SUMMARY

Rheumatoid arthritis is an inflammatory condition affecting synovial joints. Without treatment, the underlying inflammatory process leads to joint destruction, pain, deformity, disability and accelerated cardiovascular disease.

Disease-modifying antirheumatic drugs will attenuate the inflammation. Their benefits are seen at all stages of the disease, however the best outcomes are achieved when they are used shortly after the onset. Patients with suspected rheumatoid arthritis should be referred promptly.

Disease-modifying antirheumatic drugs are often used in combination and can have serious adverse effects. Their safe use requires ongoing monitoring to identify potential adverse events. >

The risk of infection is increased and vaccination is best given before starting disease-modifying antirheumatic drugs.

Introduction

Rheumatoid arthritis is a chronic autoimmune condition that classically presents as a symmetrical polyarthritis of proximal small synovial joints. It has a prevalence of 0.46% in the Australasian region, and affects women more frequently than men.1 The onset is usually between 35 and 60 years, however the majority of the disease burden in Australia is in people over 65 years.2

The cause of rheumatoid arthritis remains unknown, although our understanding of the pathological processes has advanced greatly in the last 20 years. Many pro-inflammatory cytokines are involved and some of these are therapeutic targets for the development of new drugs.3

Optimal management of rheumatoid arthritis requires an understanding of the therapeutic goals, the options available to attain them and the associated potential complications. Drugs are only one part of the management of the patient.  

The significance of inflammation

The cytokine milieu in rheumatoid arthritis influences a multitude of physiological processes. These include promoting the influx of immune effector cells into the joint synovium, and activation of osteoclasts, chondrocytes and fibroblasts.3 There is a positive feedback loop that reinforces the inflammatory process. Unabated, this process results in joint pain and destruction, ultimately causing deformity and disability.

Chronic inflammation also contributes to an increased risk of myocardial infarction, stroke and death. A Canadian population-based prospective cohort study reported an absolute increase in cardiovascular events of 5.7 per 1000 person-years (95% confidence interval 4.9–6.4) in patients with rheumatoid arthritis compared to those without.4 The use of disease-modifying antirheumatic drugs (DMARDs) to attenuate the inflammatory process has been shown to prevent joint erosions and reduce pain, cardiovascular morbidity and mortality.3,5

Nomenclature

The development of targeted monoclonal antibodies and small-molecule kinase inhibitors has widened the therapeutic options in rheumatoid arthritis. Each drug has a proven ability to modify the disease process to varying extents. However, the increase in drugs has thwarted our simple terminology of DMARDs, as the term no longer refers solely to synthetic chemical entities. A new nomenclature has been proposed6 and applied to the drugs registered in Australia for the treatment of rheumatoid arthritis (see Box).

A systematic review and meta-analysis found that corticosteroids reduce demonstrated radiographic erosions.7 While this effect defines corticosteroids as DMARDs, their toxicity profile makes routine long-term use undesirable. Other infrequently used DMARD therapies include azathioprine, ciclosporine and gold salts.

Box - Disease-modifying antirheumatic drugs

Synthetic DMARDs

Conventional

methotrexate

sulfasalazine

leflunomide

hydroxychloroquine

corticosteroids

Targeted

Janus kinase inhibitors
tofacitinib

Biologic DMARDs

Tumour necrosis factor antagonists

adalimumab

golimumab

certolizumab pegol

infliximab*

etanercept

IL-1 receptor antagonist

anakinra

IL-6 receptor antagonist

tocilizumab

Anti-CD20 monoclonal antibody

rituximab

CTLA-4-Ig fusion protein

abatacept

________________________________________________________________________________________

DMARDs    disease-modifying anti-rheumatic drugs

IL                  interleukin

CTLA            cytotoxic lymphocyte-associated antigen

*                    also available as a biosimilar

________________________________________________________________________________________

The importance of early treatment

Remission is unlikely to occur without intervention.8 Bone erosions are detectable in 25% of people within three months of onset9 and in 70% by three years.10 Delaying treatment beyond the three months causes more joint destruction and a higher chance of requiring persistent DMARDs to maintain remission.11 Early DMARD therapy during this ‘window of opportunity’ (that is within three months of onset) will more readily induce remission and delay progression.9

Methotrexate monotherapy

Methotrexate is the backbone of rheumatoid arthritis treatment. Monotherapy consistently reduces radiographic progression and improves quality of life.12 Approximately 40% of patients will respond to monotherapy.13 Limited comparative data suggest that other conventional DMARD monotherapies are as effective as methotrexate.14 However, its demonstrated long-term benefits, cost, acceptable safety profile and synergy with other DMARDs make methotrexate the recommended first choice for monotherapy in the guidelines of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR).15,16

Combination therapies

Combining DMARDs is frequently used as a first-line strategy, particularly for those with poor prognostic factors. A systematic review and network meta-analysis compared methotrexate monotherapy to methotrexate in combination with other DMARDs for patients with rheumatoid arthritis who were treatment-naïve or had an inadequate response to methotrexate alone.13 The combination of methotrexate with sulfasalazine and hydroxychloroquine, so called ‘triple therapy’, has greater efficacy than monotherapy in both early rheumatoid arthritis and non-responders, but higher toxicity.13 Combining methotrexate with biologic DMARDs has also demonstrated superior outcomes compared to methotrexate monotherapy in those with an inadequate response.13

The optimal combination of DMARDs and timing of combination therapy is debated. Unless methotrexate is poorly tolerated it should always be continued when starting other DMARDs.

Choosing the right treatment

The choice of treatment for a patient is influenced by the duration and severity of disease, previous treatments and regulatory restrictions. There are also patient-specific factors such as comorbidities, patient preference, family planning, and financial and social circumstances.

Pre-treatment evaluation

Before starting DMARDs, all patients should have baseline blood tests including full blood examination, serum creatinine and liver enzymes. Abnormalities may alter the choice of therapy and dosing (e.g. methotrexate is renally excreted). All patients should be screened for hepatitis B virus, hepatitis C virus and tuberculosis as there is a risk of reactivation of latent infections or worsening of active infection.

Other important considerations include congestive heart failure, malignancy, lymphoproliferative disease, multiple sclerosis, chronic obstructive pulmonary disease, bronchiectasis and interstitial lung disease. Further evaluation is required before treatment.

Pregnancy, contraception and lactation

The management of rheumatoid arthritis before, during and after pregnancy can be challenging. Although many women will have an improvement in disease activity during pregnancy, remission is rare.17 Poor pregnancy outcomes occur more commonly with high disease activity and include miscarriage, prematurity and pre-eclampsia.17 With the exception of sulfasalazine and hydroxychloroquine, all DMARDs are considered either unsafe or of uncertain safety during pregnancy.18 Counselling on effective methods of contraception is essential to prevent unplanned pregnancy while taking teratogenic drugs.17 Planned pregnancy is preferable and allows time for appr opriate treatment changes to be made while optimising disease control. Certain DMARDs (e.g. leflunomide, methotrexate) must be stopped at least 3–6 months before conception.18

During lactation the immunosuppressive effects of some DMARDs may affect the infant because of drug excretion into breast milk. Information on drugs and lactation can be found at United States National Institute of Health Lactmed or via local medicines information services.

Treating to target

The aim for every patient is to achieve a target of remission or low disease activity, as this leads to better outcomes.16 Disease activity is quantified by validated tools, such as the disease activity score based on a 28-joint count (DAS28), the clinical disease activity index (CDAI) and the simplified disease activity index (SDAI).16 A score is calculated from patient-reported pain and function, serum markers of inflammation (e.g. C-reactive protein or erythrocyte sedimentation rate) and physical joint examination. A score of moderate to high disease activity is an indication for more intense therapy with combination DMARDs until the target score (or lower) is achieved. While the optimal scores for defining low disease activity and remission continue to be refined, the treat-to-target approach is recommended by the ACR and EULAR guidelines.15,16 These provide a practical summary of evidence-based treatment algorithms, although they do not completely reflect the Australian regulatory restrictions. The Australian restrictions can be reviewed at Australian Government Department of Human Services.

Monitoring

Monitoring treatment with DMARDs is important to ensure their safe and effective use. The potential adverse effects of methotrexate include mouth ulcers, gastrointestinal discomfort, hepatotoxicity, myelosuppression, reversible alopecia and pneumonitis. The development of adverse drug reactions should prompt review for incorrect dosing, drug interactions or new renal impairment. Supplementation with folic acid can improve the gastrointestinal symptoms and reduce the risk of liver function abnormalities.19 Although an optimal folic acid regimen has not been identified, 5–10 mg orally once a week, preferably not on the same day as methotrexate, is generally recommended.

Details regarding adverse drug reactions and the monitoring of DMARDs can be found in the Table,20,21 or in previous Australian Prescriber articles.22-27 Patient medicine information handouts are also available from Australian Rheumatology Association.

Infection

Patients with rheumatoid arthritis have an increased incidence of infection compared to the general population, in particular those with higher disease severity, corticosteroid use and other comorbidities.28 Combination DMARD regimens, especially those that include a biologic drug, are associated with a markedly increased risk of serious infections.29 This risk is highest in the first six months of therapy.29 These infections are of concern, in particular reactivation of tuberculosis.30 The risk of reactivation of latent tuberculosis is high with DMARD use, particularly with biologic DMARDs and tofacitinib.15 Vigilance for infection is important, as its signs and symptoms may be atypical in immunosuppressed patients. In particular the febrile response may be blunted due to cytokine blockade. Patients should be advised to seek medical attention if they have localising symptoms of infection, an unexplained illness or a fever.

The management of minor infection requires ongoing clinical review until it resolves, with early consideration of antimicrobial therapy. Herpes zoster is more common in people taking tofacitinib and biologic drugs and may have multi-dermatomal presentations.31 Early antiviral treatment is required. The continuation of DMARDs with recurrent minor infections should be discussed with the treating rheumatologist.

Serious infections requiring hospitalisation or intravenous antibiotics usually lead to the discontinuation of most DMARDs, especially tumour necrosis factor antagonists. Long-term corticosteroids, if part of the current therapy, should be continued and possibly increased during infection due to the likelihood of adrenal suppression and the risk of an Addisonian crisis if they are stopped. Resumption of other DMARDs may be considered after recovery, but must be done with informed consent and close monitoring. Repeated infections, irrespective of severity, may also lead to DMARD discontinuation.

Disease flares

The definition of a ‘flare’ in rheumatoid arthritis poses a challenge, as patient and physician reports of flare do not always correlate with an increase in disease activity.32 Flares defined by increased disease activity are associated with increased pain, functional deterioration and radiographic progression.33 These flares often occur when the dose of DMARD is reduced.

Objective assessment of disease activity is essential to determine if treatment intensification is required. This should include a joint assessment, a patient- and physician-reported disease severity measure, and measures of inflammation such as C-reactive protein or erythrocyte sedimentation rate. Increases in disease activity should trigger an urgent review by a rheumatologist.

Pain may be managed with paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs). Opioid analgesia may cause adverse drug reactions without additional benefit and is best avoided.34

Glucocorticoids may be considered for disease flares. They are given either orally at low dose (e.g. prednisolone 10–15 mg daily), intramuscularly or intra-articularly. Intramuscular injections (e.g. methylprednisolone acetate) have the benefit of sustained activity without the inconvenience of daily oral dosing or a requirement for tapering the dose.

Table - Disease-modifying antirheumatic drugs and monitoring in rheumatoid arthritis

  

Drug

Adverse drug
reaction

Monitoring

Action

For all DMARDs

Myelosuppression
Hepatotoxicity

Routine unless otherwise specified:

FBE, EUC, LFTs at baseline, 2–4 weekly for 3–6 months and every 6–12 weeks thereafter. This regimen is influenced by comorbidities and changes to therapy.

Abnormalities in blood monitoring may lead to dose adjustments, treatment interruption or cessation.

Malignancy

Age-related cancer screening programs and self-reported symptoms

Infection

Self-reported fever (>38 °C), localising symptoms or unexplained illness. Fever may not always be present due to DMARD-induced alterations in cytokine profile. Maintain a high index of suspicion, particularly for reactivation of latent tuberculosis or hepatitis B infection.

Methotrexate

Alopecia

Self-reported hair loss

Usually reversible after stopping drug

Mouth ulcers

Self-reported mouth ulcers

Inspection of oral mucosa

Folic acid supplementation (not on day of methotrexate)

Pneumonitis

Symptoms of cough or dyspnoea

Routine respiratory examination

CXR, PFTs and urgent specialist review

Abnormal LFTs

Cirrhosis

LFTs as per routine for all DMARDs

Continue folic acid supplementation.

If AST or ALT <2 x ULN, repeat LFTs in a month. If normalising, continue. If persistent elevation, reduce dose.

If AST or ALT >2 x ULN, interrupt treatment and discuss with rheumatologist.

Sulfasalazine

Haemolytic anaemia

Symptoms of anaemia

Stop treatment and seek specialist advice.

Abnormal LFTs

LFTs as per routine for all DMARDs

If AST or ALT <2 x ULN, repeat LFTs in a month. If normalising, continue. If persistent elevation, reduce dose.

If AST or ALT >2 x ULN, interrupt treatment and discuss with rheumatologist.

Corticosteroids

Adrenal suppression (more likely with courses >3 weeks and prednisolone doses 7.5 mg)

No specific monitoring required

Do not stop abruptly. Consider increasing the dose during intercurrent acute illness.

Diabetes

Blood glucose and HbA1c monitoring 

If continued use is necessary, consider escalation of hypoglycaemic treatment.

Hypertension

Blood pressure checks each visit

If continued use is necessary, consider antihypertensive drugs.

Osteoporosis (when used at doses of prednisolone 7.5 mg for 3 months)

Bone mineral density assessment at baseline, repeat at 3 months

Self-reported skeletal pain suggesting fracture

If continued use is necessary, strongly consider starting a bisphosphonate.

Psychosis

Mania

Delirium

Depression

Insomnia

Vigilance for new or worsened mental health or sleep disturbance

 

Cease, or use the lowest possible dose. Seek specialist advice. Discuss with rheumatologist.

Hydroxychloroquine

Photosensitivity

Self-reported sensitivity

Sun protection strategies

Haemolytic anaemia

Symptoms of anaemia

Stop treatment and seek specialist advice.

Blue–grey skin discolouration

Self-reported skin discolouration and examination of sun-exposed sites

Stop treatment immediately and seek specialist advice.

Sun protection strategies

Corneal deposits

Retinal toxicity

Baseline ophthalmological assessment, then repeat at 5 years with annual review thereafter if therapy ongoing.20 Annual review is recommended from initiation of therapy in high-risk patients (age >70 years, macular disease, renal disease, liver disease, higher than recommended dose).20

Self-reported visual disturbance

Stop drug and seek specialist advice.

Leflunomide

Alopecia

Self-reported hair loss

Usually reversible. Reduce dose or stop drug.

Hypertension

Blood pressure assessment on each visit

Reduce dose and/or add antihypertensive.

Pneumonitis

Symptoms of cough or dyspnoea

Routine respiratory examination

CXR, PFTs and seek specialist review.

Peripheral neuropathy

Self-reported paraesthesia or weakness

Stop drug, consider NCS and EMG if not resolving, seek specialist advice.

Hepatotoxicity

LFTs every 2–4 weeks for 3 months, then every 3 months ongoing

If AST or ALT <2 x ULN, continue and repeat LFTs in a month.

If AST or ALT 2–3 x ULN, reduce dose and repeat LFTs in 2–4 weeks. Continue if normalising. If persistent elevation, discuss with rheumatologist.

If AST or ALT >3 x ULN, stop drug and repeat LFTs in 2–4 weeks. If elevated, discontinue, consider washout and discuss with rheumatologist.

Note: For any severe reactions to leflunomide consider cholestyramine washout (8 g 3 times a day for 11 days)

Tofacitinib

Abnormal LFTs

LFT frequency determined by other DMARDs used

If AST or ALT 1–2 x ULN, seek specialist advice.

If AST or ALT >2 x ULN, seek urgent advice.

Myelosuppression

FBE after 3–4 weeks, then every 3 months

Seek specialist advice, stop drug if severe.

Dyslipidaemia

Lipid profile 8 weeks after starting and then guided by results

Modify lifestyle and diet, consider lipid-lowering therapy.

Reactivated tuberculosis

Ideally detected pre-treatment, but may present during treatment as pulmonary or disseminated disease

Stop treatment immediately and seek specialist advice.

Herpes zoster

Patient-reported rash or pain

Start antiviral treatment within 72 hours of rash onset. If recurrent, discuss with rheumatologist.

Abatacept

COPD exacerbation

Symptoms of COPD exacerbation

Treat exacerbation and discuss with rheumatologist.

Hypertension

Blood pressure

Modify lifestyle, consider antihypertensive.

Injection site reactions

Visualisation of injection site

Rotation of injection sites, antihistamines, topical cold packs, topical corticosteroids

Anaphylaxis

See Australian Prescriber wallchart21

Rituximab

Infusion reactions

Stop or slow the rate of infusion, treat symptoms.

Anaphylaxis

See Australian Prescriber wallchart21

Myelosuppression

FBE before each treatment

If severe, delay treatment.

Anakinra

Myelosuppression (especially neutropaenia)

FBE frequency determined by other DMARDs used. Neutropaenia may be delayed and prolonged.

Discontinue and discuss with rheumatologist.

Injection site reactions

Visualisation of injection sites

Rotation of injection sites, antihistamines, topical cold packs, topical corticosteroids

Infection

As per routine monitoring for all DMARDs

Arrange follow-up visit, consider antimicrobial, remain vigilant for deterioration and the need for hospitalisation, stop if serious infection.

Anaphylaxis

See Australian Prescriber wallchart21

TNF inhibitors

Injection site reactions

Visualisation of injection sites

Rotation of injection sites, antihistamines, topical cold packs, topical corticosteroids

Drug-induced lupus

Self-reported rash, fever or arthralgia

Assess urine for evidence of glomerulonephritis. Assess serum lupus antibody profile and complement levels. Seek urgent advice from rheumatologist.

Demyelinating syndrome

Self-reported neurological symptoms

Consider MRI, seek specialist advice.

Malignancy

Participation in age-appropriate screening programs

Stop treatment immediately and seek specialist advice.

Infection

As per routine monitoring for all DMARDs

Arrange follow-up visit, consider antimicrobial, remain vigilant for deterioration and the need for hospitalisation, stop if serious infection.

Reactivated tuberculosis

Ideally detected pre-treatment, but may present during as pulmonary or disseminated disease without fever

Stop treatment immediately and seek specialist advice.

Herpes zoster

Self-reported rash or pain

Start antiviral treatment within 72 hours of rash onset. If recurrent, discuss with rheumatologist.

Tocilizumab

Hypertension

Blood pressure checks each visit

Modify lifestyle modification, consider antihypertensive.

Myelosuppression

FBE at baseline, then every 4–8 weeks

Interrupt treatment and discuss with rheumatologist.

Dyslipidaemia

Lipid profile at baseline. Repeat after 4–8 weeks of treatment, then as per relevant guidelines

Modify lifestyle modification, consider lipid-lowering therapy.

Gastrointestinal perforation

Self-reported abdominal pain

Stop therapy and discuss with rheumatologist.

Infection

As per routine monitoring for all DMARDs

Note: CRP is an unreliable marker for infection during tocilizumab therapy due to IL-6 blockade

Minor infection – interrupt treatment until recovered.

Serious infection – stop treatment.

Abnormal LFTs

LFTs at baseline and every 4–8 weeks for 6 months, then every 3 months

If AST or ALT >1–3 x ULN, reduce dose, or stop until normal.

If AST or ALT >3 x ULN, stop until >1–3 x ULN then reduce dose.

If AST or ALT >5 x ULN, discontinue treatment.

ALT

alanine aminotransferase

EMG

electromyography

MRI

magnetic resonance
imaging

AST

aspartate aminotransferase

EUC

electrolytes, urea, creatinine

NCS

nerve conduction study

COPD

chronic obstructive pulmonary disease

FBE

full blood examination

PFTs

pulmonary function tests

CRP

C-reactive protein

HbA1c

glycated haemoglobin

TNF

tumour necrosis factor

CXR

chest x-ray

IL-6

Interleukin-6

ULN

upper limit of normal

DMARDS

disease-modifying antirheumatic drugs

LFTs

liver function tests

-

 

Vaccination

When indicated, vaccination for pneumococcus, influenza, hepatitis A and B and human papillomavirus is recommended irrespective of DMARD choice.15 Live vaccines should be avoided in people taking DMARDs, although varicella zoster may be considered in those who are not on biologic DMARDs.15 Vaccines may be given any time during therapy, however the best time is before treatment as DMARDs may attenuate the immune response. We recommend consulting the Australian Immunisation Handbook for further details.35

Complementary medicines

Despite widespread use of complementary medicines there remains a lack of evidence of their benefit. No complementary medicines have demonstrated disease-modifying effects. Meta-analyses of the published data suggest that omega-3 polyunsaturated fatty acids are effective at improving pain and reducing NSAID use. The optimal dose is yet to be determined (reported range 1.7–9.6 g daily).36 Evening primrose oil, borage seed oil, Tripterygium wilfordii Hook F (thunder god vine) and blackcurrant seed oil may improve some symptoms of rheumatoid arthritis.36,37 Adverse effects have been reported, making the harm–benefit profile unfavourable.37

The advent of biosimilars

A biosimilar is a biologic drug that is similar, but not identical, to a registered original biologic drug. The differences may theoretically result in altered efficacy and increased immunogenicity, therefore strict regulation is essential. The Australian Therapeutic Goods Administration requires multiple criteria to be fulfilled before a biosimilar can be registered.38 Considering the current expense of biologic drugs for rheumatoid arthritis in Australia, a cheaper and effective biosimilar is an attractive option. Even if it is deemed to be equivalent to the original product, the safety and efficacy of switching between products is uncertain.

Conclusion

The advances in rheumatoid arthritis therapy over the last 20 years have markedly changed the way the disease is managed and have improved outcomes. Understanding the therapeutic goals and the options available to achieve them, pre-treatment evaluation, and the ongoing monitoring for complications of the disease and its treatment, will ensure the best outcomes for patients. Further advances in biotechnology are likely to lead to even more changes in the therapeutic landscape of rheumatoid arthritis.

Tom Wilsdon attended Editorial Executive Committee meetings as the clinical pharmacology registrar for Australian Prescriber in 2016. He is a member of the South Australian Formulary Committee.

Catherine Hill is currently the Honorary Secretary of the Australian Rheumatology Association, Chair of the South Australian Medicines Evaluation Panel, member of the South Australian Medicines Advisory Committee, member of the Drug Utilisation Subcommittee of the Pharmaceutical Benefits Advisory Committee, and previous member of the Australian Committee for Prescription Medicine for the Therapeutic Goods Administration. She has been the principal local investigator for drug trials with GSK, Servier, Axsome and Merck, and has been involved in drug trials by UCB, Roche and Abbvie. Catherine has received airfares and accommodation costs from Abbvie and Bristol-Myers Squibb to attend meetings internationally and interstate.

Acknowledgements: The authors would like to thank Bethan Richards for reviewing the manuscript and her advice on important monitoring issues and adverse drug reactions.

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