Diagnosis and management of rheumatoid arthritis
Early recognition and treatment of rheumatoid arthritis is the key to a more successful outcome. This article discusses the diagnosis of rheumatoid arthritis and its recommended management.
Of the millions of people in the UK suffering from musculoskeletal problems, up to one million have a rheumatic condition, including approximately 690,000 adults with rheumatoid arthritis.1 Rheumatoid arthritis is the most common autoimmune inflammatory arthritis in adults.2 Women are two to three times more likely to be diagnosed with rheumatoid arthritis,1 and around three-quarters of patients were first diagnosed at working age.3 The cause of rheumatoid arthritis is not known.
Susceptible patient groups:
• Female > male
• Anti-cyclic citrullinated peptide (anti-CCP)/rheumatoid factor (RF) positivity5
• Peak age 50–75 years.
In recent years, the importance of early recognition of symptoms and diagnosis has emerged. NICE recommends referral of any person with persistent synovitis with an unknown cause to a rheumatologist. Refer urgently (within two weeks), if any of the following applies:
• Small joints of the hands (see Figure 1) or feet are affected; more than one joint is affected.
• There has been a delay of three months or longer between the onset of symptoms and the person seeking medical advice.6
Figure 1. Refer a patient to rheumatology urgently (within two weeks) if the small joints of the hands (or feet) are affected
A national clinical audit of early inflammatory arthritis (EIA) is being carried out by the British Society of Rheumatology (BSR) over three years. All NHS hospitals in England and Wales that provide speciality rheumatology services have been included. NICE’s rheumatoid arthritis quality standard (QS33) statement 2 says that patients with suspected persistent synovitis should be assessed in a rheumatology service within three weeks of referral.
Early results from the audit suggest that there are frequent delays in referral and rheumatology services are struggling to see patients within three weeks of referral.7 The findings from year one suggested a large variance between areas and trusts in reaching this standard. Only 17% of patients were referred within the three days of first presentation and only 38% of patients were seen within three weeks of referral. There are also many local differences in referral criteria to EIA/rheumatology services.
American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) developed classification criteria in 2010, which can help a physician-made diagnosis. The criteria attribute points based on the number of tender or swollen joints. There has to be at least one joint with clinical synovitis. Laboratory tests are included: RF, anti-CCP antibody and acute phase reactants. However, antibody positivity and elevated acute phase reactants are not essential to make the diagnosis. A total score of more than 6 points is considered definite rheumatoid arthritis. For patients with long-standing disease, they can be classified as having rheumatoid arthritis if they previously fulfilled the diagnostic criteria (see Table 1).8
Table 1. American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 rheumatoid arthritis classification criteria8
Early recognition of symptoms and diagnosis is key to a more successful patient outcome. Early review allows faster initiation of treatment and suppression of inflammation.9 Studies have clearly demonstrated that response to DMARD therapy is related to duration of symptoms prior to diagnosis.10
The diagnosis of rheumatoid arthritis can be made with normal autoantibodies/inflammatory markers. Primary care physicians should not wait for investigation results prior to referral if rheumatoid arthritis is suspected. Early referral to a specialist rheumatology clinic has been associated with better results.7 The management of rheumatoid arthritis is summarised in Figure 2.
(click image for full-size)
Figure 2. Summary of the management of rheumatoid arthritis
When patients present with joint symptoms suggestive of inflammatory arthritis, initial treatment by primary care should focus on analgesia. This can include paracetamol, codeine or compound analgesics. Standard NSAIDs or selective COX-2 inhibitors are also options in primary care. Corticosteroids should only be initiated in secondary care after review.6
The management of rheumatoid arthritis involves a multidisciplinary approach through a rheumatology clinic (occupational therapy, physiotherapy, psychology and patient support) along with patient education.
The following professionals may be involved in the care of patients with rheumatoid arthritis as part of the multidisciplinary team:
• Occupational therapist – Help with everyday activities; splints, wrist supports, pacing advice
• Physiotherapist – Specific muscle/joint functioning, eccentric concentric exercise programmes
• GP – Assessment and management of co-morbidities including cardiovascular risk and consideration of bone health
• Podiatrist – Foot care, appropriate footwear
• Rheumatology nurse specialist – Practical advice and support
• Orthopaedic surgeon – Joint replacement surgery.
Various nonpharmacological approaches to treating rheumatoid arthritis exist, the aim being to complement drug-based therapies. These include the following:
• Weight loss
• Management of co-morbidities (eg cardiovascular risk, glycaemic control)
• Smoking cessation.
Corticosteroids are often used acutely when the diagnosis of rheumatoid arthritis has been made. Systemic steroids are often utilised (oral prednisolone, intramuscular or intravenous methylprednisolone). Intra-articular steroids can be used for particularly swollen or painful joints. Steroids have powerful anti-inflammatory effects by regulating gene transcription and stimulating the synthesis of lipocortin.11 They are usually offered in the short term when patients first present.
The side-effects of corticosteroids are well documented and include, but are not limited to:
• Weight gain
• Impaired glycaemic control
• Mood disturbances (including mania, depression and psychosis)
• Disruption of circadian rhythm
• Increased appetite.
Long-term effects of corticosteroids include the development of Cushing’s syndrome, diabetes, gastric ulcer, osteoporosis and cataracts/glaucoma.12 These long-term effects are often related to cumulative dose received and high-dose therapy.
Disease-modifying antirheumatic drugs
The first-line treatment for patients newly diagnosed with rheumatoid arthritis includes a conventional disease-modifying antirheumatic drug (DMARD) or a combination of DMARDs (one of which should be methotrexate) plus corticosteroids.6 Ideally treatment should be initiated within three months of symptom onset.
NICE now recommends that patients with newly diagnosed rheumatoid arthritis should be offered a combination of DMARDs (if appropriate), one of which should be methotrexate. If combination therapy is not an option then an emphasis needs to be placed on rapid dose escalation.
Methotrexate is a structural analogue of folic acid that competitively inhibits the binding of dihydrofolic acid to the enzyme dihydrofolate reductase.13 Its mechanism of action is likely to involve T cell suppression via its effects on purine and pyrimidine metabolism; however, the mechanism is not fully understood.14
Methotrexate is available as an oral or subcutaneous preparation. It is a once-weekly medication. The usual dosage range is 7.5mg–25mg weekly.15 There is variable oral absorption and it is excreted renally. Methotrexate usage is contraindicated if the patient’s estimated glomerular filtration rate (eGFR) is lower than 30ml/min. Higher oral doses may have decreased bioavailability.14
Side-effects of methotrexate include:
• Gastrointestinal effects (eg nausea, loose stools)
• Abnormal liver chemistry, typically mild elevations in hepatic transaminases
• Rash, often on extremities
• Central nervous system symptoms (eg headache, fatigue, malaise, reduced concentration)
• Fever (either directly drug-related or due to infection)
• Haematologic abnormalities, particularly macrocytosis, in addition to infrequent but severe myelosuppression.14
Adverse effects of methotrexate include:
• Respiratory effects – methotrexate-associated lung injury, eg pulmonary toxicity, lung fibrosis, pneumonitis
• Liver effects – hepatocellular toxicity, liver fibrosis
• Bone marrow effects – agranulocytosis, bone marrow suppression.
Folic acid is co-prescribed with methotrexate to reduce the side-effects associated with its use. It also prevents myelosuppression. It is thought to reduce circulating homocysteine levels.
Regular laboratory monitoring is needed for methotrexate (frequency may differ by local guidelines). The BSR recommends checking full blood count (FBC), urea and electrolytes, and liver function tests (LFTs) every two weeks until dose and monitoring are stable over the first six weeks; thereafter the frequency is monthly. This is because of the effects of methotrexate on liver and bone marrow. Elevated transaminases and raised mean corpuscular volume (MCV) are frequent abnormalities found on testing. Alcohol intake should be limited in patients taking methotrexate and at the very most should be within the patient’s weekly allowance.
Women of childbearing age need to be counselled on the need for adequate contraception due to the risk of teratogenicity with methotrexate. Chest X-ray at baseline is also generally recommended.
Methotrexate drug interactions include:
• Acitretin – raises concentration of methotrexate; risk of hepatotoxicity.
• Ciclosporin – risk of toxicity.
• Trimethoprim/sulfamethoxazole – risk of severe bone marrow depression and haematological toxicity.
Prescribers should refer to the BNF for a full list of methotrexate interactions.16
Hydroxychloroquine is generally considered a safe and well-tolerated DMARD, but is rarely used as monotherapy except in very mild disease. It is frequently used in combination with other DMARDs. The main side-effects include nausea, rash and headaches. The recommended dosage is 200–400mg daily. Dosing should be based on weight and the Royal College of Ophthalmologists recommends that the dosage does not exceed 6.5mg/kg daily. This is because of the rare but potentially serious complication of retinal toxicity. Early signs may be a paracentral scotoma affecting acuity and sometimes colour vision. Bull’s eye maculopathy may be noted on examination. It is recommended that patients have eye testing (reading test performance of each eye with reading spectacle correction if worn) at baseline and annually while on hydroxychloroquine.17 If a visual impairment is suspected then review by an optometrist is indicated and if warranted, onward referral to ophthalmology.
This DMARD is frequently used when patients are intolerant to methotrexate or if methotrexate is contraindicated. Leflunomide is absorbed via the gastrointestinal tract, and converted to active metabolite teriflunomide. Its mode of action is through inhibition of pyrimidine synthesis. It has a half-life of around 15 days.18 Elimination is via the gastrointestinal tract and kidneys. Teriflunomide goes through extensive enterohepatic recirculation. Similar to methotrexate, laboratory parameters should be monitored: monthly FBC, and LFT for the first six months and bimonthly after that.
Adverse effects of leflunomide include hypertension. Patients should have their blood pressure assessed and treated, if necessary, prior to initiation of treatment. Concurrent NSAID use may exacerbate this phenomenon.18 Frequent blood pressure monitoring is often advised. Other adverse effects of leflunomide include nausea, diarrhoea and rash. Hepatotoxicity can also be a serious complication of therapy.
Due to its long half-life, in the case of life-threatening complications, a washout with cholestyramine (8g three times daily for 11 days) or activated charcoal should be considered.19
Sulfasalazine is a prodrug that combines a salicylate and a sulfa antibiotic. Approximately 90% of the drug reaches the gut where it is cleaved to form sulfapyridine and 5-aminosalicylic acid (5-ASA). The mechanism of action is not fully understood.20 Sulfasalazine can cause GI upset, rash and yellow-orange discolouration of body fluids. It can lower sperm motility in men (which is reversible with drug cessation). It is considered safe in pregnancy; the BSR recommends 5mg folic acid daily for women on sulfasalazine who are trying to conceive.
As monotherapy, there is debate as to whether sulfasalazine can prevent joint erosions. However, there have been numerous trials where it has been used as part of a DMARD combination, which have shown benefit.20
It is recommended that patients taking sulfasalazine have fortnightly blood tests for the first three months, monthly for the next three months, three monthly thereafter or as clinically indicated.
Azathioprine is a derivative of thioguanine, a purine-mimic antimetabolite. Its active metabolite is 6-mercaptopurine. It is no longer considered a first-line agent in the management of rheumatoid arthritis and would mostly be used in exceptional circumstances. Azathioprine should be used with caution in patients with thiopurine methyltransferase (TPMT) deficiency (heterozygous state) as this can be associated with bone marrow depression. In general, TPMT levels are measured prior to initiation of azathioprine and, based on the results, treatment may either not be initiated or the dosage adjusted accordingly.15
For a full list of interactions, refer to the BNF. Notable interactions include allopurinol, febuxostat, co-trimoxazole and trimethoprim (which is associated with life-threatening bone marrow suppression).
Combination DMARD therapy
NICE recommends combination DMARD therapy for newly diagnosed rheumatoid arthritis (with one of the drugs being methotrexate). Where combination DMARDs are not suitable, rapid uptitration of monotherapy should be considered.10
Disease control is generally assessed using the Disease Activity Score (DAS28; see Table 2), which is a composite score that includes clinician-assessed tender and swollen joints, a visual analogue scale (VAS) and measurement of either erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) (both blood markers of inflammation). Treatment is titrated as per the DAS28 score. It is an important assessment tool for monitoring disease activity and should be used to determine whether an increase (including qualification for biological medications) or decrease of treatment is indicated.6
Table 2. The Disease Activity Score (DAS28) for the assessment of rheumatoid arthritis disease activity
NICE recommends adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept, all in combination with methotrexate, as options for treating rheumatoid arthritis, only if:
• Disease is severe, that is, a disease activity score (DAS28) greater than 5.1 and
• Disease has not responded to intensive therapy with a combination of conventional DMARDs.
Adalimumab, etanercept, certolizumab pegol or tocilizumab can be used as monotherapy for people who cannot take methotrexate because of a contraindication or intolerance, and when the criteria listed above are also met (TA375).21
NICE adds that treatment should only be continued if there is a moderate response, measured using EULAR criteria, at six months after starting therapy, and treatment should be withdrawn if a moderate EULAR response is not maintained.
Adalimumab is a fully humanised immunoglobulin (Ig) G1 monoclonal antibody that inhibits tumour necrosis factor (TNF) alpha. Adalimumab is administered every two weeks by subcutaneous injection.22
Etanercept is a recombinant fusion protein that consists of the soluble tumour necrosis factor (TNF) receptor (p75) linked to the Fc portion of human IgG1 (TNFR:Fc). Etanercept is administered subcutaneously, at either 50mg once weekly or 25mg biweekly.22
Golimumab is a human IgG1 kappa monoclonal antibody specific for human TNF alpha that neutralises TNF alpha activity.22
Certolizumab pegol is a human anti-TNF alpha antibody Fab fragment that is chemically linked to polyethylene glycol. The medication neutralises membrane-associated and soluble TNF alpha. Certolizumab pegol is administered every two weeks by subcutaneous injection, and dosing at four-week intervals can be effective in some patients for maintenance therapy.22
Infliximab is a chimeric monoclonal antibody directed against TNF. Infliximab is administered via intravenous infusion approximately every six weeks once a steady state has been achieved.22
Other biological agents
Abatacept is a T cell activation inhibitor. It is soluble fusion protein comprising cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and the Fc portion of IgG1 (CTLA4-Ig). Abatacept can be administered either by weekly subcutaneous injection or by monthly intravenous infusion following several loading doses.22
Tocilizumab is a humanised antihuman IL-6 receptor antibody of the IgG1 subclass. IL-6 is important for CRP production, therefore patients on tocilizumab may have a normal CRP in presence of infection or inflammation. In a study of postoperative patients taking tocilizumab, CRP and febrile response was blunted.23 The use of tocilizumab in patients with moderate to severe rheumatoid arthritis is associated with an increase in serum total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides. Neutropenia and deranged LFTs commonly occur in patients on tocilizumab. Tocilizumab can be given intravenously or as a subcutaneous preparation. It may be used as a monotherapy for patients intolerant of, or with a contraindication to, methotrexate.23
Rituximab is a B cell-depleting monoclonal anti-CD20 antibody. Rituximab has NICE approval for use in severe active rheumatoid arthritis in patients who have had an inadequate response to, or who are intolerant of, other DMARDS, including at least one TNF inhibitor (TA195).24 Treatment should be given no more frequently than every six months and should be continued only if there is an adequate response to therapy. Patients with seropositivity, ie RF positive25 and/or anti-CCP positive, are more likely to respond to rituximab. It is given intravenously, as a course of two infusions two weeks apart, no more frequently than every six months.
Patients on TNF inhibitors and other biological therapy are at risk of life-threatening infections. Consequently, infections should be treated early and aggressively. As patients are immunocompromised, they may not present with infection in a typical fashion.
According to NHS England, a “biosimilar medicine is a biological medicine that is developed to be highly similar and clinically equivalent to an existing biological medicine. A biosimilar contains a version of an active substance of an already approved biological medicine, which is referred to as the ‘reference medicine’ or ‘originator medicine’.” Biosimilar medicines should be of similar quality and effectiveness to the originator drug. However, the advent of biosimilars means that biological medicines should be prescribed and dispensed by brand name.
Within rheumatology services, we aim to reduce joint damage and symptoms through aggressive treat-to-target strategies. The number of medications for the treatment of rheumatoid arthritis is rapidly increasing with new targets in the immune system. The advent of biosimilars has increased competition and will likely reduce the costs of biological medication. Patients who delay seeking medical help and who experience delayed referral to rheumatology services remain among the biggest challenges to early and effective treatment.
1. National Rheumatoid Arthritis Society. Breaking down barriers: Rheumatoid arthritis and public awareness. June 2013. Available from: http://www.nras.org.uk/data/files/Publications/Breaking%20Down%20Barriers.pdf
2. Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum 2008;58:15–25.
3. National Audit Office. Services for people with rheumatoid arthritis. July 2009. Available from: https://www.nao.org.uk/wp-content/uploads/2009/07/0809823.pdf
4. Karlson EW, et al. A retrospective cohort study of cigarette smoking and risk of rheumatoid arthritis in female health professionals Arthritis Rheum 1999;42(5):910–7.
5. Aho K, et al. Rheumatoid factors antedating clinical rheumatoid arthritis. J Rheumatol 1991;18(9):1282–4.
6. National Institute for Health and Care Excellence. Rheumatoid arthritis in adults: management. CG79. February 2009, updated December 2015. Available from: https://www.nice.org.uk/guidance/cg79
7. British Society for Rheumatology. A patient and public guide to the National Clinical Audit for Rheumatoid and Early Inflammatory Arthritis. 1st Annual Report 2015. Jan 2016. Available from: http://www.hqip.org.uk/resources/a-patient-and-public-guide-to-the-national-clinical-audit-for-rheumatoid-and-early-inflammatory-arthritis/
8. Aletaha D, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62(9):2569–81.
9. Devlin J, et al. The acute phase and function in early rheumatoid arthritis. C-reactive protein levels correlate with functional outcome. J Rheumatol 1997;24:9–13.
10. Anderson JJ, et al. Factors predicting response to treatment in rheumatoid arthritis. The importance of disease duration. Arthritis Rheum 2000;43:22–9.
11. Schäcke H, et al. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 2002;96(1):23–43.
12. Saag KG, et al. Major side effects of systemic glucocorticoids. UpToDate. February 2016. Available from: https://www.uptodate.com/contents/major-side-effects-of-systemic-glucocorticoids
13. Kremer JM, et al. Use of methotrexate in the treatment of rheumatoid arthritis. UpToDate. June 2016. Available from: https://www.uptodate.com/contents/use-of-methotrexate-in-the-treatment-of-rheumatoid-arthritis
14. Cronstein BN. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev 2005;57(2):163–72.
15. Chakravarty K, et al; British Society for Rheumatology, British Health Professionals in Rheumatology Standards, Guidelines and Audit Working Group; British Association of Dermatologists. BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. Rheumatology 2008;47(6):924–5.
16. British Medical Association, Royal Pharmaceutical Society. BNF 73. March–September 2017. Appendix 1. Methotrexate interactions.
17. Royal College of Ophthalmologists. Hydroxychloroquine and ocular toxicity. Recommendations on screening. October 2009. Available from: https://www.rcophth.ac.uk/wp-content/uploads/2014/12/2009-SCI-010-Ocular-Toxicity.pdf
18. Fox R, et al. Leflunomide in the treatment of rheumatoid arthritis. UpToDate. April 2015. http://www.uptodate.com/contents/leflunomide-in-the-treatment-of-rheumatoid-arthritis
19. British Medical Association, Royal Pharmaceutical Society. BNF 73. March–September 2017. Chapter 10. Disease-modifying Anti-rheumatic drugs – leflunomide.
20. Weisman M, Rinaldi R. Sulfasalazine in treatment of rheumatoid arthritis. UpToDate. September 2016. Available from: http://www.uptodate.com/contents/sulfasalazine-in-the-treatment-of-rheumatoid-arthritis
21. National Institute for Health and Care Excellence. Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the treatment of rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed. TA375. January 2016. Available from: https://www.nice.org.uk/guidance/ta375
22. Furst DE, et al. Overview of biologic agents and kinase inhibitors in the rheumatic diseases. UpToDate. February 2017. Available from: https://www.uptodate.com/contents/overview-of-biologic-agents-and-kinase-inhibitors-in-the-rheumatic-diseases
23. Malaviya AP, et al. The 2013 BSR and BHPR guideline for the use of intravenous tocilizumab in the treatment of adult patients with rheumatoid arthritis. Rheumatology 2014;53(7):1344–6.
24. National Institute for Health and Clinical Excellence. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. TA195. August 2010. Available from: https://www.nice.org.uk/guidance/ta195
25. Solau-Gervais E, et al. Efficacy of rituximab in the treatment of rheumatoid arthritis. Influence of serologic status, coprescription of methotrexate and prior TNF-alpha inhibitors exposure. Joint Bone Spine 2012;79(3):281–4.
Declaration of interests
None to declare.
Dr Tracey is a speciality registrar in rheumatology at Weston General Hospital, Weston-super-Mare