REVIEW IN

RHEUMATOLOGY

Daphna Paran M.D

Dept. of Rheumatology

Tel Aviv Medical Center

Case 1

A 30 y old woman

April 2010: Nasal discharge and dry cough

1 month later:

o Painful swollen knee & ankle

o Rash

o Inflamed red eye

Laboratory tests

GLU 85

CREAT 0.9

Na 141

K 3.9

Ca 9.7

Prot 63

Alb 38

ALT 17

ALP 21

LDH 500

Hb 11.4

MCV 81

WBC 23000

neu 84%

lym 10%

PLT 265

Ferritin 89

ESR 56

CRP 11.7

Additional workup

• Skin biopsy - Leukocytoclastic vasculitis

• Ophthlamologic examination- Episcleritis

• Working diagnosis:

• Denies: oral ulcers, ear inflammation, sinusitis,

chest pain, dyspnea, GI symptoms, paresthesias

Susp Systemic Vasculitis

Management: Prednisone 1mg/kg

Additional Laboratory tests

Urine Prot 717mg/d

Urine sed RBC

Hepatitis B neg

Hepatitis C neg

RF 33

ANA neg

C3 159

C4 46.8

C- ANCA 1:160

Anti-PR3 157

P-ANCA neg

Anti-MPO neg

Imaging studies

CT of sinuses: mild opacification in maxillary sinus

Chest CT: single lesion with irregular borders in RLL

m/p pulmonary nodule

• Kidney biopsy- crescentic glomerulonephritis

1.5 month later

Hb 11.6

Creat 0.7

ESR 6

CRP <0.5

Urine Protein 1300 mg/24h

Summary

• Nasal discharge

• Polyarthritis

• Lung nodule

• Skin - vasculitis

• Eyes - episcleritis

• Renal involvement - Proteinuria , Hematuria

• Positive Serology- C-ANCA+ anti-PR3 +

• Elevated ESR and CRP, leukocytosis

AAV= ANCA associated Systemic Vasculitis

ANCA

Antineutrophil cytoplasmic antibodies

• Combined testing is recommended :

- indirect immunofluorescence (IIF) assays

- enzyme immunoassays (EIAs) for:

anti-proteinase 3 (anti-PR3); anti-myeloperoxidase (anti-MPO)

• Most reliable results : positivity by both IF and EIA

• Positive serologies alone are not diagnostic of vasculitis

• Negative ANCA does not preclude diagnosis of vasculitis (10%)

ANCA detection by Immunofluorescence

Cytoplasmic staining = C-ANCA Perinuclear staining = P-ANCA

Atypical ANCA : may be seen in: CTDs, IBD, autoimmune hepatitis

may be confused with P-ANCA patterns

ANCA- C, P

C - ANCA

Proteinase 3

P- ANCA

Myeloperoxidase

Elastase

Cathepsin 3

Lactoferrin

BPI

c ANCA p ANCA

• GPA )Wegener( 90%

• Infectious disorders

• Neoplasms

• MPA )Microscopic polyangiitis( 70%

• Rapidly progressive GN

• Churg Strauss syndrome -50%

• Rheumatoid arthritis

• SLE

• JRA

• IBD

• Drug induced lupus

ANCA-Associated Vasculitis

• Granulomatosis with polyangiitis = GPA

(Wegener’s granulomatosis)

• Microscopic polyangiitis = MPA

• Eosinophilic Granulomatosis with polyangiitis = EGPA

(Churg-Strauss syndrome)

• Renal-limited vasculitis:

pauci-immune necrotizing GN with little or no deposition of Ig and

complement

75 to 80 % have MPO-ANCA

Granulomatosis with polyangiitis

Chapell Hill Classification

• Granulomatous inflammation of respiratory tract and necrotizing

vasculitis of small to medium-sized vessels

capillaries, venules, arterioles, arteries

• Necrotizing glomerulonephritis is common

• GPA may affect virtually any organ system

predilection for the upper respiratory tract, lungs, kidneys

ACR 1990 classification criteria

• Nasal or oral inflammation

• Abnormal chest radiograph

• Urinary sediment

• Granulomatous inflammation on biopsy

The cornerstone of diagnosis in GPA:

A combination of typical clinical features

and histopathology

Back to Case

Management dilemmas

• Kidney biopsy?

• Treatment?

Kidney biopsy

Urine Protein- 1300 mg/24h

Active urine sediment

Kidney Biopsy: Extracapillary hypercellularity,

fibrocellular crescents and focal sclerosis

Pauci-immune crescentic glomerulonephritis

Treatment dictated by severity

Limited disease

• conductive hearing loss

• sinus disease

• cutaneous lesions

• arthritis/arthralgia

• pulmonary nodules or

infiltrates that do not

compromise lung function

significantly

Severe disease

• rapidly progressive GN

• alveolar hemorrhage

• intestinal ischemia

• necrotizing scleritis

• retro-orbital pseudotumor

• vasculitic neuropathy

Disease assessment

• Birmingham Vasculitis Activity Score for WG (BVAS/WG)

• The Vasculitis Damage Index

Milestones in the treatment of GPA

• 1950: GPA is a fatal disease - 5 month survival

• 1960: GC increased survival to 12.5 months

• 1970: Break through - NIH protocol with oral CYC

• 1997-98 : IV CYC

• 1999 : Induction with CYC, maintenance MTX

• 2003 : Induction with CYC, maintenance AZA

• 2005: MTX up to 25 mg/wk as good as oral CYC

in early AAV without critical organ disease

• 2009: CYCLOPS study:

pulse CYC 15 mg/kg q2 -3 weeks = oral CYC 2mg/kg/d plus steroids

• 2010: Rituximab

Rituximab (MabThera): CD20 Antigen as a Target for Immunotherapy

ANTIGEN INDEPENDENT ANTIGEN DEPENDENT

CD20

expression

Neoplasias: Precursor B-cell leukemias B-Cell lymphomas/CLL WM/

Myeloma

Adapted from Longo. Lymphocytic Lymphomas. In: Cancer: Principles and Practice of Oncology. 1993.

Stem

Cell

Pre-Pre-

B Cell Pre-B Cell

Immature

B Cell

Mature

B Cell

Activated

B Cell

Plasma

Cell

IgM

IgG

IgA

sIgM

sIgG

sIgA

sIgM

+ D sIgM

HCR

R/D

HCR

R/D µ HCR

HCR

Rituximab Depletion of B cells

n=166

McLaughlin et al. J Clin Oncol. 1998;16:2825.

Indications in Rheumatology

FDA approved

• Rheumatoid Arthritis

• Granulomatosis with polyangiitis

• Microscopic polyangiitis

Off label

• SLE

• Primary Sjogren syndrome

FDA News Release: April 19, 2011

• The FDA approved Rituximab with glucocorticoids

as front-line therapy for adult patients with GPA or MPA

• The first FDA-approved therapy for these diseases and

the first alternative to CYC for the treatment of severe

disease in almost 40 years!

• Rituximab -approved in Israel for AAV in :

- patients who failed cyclophosphamide treatment

- young women of childbearing age

Rationale for targeting B cells in AAV

In AAV:

• B cells have important role in pathogenesis

• B-cell activation correlates with disease activity

BAFF levels (B-cell activating factor) correlate with activity

• Effects of CYC on B lymphocytes are associated with efficacy

RAVE study

• Multicenter, randomized, double-blind non-inferiority trial

for induction of remission in severe AAV

Rituximab vs. Cyclophosphamide

• Inclusion criteria:

- GPA or MPA

- Severe disease: BVAS/WG ≥ 3

End Points

Primary

• BVAS/WG of 0 and

successful prednisone taper at 6 months

Secondary

• Rates of disease flares

• BVAS/WG of 0 with prednisone at <10 mg/day

• Cumulative glucocorticoid doses

• Rates of adverse events

• SF-36 scores

Conclusions

• Treatment with Rituximab and glucocorticoids :

Not inferior to the standard regimen in severe

AAV of recent onset

• Rituximab and glucocorticoids:

May be superior to the standard regimen for

remission induction in severe relapsing AAV

• No difference in adverse events

Standard of Care

Limited disease

• MTX, Azathioprine

• Glucocorticoids

Severe disease

• Induction : High dose CS +CYC or Rituximab

• Maintenance with MTX or azathioprine or Rituximab

Septrin

• Controversial effect in GPA

• May have a role in limited GPA in addition to other treatment

• Indicated for prevention of PCP

Back to case - Management

• T. Prednisone 60 mg/d

• IV Cyclophosphamide (CYCLOPS protocol)

• T. Septrim forte 1x3/wk

• Vaccination - Influenza, Strep Pneumonia

Initial response

Follow-up (6 mo)

• CYC (x7) + Prednisone tapering to 30 mg/d :

• Recurrence of episcleritis

• Skin rash

• Myalgia

• Proteinuria

• Increased PR3 (200)

• Consequent dose increase Prednisone 70 mg/d

Management

• Rituximab 1000 mg x2

Prompt improvement:

• normal urinalysis

• resolution of pulmonary nodule, sinusitis, rash, episcleritis

• decreased PR3

• Maintenance treatment - Rituximab

• Current treatment - Prednisone 5 mg/d

- Maintenance with methotrexate

• Single course of rituximab vs. CYC followed by AZA (n=197)

(long-term results of RAVE trial)

• Results:

similar rate of complete remission by 6 months,

maintained through 18 months.

• Conclusion:

In severe AAV- single course of rituximab as effective

as continuous immunosuppression for induction and

maintenance of remission over course of 18 months

Efficacy of Remission-Induction Regimens for

ANCA-Associated Vasculitis NEJM August 2013

MAINRITSAN

Protocol:

• Induction: CYC + GCs (n=115)

• Maintenance: AZA (n=58)

RTX (n=57)

AZA: 2mg/kg/d- 12 mo., 1.5mg/kg/d- 6 mo., 1m/kg/d- 4 mo.

RTX: 500mg at day 0,14, then every 6 mo. upto 18 mo.

Relapse rate: RTX- 5% vs AZA-29%

EGPA - Eosinophilic Granulomatosis with PolyAngiitis

( Churg- Strauss syndrome)

EGPA: evolutions in classification, etiopathogenesis, assessment and management.

Curr Opin Rheumatol 2014

ANCA associated vasculitis- ANCA positive in 30-70% of cases

Hypereosinophilic condition - frequent lung involvement (90%)

Eosinophilic vasculitis

Damage due to vasculitis and proliferation of eosinophils

Mepolizumab (Nucala) = anti- IL-5

IL-5 - has a central role in eosinophil recruitment

Mepolizumab - a humanized monoclonal antibody against IL-5

Mepolizumab has been approved by the FDA and NICE for:

add-on, maintenance treatment of severe asthma in patients

age 12 or older who have an eosinophilic phenotype

Inclusion criteria-history of relapse or refractory

disease

History of RELAPSE or REFRACTORY DISEASE

RELAPSING DISEASE

Past history of at least one confirmed

EGPA relapse

• requiring increase in CS dose;

initiation/increased dose of

immunosuppressive therapy or

hospitalisation

• occurred within the past 2 years, but at

least 12 weeks prior to the screening

visit, while receiving a dose of

prednisolone of ≥7.5 mg/day

REFRACTORY

DISEASE

Failure to attain remission

(BVAS=0 and CS dose ≤7.5 mg/day) following induction

treatment with a standard regimen, for at least 3 months

• recurrence whilst tapering CS

• occurring at any prednisone dose ≥7.5 mg/day

OR

40

Wechsler ME et al. NEJM 2017 Supplementary Appendix

Remission: BVAS=0 and OCS dose ≤4 mg/day

Results for the ITT population

Proportion of Subjects Who

Achieved Remission at Each Visit

Last dose of study treatment

Wechsler ME et al. NEJM 2017

SC Mepolizumab 300mg

q4wks + standard care

vs

Placebo + standard care

The time to first relapse was significantly

longer for patients treated with mepolizumab

vs placebo

Percentage of patients with confirmed EGPA relapse

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Pa

tie

nts

wit

h r

ela

ps

e (

%)

Weeks to event

Hazard ratio: 0.32

95% CI: 0.21–0.50

P<0.001

Placebo

Mepolizuma

b

82% of placebo patients experienced a relapse

56% of mepolizumab patients experienced a relapse

68% RRR* in relapse

26% ARR† in relapse

*RRR = Relative risk reduction;

†ARR = Absolute risk reduction

68 33 16 9

68 55 43 25

Placebo

Mepolizumab

No. at risk

Wechsler ME et al. NEJM 2017

Average prednisone dose

18

26

15

41

3 4

26

66

0

10

20

30

40

50

60

70

0 >0 to 4.0 >4.0 to 7.5 >7.5

% o

f su

bje

cts

Average CS dose (mg/day)

Average Prednisone Dose mg/day Weeks 48-52

Nucala 300 mg Placebo

Nucala vs placebo:

OR, 0.20 (95% CI: 0.09, 0.41)

P < 0.001

Mepolizumab:

• allowed reduction in prednisone dose

• reduced relapse

• increased chance of remission at 36 ,48 wks

Case 2

A 72 year old lady with:

• History of DM and hypertension

• Severe occipital and temporal/frontal pain for more

than 6 months, weight loss

• Treated in pain clinic because of suspected cervical

radiculopathy - no improvement

• Sub-febrile fever, up to 38 degrees for the past 2 months

16% of FUO cases at age > 65 years are due to GCA

Giant Cell Arteritis

• GCA - the most common form of systemic vasculitis in adults

• Age > 50 years, mean age- 72

• Females/ Males - 3 : 1

• Northern European ancestry (Caucasians)

• Incidence : 240/1 million

Systemic vasculitis

• Fever (42%)

16% of FUO cases at age > 65 years are due to GCA

• Anorexia and weight loss (43%)

• Fatigue (42%)

• Arthralgias/arthritis

• Polymyalgia Rheumatica - PMR (35%)

Clinical manifestations of GCA

Frequency (%) Symptoms

76 Headache

37 Any visual symptom

34 Jaw claudication

24 Unilateral visual loss

15 Bilateral visual loss

11 Vertigo

9 Diplopia

Unexplained fever, anemia, or other constitutional symptoms and signs

Assessment

• Clinical symptoms

• Laboratory tests:

• ESR ,CRP, CBC

• Imaging:

• US of temporal arteries

• CT angiography

• PET-CT

US in diagnosis of temporal arteritis (GCA)

CTA in diagnosis of GCA

PET-CT in diagnosis of GCA

Pathology

Pan-arteritis, most pronounced in media, fragmented internal elastic lamina

Inflammatory infiltrate of CD4+ lymphocytes and macrophages

Giant cells are common but

not required for diagnosis

Fibrinoid necrosis suggests

systemic necrotizing vasculitis

1990 criteria for classification of GCA

(at least 3 of 5)

Criterion Definition__________________

1. Age at onset>50years symptoms beginning at >50 yrs

2. New headache new onset or new type of

localized pain in head

3. Temporal artery abnormality tenderness or decreased pulsation

4. Elevated ESR ESR >50mm/h

5. Abnormal artery biopsy vasculitis with predominant

mononuclear infiltrate or

granulomatous inflammation,

usually with giant cells

New classification criteria for GCA

Clinical features: Imaging findings:

Morning stiffness shoulder/neck +2 Halo sign +5

Sudden visual loss +2 Bilateral axillary findings +3

Jaw claudication +2 PET activity in aorta +3

New temporal headache +2

Scalp tenderness +2

Laboratory:

ESR >50 or CRP>10mg/l +3

Temporal artery biopsy:

Definite vasculitis +5

Possible vasculitis +2

Classified as GCA:

Score>6

Treatment

• Glucocorticoids

• 40 -60 mg/d

• solumedrol pulses

• solumedrol pulses and lower doses of oral GCs

• Measures to prevent osteoporosis and adverse effects of GCs

• Aspirin

• Retrospective studies

• Decreases vascular events

Glucocorticoid protocol

• Prednisone: 40-60 mg/d until resolution of symptoms and APR

• Reduction by 10 mg at 2-week intervals until 20 mg

• Reduction by 2.5 mg at 2-week intervals until 10 mg

• Reduction by 1 mg per month every 4 - 8 weeks

• Most patients stop treatment by 2 years

Back to our patient

• Treated with prednisone 1 mg/kg

• Dramatic improvement in her symptoms

• However …

• Reduction of ESR and CRP but no normalization after 4 weeks of

therapy

• Still has headache

• Uncontrolled DM and hypertension

Glucocorticoid sparing agents

• MTX

• Leflunomide (Arava)

• Azathiopine (Imuran)

• Cyclophophamide

• Biologics

Study design

Primary endpoint: sustained prednisone free remission at 52wks in each TCZ group vs. PLB + 26-week prednisone

Secondary endpoint: 1. sustained prednisone free remission at 52wks in each TCZ group vs. PLB + 52-week prednisone

2. incidence of first flare after remission

3. cumulative prednisone dose

Back to our patient

• Started tocilizumab

• Complete remission , without CS

• N=49 received prednisone + abatacept

• At 12 weeks 2 arms: continued abatacept + prednisone vs. prednisone

• Both arms tapered prednisone and stopped at 28 weeks

• Relapse free survival at 12 months 48% vs. 31% (p=0.049)

Case 3

Young single woman

Presents at age 16 with:

• Arthritis

• Photosensitive rash

Lab tests:

• CBC, liver and kidney function tests, albumin- normal

• Urinalysis-normal

• ESR 42/, CRP- 0.6

• ANA+, anti-dsDNA-negative, ENAs-negative

• decreased C3

SLE ?

SLE: 1982 classification criteria - requires 4 of 11

1. Malar rash

2. Discoid rash

3. Photosensitivity

4. Oral or nasopharyngeal ulcers

5. Arthritis

6. Serositis

7. Renal disorder - proteinuria>0.5g/d or cellular casts

8. Neurologic disorder - seizures or psychosis

9. Hematologic - hemolytic anemia/ leukopenia/ lymphopenia/

thrombocytopenia

10. Immunologic disorder- anti-dsDNA/anti-Sm /APLA

11. Antinuclear antibody positive

New SLE preliminary criteria

1. Acute cutaneous lupus

2. Chronic cutaneous lupus

3. Oral or nasal ulcers

4. Non scarring alopecia

5. Synovitis

6. Serositis

7. Renal

8. Neurologic

9. Leukopenia

10. Hemolytic anemia

11. Thrombocytopenia

12. Immunological:

- ANA

- Anti ds DNA

- Anti Sm

- APLA

- Low Complement

- Coombs +

New SLE preliminary criteria

• At least 4 criteria:

at least 1 clinical and 1 immunologic

OR

• Biopsy-proven lupus nephritis in the presence of

ANA or anti-dsDNA antibodies

ACR/EULAR 2018

classification criteria

- Immunofluoresence assay (IFA)

- ELISA

- Multiplex bead assays

Antinuclear antibody

Anti-dsDNA

• Radioimmunoassay (the Farr assay)

• Crithidia luciliae kinetoplast staining assay

• ELISA

• indirect IFA on the flagellate Crithidia luciliae

• specific method to detect anti-dsDNA

• positive reaction = fluorescent kinetoplast

• Kinetoplast= network of tightly packed dsDNA

within the mitochondrion, free of nuclear proteins

Case 3- course

At age 16 :

• Arthritis, Photosensitive rash

Treatment: Hydroxychloroquine

At age 20 :

• Hemolytic anemia

• Thrombocytopenia

• Vasculitic rash

Treatment:

• Hydroxychloroquine

• Corticosteroids

• Azathioprine

• Avascular Necrosis of hip THR

Good response

Treatment of Non-renal lupus

Anti- Malarials: Hydroxychloroquine = Plaquenil

Effective for:

- Constitutional symptoms, fever

- Rash

- Arthritis

Steroid sparing

Prevents flares

Increases survival

anti-aggregant effect

Treatment of Non-renal lupus

• NSAIDs

• Low-dose Corticosteroids

• Immunosuppressive agents

MTX, Leflunomide- for arthritis, serositis

Azathioprine, Mycophenolate mofetil

• Biologics :

Belimumab

1992:

• Young 19 year old woman

• polyarthritis, pleuritis, pericarditis, fever

• Laboratory tests:

- Leukopenia- 3000

- Lymphopenia- 900

- ANA +, anti dsDNA+, low C3

Case 4

1992-1997:

- Plaquenil- partial improvement

- Recurrent episodes of pleuritis/pericarditis

- NSAIDs - No response

- Prednisone 20-30mg/d - steroid dependent

- IM Methotrexate 15-20mg/wk - partial response

Case continued

1997

Multiple Splenic infarcts

anticardiolipin IgG, lupus anticoagulant- positive

Warfarin treatment , no additional thrombotic episodes

2000

Planned pregnancy

Methotrexate switched to Imuran

2000-2008-

Four normal pregnancies with full term healthy babies

Rx during pregnancies:

T Plaquenil

T Imuran100mg/d

T Prednisone 10mg/d

SC Clexane 60mg x2/d

No flares during pregnancy

2008-

Postpartum flare with severe polyarthritis

Requiring prednisone 15-30mg/d

Switched back to Methotrexate with no improvement

Case report continued

2008-2012:

Unable to achieve remission -

polyarthritis with 6-8 swollen and tender joints despite:

Plaquenil + Methotrexate 15mg/wk + Prednisone 15mg/d

5/2012:

Severe pleuritic chest pain-

requires prednisone increase -35mg/d

Case continued

In Summary:

- Active SLE with polyarthritis, pleuritis and pericarditis

- Poor response to Plaquenil with Imuran or Methotrexate

- Steroid dependent for many years

- Unable to reduce prednisone below 12.5mg/d

- Developed significant osteoporosis

Started treatment with Benlysta (anti BLyS = Belimumab)

After 4 months able to reduce prednisone to 7.5 mg/d

Ag

TCR MHC

class II

.

Cytokines Cytokines

B cell T cell

BLyS

Belimumab

Belimumab-blocks BLyS -

a B cell survival factor

B Lymphocyte Stimulating Protein

• BLyS is over expressed in SLE

• BLyS levels correlate with:

• changes in disease activity

• anti-ds DNA antibody titers

BLISS Study Design multicentre randomized double-blind placebo-controlled phase 3 trials

Dosing: d 0, 14, 28, then every 28 d through wk 48/72, final evaluation at wk 52/76

Stratified by:

- screening SELENA-SLEDAI: 6–9 vs ≥10

- screening proteinuria: <2 vs ≥2 g/24 h

- race: African descent or indigenous American vs other

Primary endpoint: SLE Responder Index (SRI) at wk 52

aNavarra SV et al. Lancet. 2011;377;721-31; bFurie RA et al. Arthritis Rheum. 2010;62(suppl):S606, Abstract 1454; cFurie RA et al. Arthritis Care

Res. 2009;61:1143-51.

Placebo

+ routine therapy

Belimumab 1 mg/kg + routine therapy

Belimumab 10 mg/kg + routine therapy

• SELENA-SLEDAI (SS) ≥6

• Seropositive:

ANA ≥1:80 and/or anti-dsDNA ≥30 IU/mL

• No active severe lupus nephritis or

severe CNS lupus

• Stable routine SLE therapy ≥30 d

• Progressive restrictions on concurrent

medications

Treated:

BLISS-

52

n= 865

BLISS-

76

n = 819

Primary Efficacy Endpoint SLE Responder Index (SRI)

Response defined as:

> 4 point reduction from baseline in SELENA SLEDAI AND

No worsening in Physician’s global assessment (PGA)

No new BILAG A or 2 BILAG B organ domains

Primary Efficacy Results: SRI at Week 52

BLISS-52 and BLISS-76

BILAG, British Isles Lupus Assessment Group; PGA, Physician’s Global Assessment.

Petri M et al. Arthritis Rheum. 2010;62(suppl):S190, Abstract 452.

Re

sp

on

de

rs (

%)

Benlysta (Belimumab)

In SLE patients with:

- more pronounced serologic activity: low C3 C4, anti-dsDNA +

- corticosteroid use

Belimumab + routine SLE therapy significantly reduced:

- disease activity

- severe flares

- fatigue

- corticosteroid use

Back to Case 3

Age 20:

Arthritis, Malar Rash, vasculitic rash

Hemolytic anemia, thrombocytopenia Treatment: Hydroxychloroquine, low dose prednisone, AZA

Age 32:

• Fatigue, myalgia

• Leg edema

• Urinalysis: proteinuria - 3 gr/d, hematuria, RBC casts

Management of Lupus Nephritis

Joint EULAR and European Renal Association- European

Dialysis and Transplant Association

Recommendations for the management of Lupus Nephritis

Annals Rheum Dis 2012

American College of Rheumatology Guidelines for the

screening and Management of Lupus Nephritis

Arthritis Care Res 2012

• Proteinuria > 0.5 gr/d

• Especially with

glomerular hematuria and/or cellular casts

Indication for Renal Biopsy

WHO Classification of Lupus Nephritis J Am Soc Nephrol 15: 241-250, 2004

Class I - Minimal mesangial LN

Class II - Mesangial proliferative LN

Class III- Focal proliferative LN (<50% of glomeruli with focal subendothelial immune deposits)

Class IV - Diffuse proliferative segmental LN (IV-S)

- Diffuse proliferative global LN (IV-G) (> 50% of glomeruli with subendothelial immune deposits)

Class V - Membranous LN

(global or segmental subepithelial deposits)

Class VI - Advanced sclerosing LN (> 90% of glomeruli globally sclerosed)

• Activity index

• Chronicity Index

Renal disease in SLE

• Mild disease - Class II

• Serious disease - Class III, IV, V

Clinical course:

- Class II:

hematuria, sub-nephrotic proteinuria, preserved GFR

- Class III and IV:

edema, HTN

nephritic sediment, mild-mod proteinuria, acute in GFR

- Class V:

features of nephrotic syndrome, preserved/ gradual in GFR

Renal Biopsy

• Renal biopsy is essential:

- Glomerulonephritis classification ( Class I-VI)

- Activity vs. chronicity

• Other pathologies :

• Tubulo-interstitial nephritis

• Thrombotic microangiopathy

• Vasculitis

Case 3 Back to patient:

Renal Biopsy: Type IV Glomerulonephritis

Lupus Nephritis

• Affects 25% to 60% of adults with SLE

• Relapse >50%

• 10% to 30% progress to ESRD within 15 years

• X2 mortality compared to SLE without LN

• Significant morbidity due to:

• active disease

• sequelae of prolonged use of CS and IS:

• accelerated atherosclerosis

• osteoporotic fractures, DM, HTN, cataract, etc.

• infections

Treatment of Renal lupus- Induction

• Cyclophospamide :

- NIH protocol (high dose): IV 500-1000mg/m2 q month (X6)

OR

- Eurolupus (low dose): IV 500mg q 2weeks (X6)

OR

• Mycophenolate Mofetil -2-3 gr/d

• at least equivalent to CYC as induction therapy

• more favorable toxicity profile

Treatment of Renal lupus- Maintenance

AZA or MMF better maintenance therapy than CYC Contreras G et al. NEJM 2004

Treatment of Renal lupus- Maintenance

• Maintenance with either MMF or AZA well tolerated

- MMF: possibly more efficacious, especially in minorities

- AZA: drug of choice when planning pregnancy

• Extended therapy of 3-4 years protects from relapse

MAINTAIN nephritis trial ARD 2010

Maintenance phase of ALMS trial - NEJM 2011

Case 3 - Back to patient

Treatment and course:

• High dose corticosteroids

• MMF

• Resolution of proteinuria Remission

• Age 34 -switched MMF to AZA due to planned pregnancy

• Successful pregnancy

Case 5

20 year old girl with SLE since age 11

- polyarthritis, malar rash, high titer anti-dsDNA

- diffuse proliferative lupus nephritis (class IV)

Previously treated and failed to respond to:

- Plaquenil

- Prednisone 1mg/kg

- IV pulse methylprednisolone

- IV Cyclophosphamide q month

- Azathioprine

- Cellcept (MMF)

Disease course

Poor response to multiple treatments

Developed renal failure

Had persistent proteinuria: 7 grams/24 hours

Suffered severe side effects from treatment:

- marked weight gain

- cushingoid habitus

- hypertension

- psychosis

0

1

2

3

4

5

6

7

82.0

4

4 6 10

11

1.0

5

2 3 4 7 8 9 12

1.0

6

3 4

5.0

6 10.0

9

gra

ms

date

proteinuria

Stop MMF MMF 1g

fever

MMF 3g

Pred 60mg Rituximab

Pred 15mg

Pred 10mg

Stop MMF

Achieved remission!

The LUNAR trial

• phase III RCT - 144 patients

• MMF + Prednisone vs MMF +Prednisone + Rituximab in

lupus proliferative nephritis (types III/IV)

• At 52 weeks: Rituximab + MMF was not superior to MMF

BUT:

Responders RTX vs PLB 56.9% vs 45.8%

Improvement in proteinuria: RTX vs PLB: 32% vs 9%

CYC rescue at wk 52: RTX vs PLB: 0% vs 8%

Open study

LN- Class III, IV, V n=50

Rituximab 1000mg X2 +

IV Methylprednisolone 500mg

AND

MMF up to 1.5 g x2/d

At 52 weeks: CR-52% PR-34%

on days 1 and 15

Annals Rheum Dis 2013

ACR and EULAR/ ERA-EDTA guidelines for management of Class III and IV LN - 2012

Induction

IV MP 500-750mg/d for 3 days

then T Prednisone 0.5-1mg/kg

MMF 2-3gr/d OR IV CYC (high/low dose)

Maintenance

MMF 1-2gr/d OR AZA 2mg/kg/d

+ low dose pred + low dose pred

If no response

Rituximab

If no response

Case 6

• A 72 year old woman

• Joint Pain for 5 months - shoulders, wrists, MCPs

• Synovitis of 1 wrist, 2 MCPs

• Morning stiffness >1 hour

• ESR: 72, elevated CRP

• RF negative

• Anti-CCP positive (>300)

ACR criteria of RA - 1987

• Morning stiffness lasting at least 1 hour

• Soft tissue swelling of three or more joints

• Swelling of hand joints

• Symmetric swelling

• Rheumatoid nodules

• Presence of Rheumatoid Factor

• Radiographic erosions or periarticular osteopenia in hands and /or wrist joints

Definite RA 4/7 criteria

Criteria 1-4 present > 6 weeks

Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.

Rheumatoid factor in rheumatic disease

• SLE

• Systemic sclerosis

• Dermato/polymyositis

• Vasculitis

• Juvenile RA

• Rheumatoid Arthritis

• Sjogren’s syndrome

• Cryoglobulinemia

RF= autoab against Fc portion of IgG

Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.

Rheumatoid factor in non-rheumatic diseases

Normal individuals (< 5%)

Elderly

Bacterial infections

Endocarditis

Leprosy

Syphilis

Lyme disease

Viral infections

Hepatitis C (also A & B)

Parvovirus

Rubella

CMV

EBV

HIV

Parasitic diseases

Periodontal disease

Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.

Rheumatoid factor in non rheumatic diseases

• Lymphoproliferative disease

• Interstitial lung disease

• Chronic liver disease

• Sarcoidosis

• Post-vaccination

• Malignancies

Citrullination of peptides

Anti-CCP (=ACPA)

• Sensitivity : 68-89 %

• Specificity: 96-100%

• Positive in 35% of RF negative sera

Pre-clinical RA

Genetic and environmental factors

The 2010 ACR/EULAR

classification criteria for RA

A. Distribution of Joint involvement:

1 large joint- 0 2-10 large joints-1 1-3 small joints- 2

4-10 small joints-3 >10 joints (at least 1 small joint) - 5

B. Serology:

Negative RF and negative ACPA -0

Low-positive RF or low-positive ACPA- 2

High-positive RF or high-positive ACPA- 3

C. Acute-phase reactants:

Normal CRP and normal ESR- 0

Abnormal CRP or abnormal ESR- 1

D. Duration of symptoms: <6 weeks- 0 >6 weeks- 1

Definite RA

Score > 6

Treat to Target

• The primary target for treatment of RA:

clinical remission or low disease activity

• Validated composite measures

• Treatment adjustment every 3 months

TNF inhibitors- Monoclonal Abs vs. Etanercept (Infliximab, Adalimumab, Golimumab Certulizumab, vs. Etanercept )

• Efficacy in IBD and extra-articular manifestations

(uveitis, psoriasis)

• Reactivation of TB

• Immunogenicity

Non TNF inhibitor biologics

Abatacept ( Orencia) - CTLA4 Ig- Costimulation blockade

Rituximab (MabThera) - anti CD20

Tocilizumab (Actemra) - anti IL6 receptor

Small molecules

JAK Inhibitors

Tofacitinib (Xeljanz)

Baracitinib (Olumiant)

Binding of cytokines to cytokine receptors

activates JAK pathway signaling

JAK=Janus kinase; P=phosphate; STAT=signal transducer and activator of transcription. Shuai K, Liu B. Nat Rev Immunol. 2003;3(11):900-911.

Cytokine binding to its cell surface

receptor leads to receptor polymerization and

activation of associated JAKs

1

Activated JAKs phosphorylate the receptors that dock STATs

2

Activated JAKs phosphorylate STATs,

which dimerize and move to the nucleus to

activate new gene transcription

3

117

Gene transcription

JAK JAK P P

P P

STA

T

STA

T S

TA

T

STA

T

P

P

Tofacitinib is a JAK Inhibitor

119

119

Gene transcription

JAK JAK

STA

T

STA

T

JAK=Janus kinase; STAT=signal transducer and activator of transcription. 1. Shuai K, Liu B. Nat Rev Immunol. 2003;3(11):900-911; 2. Jiang JK, et al. J Med Chem. 2008;51(24):8012-8018.

Cytokine binding to its cell surface receptor

leads to receptor polymerization1

1

JAKs cannot phosphorylate the receptors that therefore cannot dock STATs

JAKs cannot phosphorylate STATs,

which cannot dimerize and move to the

nucleus to activate new gene transcription

3

Tofacitinib inhibits the autophosphorylation and

activation of JAK2

2

Targeted therapy in Rheumatology

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What’s new in SpA?

Case 7

• A 25 year old man

• Insidious onset low back pain

• Night pain

• Morning Stiffness

• Improves with exercise

New set of criteria for Inflammatory Back pain

• Age at onset <40 years

• Insidious onset

• Improvement with exercise

• No improvement with rest

• Pain at night

• If 4 out of 5 parameters are fulfilled criteria have:

- sensitivity of 77.0%

- specificity of 91.7%

Rudwaleit M, et al. Arthritis Rheum. 2005;52:1000-1008.

Time (years)

Back pain Back pain

Radiographic

sacroiliitis

Back pain

Syndesmophytes

Pre-Radiographic Stage

(Undifferentiated Axial SpA)

Radiographic Stage

(AS)

Modified New York Criteria 1984

(MRI: active sacroiliitis)

AS Changes Over Time

AS Classification:

Modified New York Criteria

Clinical criteria

Requires fulfillment of 1 the

following:

• Low back pain >3 months,

improved by exercise, not

relieved by rest

• Limitation of lumbar spine

motion, sagittal and frontal

planes

• Limitation of chest expansion

relative to normal values for

age and sex

Radiographic criteria

Requires fulfillment of 1 the following:

• Sacroiliitis grade 2 bilaterally

• Sacroiliitis grade 3–4 unilaterally

van der Linden S, et al. Arthritis Rheum. 1984;27:361-368.

Definite AS

Any of the radiographic Criteria

and any clinical criterion (1-3)

Probable AS

3 clinical criteria or

1 radiological criteria

Copyright ©2009 BMJ Publishing Group Ltd.

Classification criteria for axial spondyloarthritis

education

exercise

physical therapy

rehabilitation

patient

associations

self-help groups

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Peripheral

disease

Axial

disease

Sulfasalazine

TNF blockers

A

na

l

ge

s

i

c

s Local corticosteroids

S

u

r

g

e

r

y

Zochling J, et al. Ann Rheum Dis. 2006;65:442-452.

ASAS/EULAR Recommendations

for the Management of AS

ASA Assessment in AS; EULAR, European League Against Rheumatism

What’s new in Psoriatic

Arthritis?

Case 8

• A 25 year old man

• Pain and swelling of the 2nd digit

• Inflammatory back pain

• History of psoriasis

• Psoriatic arthritis

Moll and Wright clinical classification

• Symmetric polyarthritis: 30-60%

• Monoarticular, asymmetric oligoarticular : 20-40%

• 1 large joint

• 1 or 2 IP joints

• Dactylitis

• DIPs 5-20%

• Axial: 3-5%

• Arthritis mutilans : 5%

Treatment of PsA

Synthetic DMARDs

MTX

Leflunomide

Salazopyrine

Apremilast (Otezla)

Tofacitinib (Xeljanz)

Biologic DMARDs

TNFα blockers

IL12/23 inhibitor

Ustekinumab (Stelara)

IL-17 inhibitors:

Secukinumab (Cosentyx)

Ixekizumab (Taltz)

Brodalumab (Siliq)

Apremilast = PDE4 Inhibitor

Oral Small Molecule - works intracellularly

Modulates Pro- and Anti-inflammatory Mediators1a

cAMP

cAMP cAMP

AMP

PDE4 Apremilast

Anti-Inflammatory

Mediators

(i.e. IL-10)

Pro-Inflammatory

Mediators

(i.e. TNF-α, IL-23,

IFN-)

Immune Cell

1. Schafer P. Biochem Pharmacol. 2012;83:1583–1590.

AMP AMP

aVisual representation based on

preclinical evidence.

Apremilast is an investigational drug and is not approved for use in Europe

OTEZLA

Modified ACR 20 response over 104 weeks

141

ACR20=American College of Rheumatology 20; n/m=number of responders/number of patients with sufficient data for evaluation.

Kavanaugh A, et al. ACR 2014 [poster 1590].

PALACE 1

Patients achieving PASI-50 over 104 Weeks

142

PALACE 1

PASI=Psoriasis Area and Severity Index; BSA=body surface area; n/m=number of responders/number of

patients with sufficient data for evaluation.

Kavanaugh A, et al. ACR 2014 [poster 1590].

↑Cytokines including

IFN- TNF-

IL-2

Th17

Inflammation, keratinocyte hyperplasia, neovascularisation, vasodilatation, T cell/neutrophil influx

Naïve T cell

IL-23

IL-1b

DC

Th1

Naïve T cell

IL-12

DC

↑Cytokines including

IL-17 IL-22

TNF-

IL-12 and IL-23 in the development of psoriasis

Nestle FO, et al. J Invest Dermatol. 2004;123:xiv-xv.

Ustekinumab (Stelara)

PSUMMIT I

PSUMMIT II

* Early escape (EE) rules were used through Week 24; from Weeks 24- 52, EE rules were not used

PSUMMIT I and II - Ustekinumab in PsA ACR20 Responders Over Time Through Week 52*

Kavanaugh A et al. ACR, Washington, D.C., Nov 9-14, 2012. P4 Data on File

Patients with early active RA and PsA show

increased Th17 levels in peripheral blood

Leipe J, et al. Arthritis Rheum. 2010;62(10):2876-85.

Ex v

ivo

Th

17 (

%)

1.5

0.5

0

1.0

HC OA PsA RA

*

**

***

***

* p<0.05 ** p<0.01 *** p<0.001

HC: healthy control OA: osteoarthritis PsA: psoriatic arthritis RA: rheumatoid arthritis

Secukinumab - prevents IL-17A binding to its receptor

- inhibits production of pro-inflammatory mediators

IFN, interferon; IL, interleukin; TNF, tumor necrosis factor. Data on file, Novartis Pharma, AG;

Ivanov S, Linden A. Trends Pharmacol Sci. 2009;30:95–103

Secukinumab (bound to IL-17A)

IL-17A Delayed-type

hypersensitivity

and cellular

immunity

Tissue

inflammation

and pathogen

defense

Tissue

inflammation

and

pathogen

defense

IFN-γ

IL-2

IL-17F

IL-21

IL-22

IL-17A

Selective inhibition of IL-17A may be

associated with preservation of normal

components of the host immune response

Neutralization of IL-17A rapidly inhibits

downstream inflammatory cytokine and

chemokine networks and thus may be useful for

the treatment of several

immune-mediated diseases

IL-17A neutralized

by secukinumab

IL-12

Th17

Mast cells

Other leukocytes

Th1

IL-23

TNF

Dendritic

cells

Secukinumab:

fully human IgG1k

monoclonal Ab

against IL-17A

Target

tissue

cell

membrane

IL-17A

receptor

Secukinumab in PsA ACR20 Responses Through Week 52

*P < 0.0001 vs. placebo (P-values at Week 24 adjusted for multiplicity of testing).

Missing values were imputed as nonresponse (nonresponder imputation) up to Week 24. Observed data from Week 28–52.

80

0

60

40

20

0

4 24 40 52 8 12 16 20 28 32 36 44 48 1 2

69.5%

*

*

* *

* *

* *

* * * * *

66.9% 50.5%

50.0%

17.3%

Primary

endpoint

* *

*

Pe

rce

nta

ge

of R

esp

on

de

rs

Weeks

N = 202 202 202 202 202 202 202 188 183 181 181 178 179 174

N = 202 202 202 202 202 202 202 179 183 175 174 165 169 172

N = 202 202 202 202 202 202 202 -- -- -- -- -- -- --

Secukinumab 10/mg/kg i.v. 75 mg s.c. Secukinumab 10/mg/kg i.v. 150 mg s.c. Placebo

ACR50 Responses Through Week 52

*P < 0.0001, †P < 0.001; §P < 0.01; ‡P < 0.05 vs. placebo (P-values at Week 24 adjusted for multiplicity of testing)

Missing values were imputed as nonresponse (nonresponder imputation) up to Week 24. Observed data from Week 28–52.

60

0

50

40

20

0

4 24 40 52 8 12 16 20 28 32 36 44 48 1 2

30

10

* *

* *

* *

*

*

30.7%

34.7%

7.4%

* *

*

†

‡

§

50.0%

38.4%

Weeks

Pe

rce

nta

ge

of R

esp

on

de

rs

Secukinumab 10/mg/kg i.v. 75 mg s.c. Secukinumab 10/mg/kg i.v. 150 mg s.c. Placebo

N = 202 202 202 202 202 202 202 188 183 181 181 178 179 174

N = 202 202 202 202 202 202 202 179 183 175 174 165 169 172

N = 202 202 202 202 202 202 202 -- -- -- -- -- -- --

Resolution of Dactylitis and Enthesitis at

Weeks 24 and 52

*P < 0.0001 vs. placebo.

Resolution of dactylitis and enthesitis amongst those subjects with these symptoms at baseline

(dactylitis: n = 104 [150 mg], 104 [75 mg] and 116 [placebo]; enthesitis: n = 126 [150 mg], 129 [75 mg] and 117 [placebo]).

Missing values were imputed as nonresponse (nonresponder imputation) at Week 24. Observed data presented at Week 52.

Secukinumab 10 mg/kg i.v 150 mg s.c. Secukinumab 10 mg/kg i.v. 75 mg s.c. Placebo

100

Pe

rce

nta

ge

of S

ub

jects

80

60

20

0

100

Pe

rce

nta

ge

of S

ub

jects

80

60

20

0

Week 24 Week 24

40 40

Week 52 Week 52

82.6 79.4 87.7 89.7

* *

* *

Resolution of Dactylitis Resolution of Enthesitis

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