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Multicenter audit on the use of Leflunomide, in isolation or combination and assessment of adverse effects in rheumatoid arthritis patients
Indian Journal of Rheumatology 2011 March Volume 6, Number 1; pp. 3–6
Original Article
Multicenter audit on the use of Leflunomide, in isolation or combination and assessment of adverse effects in rheumatoid arthritis patients Dinesh Sirisena1, Tarnya Marshall2, Christopher Deighton3, Kuntal Chakravarty4,5*
ABSTRACT Background: Rheumatoid arthritis (RA) is a highly prevalent condition worldwide with significant associated morbidity and disability. In recent decades, disease modifying anti-rheumatic drugs (DMARDs) have been employed as mono or combination therapy to halt disease progression and the sequelaefrom occurring. Due to immunomodulatory effects, the frequency of monitoring adverse effects and termination of medication has long been under scrutiny. Aim: This multicentre audit considered Leflunomide use in clinical practice. Factors considered include the underlying condition treated, starting and maintenance doses, whether it was a mono or combination therapy, side effects reported and monitoring conducted. Methods: A retrospective review of case-notes from Leflunomide-treated patients was conducted at three centres in the UK. A pre-agreed proforma was completed to collect data appropriate to each aim. Results: Four hundred and twenty-seven case-notes were reviewed. Over 95% of patients received it for RA, 20 mg was the commonest loading/maintenance dose and 80% were treated with Leflunomide as mono-therapy. Gastrointestinal symptoms (18%) were the most prevalent side effects with most occurring within the first 6 weeks. A reduction in clinical efficacy was noted in 21% of patients. Monitoring varied significantly at each of the centre but little difference in the outcome was noted. Conclusion: While DMARDs have become first-line treatmentsin RA, increasing evidence suggests that monitoring does not need to be as rigorous as previously believed. This audit highlights a relative advantagein using Leflunomide in terms of dosing, its use as a mono-or combination therapy, side effects, long-term tolerability and monitoring. Keywords: Leflunomide, audit, rheumatoid arthritis
INTRODUCTION Rheumatoid arthritis (RA) is one of the commonest autoimmune diseases. The incidence of RA is less than 1% and it tends to affect women over the age of 40 years. While it is not a typically life-threatening disease, due to the cryptic nature of its progression, the quality of life can be severely compromised causing irreversible disability and handicap in some cases.1 There are a large number of disease modifying antirheumatic drugs (DMARDs) regularly used to prevent 1
deformity and long-term disability.2–5 They are designed to arrest the progression of this disease both in clinical and radiological terms and can be used as mono-therapy or in combination. However, there is no clear evidence of one DMARD being necessarily superior to another. The patient’s choice, disease activity, co-morbidity, the toxicity profile of the drug in question and also the cost of treatment and monitoring often influence the rheumatologist’s choice of DMARD. Recent evidence based on the British Society of Rheumatology (BSR)/British Health Professionals in
Sports Medicine Registrar, Hammersmith Hospital, London, 2Consultant Rheumatologist, Norfolk and Norwich University Hospital, Norwich, Consultant Rheumatologist, Derbyshire Royal Infirmary, Derby, Yorkshire, 4Consultant Rheumatologist, Queen’s Hospital, BHR NHS Trust, Romford, Essex, 5Professor of Rheumatology, Postgraduate Medical School, University of Bedfordshire. Correspondence: Dr. Kuntal Chakravarty, email: [email protected] 3
4
Indian Journal of Rheumatology 2011 March; Vol. 6, No. 1
Rheumatology (BHPR) DMARD guideline suggests less frequent monitoring is sufficient for certain drugs, particularly Leflunomide and Methotrexate.6
AIM A ‘true to life’ multicentre audit to ascertain the use of Leflunomide in patients with inflammatory arthritis was conducted. Particular note was made to the dose, frequency of monitoring, severity of the RA and incidence of adverse effects including the time at which these effects occurred when used in isolation or in combination with another DMARD.
Sirisena et al.
Duration of treatment Eighty-four (84/427; 19.6%) patients tolerated the medication for up to and beyond 24 months. One hundred and sixty-three (163/427; 38%) patients had their treatment discontinued due to side effects and of these 62 (62/163; 49%) were within the first 6 weeks of commencing treatment (Figure 1).
Mono-therapy versus combination treatment Overall almost 341 (341/427; 80%) patients commenced Leflunomide as a mono-therapy with a small proportion receiving it as combination therapy with Methotrexate (51/427; 12%) or rarely with another drug such as Sulfasalazine or Azathioprine (34/427; 8%).
METHODOLOGY
Initial loading dose
A retrospective questionnaire (Appendix 1: available on web version) survey was undertaken to assess case notes at three large Rheumatology departments in the United Kingdom, Norwich, Derby, and Romford. The questionnaire format was agreed between all three centres prior to collection of the data and information was collected anonymously at individual centres by the consultants and their team.
Across the study population, a loading dose of 100 mg once daily for 3 days was used in 145 (145/427; 34%) patients while the majority (282/427; 66%) received 20 mg once daily as a starting and maintenance dose as part of their therapy.
Clinical efficacy
RESULTS Four hundred and twenty-seven case notes were reviewed for patients who received Leflunomide and data was collected according to the agreed questionnaire.
Demographics From the 427 patients, 120 (120/427; 28%) were males and 307 (307/427; 62%) were females (male:female = 1:2.5). The mean age of patients was 67.8 years (range 15–83 years).
Primary diagnoses In this audit over 95% patients received Leflunomide for RA. Smaller numbers received this treatment for psoriatic arthritis and other undifferentiated inflammatory arthritis. There was no significant difference between centres in the choice of this drug for RA.
The clinical efficacy of mono-therapy with Leflunomide, as determined by the supervising clinician, was noted in almost 299 (299/427; 70%) of the population studied. There was no significant difference in terms of clinical benefit between genders. When comparing outcomes for those treated with or without a loading dose there was no statistically significant difference between the two groups (35% vs. 39%). Although the drug was effective and well tolerated by many patients, these patients were also receiving variable dose of non-steroidal anti-inflammatory drugs.
Choice of leflunomide Most patients were chosen for Leflunomide therapy on the back of failing to respond to other DMARDS such as Hydroxychloroquine, Methotrexate, Sulfasalazine or their combinations. The majority (358/427; 84%) had been unsuccessful with Methotrexate prior to starting Leflunomide. One centre used Leflunomide as the first-line DMARD for 25% of their patients with continued uninterrupted treatment for 2 years.
Multicenter audit on the use of Leflunomide
Original Article
5
100 90 80
Number
70 60 50 40 30 20 10 0 0–2
2–4
4–6
6–8
8–10 10–12 12–14 14–16 16–18 18–20 20–22 22–24 Weeks
24+
Figure 1 Graph showing variations in the duration of treatment with Leflunomide.
the treatment period nor were any of the patients admitted to the hospital due to any adverse effects. None of the patients included in the study developed significant pulmonary complications although at one centre two patients discontinued Leflunomide due to exacerbations of pre-existing bronchial asthma. Most patients with adverse effects were reported within the first few weeks, but some develop difficulties beyond the six-month period.
90 80
Number
70 60 50 40 30 20
Efficacy
10 0 Gastrointestinal
Skin Haematological Spectrum of side effects
Hepatic
Figure 2 Graph Showing the common side effects reported while being treated with Leflunomide.
Adverse effects Overall, adverse effects were noted in 204 (204/427; 48%) patients with 80(80/427; 18%) patients complaining of gastrointestinal (GI) symptoms in the form of diarrhoea. Fifty (50/427; 11%) patients developed haematological complaints while less than 10% (30/427; 7%) had dermatological side effects. Hepatic enzymes were elevated in 53(53/427; 12%) patients without clinically significant liver disease. There was no evidence of irreversible organ damage due to Leflunomide in this survey. Asymptomatic rises in systolic as well as diastolic blood pressure were noted in less than 10% (43/427) of patients but none required discontinuation of Leflunomide. Neither was pregnancy reported during
Of the total population, 90(90/427; 21%) patients noted a loss of efficacy to Leflunomide after variable periods.
Monitoring Most patients were monitored in the hospital setting. In two centres, this was via Specialist Nurse Clinics but at one centre, medical staff reviewed all patients and a shared-care approach with patients was employed. Three hundred and forty-one (341/427; 80%) patients had their blood pressure measured on a monthly basis. In one centre all patients had their blood tests monitored on a fortnightly basis and 50% of patients had blood tests on a monthly basis in the other two centres.
DISCUSSION This ‘true to life’ audit highlights the possibility of less rigorous drug monitoring for patients treated with Leflunomide.
6
Indian Journal of Rheumatology 2011 March; Vol. 6, No. 1
Although one centre monitored blood tests on a two-weekly basis, there was no evidence of a significantly higher ‘detection rate’ in that group or greater numbers of ‘near misses’ in patients who were monitored monthly. Gastrointestinal side effects appeared to be the primary reason for discontinuing therapy in a small proportion of patients. There were no significant pulmonary side effects noted throughout the study population. Leflunomide was also noted to be fairly safe when used in combination with Sulfasalazine and/or Methotrexate. There was no rise of blood pressure within the study group to warrant discontinuation of Leflunomide. Some patients, already within the hypertensive range for elevated blood pressure, needed more regular and closer monitoring without having to stop the drug.
Sirisena et al.
ACKNOWLEDGEMENTS We would like to thank R Dulai and G Sovilkar, both 4th year students, for their help with data collection and contribution to this paper.
REFERENCES 1.
2.
CONCLUSION This large multicentre study highlights the clinical effectiveness and efficacy of Leflunomide as a DMARD for patients with RA and other inflammatory arthritis. The efficacy, as assessed in this retrospective audit, was based on the supervising clinician’s impression of the outcome with Leflunomide. It may be a reflection of greater tolerability of Leflunomide, noticed in patients who had been given this drug as a first-line treatment rather than other DMARDs. Furthermore, Leflunomide was safe, efficacious and well tolerated in the majority of patients without any major adverse effects. It appears from this retrospective audit that there is still some anxiety about the combination therapy of Methotrexate and Leflunomide. This alleviates when used as a monotherapy.
3.
4.
5.
6.
Luqmani R, Hennell S, Estrach C, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of rheumatoid arthritis (after the first 2 years). Rheumatology 2009; 48: 436–9. Rath T, Rubbert A. Drug combinations with methotrexate to treat rheumatoid arthritis. Clin Exp Rheumatol 2010; 28(5 Suppl 61): S52–7. [Epub 2010 Oct 28] Calgüneri M, Pay S, Caliskaner Z, et al. Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis. Clin Exp Rheumatol 1999; 17: 699–704. Münster T, Furst DE. Pharmacotherapeutic strategies for disease-modifying antirheumatic drug (DMARD) combinations to treat rheumatoid arthritis (RA). Clin Exp Rheumatol 1999; 17(6 Suppl 18): S29–36. Aletaha D, Smolen JS. DMARD use in early rheumatoid arthritis. Lessons from observations in patients with established disease. Clin Exp Rheumatol 2003; 21(5 Suppl 31): S169–73. Chakravarty K, McDonald H, Pullar T, et al. BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. Rheumatology 2008; 47: 924–5. [Epub 2006 Aug 28]
Original Article
Multicenter audit on the use of Leflunomide, in isolation or combination and assessment of adverse effects in rheumatoid arthritis patients Dinesh Sirisena1, Tarnya Marshall2, Christopher Deighton3, Kuntal Chakravarty4,5*
ABSTRACT Background: Rheumatoid arthritis (RA) is a highly prevalent condition worldwide with significant associated morbidity and disability. In recent decades, disease modifying anti-rheumatic drugs (DMARDs) have been employed as mono or combination therapy to halt disease progression and the sequelaefrom occurring. Due to immunomodulatory effects, the frequency of monitoring adverse effects and termination of medication has long been under scrutiny. Aim: This multicentre audit considered Leflunomide use in clinical practice. Factors considered include the underlying condition treated, starting and maintenance doses, whether it was a mono or combination therapy, side effects reported and monitoring conducted. Methods: A retrospective review of case-notes from Leflunomide-treated patients was conducted at three centres in the UK. A pre-agreed proforma was completed to collect data appropriate to each aim. Results: Four hundred and twenty-seven case-notes were reviewed. Over 95% of patients received it for RA, 20 mg was the commonest loading/maintenance dose and 80% were treated with Leflunomide as mono-therapy. Gastrointestinal symptoms (18%) were the most prevalent side effects with most occurring within the first 6 weeks. A reduction in clinical efficacy was noted in 21% of patients. Monitoring varied significantly at each of the centre but little difference in the outcome was noted. Conclusion: While DMARDs have become first-line treatmentsin RA, increasing evidence suggests that monitoring does not need to be as rigorous as previously believed. This audit highlights a relative advantagein using Leflunomide in terms of dosing, its use as a mono-or combination therapy, side effects, long-term tolerability and monitoring. Keywords: Leflunomide, audit, rheumatoid arthritis
INTRODUCTION Rheumatoid arthritis (RA) is one of the commonest autoimmune diseases. The incidence of RA is less than 1% and it tends to affect women over the age of 40 years. While it is not a typically life-threatening disease, due to the cryptic nature of its progression, the quality of life can be severely compromised causing irreversible disability and handicap in some cases.1 There are a large number of disease modifying antirheumatic drugs (DMARDs) regularly used to prevent 1
deformity and long-term disability.2–5 They are designed to arrest the progression of this disease both in clinical and radiological terms and can be used as mono-therapy or in combination. However, there is no clear evidence of one DMARD being necessarily superior to another. The patient’s choice, disease activity, co-morbidity, the toxicity profile of the drug in question and also the cost of treatment and monitoring often influence the rheumatologist’s choice of DMARD. Recent evidence based on the British Society of Rheumatology (BSR)/British Health Professionals in
Sports Medicine Registrar, Hammersmith Hospital, London, 2Consultant Rheumatologist, Norfolk and Norwich University Hospital, Norwich, Consultant Rheumatologist, Derbyshire Royal Infirmary, Derby, Yorkshire, 4Consultant Rheumatologist, Queen’s Hospital, BHR NHS Trust, Romford, Essex, 5Professor of Rheumatology, Postgraduate Medical School, University of Bedfordshire. Correspondence: Dr. Kuntal Chakravarty, email: [email protected] 3
4
Indian Journal of Rheumatology 2011 March; Vol. 6, No. 1
Rheumatology (BHPR) DMARD guideline suggests less frequent monitoring is sufficient for certain drugs, particularly Leflunomide and Methotrexate.6
AIM A ‘true to life’ multicentre audit to ascertain the use of Leflunomide in patients with inflammatory arthritis was conducted. Particular note was made to the dose, frequency of monitoring, severity of the RA and incidence of adverse effects including the time at which these effects occurred when used in isolation or in combination with another DMARD.
Sirisena et al.
Duration of treatment Eighty-four (84/427; 19.6%) patients tolerated the medication for up to and beyond 24 months. One hundred and sixty-three (163/427; 38%) patients had their treatment discontinued due to side effects and of these 62 (62/163; 49%) were within the first 6 weeks of commencing treatment (Figure 1).
Mono-therapy versus combination treatment Overall almost 341 (341/427; 80%) patients commenced Leflunomide as a mono-therapy with a small proportion receiving it as combination therapy with Methotrexate (51/427; 12%) or rarely with another drug such as Sulfasalazine or Azathioprine (34/427; 8%).
METHODOLOGY
Initial loading dose
A retrospective questionnaire (Appendix 1: available on web version) survey was undertaken to assess case notes at three large Rheumatology departments in the United Kingdom, Norwich, Derby, and Romford. The questionnaire format was agreed between all three centres prior to collection of the data and information was collected anonymously at individual centres by the consultants and their team.
Across the study population, a loading dose of 100 mg once daily for 3 days was used in 145 (145/427; 34%) patients while the majority (282/427; 66%) received 20 mg once daily as a starting and maintenance dose as part of their therapy.
Clinical efficacy
RESULTS Four hundred and twenty-seven case notes were reviewed for patients who received Leflunomide and data was collected according to the agreed questionnaire.
Demographics From the 427 patients, 120 (120/427; 28%) were males and 307 (307/427; 62%) were females (male:female = 1:2.5). The mean age of patients was 67.8 years (range 15–83 years).
Primary diagnoses In this audit over 95% patients received Leflunomide for RA. Smaller numbers received this treatment for psoriatic arthritis and other undifferentiated inflammatory arthritis. There was no significant difference between centres in the choice of this drug for RA.
The clinical efficacy of mono-therapy with Leflunomide, as determined by the supervising clinician, was noted in almost 299 (299/427; 70%) of the population studied. There was no significant difference in terms of clinical benefit between genders. When comparing outcomes for those treated with or without a loading dose there was no statistically significant difference between the two groups (35% vs. 39%). Although the drug was effective and well tolerated by many patients, these patients were also receiving variable dose of non-steroidal anti-inflammatory drugs.
Choice of leflunomide Most patients were chosen for Leflunomide therapy on the back of failing to respond to other DMARDS such as Hydroxychloroquine, Methotrexate, Sulfasalazine or their combinations. The majority (358/427; 84%) had been unsuccessful with Methotrexate prior to starting Leflunomide. One centre used Leflunomide as the first-line DMARD for 25% of their patients with continued uninterrupted treatment for 2 years.
Multicenter audit on the use of Leflunomide
Original Article
5
100 90 80
Number
70 60 50 40 30 20 10 0 0–2
2–4
4–6
6–8
8–10 10–12 12–14 14–16 16–18 18–20 20–22 22–24 Weeks
24+
Figure 1 Graph showing variations in the duration of treatment with Leflunomide.
the treatment period nor were any of the patients admitted to the hospital due to any adverse effects. None of the patients included in the study developed significant pulmonary complications although at one centre two patients discontinued Leflunomide due to exacerbations of pre-existing bronchial asthma. Most patients with adverse effects were reported within the first few weeks, but some develop difficulties beyond the six-month period.
90 80
Number
70 60 50 40 30 20
Efficacy
10 0 Gastrointestinal
Skin Haematological Spectrum of side effects
Hepatic
Figure 2 Graph Showing the common side effects reported while being treated with Leflunomide.
Adverse effects Overall, adverse effects were noted in 204 (204/427; 48%) patients with 80(80/427; 18%) patients complaining of gastrointestinal (GI) symptoms in the form of diarrhoea. Fifty (50/427; 11%) patients developed haematological complaints while less than 10% (30/427; 7%) had dermatological side effects. Hepatic enzymes were elevated in 53(53/427; 12%) patients without clinically significant liver disease. There was no evidence of irreversible organ damage due to Leflunomide in this survey. Asymptomatic rises in systolic as well as diastolic blood pressure were noted in less than 10% (43/427) of patients but none required discontinuation of Leflunomide. Neither was pregnancy reported during
Of the total population, 90(90/427; 21%) patients noted a loss of efficacy to Leflunomide after variable periods.
Monitoring Most patients were monitored in the hospital setting. In two centres, this was via Specialist Nurse Clinics but at one centre, medical staff reviewed all patients and a shared-care approach with patients was employed. Three hundred and forty-one (341/427; 80%) patients had their blood pressure measured on a monthly basis. In one centre all patients had their blood tests monitored on a fortnightly basis and 50% of patients had blood tests on a monthly basis in the other two centres.
DISCUSSION This ‘true to life’ audit highlights the possibility of less rigorous drug monitoring for patients treated with Leflunomide.
6
Indian Journal of Rheumatology 2011 March; Vol. 6, No. 1
Although one centre monitored blood tests on a two-weekly basis, there was no evidence of a significantly higher ‘detection rate’ in that group or greater numbers of ‘near misses’ in patients who were monitored monthly. Gastrointestinal side effects appeared to be the primary reason for discontinuing therapy in a small proportion of patients. There were no significant pulmonary side effects noted throughout the study population. Leflunomide was also noted to be fairly safe when used in combination with Sulfasalazine and/or Methotrexate. There was no rise of blood pressure within the study group to warrant discontinuation of Leflunomide. Some patients, already within the hypertensive range for elevated blood pressure, needed more regular and closer monitoring without having to stop the drug.
Sirisena et al.
ACKNOWLEDGEMENTS We would like to thank R Dulai and G Sovilkar, both 4th year students, for their help with data collection and contribution to this paper.
REFERENCES 1.
2.
CONCLUSION This large multicentre study highlights the clinical effectiveness and efficacy of Leflunomide as a DMARD for patients with RA and other inflammatory arthritis. The efficacy, as assessed in this retrospective audit, was based on the supervising clinician’s impression of the outcome with Leflunomide. It may be a reflection of greater tolerability of Leflunomide, noticed in patients who had been given this drug as a first-line treatment rather than other DMARDs. Furthermore, Leflunomide was safe, efficacious and well tolerated in the majority of patients without any major adverse effects. It appears from this retrospective audit that there is still some anxiety about the combination therapy of Methotrexate and Leflunomide. This alleviates when used as a monotherapy.
3.
4.
5.
6.
Luqmani R, Hennell S, Estrach C, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of rheumatoid arthritis (after the first 2 years). Rheumatology 2009; 48: 436–9. Rath T, Rubbert A. Drug combinations with methotrexate to treat rheumatoid arthritis. Clin Exp Rheumatol 2010; 28(5 Suppl 61): S52–7. [Epub 2010 Oct 28] Calgüneri M, Pay S, Caliskaner Z, et al. Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis. Clin Exp Rheumatol 1999; 17: 699–704. Münster T, Furst DE. Pharmacotherapeutic strategies for disease-modifying antirheumatic drug (DMARD) combinations to treat rheumatoid arthritis (RA). Clin Exp Rheumatol 1999; 17(6 Suppl 18): S29–36. Aletaha D, Smolen JS. DMARD use in early rheumatoid arthritis. Lessons from observations in patients with established disease. Clin Exp Rheumatol 2003; 21(5 Suppl 31): S169–73. Chakravarty K, McDonald H, Pullar T, et al. BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. Rheumatology 2008; 47: 924–5. [Epub 2006 Aug 28]