Therapeutic Management of Rheumatoid Arthritis

1) Pathophysiology and clinical manifestations

Rheumatoid arthritis (RA) is a chronic autoimmune condition. The exact cause of RA is unknown but it is influenced by genetic, hormonal and environmental factors. RA is characterised by inflammation of the synovium joints, typically affecting the proximal interphalangeal joints (PIPs) and metacarpophalangeal joints (MCPs) of the hands, knees, wrists and joints of the feet. Extra-articular manifestations may also affect other organs of the body. There is no cure for RA (Whittlesea and Hodson, 2018). Diagnosis requires a blood test, measuring serum rheumatoid factor and anti-CCP antibodies. To determine erosions, X-ray of the hands and feet should be taken. If RA is active, healthcare professionals should measure disease activity for e.g. DAS 28 and C-reactive protein. The tool that can be used to measure the functional ability is the Health Assessment Questionnaire. The aim of treatment is to reach remission or low disease activity. This should be monitored monthly in specialist care until this target is reached (NICE, 2018).

2) Therapeutic management

In England the treatment of rheumatoid arthritis should be according to the National Institute of Health and Care Excellence (NICE) Rheumatoid arthritis in adults: management.  The aim is to improve the quality of life by slowing the progression of the disease and controlling the symptoms (NICE, 2018).

Table 1: Therapeutic management of rheumatoid arthritis (Adapted from NICE, 2018)

Methotrexate (cDMARD) has been chosen because it allows disease control and is recommended first-line in patients with rheumatoid arthritis according to NICE (2018).  Strand et al. (1999), found that methotrexate was more efficacious in improving signs and symptoms and delaying disease progression in patients with active RA in comparison to the placebo group (35% vs 19%, ARR=16, NNT=7, P<0.001). The efficacy of treatment was determined by achieving an American College of Rheumatology (ACR) ≥20% after 12 months. A limitation of this study was that patients were commonly taking NSAIDs which would have influenced the improvement in symptoms.

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Tocilizumab (biologic) has been chosen because it is recommended by NICE as a further treatment option in the management of RA. Jones et al. (2009),  found that patients taking tocilizumab 8mg/kg every 4 weeks for moderate- severe RA had a better treatment response rate,  compared to methotrexate 7.5mg-20mg/week with an NNT of only 6 people (69.9% vs 52.5%, ARR=17.4%, P<0.001). The primary endpoint was determined by the number of patients achieving ACR 20 at week 24. A Limitation of this study is that treatment was only carried out for 24 weeks, hence the result may have differed (I.e. not maintained in remission/low disease activity) if carried out for longer or if a follow up was introduced.

Prednisolone (glucocorticoid) has been chosen because it is recommended by NICE as a bridging therapy to help control the symptoms in patients with RA. Sevnsson et al. (2005) found more patients reached disease remission after 2 years of taking prednisolone, in comparison to no prednisolone (55.5% vs 32.8%, ARR=22.7, NNT=5, P<0.0005). The primary endpoint of disease remission was defined as DAS 28<2.6. A limitation of this study was that in addition to prednisolone the choice of DMARDs was left to the physicians. This may have affected the results as the prednisolone group may have had different DMARD than the no prednisolone group. Therefore the DMARD may have been responsible for the increased number of patients in remission rather than the prednisolone.

3) Pharmacist’s contribution to patient care

A side effect of methotrexate is gastrointestinal (GI) discomfort (BNF, 2018).Jones et al. (2009) found it to be the second most common adverse effect. Methotrexate inhibits the enzyme dihydrofolate reductase affecting the synthesis of cells in the GI tract. The occurrence is reduced by supplementation of folic acid. Pharmacists should inform patients to consume folic acid 24-48 hours post methotrexate dose, and consume methotrexate after meals. 

Methotrexate is cautioned in liver toxicity because it can be exacerbated leading to liver cirrhosis which is fatal (BNF, 2018). Pharmacists should identify patients with abnormal liver function tests (LFT)/biopsy and discontinue treatment. Once abnormalities have returned to normal, balance the need for methotrexate (disease control) against the risk of harm (liver toxicity). Where treatment is deemed essential patients should be monitored more frequently (i.e.LFT).

An important interaction with methotrexate is the increase risk of toxicity when given with aspirin (BNF, 2018). This is because the clearance of methotrexate is reduced. Pharmacists should warn patients and report immediately any signs of blood disorders (i.e. sore throat, bruising and mouth ulcers), liver toxicity (i.e. dark urine, nausea and vomiting) and respiratory effects (i.e. shortness of breath).

Pharmacists should educate patients to avoid self-medication with ibuprofen to reduce risk of toxicity (BNF, 2018).

A common side effect of tocilizumab is dyslipidaemia (BNF, 2018). Soubrier et al. (2016), found tocilizumab to increase lipid levels. The exact cause is unclear but it is thought to be due to the inhibition of IL-6. Pharmacists should identify these patients and advise on additional treatments (i.e. atorvastatin). 

A caution with tocilizumab is low platelet count (BNF, 2018). Pharmacists should emphasise and encourage patients to go for their regular blood tests to ensure they are monitored.

An important interaction with tocilizumab is that there is an increased risk of infection if given with influenza vaccine (live) (BNF, 2018). This is because tocilizumab supresses the immune response. Pharmacists should counsel patients not to take the vaccination unless it is essential.

Pharmacists should advise patients to store tocilizumab in the refrigerator (2-8°) ensuring it is stable to maximise the efficacy (BNF, 2018).

A common side effect of prednisolone is adrenal suppression (BNF, 2018). Leonie et al. (2015) found that prednisolone inhibits the function of the hypothalamic-pituitary-adrenal axis by negative feedback causing adrenal suppression. Pharmacists should advise patients not to stop treatment abruptly. Prior to treatment cessation, patients should discuss their tapering regimen with a healthcare professional.

Prednisolone is cautioned in diabetes mellitus as it causes hyperglycaemia (BNF, 2018).  Pharmacists should identify patients with diabetes; balance the need for prednisolone (symptom control) against the risk of harm (hyperglycaemia). Where prednisolone is deemed essential, patients should be monitored for any changes in blood glucose levels.

There is a severe interaction between prednisolone and amiodarone. When given concomitantly it causes hypokalaemia which can lead to torsade de pointes which is fatal. Pharmacists should be vigilant in checking for this interaction, suggesting alternatives (e.g. ibuprofen) to the prescriber.

Pharmacists should advise patients on long-term corticosteroids to carry a steroid treatment card (BNF, 2018). This is to minimise any risks associated with treatment i.e. before surgery.

4) Conclusion

Rheumatoid arthritis is a chronic autoimmune condition negatively impacting the patients’ quality of life. Pharmacological management must be individual taking into account their symptoms and response to medication. The use of cDMARDs and/or biological DMARDS must be tailored to suit the patient to reach target remission/low disease activity.  Pharmacists play a key role in monitoring side effects and counselling patients to optimise their treatment.

References

• Broersen, L., Pereira, A., Jorgensen, J. and Dekkers, O. (2015). Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis. The Journal of Clinical Endocrinology & Metabolism, 100(6), pp.2171-2180.
• Joint Formulary Committee (2018). British National Formulary. 76^th edition. London: BMJ group and Pharmaceutical Press.
• Jones, G., Sebba, A., Gu, J., Lowenstein, M., Calvo, A., Gomez-Reino, J., Siri, D., Tomsic, M., Alecock, E., Woodworth, T. and Genovese, M. (2009). Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Annals of the Rheumatic Diseases, 69(01), pp.88-96.
• National Institute for Health and Care Excellence (2018). Rheumatoid arthritis in adults: management [NG100]. Available at: https://www.nice.org.uk/guidance/ng100/chapter/Recommendations#initial-pharmacological-management [Accessed 10 March 2019].
• Soubrier, M., Pei, J., Durand, F., Gullestad, L. and John, A. (2016). Concomitant Use of Statins in Tocilizumab-Treated Patients with Rheumatoid Arthritis: A Post Hoc Analysis. Rheumatology and Therapy, 4(1), pp.133-149.
• Strand, V., Cohen, S., Schiff, M., Weaver, A., Fleischmann, R., Cannon, G., Fox, R., Moreland, L., Olsen, N., Furst, D., Caldwell, J., Kaine, J., Sharp, J., Hurley, F. and Loew-Friedrich,I.  (1999). Treatment of Active Rheumatoid Arthritis With Leflunomide Compared With Placebo and Methotrexate. Archives of Internal Medicine, 159(21), p.2542.
• Svensson, B., Boonen, A., Albertsson, K., van der Heijde, D., Keller, C. and Hafström, I. (2005). Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: A two-year randomized trial. Arthritis & Rheumatism, 52(11), pp.3360-3370.
• Whittlesea, C. and Hodson, K. (2018). Clinical Pharmacy and Therapeutics 6E. [S.I]: Churchill Livingstone, pp.pg 923.