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Antimalarials in the treatment of systemic lupus erythematosus: a registry-based cohort study in Denmark J C Nørgaard, K Stengaard-Pedersen, M Nørgaard and A de Thurah Lupus published online 15 October 2014 DOI: 10.1177/0961203314555351 The online version of this article can be found at: http://lup.sagepub.com/content/early/2014/10/15/0961203314555351
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Antimalarials in the treatment of systemic lupus erythematosus: a registry-based cohort study in Denmark JC Nørgaard1, K Stengaard-Pedersen1, M Nørgaard2 and A de Thurah1,3 1
Department of Rheumatology; 2Department of Clinical Epidemiology; and 3Institute of Public Health, and Department of Clinical Medicine, Aarhus University Hospital, Denmark
Background: Evidence-based international guidelines for the treatment of systemic lupus erythematosus (SLE) recommend treatment with antimalarials (AMs) for all patients with SLE irrespective of disease activity. Only a few studies have investigated the use of AMs among newly diagnosed patients with SLE. Objectives: The objective of this paper is to analyze prescription patterns of AMs in newly diagnosed SLE patients in Denmark from 2000 to 2011. Methods: Using the Danish Prescription Register (DNPR), we conducted a nationwide cohort study including all patients with a first-time diagnosis of SLE (the Danish National Registry of Patients (NPR)). We used Kaplan-Meier estimates to compute the cumulative probability of starting AM treatment within a year and Cox regression analysis to compare time to treatment between patient groups. Results: AMs were prescribed to 37.7% of the newly diagnosed SLE patients within the first year of follow-up. Approximately 20% did not receive any medical treatment. Women were more likely than men to start AM (adjusted HR of 1.28 (95% CI 1.08–1.52)). Patients diagnosed with SLE between 2005 and 2011 were more likely to start treatment than patients diagnosed between 2000 and 2004 (HR of 1.21 (95% CI 1.07–1.36)). Patients with renal disease were less likely to start AM treatment than patients without this condition (adjusted HR of 0.50 (95% CI 0.36–0.68)). Current users of corticosteroids were more likely to start AM treatment than non-users (adjusted HR 1.81 (95% CI 1.59–2.06)). Conclusion: Time to start of AM treatment following SLE diagnosis could be further reduced, especially among patients with renal disease. However, our results showed that treatment practice in recent years has changed toward initiating AM treatment earlier. Lupus (2014) 0, 1–8. Key words: Systemic lupus erythematosus; hydroxychloroquine; chloroquine; antimalarials; time to treatment
Introduction Systemic lupus erythematosus (SLE) is a complex chronic autoimmune disorder with an annual incidence rate varying from 1.4 to 5.6 per 100,000 person-years.1–3 SLE can affect any organ of the body and symptoms vary widely. Today, antimalarial (AM) treatment, mainly hydroxychloroquine (HCQ) and chloroquine, is considered a key element in the treatment of SLE, and is administered as monotherapy or together with other agents such as Correspondence to: Jens Christian Nørgaard, Department of Rheumatology, Aarhus University Hospital, Viborgvej 14, 8000 Aarhus C, Denmark. Email: [email protected] Received 10 April 2014; revised: 10 August 2014; 15 September 2014; accepted 22 September 2014
corticosteroids and immunosuppressive drugs, such as mycophenolate, azathioprine and cyclophosphamide. SLE patients have an increased mortality rate compared with the general population.4–8 During the past decades, however, a 50% reduction in five-year mortality has been observed.9,10 Today, it is generally accepted that the increased use of AM treatment has contributed to improved survival among SLE patients.11 A Canadian study12 included 47 SLE patients with mild disease activity treated with HCQ; these patients were randomized to either placebo or continued HCQ treatment. The main outcome measure was occurrence of a major flare. After 42 months, major flares had occurred in 28% in the HCQ group and in 50% in the placebo group. This supports the view that HCQ limits progression of mild or inactive disease.12
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10.1177/0961203314555351
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(LUP)
[1–8] [PREPRINTER stage]
Antimalarials in the treatment of SLE: a registry-based cohort study in Denmark JC Nørgaard et al.
2
Earlier recommendations from the European League Against Rheumatism (EULAR) restricted the use of AM to patients with non-organ involvement.13 It has, however, been suggested that AM treatment may be underused among patients with mild and with more severe disease activity.11 A recent systematic review including 95 studies of SLE patients treated with HCQ argued against the EULAR recommendations.14 The review included all available evidence of beneficial and nonbeneficial effects of AM treatment in SLE patients, and found a reduction both in lupus activity and mortality of more than 50%. Thus, recommendations were changed and AM treatment should be offered to the majority of SLE patients irrespective of disease activity.14 Further, recent American and European guidelines for the management of lupus nephritis both recommend HCQ as background therapy.15,16 To our knowledge, no studies have specifically investigated treatment patterns of AM in SLE patients during a longer period of time. Using a registry-based prescription database, we aimed to study the prescription pattern of AM treatment in newly diagnosed patients with SLE in Denmark from 2000 to 2011, focusing on the occurrence of renal disease, and use of corticosteroids and other concurrent drugs.
emergency contacts to hospitals since 1995. Data are recorded in the NPR with primary and secondary diagnoses according to the International Classification of Diseases, 10th revision (ICD-10) and ICD-8 codes. We used the ICD-10 codes DM3.2, DM32.1, DM32.8 and DM32.9 to identify patients with a first-time SLE diagnosis; both primary and secondary codes were used. Identification of AM treatment—HCQ and chloroquine
Methods
The Danish National Prescription Registry (DNPR) was used to retrieve data on AM treatment. The DNPR contains information on all prescriptive drugs redeemed at Danish community pharmacies since 1994. The DNPS is a redemption database. All pharmacies in Denmark are equipped with electronic accounting systems used to secure reimbursement from the National Health Service, which funds a variable proportion of the cost of prescribed medicine for all Danish citizens. Data are transferred to the DNPR, which thus covers all reimbursed drugs at the level of the individual user. These data include the CRS number, the type and amount of drug prescribed according to the Anatomical Therapeutical Chemical Classification System (ATC), and the date of drug redemption. Data on each redeemed prescription are transferred from the pharmacies to the DNPR.20 In our study, the ATC codes P01BA01 (HCQ) and P01BA02 (chloroquine) were used to identify AM treatment.
Study population
Concurrent drugs
This cohort study of patients with SLE was based on the entire Danish population of approximately 5.5 million inhabitants.17 The Danish health care system provides free and equal access to taxfinanced health care; in Denmark, patients with SLE are treated exclusively at public hospitals. Since 1968, a 10-digit registration number has been assigned to all Danish residents at birth or immigration from the Danish Civil Registration System (CRS). This number (which encodes gender and date of birth) enables highly valid linkage of data between Danish registries.18
Information on concurrent drugs was retrieved from the DNPR and identified by the use of ATC codes. We defined a patient as a concurrent drug user if at least one prescription was redeemed within six months from the date of SLE diagnosis. The following drugs were included: prednisolone (H02AB06), mycophenolate (L04AA06), azathioprine (L04AX01), Advagraf (L04AD02), methotrexate (MTX) (L01BA01 and L04AX03), cyclophosphamide (L01AA01) and rituximab (L01XC02). Comorbidity
Identification of patients diagnosed with SLE 19
The Danish National Registry of Patients (NPR) was used to identify all patients with a first-time diagnosis of SLE from January 1, 2000 to December 31, 2011. The NPR contains data on admission and discharge from all Danish somatic hospitals since 1977 and from outpatient and
A Charlson Comorbidity Index (CCI)21 score was completed for each patient based on data from the NPR using a five-year period before diagnosis. CCI was originally developed to predict the risk of oneyear mortality attributable to comorbidity in a longitudinal study of 604 American hospitalized patients. The CCI has, however, also been useful
Lupus Downloaded from lup.sagepub.com at LAURENTIAN UNIV LIBRARY on December 7, 2014
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(LUP)
[1–8] [PREPRINTER stage]
Antimalarials in the treatment of SLE: a registry-based cohort study in Denmark JC Nørgaard et al.
3
to identify comorbidity in a group of patients with SLE.22,23 We computed a CCI score for each SLE patient and because we had only a few patients with high levels of comorbidity prior to diagnosis, we classified comorbidity into only two groups according to CCI score: 0 (no comorbidity) and >0 (comorbidity present). Renal disease Information on renal disease was retrieved from the NPR using the ICD-10 codes N08.5, N08.8 and N08.2. A patient was categorized as having renal disease if a diagnosis was recorded in the NPR anytime within five years before SLE diagnosis until six months after. Cardiovascular disease (CVD) Using the DNPR, a patient was defined as having CVD if a prescription was redeemed for any of the following drugs (ATC code) within the first six months after SLE diagnosis: beta blockers (C07AB), angiotensin-converting enzyme (ACE) inhibitors (C09A), angiotensin II antagonists (C09C), diuretics (C03), calcium channel blockers (C08), antithrombotic agents (B01A) and statins (C10AA). We created a CVD variable on the basis of the prescribed CVD medication in the cohort. Further, we used data from the DNPR to retrieve data on severe CVD diagnosis (ICD-10: I21.0–I21.9). Age, gender and death Information on gender and age was retrieved from the CRS system. Age at the date of the diagnosis was recorded. Information on death was retrieved from the Danish Cause of Death Register. This register contains information about date and cause of death of Danish citizens; the register has a high level of completeness.24 Statistical analysis methods We included patients on the date of their first SLE diagnosis and followed them until December 31, 2011, death or start of AM treatment, whichever came first. If a patient received AM treatment before the day of the diagnosis (T0), he or she was defined as starting at T0. To determine if patients starting AM treatment differed from those who did not, we compared the two groups and analyzed for differences in age, gender, time of diagnosis, concurrent medication and comorbidity. We used Kaplan-Meier estimates to compute
cumulative probability of starting AM treatment as a function of time since first SLE diagnosis, among SLE patients receiving AM treatment during the follow-up period. We stratified by age (
http://lup.sagepub.com/
Antimalarials in the treatment of systemic lupus erythematosus: a registry-based cohort study in Denmark J C Nørgaard, K Stengaard-Pedersen, M Nørgaard and A de Thurah Lupus published online 15 October 2014 DOI: 10.1177/0961203314555351 The online version of this article can be found at: http://lup.sagepub.com/content/early/2014/10/15/0961203314555351
Published by: http://www.sagepublications.com
Additional services and information for Lupus can be found at: Email Alerts: http://lup.sagepub.com/cgi/alerts Subscriptions: http://lup.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Oct 15, 2014 What is This?
Downloaded from lup.sagepub.com at LAURENTIAN UNIV LIBRARY on December 7, 2014
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(LUP)
[1–8] [PREPRINTER stage]
Lupus (2014) 0,
1–8
http://lup.sagepub.com
PAPER
Antimalarials in the treatment of systemic lupus erythematosus: a registry-based cohort study in Denmark JC Nørgaard1, K Stengaard-Pedersen1, M Nørgaard2 and A de Thurah1,3 1
Department of Rheumatology; 2Department of Clinical Epidemiology; and 3Institute of Public Health, and Department of Clinical Medicine, Aarhus University Hospital, Denmark
Background: Evidence-based international guidelines for the treatment of systemic lupus erythematosus (SLE) recommend treatment with antimalarials (AMs) for all patients with SLE irrespective of disease activity. Only a few studies have investigated the use of AMs among newly diagnosed patients with SLE. Objectives: The objective of this paper is to analyze prescription patterns of AMs in newly diagnosed SLE patients in Denmark from 2000 to 2011. Methods: Using the Danish Prescription Register (DNPR), we conducted a nationwide cohort study including all patients with a first-time diagnosis of SLE (the Danish National Registry of Patients (NPR)). We used Kaplan-Meier estimates to compute the cumulative probability of starting AM treatment within a year and Cox regression analysis to compare time to treatment between patient groups. Results: AMs were prescribed to 37.7% of the newly diagnosed SLE patients within the first year of follow-up. Approximately 20% did not receive any medical treatment. Women were more likely than men to start AM (adjusted HR of 1.28 (95% CI 1.08–1.52)). Patients diagnosed with SLE between 2005 and 2011 were more likely to start treatment than patients diagnosed between 2000 and 2004 (HR of 1.21 (95% CI 1.07–1.36)). Patients with renal disease were less likely to start AM treatment than patients without this condition (adjusted HR of 0.50 (95% CI 0.36–0.68)). Current users of corticosteroids were more likely to start AM treatment than non-users (adjusted HR 1.81 (95% CI 1.59–2.06)). Conclusion: Time to start of AM treatment following SLE diagnosis could be further reduced, especially among patients with renal disease. However, our results showed that treatment practice in recent years has changed toward initiating AM treatment earlier. Lupus (2014) 0, 1–8. Key words: Systemic lupus erythematosus; hydroxychloroquine; chloroquine; antimalarials; time to treatment
Introduction Systemic lupus erythematosus (SLE) is a complex chronic autoimmune disorder with an annual incidence rate varying from 1.4 to 5.6 per 100,000 person-years.1–3 SLE can affect any organ of the body and symptoms vary widely. Today, antimalarial (AM) treatment, mainly hydroxychloroquine (HCQ) and chloroquine, is considered a key element in the treatment of SLE, and is administered as monotherapy or together with other agents such as Correspondence to: Jens Christian Nørgaard, Department of Rheumatology, Aarhus University Hospital, Viborgvej 14, 8000 Aarhus C, Denmark. Email: [email protected] Received 10 April 2014; revised: 10 August 2014; 15 September 2014; accepted 22 September 2014
corticosteroids and immunosuppressive drugs, such as mycophenolate, azathioprine and cyclophosphamide. SLE patients have an increased mortality rate compared with the general population.4–8 During the past decades, however, a 50% reduction in five-year mortality has been observed.9,10 Today, it is generally accepted that the increased use of AM treatment has contributed to improved survival among SLE patients.11 A Canadian study12 included 47 SLE patients with mild disease activity treated with HCQ; these patients were randomized to either placebo or continued HCQ treatment. The main outcome measure was occurrence of a major flare. After 42 months, major flares had occurred in 28% in the HCQ group and in 50% in the placebo group. This supports the view that HCQ limits progression of mild or inactive disease.12
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at LAURENTIAN UNIV LIBRARY on December 7, 2014
10.1177/0961203314555351
XML Template (2014) [14.10.2014–10:02am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/LUPJ/Vol00000/140212/APPFile/SG-LUPJ140212.3d
(LUP)
[1–8] [PREPRINTER stage]
Antimalarials in the treatment of SLE: a registry-based cohort study in Denmark JC Nørgaard et al.
2
Earlier recommendations from the European League Against Rheumatism (EULAR) restricted the use of AM to patients with non-organ involvement.13 It has, however, been suggested that AM treatment may be underused among patients with mild and with more severe disease activity.11 A recent systematic review including 95 studies of SLE patients treated with HCQ argued against the EULAR recommendations.14 The review included all available evidence of beneficial and nonbeneficial effects of AM treatment in SLE patients, and found a reduction both in lupus activity and mortality of more than 50%. Thus, recommendations were changed and AM treatment should be offered to the majority of SLE patients irrespective of disease activity.14 Further, recent American and European guidelines for the management of lupus nephritis both recommend HCQ as background therapy.15,16 To our knowledge, no studies have specifically investigated treatment patterns of AM in SLE patients during a longer period of time. Using a registry-based prescription database, we aimed to study the prescription pattern of AM treatment in newly diagnosed patients with SLE in Denmark from 2000 to 2011, focusing on the occurrence of renal disease, and use of corticosteroids and other concurrent drugs.
emergency contacts to hospitals since 1995. Data are recorded in the NPR with primary and secondary diagnoses according to the International Classification of Diseases, 10th revision (ICD-10) and ICD-8 codes. We used the ICD-10 codes DM3.2, DM32.1, DM32.8 and DM32.9 to identify patients with a first-time SLE diagnosis; both primary and secondary codes were used. Identification of AM treatment—HCQ and chloroquine
Methods
The Danish National Prescription Registry (DNPR) was used to retrieve data on AM treatment. The DNPR contains information on all prescriptive drugs redeemed at Danish community pharmacies since 1994. The DNPS is a redemption database. All pharmacies in Denmark are equipped with electronic accounting systems used to secure reimbursement from the National Health Service, which funds a variable proportion of the cost of prescribed medicine for all Danish citizens. Data are transferred to the DNPR, which thus covers all reimbursed drugs at the level of the individual user. These data include the CRS number, the type and amount of drug prescribed according to the Anatomical Therapeutical Chemical Classification System (ATC), and the date of drug redemption. Data on each redeemed prescription are transferred from the pharmacies to the DNPR.20 In our study, the ATC codes P01BA01 (HCQ) and P01BA02 (chloroquine) were used to identify AM treatment.
Study population
Concurrent drugs
This cohort study of patients with SLE was based on the entire Danish population of approximately 5.5 million inhabitants.17 The Danish health care system provides free and equal access to taxfinanced health care; in Denmark, patients with SLE are treated exclusively at public hospitals. Since 1968, a 10-digit registration number has been assigned to all Danish residents at birth or immigration from the Danish Civil Registration System (CRS). This number (which encodes gender and date of birth) enables highly valid linkage of data between Danish registries.18
Information on concurrent drugs was retrieved from the DNPR and identified by the use of ATC codes. We defined a patient as a concurrent drug user if at least one prescription was redeemed within six months from the date of SLE diagnosis. The following drugs were included: prednisolone (H02AB06), mycophenolate (L04AA06), azathioprine (L04AX01), Advagraf (L04AD02), methotrexate (MTX) (L01BA01 and L04AX03), cyclophosphamide (L01AA01) and rituximab (L01XC02). Comorbidity
Identification of patients diagnosed with SLE 19
The Danish National Registry of Patients (NPR) was used to identify all patients with a first-time diagnosis of SLE from January 1, 2000 to December 31, 2011. The NPR contains data on admission and discharge from all Danish somatic hospitals since 1977 and from outpatient and
A Charlson Comorbidity Index (CCI)21 score was completed for each patient based on data from the NPR using a five-year period before diagnosis. CCI was originally developed to predict the risk of oneyear mortality attributable to comorbidity in a longitudinal study of 604 American hospitalized patients. The CCI has, however, also been useful
Lupus Downloaded from lup.sagepub.com at LAURENTIAN UNIV LIBRARY on December 7, 2014
XML Template (2014) [14.10.2014–10:02am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/LUPJ/Vol00000/140212/APPFile/SG-LUPJ140212.3d
(LUP)
[1–8] [PREPRINTER stage]
Antimalarials in the treatment of SLE: a registry-based cohort study in Denmark JC Nørgaard et al.
3
to identify comorbidity in a group of patients with SLE.22,23 We computed a CCI score for each SLE patient and because we had only a few patients with high levels of comorbidity prior to diagnosis, we classified comorbidity into only two groups according to CCI score: 0 (no comorbidity) and >0 (comorbidity present). Renal disease Information on renal disease was retrieved from the NPR using the ICD-10 codes N08.5, N08.8 and N08.2. A patient was categorized as having renal disease if a diagnosis was recorded in the NPR anytime within five years before SLE diagnosis until six months after. Cardiovascular disease (CVD) Using the DNPR, a patient was defined as having CVD if a prescription was redeemed for any of the following drugs (ATC code) within the first six months after SLE diagnosis: beta blockers (C07AB), angiotensin-converting enzyme (ACE) inhibitors (C09A), angiotensin II antagonists (C09C), diuretics (C03), calcium channel blockers (C08), antithrombotic agents (B01A) and statins (C10AA). We created a CVD variable on the basis of the prescribed CVD medication in the cohort. Further, we used data from the DNPR to retrieve data on severe CVD diagnosis (ICD-10: I21.0–I21.9). Age, gender and death Information on gender and age was retrieved from the CRS system. Age at the date of the diagnosis was recorded. Information on death was retrieved from the Danish Cause of Death Register. This register contains information about date and cause of death of Danish citizens; the register has a high level of completeness.24 Statistical analysis methods We included patients on the date of their first SLE diagnosis and followed them until December 31, 2011, death or start of AM treatment, whichever came first. If a patient received AM treatment before the day of the diagnosis (T0), he or she was defined as starting at T0. To determine if patients starting AM treatment differed from those who did not, we compared the two groups and analyzed for differences in age, gender, time of diagnosis, concurrent medication and comorbidity. We used Kaplan-Meier estimates to compute
cumulative probability of starting AM treatment as a function of time since first SLE diagnosis, among SLE patients receiving AM treatment during the follow-up period. We stratified by age (
