Disease Modifying Anti-Rheumatic Drugs Rheumatology Shared-Care Information For General Practitioners Author: Dr A J

1. Disease Modifying Anti-Rheumatic Drugs Rheumatology Shared-Care Information For General PractitionersAuthor: Dr A J Hakim Area Prescribing Committee Approved: September 2010  This document provides information to support patient management in primary care in a ‘shared-care’ plan with specialist Rheumatology. It is a guideline as to the partnership to be developed between the Rheumatologist, General Practitioner and the patient.

2. CONTENTS Roles in Shared Care Roles of the consultant/rheumatology team pg 4 Roles of the general practitioner in shared care pg 5 Roles of the patient pg 6 Common Concerns and Side Effects General introduction to Disease Modifying Drugs pg 8 General considerations pg 9 Immunisations and assessment of infection risk pg 10 Family planning pg 11 Pregnancy and breast feeding pg 11 NSAID co-administration pg 12 Surgery and infective illness pg 12 Malignancy pg 13 Reducing/stopping a DMARD because of potential toxicity pg 14 Common side effects and recommended actions page 1, page 2 pg 15 and 16

3. Roles in Shared Care Disease Modifying Anti-Rheumatic Drugs Shared-Care Information Disease Modifying Anti-Rheumatic Drugs Rheumatology Shared-Care Information for General PractitionersRoles in Shared Care The level of ‘shared care’ may range from community re-prescribing supported by hospital follow-up, to community follow-up with assessment and dose adjustment, according to the needs of the patient and knowledge of the practitioner. The doctor who prescribes the medicine has the clinical responsibility for the drug and the consequence of its use at that time. Because of this it is important that the prescribing doctor is supported by communication and co-operation (described in this document), understands assessment and safety in relation to these drugs, and is familiar with monitoring policy.

4. Roles in Shared Care – Rheumatology TeamDisease Modifying Anti-Rheumatic Drugs Shared-Care Information Roles of the Consultant / Rheumatology Team Ensure baseline assessment including immunization status & investigations before commencing treatment. Initiate treatment and confirm dose escalation plan, putting in place appropriate follow-up assessment over the course of time whilst stabilizing the patient on a therapeutic dose. Ensure that the patient (and care-giver) is an informed recipient in therapy and that they understand their treatment regimen and any monitoring and follow up that is required. Ensure adequate laboratory forms are supplied to the patient with clear instruction as to the frequency of having tests done prior to the next appointment until such time as this role might be taken over by the General Practitioner in a ‘Shared Care’ plan. Correspond with the General Practitioner after every contact with the patient (including adjustments in dosage that may be agreed with the patient over the phone for example). Non-attendance will also be alerted to the General Practitioner. Once the dose is stable, request community support for re-prescribing and offer to the General Practitioner a ‘Shared Care’ opportunity for follow-up monitoring and assessment; in so–doing ensure that back up advice is available for reporting of adverse effects by the General Practitioner or patient and agree plan for next specialist follow-up If the General Practitioner does not wish to take part in a shared care plan, Consultant to continue routine assessment and monitoring – the General Practitioner responsible for agreeing the level of service commission incurred. Local policy for ensuring results of monitoring blood tests instigated by the Rheumatology department are available to the General Practitioner include: (Note we do not use monitoring booklets) i. Use of the “Drop Number for practices in the immediate locality – the Drop Number is placed on all request forms for hard copy results to be sent to the General Practice direct from the lab. ii. Copying in the latest blood results with each correspondence to the General Practitioner. iii. Corresponding with the General Practitioner when ever any significant abnormal result is identified, with actions taken. iv. Some Practices have IT access to the laboratories (Increasing as per Trust 2010-11 IT Strategy). v. Copies of correspondence are given to patients along with blood results, and patients are asked to take latest correspondence to their next appointment with any clinician but specifically with their General Practitioner.

5. Roles in Shared Care - GPs Disease Modifying Anti-Rheumatic Drugs Shared-Care Information Roles of the General Practitioner in a Shared Care plan In isolation of a comprehensive plan the General Practitioner is asked to be involved in community re-prescribing as per communication on dosage from the Rheumatology Department, with reassurance of on-going monitoring by the department (as is current common practice). The General Practitioner can be assured of safety by the results of blood monitoring and is asked to be alert to specific concerns outlined in Table 1 pages 1 and 2 when re-prescribing. In a more comprehensive plan the General Practitioner roles would include: Full awareness of the content this DMARD Shared-Care plan Check and reinforce patient understanding of the nature, effect and potential side effects of the drug. Prescribe as per communication from the Rheumatology Department, and adjust as required with support from the Rheumatology department: Adjustment might include: i. down in dose if side effects, and monitor for on-going control of disease ii. stop and seek advice if major side effect iii. Increase if disease not controlled and monitor (assessment schedule and monitoring). Monitor patient’s overall health and well-being and be familiar with cautions related to specific drugs. Monitoring clinical and biochemical indices, and review the patient as per shared care schedule (assessment schedule and monitoring). Discuss case with the specialist if there is a change in the patient’s condition of concern, reporting any adverse events and changes in dosage. Support the Rheumatology department in retaining a robust clinical database of disease-related and patient-related outcome measures by providing clinical information as requested, including supply of blood results to patients prior to clinic if laboratory other than Whipps Cross is used.

6. Roles in Shared Care - patientsDisease Modifying Anti-Rheumatic Drugs Shared-Care Information Roles of the Patient  Report any concerns that they think may be a side effect of their medication to their General Practitioner and/or a member of the Rheumatology team. Ensure they have a clear understanding of their treatment and the importance of monitoring and follow-up. Report changes in disease symptoms. Alert the General Practitioner and/or a member of the Rheumatology team to any changes in circumstances which might affect management of disease e.g. becoming pregnant or plans for starting a family, concerns over changes in other medications and adverse interactions, extended periods abroad requiring changes to monitoring schedule etc. Retain copies of correspondence and monitoring results and take these to appointments with clinicians, and in particular the General Practitioner and Rheumatology Team.

7. Disease Modifying Anti-Rheumatic Drugs Rheumatology Shared-Care Information for General PractitionersCommon Concerns and Common Side-Effects Author: Dr A J Hakim Area Prescribing Committee Approved: September 2010  This section provides information to support patient management in primary care in a ‘shared-care’ plan with specialist Rheumatology. It describes the clinical assessment of patients taking DMARDs and the common questions/concerns that arise. Specifically it describes Table 1 pages 1 and 2 the things to be alert to when assessing patients on treatment, enquiring as to side-effects, or responding to a patient’s concern over change in well-being. The doctor who prescribes the medicine has the clinical responsibility for the drug and the consequence of its use at that time. Because of this it is important that the prescribing doctor is supported by a system of communication and co-operation understands the general assessment and safety described here and drug-specific issues, and is familiar with monitoring policy.

8. Common Concerns and Common Side-Effects Disease Modifying Anti-Rheumatic Drugs Shared-Care Information General Introduction to Disease-Modifying Anti-Rheumatic Drugs Disease-modifying anti-rheumatic drugs (DMARDS) are a cornerstone in the treatment of destructive inflammatory rheumatic disease such as Rheumatoid Arthritis, Psoriatic Arthritis, Juvenile Idiopathic Arthritis, Systemic Lupus Erythematosus, Myositis, and Vasculitis. They are used to arrest inflammatory damage, the aim being to induce remission of disease. They are a long-term and often life-long therapies. DMARDs are slow acting drugs that typically take 8-12 weeks to begin to demonstrate benefit. For this reason, depending on severity, patients will often receive Non-steroidal Anti-Inflammatory drugs and/or Corticosteroids as well during the initial stabilization of disease. Stabilization may require escalation of DMARD over periods greater than 6 months. Patients should be informed of this, clarifying expectation over response time, in support of retaining good compliance. It is not uncommon for combinations of DMARDs to be used either by a sequential ‘step up’ (adding one after the other over time) or ‘step down’ (starting typically with 2 or 3 and reducing to 1 over time). Since the introduction of Biologics it is unlikely that more than 3 DMARDs would be used; Biologics can be considered after failure of at least 2 DMARDs. The most common drugs used are (in alphabetical order) Azathioprine, Hydroxychloroquine, Leflunomide, Methotrexate, and Sulfasalazine, quick reference guide to monitoring Amongst these Methotrexate is the drug of first choice for 50-60% of cases. It is considered the most appropriate one to initiate in the presence of erosive-joint disease. Other drugs include Ciclosporin, Cyclophosphamide, Gold, Penicillamine, and Mycophenolate Mofetil. Cyclophosphamide is used, for example, in severe Vasculitis/Myositis, and Mycophenolate in Renal Vasculitis – in both cases ‘shared care’ is unlikely to be practical given the need for regular specialty assessment, often across several disciplines.

9. Common Concerns and Common Side-Effects Disease Modifying Anti-Rheumatic Drugs Shared-Care Information Common Concerns in DMARD Prescribing DMARDs are potentially toxic. Table 1 pages 1 and 2 describes the side effects to look out for. The next section describes common concerns / questions that arise for ALL DMARDs. These include Immunization, Family Planning / Pregnancy / Breast Feeding, NSAID use, Surgery and Intercurrent Illness, and Malignancy risk. General Considerations All drugs should be used with caution in hepatic and renal impairment, blood dyscrasias (including suspected or known G6PD deficiency, and porphyria), recurrent infection, and in the elderly. Sequential (3 in a row) adverse changes in blood indices (even if in the normal range) are as important to identify as absolute changes falling outside the normal range. Whenever there is concern over the potential toxicity of a DMARD a detailed history is required as to: i. recent change in medication including over the counter preparations ii. alcohol consumption and changes in pattern iii. intercurrent illness (typically an infection) iv. a dosing error of DMARD  

10. Common Concerns and Common Side-Effects Disease Modifying Anti-Rheumatic Drugs Shared-Care Information Common Concerns in DMARD Prescribing Immunization and Assessment of Infection Risk (This assessment should be carried by the Rheumatology team before commencing therapy and managed by the General Practitioner where appropriate)   Community based: i. Patients on DMARDs must not receive live vaccine immunization (e.g. oral Polio, BCG, MMR, Yellow Fever) ii. Patients should receive the pneumococcal vaccine iii. Annual flu vaccination is recommended iv. Patients exposed to chickenpox (who have no clear history of chicken pox in the past) or to shingles, should receive passive immunization using varicella zoster immunoglobulin (VZIG) Hospital based: v. Patients should be screened for Hepatitis B and C vi. Patients should be assessed for risk of HIV and tested if applicable vii. Patients should be assessed for risk of active/latent TB

11. Common Concerns and Common Side-Effects – family planning, pregnancy, breastfeedingDisease Modifying Anti-Rheumatic Drugs Shared-Care Information Common Concerns in DMARD Prescribing Family planning In general DMARDs should be stopped in both men and women at least 3 months before trying to conceive. Contraceptive methods are advised for the 3 months. There are two exceptions from this general rule: i. Azathioprine, Hydroxychloroquine and Sulfasalzine: reports do not suggest a significant increase in risk of teratogenicity. However, pharmaceutical companies advise stopping therapy. It is then a question of weighing up risk-benefit to the patient of a disease flare if the drug is stopped. In each case the pragmatic approach should be to reduce to the lowest effective dose or stop treatment if possible. Flares in disease may require corticosteroids. These drugs may reduce male fertility. ii. Leflunomide: In women this should have been stopped 2 years before trying to conceive. In the event of conceiving on Leflunomide the drug should be stopped and the ‘washout’ protocol applied. Pregnancy ALL DMARDs are to be avoided in Pregnancy EXCEPT for the following: i. Azathioprine ii. Hydroxychloroquine iii. Sulfasalazine Reports do not suggest a significant increase in risk of teratogenicity. However, pharmaceutical companies advise stopping therapy. It is then a question of weighing up risk-benefit to the patient of a disease flare if the drug is stopped. In each case the pragmatic approach should be to reduce to the lowest effective dose or stop treatment if possible. Flares in disease may require paracetamol and corticosteroids. Breast Feeding ALL DMARDs should be avoided.

12. Common Concerns and Common Side-Effects – NSAIDS, surgery Disease Modifying Anti-Rheumatic Drugs Shared-Care Information Common Concerns in DMARD Prescribing NSAIDs co-administration Concern is often expressed over the co-administration of DMARDs and NSAIDs. Prescribing systems will ‘flag’ this association as a risk and possibly even a contraindication. The two classes of drug are commonly used together in Rheumatology. It is important that there is regular monitoring of blood indices: i. If a DMARD is introduced to a patient already on NSAIDs (the most typical case) then assessment of adverse interactions will arise anyway as a consequence of introducing the DMARD monitoring protocol. ii. If an NSAID is introduced to a patient on a stable dose of DMARD, whilst monitoring of DMARD toxicity will be on-going the next assessment may not be for several months and it is then appropriate, particularly in the elderly and infirm, to request additional blood tests (LFT, FBC, U&E) at, for example 2 and 6 weeks after commencing the NSAID. iii. Guidance related to switching NSAIDs is not clear – the pragmatic approach is to follow guidance as per ii. above. Surgery and infective illness There is conflicting evidence as to the benefit of stopping DMARD therapy for surgery. If the surgeon wishes for this to happen then, as a ‘rule of thumb’, it is reasonable to discontinue for 2 weeks before and up to 2 weeks after surgery and then re-instate at the same dose. It may be inappropriate to discontinue DMARD therapy during an infection as the autoimmune condition may ‘flare’. DMARDs should be continued during mild infection. Note that DMARDs may mask the normal responses to infection seen in laboratory indices, in particular a neutrophilia. DMARDs may need to be stopped in severe sepsis. This should be discussed with the Rheumatologist. It is not possible to predict the risk of a flare of inflammation during a short period of withholding DMARD therapy but many patients report a level of tolerance for up to 4 weeks.

13. Common Concerns and Common Side-Effects - Malignancy Disease Modifying Anti-Rheumatic Drugs Shared-Care Information Common Concerns in DMARD Prescribing Malignancy DMARDs are associated with an increased risk of lymphoma and skin malignancies. The risks are considered small and are out-weighed by the benefits. The possibility of these should be part of enquiry or alert the clinician should the patient raise concerning symptoms.

14. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationCommon Concerns and Common Side-Effects – TABLE 1 - BLOODS General considerations if reducing or stopping a DMARD because of potential toxicity i. The two Tables below show biochemical levels and clinical situations at which a DMARD should be reduced or stopped. For situations where results lie between ‘normal’ for the individual and the abnormal cut offs, the clinician may wish to reduce the DMARD dose rather than stop it. ii. Repeat blood test after 1 and 2 weeks in the first instance, and fortnightly thereafter if normalizing. iii. If the indices are worse than the abnormal cut-off values then no further DMARD should be given until the indices have normalized or are in an acceptable range similar to the pre-morbid state. iv. A detailed history is required as to recent change in medication including over the counter preparations, alcohol consumption, Inter-current illness, or dosing error of DMARD. v. Cover an inflammatory ‘flare’ with corticosteroid vi. Once abnormalities return to normal the DMARD might be re-started at a lower dose assuming efficacy in the first place or a new DMARD tried. In both cases this should be discussed with the Rheumatologist, and return to the ‘early monitoring’ phase of the Schedule.

15. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationCommon Concerns and Common Side-Effects – TABLE 1 - BLOODS

16. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationCommon Concerns and Common Side-Effects – TABLE 1 – OTHER SYMPTOMS

17. Disease Modifying Anti-Rheumatic Drugs Rheumatology Shared-Care Information For General Practitioners Specific Issues with Individual DMARDs Author: Dr A J Hakim Area Prescribing Committee Approved: September 2010  This section provides information to support patient management in primary care in a ‘shared-care’ plan with specialist Rheumatology. It describes the specific issues that relate to individual DMARDs. These drugs are considered in alphabetical order. It should be noted that the section ‘additional monitoring’ is highlighted here for the purposes of raising awareness over particular vigilance aside from common monitoring themes. The doctor who prescribes the medicine has the clinical responsibility for the drug and the consequence of its use at that time. Because of this it is also important that the prescribing doctor is supported with communication and co-operation, understands the general assessment and safety of these drugs, and is familiar with monitoring policy.

18. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationSpecific Issues with Individual DMARDs Azathioprine Azathioprine is prescribed for a number of autoimmune conditions, rheumatic, hepatic and gastro-intestinal, dermal, renal and neurological. The typical dose is 0.5-1.5 mg/kg/day oral, increasing after 4–6 weeks to 2–3 mg/kg/day with an anticipated response within 6-12 weeks. Specific cautions: Thiopurine methyl transferase (TPMT) deficiency occurs in less than 0.3% of the population The Rheumatology department does not routinely request this test, preferring close LFT and FBC monitoring in the first 6 -12 weeks (assessment schedule and monitoring). Photosensitivity reaction – patients should be advised to wear sunscreens and protective covering. Specific drug interactions to be aware of: Allopurinol – Azathioprine dose should be reduced (recommended 0.25-0.5mg/kg/day) Angiotensin converting enzyme (ACE) inhibitors – co-prescription may exacerbate anaemia Anticonvulsants – Azathioprine may reduce absorption Aminosalicylates (Mesal / Olsal / Sulfasalazine) – increase risk of bone marrow toxicity Ciclosporin – Azathioprine can decrease Ciclosporin levels Co-trimoxazole and Trimethoprim – life threatening bone marrow toxicity may occur Warfarin – Azathioprine inhibits anticoagulant effect

19. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationSpecific Issues with Individual DMARDs Ciclosporin Although rarely used it is most typically encountered in Psoriatic Arthritis, Rheumatoid Arthritis and Juvenile Idiopathic Arthritis. It is usually avoided in Psoriatic Arthritis if PUVA has been given (see below). It is dosed at 2.5 mg/kg/day in 2 divided doses for 6 weeks and then may be increased at 4-weekly intervals in 25mg increments up to a maximum dose of 4 mg/ kg/day. A response is usually observed within 12 weeks. Additional monitoring: Pre-monitoring should include fasting lipids, repeated 6 monthly and the drug discontinued if an uncontrollable significant rise occurs. Calculate creatinine clearance/GFR. A rise in creatinine > 30% above baseline on 2 consecutive readings 7 days apart warrants stopping the drug and reassessing. It is essential that blood pressure monitoring is commenced at baseline. If uncontrollable hypertension occurs the drug should be stopped. Electrolyte balance should be checked every 2 weeks until stable dose achieved and then every 3 months with other routine monitoring (assessment schedule and monitoring). If the potassium rises above the lab threshold the drug should be stopped and re-assessed (having ensured not consequent on other medication changes e.g. diuretic). Specific cautions: Grapefruit (including juice) increases the bioavailability of Ciclosporin. Grapefruit should be avoided for an hour before and after taking the drug. Specific drug interactions to be aware of: Calcium Channel Blockers – reduce the prescribed dose of Ciclosporine to 50% of normal Colchicine should be avoided Diclofenac – reduce the dose of Diclofenac to 75mg daily Digoxin – measure levels and adjust dose accordingly – Ciclosporin can increase serum digoxin levels Diuretics – caution with electrolyte imbalance Hydroxychloroquine – may increase plasma concentrations of Ciclosporin PUVA – avoid Ciclosporin given significant increase risk of invasive squamous cell carcinoma Simvastatin – avoid dosing the statin above 10 mg/day St. John’s Wort decreases Ciclosporin activity.

20. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationSpecific Issues with Individual DMARDs Cyclophosphamide This drug is usually reserved for severe autoimmune conditions, and primarily for the remission induction of vasculitis. It is unlikely therefore that the General Practitioner would enter in to a shared-care agreement given the patient will require regular specialist follow-up and often until several specialties. It is dosed at 1-1.5mg/kg/day orally and 500-1000mg intravenous. Intravenous dosing is typically once every 4 weeks for up to 6 months after which (assuming remission is achieved) patients are often switched to Azathioprine or Methotrexate. The introduction of Biologics has meant that in many cases there are viable and potentially less toxic and more effective alternatives.   Specific cautions: Gametogenesis is severely impaired and irreversible; patients should be counseled re storage of sperm / ova. Urothelial toxicity from the active metabolite Acrolein can cause haemorrhagic cystitis. Patients should be well hydrated before taking cyclophosphamide and for 24-48hrs after IV administration. Mesna is given to reduce risk of urothelial toxicity; usual dosage 2gm before and repeated 2 and 6 hours after IV therapy. Common side-effects include nausea, vomiting, diarrhoea, arthralgia, fatigue, headache, tachycardia, and hypotension.   Specific drug interactions to be aware of: Avoid Clozapine – increased risk of agranulocytosis Digoxin – check digoxin levels and adjust accordingly as Cyclophosphamide reduces absorption Phenytoin – check phenytoin levels and adjust accordingly as Cyclophosphamide reduces absorption

21. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationSpecific Issues with Individual DMARDs Gold (Auranofin and Sodium aurothiomalate) Gold is used in the management of Rheumatoid Arthritis and Juvenile Idiopathic Arthritis. It is given as a 50mg im injection (Sodium aurothiomalate), and occasionally as 3mg 2–3 times daily oral (Auranofin)   A test dose of 10mg im Sodium aurothiomalate should be given on the first occasion; thereafter 50mg is given weekly until response achieved. Thereafter the injection is given every 4 weeks. In children it should be dosed at 1mg/kg up to a maximum of 50mg. If no response is seen after a cumulative dose of 1 gram (approx 20 weekly doses) of Sodium aurothiomalate, it should be discontinued. Additional monitoring: FBC and urinalysis (for proteinuria) on each occasion before injection Specific cautions: Both agents should be used with caution if there is a history of urticaria, eczema or inflammatory bowel disease Both are contraindicated in severe renal or hepatic impairment, ulcerative colitis, history of marrow dysplasia, porphyria, exfoliative dermatitis, SLE, and pulmonary fibrosis/bronchiolitis. Specific drug interactions to be aware of: Gold should not be given with Penicillamine (rarely used now anyway) as it increases risk of toxicity. There is an increased risk of anaphylaxis in patients also taking Angiotensin-Converting-Enzyme Inhibitors.

22. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationSpecific Issues with Individual DMARDs Hydroxychloroquine Hydroxychloroquine is an antimalarial drug often encountered in the management of Rheumatoid Arthritis, Juvenile Idiopathic Arthritis and Sysytemic Lupus Erythematosus. It is dosed at 200-400mg daily, oral   Additional monitoring: At baseline there is an assessment of visual acuity. Enquiry is made as to any form of impairment that is not corrected by glasses. Near vision testing should demonstrate the capacity to read small print N8 or N6 on an acuity chart. If there are concerns at baseline the patient should be referred to an optometrist initially (possibly an ophthalmologist thereafter) and the drug withheld. Once on the drug, patients should report any changes in visual acuity / colour vision / blurring; this should trigger re-assessment by an optometrist initially. Withdraw the drug until the nature of the problem is clarified. Otherwise, visual acuity assessment should take place annually as per baseline, preferably by an optometrist. Although national guidelines suggest no indication for routine monitoring of LFTs and FBC it is prudent to do so a 3 and 6 months in to treatment or once off when commencing additional medication. Specific Cautions: It may exacerbate psoriasis. It is contra-indicated if maculopathy is present. Specific drug interactions to be aware of: Hydroxychloroquine can increase the plasma concentration of Digoxin, Methotrexate, and Ciclosporin. Avoid use with Amiodarone, Quinine, Mefloquine, and Quinolones given increased risk of hypersensitivity reaction.

23. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationSpecific Issues with Individual DMARDs Leflunomide Leflunomide is used in Rheumatoid Arthritis and Psoriatic Arthritis, and often concomitant with Methotrexate. A loading dose of 100mg daily for 3 days is described in the literature but often this causes gastrointestinal upset and most practitioners avoid it, starting at 10mg and increasing to 20mg after 6-12 weeks according to tolerability and efficacy.  It has a long half life and therefore requires washout (see below) if severe toxicity is expected. Specific cautions: Hypertension – if this cannot be controlled and other causal drugs / pathologies have been eliminated, stop drug Pneumonitis acute allergic reaction – can be acute requiring emergency referral Women planning a family should have stopped Leflunomide for 2 years (Teratogenic) (men 3 months) before trying to conceive. Specific drug interactions to be aware of: Risk of bone marrow toxicity increased by the co-use of Leflunomide and Methotrexate (NB they are nevertheless often used together for their synergy) Leflunomide can increase anticoagulation effect of Warfarin, the hypoglycaemic effects of Tolbutamide, and the concentration of Phenytoin. Washout of Leflunomide: Rapid removal of the active metabolite can be achieved using washout with Cholestyramine 8g tds or activated charcoal 50gm qds for 11 days. Blood concentrations should be checked twice, 14 days apart prior to conceiving (levels should be <0.02mg/l) Reasons for doing this might include acute toxicity or falling pregnant on treatment. Patients potentially requiring this should be discussed with the Rheumatology Team

24. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationSpecific Issues with Individual DMARDs Methotrexate (Page 1 of 2) Methotrexate is the most commonly used DMARD. The typical dosage is 7.5–25mg once a week Regimens for commencing therapy may have slight variation but typically begin at 5-10mg per week and increase by 2.5mg-5mg every 2 weeks for a period of 4-6 weeks such that at the point of next assessment the dose is 10-25mg. The typical maintenance dose is 10-25 mg once a week (occasionally split over 2 days if nausea is excessive). Some patients may be on 30mg per week as determined by their Consultant.  A lower dose and slower escalation should be considered in the elderly and frail. Gastrointestinal side effects may prohibit oral use. The drug can be given by intramuscular and subcutaneous route also. Additional monitoring: Baseline Chest Radiograph The role of liver biopsy and serum pro-collagen III testing remains unclear and does not form part of the Rheumatology Departments routine practice, preferring careful monitoring for toxicity. Specific Cautions: History should be taken at each visit for onset of shortness of breath (risk of pneumonitis / pulmonary fibrosis). Discussion with the Rheumatology Team may be required regarding further investigation (high-resolution CT and lung function tests detailing lung volume and gas transfer coefficients). Tablets should be taken whole, and not crushed or chewed. Tablets come in 2.5mg and 10mg sizes – it is recommended that only 2.5mg tablets are prescribed to avoid confusion and risk of overdose. However, it is acknowledged that this is a conversation for the clinician, pharmacist, and patient as to which is the preferred prescribing pattern for the patient already on stable treatment; most importantly this pattern should then not be altered for risk of confusion.  

25. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationSpecific Issues with Individual DMARDs Methotrexate (Page 2 of 2) Specific drug interactions to be aware of: The anti-folate effect of drugs may increase the toxicity of Methotrexate. Commonly used drugs that can induce this include Phenytoin, Co-trimoxazole, and Trimethoprim. Methotrexate concentration can be increased by NSAIDs, Penicillin and Tolbutamide Folic Acid: Folic acid (5mg) may be given, particularly in the elderly and frail. Younger patients in particular may not require the supplement. Indications for starting/increasing folic acid include: raised MCV, mildly deranged LFTs, anaemia, mucosal ulceration and hair loss. It is prescribed once weekly, preferably the day after Methotrexate, but not on the same day. It may be increased to 6 days of the week avoiding the same day as Methotrexate. Folinic Acid: Emergency Folinic acid rescue (15-25mg qds orally) should be given if any concern over toxicity (primarily pneumonitis and marrow suppression) and in overdose usually above a cumulative of 100mg Methotrexate. The patient should be discussed urgently with the Rheumatology Team and if necessary referred to the Emergency On-Call if out of hours. Although serum levels of Methotrexate can be measured this is not done routinely in the Rheumatology Department, preferring to judge response to Folinic acid by the daily improvement in haematological and LFT indices.

26. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationSpecific Issues with Individual DMARDs Mycophenolate mofetil Routinely used in organ transplantation, Mycophenolate has recently joined the armamentarium in the control of nephritis, myositis, and vasculitis. It is given at 1–3 g/day orally in divided doses, starting at 500mg daily for the first 7 days, then 500 mg bd for 7 days, building sequentially by an additional 500mg daily every 7 days over the ensuing weeks to an optimal / tolerable dose.   Additional monitoring: Urinalysis at each visit to ensure no sterile haematuria Enquiry as to skin lesions – increased risk of tumours Specific drug interactions to be aware of: Decreased absorption of the drug can occur with use of antacids (magnesium and aluminum hydroxide) and cholestyramine Increased concentration may arise with the co-use of Probenecid and Aciclovir NSAIDs may add to nephrotoxic risk

27. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationSpecific Issues with Individual DMARDs Sulfasalazine This drug tends to be used less than Methotrexate in the Rheumatology Department but most often in the context of Rheumatoid Arthritis, Psoriatic Arthritis and Ankylosing Spondylitis in the presence of tendon-insertion inflammation (enthesitis). The dosage ranges from 1-3 g/day typical starting at 500mg/day for 7 days and increasing by an additional 500mg daily every 7 days over the ensuing 4-6 weeks to an optimal / tolerable dose e.g. week 1 500mg od, week 2 500mg bd, week 3 500mg tds, week 4 1gm bd etc. Patients should be warned that bodily fluids may turn a darker yellow / orange and not to be alarmed. Specific cautions: Slow–acetylators of the drug may develop a drug-induced lupus-like syndrome. The Rheumatology department does not routinely check acetylator phenotype prior to starting the drug. It is preferable to ensure close monitoring. A history of hypersensitivity to Sulphonamides / Co-trimoxazole or Aspirin is a contra-indication to the use of the drug. There is a growing literature to suggest patients may benefit from Folic Acid at the same dosage and for the same indications as described in the section under Methotrexate (above). The Rheumatology Department dose not routinely place patients on Sulfasalazine on folic acid but its additional in the event of side-effects is an option. Specific drug interactions to be aware of: Sulfasalazine in combination with Azathioprine may potentiate the risk of bone marrow toxicity. Sulfasalazine may reduce the absorption of Digoxin.

28. Disease Modifying Anti-Rheumatic Drugs Rheumatology Shared-Care InformationQuick Reference Guidelines to Assessment Schedule and Monitoring Author: Dr A J Hakim Area Prescribing Committee Approved: September 2010  This section provides information allowing patients to be managed safely by primary care, secondary care and across the interface. It is a quick reference guideline to the common assessment schedule anticipated for most patients in routine practice and describes the nature and frequency of routine monitoring tests required. The doctor who prescribes the medicine has the clinical responsibility for the drug and the consequence of its use at that time. Because of this it is also important that the prescribing doctor is supported by a system of communication and co-operation, understands the general assessment and safety, and is familiar with issues specific to the drug in question.

29. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationQuick Reference Guidelines to Assessment Schedule and MonitoringThis section should be read in the context of all other sections to be confident of appropriate level of knowledge pertinent to service and patient safety Typical Specialty Schedule Pre-assessment & Disease activity scores Commence DMARD and instigate monitoring Follow-up at 4-8 weeks If stable establish 3-6 monthly review and plan monitoring bloods, requesting GP prescribe stable dose Monitor blood results to GP as described. If patient unstable continue close monitoring 4-8 weeks and revert to above in due course Review disease activity and scores at 12 monthly intervals Review any time if urgent concern not manageable by GP Options for General Practice in Shared-Care Schedule Basic Level: Support management by prescribing at stable dose and alerting Rheumatology Team when concerned Extended Level: Assessing patient at 3 monthly intervals between 6 monthly / annual Specialist review, monitoring efficacy and toxicity, by agreement with patient and specialist

30. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationQuick Reference Guidelines to Assessment Schedule and Monitoring  TABLE 2 – QUICK GUIDE TO MONITORING COMMONLY USED DMARDS (adapted from British Society Rheumatology Guidelines 2009)

31. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationQuick Reference Guidelines to Assessment Schedule and Monitoring  TABLE 2 – QUICK GUIDE TO MONITORING LESS COMMON USED DMARDS (adapted from British Society Rheumatology Guidelines 2009)

32. Disease Modifying Anti-Rheumatic Drugs Shared-Care InformationCONTACT INFORMATION  Rheumatology Department Contact Details Web page: www.whippsx.nhs.uk/en/our-services/clinical/rheumatology/rheumatology-information-for-gps Fax: 020 8535 6504 Email advice service (to be confirmed) Telephone Monday to Friday office hours: (Out of Hours Emergency contact Medicine On-Call) Dr Bubbear / Dr Hakim: 020 85356723 Dr Donnelly: 020 8535 6526 Dr Lanham: 020 8535 6662 Dr Tahir: 020 8535 6615 Dr Patel: 0208 535 6662 Nurse Practitioners: 020 8535 6664 Clinical Research Unit: 020 85395522 (Extn 6262 or 5168) Fax: 020 85585038 Out Patient Clinic Reception: 020 85395522 (Extn 6031)