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Advancement in Treatment of Rheumatoid Arthritis

DR A P NAVEEN KUMARCHIEF SPECIALIST ( GEN. MED. )

VISAKHA STEEL GENERAL HOSPITAL

POINTS TO PONDER

CASE

• 51 male –joint pains – 2 months• Polyarthritis – large and small , Symmetrical• No rash , fever and any drug intake• EMS – 10 joints• ESR – 32• Anti CCP - 48

Overview

• Rheumatoid Arthritis– Disease characteristics and course– Epidemiology and pathogenesis– Classification criteria– Treatment objectives & guidelines– Therapies– Biologics

Features of RA

• Multi-system autoimmune disease – inflammatory changes in the joints – Chronic, progressive and disabling disease

• Exact etiology unknown– Established role for genetic factors– Suspected role for environmental factors (smoking,

hormonal and infectious)

Alamanos Y and Drosos AA. Autoimmunity Rev 2005;4:130–136; Silman AJ and Pearson JE. Arthritis Res 2002;4(suppl 3):S265-S272.

The Burden of RA

• Pain and destruction of the joints • Loss of function• Systemic disease• Chronic disease

• Work disability

• Economic losses

Callahan. Chapter 1. In: Klippel, eds. Primer on the Rheumatic Diseases. 12th ed. Arthritis Foundation;2001.p.1-4.

Overview

• Rheumatoid Arthritis– Disease characteristics and course– Epidemiology and pathogenesis– Classification criteria– Treatment objectives & guidelines– Therapies

Features of RA

• Prevalence of 0.5-1.1% in Northern European and North American areas, 0.3-0.7% in Southern European countries and 0.1-0.5% in developing countries1

• Age of onset peaks in the fifth decade1

• Two-to-three fold more common in women1

• Exact etiology unknown1,2

– Established role for genetic factors– Suspected role for environmental factors (smoking, hormonal and

infectious agents)• Higher mortality rates1

– Shortens life span by 3 to 10 years

1Alamanos, et al. Autoimmunity Rev 2005;4:130.2Silman, et al. Arthritis Res 2002;4:Suppl 3:265-272.

An Inflamed Synovium is Central in RA: Pathophysiology

Feldmann, et al. Ann Rev of Immun 1996;14:397-440.

Pathways Involved in Inflammation and Destruction of the Rheumatoid Joint

• Five stages in disease progression:– Intracellular signaling and

proliferation– Adhesion– Inflammation– Angiogenesis– Matrix degradation

• Five key molecules involved:– TNF-α– IL-1– IL-6– MMP– Cathepsins

Muller-Ladner U, et al. Nat Clin Pract Rheum 2005;1:102-110.IL: Interleukins; MMP: Matrix Metalloproteinase

Role of TNF in the Pathogenesis of RA

Brennan FM & McInnes IB. J. Clin Invest 2008;118: 3537-45.

Overview


Clinical Course of RA

Guerne PA and Weisman MH. Am J Med 1992;16:451-460; Lee DM and Weinblatt E. The Lancet 2001; 358 : 903-911“Kelley's Textbook of Rheumatology”, 2008; “Eular Compendium on Rheumatic Diseases”, Ed. Bijlsma JWJ, 2009

91%

78 %

64 %

65 %

50 %43 %

38 %

17 %

Joint involvement in RA • Main presenting symptoms:– Swelling of the joint and/or

joint margins– Joint tenderness– Systemic malaise– Loss of energy– Severe morning stiffness

Disease Characteristics

Joints involved in RA

• Don’t forget the cervical spine!! Instability at cervical spine can lead to impingement of the spinal cord.

• Thoracolumbar, sacroiliac, and distal interphalangeal joints (DIP)of the hand are NOT involved.

Against the diagnosis of RA

• Eligibility for testing with the new criteria:– Evidence of definite clinical synovitis (swelling) in at least one

joint – The synovitis is not better explained by another disease

• Classification criteria for RA; a score of ≥6/10 needed for the classification of having definite RA Scoring based on:– Number and site of involved joints (0-5)– Serological abnormality (0-3)– Elevated acute-phase response (0-1)– Symptom duration (0-1)

2010 ACR Classification Criteria for RA

Aletaha D et al. Ann Rheum Dis 2010;69:1580-88.

Joint involvement One large joint 02-10 large joints 11-3 small joints* 24-10 small joints* 3>10 joints (at least one small joint) 5

Serology# RF- and ACPA- 0Low RF+ or low ACPA+ 2High RF+ or high ACPA+ 3

Acute-phase reactants# Normal CRP and normal ESR 0Abnormal CRP or abnormal ESR 1

Duration of symptoms <6 weeks 0≥6 weeks 1

*With or without involvement of large joints. # at least one test result needed for classification . ACPA: Anti-citrullinated protein/peptide antibodies; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate

Synovitis plus score of ≥6/10 needed for the classification of definite RA

2010 ACR Classification Criteria for RA

Aletaha D et al. Ann Rheum Dis 2010;69:1580-88.

CLINICAL MANIFESTATIONS

• Symmetrical polyarthralgia, morning stiffness, and fatigue are common

• Morning stiffness results from increases in extracellular fluid in & around joint

• Later on, there may be limitation of motion due to pain or joint destruction

• Predilection for wrists and hands; MP joints, PIP joints, and wrists are first to become symptomatic

• Ulnar deviation, and swan-neck or boutonniere deformities are common

EXTRA ARTICULAR MANIFESTATIONS:Patients with extraarticular manifestations have –• High-titer RF• More severe disability • Increased mortality rate

• Heart- pericarditis, cardiomyopathy, and valvular incompetence

• Lungs: Rheumatoid lung (Honeycombed appearance on CXR due to multiple nodules), Caplan syndrome (associated with pneumoconiosis), Idiopathic pulmonary fibrosis, interstitial fibrosis

• Eyes- scleritis (most common ocular complication of RA), scleromalacia perforans)

• Nervous system- mononeuritis multiplex, compression syndromes such as median neuropathy CTS

• Kidneys- amyloid deposition

• Hematopoietic system- Felty's syndrome (anemia, splenomegaly, and leukopenia)

• Vasculitis: usually is a non necrotising arteritis of the small terminal arterials, Skin lesions, leg ulcers, necrotizing arteritis of the viscera, digital infarctions, and fever

• Sjogren's syndrome: occurs in 15%; RA + keratoconjunctivitis sicca, xerostomia

CASE

• 48 female – tingling in hands and feet• Fever and fatigue• Bodyaches more of arthralgia• o/e s/o CTS and Peripheral neuritis• Hb 8.2 ESR 98• Anti CCP positive

CASE

• 38 female• BTLN – on evaluation restrictive lung disease• CECT chest - ILD• Hb 7.8 ESR 110• Anti CCP positive

Cervical Spine in RA• Cervical spine involvement is common in RA (upto

90%), more common with long standing disease and multiple joint involvement

Most common presentations:• Atlantoaxial subluxation: most common and may

occur in upto 40%• Atlantoaxial impaction / Basilar invagination• Lower cervical spine: Joints of Lushka & facet joints

are affected, subluxation may occur at multiple levels; more common in males, with steroid use, sero-+ RA, with RA nodules, & severe RA

• Presentation: neck pain, neurologic involvement, myelopathy, radiculopathy

• Investigation: Cross table lateral X-ray, MRI

Rheumatoid Foot

• Initially, RA involves the forefoot, then the midtarsal joints, and finally the hindfoot; forefoot is involved twice as often as the hindfoot

Rheumatoid forefoot• - Hyperpronation of rheumatoid foot• - Metatarsalgia• - Claw toesMidfoot:• - Talonavicular arthritis• - Midfoot hyperpronation • Hind foot: calcaneovalgus

Features less common in RA

1. Enthesistis

2. First MTP joint involvement

Rheumatoid Factor (RF)

• Antibodies that recognize Fc portion of IgG

• Can be IgM , IgG , IgA

• 85% of patients with RA over the first 2 years become RF+

• A negative RF may be repeated 4-6 monthly for the first two year

of disease, since some patients may take 18-24 months to become

seropositive.

• PROGNISTIC VALUE- Patients with high titres of RF, in

general, tend to have POOR PROGNOSIS, MORE EXTRA

ARTICULAR MANIFESTATION.

Causes of positive test for RF

• Rheumatoid arthritis• Sjogrens syndrome• Vasculitis such as polyarteritis nodosa• Sarcoidosis• Systemic lupus erythematosus• Cryoglobulinemia• Chronic liver disease• Infections- tuberculosis , bacterial endocarditis, infectious

mononucleosis, leprosy, syphilis, leishmaniasis.• Malignancies• Old age(5% women aged above 60)

Anti-CCP• IgG against synovial membrane peptides

damaged via inflammation• Sensitivity (65%) & Specificity (95%)• Both diagnostic & prognostic value

• Predictive of Erosive Disease

– Disease severity– Radiologic progression– Poor functional outcomes

Anti CCP• Highly specific (90 to 95%)– RA

• Low sensitivity( 60- 70%)

• RF +ve, ACCP +ve RA

• RF neg, ACCP +ve RA ( = 40% of RF negative RA)

• RF +ve, ACCP neg RA possible, but exclude other diseases

• RF –ve, ACCP neg Still RA possible(10- 15%)

• When present, CCP is very reassuring that you have RA

Acute Phase Reactants Positive acute phase reactants () Negative acute phase reactants ()Mild elevations – Ceruloplasmin – Complement C3 & C4

Moderate elevations – Haptoglobulin – Fibrinogen (ESR) – 1 – acid glycoprotein – 1 – proteinase inhibitor Marked elevations – C-reactive protein (CRP) – Serum amyloid A protein

– Albumin– Transferrin

Relationship Between Inflammation, Radiographic Progression and Disability

Seve

rity

(Arb

itrar

y U

nits

)

0

Duration of Disease (years)

5 10 15 20 25 30

InflammationDisabilityRadiographs

“In early RA irreversible damage is seen in 60% of patients within the first 2 years of diagnosis.” Kirwan J. Rheum 1999;26:720.

Saleem et al. Clin Exp Rheum 2006;24:S33.

Radiographic Features

• Peri-articular osteopenia• Uniform symmetric joint space narrowing• Marginal subchondral erosions• Joint Subluxations • Joint destruction• Collapse• Ultrasound detects early soft tissue lesions.• MRI has greatest sensitivity to detect synovitis and marrow changes.

ACR Response Criteria

≥ 20% / 50% / 70% Improvement in:• Number of swollen joints (SJC)• Number of tender joints (TJC)• Improvement of at least three of the following:

• Patient Global Assessment• Physician Global Assessment• Patient Pain Scale• Health Assessment Questionnaire (HAQ)• ESR or CRP

Felson DT et al. Arthritis Rheum. 1993; 41: 1564-1570

• Disease Activity Score of 28 joints (DAS28). It is widely used as an indicator of RA disease activity and response to treatment The joints included in DAS28 are PIP ,MCP joints ,wrists, elbows , shoulders and knees

• When looking at these joints, both the number of joints with tenderness upon touching (TEN28) and swelling (SW28) are counted.

• In addition, the ESR is measured. Score less than 3.2 means pt is inactive

3.2-5.1 means moderately active patient

more than 5.1 means pt is active

Monitoring progression

Overview


Rheumatoid Arthritis Treatment Goals

• Classical objectives:1

– Reduce disease activity– Decrease disability– Delay/prevent structural damage

• Current goals:2,3

– Suppression of inflammation and control of comorbidities and complications2

– Achieve persistent, total disease suppression resulting in remission. Remission will halt damage, prevent disability, improve quality of life (QoL) and lower mortality rates3

1van der Heijde D. Ann Rheum Dis 2001;60:iii47-iii50; 2Colmegna I et al. Clin Pharm & Therapeutics 2012;91:607-620; 3Mease PJ. J Rheumatol 2010;37:1570-1578.

Medical Management of RA Symptom control: NSAIDs, corticosteroids

Disease-modifying therapy: DMARDs

Tumor necrosis factor (TNF)-inhibitors

Other biologics/mechanisms of action

Orals: Tofacitinib (approved by FDA November 2012; Rejected by EMA in April and July 2013)

----- Not considered first line therapies, only symptom control therapies; NSAID: Non-steroidal Anti-inflammatory Drug

Non-Steroidal anti-inflammatories (NSAIDS) / Coxibs for symptom control

1) Reduce pain and swelling by inhibiting COX

2) Do not alter course of the disease.

3) Chronic use should be minimised.

4) Most common side effect related to GI tract.

Corticosteroids in RA• Corticosteroids , both systemic and intra-articular are

important adjuncts in management of RA.• Indications for systemic steroids are:-

1. For treatment of rheumatoid flares.2. For extra-articular RA like rheumatoid vasculitis and

interstitial lung disease.3. As bridge therapy for 6-8 weeks before the action of

DMARDs begin.4. Maintainence dose of 10mg or less of predinisolone daily in

patients with active RA.5. Sometimes in pregnancy when other DMARDs cannot be

used.

Disease Modifying Anti-rheumatic Agents

• Drugs that actually alter the disease course .

• Should be used as soon as diagnosis is made.

• Appearance of benefit delayed for weeks to months.

• NSAIDS must be continued with them until true remission is achieved .

• Induction of true remission is unusual .

DMARDsCommonly used Less commonly usedMethotrexate Chloroquine

Hydroxychloroquine Gold(parenteral &oral)

Sulphasalazine CyclosporineA

Leflunomide D-penicillamine/bucillamine

Minocycline/Doxycycline LevamisoleAzathioprine,cyclophosphamide, chlorambucil

Clinical information about DMARDs

NAME DOSE SIDE EFFECTS MONITORING ONSET OF ACTION

1) Hydroxycloroquine

200mg twice daily x 3 months, then once daily

Skin pigmentation , retinopahy ,nausea, psychosis, myopathy

Fundoscopy& perimetry yearly

2-4 months

2) Methotrexate 7.5-25 mg once a week orally,s/c or i/m

GI upset,hepatotoxicity,Bone marrow suppression, pulmonary fibrosis

Blood counts,LFT 6-8 weekly,Chest x-ray annually, urea/creatinine 3 monthly;Liver biopsy

1-2 months

Clinical information about DMARDs contnd..

NAME DOSE SIDE EFFECTS MONITORING ONSET OF ACTION

3)Sulphasala- 2gm daily p.o Rash, myelosuppression, may reduce sperm count

Blood counts ,LFT 6-8 weekly

1-2 months

4)Leflunomide Loading 100 mg daily x 3 days, then 10-20 mg daily p.o

Nausea,diarrhoea,alopecia, hepatotoxicity

LFT 6-8 weekly 1-2 months

zine

Recommendations for optimal followup laboratory monitoring intervals forcomplete blood count, liver transaminase levels, and serum creatinine levels for

patients with rheumatoid arthritis receiving disease-modifying antirheumatic drugs*

Monitoring interval based on duration of therapy

Therapeutic agents <3 months 3–6 months >6 months

Hydroxychloroquine None after baseline None None

Leflunomide 2–4 weeks 8–12 weeks 12 weeks

Methotrexate 2–4 weeks 8–12 weeks 12 weeks

Sulfasalazine 2–4 weeks 8–12 weeks 12 weeks

When to start DMARDs?

• DMARDs are indicated in all patients with RA who continue to have active disease even after 3 months of NSAIDS use.

• The period of 3 months is arbitary & has been chosen since a small percentage of patients may go in spontaneous remission.

• The vast majority , however , need DMARDs and many rheumatologists start DMARDs from Day 1.

How to select DMARDs?

• There are no strict guidelines about which DMARDs to start first in an individual.

• Methotrexate has rapid onset of action than other DMARD.

• Taking in account patient tolerance, cost considerations and ease of once weekly oral administration METHOTREXATE is the DMARD of choice, most widely prescribed in the world.

Should DMARDs be used singly or in combination?

• Since single DMARD therapy (in conjunction with NSAIDS) is often only modestly effective , combination therapy has an inherent appeal.

• DMARD combination is specially effective if they include methotrexate as an anchor drug.

• Combination of methotrexate with leflunamide are synergestic since there mode of action is different.

EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and

Biological Disease-Modifying Anti-Rheumatic Drugs: 2013 Update

Smolen et al. Ann Rheum Dis published online October 25, 2013

(doi: 10.1136/annrheumdis-2013-204573)

2013 EULAR Recommendations: Phase I

Newly diagnosed RA patients

Smolen J et al. Ann Rheum Dis 2013, epub 25OCT13 (doi: 10.1136/annrheumdis-2013-204573).

**The treatment target is clinical remission according the ACR-EULAR definition or, if remission is unlikely to be achievable, at least low disease activity (LDA)

2013 EULAR Recommendations: Phase II


Methotrexate inadequate responders


2013 EULAR Recommendations: Phase III


Patients failing first TNF inhibitor


Drug category Descriptions

• Triple DMARD therapy MTX,SSZ,HCQ.

• DMARD combination therapy Double or triple traditional/conventional DMARD therapy.

• Low-dose glucocorticoid <10 mg/day of prednisone (or equivalent)

• High-dose glucocorticoid >10 mg/day of prednisone (or equivalent) and up to 60 mg/day with a rapid taper

• Short-term glucocorticoid 3 month treatment.

VACCINES IN RA

• Pneumococcal• Influenza• Hepatitis B• Human papilloma• Herpes Zoster

ADJUVANT DRUGS

• Statin• Antihypertensives• Aspirin• OHA• Antibiotics• Calcium and Biphosphonates

Pregnancy, lactation and RA

• Stop methotrexate 3 months before pregnancy

• Leflunomide better avoided in child bearing age group

• Sulfasalazine, HCQ, prednisolone <15 mg/d safe in pregnancy

• Biologicals - controversial

Limitations of conventional DMARDs

1) The onset of action takes several months.2) The remission induced in many cases is partial.3) There may be substantial toxicity which requires

careful monitoring.4) DMARDs have a tendency to lose effectiveness with

time. These drawbacks have made researchers look for

alternative treatment strategies for RA- The Biologic Response Modifiers.

How long should Tt. be continued?

• Once remission is achieved , maintenance dose for long period is recommended.

• Relapse occurs in 3-5 months (1-2 months in case of MTX) if drug is discontinued in most instances.

• DMARDs are discontinued by patients because of toxicity or secondary failure(common after 1-2 yrs) and such patients might have to shift over different DMARDs over 5-10 yrs.

• Disease flare may require escalation of DMARD dose with short course of steroids.

Overview

• Rheumatoid Arthritis– Disease characteristics and course– Epidemiology and pathogenesis– Classification criteria– Treatment objectives & guidelines– Therapies– Biologics

Important points

• Biologics are effective

• Biologics may be your only medication or part of a

combination approach

• Biologics may increase your risk for infection

• Biologics are usually given by Injection or IV

• Biologics have safety issues

• Biologics require a strict follow-up schedule

• Biologics are expensive

Choy EH et al. Nat Rev Rheumatol 2013;9:154-163.

GolimumabInfliximab

AdalimumabCertolizumab

EtanerceptTocilizumab

Abatacept

Rituximab

Tofacitinib

Rheumatoid Arthritis Available Therapies

Therapeutic Window of Opportunity

• Erosive changes occur early in disease• Even a brief delay can have significant impact

on disease parameters on later life• Early DMARD therapy can reset rate of

progression for years to come

Treatment: Earlier The Better

Evolving RA Treatment Paradigm

• Current approach • Evolving paradigm

Initial treatmentTraditional DMARDs

Early aggressive treatmentBiologicsCombination therapy

TNF Blockers: Antibodies and Fusion Proteins

CDR=Complementarity-determining regionPEG=Polyethylene glycol

Human recombinant receptor/Fc fusion

protein

Humanized Fab’ fragment

Human recombinant

antibody

Humanized monoclonal

antibody

Chimeric monoclonal

antibody

CDRTNFR2 (p75)

Fc

MouseHuman

Fab

InfliximabRituximab

Tocilizumab AdalimumabGolimumab

EtanerceptCertolizumab pegol

PEG

VL VH

CH1Ck

PEG

Adapted from Keystone E and Ware C. J Rheum 2010;85:27-39.Adapted from Feldmann M. Nature 2002; 2(May):364-71.

Monoclonal Antibodies and ImmunogenicityHigh immunogenicity Low immunogenicity

golimumab4

adalimumab2

ustekinumab6tocilizumab5infliximab2

rituximab2

Fully human-umab

Humanized-zumab

Chimeric-ximab

Murine-omab

In principle, for a given agent, IV administration is associated with lower immunogenicity than SC administration3

Adapted from 1Breedveld FC. Lancet 2000; 355:735-40. 2Johnston SL. J Clin Pathol 2007; 60:8-17. 3Clark M. Immunol Today 2000;21:397-401. 4Keystone E and Ware C. J Rheum 2010;85:27-39. 5RoActemra® (tocilizumab) EU Summary of Product Characteristics (SmPC);

dated July, 2013. 6Benson JM, et al. mAbs 2011; 3(6):535-45.

Characteristics of Biologics

Golimumab Infliximab Etanercept Adalimumab Abatacept

Target TNF TNF TNF TNF T cell Activation

Half life 12-15 days 8-10 days 3-5 days 10-20 days 13-16 days

Construct Human Chimeric Human Human Human

Dosing Once monthly

Every 4-8 weeks

Once biweekly- weekly

Once biweekly- weekly

Once monthly

Route SC IV SC SC IV

Treatment Summary

• Early appropriately aggressive intervention in inflammatory arthritis: Critical to best possible outcome

• Combination of biologic plus MTX is frequently more effective than either alone

TNFα inhibitors

• Etanercept (Enbrel) :

• MOA: It is recombinant fusion protein consisting of two

soluble TNF p75 receptor moieties linked to Fc portion of

human IgG1, it binds TNFα molecule

• It decreases rate of formation of new erosion

• DOSE: 25 mg twice weekly given s.c.

• SIDE EFFECTS : “Injection site reactions, Increased risk of

infections (Tuberculosis (TB) and fungal infections)

Adalimumab

• MOA: It is fully human IgG1 anti TNF monoclonal

antibody complexes with soluble TNFα and prevents its

interaction with cell surface receptors causing down

regulation of macrophages and T-cell function

• DOSE: 40 mg given every 2 weekly given s.c.

• Common side effect : Redness, itching, pain, or swelling

at the injection site, Respiratory infection

• Combination with MTX to improve response

Infliximab

• MOA: It is chimeral IgG1 monoclonal antibody that binds

with TNFα

• DOSE:3 mg/kg IV infusion, Weeks 0, 2 and 6; then every

8 weeks Combine with Methotrexate

• SIDE EFFECT: URTI, nausea, headache, sinusitis,

activation of latent , severe allergic reaction with swelling

of the lips, difficulty breathing and low blood pressure

• Anakinra (Kineret)- It is recombinant human IL-1 receptor antagonist.

• Used in cases who have failed on others drugs.• Side effects: local reaction on s/c inj. & chest

infection S.NO AGENT CLASS DOSE FREQUENCY

1 Anakinra IL-1 receptor antagonist

100 mg SC Daily

IL-1 RECEPTOR ANTAGONIST

IL-6 RECEPTOR ANTAGONIST : TOCILIZUMAB (Actmera)

• Tocilizumab is a Humanized anti IL-6 monoclonal Ab that specifically inhibits the action of 1L-6

• It is reserved for Resistant RA • Side effects : Infusion related reaction (flushing,

headache, fever, nausea, fatigue)

S.NO AGENT CLASS DOSE FREQUENCY

1 Tocilizumab IL-6 receptor antagonist

IV: 4 mg/kg; may increase to 8 mg/kg

Every 4 weeks

SC: 162 mg < 100 kg: every other week; increase to every week based on clinical response ≥ 100 kg: every week

• It is recombinant fusion protein.• MOA: inhibits activation of T cell• Used when there is inadequate response to DMARDSA/e : Risk of infections• Hypersensitivity reaction


1 Abatacept T-Cell co-stimulation inhibitor

IV: < 60 kg: 500 mg 60–100 kg: 750 mg > 100 kg: 1000 mg

Weeks 0, 2, 4, then monthly

SC: 125 mg Weekly May be initiated with or without single IV loading dose If using loading dose, use weight-based dose above and start SC injection within 24 hours of the initial IV infusion

T-Cell co-stimulation inhibitor : Abatacept (Orencia)

RITUXIMAB (RITUXAN OR MABTHERA)B CELL DEPLETION THERAPY

• Targeting B-lymphocytes in these patients has opened a new therapeutic window

• Chimeric monoclonal Ab, targets CD20 B cells

• Used in resistant RA .

• Combination therapy with Methotrexate

• Dose: 2 IV infusions 2 wks apart • Side effects: Mild infusion reactions (flushing, headache, fever, nausea,

fatigue)


1 Rituximab Anti-CD 20 1000 mg IV plus 2 IV infusions 2 wks apart Combine with Methotrexate

Janus Kinase enzyme inhibitor/ SYK inhibitor

S.NO AGENT CLASS DOSE FREQUENCY1 Tofacitinib Janus Kinase

enzyme inhibitor5 mg PO Days 1 and 15 may retreat every

24 weeks (no sooner than every 16 weeks) Combine with Methotrexate

• Tofacitinib (Xeljanz) JAK inhibitor• USE: Similar to biologics in effectiveness and side effects• Mechanism: Oral disease modifying medication Targets inflammation signaling pathway• Oral agents (Biosimiliar): Tofacitinib (Pfizer) Baricitinib (Eli lilly)• SYK inhibitor (spleen tyrosine kinase (Syk) inhibitors): Fostamatinib

Adverse Effects of Biologics

Infusion related reactions : Dyspnoea , chest pain , headache, high blood

pressure, dizziness, rash, flushing, hypotension or a “tickle in the throat.” Serious Infections

– Tuberculosis and sepsis Malignancy : Lymphoma ?, Solid Tumors ?

OTHERS:

Optic neuritis, Increase LFT

Severe allergic reaction

Numbness and Tingling

• Pregnancy: stop before 3 months

• No live vaccines should be given

Antibody Formation Across All Indications

REMICADE® (infliximab) EU Summary of Product Characteristics (SmPC); dated August, 2013. HUMIRA® (adalimumab) EU Summary of Product Characteristics (SmPC); dated April, 2013. CIMZIA® (certolizumab) EU Summary of Product Characteristics (SmPC); dated Nov, 2013.

SIMPONI® (golimumab) EU Summary of Product Characteristics (SmPC); dated August, 2013. ENBREL® (etanercept) EU Summary of Product Characteristics (SmPC); dated April, 2013. MabThera® (rituximab) EU Summary of Product Characteristics (SmPC); dated April, 2013.

Stelara® (ustekinumab) EU Summary of Product Characteristics (SmPC); dated March, 2013. ORENCIA® (abatacept) EU Summary of Product Characteristics (SmPC); dated July, 2013. RoActemra® (tocilizumab) EU Summary of Product Characteristics (SmPC); dated July, 2013.

Range of antibody formation in all clinical trials with or without co-medication (immunosuppressor) as indicated in the most recent European SmPCs (PIs)

Infliximab

Adalimumab

Certolizumab

Golimumab

Etanercept

Rituximab

Ustekinumab

Tocilizumab

Abatacept

0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0%

Only infliximab has been studied with an episodic

treatment strategy.

Since immunogenicity analyses are product-specific,

comparison of antibody rates with those from other products

is not appropriate. (HUMIRA® (Adalimumab) EU Summary of

Product Characteristics (SmPC); April 2013.)

Percentage of Antibody Formation (%)

Monoclonal Antibodies and ImmunogenicityHigh immunogenicity Low immunogenicity

golimumab4

adalimumab2

ustekinumab6tocilizumab5infliximab2

rituximab2

Fully human-umab

Humanized-zumab

Chimeric-ximab

Murine-omab

In principle, for a given agent, IV administration is associated with lower immunogenicity than SC administration3

Adapted from 1Breedveld FC. Lancet 2000; 355:735-40. 2Johnston SL. J Clin Pathol 2007; 60:8-17. 3Clark M. Immunol Today 2000;21:397-401. 4Keystone E and Ware C. J Rheum 2010;85:27-39. 5RoActemra® (tocilizumab) EU Summary of Product Characteristics (SmPC);

dated July, 2013. 6Benson JM, et al. mAbs 2011; 3(6):535-45.

Although there is clear evidence that chimeric antibodies are less immunogenic than murine monoclonal antibodies, little evidence exists to support claims for further improvement as a result of more elaborate

humanization protocols3

Evolution of Antibody Technology

1975 1980 1985 1990 1995 2000 2005 2010

ears

1986

Mouse monoclonal antibodies IbritumomabTositumomab

1994

Chimeric recombinant antibodies Infliximab

2002

Phage display synthetic antibodies

Transgenic human antibodies

2009

Adalimumab

Golimumab

Adapted from Lonberg N. Nat Biotechnol 2005;23:1117–25.SIMPONI® (golimumab) EU Summary of Product Characteristics (SmPC); dated August, 2013.

Concentration and Injection Volume

• Highly concentrated subcutaneous formulation:

– Golimumab 100 mg/mL– Adalimumab 50 mg/mL– Etanercept 50 mg/mL

• Low injection volume:

– Golimumab (Monthly) 50 mg/0.5 mL– Adalimumab (EOW) 40 mg/0.8 mL– Etanercept (Weekly) 50 mg/1.0 mL

Note: SIMPONI does not contain citric acidHUMIRA (adalimumab) Prescribing Information (PI); Abbott Laboratories., dated April, 2013.

ENBREL® (etanercept) Prescribing Information (PI); Amgen Inc., dated April, 2013. SIMPONI® (golimumab) Prescribing Information (PI); dated August, 2013.

Kay J, and Rahman, M. Core Evidence Arthritis Rheum 2009;4:159-170.

Unlike HUMIRA, SIMPONI requires no (painful) citrate as a stabilizer to prevent

aggregation.

EOW=every other week

Dosing Schedule of Various Drugs Including Golimumab Over One Year

For each product: respective EU SPC

Etanercept 50 mgTotal injections/year =52

Adalimumab 40 mgTotal injections/year=26

Certolizumab pegol 200 mgTotal injections/year =26*

Golimumab 50 mgTotal injections/year =12

HUMIRA (adalimumab) Summary of Product Characteristics (SmPC), August, 2013. ENBREL® (etanercept) Summary of Product Characteristics (SmPC), April, 2013.

CIMZIA® (certolizumab pegol) Summary of Product Characteristics (SmPC), November, 2013. SIMPONI® (golimumab) Summary of Product Characteristics (SmPC), August 2013.

* EU and US labeling allows consideration of 400 mg q4 dosing after initial response has been confirmed.

Patient Experience and Satisfaction with GLM

A study on patient satisfaction with GLM, ETN, and ADA in RA, AS, and PsA patients

Patient Injection Experience and Satisfaction with GLM, ADA, and ETN

Most Recent Injection Experience

Bolge S, et al. ACR 2012 [abstract] 1925, poster presentation.

Discomfort Pain

GLM ADA ETN0

20

40

60

80

100

4932

18

38

4359

1023 23

3 2 0

None Mild Moderate Severe

Perc

enta

ge o

f Pati

ents

(%)

*

*

**

#

*p<0.05 vs. GLM; #p<0.10 vs. GLM

GLM ADA ETN0

20

40

60

80

100

49 4428

3932 57

723

154 1 0


Perc

enta

ge o

f Pati

ents

(%)

*

*

#

Patient Injection Experience and Satisfaction with GLM, ADA, and ETN (Cont’d)

Most Recent Injection Experience

Bolge S, et al. ACR 2012 [abstract] 1925, poster presentation.

Stinging Burning

Conclusions: GLM patients reported comparable satisfaction with effectiveness, and less discomfort, pain, burning and stinging compared to ETN and ADA patients

GLM ADA ETN0

20

40

60

80

100

41

16 12

49

53 59

428 26

6 3 3


Perc

enta

ge o

f Pati

ents

(%)

*p<0.05 vs. GLM; #p<0.10 vs. GLM

* *

* *

GLM ADA ETN0

20

40

60

80

100

5841 40

30

36 34

920 24

3 3 2


Perc

enta

ge o

f Pati

ents

(%)

*#

# *

Conclusions – Monoclonal Antibody Technologies

• Monoclonal antibodies, including human mAbs, are not born equal

• The characteristics of an antibody are linked to the technology used for its development and to the antibody itself

• These characteristics, including half- life, affinity ,stability, solubility and immunogenicity, combine to determine possible routes of administration and dosing regimens of an antibody

Antibodies with similar half-lives can have different dosing schedules

Conclusions – Golimumab

• Through careful selection and testing, Janssen was able to identify and develop an antibody with characteristics favorable to clinical use:– Affinity– Stability– Solubility– Immunogenicity

• Resulting in an agent with:– A monthly dosing schedule– Low injection volumes– Less pain for the patient– Expected anti-TNF efficacy and safety, both over the short and

long-term

• Treatment should start early and aggressively to prevent functional limitations and structural damage

• Methotrexate is the first line drug, but in high risk patients early combination of Methotrexate with prednisone or a tumour necrosis factor inhibitor improves outcomes

• The goal of treatment today is remission, which has been defined in several ways, including the DAS28 score, SDAI, CDAI, and a provisional ACR/EULAR definition

Summary

• There are currently five TNF inhibitors on the market, which vary in mode and frequency of administration. The drugs are generally similar in efficacy and side effect profiles

• A safety concern with the biologic drugs is the potential for serious infections, so monitoring is needed

Summary

Thank you THANK YOU

JUVENILE RHEUMATOID ARTHRITIS

ACR dignostic criteria• Age < 16• Arthritis of 1 or more joints• Symptoms of at least 6 weeks• An onset type after 6 months of observation –

pauciarticular, polyarticular or sysytemic• Exclusion of other forms of arthritis

Types: • Pauciarticular – less than 5 joints involved;

with ANA + iridocyclitis or HLA B 27 + spondylitis

• Polyarticular –5 or more joints affected; RA factor + or -

• Systemic (Still’s disease)• < 20% have progressive destructive disease;

mostly systemic

Pauciarticular:A. With ANA + iridocyclitis• F>M• Onset age < 5yr• Fewer joint involved• 30-35% have chronic iridocyclitis; complications- posterior

synechia, band shaped keratopathy, cataract, glaucoma, blindnessB. With HLA B 27 + spondylitis• M>F• Onset age- >8 years• Arthritis involve lower limbs• Radiographic sacroiliitis• Iridocyclitis, reiter’s seen

Polyarticular:A. Rh factor -ve• F>>M• Symmetrical polyarthritis of small joints of hand, feet, elbow, ankle, knee• Low grade extraarticular manifestation• Inv of temporomandibular joint & cervical spine common• 10-15% develop severe destructive arthritisB. Rh factor +ve• F>M• Onset: late in childhood• Childhood equivalent of adult RA• Symmetric small joint arthritis with rheumatoid nodules, Felty’s synd,

fibrosing pneumonitis• >50% develop destructive arthritis

Systemic (Still’s disease)• M>=F• Intermittent quotidian fever (>1030 F) with chill &

evanescent rash• During fever- myalgia, arthralgia, transient arthritis,

pleuritis, pericarditis, adenitis, abdominal pain• Hepatosplenomegaly• Multiple symmetric joint involvement• Recur in > 50% cases• No iridocyclitis• Inv: leucocytosis, anaemia

Advancement in treatment of ra (1)

Health & Medicine

Transcript of Advancement in treatment of ra (1)