1. 2018 update of the EULAR recommendations for the management of systemic lupus erythematosus

2. Target population/question
Patients with systemic lupus erythematosus (SLE).
To update the previous (2007) EULAR recommendations for the management of SLE, based on available evidence and expert opinion.
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3. Systematic literature research (SLR) FINAL Recommendations
2017 Update of the EULAR Recommendations for the management of SLE
Methods/methodological approach
Consensual approach
Main research questions (including specific topics of interest)
Systematic literature research (SLR)
Extrapolation of the SLR results to inform clinically relevant topics
Draft of initial statements based on available evidence and expert opinion
Consensual approach
FINAL Recommendations
van der Heijde D, et al. Ann Rheum Dis. 2015; 74: 8-13

4. Methods/methodological approach
2017 Update of the EULAR Recommendations for the management of SLE
Methods/methodological approach
Pharmacologic treatment of SLE (Questions 1 to 5)
Glucocorticoids (different regimens; acute versus chronic treatment; “safe” dose; tapering schemes; steroid-free regimens)
Antimalarials (optimal dose during maintenance)
Immunosuppressives/cytotoxics (methotrexate, azathioprine, mycophenolate, cyclophosphamide)
Calcineurin inhibitors (CNIs) (use in renal and non-renal lupus)
Biologics (evidence on belimumab and off-label agents; indications and use as induction versus maintenance)
Management of specific manifestations (Questions 6 to 10)
Skin manifestations (topical and systemic treatments; according to different subtypes)
Lupus Nephritis (comparative efficacy of induction regimens; long-term efficacy data; role of CNIs in multi-target regimens)
NPSLE (attribution of NP events; indications for immunosuppressive or biologic treatment)
APS
SLE flares (prevention of flares; therapeutic agents specifically tested for flares)

5. Methods/methodological approach
2017 Update of the EULAR Recommendations for the management of SLE
Methods/methodological approach
Monitoring SLE and treatment targets (Questions 11 to 13)
Assessment of disease activity and organ damage (how often, by what means)
Therapeutic target(s)
Duration of maintenance immunosuppressive/biologic treatment
Comorbidities and adjunct therapy (Question 14)
Focus on cardiovascular disease and infections (risk stratification, prevention)

6. Overarching principles
SLE is a multisystem disease - occasionally limited to one or few organs - diagnosed on clinical grounds in the presence of characteristic serologic abnormalities.
SLE care is multidisciplinary, based on a shared patient-physician decision, and should consider individual, medical and societal costs.
Treatment of organ-/life-threatening SLE includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses.
Treatment goals include long-term patient survival, prevention of organ damage and optimization of health-related quality of life.
24/05/2019

7. Individual Recommendations 1. Goals of treatment
LoE
GoR
1.1 Treatment in SLE should aim at remission or low disease activity and prevention of flares in all organs, maintained with the lowest possible dose of glucocorticoids. 2b B
1.2 Flares of SLE can be treated according to the severity of organ(s) involvement by adjusting ongoing therapies (glucocorticoids, immunomodulating agents) to higher doses, switching, or adding new therapies. C
LoE: Level of Evidence; GoR: Grade of Recommendation
24/05/2019

8. Individual Recommendations 2. Treatment of SLE (general)
2.1 Hydroxychloroquine
Recommendation
LoE
GoR
2.2.1 HCQ is recommended for all patients with SLE,
at a dose not exceeding 5 mg/kg/real BW. 1b A 3b C
2.2.2 In the absence of risk factors for retinal toxicity, ophthalmologic screening (by visual fields examination and/or spectral domain-optical coherence tomography) should be performed at baseline, after 5 years, and yearly thereafter. 2b B
LoE: Level of Evidence; GoR: Grade of Recommendation
24/05/2019

9. Individual Recommendations 2. Treatment of SLE (general)
2.2 Glucocorticoids
Recommendation
LoE
GoR
2.2.1 Glucocorticoids can be used at doses and route of administration that depend on the type and severity of organ involvement. 2b C
2.2.2 Pulses of intravenous methylprednisolone (usually 500–1000 mg per day, for 1–3 days) provide immediate therapeutic effect and enable the use of lower starting dose of oral glucocorticoids. 3b
2.2.3 For chronic maintenance treatment, glucocorticoids should be minimized to less than 7.5 mg/day (prednisone equivalent) and, if possible, withdrawn. 1b B
2.2.4 Prompt initiation of immunomodulatory agents can expedite the tapering/discontinuation of glucocorticoids.
LoE: Level of Evidence; GoR: Grade of Recommendation
24/05/2019

10. Individual Recommendations 2. Treatment of SLE (general)
2.3 Immunosuppressive therapies
Recommendation
LoE
GoR
2.3.1 In patients not responding to HCQ (alone or in combination with glucocorticoids) or patients unable to reduce glucocorticoids below doses acceptable for chronic use, addition of immunomodulating/immunosuppressive agents such as
methotrexate 1b B
azathioprine 2b
or mycophenolate should be considered. 2a
2.3.2 Immunomodulating/immunosuppressive agents can be included in the initial therapy in cases of organ-threatening disease. C
2.3.3 Cyclophosphamide can be used for severe organ- or life-threatening SLE as well as “rescue” therapy in patients not responding to other immunosuppressive agents.
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LoE: Level of Evidence; GoR: Grade of Recommendation

11. Individual Recommendations 2. Treatment of SLE (general)
2.4 Biologics
Recommendation
LoE
GoR
2.4.1 In patients with inadequate response to standard-of-care (combinations of hydroxychloroquine, glucocorticoids, other immunomodulating agents), defined as residual disease activity not allowing tapering of glucocorticoids and/or frequent relapses, add-on treatment with belimumab should be considered. 1a A
2.4.2 In organ-threatening disease refractory or with intolerance/contra-indications to standard immunosuppressive agents, rituximab can be considered. 2b C
LoE: Level of Evidence; GoR: Grade of Recommendation
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12. Individual Recommendations 3. Specific manifestations
3.1 Skin disease
Recommendation
LoE
GoR
3.1.1 First-line treatment of skin disease in SLE includes
topical agents (glucocorticoids, calcineurin inhibitors) 2b B
antimalarials (HCQ, quinacrine) 1a A
systemic glucocorticoids. 4 C
3.1.2 In non-responsive cases or cases requiring high-dose glucocorticoids,
methotrexate, 3a
retinoids, dapsone, or mycophenolate can be added.
LoE: Level of Evidence; GoR: Grade of Recommendation
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13. Individual Recommendations 3. Specific manifestations
3.2 Neuropsychiatric disease
Recommendation
LoE
GoR
3.2.1 Attribution to SLE - as opposed to non-SLE - related neuropsychiatric manifestations, can be facilitated by neuroimaging, investigation of cerebrospinal fluid, consideration of risk factors [type and timing of the manifestation in relation to the onset of lupus, patient age, non-neurological lupus activity, presence of antiphospholipid antibodies (aPL)] and exclusion of confounding factors. 2b C
3.2.2 Treatment of SLE-related neuropsychiatric disease includes glucocorticoids/immunosuppressive agents for manifestations considered to reflect an inflammatory process 1b A
and antiplatelet/anticoagulants for atherothrombotic/aPL-related manifestations.
LoE: Level of Evidence; GoR: Grade of Recommendation
24/05/2019

14. Individual Recommendations 3. Specific manifestations
3.3 Haematologic disease
Recommendation
LoE
GoR
3.3.1 Acute treatment of lupus thrombocytopenia includes high-dose glucocorticoids (including pulses of intravenous methylprednisolone) and/or intravenous immunoglobulin. 4 C
3.3.2 For maintenance of response, IS/GC-sparing agents such as mycophenolate, azathioprine, 2b
or cyclosporine can be used.
3.3.3 Refractory cases can be treated with rituximab 3a
or cyclophosphamide.
LoE: Level of Evidence; GoR: Grade of Recommendation
24/05/2019

15. Individual Recommendations 3. Specific manifestations
3.4 Renal disease
Recommendation
LoE
GoR
3.4.1 Early recognition of signs of renal involvement and - when present - performance of a diagnostic renal biopsy are essential to ensure optimal outcomes. 2b B
3.4.2 Mycophenolate 1a A
or low-dose IV cyclophosphamide are recommended as initial (induction) treatment, as they have the best efficacy/toxicity ratio. 2a
3.4.3 In patients at high risk for renal failure (reduced glomerular filtration rate, histologic presence of crescents or fibrinoid necrosis, or tubular atrophy/interstitial fibrosis], mycophenolate
or high-dose IV cyclophosphamide can be used. 1b
3.4.4 For maintenance therapy, mycophenolate or azathioprine should be used.
24/05/2019
LoE: Level of Evidence; GoR: Grade of Recommendation

16. Individual Recommendations 3. Specific manifestations
3.4 Renal disease
Recommendation
LoE
GoR
3.4.5 In cases with stable/improved renal function but incomplete renal response (persistent proteinuria >1 g/24h after at least one year of immunosuppressive treatment), repeat biopsy can distinguish chronic from active kidney lesions. 4 C
3.4.6 Mycophenolate may be combined with low dose of a calcineurin inhibitor in severe nephrotic syndrome 2b
or incomplete renal response,
in the absence of uncontrolled hypertension, high chronicity index at kidney biopsy, and/or reduced GFR.
LoE: Level of Evidence; GoR: Grade of Recommendation
24/05/2019

17. Individual Recommendations 4. Comorbidities
4.1 Antiphospholipid antibodies and antiphospholipid syndrome
Recommendation
LoE
GoR
4.1.1 All SLE patients should be screened at diagnosis for aPL. 1a A
4.1.2 SLE patients with high-risk aPL profile (persistently positive medium/high titres or multiple positivity) may receive primary prophylaxis with antiplatelet agents, especially if other atherosclerotic/thrombophilic factors are present, after balancing the bleeding hazard. 2a C
4.1.3 For secondary prevention (thrombosis, pregnancy complication/loss), the therapeutic approach should be the same as for primary anti-phospholipid syndrome. 1b B
LoE: Level of Evidence; GoR: Grade of Recommendation
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18. Individual Recommendations 4. Comorbidities
4.2 Infectious diseases
Recommendation
LoE
GoR
4.2.1 SLE patients should be assessed for general and disease-related risk factors for infections such advanced age/frailty (–/D), comorbidities (–/D), renal involvement (2b/B), immunosuppressive/biologic therapy (1b-2b/B-C) and high-dose glucocorticoids (1a/A).
4.2.2 General preventative measures (including immunizations) and early recognition and treatment of infection/sepsis are recommended (–/D). - D
LoE: Level of Evidence; GoR: Grade of Recommendation
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19. Individual Recommendations 4. Comorbidities
4.3 Cardiovascular disease
Recommendation
LoE
GoR
4.3.1 Patients with SLE should undergo regular assessment for traditional (1b/B-C) and disease-related risk factors for cardiovascular disease, including persistently active disease (1b/B), increased disease duration (1b/A), medium/high titres of aPL (1b/A), renal involvement (1b/B) (especially, persistent proteinuria and/or GFR <60 ml/min) and chronic use of glucocorticoids (1b/B).
4.3.2 Based on their individual cardiovascular risk profile, SLE patients may be candidates for prevention with low-dose aspirin 2b D
and/or lipid-lowering agents.
LoE: Level of Evidence; GoR: Grade of Recommendation
24/05/2019

20. Summary Table Oxford Level of Evidence and Agreement
Overarching principles
SLE is a multisystem disease - occasionally limited to one or few organs - diagnosed on clinical grounds in the presence of characteristic serologic abnormalities.
SLE care is multidisciplinary, based on a shared patient-physician decision, and should consider individual, medical and societal costs.
Treatment of organ-/life-threatening SLE includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses.
Treatment goals include long-term patient survival, prevention of organ damage and optimization of health-related quality of life.
Recommendation/Statement
Level of agreement
Goals of treatment
Treatment in SLE should aim at remission or low disease activity (2b/B) and prevention of flares (2b/B) in all organs, maintained with the lowest possible dose of glucocorticoids.
10.0
1.2 Flares of SLE can be treated according to the severity of organ(s) involvement by adjusting ongoing therapies (glucocorticoids, immunomodulating agents) to higher doses, switching, or adding new therapies (2b/C).
9.95
Treatment of SLE
Hydroxychloroquine (HCQ)
HCQ is recommended for all patients with SLE (1b/A), unless contraindicated, at a dose not exceeding 5 mg/kg/real BW (3b/C).
9.65
In the absence of risk factors for retinal toxicity, ophthalmologic screening (by visual fields examination and/or spectral domain-optical coherence tomography) should be performed at baseline, after 5 years, and yearly thereafter (2b/B).
9.75
Glucocorticoids (GC)
GC can be used at doses and route of administration that depend on the type and severity of organ involvement (2b/C).
Pulses of intravenous methylprednisolone (usually 250–1000 mg per day, for 1–3 days) provide immediate therapeutic effect and enable the use of lower starting dose of oral GC (3b/C).
9.85
For chronic maintenance treatment, GC should be minimized to less than 7.5 mg/day (prednisone equivalent) (1b/B) and, when possible, withdrawn.
Prompt initiation of immunomodulatory agents can expedite the tapering/discontinuation of GC (2b/B).
9.90
Immunosuppressive therapies
In patients not responding to HCQ (alone or in combination with GC) or patients unable to reduce GC below doses acceptable for chronic use, addition of immunomodulating/immunosuppressive agents such as methotrexate, (1b/B) azathioprine (2b/C) or mycophenolate (2a/B) should be considered.
Immunomodulating/immunosuppressive agents can be included in the initial therapy in cases of organ-threatening disease (2b/C).
Cyclophosphamide can be used for severe organ- or life-threatening SLE as well as “rescue” therapy in patients not responding to other immunosuppressive agents (2b/C).
Biologics
In patients with inadequate response to standard-of-care (combinations of HCQ and GC with or without immunosuppressive agents), defined as residual disease activity not allowing tapering of glucocorticoids and/or frequent relapses, add-on treatment with belimumab should be considered (1a/A).
9.20
In organ-threatening disease refractory or with intolerance/contraindications to standard immunosuppressive agents, rituximab can be considered (2b/C).
Specific manifestations
Skin disease
First-line treatment of skin disease in SLE includes topical agents (GC, calcineurin inhibitors) (2b/B), antimalarials (HCQ, quinacrine) (1a/A) and/or systemic GC (4/C).
In non-responsive cases or cases requiring high-dose GC, methotrexate (3a/B), retinoids (4/C), dapsone (4/C) or mycophenolate (4/C) can be added.
Neuropsychiatric disease
Attribution to SLE - as opposed to non-SLE - related neuropsychiatric manifestations, is essential and can be facilitated by neuroimaging, investigation of cerebrospinal fluid, consideration of risk factors [type and timing of the manifestation in relation to the onset of lupus, patient age, non-neurological lupus activity, presence of antiphospholipid antibodies (aPL)] and exclusion of confounding factors (2b/C).
Treatment of SLE-related neuropsychiatric disease includes glucocorticoids/immunosuppressive agents for manifestations considered to reflect an inflammatory process (1b/A), and antiplatelet/anticoagulants for atherothrombotic/aPL-related manifestations (2b/C).
Hematologic disease
Acute treatment of lupus thrombocytopenia includes high-dose GC (including pulses of intravenous methylprednisolone) (4/C) and/or intravenous immunoglobulin G (4/C).
For maintenance of response, immunosuppressive/GC-sparing agents such as mycophenolate (2b/C), azathioprine (2b/C), or cyclosporine (4/C) can be used.
Refractory cases can be treated with rituximab (3a/C) or cyclophosphamide (4/C).
Renal disease
Early recognition of signs of renal involvement and - when present - performance of a diagnostic renal biopsy are essential to ensure optimal outcomes (2b/B).
Mycophenolate (1a/A) or low-dose IV cyclophosphamide (2a/B) are recommended as initial (induction) treatment, as they have the best efficacy/toxicity ratio.
In patients at high risk for renal failure (reduced glomerular filtration rate, histologic presence of fibrous crescents or fibrinoid necrosis, or tubular atrophy/interstitial fibrosis], similar regimens may be considered but high-dose IV cyclophosphamide can also be used (1b/A).
9.45
For maintenance therapy, mycophenolate (1a/A) or azathioprine (1a/A) should be used.
In cases with stable/improved renal function but incomplete renal response (persistent proteinuria >0.8-1 g/24h after at least one year of immunosuppressive treatment), repeat biopsy can distinguish chronic from active kidney lesions (4/C).
Mycophenolate may be combined with low dose of a calcineurin inhibitor in severe nephrotic syndrome (2b/C) or incomplete renal response (4/C), in the absence of uncontrolled hypertension, high chronicity index at kidney biopsy and/or reduced GFR.
9.50
Comorbidities
Antiphospholipid syndrome
All SLE patients should be screened at diagnosis for aPL (1a/A).
SLE patients with high-risk aPL profile (persistently positive medium/high titres or multiple positivity) may receive primary prophylaxis with antiplatelet agents (2a/C), especially if other atherosclerotic/thrombophilic factors are present, after balancing the bleeding hazard.
For secondary prevention (thrombosis, pregnancy complication/loss), the therapeutic approach should be the same as for primary anti-phospholipid syndrome (1b/B).
Infectious diseases
SLE patients should be assessed for general and disease-related risk factors for infections, such as advanced age/frailty (–/D), diabetes mellitus (–/D), renal involvement (2b/B), immunosuppressive/biologic therapy (1b-2b/B-C) and use of GC (1a/A).
General preventative measures (including immunizations) and early recognition and treatment of infection/sepsis are recommended (–/D).
Cardiovascular disease
Patients with SLE should undergo regular assessment for traditional (1b/B-C) and disease-related risk factors for cardiovascular disease, including persistently active disease (1b/B), increased disease duration (1b/A), medium/high titres of aPL (1b/A), renal involvement (1b/B) (especially, persistent proteinuria and/or GFR <60 ml/min) and chronic use of GC (1b/B).
Based on their individual cardiovascular risk profile, SLE patients may be candidates for preventative strategies as in the general population, including low-dose aspirin (2b/D) and/or lipid-lowering agents (2b/D).
Summary Table Oxford Level of Evidence and Agreement
Recommendation
Level of agreement
1. Goals of treatment
1.1 Treatment in SLE should aim at remission or the lowest possible level of disease activity and prevention of flares in all organs, maintained with the lowest possible dose of glucocorticoids.
10.0
1.2 Flares of SLE can be treated according to the severity of organ(s) involvement by adjusting ongoing therapies (glucocorticoids, immunomodulating agents) to higher doses, switching, or adding new therapies (2b/C).
9.95
2. Treatment of SLE (general)
2.1 Hydroxychloroquine
2.1.1 HCQ is recommended for all patients with SLE (1b/A), unless contraindicated, at a dose not exceeding 5 mg/kg/real BW (3b/C).
9.65
2.1.2 In the absence of risk factors for retinal toxicity, ophthalmologic screening (by visual fields examination and/or spectral domain- optical coherence tomography) should be performed at baseline, after 5 years, and yearly thereafter (2b/B).
9.75
2.2 Glucocorticoids
2.2.1 GC can be used at doses and route of administration that depend on the type and severity of organ involvement (2b/C).
2.2.2 Pulses of intravenous methylprednisolone (usually 250–1000 mg per day, for 1–3 days) provide immediate therapeutic effect and enable the use of lower starting dose of oral GC (3b/C).
9.85
2.2.3 For chronic maintenance treatment, GC should be minimized to less than 7.5 mg/day (prednisone equivalent) (1b/B) and, when possible, withdrawn.
2.2.4 Prompt initiation of immunomodulatory agents can expedite the tapering/discontinuation of GC (2b/B).
9.90
2.3 Immunosuppressive therapies
2.3.1 In patients not responding to HCQ (alone or in combination with GC) or patients unable to reduce GC below doses acceptable for chronic use, addition of immunomodulating/immunosuppressive agents such as methotrexate, (1b/B) azathioprine (2b/C) or mycophenolate (2a/B) should be considered.
2.3.2 Immunomodulating/immunosuppressive agents can be included in the initial therapy in cases of organ-threatening disease (2b/C).
2.3.3 Cyclophosphamide can be used for severe organ- or life-threatening SLE as well as “rescue” therapy in patients not responding to other immunosuppressive agents (2b/C).
24/05/2019

21. Summary Table Oxford Level of Evidence and Agreement
Overarching principles
SLE is a multisystem disease - occasionally limited to one or few organs - diagnosed on clinical grounds in the presence of characteristic serologic abnormalities.
SLE care is multidisciplinary, based on a shared patient-physician decision, and should consider individual, medical and societal costs.
Treatment of organ-/life-threatening SLE includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses.
Treatment goals include long-term patient survival, prevention of organ damage and optimization of health-related quality of life.
Recommendation/Statement
Level of agreement
Goals of treatment
Treatment in SLE should aim at remission or low disease activity (2b/B) and prevention of flares (2b/B) in all organs, maintained with the lowest possible dose of glucocorticoids.
10.0
1.2 Flares of SLE can be treated according to the severity of organ(s) involvement by adjusting ongoing therapies (glucocorticoids, immunomodulating agents) to higher doses, switching, or adding new therapies (2b/C).
9.95
Treatment of SLE
Hydroxychloroquine (HCQ)
HCQ is recommended for all patients with SLE (1b/A), unless contraindicated, at a dose not exceeding 5 mg/kg/real BW (3b/C).
9.65
In the absence of risk factors for retinal toxicity, ophthalmologic screening (by visual fields examination and/or spectral domain-optical coherence tomography) should be performed at baseline, after 5 years, and yearly thereafter (2b/B).
9.75
Glucocorticoids (GC)
GC can be used at doses and route of administration that depend on the type and severity of organ involvement (2b/C).
Pulses of intravenous methylprednisolone (usually 250–1000 mg per day, for 1–3 days) provide immediate therapeutic effect and enable the use of lower starting dose of oral GC (3b/C).
9.85
For chronic maintenance treatment, GC should be minimized to less than 7.5 mg/day (prednisone equivalent) (1b/B) and, when possible, withdrawn.
Prompt initiation of immunomodulatory agents can expedite the tapering/discontinuation of GC (2b/B).
9.90
Immunosuppressive therapies
In patients not responding to HCQ (alone or in combination with GC) or patients unable to reduce GC below doses acceptable for chronic use, addition of immunomodulating/immunosuppressive agents such as methotrexate, (1b/B) azathioprine (2b/C) or mycophenolate (2a/B) should be considered.
Immunomodulating/immunosuppressive agents can be included in the initial therapy in cases of organ-threatening disease (2b/C).
Cyclophosphamide can be used for severe organ- or life-threatening SLE as well as “rescue” therapy in patients not responding to other immunosuppressive agents (2b/C).
Biologics
In patients with inadequate response to standard-of-care (combinations of HCQ and GC with or without immunosuppressive agents), defined as residual disease activity not allowing tapering of glucocorticoids and/or frequent relapses, add-on treatment with belimumab should be considered (1a/A).
9.20
In organ-threatening disease refractory or with intolerance/contraindications to standard immunosuppressive agents, rituximab can be considered (2b/C).
Specific manifestations
Skin disease
First-line treatment of skin disease in SLE includes topical agents (GC, calcineurin inhibitors) (2b/B), antimalarials (HCQ, quinacrine) (1a/A) and/or systemic GC (4/C).
In non-responsive cases or cases requiring high-dose GC, methotrexate (3a/B), retinoids (4/C), dapsone (4/C) or mycophenolate (4/C) can be added.
Neuropsychiatric disease
Attribution to SLE - as opposed to non-SLE - related neuropsychiatric manifestations, is essential and can be facilitated by neuroimaging, investigation of cerebrospinal fluid, consideration of risk factors [type and timing of the manifestation in relation to the onset of lupus, patient age, non-neurological lupus activity, presence of antiphospholipid antibodies (aPL)] and exclusion of confounding factors (2b/C).
Treatment of SLE-related neuropsychiatric disease includes glucocorticoids/immunosuppressive agents for manifestations considered to reflect an inflammatory process (1b/A), and antiplatelet/anticoagulants for atherothrombotic/aPL-related manifestations (2b/C).
Hematologic disease
Acute treatment of lupus thrombocytopenia includes high-dose GC (including pulses of intravenous methylprednisolone) (4/C) and/or intravenous immunoglobulin G (4/C).
For maintenance of response, immunosuppressive/GC-sparing agents such as mycophenolate (2b/C), azathioprine (2b/C), or cyclosporine (4/C) can be used.
Refractory cases can be treated with rituximab (3a/C) or cyclophosphamide (4/C).
Renal disease
Early recognition of signs of renal involvement and - when present - performance of a diagnostic renal biopsy are essential to ensure optimal outcomes (2b/B).
Mycophenolate (1a/A) or low-dose IV cyclophosphamide (2a/B) are recommended as initial (induction) treatment, as they have the best efficacy/toxicity ratio.
In patients at high risk for renal failure (reduced glomerular filtration rate, histologic presence of fibrous crescents or fibrinoid necrosis, or tubular atrophy/interstitial fibrosis], similar regimens may be considered but high-dose IV cyclophosphamide can also be used (1b/A).
9.45
For maintenance therapy, mycophenolate (1a/A) or azathioprine (1a/A) should be used.
In cases with stable/improved renal function but incomplete renal response (persistent proteinuria >0.8-1 g/24h after at least one year of immunosuppressive treatment), repeat biopsy can distinguish chronic from active kidney lesions (4/C).
Mycophenolate may be combined with low dose of a calcineurin inhibitor in severe nephrotic syndrome (2b/C) or incomplete renal response (4/C), in the absence of uncontrolled hypertension, high chronicity index at kidney biopsy and/or reduced GFR.
9.50
Comorbidities
Antiphospholipid syndrome
All SLE patients should be screened at diagnosis for aPL (1a/A).
SLE patients with high-risk aPL profile (persistently positive medium/high titres or multiple positivity) may receive primary prophylaxis with antiplatelet agents (2a/C), especially if other atherosclerotic/thrombophilic factors are present, after balancing the bleeding hazard.
For secondary prevention (thrombosis, pregnancy complication/loss), the therapeutic approach should be the same as for primary anti-phospholipid syndrome (1b/B).
Infectious diseases
SLE patients should be assessed for general and disease-related risk factors for infections, such as advanced age/frailty (–/D), diabetes mellitus (–/D), renal involvement (2b/B), immunosuppressive/biologic therapy (1b-2b/B-C) and use of GC (1a/A).
General preventative measures (including immunizations) and early recognition and treatment of infection/sepsis are recommended (–/D).
Cardiovascular disease
Patients with SLE should undergo regular assessment for traditional (1b/B-C) and disease-related risk factors for cardiovascular disease, including persistently active disease (1b/B), increased disease duration (1b/A), medium/high titres of aPL (1b/A), renal involvement (1b/B) (especially, persistent proteinuria and/or GFR <60 ml/min) and chronic use of GC (1b/B).
Based on their individual cardiovascular risk profile, SLE patients may be candidates for preventative strategies as in the general population, including low-dose aspirin (2b/D) and/or lipid-lowering agents (2b/D).
Summary Table Oxford Level of Evidence and Agreement
Recommendation
Level of agreement
2.4 Biologics
2.4.1 In patients with inadequate response to standard-of-care (combinations of HCQ and GC with or without immunosuppressive agents), defined as residual disease activity not allowing tapering of glucocorticoids and/or frequent relapses, add-on treatment with belimumab should be considered (1a/A).
9.20
2.4.2 In organ-threatening disease refractory or with intolerance/contraindications to standard immunosuppressive agents, rituximab can be considered (2b/C).
9.85
3. Specific manifestations
3.1 Skin disease
3.1.1 First-line treatment of skin disease in SLE includes topical agents (GC, calcineurin inhibitors) (2b/B), antimalarials (HCQ, quinacrine) (1a/A) and/or systemic GC (4/C).
10.0
3.1.2 In non-responsive cases or cases requiring high-dose GC, methotrexate (3a/B), retinoids (4/C), dapsone (4/C) or mycophenolate (4/C) can be added.
3.2 Neuropsychiatric disease
3.2.1 Attribution to SLE - as opposed to non-SLE - related neuropsychiatric manifestations, is essential and can be facilitated by neuroimaging, investigation of cerebrospinal fluid, consideration of risk factors [type and timing of the manifestation in relation to the onset of lupus, patient age, non-neurological lupus activity, presence of antiphospholipid antibodies (aPL)] and exclusion of confounding factors (2b/C).
9.65
3.2.2 Treatment of SLE-related neuropsychiatric disease includes glucocorticoids/immunosuppressive agents for manifestations considered to reflect an inflammatory process (1b/A), and antiplatelet/anticoagulants for atherothrombotic/aPL-related manifestations (2b/C).
3.3 Haematologic disease
3.3.1 Acute treatment of lupus thrombocytopenia includes high-dose GC (including pulses of intravenous methylprednisolone) (4/C) and/or intravenous immunoglobulin G (4/C).
9.95
3.3.2 For maintenance of response, immunosuppressive/GC-sparing agents such as mycophenolate (2b/C), azathioprine (2b/C), or cyclosporine (4/C) can be used.
9.75
3.3.3 Refractory cases can be treated with rituximab (3a/C) or cyclophosphamide (4/C).
24/05/2019

22. Summary Table Oxford Level of Evidence and Agreement
Overarching principles
SLE is a multisystem disease - occasionally limited to one or few organs - diagnosed on clinical grounds in the presence of characteristic serologic abnormalities.
SLE care is multidisciplinary, based on a shared patient-physician decision, and should consider individual, medical and societal costs.
Treatment of organ-/life-threatening SLE includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses.
Treatment goals include long-term patient survival, prevention of organ damage and optimization of health-related quality of life.
Recommendation/Statement
Level of agreement
Goals of treatment
Treatment in SLE should aim at remission or low disease activity (2b/B) and prevention of flares (2b/B) in all organs, maintained with the lowest possible dose of glucocorticoids.
10.0
1.2 Flares of SLE can be treated according to the severity of organ(s) involvement by adjusting ongoing therapies (glucocorticoids, immunomodulating agents) to higher doses, switching, or adding new therapies (2b/C).
9.95
Treatment of SLE
Hydroxychloroquine (HCQ)
HCQ is recommended for all patients with SLE (1b/A), unless contraindicated, at a dose not exceeding 5 mg/kg/real BW (3b/C).
9.65
In the absence of risk factors for retinal toxicity, ophthalmologic screening (by visual fields examination and/or spectral domain-optical coherence tomography) should be performed at baseline, after 5 years, and yearly thereafter (2b/B).
9.75
Glucocorticoids (GC)
GC can be used at doses and route of administration that depend on the type and severity of organ involvement (2b/C).
Pulses of intravenous methylprednisolone (usually 250–1000 mg per day, for 1–3 days) provide immediate therapeutic effect and enable the use of lower starting dose of oral GC (3b/C).
9.85
For chronic maintenance treatment, GC should be minimized to less than 7.5 mg/day (prednisone equivalent) (1b/B) and, when possible, withdrawn.
Prompt initiation of immunomodulatory agents can expedite the tapering/discontinuation of GC (2b/B).
9.90
Immunosuppressive therapies
In patients not responding to HCQ (alone or in combination with GC) or patients unable to reduce GC below doses acceptable for chronic use, addition of immunomodulating/immunosuppressive agents such as methotrexate, (1b/B) azathioprine (2b/C) or mycophenolate (2a/B) should be considered.
Immunomodulating/immunosuppressive agents can be included in the initial therapy in cases of organ-threatening disease (2b/C).
Cyclophosphamide can be used for severe organ- or life-threatening SLE as well as “rescue” therapy in patients not responding to other immunosuppressive agents (2b/C).
Biologics
In patients with inadequate response to standard-of-care (combinations of HCQ and GC with or without immunosuppressive agents), defined as residual disease activity not allowing tapering of glucocorticoids and/or frequent relapses, add-on treatment with belimumab should be considered (1a/A).
9.20
In organ-threatening disease refractory or with intolerance/contraindications to standard immunosuppressive agents, rituximab can be considered (2b/C).
Specific manifestations
Skin disease
First-line treatment of skin disease in SLE includes topical agents (GC, calcineurin inhibitors) (2b/B), antimalarials (HCQ, quinacrine) (1a/A) and/or systemic GC (4/C).
In non-responsive cases or cases requiring high-dose GC, methotrexate (3a/B), retinoids (4/C), dapsone (4/C) or mycophenolate (4/C) can be added.
Neuropsychiatric disease
Attribution to SLE - as opposed to non-SLE - related neuropsychiatric manifestations, is essential and can be facilitated by neuroimaging, investigation of cerebrospinal fluid, consideration of risk factors [type and timing of the manifestation in relation to the onset of lupus, patient age, non-neurological lupus activity, presence of antiphospholipid antibodies (aPL)] and exclusion of confounding factors (2b/C).
Treatment of SLE-related neuropsychiatric disease includes glucocorticoids/immunosuppressive agents for manifestations considered to reflect an inflammatory process (1b/A), and antiplatelet/anticoagulants for atherothrombotic/aPL-related manifestations (2b/C).
Hematologic disease
Acute treatment of lupus thrombocytopenia includes high-dose GC (including pulses of intravenous methylprednisolone) (4/C) and/or intravenous immunoglobulin G (4/C).
For maintenance of response, immunosuppressive/GC-sparing agents such as mycophenolate (2b/C), azathioprine (2b/C), or cyclosporine (4/C) can be used.
Refractory cases can be treated with rituximab (3a/C) or cyclophosphamide (4/C).
Renal disease
Early recognition of signs of renal involvement and - when present - performance of a diagnostic renal biopsy are essential to ensure optimal outcomes (2b/B).
Mycophenolate (1a/A) or low-dose IV cyclophosphamide (2a/B) are recommended as initial (induction) treatment, as they have the best efficacy/toxicity ratio.
In patients at high risk for renal failure (reduced glomerular filtration rate, histologic presence of fibrous crescents or fibrinoid necrosis, or tubular atrophy/interstitial fibrosis], similar regimens may be considered but high-dose IV cyclophosphamide can also be used (1b/A).
9.45
For maintenance therapy, mycophenolate (1a/A) or azathioprine (1a/A) should be used.
In cases with stable/improved renal function but incomplete renal response (persistent proteinuria >0.8-1 g/24h after at least one year of immunosuppressive treatment), repeat biopsy can distinguish chronic from active kidney lesions (4/C).
Mycophenolate may be combined with low dose of a calcineurin inhibitor in severe nephrotic syndrome (2b/C) or incomplete renal response (4/C), in the absence of uncontrolled hypertension, high chronicity index at kidney biopsy and/or reduced GFR.
9.50
Comorbidities
Antiphospholipid syndrome
All SLE patients should be screened at diagnosis for aPL (1a/A).
SLE patients with high-risk aPL profile (persistently positive medium/high titres or multiple positivity) may receive primary prophylaxis with antiplatelet agents (2a/C), especially if other atherosclerotic/thrombophilic factors are present, after balancing the bleeding hazard.
For secondary prevention (thrombosis, pregnancy complication/loss), the therapeutic approach should be the same as for primary anti-phospholipid syndrome (1b/B).
Infectious diseases
SLE patients should be assessed for general and disease-related risk factors for infections, such as advanced age/frailty (–/D), diabetes mellitus (–/D), renal involvement (2b/B), immunosuppressive/biologic therapy (1b-2b/B-C) and use of GC (1a/A).
General preventative measures (including immunizations) and early recognition and treatment of infection/sepsis are recommended (–/D).
Cardiovascular disease
Patients with SLE should undergo regular assessment for traditional (1b/B-C) and disease-related risk factors for cardiovascular disease, including persistently active disease (1b/B), increased disease duration (1b/A), medium/high titres of aPL (1b/A), renal involvement (1b/B) (especially, persistent proteinuria and/or GFR <60 ml/min) and chronic use of GC (1b/B).
Based on their individual cardiovascular risk profile, SLE patients may be candidates for preventative strategies as in the general population, including low-dose aspirin (2b/D) and/or lipid-lowering agents (2b/D).
Summary Table Oxford Level of Evidence and Agreement
Recommendation
Level of agreement
3.4 Renal disease
3.4.1 Early recognition of signs of renal involvement and - when present - performance of a diagnostic renal biopsy are essential to ensure optimal outcomes (2b/B).
9.95
3.4.2 Mycophenolate (1a/A) or low-dose IV cyclophosphamide (2a/B) are recommended as initial (induction) treatment, as they have the best efficacy/toxicity ratio.
9.85
3.4.3 In patients at high risk for renal failure (reduced glomerular filtration rate, histologic presence of fibrous crescents or fibrinoid necrosis, or tubular atrophy/interstitial fibrosis], similar regimens may be considered but high-dose IV cyclophosphamide can also be used (1b/A).
9.45
3.4.4 For maintenance therapy, mycophenolate (1a/A) or azathioprine (1a/A) should be used.
9.75
3.4.5 In cases with stable/improved renal function but incomplete renal response (persistent proteinuria >0.8-1 g/24h after at least one year of immunosuppressive treatment), repeat biopsy can distinguish chronic from active kidney lesions (4/C).
3.4.6 Mycophenolate may be combined with low dose of a calcineurin inhibitor in severe nephrotic syndrome (2b/C) or incomplete renal response (4/C), in the absence of uncontrolled hypertension, high chronicity index at kidney biopsy and/or reduced GFR.
9.50
24/05/2019

23. Summary Table Oxford Level of Evidence and Agreement
Overarching principles
SLE is a multisystem disease - occasionally limited to one or few organs - diagnosed on clinical grounds in the presence of characteristic serologic abnormalities.
SLE care is multidisciplinary, based on a shared patient-physician decision, and should consider individual, medical and societal costs.
Treatment of organ-/life-threatening SLE includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses.
Treatment goals include long-term patient survival, prevention of organ damage and optimization of health-related quality of life.
Recommendation/Statement
Level of agreement
Goals of treatment
Treatment in SLE should aim at remission or low disease activity (2b/B) and prevention of flares (2b/B) in all organs, maintained with the lowest possible dose of glucocorticoids.
10.0
1.2 Flares of SLE can be treated according to the severity of organ(s) involvement by adjusting ongoing therapies (glucocorticoids, immunomodulating agents) to higher doses, switching, or adding new therapies (2b/C).
9.95
Treatment of SLE
Hydroxychloroquine (HCQ)
HCQ is recommended for all patients with SLE (1b/A), unless contraindicated, at a dose not exceeding 5 mg/kg/real BW (3b/C).
9.65
In the absence of risk factors for retinal toxicity, ophthalmologic screening (by visual fields examination and/or spectral domain-optical coherence tomography) should be performed at baseline, after 5 years, and yearly thereafter (2b/B).
9.75
Glucocorticoids (GC)
GC can be used at doses and route of administration that depend on the type and severity of organ involvement (2b/C).
Pulses of intravenous methylprednisolone (usually 250–1000 mg per day, for 1–3 days) provide immediate therapeutic effect and enable the use of lower starting dose of oral GC (3b/C).
9.85
For chronic maintenance treatment, GC should be minimized to less than 7.5 mg/day (prednisone equivalent) (1b/B) and, when possible, withdrawn.
Prompt initiation of immunomodulatory agents can expedite the tapering/discontinuation of GC (2b/B).
9.90
Immunosuppressive therapies
In patients not responding to HCQ (alone or in combination with GC) or patients unable to reduce GC below doses acceptable for chronic use, addition of immunomodulating/immunosuppressive agents such as methotrexate, (1b/B) azathioprine (2b/C) or mycophenolate (2a/B) should be considered.
Immunomodulating/immunosuppressive agents can be included in the initial therapy in cases of organ-threatening disease (2b/C).
Cyclophosphamide can be used for severe organ- or life-threatening SLE as well as “rescue” therapy in patients not responding to other immunosuppressive agents (2b/C).
Biologics
In patients with inadequate response to standard-of-care (combinations of HCQ and GC with or without immunosuppressive agents), defined as residual disease activity not allowing tapering of glucocorticoids and/or frequent relapses, add-on treatment with belimumab should be considered (1a/A).
9.20
In organ-threatening disease refractory or with intolerance/contraindications to standard immunosuppressive agents, rituximab can be considered (2b/C).
Specific manifestations
Skin disease
First-line treatment of skin disease in SLE includes topical agents (GC, calcineurin inhibitors) (2b/B), antimalarials (HCQ, quinacrine) (1a/A) and/or systemic GC (4/C).
In non-responsive cases or cases requiring high-dose GC, methotrexate (3a/B), retinoids (4/C), dapsone (4/C) or mycophenolate (4/C) can be added.
Neuropsychiatric disease
Attribution to SLE - as opposed to non-SLE - related neuropsychiatric manifestations, is essential and can be facilitated by neuroimaging, investigation of cerebrospinal fluid, consideration of risk factors [type and timing of the manifestation in relation to the onset of lupus, patient age, non-neurological lupus activity, presence of antiphospholipid antibodies (aPL)] and exclusion of confounding factors (2b/C).
Treatment of SLE-related neuropsychiatric disease includes glucocorticoids/immunosuppressive agents for manifestations considered to reflect an inflammatory process (1b/A), and antiplatelet/anticoagulants for atherothrombotic/aPL-related manifestations (2b/C).
Hematologic disease
Acute treatment of lupus thrombocytopenia includes high-dose GC (including pulses of intravenous methylprednisolone) (4/C) and/or intravenous immunoglobulin G (4/C).
For maintenance of response, immunosuppressive/GC-sparing agents such as mycophenolate (2b/C), azathioprine (2b/C), or cyclosporine (4/C) can be used.
Refractory cases can be treated with rituximab (3a/C) or cyclophosphamide (4/C).
Renal disease
Early recognition of signs of renal involvement and - when present - performance of a diagnostic renal biopsy are essential to ensure optimal outcomes (2b/B).
Mycophenolate (1a/A) or low-dose IV cyclophosphamide (2a/B) are recommended as initial (induction) treatment, as they have the best efficacy/toxicity ratio.
In patients at high risk for renal failure (reduced glomerular filtration rate, histologic presence of fibrous crescents or fibrinoid necrosis, or tubular atrophy/interstitial fibrosis], similar regimens may be considered but high-dose IV cyclophosphamide can also be used (1b/A).
9.45
For maintenance therapy, mycophenolate (1a/A) or azathioprine (1a/A) should be used.
In cases with stable/improved renal function but incomplete renal response (persistent proteinuria >0.8-1 g/24h after at least one year of immunosuppressive treatment), repeat biopsy can distinguish chronic from active kidney lesions (4/C).
Mycophenolate may be combined with low dose of a calcineurin inhibitor in severe nephrotic syndrome (2b/C) or incomplete renal response (4/C), in the absence of uncontrolled hypertension, high chronicity index at kidney biopsy and/or reduced GFR.
9.50
Comorbidities
Antiphospholipid syndrome
All SLE patients should be screened at diagnosis for aPL (1a/A).
SLE patients with high-risk aPL profile (persistently positive medium/high titres or multiple positivity) may receive primary prophylaxis with antiplatelet agents (2a/C), especially if other atherosclerotic/thrombophilic factors are present, after balancing the bleeding hazard.
For secondary prevention (thrombosis, pregnancy complication/loss), the therapeutic approach should be the same as for primary anti-phospholipid syndrome (1b/B).
Infectious diseases
SLE patients should be assessed for general and disease-related risk factors for infections, such as advanced age/frailty (–/D), diabetes mellitus (–/D), renal involvement (2b/B), immunosuppressive/biologic therapy (1b-2b/B-C) and use of GC (1a/A).
General preventative measures (including immunizations) and early recognition and treatment of infection/sepsis are recommended (–/D).
Cardiovascular disease
Patients with SLE should undergo regular assessment for traditional (1b/B-C) and disease-related risk factors for cardiovascular disease, including persistently active disease (1b/B), increased disease duration (1b/A), medium/high titres of aPL (1b/A), renal involvement (1b/B) (especially, persistent proteinuria and/or GFR <60 ml/min) and chronic use of GC (1b/B).
Based on their individual cardiovascular risk profile, SLE patients may be candidates for preventative strategies as in the general population, including low-dose aspirin (2b/D) and/or lipid-lowering agents (2b/D).
Summary Table Oxford Level of Evidence and Agreement
Recommendation
Level of agreement
4. Comorbidities
4.1 Antiphospholipid antibodies and antiphospholipid syndrome
4.1.1 All SLE patients should be screened at diagnosis for aPL (1a/A).
10.0
4.1.2 SLE patients with high-risk aPL profile (persistently positive medium/high titres or multiple positivity) may receive primary prophylaxis with antiplatelet agents (2a/C), especially if other atherosclerotic/thrombophilic factors are present, after balancing the bleeding hazard.
9.45
4.1.3 For secondary prevention (thrombosis, pregnancy complication/loss), the therapeutic approach should be the same as for primary anti-phospholipid syndrome (1b/B).
4.2 Infectious diseases
4.2.1 SLE patients should be assessed for general and disease-related risk factors for infections, such as advanced age/frailty (–/D), diabetes mellitus (–/D), renal involvement (2b/B), immunosuppressive/biologic therapy (1b-2b/B-C) and use of GC (1a/A).
9.85
4.2.2 General preventative measures (including immunizations) and early recognition and treatment of infection/sepsis are recommended (–/D).
9.90
4.3 Cardiovascular disease
4.3.1 Patients with SLE should undergo regular assessment for traditional (1b/B-C) and disease-related risk factors for cardiovascular disease, including persistently active disease (1b/B), increased disease duration (1b/A), medium/high titres of aPL (1b/A), renal involvement (1b/B) (especially, persistent proteinuria and/or GFR <60 ml/min) and chronic use of GC (1b/B).
4.3.2 Based on their individual cardiovascular risk profile, SLE patients may be candidates for preventative strategies as in the general population, including low-dose aspirin (2b/D) and/or lipid-lowering agents (2b/D).
24/05/2019

24. Summary of Recommendations in lay format*
The goal of treatment in lupus is to control activity of the disease and prevent flares
****
All patients with SLE should receive hydroxychloroquine, with regular monitoring for eye toxicity
Glucocorticoids (GC, cortisone) can help to control symptoms when the disease is active. In the long-term its dose must not exceed 7.5 mg/day of prednisone
Immunosuppressive drugs such as methotrexate, azathioprine and mycophenolate can be used to better control the disease and allow using less glucocorticoids
***
When lupus cannot be controlled with the conventional drugs biologic drugs like belimumab or rituximab can be used
Skin disease in lupus is initially treated with creams/ointments or hydroxychloroquine, with or without oral glucocorticoids. When these do not control the disease, immunosuppressives or biologics can be used
Symptoms involving the brain and nervous system are not always due to lupus. When caused by lupus, immunosuppressive drugs or aspirin/anticoagulants are used
1 star (*) means it is a weak recommendation with limited scientific evidence; 2 stars (**) means it is a weak recommendation with some scientific evidence; 3 stars (***) means it is a strong recommendation with quite a lot of scientific evidence; 4 stars (****) means it is a strong recommendation supported with a lot of scientific evidence. Recommendations with just 1 or 2 stars are based mainly on expert opinion and not backed up by appropriate clinical studies, but may be as important as those with 3 and 4 stars.
24/05/2019

25. Summary of Recommendations in lay format*
Severe drops in platelets or low blood counts from SLE are treated with GC and immunosuppressive drugs; in case of relapses, rituximab should be considered
***
Biospy of the kidney is essential to diagnose kidney involvement in lupus.Immunosuppressive drugs of first-choice are mycophenolate mofetil and cyclophosphamide
****
A second kidney biopsy may be considered in cases of incomplete response after one year of treatment **
Patients with lupus should be tested for antiphospholipid antibodies, because the latter are associated with blood clots (thrombosis), pregnancy loses s and other complications such as strokes.
Patients with SLE have an increased risk for infections and should be vaccinated against influenza and pneumococcus, as well as human papilloma virus (adolescents)
Patients with SLE may suffer more from heart attacks and strokes. To decrease the risk for these complications, quitting smoking, and control of high blood pressure, dyslipidaemia, diabetes are essential.
1 star (*) means it is a weak recommendation with limited scientific evidence; 2 stars (**) means it is a weak recommendation with some scientific evidence; 3 stars (***) means it is a strong recommendation with quite a lot of scientific evidence; 4 stars (****) means it is a strong recommendation supported with a lot of scientific evidence. Recommendations with just 1 or 2 stars are based mainly on expert opinion and not backed up by appropriate clinical studies, but may be as important as those with 3 and 4 stars.
24/05/2019

26. Acknowledgements Task Force M. Kostopoulou (SLR fellow #2)
JN. Larsen (nurse)
A. Alunno (EMEUNET)
K. Lerstrom (patient)
M. Aringer
G Moroni
I. Bajema
M. Mosca
JN. Boletis
M. Schneider
R. Cervera
JS. Smolen
A. Doria
E. Svenugsson
C. Gordon
V. Tesar
M. Govoni
A. Tincani
F. Houssiau
AM. Troldborg (EMEUNET)
D. Jayne
R. Van Vollenhoven
M.Kouloumas (patient)
G. Bertsias (methodologist)
A. Kuhn
D. Boumpas (convenor)
24/05/2019