18th January 2024

Management

The first step in the primary care management of RA is to refer any patient with suspected persistent synovitis for specialist opinion, even if the patient shows a normal acute phase response. Any investigations requested in primary care should not delay referral to secondary care services.

Management of RA is based on the ‘treat-to-target’ strategy. This means that the aim of treatment should be to achieve a target of remission or low disease activity if remission is not possible. Remission should be the target, particularly in patients at high risk of progression, including patients who are anti-CCP positive or have erosion on their X-rays at baseline assessment.

Pharmacological management 

Disease-modifying anti-rheumatic drugs (DMARDs) can be classified as either conventional DMARDs or biologic DMARDs. The first-line therapy is with conventional DMARD monotherapy, either with oral methotrexate, leflunomide, or sulfasalazine, but in practice is usually Methotrexate. Treatment should be started as soon as possible and ideally within 3 months of onset of persistent symptoms. Hydroxychloroquine is an alternative for mild or palindromic disease. The dose of the initial DMARD can be escalated as tolerated. If this is not sufficient, a second DMARD can be added as combination therapy.

The beneficial effect of DMARD therapy may not be seen immediately. Therefore, short-term bridging therapy with glucocorticoids can be started when initiating therapy with a DMARD. A step-down strategy can be considered in patients who stay in remission for at least a year without requiring glucocorticoids.

Biological therapy can be considered, usually in addition to Methotrexate, if the treatment target has not been achieved despite intensive therapy with 2 or more conventional DMARDs and the DAS28 score is between 3.2 and 5.1 (moderate activity). TNF-alpha inhibitors (including Infliximab, Adalimumab and Etanercept)  are usually 1st line biologic therapy. If there is a contraindication to the use of Methotrexate, Adalimumab and Etanercept can be used as monotherapy. In cases where conventional DMARDs and TNF-alpha inhibitors have failed, Rituximab (B cell depletion) can be used- again in combination with Methotrexate. Other rarer biological DMARDs include Tocilizumab (IL-6 receptor blocker) and Abatacept (disruption of T cell function). These agents may be called upon when none of conventional DMARDs, TNF alpha- inhibitors or Rituximab have managed to achieve the treatment target.

Symptom control

There is limited evidence for the use of paracetamol, opioids, and tricyclic antidepressants in symptom control. Non-steroidal anti-inflammatory drugs (NSAIDs) can be considered for pain control and stiffness. However, potential GI, liver and cardiorenal adverse effects should be considered, and a proton pump inhibitor (PPI) should be offered.

Adverse effects of DMARDs

Conventional DMARDs

Most conventional DMARDs have a similar side effect (SE)  profile, including increased risk of infection and GI upset. Certain DMARDs (particularly Methotrexate and Leflunomide) are also teratogenic, so women of childbearing age should ensure they are using adequate contraception. However, there are some adverse effects which are unique to each agent.

Methotrexate, Sulfasalazine and Leflunomide share a similar adverse effect profile, including GI upset, increased incidence of common and serious infections, allergic reactions, bone marrow suppression and hepatotoxicity. Alopecia is a SE of both Methotrexate and Leflunomide. The following unique SEs are also seen:

• Methotrexate- pneumonitis and interstitial lung disease, folic acid deficiency, liver cirrhosis, oral ulcers
• Leflunomide- hypertension, peripheral neuropathy, weight loss
• Sulfasalazine- high risk of GI upset. Can cause decreased sperm count and rarely Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome.

Hydroxychloroquine has perhaps the best safety profile compared to other conventional DMARDs; it does not increase the risk of serious infections or cause renal or liver dysfunction. Common SEs include rash and diarrhoea. The most serious but rare adverse effect associated with Hydroxychloroquine is retinopathy/ maculopathy. This is associated with a higher cumulative dose and greater than 5 years of therapy. Other rare adverse effects of Hydroxychloroquine include anaemia, leukopenia, myopathy and cardiomyopathy.

Biologic DMARDs

All biologic DMARDs can increase the risk of common and serious infections from bacterial, fungal and viral agents. This can also include reactivation of tuberculosis, herpes zoster and hepatitis B and C. Rarer SEs include bone marrow suppression and hepatotoxicity.

Whilst it is acceptable to use a combination of conventional DMARDs or a combination of conventional DMARD and biologic DMARD, a combination of different biologic DMARDs should not be used as the risk of severe immunosuppression reading to severe life-threatening infections is too high.

Specific SEs associated with Anti-TNF agents include:

• Worsening of severe congestive heart failure
• Drug-induced SLE
• Demyelinating central nervous system diseases
• Lymphomas and non-melanoma skin cancers

Specific SEs associated with IL-6 and JAK inhibitors include:

• Hyperlipidemia
• Deranged liver function tests
• Pancytopenia

Other miscellaneous SEs associated with particular Biologic DMARDs

• Abatacept- worsening of COPD
• IL-17 inhibitors- cause or worsen inflammatory bowel disease
• Rituximab- progressive multifocal leukoencephalopathy

Drug monitoring 

In order to minimise the risk of the above adverse effects, DMARD therapy requires screening before initiation as well as monitoring during therapy.

Baseline assessment before initiating any DMARD should include height, weight, BP and blood tests (FBC, U&Es, LFTs). Any comorbidities should also be noted as this may influence DMARD choice- this should include screening for occult viral infections. Anti-Pneumococcal and Influenza vaccines are also advised.

Standard blood monitoring schedule when starting or adding a new DMARD

• Check FBC, U&Es, LFTs and albumin every 2 weeks until on stable dose for 6 weeks
• Once on a stable dose, check  FBC, U&Es, LFTs and albumin every month for 3 months
• After this, check  FBC, U&Es, LFTs and albumin at least every 12 weeks

In patients at higher risk of toxicity, blood monitoring should be more frequent. In addition, certain drugs require specific considerations:

• Methotrexate- all patients should be co-prescribed at least 5mg once weekly dose of folic acid supplementation.
• Azathioprine- measure a baseline thiopurine methyltransferase (TPMT)
• Hydroxychloroquine- baseline ophthalmic examination within 1 year of starting therapy

Table 1: Summary of standard blood monitoring schedule for common DMARDs. Adapted from: Ledingham J, Gullick N, Irving K, Gorodkin R, Aris M, Burke J et al. BSR and BHPR guideline for the prescription and monitoring of non-biologic disease-modifying anti-rheumatic drugs. Rheumatology. 2017;56(6):865-868.BSR and BHPR guideline for the prescription and monitoring of non-biologic disease-modifying anti-rheumatic drugs | Rheumatology | Oxford Academic (oup.com)

Other considerations when prescribing and monitoring DMARDs

Prescribing DMARDs in patients with co-morbidities requires some specific considerations. Caution is required, particularly in patients with pre-existing lung disease (particularly with drugs known to cause pneumonitis) and deranged liver function tests. In patients who have chronic viral hepatitis, anti-viral therapy should be initiated before commencing immunosuppressive DMARDs. In patients with chronic kidney disease, dose reduction and increased frequency of blood monitoring may be required.

In the perioperative period, DMARD therapy does not usually need to be stopped, but each case should be assessed on an individual basis. In the case of serious infections, many of the DMARDs, including methotrexate, leflunomide,  and sulfasalazine, should be paused while the patient recovers from the infection.

References

• Ledingham J, Gullick N, Irving K, Gorodkin R, Aris M, Burke J et al. BSR and BHPR guideline for the prescription and monitoring of non-biologic disease-modifying anti-rheumatic drugs. Rheumatology. 2017;56(6):865-868.
• Rheumatoid arthritis – NICE Pathways [Internet]. Pathways.nice.org.uk. 2021 [cited 10 November 2021]. Available from: https://pathways.nice.org.uk/pathways/rheumatoid-arthritis
• Allen A, Carville S, McKenna F. Diagnosis and management of rheumatoid arthritis in adults: summary of updated NICE guidance. BMJ. 2018;:k3015.
• Benjamin, O., Bansal, P., Goyal, A. and Lappin, S., 2021. Disease Modifying Anti-rheumatic Drugs (DMARD). [online] Ncbi.nlm.nih.gov. Available at: <https://www.ncbi.nlm.nih.gov/books/NBK507863/> [Accessed 3 November 2021].