arthur l. weaver md, ms, facp, macr clinical professor of...

Arthur L. Weaver MD, MS, FACP, MACR

Clinical Professor of Medicine Emeritus

Department of Medicine

Section of Rheumatology

University of Nebraska Medical Center

Omaha, Nebraska

A systemic disease in which immune system mistakenly attacks body tissues, causing chronic inflammation of the joints, tissue, and other organs1-3

Ongoing features include:1-3 Chronic destructive synovitis

Chronic joint destruction

Functional disability in untreated patients

Etiology of RA is unknown, although RA may be linked to genetic factors and environmental influences4

1. Helmick CG, et al. Arthritis Rheum. 2008;58:15-25. 2. Kavanaugh A. Rheum Dis Clin North Am. 2006;32:45-56. 3. Verstappen SMM, et al. Ann Rheum Dis. 2007;66:1443-1449. 4. Kountz DS, et al. J Fam Pract. 2007;56(10 suppl A):59a-73a.

Affects 1.3 million adults in the United States1

Left untreated, 20% to 30% of RA patients become permanently unable to work within 3 years of diagnosis2

Life expectancy may be substantially reduced2

Early diagnosis and appropriate therapy can stave off joint damage and reduce comorbidities2

1. Helmick CG, et al. Arthritis Rheum. 2008;58:15-25.

2. Harris ED, et al, eds. Kelley’s Textbook of Rheumatology. 7th ed. Philadelphia, PA: Elsevier/Saunders; 2005.

3. Combe B, et al. Ann Rheum Dis. 2007;66:34-45.

Patients presenting with arthritis of more than 1 joint should be referred

to and seen by a rheumatologist, ideally within 6 weeks after the onset

of symptoms3 - European League Against Rheumatism (EULAR)

recommendations for the management of early arthritis

The prevalence of rheumatoid arthritis in the general population of the United States is estimated to be 0.6%1

The incidence of rheumatoid arthritis in the general population of the United States is 0.041 of every 100 inhabitants2

The prevalence among women is approximately twice that of men2

Average age of persons with RA may be increasing1

1Helmick CG, et al. Arthritis Rheum. 2008;58:15-25. 2http://www.cdc.gov/arthritis/basics/rheumatoid.htm#5. Accessed 1/23/2012

Etiology of RA not understood: Genetic and environmental are involved1

Genetic factors

Hereditability of RA from studies in twins is 53-65%2

Concordance rate in fraternal twins is 2-5%, the same as in 1st degree relatives1

Higher prevalence in Pima Indians also indicates genetic factor3

40% of the genetic influence (susceptibility and severity) is due to class II major histocompatibility complex (MHC) antigens1

70% of RA patients have HLA-DR versus 30% of controls1

1Kelley’s Textbook of Rheumatology, Elsevier Saunders, Harris Jr. ED et al. (ed), 7th edition: p. 996-998. 2MacGregor AJ, et al. Arthr Rheum. 2000;43:30-37. 3Jacobsson LTH, et al. Arthr Rheum. 1994;37:1158-1165.

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Genetics: 53-65% heritability in twins1

Rheumatoid factor positive1,2

Anti-cyclic citrullinated peptide1,2

Age of onset: Peaks in the 5th decade of life3

Higher in urban than rural populations1

Higher incidence in women than men1,2

Breastfeeding increases onset 5X after 1st pregnancy and 2X after second pregnancy, but no increased risk thereafter1

Cigarette smoking: heavy smoking 13X increased risk1

Prenatal exposure to cigarette smoke1

Low fruit and vitamin C intake1 1Oliver JE and Silman AJ. Scan J Rheumatol. 2006;35:169-174. 2Kelley’s Textbook of Rheumatology, Elsevier Saunders, Harris Jr. ED et al. (ed), 7th edition: p. 1043-1045. 3Alamanos Y, Drosos AA. Autoimmun Rev. 2005;4:130-136.

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Polyarticular disease

Systemic extra-articular disease (nodules, neuropathy,

vasculitis, eye disease, cryoglobulinemia)

RF positive high titer

Anti-CCP antibody positive high titer

Persistent disease activity (high ESR, CRP, disease activity

scores)

HLA-DRB1 ―shared epitope‖ positive

(strongest known genetic risk factor for RA)

Early erosive disease on radiographs

Poor functional status

Advanced age at onset

Comorbid cardiovascular disease

Lindqvist E, Eberhardt K, Bendtzen K, Heinegard D, Saxne T. Ann Rheum Dis. 2005;64:196-201; Erhardt CC, Mumford PA,

Venables PJ, Maini RN. Ann Rheum Dis. 1989;48:7-13; Wolfe F, Michaud K, Gefeller O, Choi HK. Arthritis Rheum.

2003;48:1530-1542.

Most deaths in RA are caused by comorbidities1

Deaths could be attributed to disease process, or effects of pharmacotherapies1

58% of patients with RA have ≥ 1 comorbidity, and 25% have ≥ 2 comorbidities2

1. Blom M. Best Pract Res Clin Rheumatol. 2007;21:43-57. 2. Hyrich K, et al. Ann Rheum Dis. 2006;65:895-898.

Comorbidity

Mortalit

y Rate

(%)1

Cardiovascular disease

(CVD)

17-42

Infections 9-24

Renal disease 8-10

Pulmonary disease 7-10

Gastrointestinal disease 4-10

Chronic, debilitating, autoimmune nature

of RA affects almost all organ systems1

Patients with RA are1-3:

Twice as likely to have a myocardial infarction

More likely to develop non-Hodgkin lymphoma

More likely to develop osteoporosis

70% more likely to have a stroke

70% more likely to develop an infection (TBc and H Zoster)

More likely to have their life spans reduced

1. Maradit-Kremers H, et al. Arthritis Rheum. 2005;52:402-411.

2. Turesson C, et al. Curr Opin Rheumatol. 2007;19:190-196.

3. Gonzalez A, et al. Ann Rheum Dis. 2008;67:64-69.

People with RA are two times more likely to die than people of the same age in the general population1

The mortality gap is widening between rheumatoid arthritis RF+ patients and the general population

Due mostly to cardiovascular and respiratory deaths2

Primary Cause of Mortality

Cardiovascular Disease3

Infection3

Malignancy3,4

Pulmonary Disease3,5

1www.cdc.gov/arthritis/arthritis/rheumatoid.htm. Accessed 3/6/2009. 2Gonzalez A, et al. J Rheumatol. 2008;35:1009-1014. 3Naz SM, Symmons DPM. Bes Prac.Res Clin. Rheumatol. 2007;21:871-883. 4Smitten AL, et al. Arthr Res Ther. 2008;10:R45-R52. 5Kelley’s Textbook of Rheumatology, Elsevier Saunders, Harris Jr. ED et al. (ed), 7th edition: p. 1059-1060.

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Refer to a rheumatologist if the patient shows these symptoms:

• ≥ 3 swollen joints

• Positive “squeeze” test

• Morning stiffness ≥ 30 minutes

Squeeze test indicates pain across second to fifth

metacarpals (MCP), metatarsals (MTP)

What should you ask the patient? • What hurts when you get out

of bed?

• How long does it take to feel

as limber as you are going to

feel for the day?

• When is your pain the worst

(morning or night)?

• Do you smoke?

• Do any members of your

family have RA?

• Can you perform daily

activities (turn faucet handles,

hold toothbrush, dress/bathe

independently)? • What are the things you

cannot do because of your

symptoms?

Kountz DS, et al. J Fam Pract. 2007;56(10 suppl A):59a-73a.

Swollen/Tender Joints (0-5) 1 Large joint 0 2-10 Large joints 1 1-3 Small joints 2 4-10 Small joints 3 >10 Joints (≥1 small joint) 5 Serology (0-3) Negative RF AND ACPA 0 Low-positive RF OR ACPA 2 High-positive RF OR ACPA 3 Symptom Duration (0-1) <6 Weeks 0 ≥6 Weeks 1

Acute Phase Reactants (0-1)

Normal CRP AND normal ESR 0 Abnormal CRP OR abnormal ESR 1

Patients with a score of ≥6

have ―definite‖ RA Aletaha D, et al. Arthritis Rheum. 2010;62(9):2569-2581.

2010 RA Classification Criteria

≥1 joint with synovitis

(excluding the DIP, first MTP

and first CMC joints)

Absence of alternative

diagnosis that better

explains synovitis

Achievement of total score

of ≥6 (of 10) from individual

scores in 4 domains

Joint involvement patterns

Serologic abnormality

Elevated acute-phase

response

Symptom duration

Order laboratory tests

Complete blood count

Rheumatoid factor

Anticyclic citrullinated peptide

antibody

C-reactive protein (CRP)

Erythrocyte sedimentation

rate (ESR)

Order imaging studies

X-rays

1. Kountz D, et al. J Fam Pract. 2007;56(10 suppl A):59a-73a.

Joints involved

in ≥ 80% of

RA cases

Joints involved

in 50%-80% of

RA cases

Tender, warm, swollen joints

Symmetrical pattern of affected joints

Joint inflammation often affecting the wrist and finger joints closest to the hand

Joint inflammation sometimes affecting other joints, including the neck, shoulders, elbows, hips, knees, ankles, and feet

Fatigue, occasional fevers, a general sense of not feeling well

Pain and stiffness lasting for more than 30 minutes in the morning or after a long rest

Symptoms that last for many years

Variability of symptoms among people with the disease

http://www.niams.nih.gov/Health_Info/Rheumatic_Disease/default.asp. Accessed 3/6/2009

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Hochberg et al. Rheumatology. 3rd ed. 2003;68:743-746.

Courtesy of J. Cush, 2002.

® ACR

Risk of infections in RA patients is increased compared with control

populations (up to 6- to 9-fold) and with increased disease activity

Underlying immune dysfunction

Corticosteroids

Immunomodulatory drugs

Associated comorbidities

Assessing a patient with RA with suspected infection

Prompt and thorough evaluation of symptoms

Prompt initiation of appropriate antibiotics (especially for patients

on biological therapeutics)

Consider usual bacterial culprits (peridontitis)

Consider opportunistic organisms (especially with biologicals)

Mycobacterial (atypical or disseminated presentation)

Fungal (eg, Histoplasma, Coccidioides, Cryptococcus,

Aspergillus, Candida)

Viral (eg, zoster)

Strangfeld A, et al. 2006;20:1181-1195; Kroesen S, et al. Rheumatology (Oxford). 2003;42:617-621; Weaver A et al. J

Rheum, 40(8), 1275-1281, 2013. Chen H et al. J Clin Rheum 11/25/2013.

No evidence that vaccinations exacerbate or precipitate

rheumatic disease---need to update before biologic therapy

Influenza and pneumococcal vaccinations are recommended

Postimmunization titers may be lower with biologics

Hepatitis B immunization if appropriate

Live virus vaccines should be avoided in patients on

immunomodulatory therapy:

Intranasal influenza (FluMist®), zoster (Zostrix®),

mumps/measles/rubella (MMR), yellow fever, typhoid

Other immunizations are safe:

Influenza (injection), tetanus, pneumococcus,

meningococcus, hepatitis A, hepatitis B, H influenza B (HiB),

human papillomavirus (HPV; Gardasil®)

Ravikumar R, et al. Curr Rheumatol Rep. 2007;9:407-415. CDC. MMWR. 2004;53:Q1-Q4; Avery RK. Rheum Dis Clin North Am. 1999;25:567-584; Chalmers A, Scheifele D, Patterson C, et al. J Rheumatol. 1994;21:1203-1206.

2-3x lymphoproliferative disease, in particular, diffuse large B-

cell lymphoma. Increases with increased disease activity

EBV-associated lymphomas increased in patients on

methotrexate

Chronic inflammation may be responsible for increased rate of

lymphoma

Lung cancer more common in RA, but may be due to cigarette

smoking, a common risk factor

Anti-TNF medications may be associated with increased risk of

lymphoma, skin cancer, and possibly other solid tumors

RA patients at higher risk than general population RR = 1.05

Hernandez-Garcia C, Vargas E, Abasolo L, et al. J Rheumatol. 2000;27:2323-2328; Callahan LF. Curr Opin Rheumatol.

2003;15:110-115; Coulton CJ, Zborowsky E, Lipton J, Kushner I, Moskowitz RW. Arthritis Care Res. 1989;2:54-59; Emery P.

Pharmacoeconomics. 2004;22(suppl 2):55-69; Smitten A et al. Arthr Res Ther, 2008:10:R45

Comparison of the incidence rates

of overall malignancy and site-

specific malignancies in RA (N=

38,622) and non-RA (N = 231,282)

cohorts

RA patients are at an increased risk

of both lung cancer and lymphoma

Association of NSAID and traditional

DMARD therapy on overall

malignancy rates:

DMARD, adjusted OR = 0.94

NSAIDs / COX-2s, adjusted OR =

0.79

Biologics excluded from

analyses

Hochberg MC, et al. Presented at the 2006 European League Against Rheumatism annual meeting. Amsterdam, Netherland. Abstract OP0199.

Retrospective analysis of data from the

United Kingdom General Practice Research

Database (GPRD) collected between 1987

and 2001

1.1

1.28

1.96

0

0.5

1

1.5

2

Any Malignancy Lung Cancer Lymphoma

Od

ds

Ra

tio

Risk of Cancer in RA Patients

RA patients have an increased incidence of cardiovascular

disease1

Both traditional cardiovascular risk factors and manifestations of

RA contribute to cardiovascular disease in RA patients2

High grade systemic inflammation in RA may accelerate

atherogenesis3

RA is associated with an unfavorable atherogenic index, with low

HDL. This starts in a pre-RA disease phase4

Venous thromboembolism incidence rate (IR) in RA was 2.4x higher than in

non-RA patients 5

Incidence rates for DVT (RR 2.2) & PE (RR 2.7) higher in RA than in non-RA

patients 5

1Dhawan SS, Quyyumi AA. Curr Atherosclerosis Rep. 2008;10:128-133. 2del Rincon I, et al. Arthr Rheum. 2005;52:3413-3423. 3Sattar N, et al. Circulation 2003;108:2957-2963. 4van Halm, et al. Ann Rheum Dis 2007;66:184-188. 5 Kim S et al. EULAR, Berlin, 2012

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Cardiovascular (CV) risk was approximately 2X

higher in RA with no risk factors compared to non-

RA patients at all age groups from 40-80 years of

age

CV risk increases with age in RA patients

Smoking, hypertension, dyslipidemia, diabetes

mellitus, and low body mass index greatly

increased CV risk in RA patients in all age groups

The CV risk in RA patients was similar to that to

non-RA patients who were 5-10 years older

Kremers HM, et al. Arthr Rheum. 2008;58:2268-2274.

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Strategies to prevent CVD and mortality must focus on

controlling both traditional CV factors and unique issues

related to RA1

Combination of anti-TNF*-α therapies and methotrexate is

associated with a reduction in the risk of acute myocardial

infarction2-5,8

In long-term outcome study of 19,580 patients with RA, anti-

TNF use associated with reduced risk of mortality (hazard

ratio 0.69), as was methotrexate (hazard ratio 0.84)2

Atherosclerosis in RA may be mediated through conventional

CV risk factors, disease activity, corticosteroid use, and

unfavorable body composition6,7

1. Gonzalez A, et al. Ann Rheum Dis. 2008;67:64-69. 2. Michaud K, Wolfe F. 2005 ACR/ARHP Annual Scientific Meeting; November 12-17; San Diego, CA.

Poster 296. 3. Dixon WG, et al. Arthritis Rheum. 2006;54:2368-2376. 4. Nurmohamed MT, et al. Drugs. 2002;62:1599-1609. 5. Singh G, et al. EULAR 2007 meeting. http://www.eular.org/. Abstract OP0106. 6. Warrington KJ, et al. Arthritis Res Ther. 2005;7:R984-R991. 7. del Rincón I, et al. Arthritis Rheum. 2001;44:2737-2745. 8. Solomon D et al. Ann Rheum Dis, 10/30/2013. * TNF = tumor necrosis factor

Pneumonia1

Chronic obstructive pulmonary disease1

Pulmonary fibrosis1,2

Pleuritis2

Nodular lung disease2

Pulmonary hypertension2

1Naz SM, Symmons DPM. Bes Prac.Res Clin. Rheumatol. 2007;21:871-883. 2Kelley’s Textbook of Rheumatology, Elsevier Saunders, Harris Jr. ED et al. (ed), 7th edition: p. 1059-1060.

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100 patients with early RA studied over 2-year span

Despite treatment, smokers still had higher disease activity and more radiographic joint damage (independent of age, sex,

education level, alcohol, or duration of follow-up)

Manfredsdottir VF, et al. Rheumatology. 2006;45:734-740.

Current smokers Former smokers Never smokers

P = 0.03*

SJC

sc

ore

(m

ean

)

0

5

10

15

20

25

30

Entry 6 months 24 months

P = 0.02* P = 0.08*

P = 0.02

TJC

sco

re (

mean

) 0

5

10

15

20

25

30

Entry 6 months 24 months

P = 0.04*

P = 1.0*

6 months 24 months

SDAI = Simplified Disease Activity Index; CDAI = Clinical Disease Activity Index; GAS = Global Arthritis Score, ERAM = Easy Rheumatoid Arthritis Measure; RADAI = Rheumatoid Arthritis Disease Activity Index; RADARA = Real-Time Assessment of Disease Activity in Rheumatoid Arthritis; RAPID = Routine Assessment of Patient Index Data. Cush JJ. Presented at: 2005 ACR Annual Scientific Meeting. November 12-17, 2005. San Diego, CA. Abstract 1854; Sesin CA, et al. Semin Arthritis Rheum. 2005;35:185-196; Makinen H, et al. Clin Exp Rheumatol. 2006;24(S43):22-28;Yazici Y. Bull NYU Hosp Jt Dis. 2007;65(suppl 1):25-28; Call S, et al. Presented at : 2007 ACR Annual Scientific Meeting. Boston, MA. Abstract 425. Fransen J, et al; Rheumatol. 2000;39:321-327.

+

ACR20 DAS28 SDAI CDAI GAS ERAM RADAI RADARA RAPID

Outcome Measures in RA

Patient

function

Patient pain

Patient global

MD global

# Tender joints

# Swollen

joints

ESR or CRP

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

*Median. DAS = Disease Activity Score 28-defined remission; SDAI = Simplified Disease Activity Index; CDAI = Clinical Disease Activity Index; RADAI = Rheumatoid Arthritis Disease Activity Index; PAS = Patient Activity Scale; RAPID = Routine Assessment Patient Index Data.

Saag KG, et al. Arthritis Rheum. 2008;59(6):762-784. Mireau M, et al. Rheumatology. 2007;46:975-979. Rintelen B, et al. Journal of Rheumatology.

2009;36(5):918–924. Wolfe F, et al. Arthritis Rheum. 2007;57(6):935-942. Pincus T, et al. Journal of Rheumatology. 2008;35(11):2136-2147.

Instruments Used to Measure RA Disease Activity

Thresholds of Disease Activity

Instrument Score

Range Remission Low Moderate High

DAS in 28

Joints 0-9.4 ≤2.6 >2.6 and ≤3.2 >3.2 and ≤5.1 >5.1

SDAI 0.1-86 ≤3.3 >3.3 and ≤11 >11 and ≤26 >26

CDAI 0-76 ≤2.8 >2.8 and ≤10 >10 and ≤22 >22

RADAI 0-10 ≤1.4 >1.4 and <2.2 ≥2.2 and ≤4.9 >4.9*

PAS or PASII 0-10 ≤0.5 >0.5 and <1.9 ≥1.9 and ≤5.3 >5.3

RAPID 0-30 ≤1 >1 and <6 ≥6 and ≤12 >12

Aletaha D, et al. Clin Exp Rheumatol. 2005;23(suppl 39):S100-S108.

Cush JJ. Arthritis Rheum. 2005;52(9 suppl):S686.

Low Disease

Activity

Moderate Disease

Activity

High Disease

Activity

Remission

CDAI ≤ 2.8 > 22 2.9-10 11-22

DAS ≤ 2.4 SDAI >22

> 5.5 < 3.6 N/A

SDAI ≤ 3.3 3.4-11 12-26 > 26

9

8

7

6

2

1

0

3

5

4

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

TICORA study: a single-blind, 18-month controlled trial with 110 patients with RA

< 5 years randomized to either intensive management with protocol-based

escalation of DMARDs or routine care

64

18 16

71 65

91

0

20

40

60

80

100

ACR20 ACR70 Remission

Perc

ent

of

patients

8.5

4.5

Incre

ase

in

media

n T

SS

from

baselin

e

Routine group (n = 55)

Intensive group (n = 55)

P = 0.02

Routine group (n = 50)

Intensive group (n = 53)

P < 0.0001

TSS = total Sharp score

Conventional x-ray (XR), ultrasound (US), or MRI can be used to improve certainty of diagnosis

The presence of inflammation seen on US or MRI can predict RA progression and are superior to clinical examination

XR of the hands and feet should be obtained initially and should be repeated periodically; if negative US or MRI may be helpful

US and MRI may be used to predict response to treatment and may be useful in measuring disease activity

XR in flexion and neutral of cervical spine in patients with suspicion of cervical involvement

US and MRI may be positive even in patients with clinical remission

*EULAR Recommendations

Colebatch A et al. Ann Rheum Dis. 2013;72:804-818

US = ultrasound; MRI = magnetic resonance imaging. Brown AK, et al. Arthritis Rheum. 2008;58(10):2958-2967.

102 patients with RA judged to be in remission by their

physician

Patients followed prospectively for 1 year

Radiographic joint damage developed in 19% of patients

Damage correlated with US and MRI evidence of synovitis at

baseline

Conclusions

Clinical assessment of remission may not be sufficient to

identify patients at risk of disease progression

Should MRI and/or US be used to identify patients at low

risk of progression?

191 pts with <1 y disease at baseline on MTX, SSZ or both

Follow-up for 3 and 5 years

30 (22.4%) in remission at 3 and 5 years; 104 (77.6%) not in remission

SvdH scores not different comparing the two groups

Conclusion: DAS remission at one or 2 points does not always mean no X-ray progression

16.7

53.3

0

20

40

60

Radiographic

Damage*

New Erosions

% o

f P

ati

en

ts

*Change in SvdH Scores > 4.1

Cohen G, Gossec L, Dougados M, et al. Radiological damage in patients with rheumatoid arthritis on sustained remission. Ann Rheum Dis. 2007;66:358-363.

Among pts in ―DAS remission‖

Early diagnosis

Newly established 2010 RA classification criteria

Measuring RA disease activity

Quantitatively establish and document a baseline

Compare quantitative RA measurements at progressive time points

Identify ultimate target of therapy—remission (T2T)

Remission or at least low disease activity is the goal

Goal can be reached with monotherapy or combination therapy but

latter is better

Treatment strategy to continuously strive to push disease toward

improvement

Advance therapy in stepwise fashion while continuously measuring

disease to achieve goal—or as close as is reasonably feasible

Can we withdraw biologic if remission obtained? *OPTIMA Trial

*Smolen J et al. Lancet, October 25, 2013

When preliminary diagnosis is made, treatment

begins1

Nonsteroidal anti-inflammatory drugs (NSAIDs) for

pain relief

Glucocorticoids to suppress inflammation

Monitor patient for adverse events

Advise patient on exercise, lifestyle

If there is any evidence of inflammatory

arthritis, refer to rheumatologist < 3 months

after initial diagnosis2

1. Kountz D, et al. J Fam Pract. 2007;56(10 suppl A):59a-73a. 2. Cush JJ. J Rheumatol. 2007;34(suppl 80):1-7.

Kountz D, et al. J Fam Pract. 2007;56(10 suppl A):59a-73a.

Three Main Classes of Pharmacologic Therapy for Treating RA

DMARDs

Nonbiologics (first line)

• Target immune cells, usually by an

unknown mechanism

• Examples include: methotrexate,

hydroxychloroquine, sulfasalazine,

leflunomide, gold

Biologics (second line)

• Target specific parts of inflammatory

cascade

• Examples include: infliximab,

etanercept, adalimumab, anakinra,

abatacept, rituximab

NSAIDs Low-dose

Corticosteroids

Adjunctive

(PCP may initiate)

All RA patients are candidates for DMARD therapy

Used as initial therapy

Often used in combination to maximize efficacy

Selection of DMARD therapy is based on: Individual patient Efficacy Convenience of administration Monitoring Time until expected benefit Frequency and severity of adverse events Costs Insurance coverage

American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46:328-346.

1. Pisu M, et al. Rheumatology. 2005;44:781-788. 2. Da Silva JAP, et al. Ann Rheum Dis. 2006;65:285-293. 3. Saag KG. Arthritis Care Res. 2001;45:468-471. 4. Conn DL. Arthritis Care Res. 2001;45:462-467. 5. Pincus T, et al. Ann Intern Med. 2002;136:76-78. 6. Jacobs JW, et al. Arthritis Rheum. 2006;54:1422-1428. * Expert opinion

• No agreement on:

– Efficacy, safety, and adverse effects of low-dose corticosteroids1-4

– Definition of low-dose corticosteroids5

• Low-dose corticosteroids (less than 7.5 mg per day*) may

provide initial relief to RA patients, but relief may mask

disease progression

• Corticosteroids slow radiographic progression (Sharp scores)

in early disease6

– However, not to the degree of traditional DMARDs and/or biologics

• Clinicians must weigh the benefits corticosteroids provide

versus the risk of treatment complications*

The nonbiologic DMARD methotrexate (MTX) is the cornerstone of RA treatment; start with 7.5 mg for better tolerance and increase to 20-25 mg (consider parenteral MTX)

Combination therapy of traditional DMARDs (triple therapy) is more effective than MTX monotherapy

Monotherapy with TNF-α inhibitors has similar efficacy compared with MTX monotherapy

Combination therapy with MTX and a TNF-α inhibitor appears to be more effective than either monotherapy alone, based on ACR criteria

Combination therapy also results in significantly less joint damage, as measured by Sharp scores

Early and aggressive treatment of inflammation reduces hazard ratios for early mortality

DMARD = disease-modifying antirheumatic drug; RA = rheumatoid arthritis; TNF = tumor necrosis factor; ACR = American College of Rheumatology. 1. Bathon JM et al. N Engl J Med. 2000;343(22):1586-1596; 2. St Clair EW et al. Arthritis Rheum. 2004;50(11):3432-3443; 3. Breedveld EC et al. Arthritis Rheum. 2006;54(1):37; 4. Klareskog L et al. Lancet. 2004;363(9410):675-681; 5. Michaud K, Wolfe F.; June 8-11, 2005; Vienna, EULAR; 6. Gonzalez A et al. Arthritis Rheum. 2007 Nov;56(11):3583-3587.

Treat signs and symptoms in

established disease

Aggressive

MTX dosing

Early DMARD

treatment

Emerging RXs

Remission/Cure?

Combination

therapy

1930s

Injectable gold

1950s

HCQ, Steroids

1970s

D-Pen, AZA

1980s

MTX, Oral gold

1990s

TNF antagonists, LEF, IL-1ra Cyclosporin

2000s

B-cell antagonists, CTLA4-IG,

IL-6 receptor Antagonist J Kinase inhibitor

AZA, azathiopine; HCQ, hydroxychloroquine; LEF, leflunomide; SSZ, sulfasalazine.

1960s

SSZ

Sulfasalazine 2000 mg/d

Methotrexate 7.5 mg/wk

6 28 40 56 0

1.6

Weeks

0.0

0.4

0.8

1.2

Po

ole

d in

de

x

60 mg/d

Step-down

therapy

Sulfasalazine

(n = 79)

Step-down (n = 76)

Multicenter, double-blind, randomized trial comparing the

combination of sulfasalazine (2000 mg/day), methotrexate

(7.5 mg/week), and prednisolone (60 mg/day, tapered in

6 weekly steps to 7.5 mg/day) with sulfasalazine alone1

COBRA = Combinatietherapie Bij Reumatoide Artritis 1. Boers M, et al. Lancet. 1997;350:309-318. 2. Landewé RBM, et al. Arthritis Rheum. 2002;46:347-356.

0

10

20

30

40

50

1 2 3 4 5

Years

To

tal S

ha

rp s

co

re

SSZ alone

MTX + SSZ + prednisolone

N = 148

5-year follow-up to determine if COBRA

benefits are sustainable2

Prednisolone 7.5 mg/d

0

20

40

60

80

100

ASPIRE PREMIER COMET

0

20

40

60

80

100

ASPIRE PREMIER COMET

Newly instituted methotrexate therapy and methotrexate plus TNF-inhibitor therapy from 12-month clinical trials of infliximab (ASPIRE, N = 1049),1,2 adalimumab (PREMIER, N = 799),1,3 and etanercept (COMET, N = 542)4

Methotrexate monotherapy

Pati

en

t re

sp

on

se (

%)

Pati

en

t re

sp

on

se (

%)

TNF-inhibitor + methotrexate

ACR20 ACR70

1. Smolen JS, et al. Lancet. 2007;370:1861-1874.

2. St. Clair EW, et al. Arthritis Rheum. 2004;50:3432-3443.

3. Breedveld FC, et al. Arthritis Rheum. 2006;54:26-37. 4. Emery P, et al. ACR 2007 meeting.

http://www.rheumatology.org. Abstract L17.

50%

18%

36%

66%*

30%

52%*

0

20

40

60

80

100

ACR20 ACR50 ACR70

Arm A

Arm B

Summary

For pts with early RA who fail to respond to 3 month MTX monotherapy, the addition of an anti-TNF is clinically superior to the addition of conventional DMARDs

*p<0.05

42%*

26%

0

20

40

60

80

100

Arm A Arm B

Pts

with

EU

LA

R

Go

od

re

sp

on

se

(%

) Primary endpoint: EULAR

Good response (NRI ITT population)

*p<0.01

(32/

123)

(50/

120)

ACR response at 12 months

(from baseline, NRI ITT population)

Re

sp

on

de

rs (

%)

0

20

40

60

80

100

Arm A Arm B

High

Moderate

Low

Remission

EULAR disease activity at 12 months

(LOCF ITT population)

Pa

tie

nts

(%

)

van Vollenhoven R, et al. ACR 2008, San Francisco #717; ibid #1003

Etanercept

Infliximab

Adalimumab

Golimumab

Certolizumab

Abatacept

Rituximab

Tocilimumab

Anakinra

Tofacitinib*

High cost

SubQ or IV or oral*

Better with MTX

Moderate/severe disease

Check for hepatitis B and

C, immunizations, TBc, HIV

before administration

Emerging Therapies

Additional Kinase inhibitors

Additional IL-6 inhibitors

Additional B-cell antagonists

Additional small molecules

IL-17 inhibitors

Emerging Therapies

• Patients who have an inadequate response or

intolerance to therapy with one TNF-α inhibitor may

have an improved response or tolerance when

switched to another TNF-α inhibitor or an alternative

biologic agent from another class

• All of the biologics, with the probable exception of

tocilimumab, work better in combination with MTX

than as monotherapy

Triple therapy (MTX,SSZ,HCQ) as effective as biologic + MTX in RA patients with active disease in 50% of patients *1*2*3*4

Triple Rx $10,200 less per patient-year *5

Should we use triple therapy initially and if response is not adequate then switch to a biologic?

Many rheumatologists uncomfortable with using triple RX and have adopted the anti-TNF agents in combination with MTX as the treatment of choice after MTX monotherapy

The biologic agents have significantly improved the lives of our patients and have proven surprisingly safe

Will cost-conscious governments and third party carriers dictate our options?

However, biologics are not the final answer as only about 70% of patients respond adequately

*1 O’Dell J et al. N Eng J Med;2013;369:307-318

*2 Moreland L et al. Arth Rheum 2012;64:2824-2835

*3 Matteson E, O’Dell J, van Vollenhoven R. ACR San Diego October 25-30, 2012

*4 van Vollenhoven R. Lancet;2009:374;459-456

*5 Kaleb M. ACR San Diego October 25-30, 2012

Pregnancy

Perioperative management

Previous malignancies

Intercurrent infections

Interruption of therapy

Sequential therapies

Safety monitoring

TB = tuberculosis. Saag K, et al. Arthritis Rheum. 2008;59(6):762-784. Furst DE, et al. Ann Rheum Dis. 2007;66(suppl III):iii2-iii22.

Infections

Screen and monitor for bacterial infections, fungal

infections, TB, herpes zoster infection, Hepatitis B and C

Avoid use of biologic agents at least 1 week before and

after surgery (data not evidence-based)

Malignancy

Are there any methods to monitor patients for the

occurrence of malignancy?

Is regular monitoring for malignancy appropriate?

Cardiovascular disease

Screen lipid panel and examine baseline cardiac function

There is a small increased risk of SIEs in large, observational

cohorts, but not in RCTs

This difference is explained by patient selection,

comorbidities, and concomitant drugs

Opportunistic infections rare in patients with RA on TNF

inhibitors, but have unusual presentations and high mortality

No clear malignancy signal, but total length of exposure is

still short

Uncertainty about safety in patients with prior cancer

remains as numbers are small

Ongoing concerns regarding TB, fungal infections, Hepatitis

B and C, pregnancy, congestive heart failure, and PML

Older biologic agents approaching expiration of

patents (monoclonal AB and soluble receptors)

ACA includes more rapid pathway for approval

of very similar but not identical products

Biosimilars in development for infliximab,

etanercept, adalimumab, and rituximab

Cost-savings, safety, and interchangeability all

very critical

Two biosimilars to infliximab approved in

Europe in 2013-none in US

Many therapeutic advances in the treatment of RA

Alternative dosing strategies

Novel therapeutics

Combination therapies

Remission has become a realistic goal for therapy

Despite advances

Many patients fail to achieve a substantial clinical response

(ACR50), even initially

Therapy must be ongoing—no cure or long-lasting response

Joint damage does not heal (ie, treatment delay results in

irreversible damage)

A need for novel strategies to treat RA still exists

Risk of lymphoma in RA patients not increased with use of anti-TNF agents *1

Risk of CHF in RA ,patients increased with steroids (dose related) but not with anti-TNF agents *2

Disability in RA patients has decreased in past three decades (Combinations>Biologics>DMARDs>NSAIDs) *3

Risk of herpes zoster increased in RA patients and with age>60 (HZ vaccination indicated and advised) *4

Infection risk with elective orthopedic surgery in RA patients appears lower if anti-TNF agents withheld *5

Treating to target with tight control decreases disease activity to a greater degree and shortens time to remission *6

Anti-carbamylated protein (anti-CarP) antibodies precede the onset of RA often by many years similar to anti-CCP and IgM-RF *7

*1 Hellgren K et al. ACR Washington DC, 2012

*2 Solomon D et al. Ann Rheum Dis 2012 Nov

*3 Krishnan E et al. Ann Rheum Dis 2012:71;213-218

*4 Zhang J et al. JAMA 2012:308;43-49

*5 Scherrer C et al. ACR Washinton DC, 2012

*6 Shipper L et al. Ann Rheum Dis 2012:71;845-850

*7 Shi J et al. Ann Rheum Dis 12/26/2013

Smolen JS, et al. Ann Rheum Dis. 2010;69(4):631-637.

1. The primary target for treatment of RA should

be a state of clinical remission

2. Clinical remission is defined as the absence of

signs and symptoms of significant inflammatory

disease activity

3. While remission should be a clear target, based

on available evidence, LDA may be an

acceptable alternative therapeutic goal,

particularly in established long-standing disease


4. Until the desired treatment target is reached,

drug therapy should be adjusted at least every

3 months

5. Measures of disease activity must be obtained

and documented regularly, as frequently as

monthly for patients with high/moderate

disease activity or less frequently (such as

every 3-6 months) for patients in sustained

LDA or remission


6. The use of validated composite measures of

disease activity, which include joint

assessments, is needed in routine clinical

practice to guide treatment decisions

7. Structural changes and functional impairment

should be considered when making clinical

decisions, in addition to assessing composite

measures of disease activity


8. The desired treatment target should be maintained

throughout the remaining course of the disease

9. The choice of the (composite) measure of disease

activity and the level of the target value may be

influenced by consideration of comorbidities,

patient factors, and drug-related risks

10. The patient has to be appropriately informed about

the treatment target and the strategy planned to

reach this target under the supervision of the

rheumatologist

Early, aggressive combination treatment affords RA patients the best chance of limiting joint damage, preventing further radiographic progression of disease, and improving quality of life

Recognizing warning signs of RA enables primary care physicians (PCPs) to diagnose the disease early and refer patients to rheumatologists

Close coordination between PCPs and rheumatologists in monitoring toxicities and comorbidities is essential to managing RA patients

There is a disconnect between controlling signs and symptoms and controlling radiographic progression; clinicians need to control both

Therapy decisions based on clinical measurements are superior to decisions based solely on clinician judgment and REMISSION now the goal

True remission should include not only the absence of clinical disease, but cessation of radiographic progression

Knowledge of the basic immunologic mechanisms involved in rheumatic diseases and pharmaco-genomics will permit the development of targeted and individualized therapies

Do not test for ANA sub-serologies without a positive ANA and suspicion of immune-mediated disease

Do not test for Lyme disease without history of exposure/physical exam findings

Do not prescribe biologics for RA before a trial of MTX

Do not monitor peripheral inflammatory arthritis with MRI on a regular basis

Do not repeat DEXA scans more often than every two years

*American College of Rheumatology Task Force

Arthritis Care and Research,65:3:329-339 March 2013

arthur l. weaver md, ms, facp, macr clinical professor of...

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