the new eular/acr criteria for classification of sle in action · •acute cutaneous lupus: malar...

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The New EULAR/ACR Criteria for Classification of SLE in Action

Karen H. Costenbader, MD, MPHLupus Program Director & Professor of Medicine

Brigham and Women’s Hospital, Harvard Medical SchoolBoston, MA

On behalf of the EULAR/ACR SLE Criteria Development Subcommittee

Disclosures

• EULAR/ACR support for the development of SLE classification criteria

• No other financial or other relationships to disclose

Pondering whether you have SLE patients eligible for the new quasilimumab trial…

Your first patient

• A 44 year old woman with a 10 year history of mild SLE. She originally came to see you for fatigue and arthralgias.

• She had a +ANA 1:160 speckled on HEp2 immunofluorescence (IF) several years ago. She has recurrent oral ulcers, Raynaud's phenomenon, headaches, and one episode of idiopathic pericarditis with a small pericardial effusion on ECHO several years ago.

• She is now taking hydroxychloroquine.

• Her labs show lowest WBC count 3,200/mm3, normal hemoglobin, normal platelet count, normal kidney function.

• Anti-Ro, anti-La, anti-dsDNA are positive and C4 has been low in the past. Anti-Smith is negative.

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orApp Website

Your first patient• A 44 year old woman with a 10 year history of mild SLE. She

originally came to see you for fatigue and arthralgias.

• She has a +ANA 1:160 speckled on HEp2 IF several years ago. She has recurrent oral ulcers, Raynaud's phenomenon, headaches, and one episode of idiopathic pericarditis with a small pericardial effusion on ECHO several years ago.




Inclusion Criterion

• + ANA 1:80 or greater on HEp2 IF

“Opening Statements”

• For each criterion, do not score if a cause more likely than SLE exists (such as infection, malignancy, medication, rosacea, endocrine disorder, other autoimmune disease).

• Occurrence of a criterion on at least one occasion is sufficient.

• Individual criteria need not occur simultaneously.

• At least one clinical criterion must be present.

• Within each domain, only the highest weighted criterion is counted toward the total score.







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> = 1 Clinical Criterion

• Oral ulcers

Muco-cutaneous Domain Definitions• Non-scarring alopecia*

• Oral ulcers*

• Subacute cutaneous lupus (SCLE) or discoid lupus (DLE):• SCLE: annular or papulosquamous (psoriasiform) cutaneous

eruption, usually photodistributed.*, **

• DLE: erythematous-violaceous cutaneous lesions with secondary changes of atrophic scarring, dyspigmentation, often follicular hyperkeratosis/plugging (scalp), leading to scarring alopecia on the scalp.*, **

• Acute cutaneous lupus: Malar rash (localized) or maculopapular rash (generalized) with or without photosensitivity.*, **

*Observed by clinician. Direct observation may include physical examination or review of a photograph.

**If skin biopsy is performed, typical changes must be present.

Merola J et al, proposed Cutaneous Lupus Definitions







Serositis Domain Definitions

• Pleural or pericardial effusion: imaging evidence (such as ultrasound, x-ray, CT scan, MRI) of pleural or pericardial effusion, or both, not meeting the definition of acute pericarditis below

• Acute pericarditis: ≥2 of (1) pericardial chest pain (typically sharp, worse with inspiration, improved by leaning forward), (2) pericardial rub, (3) EKG with new widespread ST-elevation or PR depression, (4) new or worsened pericardial effusion on imaging (such as ultrasound, x-ray, CT scan, MRI)







Hematologic Domain Definitions

• Leukopenia: WBC <4,000/mm3

• Thrombocytopenia: Platelets <100,000/mm3

• Autoimmune hemolysis with: (1) evidence of hemolysis, such as reticulocytosis, low haptoglobin, elevated indirect bilirubin, elevated LDH and (2) positive Coomb’s (direct antiglobulin test)

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Immunologic Domains DefinitionsAntiphospholipid antibodiesAnticardiolipin antibody positive (medium or high units) oranti-β2 GP1 positive or lupus anticoagulant positive

Complement proteinsLow C3 or low C4Low C3 and low C4

Highly specific antibodiesAnti-dsDNA Anti-Smith antibody

1. Constitutional: Unexplained fever >38.3 C2. Muco-cutaneous:

Non-scarring alopeciaOral ulcersSub-acute cutaneous lupus or discoid lupusAcute cutaneous lupus

3. Arthritis: Synovitis in 2 or more joints4. Neurologic:

DeliriumPsychosisSeizure

5. Serositis:Pleural or pericardial effusionAcute pericarditis

6. Hematologic:Leukopenia ThrombocytopeniaAutoimmune hemolysis

7. Renal:ProteinuriaRenal biopsy - Class II or V lupus nephritisRenal biopsy - Class III or IV lupus nephritis

Clinical Domains

8. Antiphospholipid Antibodies:

Present

9. Complement levels:

Low C3 or C4

Low C3 and C4

10. Specific antibodies

Anti-dsDNA

Anti-Smith

Immunologic Domains

SUBMIT

processing…

Your patient has 20 points, enough to be classified as SLE.

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Your second patient• A 32 year old man is newly seen for a + ANA of 1:320 on

HEp2 IF. He has had no fevers, oral ulcers, alopecia, or malar rash.

• On physical exam, there were no lesions of subacute cutaneous lupus or discoid lupus. A diffuse maculopapular rash was observed, but was not biopsied. The musculoskeletal exam revealed no synovitis. The neurologic exam was normal. He reported no chest pain and there was no evidence of pleural or pericardial effusion.

• Complete blood counts were notable for lowest white blood cell count 4200/mm3, platelet count 11,000/mm3, and no evidence of hemolysis.

• Urinalysis revealed no red blood cells or proteinuria. Anti-phospholipid antibodies, C3, C4, anti-dsDNA, and anti-Smith were all normal/negative.


HEp2 IF. He has had no fevers, oral ulcers, alopecia, or malar rash.

• On physical exam, there were no lesions of subacute cutaneous lupus or discoid lupus. A diffuse maculopapular rash was observed, but was not biopsied. The musculoskeletal exam revealed no synovitis. The neurologic exam was normal. He reported no chest pain and there was no evidence of pleural or pericardial effusion.



Inclusion Criterion

• + ANA 1:80 or greater on HEp2 IF


HEp2 IF. He had no fever, oral ulcers, alopecia, or malar rash.

• On physical exam, there were no lesions of subacute cutaneous lupus or discoid lupus. A diffuse maculopapular rash over his chest and arms was observed on physical exam, but was not biopsied. The musculoskeletal exam revealed no synovitis. The neurologic exam was normal. She reported no chest pain and there was no evidence of pleural or pericardial effusion.



Muco-cutaneous Domain Definitions• Non-scarring alopecia*

• Oral ulcers*

• Subacute cutaneous lupus (SCLE) or discoid lupus (DLE):• SCLE: annular or papulosquamous (psoriasiform) cutaneous eruption,

usually photodistributed.*,**• DLE: erythematous-violaceous cutaneous lesions with secondary

changes of atrophic scarring, dyspigmentation, often follicular hyperkeratosis/plugging (scalp), leading to scarring alopecia on the scalp.*,**

• Acute cutaneous lupus: Malar rash (localized) ormaculopapular rash (generalized) with or without photosensitivity.*,**

*Observed by clinician. Direct observation may include physical examination or review of a photograph.

**If skin biopsy is performed, typical changes must be present.

Merola J et al, proposed Cutaneous Lupus Definitions

Hematologic Domain Definitions

• Leukopenia: WBC <4,000/mm3

• Thrombocytopenia: Platelets <100,000/mm3

• Autoimmune hemolysis with: (1) evidence of hemolysis, such as reticulocytosis, low haptoglobin, elevated indirect bilirubin, elevated LDH and (2) positive Coomb’s (direct antiglobulin test)

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Clinical Domains


Present


Low C3 or C4

Low C3 and C4


Anti-dsDNA

Anti-Smith

Immunologic Domains

SUBMIT

Your patient has 10 points, enough to be classified as SLE.

Your third patientA 24 year old woman with a + ANA of 1:80 on HEp2 IF.

She had no history of fevers, oral ulcers, alopecia, or other rashes. She had not had any arthritis. She had not had any symptoms of delirium, psychosis, or seizures, or other neurologic abnormalities. She had had no symptoms of pleuritis or pericarditis. Her blood counts had been normal. She had had heavy proteinuria and a renal biopsy showed membranous glomerulonephritis with immunofluorescent deposits, consistent with class V lupus nephritis.

She did not have any antiphospholipid antibodies. Her complement levels were normal. Anti-dsDNA and anti-Smith antibodies were negative.

Your third patientA 24 year old woman with a + ANA of 1:80 on HEp2 IF.

She had no history of fevers, oral ulcers, alopecia, or other rashes. She had not had any arthritis. She had not had any symptoms of delirium, psychosis, or seizures, or other neurologic abnormalities. She had had no symptoms of pleuritis or pericarditis. Her blood counts had been normal. She had had heavy proteinuria and a renal biopsy showed membranous glomerulonephritis with immunofluorescent deposits, consistent with class V lupus nephritis.

She did not have any antiphospholipid antibodies. Her complement levels were normal. Anti-dsDNA and anti-Smith antibodies were negative.

Renal Domain Definitions• Proteinuria >0.5g/24h: on 24 hour urine collection or spot urine

protein-to-creatinine ratio representing >0.5g protein/24h• Renal Biopsy with Class II or V lupus nephritis• Renal Biopsy with Class III or IV lupus nephritis

International Society of Nephrology/Renal Pathology Society definitions Class II: Mesangial proliferative lupus nephritis: Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy, with mesangial immune deposit. A few isolated subepithelial or subendothelial deposits may be visible by immunofluorescence or electron microscopy, but not by light microscopy.Class III: Focal lupus nephritis: Active or inactive focal, segmental or global endo- or extracapillaryglomerulonephritis involving <50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations. Class IV: Diffuse lupus nephritis: Active or inactive diffuse, segmental or global endo- or extracapillaryglomerulonephritis involving ≥50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations. This class includes cases with diffuse wire loop deposits but with little or no glomerular proliferation.Class V: Membranous lupus nephritis: Global or segmental subepithelial immune deposits or their morphologic sequelae by light microscopy and by immunofluorescence or electron microscopy, with or without mesangial alterations(Class VI: Advanced sclerotic lupus nephritis: ≥90% of glomeruli globally sclerosed without residual activity)

(Weening JJ, et al. Kidney International. 2004;65:521-30)

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Clinical Domains


Present


Low C3 or C4

Low C3 and C4


Anti-dsDNA

Anti-Smith

Immunologic Domains

SUBMIT

Your patient has 8 points, notenough to be classified as SLE.

Your last patientA 56 year old man patient had a + ANA of 1:2560 on HEp2 IF.

He did not have fevers, oral ulcers, alopecia, or any rashes. He had had arthritis of the small joints of the hands and feet, with physician-observed synovitis in the right MCP2 and 4, in the left MCP3 and 4 and PIP4, in the right wrist, and the right forefoot. Plain radiographs were obtained and showed erosions. An anti-CCP antibody was obtained and was in the high positive range (greater than 3 times the upper limit of normal).

The patient had had no delirium, psychosis or delusions, or motor or sensory nerve disturbances. He has a history of grand mal seizures. He had not had any pleuritis or pericarditis.

His anti-cardiolipin IgG was elevated at 81 units. Anti-β2 GP1 and lupus anticoagulant antibodies were negative. His complements were in the normal ranges. His anti-dsDNA and anti-Smith antibodies were negative.



The patient had had no delirium, no psychosis or delusions, or motor or sensory nerve disturbances. He has a history of grand mal seizures. He had not had any pleuritis or pericarditis.

His anti-cardiolipin IgG was elevated at 81 units. Anti-β2 GP1 and lupus anticoagulant antibodies were negative. His complements were in the normal ranges. His anti-dsDNA and anti-Smith antibodies were negative.


He did not have fevers, oral ulcers, alopecia, or any rashes. He had had arthritis of the small joints of the hands and feet, with physician-observed synovitis in the right MCP II and IV, in the left MCPIII and IV and PIP IV, in the right wrist, and the right forefoot. Plain radiographs were obtained and showed erosions. An anti-CCP antibody was obtained and was in the high positive range (greater than 3 times the upper limit of normal).

The patient had had delirium, no history of psychosis or delusions, or motor or sensory nerve disturbances. He has a history of grand mal seizures. He had not had any pleuritis or pericarditis.

His anti-cardiolipin IgG was elevated at 81 units. Anti-β2 GP1 and lupus anticoagulant antibodies were negative. His complements were in the normal ranges. His anti-ds DNA and anti-Smith antibodies were negative.

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Arthritis Domain Definition

• Synovitis in ≥2 joints: characterized by joint swelling and tenderness, directly observed.

• “Opening statement”: For each criterion, do not score if a cause more likely than SLE exists.

• You think he has seropositive, erosive RA causing his small joint polyarthritis.



The patient had had no delirium, psychosis or delusions, or motor or sensory nerve disturbances. He has a history of grand mal seizures. He had not had any pleuritis or pericarditis.

His anti-cardiolipin IgG was elevated at 81 units. Anti-β2 GP1 and lupus anticoagulant antibodies were negative. His complements were in the normal ranges. His anti-ds DNA and anti-Smith antibodies were negative.

Neurologic Domain Definitions

• Delirium: (1) change in consciousness or level of arousal with reduced ability to focus, (2) symptom development over hours to < 2 days, (3) symptom fluctuation throughout the day, and either (4a) acute/subacute change in cognition or (4b) change in behavior, mood or affect

• Psychosis: (1) delusions and/or hallucinations without insight and (2) absence of delirium

• Seizure: primary generalized seizures or partial/focal seizures with independent description by a reliable witness.

Your last patientA 56 year old man patient had a positive ANA of 1:2560 on HEp2 immunofluorescence. He did not have fevers, oral ulcers, alopecia, or any rashes. He had had arthritis of the small joints of the hands and feet, with physician-observed synovitis in the right MCP II and IV, in the left MCPIII and IV and PIP IV, in the right wrist, and the right forefoot. Plain radiographs were obtained and showed erosions. An anti-CCP antibody was obtained and was in the high positive range (greater than 3 times the upper limit of normal).

The patient had had delirium, no history of psychosis or delusions, or motor or sensory nerve disturbances. He has a history of grand mal seizures. He had not had any pleuritis or pericarditis. His anti-cardiolipin IgG was elevated at 81 units. Anti-β2 GP1 and lupus anticoagulant antibodies were negative. His complements were in the normal ranges. His anti-ds DNA and anti-Smith antibodies were negative.

Immunologic Domains Definitions

Antiphospholipid antibodiesAnticardiolipin antibody positive (medium or high units) oranti-β2-GP1 positive or lupus anticoagulant positive

Complement proteinsLow C3 or low C4 Low C3 and low C4

Highly specific antibodiesAnti-dsDNA Anti-Smith antibody








Clinical Domains

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Present


Low C3 or C4

Low C3 and C4


Anti-dsDNA

Anti-Smith

Immunologic Domains

SUBMIT

Your patient has 7 points, notenough to be classified as SLE.

Strengths• Combination of expert-based and data-driven multi-

step rigorous criteria development process

• Started from scratch with new item generation, and iterative process to reduce, define and determine independence and weights of criteria

• > 150 SLE experts and centers from around the world participated

• Real cases

• Weighted criteria with ability to classify patients with single organ system involvement

• Excellent performance characteristics (to date)

• Ongoing large and rigorous validation

Limitations and Points for Discussion

• SLE is heterogeneous: large spectrum of disease including overlap syndromes, incomplete lupus, pre-SLE, possible SLE, cutaneous-only lupus

• Overlap syndromes can be classified as SLE if meet SLE criteria. Could be excluded in specific studies.

• Newer biomarkers and assays, such as complement deposition products and interferon signatures, may be very helpful in distinguishing SLE from non-SLE, but not widely used and available at this time.

• Somewhat complicated system (but that’s what computers and smart phones are for!)

AcknowledgmentsSteering Committee: Martin Aringer (EULAR lead) Sindhu Johnson (ACR Lead), Dimitrios Boumpas, Karen Costenbader, Thomas Dörner, David Daikh, David Jayne, Diane Kamen, Marta Mosca, Rosalind Ramsey-Goldman, Josef Smolen, David Wofsy

Delphi Investigators: Elisabeth Aberer, Graciela Alarcon, Cynthia Aranow, Seher Arat, Martin Aringer, Anca Askanase, Tadej Avcin, Juan Antonio Avina-Zubieta, April Barnado, Christie Bartels, Ashley Beal, Anders Bengtsson, Jo Berden, Bonnie Bermas, George Bertsias, Hendrika Bootsma, Dimitrios Boumpas, Piergiacomo Calzavara-Pinton, Mary Carmen Amigo, Ricard Cervera, Eliza Chakravarty, Winn Chatham, Rolando Cimaz, Megan Clowse, Gabriel Contreras, Karen Costenbader, Joseph Craft, Peggy Crow, Melissa Cunningham, David Daikh, Maria Dall’Era, Rodney Daniel, Thomas Dorner, Mary Ann Dooley, Andrea Doria, Amy Elliott, Doruk Erkan, Gerard Espinosa, Dominique Farge, David Fiorentino, Rebecca Fischer-Betz, Brent Flickinger, Franco Franceschini, Richard Furie, Cybele Ghossein, Gary Gilkeson, Dafna Gladman, Jose Gomez-Puerta, Tania Gonzalez Rivera, Caroline Gordon, Winfried Graninger, Jennifer Grossman, Iva Gunnarsson, Anna Haemel, Bevra Hahn, Falk Hiepe, Lawrence Holzman, Gerd Horneff, Frederic Houssiau, Bimba Hoyer, Christine Hsieh, Thomas Huizinga, David Isenberg, Soeren Jacobsen, David Jayne, Pia Johnsson, Meenakshi Jolly, Heikki Julkunen, Michelle Kahlenberg, Tilmann Kallinich, Kenneth Kalunian, Diane Kamen, Mariana Kaplan, Hans Kiener, Anne-Sophie Korganow, Matthias Kretzler, Annegret Kuhn, Anne Laumann, Helle Laustrup, Karen Law, L Lightstone, Jozef Lukac, Mary Mahieu, Bernhard Manger, Xavier Mariette, Thierry Martin, Ellen Massarotti, Joseph McCune, Joan Merrill, Barbara Mittlemen, Chi Chiu Mok, Marta Mosca, Yakov Naparstek, Ola Nived, Katarzyna Nowicka-Sauer, James C. Oates, Seza Özen, Omer Pamuk, Samir Parikh, Jean-Louis Pasquali, Christine Peschken, Rosalind Ramsey-Goldman, Angelo Ravelli, Westley Reeves, Bruce Richardson, Lars Rönnblom, Jozef Rovenský, Brad Rovin, Blaž Rozman, Jane Salmon, Jorge Sanchez-Guerrero, Amr Sawalha, Gabby Schmajuk, Matthias Schneider, Peter Schur, Andreas Schwarting, Yehuda Shoenfeld, Earl Silverman, Josef Smolen, Stephen Soloway, William Stohl, Georg Stummvoll, Gunnar Sturfelt, Cord Sunderkötter, Elisabet Svenungsson, Onno Teng, James Tumlin, Murray Urowitz, Tammy Utset, PJ Utz, Ronald van Vollenhoven, Carlos Vasconcelos, Luis Vila, Ruth Ann Vleugels, Reinhard Voll, Joan VonFeldt, Alexandre Voskuyl , Ewa Walczak, Daniel Wallace, Doris Weber, Victoria Werth, David Wofsy, Peggy Wu, Sule Yavuz, Jinoos Yazdany, Neslihan Yilmaz, Eric Zollars

Early SLE Cohort Investigators: George Bertsias, Eloisa Bonfa, Karen Costenbader, Annika Hoyer, Bimba Hoyer, Valentina Lorenzoni, Jorge Medina-Rosas, Marta Mosca, Sandra Navarra, Nicolai Leuchten, Chiara Tani, Gabby Schmajuk, Sara Tedeschi, Zahi Touma

Nominal Group Technique Investigators: Ricard Cervera, Nathalie Costedoat-Chalumeau, Bevra Hahn, Falk Hiepe, Dafna Gladman, Jorge Sanchez-Guerrero, Dinesh Khanna, Elena Massarotti

Multicriteria Decision Analysis Investigators: Betty Diamond, Søren Jacobsen, W. Joseph McCune, Ray Naden, Guillermo Ruiz-Irastorza, Matthias Schneider, Murray Urowitz (with assistance of: Alison Hendry, Amy Miller, Sara Tedeschi, Zahi Touma)

Derivation and Validation Cohort Investigators: Branimir Anic, Florence Assan, Ralph Brinks, Daniel Chan, Ann Clarke, Peggy Crow, Lászlo Czírják, Andrea Doria, Winfried Graninger, Sarfaraz Hasni, Michelle Jung, Bernadett Kiss, Peter Izmirly, Xavier Mariette, Ivan Padjen, José Maria Pego-Reigosa, Juanita Romero-Díaz, Iñigo Rúa-Figueroa Fernández de Larrinoa, Raphaèle Seror, Georg Stummvoll, Yoshiya Tanaka, Maria Tektonidou, Carlos Vasconcelos, Edward Vital, Sule Yavuz

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Muco-cutaneous Domain Definitions+Typical skin biopsy histopathology (based upon an international Delphi consensus process at the 2013 International Meeting on Cutaneous Lupus Erythematosus):

• SCLE: interface vacuolar dermatitis consisting of a peri-vascular lymphohistiocytic infiltrate, often with dermal mucin noted

• DLE: interface vacuolar dermatitis consisting of a peri-vascular and/or peri-appendageal lymphohistiocytic infiltrate. In the scalp, follicular keratin plugs may be seen. In longstanding lesions, mucin deposition and basement membrane thickening may be noted.

• Acute cutaneous lupus: interface vacuolar dermatitis consisting of a peri-vascular lymphohistiocytic infiltrate, often with dermal mucin noted. Peri-vascular neutrophilic infiltrate may be present early in the course.

ACR 1997

Patient

1 5/11 yes

2 2/11 no

3 2/11 no

4 3/11 no

SLICC 2012

Patient

1

2

3

4

the new eular/acr criteria for classification of sle in action · •acute cutaneous lupus: malar...

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