biologic agents in rheumatology: a virtual reality tour ... · biologic agents in rheumatology: a...

Biologic Agents in Rheumatology: A Virtual Reality Tour through Psoriatic Arthritis and

Rheumatoid Arthritis

Joseph F. Merola, MD, MMSc

Assistant Professor, Harvard Medical SchoolDirector, Clinical Unit for Research Innovation and Trials (CUReIT), Dermatology

Co‐Director, Center for Skin and Related Musculoskeletal DiseasesDept of Dermatology and Dept of Medicine, Division of Rheumatology

Associate Program Director, Combined Medicine‐Dermatology Residency ProgramBrigham and Women's Hospital

Boston, MA

Disclosures Consultant for Biogen IDEC, AbbVie, Eli Lilly, Novartis, Pfizer, Janssen, UCB,

Samumed, Science 37, Celgene, Sanofi‐Genzyme / Regeneron and GSK. Investigator for Biogen IDEC, Pfizer, Sanofi Genzyme / Regeneron, Incyte,

Novartis. Licensed outcome measure to Abbvie and Lilly. Medical Board: National Psoriasis Foundation, Lupus Foundation of

America Steering Committee: GRAPPA Board of Directors: IDEOM (International Dermatology Outcome

Measures), PPACMAN Expert Panel: ACR PsA Guidelines

Several of the therapies reviewed in this presentation may involve off‐label use of medications

This activity is supported by an educational grant from Lilly.

Psoriatic Arthritis: Pathophysiology and Diagnosis

Psoriasis: Pathogenesis

• Immune dysregulation (TH‐1 and TH‐17)

• Inflammation– Cytokines

• Keratinocyte hyperproliferation

• Inflammatory/auto‐inflammatory disorder• Systemic disease

TH = T‐helper (cell)

(keratinocyte‐derived)ADAMTSL5 (melanocyte‐derived)

T cells

Psoriasis

Immunopathogenesis of Psoriasis

KC = keratinocyte; DC = dendritic cell; IL = interleukin; IFN = interferon; TNF = tumor necrosis factor; AMP = antimicrobial peptide.

Lowes MA et al. Annu Rev Immunol. 2014;32:227‐255. Lande R et al. Nat Commun. 2014;3(5):5621. Arakawa A et al. JEM. 2015;212(13):2203.

Insert virtual reality “how‐to” video

Insert video: Psoriatic Arthritis

Psoriatic Arthritis: Timing

• Usually skin changes/PsO before arthritis (70%)1

• Subset with skin and joints concurrently (15%)1

• Inflammatory joint symptoms prior to skin changes (15%)1

• Typical lag time of 7–10 years from the onset of psoriasis to diagnosis of PsA1,2

1. Anandarajah AP, Ritchlin CT. Nat Rev Rheumatol. 2009;5:634‐641. 2. Mease P, et al. Drugs. 2014;74(4):423‐41.

PsO = psoriasis.

Predictors of PsA• Involvement of certain body sites

– Scalp– Intergluteal areas (‘inverse / intertriginous’ psoriasis)

• Psoriatic nail lesions– Onycholysis– Nail pitting

• Younger age of psoriasis onset • Greater BSA involvement of psoriasis• Family history of psoriatic arthritis• All studies had limitations

– Case‐control studies, recall bias, possible misclassification bias (OA)

Wilson FC et al. Arthritis Rheum. 2009;61: 233‐239. Soltani‐Arabshahi R et al. Arch Dermatol. 2010;146:721‐726. Tey HL et al. J Dermatol. 2010;37:426‐430. Ogdie A, Gelfand JM. Curr Rheumatol Rep. 2015;17:64.

OA = osteoarthritis.

Clinical Features of PsA

Symptoms• Fatigue• Joint pain • Joint swelling• Morning stiffness

(joint stiffness) lasting >30 minutes

Peripheral joint disease• Joint tenderness• Joint swelling• Number of affected joints• Joint distribution

McArdle A, et al. Clin Rev Allergy Immunol. 2017 Jul 27. doi: 10.1007/s12016‐017‐8630‐7. Gladman D, et al. Ann Rheum Dis. 2005;64(Suppl 2): ii14–ii17.

Metabolic syndrome Diabetes

HypertensionHypercholesterolemia

Crohn’s,cutaneous

Neutrophilic dermatoses,Hidradenitis suppurativa

PsoriaticArthritis

Spondyloarthritis

Cardiovasculardisease

(MI/stroke)

Sleep

Chronic kidney disease

Gout

Mental health

Psoriasis(plaque, nail,inverse, scalp)

MI = myocardial infarction.

Rheumatoid Arthritis: Pathophysiology and Diagnosis

Rheumatoid Arthritis Pathogenesis

HLA = human leukocyte antigen; ACPAs = anti‐citrullinated protein antibodies; GI = gastrointestinal; TNF = tumor necrosis factor; IL = interleukin.

Pianta, S et al. Arthritis Rheumatol. 2017;69(5):964‐975. Peizek, C et al. Arthritis Rheumatol. 2017;69(6): 1176‐1186.

Genetic susceptibility (HLA‐DRB1, etc.)

Adaptive immunity and citrullination (ACPAs) occur due to:• Smoking• Gingivitis

Lymphocyte activationMacrophage activationNeutrophil activationDendritic cell activation

Release of cytokines (TNF/IL‐1/IL‐6/IL‐17)Interferon release

Synoviocytes

RA Pathobiology

B cell

MΦImmune complexes

Complement fixationAttract inflammatory

cell infiltrates

IL-2IFNγTNFIL-17

RANKL

Pannus

Articularcartilage

TNF, IL-1, IL-6,Metalloproteinases(MMPs)

IL-4IL-6IL-10

IL-6, TNF,IFNγ, IL-10,

Lymphotoxin

Plasma cell

Antigen-presentingCells– B cells– Dendritic cells– Macrophages

OsteoclastChondrocytes

Production of MMPs and other effector moleculesMigration of polymorphonuclear cells

Erosion of bone and cartilage

Rheumatoid factor,ACPAs

T cellAPC

Adapted from Smolen JS, Steiner G. Nat Rev Drug Discov. 2003;2;473‐488. Choy EH, Panayi GS. N Engl J Med. 2001;344:907‐916. Silverman GJ, Carson DA. Arthritis Res Ther. 2003;5(suppl 4):S1‐S6.

RA = rheumatoid arthritis; IL = interleukin; IFN = interferon; TNF = tumor necrosis factor; APC = antigen‐presenting cell; RANKL = receptor activator of nuclear factor‐κB ligand; ACPA = anti‐citrullinated protein antibody.

Joint capsule

Synovial membrane

Joint space

Cartilage

Synoviocytes

Bone

Osteoclast

Fibroblast‐like synoviocyteMacrophage

Dendritic cell

T cell

Plasma cell

B cell

Mast cell

Pannus

Neutrophils

Synoviocytes

15

Normal Joint vs Rheumatoid Synovitis

15Strand V, et al. Nat Rev Drug Discov. 2007;6(1):75‐92.

Aletaha D et al. Arthritis Rheum. 2010;62:2569‐2581.

Negative RF AND ACPA 0Low‐positive RF OR ACPA 2

3High‐positive RF OR ACPA

(0–1)

<6 weeks 0≥6 weeks 1

Normal CRP AND normal ESR 0Abnormal CRP OR abnormal ESR

1

Serology (0–3)

Symptom duration (0–1)

Acute‐phase reactants

Swollen/tender joints (0–5)

Patients with a score of ≥6have “definite” RA.

2010 ACR/EULAR RA Classification Criteria

1 large joint 02–10 large joints 11–3 small joints 24–10 small joints 3>10 joints 5

Composite Measures of Disease Activity

Yazici Y. Bull NYU Hosp Jt Dis. 2007;65(suppl 1):S25‐S28. Zatarain E, Strand V. Nat Clin Pract Rheumatol. 2006;2:611‐618. Pincus T et al. Rheum Dis Clin North Am. 2009;35:773‐778.

Outcome Measures in RAACR20/50/70 DAS28 SDAI CDAI RAPID

Patient function + +Patient pain + +Patient global + + + + +Physician global + + +# tender joints + + + +# swollen joints + + + +ESR or CRP + + +

DAS = Disease Activity Score; SDAI = Simplified Disease Activity Index; CDAI = Clinical Disease Activity Index; RAPID = Routine Assessment of Patient Index Data.

Measures of RA Disease Activity

Anderson J et al. Arthritis Care Res (Hoboken). 2012;64:640‐647. Singh JA et al. Arthritis Care Res (Hoboken). 2012;64:625‐639.

Categories of Disease ActivityInstrument Remission Low Moderate HighDAS28 <2.6 ≥2.6 to <3.2 ≥3.2 to ≤5.1 >5.1CDAI ≤2.8 >2.8 to 10.0 >10.0 to 22.0 >22.0RAPID 0 to 1.0 >1.0 to 2.0 >2.0 to 4.0 >4.0 to 10.0

SDAI ≤3.3 >3.3 to ≤11.0 >11.0 to ≤26.0 >26.0

Examples of Tools Measuring PsA

• Peripheral joints:– ACR joint count (TJC, SJC, VAS

pain, PtGA, PGA, HAQ, CRP or ESR)

– PsARC– DAS

• Spine / axial:– BASDAI– ASAS-N

• Enthesitis:– MASES index (Maastrict

Ankylosing Spondylitis Enthesitis Score)

– LEI

• Dactylitis:– LDI

• QOL:– SF36– PsAQoL– HAQ– Fatigue: FACIT– Work / WPAI– PSAID

– RAPID3, PtGA of arthritis, etc

NOTE: PsA Symptom Measurement can be performed by dermatologists in the clinic –On‐going work with IDEOM* ‐JF Merola

PsA Disease Measurement/Disease Activity

*This study used a modified CPDAI (for peripheral PsA only) which used a 3‐point scale for each limb (total of 12)**Includes # of tender joints, CRP, and patient assessment on two 1‐10 scales

Minimal Disease Activity RemissionMeasure(Range)

Optimal Cut‐Off

Sensitivity (%)

Specificity (%)

Optimal Cut‐Off

Sensitivity (%)

Specificity (%)

DAS28‐CRP(0.96‐8.79) ≤3.6 76 89 <2.4 72 89

DAS28‐ESR(0.49‐9.07) ≤3.6 73 89 <2.4 71 89

SDAI(0‐86) ≤11 79 89 <3.3 74 90

mCPDAI*(0‐12) ≤5 68 84 <2 69 85

DAPSA** ≤15 77 89 <4 73 89

PASDAS(0‐10) ≤3.6 76 86 <2.4 75 85

Criterion values and coordinates of the ROC curve for MDA and remission criteria.

Salaffi F, et al. BioMed Res Int. 2014(2014). 12 Pages

Psoriatic Arthritis: Treatment Options

Video: Psoriatic ArthritisTreatment Options

Not disease‐modifying• NSAIDs• Corticosteroid injections

• Corticosteroids (oral)

Traditional DMARDs• Methotrexate• Leflunomide• Sulfasalazine• Cyclosporine

Anti‐TNFa• Etanercept• Adalimumab• Infliximab• Golimumab• Certolizumab Nonpharmacologic

measures• PT and OT• Obesity control• Depression treatment• Cardiovascular risk factor mod

• Smoking cessation• Microbiome modification

Newer therapies• Ustekinumab (IL12/23)• Secukinumab (IL17A)• Abatacept (CTLA4‐Ig)• Apremilast (PDE4)• Ixekizumab (IL17)• Tofacitinib (JAK3)

In development• Brodalumab (IL17R)• Guselkumab (IL23)• Risankizumab (IL23)• Tildrakizumab (IL23)• Upadacitinib (JAK1)

PsA Treatment Options

NSA

IDs a

nd IA

I cortic

osteroids a

s ind

icated

DMARDs (MTX, SSZ, LFN), TNFi

or PDE4i

Biologics (TNFi, IL‐12/23i IL‐

17i) or PDE4i

Switch biologic (TNFi, IL‐12/23i

or IL‐17i)

Peripheral Arthritis

Physiotherap

y an

d NSA

IDs

NSAIDs only

TNFi, IL‐17i or IL‐12/23i*

Switch biologic (TNFi, IL‐17i orIL‐12/23i*)

No direct evidence for therapies in axial PsA:recommendations based on axial SpAliterature

Axial Disease

Physiotherap

y

NSAIDs

Biologics (TNFi, IL‐12/23i, IL‐17i) or PDE4i

Corticosteroid injections: consider on an individual basis due to potential for serious side effects; no clear evidence for efficacy

Switch biologic (TNFi, IL‐

12/23i, IL‐17i) or PDE4i

Enthesitis

Corticosteroid injections as ind

icated

NSAIDs

DMARDs (MTX, LEF, SSZ) or PDE4i

Biologics (TNFi, IL‐12/23i)



Dactylitis

Biologics (TNFi, IL‐12/23i, IL‐17i) or PDE4i

Topical or procedural

or DMARDs (CSA, LEF, MTX,

acitretin)



Nails

Topicalsas indicated

Topicals(keratolytics, steroids, vitamin D analogues, emollients, calcineurin)

Phototherapy or DMARDs (MTX, CSA, acitretin, fumaric acid

esters) or PDE4i

Biologics (TNFi, IL‐12/23i, IL‐17i) or

PDE4i

Switch biologics (TNFi, IL‐12/23i, IL‐17i) or

PDE4i

Skin

Which domains are involved?

Assess activity

, impa

ct, and

progn

ostic

factors

Standard therapeutic route Expedited therapeutic route

*Open‐label data available.White text identifies conditional recommendations for drugs without current regulatory approvals or where recommendations are based on abstract data only.MTX=methotrexate. SSZ=sulfasalazine. LFN=leflunomide. TNFi=tumor necrosis factor inhibitor. PDE4i=phosphodiesterase 4 inhibitor. CSA=cyclosporine A.

Coates LC, et al. Arthritis Rheumatol. 2016 May;68(5):1060‐71.

GRAPPA Treatment Schema for Active PsA

Traditional DMARDs

• Methotrexate

• Leflunomide

• Sulfasalazine

• Cyclosporine

TNFαI = TNF alpha inhibitor; MTX = methotrexate.

Kumar P, et al. Clin Med Insights Arthritis Musculoskelet Disord. 2013;6:35–43. Parida J, et al. World J Orthop. 2015;6(2):278–283. Eder L et al. Ann Rheum Dis.2014;73:1007‐11. Finzel S, et al. Ann Rheum Dis. 2013;72:1176‐81.

POSITIVES• Many years of use• Helpful in some cases• Inexpensive• Prevent antibody

generation, increase retention of TNFαI drugs (MTX)

NEGATIVES• Lack of high‐quality data• Suboptimal dosing• Not disease modifying

Methotrexate in PsA (MIPA) Trial

Kingsley GH et al. Rheumatology (Oxford). 2012; 51:1368‐1377.

Methotrexate goal of 15 mg/week

0

2

4

6

8

10 Swollen joint count

02468

10121416

0 3 6

Tender joint count

Months

0

10

20

30

40

50

60Patient global assessment*

Global Index OR (95%CI) P-valuePsARC 1.77 (0.97–3.23) 0.06ACR 20 2.00 (0.65–6.22) 0.23DAS 28 response 1.70 (0.90–3.17) 0.10

PsARC = PsA response criteria; OR = odds ratio; CI = confidence interval.*100‐mm visual analogue score (VAS).

MTX

Placebo

0 063 63

MIPA Trial: Skin

Kingsley GH et al. Rheumatology (Oxford). 2012; 51:1368‐1377.

MTX Placebo

Significant reduction in PASI 75 for MTX users: Adjusted treatment difference was −0.93 (95% CI −1.71, −0.15) P = 0.02

PASI 75 response rates were not significant (OR 1.26, 95% CI 0.58–2.72).

PASI 753.76

2.22

3.79

3.13

0

1

2

3

4

Baseline Follow up

Score

Tight Control in PsA Trial (TiCOPA)

Coates LC et al. Lancet. 2015;386:2489‐2498.

MTX+CyA or MTX+LEF

6259

44

33

0

10

20

30

40

50

60

70

ACR20 PASI75

Tight Control Standard

MTX

MTX+SSZ

Second aTNFa

aTNFa

SSZ = sulfasalazine; CyA = cyclosporine; LEF = leflunomide.

Respon

se at 4

8 wee

ks (%

)

Serious Adverse Events

Tight Control Standard CareDeaths 0 0

SAE 25 8

SAE related to drug 8 2

Blood/lymph systemCardiacGIHepatobiliaryImmune systemInfection/infestationInjury/poisoningMSK and CTDNeoplasmsNervous systemRenal/urinaryReproductive/breastRespiratory and thoracic

1152131401114

0020010212000

Coates L, et al. Lancet. 2015 Dec 19;386(10012):2489‐98

Leflunomide for PsA

Kaltwasser JP et al. Arthritis Rheum. 2004;50:1939‐1950.

20.1

14.5

18.5

15.5

0

5

10

15

20

25

30

35

40

Baseline Follow up

Tender joints

LEF Placebo

11.6

7.3

13.3

10.5

0

5

10

15

20

25

30

35

40

Baseline Follow up

Swollen joints

LEF Placebo

36.3

17.420

7.8

0

5

10

15

20

25

30

35

40

ACR20 PASI

LEF Placebo

P=0.014

P=0.048

Respon

se (%)

Joint c

ount

ACR 20; PASI

TNF Inhibitors in PsA

Mease PJ. Rheum Dis Clin North Am. 2015;41:723‐738.

59 58 58

52

58

1511

14

8

24

0

10

20

30

40

50

60

70

ETA IFX ADA GOL CER

TNFi Placebo

1115

20 18

25

0 1 1 1 3

0

10

20

30

40

50

60

70

ETA IFX ADA GOL CER

TNFi Placebo

ACR 20 ACR 70

TNFi = tumor‐necrosis‐factor inhibitor; ETA = etanercept; IFX = infliximab; ADA = adalimumab; GOL = golimumab; CER = certolizumab.

Respon

se

Respon

se

IL‐12 receptor IL‐23 receptor

TH1 cell signaling TH17 cell signaling

Ustekinumab: IL12/23 InhibitorTargets p40 Subunit

p40 p40p35 p19

Koutruba N, et al. Ther Clin Risk Manag. 2010;6:123‐41.

Ustekinumab: Efficacy in PsA

McInnes IB et al. Lancet. 2013;382:780‐789. Ritchlin C et al. Ann Rheum Dis. 2014;73:990‐999.

42.4 43.7

22.820.2

0

10

20

30

40

50

60

70

PSUMMIT‐1 PSUMMIT‐2

ACR 20

UST 45mg Placebo

57.2

51.3

11

5

0

10

20

30

40

50

60

70

PSUMMIT‐1 PSUMMIT‐2

PASI 75

UST 45mg Placebo

% %

UST = ustekinumab.

IL17RA IL17RCIL17RA IL17RAIL17RCIL17RC

IL‐17A/ IL‐17FIL‐17FIL‐17 A

Anti‐IL17

Anti‐IL17

Anti‐IL17RA

SecukinumabIL17Ai

IxekizumabIL17Ai

BrodalumabIL17RAi

IL17 Inhibitors

Ixekizumab: ACR 20/50/70 Response80 mg Q4W; 24‐Week Response

Ixekizumab Prescribing Information. Eli Lilly and Company. December, 2017.

Respon

se (%

)

*P<0.05 vs Placebo

5853

4035

23 22

0

10

20

30

40

50

60

70

Anti‐TNF Naïve Anti‐TNF ExperiencedACR 20 ACR 50 ACR 70

*

*

*

*

*

*

IL17A Inhibitor: Ixekizumab in PsA

Mease PJ et al. Ann Rheum Dis. 2017;76:79‐87.

57* 60*52*

31

58*62*

57*

30

010203040506070

IXE Q4W IXE Q2W ADA Q2W Placebo

SPIRIT1‐ACR 20

Respon

ders (%

)

Weeks Weeks Weeks

PASI 75 PASI 90 PASI 100A B C100

242016

Placebo IXE Q4W IXE Q2W ADA Q2W

12840

806040200

100

24201612840

806040200

100

24201612840

806040200

IXE = ixekizumab; ADA = Adalimumab.

%

12 Weeks

24 Weeks

*P<0.05 vs Placebo

Secukinumab: Efficacy in PsA

Mease PJ et al. N Engl J Med. 2015;373:1329‐1339. McInnes IB et al. Lancet. 2015;386:1137‐1146.

50 51

17.315

0

10

20

30

40

50

60

70

FUTURE‐1 FUTURE‐2

ACR 20

SEC 150 Placebo

61.1

48

8.3

16

0

10

20

30

40

50

60

70

FUTURE‐1 FUTURE‐2

PASI 75

SEC 150 Placebo

SEC = secukinumab.

% Respo

nse

% Respo

nse

Secukinumab: FUTURE 5Reduced Progression of Joint Structural Damage

Mease P, et al. Presented as a late‐breaker at the 2017 ACR/ARHP Annual Meeting. November 7, 2017.

SEC = secukinumab; LD = with Loading Dose; mTSS = modified total van der Heijde Sharp score

88%

80%84%

74%

30%

40%

50%

60%

70%

80%

90%

100%

300 mg (LD) 150 mg (LD) 150 mg Placebo

% with

No Worsening

of Joint Dam

age

on m

TSS

*

**

ApremilastPhosphodiesterase 4 inhibitor

PDE4 = phosphodiesterase 4; cAMP = cyclic adenosine monophosphate; PKA = protein kinase A; NF‐κB = nuclear factor‐kappa B; ATF‐1 = ; activating transcription factor 1; CREB = cAMP responsive element binding (protein); IFN = interferon.

PDE4

Accumulation of cAMP

NF‐B

CREB

ATF‐1

Decreases inflammatory cytokines: TNF, IFNɣ, IL12, IL17, IL22, IL23

PKA

N

NH

HS OO

O

O

O

OO

Perez‐Aso M, et al. Arthritis Res Ther. 2015;17:249.

Apremilast for PsA: PALACE Trials

Kavanaugh A et al. Ann Rheum Dis. 2014;73:1020‐1026. Cutolo M et al. J Rheumatol. 2016;43:1724‐1734. Edwards CJ et al. Ann Rheum Dis. 2016;75:1065‐1073.

40

32.1

41

19 18.9 18

0

5

10

15

20

25

30

35

40

45

PALACE1 PALACE2 PALACE3

ACR 20

APR 30 BID Placebo

P<0.001

P=0.006

21 21

4.6

8

0

5

10

15

20

25

30

35

40

45

PALACE1 PALACE3

PASI 75

APR 30 BID Placebo

P<0.05P=0.004

Apremilast is not preferred in erosive disease. Its ability to prevent joint injury is unproven.

P<0.001

% %

Abatacept: Phase III Trial(FDA Approved for PsA on 7‐6‐2017)

Mease PJ et al. Ann Rheum Dis. 2017;76:1550‐1558.

39.4

26.7

22.319.6

0

5

10

15

20

25

30

35

40

45

ACR20 PASI50

ABTPlacebo

%

P<0.001

ABT = abatacept.Note: Possibly more refractory population – 60% had prior anti‐TNF exposure. Benefits (but not equal responses) were seen regardless of exposure.

50.5

60.6

51.9

33.3

49.647

23.7

0

10

20

30

40

50

60

70

Tofa‐5 Tofa‐10 ADA Placebo

Tofacitinib for PsA

Mease PJ et al. ACR Annual Meeting 2016, Abstract 2983 (http://acrabstracts.org/abstract/efficacy‐and‐safety‐of‐tofacitinib‐an‐oral‐janus‐kinase‐inhibitor‐or‐adalimumab‐in‐patients‐with‐active‐psoriatic‐arthritis‐and‐an‐inadequate‐response‐to‐conventional‐synthetic‐dmards‐a‐randomized/). Gladman D et al. ACR Annual Meeting 2016 Abstract 10L (http://acrabstracts.org/abstract/efficacy‐and‐safety‐of‐tofacitinib‐an‐oral‐janus‐kinase‐inhibitor‐in‐patients‐with‐active‐psoriatic‐arthritis‐and‐an‐inadequate‐response‐to‐tumor‐necrosis‐factor‐inhibitors‐opal‐beyond‐a‐randomize/).

42.744.3

39

14.6

21.3

43.2

14

0

5

10

15

20

25

30

35

40

45

50

Tofa‐5 Tofa‐10 ADA Placebo

ACR 20 PASI 75TNF naïve

TNF IR

TNF naïve

TNF IR

% %

IR = inadequate response.

Rheumatoid Arthritis: Treatment Options

The Principles of Treating to Target

• Treating to target by measuring disease activity and adjusting therapy accordingly will result in better patient outcomes.

• The primary target for treatment should be clinical remission (CR), defined as the absence of signs and symptoms of significant inflammatory disease activity.

• In some cases, low disease activity (LDA) may be an acceptable treatment goal, particularly in patients with long‐standing established disease.

Smolen JS et al. Ann Rheum Dis. 2010;69:631‐637.

Oral non‐biologicsMethotrexateSulfasalazineHydroxychloroquineLeflunomideAzathioprineCyclosporineTacrolimusCyclophosphamide

Prednisone

Selective cytokine inhibitors

TNF inhibitorsEtanerceptInfliximabAdalimumabCertolizumabGolimumab

IL‐1 inhibitorsAnakinra

IL‐6 inhibitorTocilizumab

B cell cepletionRituximab

T cell co‐stimulation blockadeAbatacept

JAK inhibitionTofacitinib

Disease‐Modifying Pharmacotherapies for RA

Classes of Biologics for RA

*Baricitinib is not FDA‐approved for RA.Woodrick RS, Ruderman EM. Nat Rev Rheumatol. 2011;7:639‐652. Shuai K, Liu B. Nat Rev Immunol. 2003;3:900‐911.

TNF inhibitors

Other biologic agents

Infliximab

TNFAdalimumab

Etanercept

Certolizumab pegol

Golimumab

Tocilizumab

IL‐6RIL‐1R

AnakinraIL‐1 IL‐6

IL‐6 signaling

Antigen

MHC

APC

IL‐1 signaling

B cell

RituximabT‐cell receptor

B‐cell depletionCo‐stimulatory signal

T cell

Abatacept

CD80or CD86 CD28

CD20Cytokine receptor

JAK JAK

TofacitinibBaricitinib*

JAK inhibitors

2015 ACR RA Treatment Recommendations for Early RA

Singh JA et al. Arthritis Rheumatol. 2016;68:1‐26. (Also published in Arthritis Care Res [Hoboken]. 2016;68:1‐25.)

DMARD monotherapyb

DMARD monotherapyb

Moderate or high disease activityb,c

T2Ta

Low disease activity

Moderate or high disease activity

DMARD‐naïve early RA

aTreatment target should ideally be LDA or remission. bConsider using short‐term glucocorticoids (GCs) (<3 months) for flares. cConsider adding low‐dose GCs (≤10 mg/day of prednisone or equivalent) in patients with moderate or high disease activity when starting DMARDs and in patients with DMARD failure or biologic failure.

2015 ACR RA Treatment Recommendations for Early RA (Continued)

Singh JA et al. Arthritis Rheumatol. 2016;68:1‐26. (Also published in Arthritis Care Res [Hoboken]. 2016;68:1‐25.)

Combination traditional DMARDsb,c orTNFi +/– MTXb,c or

non‐TNF biologic +/– MTXb,c

See established RA algorithm

T2Ta



aTreatment target should ideally be LDA or remission. bConsider using short‐term glucocorticoids (GCs) (<3 months) for flares. cConsider adding low‐dose GCs (≤10 mg/day of prednisone or equivalent) in patients with moderate or high disease activity when starting DMARDs and in patients with DMARD failure or biologic failure.

Are Some TNFis Better Than Others?

EXXELERATE™ Trial: ADA + MTX vs CZP + MTX in MTX‐IR Patients

• MTX IR patients (n = 915)

• Superiority endpoint: ACR20/50/70 response rates NOT MET

CZP = certolizumab pegol.

NCT01500278 (https://clinicaltrials.gov/ct2/show/NCT01500278?term=NCT01500278&rank=1). www.ucb.com/presscenter/News/article/UCB‐Announces‐Results‐from‐First‐Head‐to‐Head‐study‐of‐Cimzia‐certolizumab‐pegol‐and‐Humira‐adalimumab‐in‐Bio‐Na‐ve‐Rheumatoid‐Arthritis‐Patients

Head‐to‐headcomparison

ACR ResponseWeek 12 ACR 20 ACR 50 ACR 70

LDAS at 2 Years

CZP NR ADA 40 17 8 35.5%

ADA NR CDP 44 23 11 33.5%

TNF‐Inhibitors vs. Non‐TNF Inhibitors: Comparative Data

100

80

40

20

0

0AC

R respon

se ra

te (%

)Visit day

60

ADASC ABA

64.8%

63.4%ACR20

64.8%

63.4%ACR50

64.8%

63.4%ACR70

85 197 36529 141 253 309

AMPLE Study: Outcomes

Weinblatt ME et al. Arthritis Rheum. 2013;65:28‐38.

100

80

40

20

0

ABA SC ADA SC

ACR2

0 Re

spon

se Rate (%

)

Estimate of difference (95% CI) between groups was 1.8 (–5.6 to 9.2);intent‐to‐treat, confirmed with per protocol populations

64.8 63.4

206/318 208/328

60

Primary endpoint:ABA SC is non‐inferior to ADA SC

Comparable efficacy and kinetics of response:ACR scores over 1 year

• No difference in safety• No difference in radiographic progression• ADA was more likely to be discontinued due to adverse events (3.0% vs 1.3%)

LOCF used for TJC and SJC. ESR and patient's global assessment of disease activity VAS, if ESR = 0, then ESR = 1 is substituted into the DAS28 calculation to enable a nonmissing DAS28.

ADACTA DAS28: Mean over Time

Gabay C et al. Lancet. 2013;381:1541‐1550.

8

7

6

4

2

1

0

DAS2

8 5

3

Baseline 4 8 12 16 20 24

Week

TZC 8 mg/kg + PBO (SC) (N =163)ADA 40 mg + PBO (IV) (N = 162)

Head‐to‐head comparison

JAK Inhibitors and Signaling by Type I/II Cytokine Receptors (Tofacitinib and Baricitinib)

γc familyIL‐2, etc.

GH,Epo,

GM‐CSFIL‐6

familyIL‐12,IL‐23

INF‐γ

Tofacitinib + + +Baricitinib + + + + +

JAK‐independent cytokine signaling: IL‐1, IL‐17, IL‐18, TGF‐β, TNFTofacitinib in vitro selectivity JAK3, JAK1>JAK2>>Tyk2Baricitinib in vitro selectivity JAK1, JAK2 >Tyk2>>JAK3

Furumoto Y, et al. BioDrugs. 2013;27:431‐8.

ORAL STANDARD: Outcomes at 6 Months

van Vollenhoven RF et al. N Engl J Med. 2012;367:508‐519.

DAS28‐4 (ESR) at month 6

11 / 177 13 / 178

16

12

8

4

0

NRI (without advancement penalty)

6.2 7.3

HAQ‐DI improvement at month 3

‐0.8

Placebo

ADA 40 mgTFA 5 mg

1 / 92

DAS28‐4(ESR) <2.6

(% of p

atients)

16

12

8

4

0

NRI (with advancement penalty)

6.2 6.7

11 / 177 12 / 178

1.1

Chan

ge in

HAQ‐DI Score

from

Baseline

(points) –0.24

–0.55–0.49

0.0

‐0.2

‐0.4

‐0.6

Head‐to‐headcomparison

RA‐BEAM: Efficacy

Taylor PC et al. Arthritis Rheumatol. 2015;67(suppl 10):abstract 2L.

PlaceboBARI 4 mgADA

Week 12 Week 24

Patie

nts (NRI)(%

)

vs placebo: ***P≤0.001; ** P≤0.01; * P≤0.05. vs adalimumab: ++ P≤0.01; + P≤0.05.

ACR20 ACR50 ACR70 ACR20 ACR50 ACR70

80

60

40

20

0

+***70

+***74

+***30

+***19

++***45

***61

***66

***35

***51 ***

45

***22

***13

5

17

4037

19

8

Non‐TNF Options for MTX‐IR: Summary

• With MTX– ABA vs ADA is neutral (AMPLE)1

– Phase III—TFA 5 mg bid over ADA (ORAL STANDARD)2

• ACR20 response rates were 51.5% with tofacitinib 5 mg, 47.2% with ADA, and 28.3% with placebo.

• No significant differences in DAS remission

– Phase III—BARI*over ADA (RA‐BEAM)3

• Without MTX– TCZ vs ADA favored TCZ (ADACTA)4

• ACR50 of 47.2 vs 27.8%

– Sarilumab* vs ADA (MONARCH)5

1. Schiff M et al. Ann Rheum Dis. 2014;73:86‐94. 2. van Vollenhoven RF et al. N Engl J Med. 2012;367:508‐519. 3. Taylor PC et al. Arthritis Rheumatol. 2015;67(suppl 10):abstract 2L. 4. Gabay C et al. Lancet. 2013;381:1541‐1550. 5. NCT02332590 (https://clinicaltrials.gov/ct2/show/NCT02332590?term=NCT02332590&rank=1).

*Baricitinib and sarilumab are not FDA‐approved for RA.

When a TNFi Fails

Options After TNF Inhibitor Failure (Partial List)

• Triple therapy– RACAT (ETA → TT)1

• Second TNF:– EXXELLERATE (ADA ↔ CDP in nonresponders)2

– GO‐FORWARD (TNF → GLM)3

– OPPOSITE (TNFIR → TNF)4

• Change MOA– REFLEX (TNFIR → RTX)5

– RADIATE (TNFIR → TCZ)6

– ATTAIN (TNFIR → ABA)7

– ORAL Step (TNF IR → TFA)8

– BEACON (TNF IR → Bari)9

• Multiple options:– French ROC (rotation of TNFi or change of biologic)10

1. O’Dell JR et al. N Engl J Med. 2013;369:307‐318. 2. NCT01500278. 3. Keystone EC et al. J Rheumatol. 2016;43:298‐306. 4. Furst DE et al. Ann Rheum Dis. 2007;66:893‐899. 5. Cohen SB et al. Arthritis Rheum. 2006;54:2793‐2806. 6. Emery P et al. Ann Rheum Dis. 2008;67:1516‐1523. 7. Genovese MC et al. N Engl J Med. 2005;353:1114‐1123. 8. Burmester GR et al. Lancet. 2013;381:451‐460. 9. Genovese MC et al. N Engl J Med. 2016;374:1243‐1252. 10. Gottenberg J et al. Arthritis Rheumatol. 2015;67(suppl 10): abstract 3110.

2015 ACR/2016 EULAR GuidelinesKey Principles

• Perform disease activity measurements and functional assessments frequently.

• Simplification of therapy in patients with LDA or remission at the physician’s discretion

• Arbitrary switching based on payer/insurance is not recommended.

• Patients at risk of persistent arthritis should start DMARDs within 3 months, even if classification criteria are not fulfilled.

• Oral CS can be added at the lowest effective dose and tapered.

• Aim for remission within 3 months.

• Maximize non‐pharmacologic interventions (eg, PT/OT, smoking cessation, dental care, weight control, vaccination updates) patient education.

Singh JA et al. Arthritis Rheumatol. 2016;68:1‐26. (Also published in Arthritis Care Res [Hoboken]. 2016;68:1‐25.). Combe B. Ann Rheum Dis. 2016;75(suppl 2):44 (abstract SP0183).

Patient Satisfaction

Patient Satisfaction

Mercy KM et al. JAMA. 2014;312:2676‐2677. Smolen JS et al. Ann Rheum Dis. 2010;69:631‐637.

• Patient satisfaction is rarely incorporated in practice guidelines.

• Studies rely on clinician‐centered measures to determine treatment adequacy.

• Patient satisfaction is an important consideration, linked with: – Patient adherence to therapy – Treatment outcomes

• Satisfaction contributes to responses in HRQoL indices (e.g., DLQI)

• Skin clearance and joint preservation matter to patients– E.g. 52.3% and 45.5% of pts are dissatisfied with PsO/PsA treatment

• T2T by measuring disease activity and adjusting therapy will result in better patient outcomes

DLQI = Dermatology Life Quality Index.

• Maintain patient motivation and engagement in care.

• Understand/explore reasons for declines in adherence.

• Set up realistic expectations.

• Take a health literate approach to prescribing and educating patients.

Building a trusting one‐on‐one relationship with the patient is essential for long‐term management.

Communication in Practice

Thank You!

Biologic Agents in Rheumatology: A Virtual Reality Tour through Psoriatic Arthritis and Rheumatoid Arthritis

Additional Reading

1. Cantini F, et al. Second-line biologic therapy optimization in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Semin Arthritis Rheum. 2017;47(2):183-92.

2. Cantini F, et al. Tailored first-line biologic therapy in patients with rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis. Semin Arthritis Rheum. 2016;45(5):519-32.

3. Coates L, et al. Psoriasis, psoriatic arthritis, and rheumatoid arthritis: Is all inflammation the same? Semin Arthritis Rheum. 2016;46(3):291-304.

4. Jafri K, et al. Incidence and management of cardiovascular risk factors in psoriatic arthritis and rheumatoid arthritis: A population-based study. Arthritis Care Res (Hoboken). 2017;69(1):51-57.

5. Lauper K, et al. Incidence and prevalence of major adverse cardiovascular events in rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis. Arthritis Care Res (Hoboken). 2018 Apr 2. doi: 10.1002/acr.23567. [Epub ahead of print]

6. Lopez-Gonzalez R, et al. Adherence to biologic therapies and associated factors in rheumatoid arthritis, spondyloarthritis and psoriatic arthritis: a systematic literature review. Clin Exp Rheumatol. 2015;33(4):559-69.

7. Lubrano E, et al. Clinical remission in rheumatoid arthritis and psoriatic arthritis. Clin Exp Rheumatol. 2018 Mar 16. [Epub ahead of print].

8. Madan J, et al. Consensus decision models for biologics in rheumatoid and psoriatic arthritis: Recommendations of a multidisciplinary working party. Rheumatol Ther. 2015;2(2):113-25.

9. Nas K, et al. Comorbidities in patients with psoriatic arthritis: a comparison with rheumatoid arthritis and psoriasis. Int J Rheum Dis. 2015;18(8):873-9.

10. Ogdie A, et al. Cause-specific mortality in patients with psoriatic arthritis and rheumatoid arthritis. Rheumatology (Oxford). 2017;56(6):907-11.

11. Roubille C, et al. Evidence-based recommendations for the management of comorbidities in rheumatoid arthritis, psoriasis, and psoriatic arthritis: Expert opinion of the Canadian Dermatology-Rheumatology Comorbidity Initiative. J Rheumatol. 2015;42(10):1767-80.

12. Veale D, et al. What makes psoriatic and rheumatoid arthritis so different? RMD Open. 2015;1(1):e000025.

13. Verheul M, et al. Biomarkers for rheumatoid and psoriatic arthritis. Clin Immunol. 2015;161(1):2-10.

Psoriatic/Rheumatoid Arthritis Resources: Associations/Foundations American Academy of Dermatology

https://www.aad.org/ American College of Rheumatology

https://www.rheumatology.org/ Rheumatology Research Foundation

https://www.rheumresearch.org/ Arthritis Foundation

https://www.arthritis.org/ World Health Organization

http://www.who.int/chp/topics/rheumatic/en/

biologic agents in rheumatology: a virtual reality tour ... · biologic agents in rheumatology: a...

Documents