COPYRIGHT · Many patients have erosions at presentation 2. Decline in functional status 80%...

Lisa Fitzgerald, MD

Division of Rheumatology

Beth Israel Deaconess Medical Center

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Pierre-Auguste Renoir: Luncheon of the Boating Party, 1881

Source: http://www.openculture.com/2012/07/astonishing_film_of_arthritic_impressionist_painter_pierre-auguste_renoir_1915.html

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RheumatoidArthritis

OverviewofLecture

1. Review of pathogenesis, natural history and diagnosis of rheumatoid arthritis

2. Current DMARD therapy and biologics

3. Changing treatment strategies

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1980

Treatment of RA

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Inflammatory Synovium

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EtiologyofRA� Genetic HLA DRB1 “Shared Epitope”

and Susceptibility Genes

� Environmental Smoking

� Hormonal Estrogen/Progesterone

� Immunologic Tcells, Bcells, Cytokines

� Infectious Bacteria: Oral and Intestine

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HowDoesRAdevelopinour

patients?

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ACR Criteria for the Classification

of Rheumatoid Arthritis

�Need at least four of seven criteria for diagnosis:

1. Morning stiffness lasting at least 1 hr

2. Soft- tissue swelling or fluid in at least 3 joint areas simultaneously

3. At least one area swollen in a wrist, MCP, or PIP joint

4. Symmetric arthritis

5. Rheumatoid nodules

6. Abnormal amounts of serum rheumatoid factor

7. Erosions or bony decalcification on radiographs of the hand and

wrist

* Criteria 1 through 4 must have been present for at least 6 weeks.

� Point system out of 10

1 .Confirmed presence of 1 or morejoints with synovitis

2. Absence of alternative diagnosis

3. Number and site of involved joints

4. Serology (RF and CCP)

5. Acute phase reactants

6. Symptom duration

1987 2010

Neogi T, Aletaha D, Sillman AJ et al. Arthritis Rheum 2010; 62:2569-2581, 2582-2591

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III.5III.5Adapted with permission from Choy EH, Panayi GS. N Engl J Med. 2001;344:907–916.Adapted with permission from Choy EH, Panayi GS. N Engl J Med. 2001;344:907–916.

Disease ProgressionDisease Progression

Capillary formationCapillary formation

Hyperplastic

synovial

membrane

Hyperplastic

synovial

membrane

Hypertrophic

synoviocyte

Hypertrophic

synoviocyte

NeutrophilsNeutrophils

T CellsT Cells B CellsB Cells

Early RAEarly RA

Established RAEstablished RA

Synovial villiSynovial villi

Extensive

angiogenesis

Extensive

angiogenesis

Plasma cellPlasma cell

PannusPannusEroded boneEroded bone

NeutrophilsNeutrophils

CapsuleCapsule

BoneBone

Synovial

membrane

Synovial

membrane

SynoviocytesSynoviocytes

Normal JointNormal Joint

CartilageCartilage

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ClinicalSpectrumofRA

Images Courtesy ofJohn Cush, MD

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ASSESSMENT OF DISEASE ACTIVITY IN RA

Physical Exam

Joint swelling and tenderness, loss of motion, deformity

Functional status

Joint pain, morning stiffness, fatigue

Extra-articular Findings

Fever, weight loss, nodules, pulmonary nodules,pleural effusion, ILD, vasculitis

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Hochberg, Marc C. et al Editors. Rheumatology 4th Edition, Vol 1, pg798. Mosby Elsevier, 2008

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ASSESSMENT OF DISEASE ACTIVITY IN RA

Imaging Techniques

Radiographs, Ultrasound, MRI

Laboratory Tests

Acute phase reactants, CBC, RF, Anti CCP(Cyclic Citrullinated Peptide)

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ASSESSMENTOFDISEASEACTIVITYINRA

Assessing Disease

Early, Intermediate or Long-standingMild, Moderate or Severe

DAS Score

Measures tender and swollen joints, global assessment and ESR/CRP.

Used in clinical trials and helpful in daily clinical practice.

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RA Progression RA Progression

Adapted from Kirwan JR. J Rheumatol. 2001;28:881–886.Adapted from Kirwan JR. J Rheumatol. 2001;28:881–886.

Severi

ty (

arb

itra

ry u

nit

s)

Severi

ty (

arb

itra

ry u

nit

s)

00

Duration of Disease (years)Duration of Disease (years)

55 1010 1515 2020 2525 3030

Inflammation

Disability

Radiographs

Inflammation

Disability

Radiographs

I.6I.6

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1. Joint destructionJoint erosions seen within 2 yearsMany patients have erosions at presentation

2. Decline in functional status80% decline in functional status over 5 years

3. Increased work disabilityDisability is >7 fold increased in RA patients comparedto general populationearnings 50% lower for RA patients

4. Comorbid diseaseincreased cardiovascular diseaseincreased risk of infection

5. Increased mortality ratesevere disease associated with mortality rate comparable to 3V CVD or Stage IV Hodgkin’s lymphomaLife expectancy decreased by 5-15 years

Pincus et al, Clin Exp Rheumatol 2004;22(suppl 35):s2-s11.

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Nonpharmacologictreatment� Education and counseling

� Stop Smoking

� Rest

� Exercise, physical and occupational therapy

� Bone protection

� Immunizations

� Modifying cardiovascular risk factors: Cardiovascular risk assessment should be performed yearly; risk modification according to accepted guidelines

Peters MJL, et al Ann Rheum Dis. 2010; 69:325-331.

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Treatment of Rheumatoid Arthritis

• Non pharmacologic treatment

• Medications

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Pharmacologic TherapyCOPYRIGHT

GoalsofRATherapy� Prevent chronic joint damage

� Reduce Disability

� Reduce Extra-articular manifestations

� Future and present work is focused on preventing associated cardiovascular disease

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TRIPLETHERAPY

� If first DMARD (MTX) is not working

� Add another (HCQ and/or SSZ) or two!

� THREE is NOT a crowd in this scenario

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DramaticGameChangingEffectsThe introduction of biologics (in ADDITION TO aggressive use of DMARDS) has caused a dramatic effect:

� We can actually achieve an RA remission and aim for remission as a goal in newly diagnosed patientsCO

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“Window of Opportunity” for Treating RA

“window of

opportunity”

Earl

y

Established End Stage

O’Dell, JR, Treating rheumatoid arthritis early: a window of opportunity?; Arthritis Rheum. 2002 Feb;46(2):283-5

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TheDecisionProcessinTreatment

ofRA“TightControl”� After DX is established, begin DMARD within <3 mos and

assess every 3 months and push for low disease activity:

DAS 28

CDAI

Rapid 3

HAQ scores

CRP/ESR (No need to “follow” RF levels or CCP levels)

� Excellent studies such as the Be St trial and the FIN-RACoand TICORA trials have proved decisively that tight control early on achieves better disease control in the ensuing months to years

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BiologicResponseModifiersCOPYRIGHT

MajorCategoriesofBiologicsforRA

� Anti IL 1

� Anti TNF alpha (TNFi)

� Anti B cell

� Anti T cell

� Anti IL 6

� JAK Inhibitors (SMALL MOLECULES)

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BeforeInitiationofBiologics� ? CHF (NYHA III/IV)

� ? Hepatitis B or C

� ? +PPD or +Quantiferon Gold

� ? Melanoma

� ? Solid Malignancy

� ? Evidence of Demyelinating Disease

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VaccineUseandRecs/Biologics� Inactivated vaccines should be administered to RA pts

on DMARDs and Biologics, preferably before treatment for ultimate efficacy but during the course regardless.

� Pneumovax (+every 5 yrs when on biologics)

� Influenza vaccine yearly

� HPV in susceptible pts

� Hepatitis B vaccine

� Recombinant Shingles Vaccine (Shingrix)

� AVOID LIVE Vaccines

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WhichONEtochoose?� Anakinra is the oldest biologic for RA but only with modest

efficacy and must be given daily � TNFi ARE USUAL FIRST CHOICE� All are excellent and well tolerated� Possible side effects that are usually short lived:� Injection site reactions for the SQ versions, if a problem a switch

to another will work

Infusion reactions (INFLIXIMAB-Remicade): rash, fever,anaphylaxis. Infusion center must have skilled nursing and medical personnel to assess and give steroids, etc

There are fewer infusion reactions in pts on MTX with an IVbiologic and those pre-medicated with antihistamnes

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Biologics:TNFi andantiIL1� IL-1 RA SQ Anakinra (Kineret) daily

� TNFi Etanercept (Enbrel) q wk

Adalimumab (Humira) q 2 wks

Infliximab (Remicade) q 4-8 wks

Certolizumab (Cimzia) q 2 wks

Golimumab (Simponi) q 4 wks

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BIOLOGICSAnti-Tcell

� Abatacept (2006) Prevents T cell activation

� IV or SQ

� Can take up to 4-6 months to reach efficacy

� Overall PROBABLY fewer infections than TNFi

� Monitoring of CBC

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AntiBcellBiologics�Rituximab Anti-CD 20 Mab approved for

NHL since 1994 and RA since 2006

�Very effective and given IV q 2wks for 2 doses and then reassess at 6 mos. If remission achieved, wait on retreating

�Side effects: Serious infections, Hep B reactivation, Zoster

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AntiIL6Biologic� Tocilizumab 2009 (anti IL-6 Ab) IV or SQ (Actemra)

� (Sarilumab) 2017 (anti IL-6 ab) SQ (Kevzara)

� Very effective

� Side effects include Serious Infections, elevated cholesterol

LDL/HDL ratio. In trials 25% required lipid lowering

meds), elevated LFTS, neutropenia

� History of Diverticulitis is a contraindication

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� Tofacitinib (2012)� Baricitinib (2018)� Upadacitinib (2019)�

� All are well tolerated

� Infections (slight increase in zoster) � Hx diverticulitis is a relative contraindication

� Elevated cholesterol, elevated LFTs� No long term data yet on lymphoma or other malignancy

rates

AND:JAKInhibitors(Small

Molecules-oral)

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SwitchingBetweenNon-Biologic

andBiologicDMARDs

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Anti-TNFmedmonitoring(1)� Cytopenias (esp neutropenia) CBC w/diff q 1-3 mos

� INFECTION:

� Serious:

� Bacterial Pneumonia

� Herpes Zoster

� TB and Atypical mycobacteria

� Opportunistic Infections (OI) ie: fungal, viral, parasitic

� Cellulitis

� Less Serious:

� URI uncomplicated, ie. sinusitis

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Anti-TNFmonitoring(2)� Watch for neurological manifestations of demyelinating disease

(rare: 19 cases in the early years associated with ETANERCEPT AND INFLIXIMAB)

� The other TNFs were not available at that time

� RECS: Screen patients closely and do not treat pts with RA/SLE overlap with anti TNFs as SLE can have an MS-like feature

� Rare peripheral neuropathy

� Possible exacerbation of Psoriasis (also lichen planus and LCV)

� Rare autoimmune reactions: Myositis and SLE with antiDNAAbs

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SafetyConsiderationswith

Anti-TNFTreatment

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Infection� Up to 1/3 in clinical trials report minor infection,

same rate as placebo.� RA patients are more susceptible to serious

infections; most individual trials did not show significant difference in compared to methotrexate.

� Possibly, patients with comorbid disease are more susceptible to infection while on anti TNF therapy.

� Post marketing studies/observational studies suggest increased risk of serious infection compared to DMARDs, occurs early in treatment; may be higher risk of upper respiratory infections, soft tissue and skin infections

� Patients on anti TNF medications should not receive live vaccines.

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OpportunisticInfection� Cases of bacterial, fungal, parasitic, viral all reported

� Mycobacterial infection most widely described in association with therapy

� TB: reactivation of TB, occurs early in therapy, and is commonly disseminated

� PPD testing (or T spot or Quantiferon Gold) is mandatory

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CardiovascularDisease

� RA patients have increased risk; higher risk in patients with more severe disease.

� Anti TNF agents have been associated with worsening CHF (patients without RA)

� ? Anti TNF protection against cardiac disease

� Recent prospective study of >12,000 patients with RA found no evidence of association between anti-TNF treatment and mortality in patients with rheumatoid arthritisNicola, PJ et al. Arthritis Rheum 2005;52:412-420

Jacobsson J , et al J Rheum 2005; 32: 1213-18Peters MJL, et al Ann Rheum Dis. 2010;69:325-331Lunt M, Watson KD, Dixon WG, Symmons DP, Hyrich KL. Arthritis Rheum. Nov 2010;62(11):3145-53.

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Demyelination SLE-likeIllness

� Optic neuritis, MS, transverse myelitis

� Improvement with discontinuation

� Very few cases reported overall; relationship not known

� Avoid use in patients with history of demyelinating disease

� ANA found in RA patients (20-40%)

� Does not indicate disease

� Rare cases of SLE; usually arthritis, rash, serositis, anti DNA antibodies

� Resolves with discontinuation of therapy

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Malignancy

� No increased rate of solid tumor to date (when compared to NCI database rates).

� Lymphoma: increased rate in RA patients, risk increases with severity of disease

� Lymphoma rates observed in patients treated with TNF antagonists are higher than in the general population, but appear to approximate those seen in RA patients in general

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SpecialRAPopulations� PREGNANT RA Patients: Arthritis usually remits

� But… if active

� well-timed NSAIDs

� Hydroxychloroquine

� low-dose Prednisone

� ARE SAFE

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SpecialRAPopulations� PERI-OPERATIVE RA

� Order pre-op flexion/extension x-rays of C-Spine to look for C1-C2 subluxation

� MTX typically needs no adjustment pre-op

� Prompt post-op resumption unless overt infection

� LEFLUNOMIDE

� hold 2 days prior to surgery because of long half-life

� BIOLOGICS

� hold 1-2 wks prior for SQ meds and 2-4 wks for IV meds

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Order pre-op f lexion/extension x-rays of C-Spine to look for C1-C2 subluxationCO

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Conclusion� Early and aggressive treatment of RA slows progression.� Treatment goals in 2019: decrease risk of joint damage

as well as symptomatic relief.� Prevent extra-articular disease.� Prevent and treat bone loss.� Future research: Better identification of patients at

high risk of developing erosive disease (biomarkers, MRI/ultrasound, genetic markers) in order to individualize therapy. Discover why meds lose effectiveness

� How to manage treatment resistant patients.� How to manage cardiovascular disease associated with

RA

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BeforeInitiation/SCREENING

Does my patient have CHF?

� If NYHA III/IV, then TNFi are contraindicated but not other biologics or JAK inhibitors

� Does my pt have a hx of Hep B or C?

� Check for Hep B Sab, Sag, and Core Ab and Hep C Ab

� For Hep B, consult with Liver specialist and treat with concomitant antivirals if needed. For Hep Bsag+ patient-DEFINITE CONTRAINDICATION to Biologics

� For Hep C, avoid TNFi that are antibodies and consider Etanercept (Enbrel) a fusion protein

� Does my pt have a history of a solid malignancy or melanoma within the past 5 (five) years?

� Then wait…… at least until the five year mark

� Rituximab (but not TNFs ------may be possible to give in a pt who has had melanoma in the past and pts with a hx of a lymphoproliferative disorder or pts with a solid malignancy within the past five yrs with very active disease.

� Caveat is that evidence for this approach is not extensive.

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206 patients dx with RA; cohort study

1993-1996: Treatment with analgesics then DMARD (median timeto treat 123 days)

1996-1998: Treatment with DMARD (median time to treat 15 days)CONCLUSION:

DECREASED RADIOLOGIC DAMAGE in EARLY TREATMENT GROUP

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Data from 14 randomized controlled trials of DMARD therapy1400 patients analyzedPatients receiving treatment within 1 year of disease responded best to treatment.Patient with long term disease receiving treatment has less response.

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Randomized controlled trial of 155 patients with early active RA (pre anti TNF era)2 treatment arms2 year trial with extension to 5 yearsAssess clinical and radiographic outcome11 year data: suggestion that there is improved mortality rate in patients on combination therapy

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INDICATIONSFOR INITIATINGANDSWITCHING

NON-BIOLOGICANDBIOLOGICDMARDsDISEASE ACTIVITY RECOMMENDATIONS

Early RA (< 6 mo) • Administer DMARD combination therapy (eg, double or triple therapy) in those with moderate or high disease activity and poor prognostic features (functional limitation, extra-articular disease, positive RF or anti-CCP antibodies, bony erosions on x-ray)

• Use an anti-TNF agent ± MTX in those with high disease activity and poor prognostic features— except for infliximab, which is used in combination with MTX only (ie, do not use infliximab as monotherapy)

Established RA (=6 moor meets 1987 ACR RA classification criteria)• If prognosis is not

mentioned, use or switch to a nonbiologic or biologic DMARD regardless of prognostic features

Initiating and switching among nonbiologic DMARDs• In patients without prognostic features who deteriorate after

3 mo of DMARD monotherapy from low to moderate/high disease activity, add MTX, hydroxycholoroquine, or leflunomide

• In patients with persistent moderate/high disease activity after 3 mo of MTX or MTX-DMARD combination therapy, either add or switch to another non-MTX DMARD

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ResponsetoAnti-TNF:Early RA

ACR 70:

-methotrexate monotherapy 19-28%

-TNF inhibitors with methotrexate 33-48%

-Significant reduction in progression of erosions radiographically

-Significant improvement of functional scores compared to MTX monotherapy

COMET, ERA,ASPIRE, Premier trials

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ResponsetoAnti-TNF:Established RA

ACR 70:

� Methotrexate monotherapy <5%

� TNF inhibitors with methotrexate 10-27%

� Decrease in radiographic erosive changes

� Functional scores improved compared to MTX monotherapy (not as robust as in early RA)

Tempo, Attract, Armada trials

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AdministrationReactions

� Most common side effect, 20-37%.

� Rarely lead to discontinuation of drug.

� Decrease with time.

� Reactions include erythema, pruritis, swelling, recall reactions.

� Infliximab associated with infusion reaction: premedicate with steroids, antihistamines or tylenol.

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TICORA: Intensive vs Routine Control of Disease Activity in RA

Objective:• 18-month study to determine whether closely monitored

step-up therapy with nonbiologic DMARDs would result in significantly better outcomes than routine care

Study Population:• 110 patients aged 18–75 years with RA of < 5 years’ duration and active

disease (DAS > 2.4)

Outcomes:% of patients achieving a DAS score of < 2.4

% of patients achieving remission (DAS score < 1.6)

Intensive Care Group:

• Monthly review of disease activity and measurement of DAS

• Structured escalation of therapy if DAS > 2.4 after 3 months of a new DMARD.

Routine Care Group:

• Review every 3 months (with no measure of disease activity)

• Management at the discretion of attending rheumatologist (ie, DMARD therapy; intra-articular, intramuscular, and/or oral corticosteroids)

TICORA = Tight Control for Rheumatoid Arthritis.

Grigor C, et al. Lancet. 2004;364:263–269.

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TICORA: Disease Activity ScoresIntensive vs Routine Therapy

TICORA = Tight Control for Rheumatoid Arthritis.

Grigor C, et al. Lancet. 2004;364:263–269.

6

5

4

3

2

1

0

0 3 6 9 12 15 18

Me

an

DA

S S

co

re

Month

Intensive Therapy

Routine Therapy

P < 0.0001 for intensive therapy vs

routine therapy after month 3

Primary end point

Remission

Intensive Routine

Therapy Therapy P Value

DAS < 2.4 82% 44% < 0.0001

DAS < 1.6 65% 16% < 0.0001

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BeSt Trial:TreatmentStrategies

forEarlyRA

� Randomized clinical trial of 508 patients comparing four treatment strategies with evaluation and treatment changes according to strict guidelines.

� Goal: to attain DAS score<2.4 (low disease activity); assessed every 3 months

� Treatments:� Group 1 single DMARD; sequential monotherapy

� Group 2 step up to combination therapy

� Group 3 initial MTX, sulfasalazine, prednisone

� Group 4 initial MTX/ infliximab

Goekoop- Ruiterman YP et al Ann intern Med 2007; 146: 406-415American College f Rheumatology metting Atlanta 2010 abstract #334.

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BeSt Trial:Results� At 1 year:� Patients on initial combination therapy had better

response in faster time.� At 2 years:� The same proportion of patients in all groups attained

low level of disease activity� At 3 years:� Patients who responded had less progression of xray

changes compared to non responders� Rate of radiologic progression was slower in

combination groups. 51% in group with infliximab discontinued treatment and maintained remission for average 2.5 years.

� At 7 years:� 16-17% of patients in all groups achieved remission� Radiological damage progression rates were similar in

all groups. (no difference in total damage after 7 years)� Patients treated initially with infliximab maintained

improved function compared to other groups and a greater percentage remained on initial therapy.

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ACRTreatmentAlgorithm

Adapted from: American College of Rheumatology

Subcommittee on

Rheumatoid Arthritis Guidelines. Arthritis Rheum.

2002;46:328–346.

Change/Add DMARDs

MTX naive Suboptimal MTX response

MTX Other

mono

Combination Combination Other

mono

Biologics

MonoCombination

Adequate response

Inadequate response

R

h

e

u

m

a

t

o

l

o

g

i

s

t

Establish diagnosis of RA early

Initiate therapy (3 months)

Periodically assess disease activity

P

C

P

Multiple DMARD failure

Symptomatic and/or structural joint damage

surgery

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MalignancyRiskwithBiologics� Lymphoma

� Solid Malignancy

� Melanoma

� Non Melanoma SKIN Cancers (NMSC) Basal/Squamous

This is the only category for which there is solid

evidence for association with BIOLOGIC USE

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Conclusion

� Early and aggressive treatment of RA slows progression.

� Treatment goals in 2019: decrease risk of joint damage as well as symptomatic relief.

� Future research: Better identification of patients at high risk of developing erosive disease (biomarkers, MRI/ultrasound, genetic markers) in order to individualize therapy.

� How to manage treatment resistant patients.

� How to manage cardiovascular disease associated with RA

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ChecklistforPCP/RheumatoidArthritis

� Pain, Stiffness and swelling for ≥ 6 wks

� ESR or CRP

� CCP

� RF

� History of Hepatitis B or C/Serologies

� PPD (T spot or Quantiferon Gold)

� Hx CHF?

� Hx Melanoma or solid malignancy

� Vaccines (Influenza, Pneumovax, HPV, Shingrix)

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Questions

� 58 M with RA on 20mg MTX and 1.5 gm sulfasalazine has persistent swelling and tenderness at all MCPs, bilateral wrist and bilateral knees. ESR is 50.

� What would be the next intervention?

a) Begin Azathioprine

b) Begin a TNF-inhibitor

c) Begin Prednisone 60mg QD

d) Begin Rituximab

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� All of the following screening tests should be done prior to DMARD or Biologic therapy except:

a) Hepatitis B and C testing

b) PPD and/or Quantiferon Gold testing

c) a and b

d) Physical Therapy Screening Evaluation

Questions

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RAVignettesLM:52Fseronegative polyarticular erosiveRAsinceage

19

MTXbeguninthe90sandEnbrelsince2000withvgcontrol

ofRA

2004Rfacialparesthesias andReyevisualblurring

Thoughts?

Whattodo?

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RAcases• BrainMRI:MultipleT2highsignalintensityfoci.

Nonspecificbutc/wdemyelinatingdisease.

• Actionstotake?

• RAworsened2007-2008onPred 2.5mg,MTX15mgand

mobic

• BrainMRINonewlesions-stable

• Whattodo?

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PtJW� 30 F dx with polyarticular JRA age 13

� Hands, ankles, L knee. Eventual Synovectomy required L knee.

� Treated with NSAIDs and MTX

� MTX seemed to cause ?memory loss and extreme fatigue

� What to do?

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JW� Brand New med begun: Enbrel (1998) age 14

� She did well for 13 years!!!

� Pregnant at age 26 (2009)

� How to proceed?

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JW� Enbrel stopped

� Major flare during entire pregnancy requiring Predtitrated up to 20 mg QD

� Delivered healthy baby boy 2010

� RA persisted, unable to dec Pred

� Enbrel restarted without help.

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JW� Remicade begun 2010 with inc dosing and SSZ started

� Developed UGI sx on SSZ so had to be stopped (? Try BRAND but could not get coverage)

� So…..No DMARD! Bad situation

� How to control RA and continue to lower Pred?COPYRIGHT

JW� Leflunomide began 2012

� Initially tolerated and then LFTs rose 2x nl and developed Hair loss. Med stopped in June 2012

� Ideas?

� JW would like to have another child….how to advise?COPYRIGHT

JW� Drug level (teriflunomide) <10 x2 14 days apart so go

ahead given

� Pregnant March 2013. Delivers Dec 2013.

� Ongoing steroid use.

� Delivers healthy baby girl in Nov 2013

� Remicade no longer working at full dose

� Through he winter of 2014

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JB� 58 F with RA since her 20s, polyarticular severe with

multiple joint replacements and revisions. However still works part time

� Treatment with Gold, NSAIDs and MTX

� Idea of biologics raised in 2000 (age 46) but she said she

� “wanted to avoid these at this time in case she got worse and needed them later!”

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JB� PMH: 2002 + PPD (she grew up in Indonesia, Japan)

� JB now willing to try biologics. Cont on MTX

� How to proceed?

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JB� INH for 9 mos

� Humira is on board from Month #2 and well tolerated

� 2006: report of paresthesias in arms and legs and husband reports she is walking as if she’s been drinkingCO

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ClinicalPearl� From an “old school” neurologist with excellent

clinical skills

� “If the patient walks like a drunk but hasn’t had a drink, focus on their ______”CO

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UsingTechnology

forRAQuality

¨ Engage patients in RA disease management¨ Utilize waiting room time more effectively¨ Systematically collect data from all RA patients on

functional status and disease activity at most clinic visits¨ Link this patient-derived data with the electronic medical

record¨ Use data on RA quality indicators for documentation and

reporting on quality of care

Help develop a guideline of reasonable non-biologic and biologic DMARD use for RA

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Drug

Response

Rate;

Onset

of

Action

Magnitude

of

Efficac

y (0 to

++++) Major Toxicities Dosage

Cyclosporine 30%; 2-3 mo ++

Renal (irreversible), hypertension,

hypertrichosis, immunosuppression 2.5-5.0 mg/kg/day

Gold 30%; 3-6 mo ++ Skin rash, hematologic, renal5.0 mg/wk I.M. x 6

mo

Hydroxychloroquine 30%-50%; 2-6 mo ++Retinopathy, myopathy,

hyperpigmentation 200 mg b.i.d.

Leflunomide 50%; 2-3 mo ++Liver, teratogen, gastrointestinal,

skin rash 20 mg/day

Methotrexate > 70%; 6-8 wk +++

Liver (fibrosis, elevated

enzymes), hematologic, oral ulcers 7.5-20 mg/wk

Sulfasalazine > 30%; 2-3 mo ++

Dyspepsia, hemolysis in glucose-

6-phosphate dehydrogenase deficiency 1 g b.i.d. or t.i.d.

DMARDs

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2012ACRRecommendationsforFurtherEvaluationAfterInitial/RepeatTBScreeningResultsResult of Initial/Repeat TST or IGRA

Recommendation

Positive • Obtain chest x-ray • If the chest x-ray is suspicious for active TB, obtain sputum examination for

active disease

Negative In patients with RA but without risk factors or clinical suspicion for TB• No further workup is needed In patients with RA and immunosuppression plus LTBI risk factors • Repeat the TST or IGRA 1-3 wk after an initial negative test result

Active/latent TB • Treat with appropriate anti TB therapy• Refer to a specialist as necessary• Initiate or resume biologic agents after either 1 month of treatment of LTBI

with anti TB regimen or completion of treatment for active TB• Screen annually in individuals with RA who (1) are continuing on biologic

agents while living, traveling, or working in situations of likely TB exposure and (2) have a positive baseline for TST or IGRA; TST or IGRA may still be positive after successful TB therapy; monitor for clinical signs or symptoms of recurrent TB

Medscape RA Treatment &ManagementAuthor: Katherine K. Temprano, MD, et alChief Editor: Herbert S. Diamond, MD Copyright © 1994-2014 by WebMD LLC.This website also contains material copyrighted by 3rd parties.

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Switching among biologic agents because of adverse effects� In patients with high disease activity after failure of anti-TNF

biologic therapy because of a serious adverse event, switch to a non-TNF biologic agent

� In patients with moderate or high disease activity after failure of anti-TNF biologic therapy because of a non-serious adverse event, switch to another anti-TNF biologic agent or a non-TNF biologic agent

� In patients with moderate or high disease activity after failure of non-TNF biologic therapy because of either a serious or a nonserious adverse event, switch to another non-TNF biologic agent or Tofacitinib (JAK inihibitor) or another anti-TNF biologic agent

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Switching among biologic agents because of lack of or loss of benefit

� In patients with persistent moderate/high disease activity after 3 mo of anti-TNF biologic therapy because of lack of or loss of treatment benefit, switch to another anti-TNF biologic agent or a non-TNF biologic agent

� In patients with persistent moderate/high disease activity after 6 mo of non-TNF biologic therapy because of lack of or loss of treatment benefit, switch to another non-TNF biologic agent or an anti-TNF biologic agent

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Switching from nonbiologic to biologic DMARDs

� Alternatively, in patients with persistent moderate/high disease activity after 3 mo of MTX monotherapy or MTX-DMARD combination therapy, add or switch to an anti-TNF biologic agent, abatacept, an anti IL-6 agent, JAKi or Rituximab

� In patients with persistent moderate/high disease activity after 3 mo of intensified DMARD combination therapy or after a second DMARD, add or switch to an anti-TNF biologic agent

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