GUIDELINES ■

Prescribing and monitoring non-biological DMARDs

STEVE CHAPLIN

The British Society for • The decision to initiate a DMARD should be made with the patient/carer and be Rheumatology and British supervised by an expert in the management of rheumatic diseases Health Professionals • Patients should be provided with education about their treatment to promote in Rheumatology self-management • When appropriate, patients should be advised about the impact of DMARD (BSR/BHPR) recently therapy upon fertility, pregnancy and breastfeeding updated their guidance • Baseline assessment should include height, weight, blood pressure and on prescribing and laboratory evaluation (full blood count, calculated glomerular filtration rate, monitoring non-biological alanine aminotransferase and/or aspartate aminotransferase, albumin) • Patients should be assessed for co-morbidities as these may influence disease-modifying DMARD choice, including evaluation for respiratory disease and screening for antirheumatic drugs occult viral infection (DMARDs) for patients • Vaccinations against pneumococcus and influenza are recommended with rheumatic disease. Table 1. Recommended measures before prescribing any DMARD1

This article provides an shared care guidelines. It is intended for overview of the main all healthcare professionals involved in recommendations of the the care of patients with rheumatic dis- new guideline. ease in primary and secondary care; it is also for patients (the authors included a patient representative), though they will hen medicines are introduced, probably find the executive summary2 Wthey tend to draw the focus of more accessible than the full guideline scientific and clinical attention away summarising the evidence base. from the old and familiar to what is The guideline covers 12 agents: new and exciting. Biological disease- apremilast, , ciclosporin, modifying antirheumatic drugs (DMARDs) , , mepa- are a case in point and the spotlight crine, , minocycline, has recently spared the older non- mycophenolate mofetil, sodium aurothio­ biological DMARDs. This has now been malate (), and tac- rectified with the publication of a new evi- rolimus. It does not consider their dence-based guideline from the British indications or drug interactions, nor does Society for Rheumatology and British it cover biological DMARDs, new non-bio- Health Professionals in Rheumatology logical DMARDs such as the janus kinase (BSR/BHPR) on the use of non-biological (JAK) inhibitors, treatment in the under- DMARDs in rheumatic disease.1 16s, or prescribing for women who are pregnant or breastfeeding (most of which Overview is covered in separate guidelines). The guideline, an update to the BSR/ BHPR 2008 document, describes Pretreatment and initiating measures to ensure safe prescribing DMARDs of non-biological DMARDs in adults Some measures are recommended (>16 years old), covering pretreatment before prescribing any DMARD (see screening, the impact of co-morbidities, Table 1). Although the guideline pro- monitoring for toxicity, treatment dur- vides supporting evidence, several ing intercurrent illness or surgery, and need no justification (eg the value of prescriber.co.uk Prescriber February 2018 ❚ 29 ■ GUIDELINES l Non-biological DMARDs

specialist supervision) and others are cialist. Current smokers should be A low level of immunosuppression (eg recommended in NICE guidance. The offered smoking cessation services. standard-dose DMARDs, prednisolone co-morbidities most relevant to prescrib- Patients should be screened for up to 20mg daily) is not considered an ing a DMARD are cardiovascular, liver hepatitis B and C and for HIV infection. absolute contraindication to vaccination and kidney disorders. DMARDs can reactivate hepatitis B (lit- but clinician discretion is advised. People Taking a history of respiratory tle is known about their impact on hep- with rheumatic diseases are at increased symptoms and respiratory examination atitis C) and may increase the risk of risk of shingles but there is no recom- is recommended for all patients. The infection for people living with HIV. mendation to offer the vaccine below the extent of screening for lung disease People with rheumatic disease who usual age threshold of 69 years. should be determined by the patient’s are taking a DMARD are included in the There are also specific measures to characteristics not the DMARD most group of under-65s considered at risk take before prescribing some DMARDs. likely to be prescribed. People with and who should receive vaccination. All patients to be treated with methotrex- have a lifetime risk This is the responsibility of primary care ate should take folic acid 5mg weekly of interstitial lung disease of 10% and but uptake among people with rheu- (taken on a different day from metho- the risk is greater in other connective matic disease is low. Ideally, pneumo- trexate); methyltransferase tissue disorders. Furthermore, smok- coccal vaccine should be administered status should be assessed before pre- ing is a shared risk factor for lung dis- before starting a DMARD; individuals scribing azathioprine (0.3% of people ease and rheumatoid arthritis. Patients who are severely immunocompromised have low activity and cannot metabolise in whom parenchymal lung disease is require a different schedule (as set out azathioprine); and a formal ophthalmic suspected should undergo lung func- in The Green Book2). examination including objective retinal tion testing and appropriate imaging Live vaccines are normally avoided assessment (not simple visual acuity (chest radiograph with or without high- in immunocompromised individuals tests) should be carried out within one resolution CT imaging) and be consid- and this includes those travelling to year of starting treatment with hydroxy- ered for referral to a respiratory spe- areas where yellow fever is prevalent. .

Drug Accumulates in Nephrotoxic GFR category* renal failure G3 (30–59) G4 (15–29) G5 (<15)

Recommended adjustment (% standard dose)

Apremilast yes no 50

Azathioprine no no normal dose 75–100 50–100

Ciclosporin no yes normal dose

Sodium yes no no data avoid aurothiomalate

Hydroxychloroquine yes no 75 25–50 25

Leflunomide no no normal dose use with caution

Methotrexate yes yes 50 contraindicated

Minocycline yes no use with caution contraindicated

Mycophenolate yes no normal dose max 1g twice daily mofetil

Sulfasalazine not stated in SPC no normal dose use with caution

Tacrolimus no yes use with caution contraindicated

* Calculated glomerular filtration rate (GFR) in ml/min/1.73m2. See NICE guideline CG182 for new GFR categories of chronic kidney disease.3 NB. Categories G1–G5 have the same GFR thresholds as the old chronic kidney disease stages I to V

Table 2. Recommended dose adjustment for DMARDs in chronic kidney disease, according to the summaries of product characteristics1

30 ❚ Prescriber February 2018 prescriber.co.uk Non-biological DMARDs l GUIDELINES ■

Co-morbidities Check FBC, creatinine/calculated GFR, ALT and/or AST and albumin every: Co-morbidities are generally not an • Two weeks until on stable dose for six weeks absolute contraindication to DMARD • Then, once on stable dose, monthly FBC, creatinine/calculated GFR, ALT and/or treatment but there is a need for cau- AST and albumin for three months tion. Drugs associated with pneumonitis • Thereafter, FBC, creatinine/calculated GFR, ALT and/or AST and albumin at least (most DMARDs are, though the risk with every 12 weeks methotrexate has been overestimated) • More frequent monitoring is appropriate in patients at higher risk of toxicity should be used with care in patients • Dose increases should be monitored by FBC, creatinine/calculated GFR, ALT with poor respiratory reserve. The under- and/or AST and albumin: lying cause of abnormal liver biochemis- – every two weeks until on stable dose for six weeks try should be sought and treated before – then revert back to previous schedule prescribing a DMARD. If viral hepatitis is evident, a DMARD with low immuno- FBC = full blood count; GFR = glomerular filtration rate; ALT = alanine suppression risk such as hydroxychloro- aminotransferase; AST = aspartate aminotransferase quine or sulfasalazine may be preferred. Table 3. Standard schedule for blood monitoring when starting DMARD treatment (see text Extreme caution is advised in patients for exceptions)1 with impaired liver synthetic function (eg cirrhosis), who are at greater risk of tox- sodium aurothiomalate, leflunomide may be greater with leflunomide than icity; sulfasalazine may be an option in and mycophenolate mofetil, and for 12 methotrexate (for which there is most such cases. months for sulfasalazine. evidence). There is relatively little evi- Most DMARDs undergo some renal Monthly monitoring should be dence on which to base a decision for excretion, and patients with chronic kid- extended long-term for ciclosporin, other DMARDs. ney disease often require dose reduc- methotrexate plus leflunomide and The guideline recommends that tion and more frequent monitoring. tacrolimus but less frequent monitor- DMARDs should not be stopped rou- Table 2 summarises the manufacturers’ ing can be considered for patients who tinely during the perioperative period recommendations for dose adjustment, have been stable for 12 months. There but the decision should be individual- depending on the stage of chronic kid- are also recommendations for addi- ised for patients undergoing a high-risk ney disease. tional monitoring for ciclosporin and procedure. Risk factors include longer Cardiovascular disease is not a con- tacrolimus (blood pressure and glucose duration surgery, class 3/4 procedures, traindication to DMARD therapy: treat- at every visit), leflunomide (blood pres- older age, impaired renal function and ment of rheumatoid arthritis – notably sure and weight at every visit), sodium co-morbidity. Steroid exposure should with methotrexate, leflunomide or sul- aurothiomalate (urinalysis for blood and be minimised before surgery and it is fasalazine – is associated with a reduc- protein before each dose) and when not usually necessary to increase the tion in cardiovascular risk. The risk of hydroxychloroquine is taken for more dose to prevent adrenal insufficiency. new cancers during DMARD treatment than five years (annual eye assess- is no greater than in the population at ment, ideally including optical coherence Intercurrent infection large. Prior malignancy is generally not a tomography). The risk of serious infection (eg infec- contraindication but evidence is limited Therapeutic drug monitoring is use- tion requiring intravenous antibiotics or and there are exceptions: lymphoprolif- ful with ciclosporin and tacrolimus but, hospitalisation) is increased in many erative disorder induced by methotrex- compared with the transplantation set- people with inflammatory arthritis and ate is a clear contraindication to further ting, the doses used in rheumatology 9 treatment and a patient with skin cancer are smaller and blood levels have not • White cell count <3.5 x 10 /L should be monitored by a dermatologist. been correlated with efficacy; monitoring • Mean cell volume >105fl 9 The risk should be assessed individually frequency may therefore be lower. • Neutrophils <1.6 x 10 /L for each patient. • Creatinine rise >30% over 12 months and/or Perioperative management calculated GFR <60ml/min/1.73m2 9 Monitoring Most patients who undergo arthro- • Unexplained eosinophilia >0.5 x 10 /L The guideline recommends a standard plasty are being treated with a DMARD • ALT and/or AST >100 U/L 9 schedule for monitoring patients newly and/or a steroid at the time. The deci- • Platelet count <140 x 10 /L prescribed a DMARD or when a second sion whether to stop or continue ther- • Unexplained reduction in albumin <30g/L DMARD is initiated (see Table 3) but apy depends on the risks of a disease GFR = glomerular filtration rate; ALT = alanine again there are many exceptions. No flare (affecting 10–20% of patients aminotransferase; AST = aspartate aminotransferase routine monitoring is necessary with with rheumatoid arthritis) or an infec- apremilast, hydroxychloroquine, mepa- tion (more likely with active rheumatoid Table 4. Criteria for contacting the rheumatology team crine or minocycline. Standard monitor- arthritis and immunosuppression). to consider suspending DMARD treatment under a ing is recommended for azathioprine, These risks vary between DMARDs and shared care agreement1 prescriber.co.uk Prescriber February 2018 ❚ 31 ■ GUIDELINES l Non-biological DMARDs

When initiating treatment, information is available to provide to the patient on in these parameters should also be the risks and benefits of methotrexate, confirmation of understanding/consent, taken into account. baseline tests conducted, the need for monitoring and the monitoring schedule. A Methotrexate, the most frequently patient-held recording document is issued and its use explained. prescribed DMARD, has been associated with clinically significant prescribing and Shared care guidelines should clearly state: administration risks and the National • Prescribing and monitoring responsibilities Patient Safety Agency has published • How often will blood tests be conducted and in which location guidance to support safer prescribing • Which clinician will be responsible for receipt and review of the results (see Table 5).4 This guidance also warns • Who will communicate necessary dosage changes to the patient (and to the GP of the potential for confusion between if hospital reviewed for the GP prescriber) the two strengths of methotrexate tablet • Who will record test results in the patient-held record document (2.5mg and 10mg) and different devices • Trusts without shared care guidelines must make similar appropriate for parenteral use. arrangements Summary When prescribing: When expensive biological DMARDs • All prescribers should avoid the use of ‘as directed’ in prescribing – a specific steal the limelight, the mundane non- dose must be applied to each prescription biologicals can be underestimated but • Patients often understand their dose by number of tablets rather than they remain effective though potentially milligrams; quantity and frequency of dose should be regularly discussed with toxic drugs. This guideline provides a the patient clear description of the practicalities • Repeat prescriptions should be removed from the surgery repeats pile and involved in prescribing DMARDs in adults, retained separately for prescriber review prior to authorising by signature including both general and drug-specific (shading the prescription signature space on FP10 or WP10 forms to alert the points for best clinical practice. It is rele- prescriber to high-risk drugs might help) vant to everyone involved in using these • Beware patients attending with other symptoms – signs of toxicity or intolerance agents, establishing the principle that may present as, for example, breathlessness, dry persistent cough, vomiting care and vigilance are needed to ensure and diarrhoea both appropriate and safe use. • Patients receiving methotrexate may be admitted to any ward or receive outpatient treatment for co-existing conditions, and staff in all areas may References therefore be involved in continuity of prescribing, monitoring or administration 1. Ledingham J, et al. BSR and BHPR guide- • Full medicines reconciliation, conducted by pharmacists, should be undertaken line for the prescription and monitoring of on admission, and prescribing, monitoring and administration requirements non-biologic disease-modifying anti-rheu- recorded in the patient’s notes matic drugs. Rheumatology 2017;56:865–8. • It is the prescriber’s responsibility to record the correct dosage and frequency Available from: https://academic.oup.com/ on the hospital drug administration chart and to strike out the six days of the rheumatology/article/56/6/865/3053478 week when a dose must not be administered in the administration section on 2. Public Health England. The Green Book. Available from: https://www.gov.uk/ the chart government/collections/immunisation- • Handwritten prescriptions and discharge summary information must be against-infectious-disease-the-green- complete and legible and include in full the form, strength, dose and directions book#the-green-book 3. National Institute for Health and Care 4 Table 5. National Patient Safety Agency checklist for safe prescribing of methotrexate Excellence. Chronic kidney disease in adults: even more so in those with rheumatoid Shared care assessment and management. CG182. July arthritis. Risk factors include co-morbid- Treatment with a DMARD is usually 2014 (updated January 2015). Available from: https://www.nice.org.uk/guidance/ ity, use of steroids, increased disease initiated in secondary care and contin- cg182 activity and longer use of some DMARDs. ued long-term in primary care. When 4. National Patient Safety Agency. Towards Methotrexate, leflunomide, sul- this occurs, a local written shared care the safer use of oral methotrexate. July 2004. fasalazine, azathioprine, apremilast, agreement should specify the respon- Available from: http://www.nrls.npsa.nhs. mycophenolate mofetil, ciclosporin and sibilities of the patient, the primary uk/ tacrolimus should be temporarily discon- care team and the rheumatology team. tinued during a serious infection (but not Responsibility for ensuring adherence in minor infections) until the patient has to monitoring guidance rests with the Declaration of interests recovered. Treatment with minocycline, prescriber. Table 4 lists the criteria for None to declare. hydroxychloroquine or sodium aurothio- urgently contacting the rheumatology malate can be continued during minor or team for action within one day but these Steve Chaplin is a medical writer spe- serious infections. should not be interpreted rigidly: trends cialising in therapeutics

32 ❚ Prescriber February 2018 prescriber.co.uk