength and decreasing ESR compared to placebo16.
Adverse effects happen in one third of patients treated and 1 of patients will experience serious toxic effects1. Common side effects are mouth ulcers, skin rashes, diarrhoea (oral gold), colitis, proteinuria, stomatitis and blood disorder9, 10. Gold should not be used in patients with history of renal or hepatic disease, blood dyscrasias or severe skin rashes4. There will be no benefits until about 300-500mg has been given and should be terminated after 1g has been given without remission occurring10. Monitoring includes full blood count and urinalysis to avoid toxicity and drug should be terminated at earliest sign of harm2. Advantages include patient preference and compliance due to its weekly to monthly dosing intervals1, 9 (for sodium aurothiomalate). The advantage of auranofin is its oral gold usage.
Penicillamine is a dimethylcysteine, a compound produced by penicillin hydrolysis1. It decreases the rheumatoid factor as well as the accumulation of immune complexes in synovial fluid and plasma2. Around 75% of RA patients respond to this drug1. More patients are able to continue treatment with penicillamine compared to gold10. Evidence showed that penicillamine has statistically significant benefit in tender joint count, ESR and pain in RA patients compared to placebo17.
Side effects occur in about 40% of patients treated1. Allergic reactions which include fever and rashes happen during early treatment stage2. Other side effects are aneroxia, taste loss, nausea, proteinuria and blood disorder4, 9. Treatment should be terminated when bone marrow disorder (leucopenia, aplastic anemia), haematuria (which occurs rarely) and late rashes happen1, 10. Monitoring include full blood count, urea and electrolytes test as well as urinalysis9.
Leflunomide has nearly specific suppressive effect on activated T-cells1 which reduces immune process. It binds to dehydroorotate dehydrogenase thus inhibiting de novo synthesis of pyrimidine which is needed in the proliferation of activated lymphocytes1, 4. Leflunomide is a prodrug and has a long half life of 15 days which is excreted by bile and kidney. It may be used when sulfasalazine and mehotrexate cannot be used10. Clinical studies showed that leflunomide is statistically significant in improving active RA symptoms and slowing disease development compared to placebo and also equivalent to methotrexate18.
Common side effects are alopecia, diarrhoea, nausea, rash and raise in blood pressure9, 10. Bone-marrow toxicity and hepatic failure may occur rarely1, 10. Monitoring include full blood count, liver and kidney test and blood pressure monitoring9.
Cyclosporin binds to protein cyclophilin and inhibits calcineurin thus causing inhibition of IL-2 production and T-cell cycle progression1, 4. Cyclosporin also suppresses other cellular mitogen-activated protein kinase triggered by TNF-α and IL-1 1. It is licensed for severe acute RA when conventional second-line therapy is ineffective10. Evidence show that cyclosporin may decrease the erosive rate and improve symptom control in patients who respond partially to methotrexate10. Evidence showed that there is significant improvement in pain (24%) and active joint (23%) compared to placebo19.
The most important side effects are nephrotoxicity, hepatotoxicity and hypetension1. Other side effects include tremor, paraesthesia, gum hypertrophy and gastrointestinal disturbances9. Liver and kidney function test and blood pressure monitoring are needed9. It has no depressant effect on bone marrow which may be the advantage1.
Azathioprine is an immunosuppressant which interferes with purine synthesis and is cytotoxic1. It is a prodrug and is metablosised to form mercaptopurine that inhibits DNA synthesis1. It suppresses clonal proliferation that happens during induction phase of immune response1. Evidence showed that azathioprine has statistically significant improvement in the joints of RA patients; however it has a high risk to benefit ratio20.
Adverse effects are nausea, hypersensitivity reactions, bone-marrow suppression and increased susceptibility to infections10. Advantage of this drug is it can be used in renal disease patients9.
The drugs in this category are adalimumab, etanercept and infliximab which are TNF-α inhibitors1. Anakinra is another anticytokine drug which is an IL-1 antagonist4. In UK, these drugs are restricted to patients who have failed to respond to at least 2 DMARDs10. Studies showed that anticytokines are significantly better than placebo in morning stiffness, pain score, swollen joint count, ESR and C-reactive protein21, 22.
The side effects of TNF-α inhibitors are associated with infections, fever, nausea, pruritus, injection site reaction and blood disorders1, 10. Anakinra may cause injection site reaction, infection and neutropenia4, 10. The disadvantages are difficult and expensive in producing because they are recombinant engineered antibodies1.
It is well known that corticosteroids are useful in relieving effects of inflammation. Corticosteroids inhibit IL-2 production and T-cell cycle progression. They also reduce transcription of various cytokine genes in phases of immune response1. Steroids are used as adjunct for NSAIDs or DMARDs and bridge therapy is used for symptom control while waiting for DMARDs to take effect2. Spaced single enormous dose are used for fast and sustained relief of acute exacerbations known as'flare' 2. Some studies significantly showed that low dose oral prednisolone reduce the short-term disease activity in 60% of RA patients as well as temporary relief23, 24, 25. Prednisolone 7.5g daily when added to standard treatment may decrease the joint destruction progress2.
Although symptom relief is effective, long term treatment is not recommended due to serious adverse effects in systemic steroids for RA2. Side effects include adrenal suppression, osteoporosis and diabetes10.
According to NICE guideline, in newly diagnosed active RA patients, a combination of DMARDs which include methotrexate and at least one other DMARDs plus short-term glucocorticoids (oral, intramuscular or intra-articular) is used as first line treatment26. If a DMARD does not have any benefits within 6 months, it should be replaced by a different drug10. Corticosteroids are not recommended for long term use and the administration of the lowest possible dose should be given at the shortest time possible to rapidly reduce inflammation9. Patient should be monitored closely. Oral corticosteroids should be withdrawn step by step to avoid rebound flare9. Intra-articular injections should not be given more than 3 times a year in any joints9.
It is usual to start with NSAIDs for pain management until diagnosis and progression of disease is confirmed. The lowest NSAIDs dose and only one NSAID should be prescribed at a time for sufficient symptom relief and it should be reduced or withdrawn if there is good response to DMARDs. A proton pump inhibitor should also be co-prescribed with NSAIDs in RA patients elder than 65 years old and those with history of peptic ulcer. Other analgesics for example paracetamol and codeine can be given for patients with inadequate pain control to reduce need of long-term therapy with NSAIDs26.
In this case, a 64 years old female had failed to response to 6 months sulphasalazine therapy. Hence, an alternative drug therapy should be given. A CORRONA database study found that a change of drug was associated with an improvement in functional ability of RA patients27. Evidence showed that combination DMARDs therapy is better in remission in RA symptoms and less harmful than monotherapy28. It is found that methotrexate and antimalarials had highest efficacy relative to toxicity when compared to other DMARDs and placebo29. Methotrexate has highest efficacy and least toxicity while antimalarials has moderate efficacy with lowest toxicity rate29. A study found that the triple combination of methotrexate, sulphasalazine and hydroxychloroquine is significantly well tolerated and is superior in efficacy compared to monotherapy, double combination of methotrexate and sulphasalazine as well as methotrexate and hydroxychloroquine. Another study showed that the best treatment for RA will be methotrexate, adding other DMARDs and a prednisolone due to functional improvement in RA patients31.
Methotrexate has a half life of 9 hours and it is to be given 7.5mg once weekly orally to maximum of 20mg weekly10. Hydroxychloroquine has a half life of 18 days and is administered 6.5mg/kg daily by mouth up to a maximum of 400mg daily10. Sulphasalazine is given by oral 500mg daily up to maximum of 2-3g daily in divided dose10. Oral prednisolone can be given 7.5mg daily for rapid inflammation reduction and is to be withdrawn slowly. Patient should be monitored closely by full blood count and renal liver function test weekly until treatment stabilized and also eye check9. Alcohol intake should also be restricted9.