1. Living with Rheumatoid Arthritis: Understanding Options, Understanding Goals
Eric Ruderman, M.D.
Professor of Medicine, Rheumatology
Northwestern University Feinberg School of Medicine

2. The Burden of Rheumatoid Arthritis
Systemic inflammatory disease1
Autoimmune etiology1
Affects 2 million people in the United States1
Age of onset years
Lifetime cost approaches that of cardiovascular diseases2
Associated with an increased mortality risk3
RA is a systemic inflammatory disease whose underlying etiology is incompletely understood but is known to have strong autoimmune components.1
RA is characterized by inflammation and destruction of the joints and affects approximately 1% of the population.1
Although the incidence of RA increases with age, onset can occur at any age.1
The chronic and progressive nature of RA not only results in pain and reduced QOL, but is associated with an economic burden due to high direct medical costs (health resource utilization) as well as substantial indirect costs from mortality and reduced productivity.2
Because there is no cure, disability and treatment occur over the lifetime of the patient, and it has been suggested that the lifetime cost of RA is similar to that of cardiovascular diseases.2
RA is also associated with a significant risk of mortality.3
It has been estimated that the 10-year survival rate in patients with severe RA, defined as >20 actively inflamed joints, is comparable to patients with 3-vessel coronary artery disease or stage IV Hodgkin’s lymphoma.4
1. Arthritis Foundation. At: Accessed June 4, 2007.
2. Kvien. Pharmacoeconomics. 2004;22(suppl 2):1.
3. Gabriel et al. Arthritis Rheum. 2003;48:54.
1. Arthritis Foundation. Accessed June 4, 2007.
2. Kvien TK. Epidemiology and burden of illness of rheumatoid arthritis. Pharmacoeconomics. 2004; 22(suppl 2):1-12.
3. Gabriel SE, Crowson CS, Kremers HM, et al. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum. 2003;48:54-58.
4. Marra C. Rheumatoid arthritis: a primer for pharmacists. Am J Health Syst Pharm. 2006;63(suppl 4):S4-S10.

3. Clinical Course of RA Chronic and progressive disease
50% of patients have irreversible joint damage at 2 years
The true cause of late disability
If not treated early and aggressively, RA leads to
Increasing joint destruction and deformity
Progressive physical disability
Reduced QOL
The clinical course of RA is characterized by its chronicity and progressive nature leading to irreversible joint damage and disability.
It has been estimated that 50% of patients with diagnosed RA have irreversible joint damage within 2 years, and this joint damage is the source of the severe disability that occurs late in the disease.
If not treated early and aggressively, RA inevitably leads to increased joint destruction and deformity, and functional impairment leading to severe physical disability and reduced QOL.
Since there is no cure for RA, the goals of patient management have been to alleviate the signs and symptoms and to slow progression, and treatment occurs over the patient’s lifetime.
Doran et al. Arthritis Rheum. 2002;46:625; Hulsmans et al. Arthritis Rheum. 2000;43:1927; Marra. Am J Health Syst Pharm. 2006;63:S4.
Doran MF, Pond GR, Crowson CS, O'Fallon WM, Gabriel SE. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum. 2002; 46:
Hulsmans HM, Jacobs JW, van der Heijde DM, van Albada-Kuipers GA, Schenk Y, Bijlsma JW. The course of radiologic damage during the first six years of rheumatoid arthritis. Arthritis Rheum ;43:
Marra C. Rheumatoid arthritis: a primer for pharmacists. Am J Health Syst Pharm. 2006; 63(suppl 4):S4-S10.

4. The Clinical Spectrum of RA
Active with some deformity
Early PIP swelling
Late-stage deformities
RA is a systemic, immune-mediated, inflammatory disease that is characterized by a continuum of signs and symptoms of increased worsening as the disease progresses.
Swelling of the proximal interphalangeal joint is an early manifestation of RA and is associated with pain, tenderness, and functional limitations, although joint erosion is usually absent on x-ray.
As the disease progresses, there is more swelling, more joints may become involved, and there is deformity of the joint resulting from changes in the bone and soft tissues of the joint. This increases the functional limitations that are experienced by patients.
Late-stage disease is characterized by severe deformities of the joints due to more severe degradative changes to the bone and soft tissue structure, and this stage often results in severe disability.
Images courtesy of J. Cush, 2005.
Marra C. Rheumatoid arthritis: a primer for pharmacists. Am J Health Syst Pharm. 2006;63(suppl 4):S4-S10.

5. Severity (arbitrary units)
Progression of RA
Inflammation and subsequent radiographic progression are dominant contributors to disability in RA patients
Disability
Inflammation
Joint damage
Severity (arbitrary units)
In the progression of RA, inflammation will dominate in the early stages of the disease, but joint destruction will dominate later.
The figure shown on this slide, adapted from a study by Kirwan, shows that inflammation paralleled disability for the first 2 to 3 years, but then paralleled radiographic progression later on. 5 10 15 20 25 30
Years of disease
Effect of joint destruction dominates disability late in disease
Inflammatory joint symptoms determine disability early in disease
Adapted from Kirwan JR. J Rheumatol. 2001;28: 5

6. New ACR/EULAR RA criteria
JOINT DISTRIBUTION
1 Large Joint
2-10 Large Joints 1
1-3 Small Joints (large jts excluded) 2
4-10 Small Joints (large jts excluded) 3
>10 Joints (at least 1 small joint) 5
SEROLOGY
Negative RF and Negative ACPA
Low Positive RF or ACPA (≤3x ULN)
High Positive RF or ACPA (>3x ULN)
SYMPTOM DURATION
<6 weeks
≥6 weeks
ACUTE PHASE REACTANTS
Normal CRP and ESR
Abnormal CRP or ESR
RA is classified or diagnosed with a score ≥6
Presented as a “scientific program”. To use these criteria, you have to start with at least one joint that has “define synovitis”. After that, the joint count is ANY joint, with the exception of the mtp1, cmc, and the dip’s.
Also… if a patient has a “classic erosion: on X-ray, this would be all that would be needed. If a patient has inactive disease, if they ever met these criteria, then that would count.
For serology. High titer is defined as >3x ULN.
Final caveat…these are not to be considered absolute criteria. Physician opinion still counts.
What is RA?
Let’s first start by reviewing what exactly rheumatoid arthritis is. A blue-ribbon panel from the ACR and EULAR recently developed new guidelines for the diagnosis of RA. They used a Delphi technique, using clinical vignettes to determine which features were most specific for RA. Based on this, along with regression analyses, they developed the following criteria…
One final note…although there were multiple posters at EULAR which showed the utility of these criteria in diagnosing RA, the criteria have never been formally VALIDATED. To do that, it would be necessary to test the criteria in other conditions besides RA.
Aletaha D, et al. EULAR 2010, Rome, Plenary session 6

7. Inflammatory Arthritis - Clues
Osteoarthritis
Mode of onset
Subacute
Insideous
Diurnal variation
AM worst
PMworst
AM stiffness
> 45 minutes
< 15 minutes
Effect of activity
better
worse
Systemic symptoms
Yes No

8. Traditional Non-Biologic DMARDs
Benefits
Considerations
Hydroxychloroquine
Effective for mild disease and in combination with methotrexate
Takes 3-6 months to become effective
No evidence of halting radiographic progression
Sulfasalazine
Effective for mild-to-moderate disease
May be used in combination with other agents
Slows radiographic damage
Contraindicated in patients who have sulfa allergies
Methotrexate
Cornerstone of most treatment regimens for RA
Well-tolerated once-weekly medication
Contraindicated in potentially childbearing women
Usually administered with folic acid supplementation
Leflunomide
For moderate-to-severe disease
Slows radiographic progression
Greater cost
Long half-life
Bykerk VP, et al. J Musculoskelet Med. 2004;21:
O’Dell JR. N Engl J Med. 2004;350:
Bingham CO, et al. J Fam Pract. 2007;59(suppl 10):S1-S8. 8

9. Inflamed synovial membrane
The Pathogenesis of RA
RHEUMATOID ARTHRITIS
NORMAL
Inflamed synovial membrane
Synovial membrane
Major cell types:
T lymphocytes Macrophages
Pannus
Minor cell types:
Fibroblasts Plasma cells
Endothelium Dendritic cells
Cartilage
Main message – The current pathogenetic model for RA is one of a chronic, tissue-specific inflammatory process to which a variety of immune responses can contribute
Rheumatoid arthritis (RA), a chronic autoimmune disease characterized by severe joint destruction, pain, and disability, involves reactive inflammation and destruction of bone, cartilage, and the synovial membrane of the affected joint. Cytokines have been found to play a key role in promoting the RA disease process. Cytokines regulate immune responses as a consequence of proinflammatory as well as immunosuppressive and anti-inflammatory properties.
An imbalance between the proinflammatory and anti-inflammatory/immuno- suppressive effects likely contributes to the chronicity of disease. Hence, the current pathogenetic model for RA is one of a chronic, tissue-specific inflammatory process to which a variety of immune responses can contribute. This slide depicts the the unique pathophysiologic elements of RA that arise from interactions between (1) the variety of leukocytes that invade the joint, and (2) the native cellular components of joint tissue as compared to the pathophysiologic aspects of a normal joint.
Adapted from Feldmann M, et al. Annu Rev Immunol. 1996;14:
Synovial
fluid
Major cell type: Neutrophils
Capsule
Cartilage Thinning 9

10. Synoviocyte accumulation
Pathophysiology of RA
Normal Joint RA
Early
Established
Capsule
Angiogenesis
Neutrophils
In the normal joint, few immune cells are present, and the synovium consists of the synovial membrane with a thin lining of synovial cells.
Initiation of RA is characterized by several events within the joint that promote an inflammatory response as a result of immune activation.
Both the size and number of synoviocytes increase.
There is infiltration by a variety of immune cells, including neutrophils, which produce proinflammatory cytokines and degradative molecules; T cells, which can become activated when an antigen is presented by dendritic cells; and B cells, which can activate T cells, produce autoantibodies, and release cytokines.
Angiogenesis starts to occur.
Pannus formation is initiated when the synovial tissue begins to invade and degrade the cartilage.
In established disease, there is additional recruitment and infiltration of immune cells, and the pannus becomes a highly developed inflammatory tissue.
Proinflammatory cytokines, such as TNFα and IL-1 and -6, are released.
Enzymes that degrade bone and cartilage, such as matrix metalloproteinases, are released.
T cells
B cells
Synovial membrane
Synoviocyte accumulation
Plasma cell
Neutrophils
Dendritic cell
Bone erosion
Synoviocytes
Cartilage
Pannus
Adapted with permission from Choy and Panayi. N Engl J Med. 2001;344:907. Copyright © 2001 Massachusetts Medical Society. All rights reserved.
Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344:

11. Periarticular osteoporosis
Bone Damage in RA
Periarticular osteoporosis
Schematic representation of types of bone damage in RA
The panel on the left shows the structural integrity of a normal joint, which has normal bone mass density with no signs of skeletal abnormalities.
The panel on the right depicts the compromised bone structure representative of RA, including generalized skeletal osteoporosis, which is typical in these patients. Bone mass density and bone mass are reduced in patients with RA, and there is also obvious periarticular osteoporosis, low bone mass density, and bone loss around the joint.
Low bone mass density and bone mass are additionally associated with increased risk of hip and vertebral fracture.
Erosion, a type of bone damage that is characteristic of RA, is depicted on the right. One can see the obvious bone indentation around the joints.
Generalized skeletal osteoporosis
Bone erosion
Goldring. Curr Opin Rheumatol. 2002;14:406.
The Association of the British Pharmaceutical Industry. At:
Goldring SR. Pathogenesis of bone erosions in rheumatoid arthritis. Curr Opin Rheumatol ;14:

12. Most RA Patients Develop Bone Erosions During First 2 Years of Disease
A prospective study was designed to characterize the radiologic course of disease in a large cohort of patients with early RA, defined as disease duration <1 year.
Bone damage in 502 patients with recent onset of RA was assessed radiologically over a duration of 6 years.
Radiographs of the hands and feet were scored according to the modified Sharp/van der Heijde method (SHS; range, 0 to 448). A mean of 2.9 (range, 1 to 7) radiographs were read per patient.
Stable rates of progression were found over the course of RA based on the SHS, erosion score, and narrowing score.
The rate of progression of already damaged joints increased during the 6-year follow-up.
The study showed that in patients with early disease, there is rapid radiologic progression and clear evidence of bone damage.
Most patients developed bone erosions by the first 2 years after diagnosis.
Erosion of the hands developed in 76%.
Erosion of the feet developed in 72%.
Erosion of the hands or feet developed in 92%.
Erosion of the hands and feet developed in 61%.
Patients with RA <1 year underwent annual radiologic assessment of hands and feet.
Hulsmans et al. Arthritis Rheum. 2000;43:1927.
Hulsmans HM, Jacobs JW, van der Heijde DM, van Albada-Kuipers GA, Schenk Y, Bijlsma JW. The course of radiologic damage during the first six years of rheumatoid arthritis. Arthritis Rheum. 2000;43:

13. Therapeutic Aim in RA Signs and symptoms
Improvement
Remission
Requires a comprehensive approach
Type of intervention
Timing
Follow-up management
Assessment of comorbid conditions
Joint damage
Retardation
Prevention
Reversal
While the ideal goal of RA treatment has been disease modification with the purpose of slowing or preventing disease progression, the more realistic goal has been improvement in the signs and symptoms of the disease.
With the newer biologic DMARDs, the ideal goal has become potentially more realistic. Therapeutic aims have been expanded so that they not only include the signs and symptoms, with the hope of disease remission, but also the prevention, retardation, and even reversal of joint damage. Greater improvement in disability, which substantially contributes to patient function and quality of life, has also become a more realistic goal.
However, these goals may require a comprehensive strategy that incorporates several clinically defined approaches to patient management, including decisions on type and timing of intervention, as well as a routine program of follow-up that also evaluates the presence of comorbid conditions that may contribute to disease progression and overall health status.
Disability
Improvement
Prevention
Reversal

14. Global RA Management Goals
Prevent or control joint damage
Prevent loss of function
Decrease pain
Treat comorbidities along with RA
Improve functional status
The ideal objective: disease remission
Tutuncu Z, et al. Rheum Dis Clin North Am. 2007;33:57-70.

15. The Traditional Treatment Pyramid for RA: Sequential Drug Therapy
Methotrexate,
azathioprine, penicillamine
Antimalarials, gold, sulfasalazine
Surgery
Corticosteroids for flares
Analgesics
Intra-articular
steroids
Experimental
drugs,
Biologics
Salicylates or other NSAIDs
Adapted from Primer on Rheumatic Diseases. 10th ed. The Arthritis Foundation; 1993.

16. Expert Panel Algorithm for Treating RA to Target
Primary target in treating RA now defined as a state of clinical remission
Low disease activity (LDA) may be an alternative therapeutic goal to remission, particularly in established long-standing disease
Main
target
Adapt therapy
according to
disease activity
Adapt therapy
if state is lost
Sustained
remission
Active RA
Remission
Use a
composite measure
of disease activity
every 1-3 months
Assess
disease activity about
every 3-6 months
Low disease
activity
Sustained low
disease activity
Alter-
native
target
Adapt therapy
according to
disease activity
Adapt therapy
if state is lost
Smolen et al. Ann Rheum Dis 2010;69:631–637.

17. Rheumatoid Arthritis: Where Are We Now With Treatment?
Nonbiologic DMARDs
Monotherapy
MTX
SSZ
Leflunomide
Hydroxychloroquine
Combination therapy
Dual therapy
Triple therapy
Glucocorticoids
Local
Systemic
Combined with DMARDs
Biologic DMARDs
TNF antagonists
Adalimumab
Certolizumab
Etanercept
Golimumab
Infliximab
IL-6 antagonist
Tocilizumab
IL-1 antagonist
Anakinra
Costimulation modulator
Abatacept
B-cell depletion
Rituximab
Emerging targets
Kinase inhibitors - Tofacitinib
MTX and other traditional DMARDs have been the mainstay of RA therapy.
Traditional DMARDs used as monotherapy, in combination therapy, and together with glucocorticoids have demonstrated efficacy but remain less than optimal therapy.
Mechanism of DMARDs action is downstream of the processes responsible for RA pathogenesis.
DMARDs slow RA progression, but the disease process is not adequately modified.
DMARDs lose efficacy with long-term use in a substantial proportion of patients.
DMARDs are associated with toxicity, especially with long-term use.
The need for better therapies, and advances in understanding the immune response, have led to development of biologic DMARDs that target specific mechanisms involved in RA pathogenesis.
Currently available biologic DMARDs include agents that target proinflammatory cytokines; these DMARDs comprise the anti-TNF agents adalimumab, etanercept, and infliximab and the IL-1– blocking agent anakinra.
Two recently approved biologic DMARDs, abatacept and rituximab, target T-cell activation and B cells, respectively.
Additionally, several other biologic DMARDs are in clinical trials or under development, including tocilizumab, which targets IL-6; certolizumab and golimumab, which target TNF; and ocrelizumab, which is a follow-up to rituximab that targets B cells.

18. TNF and TNF Receptors Activated Target Macrophage Cell sTNFR TNF TACE
Signal
sTNFR
TNF
TACE
Triggering a TNF-mediated signal requires cross-linking of two or more adjacent receptors. Soluble TNF receptor (p55 or p75) can bind soluble or cell-bound TNF, and potentially inhibit its ability to bind to cell bound TNF receptors.

19. Structures of TNF-α Inhibitors
Human recombinant receptor/Fc fusion protein
Humanized Fab’ fragment
Human recombinant antibodies
Chimeric monoclonal antibody
Receptor VL VH CL
CH1
Constant 2 Fc
CDR
Constant 3
PEG
PEG
Infliximab
IgG1
Adalimumab
IgG1
Golimumab
IgG1
Etanercept
IgG1
Certolizumab
Mouse
Human
CDR=Complementarity–determining region
PEG=Polyethylene glycol
Adapted from Tracey D et al. Pharmacol Ther. 2008;117:

20. TNF Inhibition: Monoclonal Antibodies
Activated
macrophage
p55
Target
cell
One approach to inhibiting the activity of TNF on responder cells is through the use of monoclonal antibodies. These antibodies are capable of binding TNF that is bound to the cell that produced it or to soluble TNF after it has been released from the cell surface. Tumor necrosis factor bound in such a fashion is unable to bind to either the p55 or the p75 receptor.
TNF
p75
anti-TNF Ab

21. Targeting B Cells: Rituximab - A Chimeric Anti-CD20 Monoclonal Antibody
Antigen B
Rituximab
Antibodies
CD20
Transiently depletes pre-B and mature B cells only
Progenitor and plasma cells not affected
Rituximab is a mouse-human chimeric monoclonal antibody that targets the CD20 B cell antigen.
CD20 is a cell-surface antigen that is not present on stem cells.
CD20 is lost before differentiation of B cells into plasma cells.
Rituximab results in a rapid and transient depletion of pre-B and mature B cells only without affecting progenitor or plasma cells.1,2
Several mechanisms have been proposed for the depletion of B cells by rituximab.3-5
Antibody-dependent cellular cytotoxicity (ADCC)
Complement-dependent cytotoxicity (CDC)
Induction of apoptosis
Rituximab has been approved for the treatment of non-Hodgkin’s lymphoma, and for the treatment of RA in patients for whom therapy with TNF inhibitors has failed.
Edwards and Cambridge. Rheumatology (Oxford). 2001;40:205; Edwards et al. N Engl J Med. 2004;350:2572;
Johnson and Glennie. Semin Oncol. 2003;30(suppl 2):3; Shanahan et al. Curr Opin Rheumatol. 2003;15:226; Silverman and Weisman. Arthritis Rheum. 2003;48:1484.
1. Edwards JC, Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology (Oxford). 2001;40:
2. Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350:
Johnson P, Glennie M. The mechanisms of action of rituximab in the elimination of tumor cells. Semin Oncol. 2003;30:3-8.
Shanahan JC, Moreland LW, Carter RH. Upcoming biologic agents for the treatment of rheumatic diseases. Curr Opin Rheumatol. 2003;15:
5. Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum. 2003;48:1484–1492.

22. Targeting T Cells: Abatacept—a Human Immunoglobulin Receptor Fusion Protein
Without Abatacept
With Abatacept T DC DC T
Abatacept (CTLA4-Ig) is a novel fusion protein with a mechanism of action that is mechanistically distinct from other biologic DMARDs.
Abatacept consists of the extracellular domain of the CTLA4 molecule complexed to the Fc domain of human IgG1.
The CTLA4 domain is similar to the naturally occurring protein and avidly binds to CD80/CD86 on antigen-presenting cells.
The IgG1 domain functions to solubilize the molecule.
The putative mechanism of action of abatacept is based on its ability to block the costimulatory signal required for activation of T cells.
Absence of the second costimulatory signal results in T-cell anergy, a state where T cells remain functionally inactivated.
In contrast to the natural molecule CTLA4, abatacept does not bind to the membrane of T cells. Thus, binding of abatacept to CD80/CD86 does not send a negative signal to T cells.
CD80/86
CD28
Abatacept
(CTLA4Ig)
Activated
T cell
Competes for CD28 binding to CD80/86
Attenuate T-cell–mediated autoimmunity
Carreno BM, Collins M. The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu Rev Immunol. 2002;20:29-53.
Greene JL, Leytze GM, Emswiler J, et al. Covalent dimerization of CD28/CTLA-4 and oligomerization of CD80/CD86 regulate T cell costimulatory interactions. J Biol Chem. 1996;271:
Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991;174:
Orencia® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2005.
Walunas TL, Lenschow DJ, Bakker CY, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994;1:

23. Cytokine Signaling
1/Leonard/ p201/col2/ para1;
P201/col1/ para2;
p202/Box1
Many cytokine receptors relay on associated tyrosine kinases, such as JAKs, to transmit signals from the extracellular environment to the nucleus1,2
2/Mavers/p379/Fig1
MAPK
Signaling
cascade
SYK
Signaling cascade
NF-KB
signaling
JAK
signaling cascade
Key Point:
The JAK pathways are one of several hubs in the inflammatory cytokine network.
Slide Overview:
Cytokines regulate many biological processes, including immune and inflammatory responses.3
Many cytokine receptors lack intrinsic kinase activity, instead relying on association with receptor-associated tyrosine kinases, such as JAKs, to transmit extracellular signals to the nucleus of the cell.1
Intracellular pathways transmit extracellular signals into the cell, where they regulate cellular responses and gene expression.2
The complexity of intracellular signaling offers many options for new molecular targets, including kinases, transcription factors, and inducers of apoptosis.2
Small-molecule, oral inhibitors of a number of signaling pathways involved in the pathogenesis of RA, including the mitogen-activated protein (MAP) kinase p38, spleen tyrosine kinase (Syk), and Janus kinase (JAK), are currently being developed and tested in the clinic.2
References:
Leonard WJ. Cytokines and immunodeficiency diseases. Nat Rev Immunol. 2001;1(3):
Mavers M, Ruderman EM, Perlman H. Intracellular signal pathways: potential for therapies. Curr Rheum Rep. 2009;11(5):
O'Shea JJ. Targeting the Jak/STAT pathway for immunosuppression. Ann Rheum Dis. 2004;63(suppl 2):ii67-ii71.
3/O’Shea/ pii67/col 1/ para 3
1/Leonard/ p201/col2/ para1;
P201/col1/ para2;
p202/Box1
2/Mavers/p379/fig1;
p378/col2/para2
2/Mavers/p380/table1
2/Mavers/p381/col2para4
1. Leonard WJ. Nat Rev Immunol. 2001;1(3): ; 2. Mavers M et al. Curr Rheum Rep. 2009;11(5): 23

24. Monitoring the Safety of Methotrexate Therapy
Laboratory monitoring: every 6-8 weeks
Complete blood counts
Serum transaminase levels
Serum albumin
Serum creatinine
Folic acid supplementation should be:
At least 5 mg weekly
Stop treatment in case of respiratory symptoms possibly related to MTX
Admit or consult with pulmonologist immediately in case of serious disease
In addition to tests prior to therapy, guidelines on the utilization of MTX also recommend that blood cell counts and serum levels of transaminases and creatinine should be monitored every 6 to 8 weeks to detect evidence of MTX-induced hepatic and hematologic toxicity and to check for renal dysfunction.
Folic acid supplementation is recommended in patients taking MTX, since some of the GI side effects associated with MTX may result from its ability to deplete folate.
Monitoring of pulmonary function is also recommended, and treatment should be stopped if respiratory symptoms develop that may be related to use of MTX.
Pavy et al. Joint Bone Spine. 2006;73:388.
Pavy S, Constantin A, Pham T, et al. Methotrexate therapy for rheumatoid arthritis: clinical practice guidelines based on published evidence and expert opinion. Joint Bone Spine. 2006;73:

25. Safety Considerations With Biologic Agents
Serious infections
Patients with RA are at higher risk than the general population
Do not initiate in patients with active infections
Monitor closely, hold and consider discontinuing if a serious infection develops
Opportunistic infections (TB)
Includes histoplasmosis, listeriosis, pulmonary aspergillosis, Pneumocystis carinii pneumonia
Patients should be screened for TB prior to use
Reevaluation on a yearly basis?
Hepatitis B screening
As with conventional DMARDs, certain safety considerations with biologic DMARDs need to be evaluated prior to their use and/or monitored after initiation of therapy.
Since biologic DMARDs modulate the immune response, it is important to consider the effects of these drugs on the risk of serious infections.
Because of a potentially compromised immune response due to the disease or immunosuppressive therapies, RA patients are already at higher risk for infections than the general population.
The potential role of TNF in the host defense of TB suggests that patients should be screened for TB and subsequently treated if found to be positive prior to initiating biologic DMARD therapy.
It has also been suggested that patients initiated on these drugs undergo TB screening on a yearly basis, especially if risk factors are present, but there is no consensus regarding this recommendation.
Similarly, because of the potential for reactivation of latent infections, hepatitis screening should be performed.
Patient evaluation for other active infections prior to initiating treatment is warranted, and if found positive, treatment should not be initiated.
Because of the immunomodulatory effects of biologic agents, the risk of opportunistic infections should also be considered, and patients should be monitored for these after initiation of treatment with biologic DMARDs.
Hochberg, et al. Semin Arthritis Rheum. 2005;34:819; Keystone et al. J Rheumatol Suppl. 2005;74:8; Schiff et al. Ann Rheum Dis. 2006;65:889; Scott and Kingsley. N Engl J Med. 2006;355:704.
Hochberg MC, Lebwohl MG, Plevy SE, Hobbs KE, Yocum DE. The benefit/risk profile of TNF-blocking agents: findings of a consensus panel. Semin Arthritis Rheum. 34:
Keystone EC. Safety of biologic therapies--an update. J Rheumatol Suppl. 2005;74:8-12.
Schiff MH, Burmester GR, Kent JD, et al. Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65:
Scott DL, Kingsley GH. Tumor necrosis factor inhibitors for rheumatoid arthritis. N Engl J Med. 2006;355:

26. Safety Considerations With Biologic Agents (cont'd)
Lymphoma
Patients with RA are at higher risk for lymphoma than the general population
Risk for lymphoma may be increased in patients receiving TNF antagonists
Administration reactions
Live vaccines are contraindicated
Pneumovax/influenza vaccination encouraged
Demyelination
Rare; includes exacerbation of previously quiescent Multiple Sclerosis, optic neuritis, Guillain-Barre syndrome
With respect to the general population, patients with RA have approximately a 2-fold higher risk of lymphoma, with greater disease severity possibly associated with an increased risk.
Data from several studies, including observational patient registries, have suggested that the risk for lymphoma may be additionally increased in patients on anti-TNF therapies.
Since the biologic DMARDs are administered intravenously or subcutaneously, health care providers should be alert for the possibility of administration reactions, which may be immediate or delayed, and although generally mild or moderate in severity, have the potential to be life- threatening.
Rotation of injection sites may help reduce the risk especially for acute injection-site reactions.
Because of the immunomodulatory effects of these agents, use of live vaccine immunization is contraindicated, but pneumovax/influenza vaccination is encouraged to reduce the risk of a common pathogen.
Although demyelination events are rare, physicians should be aware of the possibility for exacerbations in patients with previous history of such events, and the potential risk for new onset demyelinating disease in a small proportion of patients.
Hochberg et al. Semin Arthritis Rheum. 2005;34:819; Keystone et al. J Rheumatol Suppl. 2005;74:8; Schiff et al. Ann Rheum Dis. 2006;65:889; Scott and Kingsley. N Engl J Med. 2006;355:704.
Hochberg MC, Lebwohl MG, Plevy SE, Hobbs KE, Yocum DE. The benefit/risk profile of TNF-blocking agents: Findings of a consensus panel. Semin Arthritis Rheum. 34:
Keystone EC. Safety of biologic therapies--an update. J Rheumatol Suppl. 2005;74:8-12.
Schiff MH, Burmester GR, Kent JD, et al. Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65:
Scott DL, Kingsley GH. Tumor necrosis factor inhibitors for rheumatoid arthritis. N Engl J Med. 2006;355:

27. Safety Considerations With Biologic Agents (cont'd)
Hematologic abnormalities
Rare; includes cytopenia and pancytopenia (including aplastic anemia)
CHF
Autoantibodies, SLE, and lupus-like syndrome
Rare; symptoms include cutaneous lesions, photosensitivity, and pleural/pericardial serositis
Combination of biologics not to be used
Increased risk of infection
Further safety considerations include blood abnormalities, CHF, and autoantibody-related syndromes.
Although the risk for occurrence of blood abnormalities including cytopenia and aplastic anemia is rare, they have been reported with the use of TNF inhibitors.
Because of the presence of inflammation, risk of cardiovascular events and cardiovascular- related mortality is elevated in RA patients compared with the general population. However, the association between use of biologic DMARDs and changes in risk of CHF in the RA population is unclear. Although it has been hypothesized that TNF contributes to CHF and therefore TNF inhibitors may reduce the risk of CHF, several trials have suggested that CHR risk is actually increased with use of these drugs. However, there are still inadequate data to make any conclusions or recommendations, and the risk of CHF remains a safety consideration with the use of biologic DMARDs.
As with blood abnormalities, the risk of syndromes derived from the presence of autoantibodies is low, but both patients and physicians should be alerted to the potential for symptoms that may be indicative of such events.
Based on current information, the combination of biologic DMARDs is not indicated because of the potential for synergistic activity that may result in an increased risk of infection.
Hochberg et al. Semin Arthritis Rheum. 2005;34:819; Keystone et al. J Rheumatol Suppl. 2005;74:8; Schiff et al. Ann Rheum Dis. 2006;65:889; Scott and Kingsley. N Engl J Med. 2006;355:704.
Hochberg MC, Lebwohl MG, Plevy SE, Hobbs KE, Yocum DE. The benefit/risk profile of TNF-blocking agents: Findings of a consensus panel. Semin Arthritis Rheum. 34:
Keystone EC. Safety of biologic therapies--an update. J Rheumatol Suppl. 2005;74:8-12.
Schiff MH, Burmester GR, Kent JD, et al. Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65:
Scott DL, Kingsley GH. Tumor necrosis factor inhibitors for rheumatoid arthritis. N Engl J Med. 2006;355:

28. RA Is an Independent Risk Factor for Cardiovascular Events*
18-49
50-64
65-74
75+
Incidence Rate (per 1000 person-years)
Age Range (y)
Patients With RA (n=25,385)
Patients Without RA (n=252,976) 10 20 30 40 50 60 70
*Myocardial infarction, stroke.
Solomon DH et al. Ann Rheum Dis. 2006;65:

29. Risk of MI in RA Patients Comparable to Risk of MI in Diabetics
A nationwide cohort of > 4 million patients was followed for ~10 years to examine risk of MI (heart attack)
Risk of MI in RA patients was similar to the risk in those without RA who were 10 years older
100 80 60 40 20
General population
Rheumatoid arthritis
Incidence rate ratio (IRR)
Results from fully adjusted Poisson regression analysis (stratified by age in 10-year intervals).
< >80
Age group (years)
Lindharsen J et al. Ann Rheum Dis 2011;70:929–934.

30. Mortality in Patients With RA: Impact of Treatment
Mortality hazard ratio*
To investigate questions that have been raised regarding the potential long-term effects of RA therapies on the risk of mortality, a study evaluated the risk associated with different therapies in a large RA population.
A total of 1129 deaths occurred among 19,580 patients representing 63,811 patient-years of follow-up.
The referent was no MTX or anti-TNF agent use.
Multivariate modeling with adjustment for baseline disease and demographic variables showed that prednisone was associated with a significantly increased risk for death.
MTX as well as TNF inhibitors as a group were associated with a significantly reduced mortality risk.
Prednisone
MTX
TNF Inhibitors
*Adjusted for severity, comorbidity, and demographic variables.
Michaud and Wolfe. EULAR, Abstract OP0095.
Michaud K, Wolfe F. Reduced mortality among RA patients treated with anti-TNF inhibitors and methotrexate. Presented at: Annual Meeting of the European League Against Rheumatism; June 8-11, 2005; Vienna, Austria. Abstract OP0095.

31. Conclusions
RA is more than just a joint disease, but has important systemic implications
Traditional drug therapy, despite its effectiveness, has limitations
Improved understanding of pathogenesis has led to new biologic therapies with targeted mechanisms of action
Safety issues are important with all therapies
Current and future research is aimed at finding better ways to select and apply available options

32. Working with your physicians
Goal-directed therapy leads to the best outcomes – Know your goals
Understand your medications – all medications have side effects, but so does untreated disease
Beyond medications – a comprehensive approach to healthy living is important: diet, activity, cardiovascular risks
Know your team – rheumatologist, primary care physician, physical therapist, you: all have an important role to play