S Lecture

Systemic Lupus Systemic Lupus ErythematosusErythematosus

SLESLE

Incurable Multisystemic Incurable Multisystemic autoimmune diseaseautoimmune disease

Predominantly women 1:9Predominantly women 1:9

Median age of disease onsetMedian age of disease onset

•Afro-carribean: 26yrsAfro-carribean: 26yrs

•Asian: 33yrsAsian: 33yrs

•Caucasian: 33yrsCaucasian: 33yrs

MortalityMortality10 year survival rate10 year survival rate

50

55

60

65

70

75

80

85

90

95

1960 1970 1980 1990 2000 2010

Year

Pe

rce

nta

ge

su

rviv

al

SLE- Emerging SLE- Emerging therapiestherapies

Mycophenolate mofitilMycophenolate mofitilAnti-CD20Anti-CD20

CTLA4IgCTLA4IgAnti-IL6RAnti-IL6RAnti-BlySAnti-BlySAbetimus (LJP-394)Abetimus (LJP-394)

SLESLE

•Commonest CTD after Commonest CTD after RheumatoidRheumatoid

Prevalence of SLE in South Prevalence of SLE in South LondonLondon

Afro-CaribbeansAfro-Caribbeans 1.7 / 1,0001.7 / 1,000 (CI 1.3-2.2)(CI 1.3-2.2)

West AfricanWest African 1.1 / 1,0001.1 / 1,000 (CI 0.58-(CI 0.58-1.6)1.6)

CaucasiansCaucasians 0.35 / 1,0000.35 / 1,000 (CI 0.26-0.4)(CI 0.26-0.4)

Molokhia M et al. Systemic lupus erythematosus in Molokhia M et al. Systemic lupus erythematosus in migrants from west Africa compared with Afro-Caribbean migrants from west Africa compared with Afro-Caribbean people in the UK.people in the UK.

Lancet. 2001 May 5;357(9266):1414-5.Lancet. 2001 May 5;357(9266):1414-5.

What is Lupus?What is Lupus?

Multisystemic autoimmune diseaseMultisystemic autoimmune diseaseMarkedly Heterogeneous Markedly Heterogeneous No definitionNo definition

American College of RheumatologyAmerican College of RheumatologyThe 1982 revised criteria for the classification

of systemic lupus erythematosus

Classification criteria (Classification criteria (4 of 4 of 11)11)1.1. Malar rashMalar rash2.2. Discoid rashDiscoid rash3.3. PhotosensitivityPhotosensitivity4.4. Oral ulcersOral ulcers5.5. ArthritisArthritis6.6. SerositisSerositis7.7. Renal disorderRenal disorder8.8. Neurological disorderNeurological disorder

American College of Rheumatology The 1982 revised criteria for classification of systemic lupus erythematosus

Classification criteria (Classification criteria (4 of 4 of 11)11)

9. 9. HaematologicalHaematological

10. 10. ANA positivity ANA positivity

11.11. ImmunologicalImmunological

American College of Rheumatology

The 1982 revised criteria for classification of systemic

lupus erythematosus


Erythematous raised patches withadherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions


Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion

Lupus NephritisLupus Nephritis

•Detected in clinic by:Detected in clinic by:

UrinalysisUrinalysis -blood, protein-blood, protein

Blood pressureBlood pressure

MicroscopyMicroscopy

GlomerulonephritisGlomerulonephritis

Class IClass I NormalNormalClass IIClass II MesangioproliferativeMesangioproliferative

Class IIIClass III Focal ProliferativeFocal ProliferativeClass IVClass IV Diffuse ProliferativeDiffuse Proliferative

Class VClass V MembraneousMembraneous

Class VIClass VI Sclerosing nephropathySclerosing nephropathy

Neurological manifestationsNeurological manifestations

•FitsFits

•PsychosisPsychosis

Neurological manifestationsNeurological manifestations

• HeadacheHeadache

• ChoreaChorea

• Cerebrovascular diseaseCerebrovascular disease

• Cognitive dysfunctionCognitive dysfunction

• Transverse myelitis, optic neuritisTransverse myelitis, optic neuritis

• Sensorineural hearing lossSensorineural hearing loss

• ComaComa


9. 9. HaematologicalHaematological– Haem. Haem. HbHb– WBC,lymphosWBC,lymphos– PltsPlts

10. 10. ANA positivity ANA positivity 11.11. ImmunologicalImmunological

– Anti-DNA, anti-SmAnti-DNA, anti-Sm– Anti-phospholipidAnti-phospholipid

HaematologicHaematologicalal

• Autoimmune cytopeniasAutoimmune cytopenias

• LymphopeniaLymphopenia

• Autoimmune haemolytic anaemiaAutoimmune haemolytic anaemia

• Immune thrombocytopeniaImmune thrombocytopenia


9. 9. HaematologicalHaematological– Haem. Haem. HbHb– WBC,lymphosWBC,lymphos– pltsplts

10. 10. ANA positivity ANA positivity 11.11. ImmunologicalImmunological

– Anti-DNA, anti-SmAnti-DNA, anti-Sm– Anti-cardiolipinAnti-cardiolipin


9. 9. HaematologicalHaematological– Haem. Haem. HbHb– WBC,lymphosWBC,lymphos– pltsplts

10. 10. ANA positivity ANA positivity

11.11. ImmunologicalImmunological– Anti-DNA, anti-SmAnti-DNA, anti-Sm– Anti-cardiolipinAnti-cardiolipin– Lupus anticoagulantLupus anticoagulant

Anti-Double stranded DNAAnti-Double stranded DNA

• Highly specific for SLEHighly specific for SLE

• Occurs in up to 80% of patientsOccurs in up to 80% of patients

• Particularly associated with renal Particularly associated with renal diseasedisease

• Titres correlate with activityTitres correlate with activity

Anti-Smith (Anti-Sm)Anti-Smith (Anti-Sm)

• Highly specific for SLEHighly specific for SLE

• Only occurs in 10-30% casesOnly occurs in 10-30% cases

• Strong association with renal diseaseStrong association with renal disease

• Levels stable, no correlation to Levels stable, no correlation to disease activitydisease activity

Anti-cardiolipin and Lupus Anti-cardiolipin and Lupus anticoagulantanticoagulant

• Strongly associated with anti-Strongly associated with anti-phospholipid syndromephospholipid syndrome

• May occur in the absence of SLEMay occur in the absence of SLE

• False positive VDRLFalse positive VDRL

General featuresGeneral features

• Fever Fever

• LNLN

• Weight lossWeight loss

• Myalgia (rarely myositis)Myalgia (rarely myositis)

• Fatigue (common, acute, chronic)Fatigue (common, acute, chronic)

Laboratory featuresLaboratory features

•ESR/CRPESR/CRP•CRP>30-40=infectionCRP>30-40=infection

•IgG/autoab (ANA)IgG/autoab (ANA)

•Anti-dsDNA Anti-dsDNA

•ComplementComplement•C3,C4C3,C4

Extractable nuclear Extractable nuclear antigens -ENAantigens -ENA

•Smith - SmSmith - Sm

•Ro Ro

•LaLa

•Ribonuclear protein - Ribonuclear protein - RNPRNP

ManagementManagement

• No drug is licensed for SLENo drug is licensed for SLE

• Proliferative GlomerulonephritisProliferative Glomerulonephritis

-Class III/IV-Class III/IV

ManagementManagement

• Sunblock, educationSunblock, education• NSAIDNSAID• Antimalarials Antimalarials

•Hydroxychloroquine, mepacrineHydroxychloroquine, mepacrine

• ThalidomideThalidomide• CorticosteroidsCorticosteroids

•Topical, low dose, or high dose (oral/im/iv)Topical, low dose, or high dose (oral/im/iv)

HydroxychoroquineHydroxychoroquine

• No double blind prospective trialsNo double blind prospective trials• Double blind prospective withdrawal studyDouble blind prospective withdrawal study47patients-25 continued, 24 stopped 47patients-25 continued, 24 stopped 24 wks24 wks

Risk of flare X2.5 higher placeboRisk of flare X2.5 higher placebo(95% CI 1.08-5.58)(95% CI 1.08-5.58)

Risk of severe flare X6.1 higher Risk of severe flare X6.1 higher (95% CI , 0.72-52.44) (95% CI , 0.72-52.44)

The Canadian Hydroxychloroquine Study Group. N Engl J Med. 1991 Jan 17;324(3):150-4.

Hydroxychoroquine-ToxicityHydroxychoroquine-Toxicity

• AlopeciaAlopecia

• Deposition in the corneaDeposition in the cornea

• DiarrhoeaDiarrhoea

• RashRash

• MyopathyMyopathy

• Liver and haematological toxicityLiver and haematological toxicity

Hydroxychoroquine-Hydroxychoroquine-Retinal toxicityRetinal toxicityIncrease riskIncrease risk• Doses over 6.5mg/kgDoses over 6.5mg/kg• Cumulative dose over 800gCumulative dose over 800g• Increased ageIncreased age

Incidence of hydroxychloroquine retinopathy in Incidence of hydroxychloroquine retinopathy in 1,207 patients in a large multicenter outpatient 1,207 patients in a large multicenter outpatient practice. Arthritis Rheum. practice. Arthritis Rheum.

1997 Aug;40(8):1482-6.1997 Aug;40(8):1482-6.• 1 patient with definite toxicity (1 of 1,207; 0.08%)1 patient with definite toxicity (1 of 1,207; 0.08%)• other patients with indeterminate but probable toxicity other patients with indeterminate but probable toxicity

(5 of 1,207; 0.4%).(5 of 1,207; 0.4%).

HydroxychoroquineHydroxychoroquine

• Rare instances of congenital defects in Rare instances of congenital defects in malarial prophylaxis dosesmalarial prophylaxis doses

Sensorineural hearing loss and cleft plateSensorineural hearing loss and cleft plate

• Reduce dose in renal impairmentReduce dose in renal impairment

• Caution hepatic diseaseCaution hepatic disease

• Mepacrine negligible retinal toxicityMepacrine negligible retinal toxicity

Effect of prednisone and Effect of prednisone and hydroxychloroquine on coronary artery hydroxychloroquine on coronary artery disease risk factors in systemic lupus disease risk factors in systemic lupus erythematosus: a longitudinal data erythematosus: a longitudinal data analysis.analysis.

Petri et al. Am J Med. 1994 Petri et al. Am J Med. 1994 Mar;96(3):254-9.Mar;96(3):254-9.

longitudinal cohort study of 264 longitudinal cohort study of 264 patients patients

3,027 patient visits 3,027 patient visits Regression analysis Regression analysis

HCQ 200+ 400mg associated with HCQ 200+ 400mg associated with lower serum cholesterollower serum cholesterol

(8.9 +/- 3.44 SE mg%). (8.9 +/- 3.44 SE mg%). A change in prednisone dose of 10 A change in prednisone dose of 10 mg was associated with a change in mg was associated with a change in cholesterol of 7.5 +/- 1.46 (SE) mg%cholesterol of 7.5 +/- 1.46 (SE) mg%

A 10-mg change in prednisone dose A 10-mg change in prednisone dose led to a change in mean arterial led to a change in mean arterial blood pressure of 1.1 mm Hgblood pressure of 1.1 mm Hg

ImmunosuppressantsImmunosuppressants

• CyclophosphamideCyclophosphamide

• AzathioprineAzathioprine

• MethotrexateMethotrexate

• Mycophenolate MofetilMycophenolate Mofetil

CyclophosphamideCyclophosphamide

• NIH trials NIH trials

Superiority in Prolif NephritisSuperiority in Prolif Nephritis

High dose iv cyclopho VS steroid aloneHigh dose iv cyclopho VS steroid alone

For inductionFor induction

Austin et al NEJM 1986Austin et al NEJM 1986

MaintenanceMaintenance

Boumpas et al Lancet 1992Boumpas et al Lancet 1992

CyclophosphamideCyclophosphamideSide effectsSide effects

•High doseHigh dose 0.5-1g/m20.5-1g/m2

•Monthly thence quarterlyMonthly thence quarterly

•Estimates of infertility 23-41%Estimates of infertility 23-41%

• InfectionInfection

•Bladder cancerBladder cancer -Mesna-Mesna

Randomized study of maintenance RxRandomized study of maintenance RxCyclo, azathioprine and MMFCyclo, azathioprine and MMF

Contreras, G. et al. N Engl J Med 2004;350:971-980

Contreras, G. et al. N Engl J Med 2004;350:971-980Contreras, G. et al. N Engl J Med 2004;350:971-980

Kaplan-Meier Estimates of Relapse-free Survival

Randomized study of maintenance RxRandomized study of maintenance RxCyclo, azathioprine and MMFCyclo, azathioprine and MMF

Chan, T. M. et al. N Engl J Med 2000;343:1156-1162

Outcome of Treatment

Induction therapy:Induction therapy:Mycophenolate Mofetil Vs Mycophenolate Mofetil Vs CyclophosphamideCyclophosphamide



Mean ({+/-}SD) Serum Albumin Concentration and Urinary Protein Excretion in Patients with Diffuse Proliferative Lupus Nephritis Who Were Treated with Mycophenolate Mofetil and

Prednisolone (Group 1) or with Cyclophosphamide and Prednisolone Followed by Azathioprine and Prednisolone (Group 2)

Long-Term Study of Mycophenolate Mofetil as Long-Term Study of Mycophenolate Mofetil as Continuous Induction and Maintenance Continuous Induction and Maintenance Treatment for Diffuse Proliferative Lupus Treatment for Diffuse Proliferative Lupus Nephritis.Nephritis.Chan TM, Tse KC, Siu-On Tang C, Mok MY, Li FK.Chan TM, Tse KC, Siu-On Tang C, Mok MY, Li FK.

J Am Soc Nephrol. 2005 Feb 23J Am Soc Nephrol. 2005 Feb 23

Cyclo + azathioprineCyclo + azathioprine 31pts31pts

Mycophenolate Mycophenolate 33pts33pts

All class IVAll class IV

63 month median F/U63 month median F/U

Long-Term Study of Mycophenolate Mofetil as Long-Term Study of Mycophenolate Mofetil as Continuous Induction and Maintenance Continuous Induction and Maintenance Treatment for Diffuse Proliferative Lupus Treatment for Diffuse Proliferative Lupus Nephritis.Nephritis.Chan TM, Tse KC, Siu-On Tang C, Mok MY, Li FK.Chan TM, Tse KC, Siu-On Tang C, Mok MY, Li FK.

J Am Soc Nephrol. 2005 Feb 23J Am Soc Nephrol. 2005 Feb 23

• No difference in outcomesNo difference in outcomes• ESRF or death 4 vs 0 (NS P=0.062)ESRF or death 4 vs 0 (NS P=0.062)

Significantly less Significantly less • infections (p = 0.013)infections (p = 0.013) • infections requiring hospitalisation infections requiring hospitalisation

(p=0.014(p=0.014))

Mycophenolate MofetilMycophenolate Mofetil

• Hydrolysed to Mycophenolic acidHydrolysed to Mycophenolic acidInhibits inosine monophosphate dehydrogenaseInhibits inosine monophosphate dehydrogenase

Blocks Blocks de novode novo synthesis guanosine nucleosides synthesis guanosine nucleosides

• Suppresses lymphocyte proliferationSuppresses lymphocyte proliferation

• Suppresses glycosylation of adhesion Suppresses glycosylation of adhesion moleculesmolecules

Mycophenolate Mofetil Mycophenolate Mofetil

Side effectsSide effects •DiarrhoeaDiarrhoea

•LymphopeniaLymphopenia

• InfectionInfection

Increasingly used in non-renal lupusIncreasingly used in non-renal lupus

AzathioprineAzathioprine

• Maintenance therapy, steroid sparing, Maintenance therapy, steroid sparing, Class II LNClass II LN

• Bone marrow suppression- neutropeniaBone marrow suppression- neutropenia

• Hepatitic liver toxicityHepatitic liver toxicity

• Thiopurine methyl transferase (TPMT)Thiopurine methyl transferase (TPMT)

Anti-CD20 therapyAnti-CD20 therapyRituximabRituximab

• Chimeric mouse/human antibodyChimeric mouse/human antibody

• IgG1/IgG1/κκ

• Anti-CD20Anti-CD20

• Depletes pre-B - mature B-lymphocytesDepletes pre-B - mature B-lymphocytes

• Spares lymphoid precursors and Spares lymphoid precursors and plasma cells.plasma cells.

RituximabRituximab

• Licensed for use in B-cell NHLLicensed for use in B-cell NHL

• Not associated with increased risk of Not associated with increased risk of infection.infection.

B-Cell CharacteristicsB-Cell Characteristics

• Express surface immunoglobulinExpress surface immunoglobulin• Antigen uptake via surface Antigen uptake via surface

immunoglobulin for processing and immunoglobulin for processing and presentationpresentation

• Provides cognitive help for T-cellsProvides cognitive help for T-cells• Produces cytokines e.g. IL-4 and IL-10Produces cytokines e.g. IL-4 and IL-10• Constitutive production of antibodies Constitutive production of antibodies

by plasma cellsby plasma cells

Rituximab in SLERituximab in SLE

• No control clinical trials in SLENo control clinical trials in SLE• Several case series suggesting benefitSeveral case series suggesting benefitLeandro et al Leandro et al 21 patients21 patientsLooney et al Looney et al 17 patients17 patientsVan Vollenhoven et alVan Vollenhoven et al 15 patients15 patientsSfikakis et alSfikakis et al 10 patients10 patientsAlbert et al Albert et al 8 patients8 patientsTanaka et al Tanaka et al 7 patients7 patientsRyan et al Ryan et al 4 patients4 patients

Leandro et al Leandro et al ACR 2004 Abs1126ACR 2004 Abs1126

• 21 patients with active SLE21 patients with active SLE

TreatedTreated

• Day 1Day 1 Methylpred 750mgMethylpred 750mg

Rituximab 1gRituximab 1g

• Day 2Day 2 Cyclophosphamide 750mgCyclophosphamide 750mg

• Day 14 Day 14 Rpt day 1Rpt day 1

• Day 15 Day 15 Rpt day 2Rpt day 2


• 20/21 successfully B-cell depleted 20/21 successfully B-cell depleted

(<5 CD19+ B cells/(<5 CD19+ B cells/μμl).l).

• Time to repopulation 3-8/12, 1pt >3yrsTime to repopulation 3-8/12, 1pt >3yrs

• Mean serum Ig levels decreased within Mean serum Ig levels decreased within Normal rangeNormal range


• Follow up 3-46 months (mean 19) Follow up 3-46 months (mean 19)

• Response in all patients with B-cell Response in all patients with B-cell depletiondepletion

• 9 pts - no other I/S therapy at 12-9 pts - no other I/S therapy at 12-46/1246/12


• Response seen in all aspects of the BILAGResponse seen in all aspects of the BILAG

Particularly:Particularly:

• FatigueFatigue

• arthralgia/arthritisarthralgia/arthritis

• serositis serositis

• nephritisnephritis

• thrombocytopenia and haemolytic thrombocytopenia and haemolytic anaemiaanaemia


• 1 serious infusion reaction1 serious infusion reaction

• No serious or opportunistic infectionsNo serious or opportunistic infections

• 1 patient HACA on retreatment1 patient HACA on retreatment

First 7 patients First 7 patients

• dsDNA reduced by 53% (0-93%) at dsDNA reduced by 53% (0-93%) at 6/126/12

• dsDNA, histone dsDNA, histone

signif reduced(p<0.005) signif reduced(p<0.005) at 12/12at 12/12

Cambridge et al. ACR 2004 Cambridge et al. ACR 2004 abs1723abs1723

ENA behaved differently in different patientsENA behaved differently in different patientsRNP, SSARNP, SSA NSNSSignificant rise in Sm at 6 months (p<0.05)Significant rise in Sm at 6 months (p<0.05)

PCP, TT no changePCP, TT no change

Cambridge et al. ACR 2004 abs1723Cambridge et al. ACR 2004 abs1723

Looney et al Looney et al Arthritis Rheum. Arthritis Rheum. 2004;50:2580-92004;50:2580-9

• A phase I/II dose-escalation trial A phase I/II dose-escalation trial • RituximabRituximab

single infusion of 100 mg/msingle infusion of 100 mg/m22 (low dose) (low dose)

single infusion of 375 mg/msingle infusion of 375 mg/m22 (intermediate dose)(intermediate dose)

4 infusions(1 wk apart) of 375 4 infusions(1 wk apart) of 375 mg/mmg/m22(high dose). (high dose).


•11/17 had profound B cell depletion (<5 11/17 had profound B cell depletion (<5 CD19+ CD19+

B cells/B cells/μμl).l).

•Low doseLow dose 4/64/6•IntermediateIntermediate 4/74/7•High doseHigh dose 3/43/4


B-cell depletersB-cell depleters• SLAM score improved at 2/12 and 3/12 SLAM score improved at 2/12 and 3/12 • P = 0.0016 and P = 0.002, paired t-testP = 0.0016 and P = 0.002, paired t-test• Improvement persisted for 12 monthsImprovement persisted for 12 months

• Arthritis, rashes, mucositis and Arthritis, rashes, mucositis and alopecia.alopecia.


•Absence of a significant change in Absence of a significant change in anti-double-stranded DNA antibody anti-double-stranded DNA antibody and complement levelsand complement levels

• Six patients developed human Six patients developed human antichimeric antibodies (HACAs) at a antichimeric antibodies (HACAs) at a level > / =100 ng/mllevel > / =100 ng/ml

Cyclophosphamide and Cyclophosphamide and RituximabRituximabLeandro et al Leandro et al 20/2120/21 cyclocyclo

Van Vollenhoven et alVan Vollenhoven et al 15/1515/15 cyclocyclo

Looney et al Looney et al 11/1711/17

Sfikakis et alSfikakis et al 8/108/10

Albert et al Albert et al 6/8 6/8

Tanaka et al Tanaka et al 7/77/7

Ryan et al Ryan et al 4/44/4

71/82 = 85%71/82 = 85%

Cyclophosphamide and Cyclophosphamide and RituximabRituximab

• CyclophosCyclophos 35/3635/36 97%97%

• No Cyclophos No Cyclophos 36/4636/46 78% 78% p=0.019p=0.019

Exclude dose escalating trialExclude dose escalating trial• No CyclophosNo Cyclophos 25/2925/29 86%86%

p=0.164p=0.164

RituximabRituximab

• Preliminary data promising in SLEPreliminary data promising in SLE

• Role of cyclophosphamide unclearRole of cyclophosphamide unclear

• Remission up to 3 yearsRemission up to 3 years

• HACA HACA 1% Lymphoma1% Lymphoma

4% RA4% RA

8% SLE8% SLE

RituximabRituximab

• Needs double blind controlled clinical Needs double blind controlled clinical

trialtrial

SEcond Line Agents in Myositis

Sponsored by Arthritis Research Campaign

TRIAL DESIGN:TRIAL DESIGN:A double-blind, randomised, A double-blind, randomised,

placebo controlled trial placebo controlled trial comparing:comparing: steroids alone, steroids alone, steroids plus methotrexate, steroids plus methotrexate, steroids plus ciclosporin, steroids plus ciclosporin, steroids plus methotrexate plus steroids plus methotrexate plus

ciclosporinciclosporin..

INCLUSION CRITERIAINCLUSION CRITERIA

• Polymyositis or DermatomyositisPolymyositis or Dermatomyositis

• Myositis secondary to other CTDMyositis secondary to other CTD

• Receiving prednisoloneReceiving prednisolone

• Active disease and muscle Active disease and muscle weaknessweakness

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