BSR and BHPR guideline for the prescription and monitoring of non-biologic disease-modifying anti-rheumatic drugs

The mainstay of treatment for inflammatory rheumatic disease involves DMARDs. The last 30 years have seen enormous shifts in the use of DMARDs, with earlier initiation in disease course as well as combination strategies. Many of the drugs used have potential for harm as well as benefit. Appropriate screening prior to DMARD initiation, as well as vigilant monitoring during therapy, are required to minimize the risk of harm. This current guideline supersedes the previous 2008 BSR/BHPR guideline [1]. NICE has accredited the process used by the BSR to produce its guidance for the use of non-biologic DMARDs. Accreditation is valid for 5 years from 10 June 2013. More information on accreditation can be viewed at www.nice.org.uk/accreditation. For full details on our accreditation visit: www.nice.org.uk/accreditation. The aim is to provide evidence-based recommendations, which do not imply a legal obligation, for clinicians to follow when prescribing synthetic, non-biologic, anti-rheumatic drugs commonly used in management of multisystem rheumatic conditions. The following DMARDs are covered in this guideline: apremilast, AZA, CSA, HCQ, LEF, mepacrine, MTX, Minocyline, MMF, sodium aurothiomalate/myocrisin (gold), SSZ and tacrolimus. The target audience is health professionals directly involved in managing patients with rheumatic disease in the UK, including rheumatologists, specialist nurses, pharmacists and general practitioners. This guideline does not cover the indications for DMARD therapy or the use of biologic therapy and other selective non-biologic DMARDs (e.g. kinase inhibitors). The guideline also does not cover prescribing in relation to pregnancy because this is covered by an existing guideline [2, 3]. Specific questions were considered in relation to each drug. What baseline screening is needed prior to drug initiation? What impact does co-morbidity have for prescribers? What routine monitoring is needed? When should therapy be interrupted? Recommendations based on systematically reviewed evidence are given below. A description of evidence and full recommendations are given in the full guideline, available at Rheumatology online. The decision to initiate DMARDs should be made in conjunction with the patient/carer and be supervised by an expert in the management of rheumatic diseases (GRADE 1B, 100%). Patients should be provided with education about their treatment to promote self-management (GRADE 1B, 100%). When appropriate, patients should be advised about the impact of DMARD therapy upon fertility, pregnancy and breastfeeding (GRADE 1B, 100%). Baseline assessment should include height, weight, blood pressure and laboratory evaluation [full blood count (FBC), calculated glomerular filtration rate (GFR), alanine aminotransferase (ALT) and/or asparate aminotransferase (AST), albumin; GRADE 1C, 97%]. Patients should be assessed for co-morbidities because these may influence DMARD choice, including evaluation for respiratory disease and screening for occult viral infection (GRADE 1C, 97%). Vaccinations against pneumococcus and influenza are recommended (GRADE 1C, 97%). MTX: All patients should be co-prescribed folic acid supplementation at a minimal dose of 5 mg once weekly (GRADE 1B, 97%). AZA: Patients should have baseline thiopurine methyltransferase (TPMT) status assessed (GRADE 1A, 97%). HCQ: Patients should have baseline formal ophthalmic examination, ideally including objective retinal assessment for example using optical coherence tomography, within 1 year of commencing an antimalarial drug (GRADE 2C, 88%). Pre-existing lung disease is not a specific contraindication to DMARD therapy; however, caution is advised when using drugs associated with pneumonitis in patients with poor respiratory reserve (GRADE 1B, 95%). In patients with deranged liver biochemistry, hepatotoxic DMARDs should be used with caution, with careful attention to trends in test results (GRADE 1C, 100%). In patients with impaired liver synthetic function (e.g. cirrhosis), DMARD therapy should be used with extreme caution (GRADE 1C, 97%). Patients with chronic viral hepatitis infection should be considered for anti-viral treatment prior to immunosuppressive DMARD initiation (GRADE 1B, 99%). DMARDs must be used with caution in chronic kidney disease, with appropriate dose reduction and increased frequency of monitoring (GRADE 1C, 97%). Cardiovascular disease and prior malignancy are not considered contraindications to DMARD therapy (GRADE 1C, 95%) Summary of monitoring requirements Standard monitoring as per recommendations I and II for DMARD blood monitoring schedule when starting or adding a new DMARD. Patients who have been stable for 12 months can be considered for reduced frequency monitoring on an individual patient basis. BP: blood pressure. Summary of monitoring requirements Standard monitoring as per recommendations I and II for DMARD blood monitoring schedule when starting or adding a new DMARD. Patients who have been stable for 12 months can be considered for reduced frequency monitoring on an individual patient basis. BP: blood pressure. Check FBC, creatinine/calculated GFR, ALT and/or AST and albumin every 2 weeks until on stable dose for 6 weeks; then once on stable dose, monthly FBC, creatinine/calculated GFR, ALT and/or AST and albumin for 3 months; thereafter, FBC, creatinine/calculated GFR, ALT and/or AST and albumin at least every 12 weeks. More frequent monitoring is appropriate in patients at higher risk of toxicity (GRADE 2B, 97%). Dose increases should be monitored by FBC, creatinine/calculated GFR, ALT and/or AST and albumin every 2 weeks until on stable dose for 6 weeks then revert to previous schedule (GRADE 2B, 97%). Exceptions/additions to the monitoring schedule for specific DMARDs are included in Table 1 (GRADE 2B and C, 100%). Steroid exposure should be minimized prior to surgical procedures, and increases in steroid dose to prevent adrenal insufficiency are not routinely required (GRADE 2B, 95%). DMARD therapy should not routinely be stopped in the perioperative period, although individualized decisions should be made for high-risk procedures (GRADE 2B, 95%). During a serious infection, MTX, LEF, SSZ, AZA, apremilast, MMF, CSA and tacrolimus should be temporarily discontinued until the patient has recovered from the infection (GRADE 1A–C, 97%). The prescriber has responsibility for ensuring patients are adhering to monitoring guidance (GRADE 1C, 97%). When prescribing takes place in primary care, it should be supported by local written shared care agreements, highlighting responsibilities of each party (patient, secondary care, primary care; GRADE 1C, 97%). Contact rheumatology team urgently and consider interruption in treatment if any of the following develop: white cell count <3.5 × 109/l; mean cell volume >105 fL; neutrophils <1.6 × 109/l; creatinine increase >30% over 12 months and/or calculated GFR <60 ml/min; unexplained eosinophilia >0.5 × 109/l; ALT and/or AST >100 U/l; platelet count <140 × 109/l; unexplained reduction in albumin <30 g/l (GRADE 1C, 99%). For clinically urgent abnormalities, emergency access to specialist rheumatology advice, with response within one working day, should be available as per National Institute for Health and Care Excellence guidelines. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: J.G. has received honoraria from MSD and Pfizer. J.M. has received honoraria from Bristol Myers Squibb and Pfizer. S.M. received honoraria from AbbVie, Pfizer, Roche and MSD. All other authors have declared no conflicts of interest. The full guideline is available as supplementary data at Rheumatology Online.

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