1. Rheumatoid Arthritis - Epidemiology, pathogenesis and clinical manifestations
Dror Mevorach, M.D.
November, 2013

2. RHEUMATOID ARTHRITIS Overview
Chronic inflammatory disease of unknown etiology
Complex, multifactorial pathogenesis
Fluctuating clinical course
Characterized by
Progressive destruction of synovial joints with loss of cartilage and bone
Damaged ligaments and tendons
Loss of physical function and quality of life
Premature death
Slide 2 Notes. Rheumatoid Arthritis: Overview
RA is a chronic inflammatory disease that most frequently affects the joints primarily but also other body systems. The cause of RA is unknown, but much progress in elucidating its pathogenesis has been made in the past decade.
It is likely that many pathogenetic and environmental mechanisms are involved.
The clinical course of RA is highly variable and unpredictable for an individual. Typically, joint symptoms progress slowly.
The disease is characterized by progressive destruction of the synovial joints. This damage causes loss of cartilage and bone. The radiological signs are loss of joint space and bone density.
In addition to joint destruction, RA also causes ligaments and tendons to be destroyed.
Loss of joint function eventually occurs as a result of destruction of bone and cartilage. Patients also experience reduced quality of life as a result of their loss of function. In addition, RA also may be associated with increased mortality and premature death.
Grassi W, De Angelis R, Lamanna G, Cervini C. The clinical features of rheumatoid arthritis. Eur J Radiol. 1998;27(suppl 1):S18-S24.

3. RHEUMATOID ARTHRITIS Epidemiology
Affects approximately 1% (0.3%-1.5%) of the global adult population
Occurs 2 to 3 times more often in women than in men
Estimated annual incidence
Males: 0.1–0.2 per 1000
Females: 0.2–0.4 per 1000
Monozygotic twins concordance of 15%-30%.
R.R of 2.5 of monozygotic compared to dizygotic twins.
Incidence largely consistent racially and geographically
Increases with age, peaks between the ages of 45 and 65 years.
Slide 3 Notes. Rheumatoid Arthritis: Epidemiology
RA affects about 1% of the global adult population.1
The annual incidence of RA is estimated to be 0.1 to 0.2 per 1000 in males and 0.2 to 0.4 per 1000 in females.2
The incidence and prevalence of RA are 2 to 3 times higher in women than in men.1
The disease has been found around the world in many different races and cultures.2
The peak age of onset of RA is between 45 and 65 years.2
1. Sangha O. Epidemiology of rheumatic diseases. Rheumatology. 2000;39(suppl 2):3-12.
2. MacGregor AJ, Silman AJ. Classification and epidemiology. In: Klippel JH, Dieppe PA, eds. Rheumatology. Vol 1. 2nd ed. London, UK: Mosby; 1998:

4. RHEUMATOID ARTHRITIS Worldwide Incidence and Prevalence
Prevalence (per 100)
W. Europeans/ 0.8–1.1
North Americans (Whites)
Chinese 0.3–0.4
Amerindians (Chippewa, Pima) 5–8
Slide 4 Notes. Rheumatoid Arthritis: Worldwide Incidence and Prevalence
Prevalence rates of RA are consistent geographically and among different races, with the exception of certain Amerindian tribes such as the Chippewa and the Pima, which have a very high prevalence of RA.
The prevalence of RA among whites of Western Europe and North America, has been estimated to range from 0.8 per 100 persons to 1.1 per 100 persons.
RA prevalence among the Chinese ranges from 0.3 per 100 persons to 0.4 per 100 persons.
The highest prevalence of RA is among the Chippewa and Pima Amerindian tribes; rates range from 5 per 100 persons to 8 per 100 persons.
The worldwide annual incidence of rheumatoid arthritis is estimated to be between 0.24 per 1000 persons to 3.34 per 1000 persons in women in Western Europe or North America. As expected, these figures are about 2 to 3 times lower in men. Among white men in Western Europe and North America, the annual incidence of RA ranges from 0.1 per 1000 to 1.5 per 1000.
Incidence (per 1000/year)
Women Men
W. Europeans/ 0.24– – North Americans (Whites)
Maini RN. Rheumatoid arthritis. A paradigm of inflammatory disease of the musculoskeletal system. Acta Orthop Scand Suppl. 1998:281:6-13.

5. RHEUMATOID ARTHRITIS Etiology and Pathogenesis
Suspected infectious agents
Bacteria (Mycoplasma, Mycobacteria, enteric bacteria)
Viruses (HTLV, Retrovirus, Herpesvirus, Epstein-Barr virus, rubella, parvovirus)
Defective recognition of autoantigen
Pregnancy induced remission linked to maternal-fetal HLA mismatch? Hormones?

6. RHEUMATOID ARTHRITIS Genetic Factors
Strong association with class II major histocompatibility complex human leukocyte antigen on chromosome 6
HLA-DR4 - N European and Americans
HLA-DR1 - Italian, Israeli Jewish, some Hispanics
HLA-DR14 - Yakima Indians
DRB1*04 (DR4) alleles are markers for severe, erosive RA

7. RHEUMATOID ARTHRITIS Twin Studies in RA

8. RHEUMATOID ARTHRITIS Shared Epitope Hypothesis
Alleles associated with RA
Lipsky PE. In: Harrison’s Principles of Internal Medicine

9. Pathophysiology of Rheumatoid Arthritis
excised synovial membrane shows many villous folds projecting above the synovial surface
compact nodular clusters of lymphocytes and plasma cells near the surface of synovial villi.

10. Pathophysiology of Rheumatoid Arthritis: knee synovitis
Hyperplastic, hypertrophic synoviocytes with occasional multi-nucleated giant cells. The enlarged villi are diffusely infiltrated by lymphocytes and plasma cells. Moderate capillary proliferation is seen.

11. Pathophysiology of Rheumatoid Arthritis: Late Destruction
A sagittal section through a proximal interphalangeal joint demonstrates complete bony union of the phalanges.
Finger joint, bony ankylosis, photomicrograph

12. Pathophysiology of Rheumatoid Arthritis- Panus formation
A portion of the fibrous tissue extends over the surface of the cartilage, which shows death of chondrocytes and loss of basophilia of the matrix.
Typical pannus formation. Fibrovascular tissue protrudes from the inflamed synovium into the articular cartilage. Note the inflammatory exudate in the subchondral bone (hematoxylin-eosin, medium power).

13. RHEUMATOID ARTHRITIS Pathogenesis of Rheumatoid Arthritis

14. Chronic Inflammation in the Rheumatoid Synovium
Activated T cells
Pannus
Macrophage
PMN
B cell
Cytokine
Inflamed
synovial membrane
Bone
Eroding cartilage

15. Cellular Interactions in the Rheumatoid Synovium
Inflammation
Acute phase protein synthesis
Cachexia
Antigen
IL-1
TNF
IL-6
IL-8
Macrophage
T cell
Lymphocyte
IL-2
IFN
Other cytokines
Rheumatoid Factor production
B cell differentiation and activation
Antibody production
Plasma cells

16. RHEUMATOID ARTHRITIS Disease Progression
Normal Knee Joint
Bone
Early Rheumatoid Arthritis
Cartilage
Neutrophils
Capsule
Hyperplastic
Synovial
Membrane
Synovial
Membrane
Synoviocytes
Capillary Formation
Established Rheumatoid Arthritis
Hypertrophic
Synoviocyte
T Cells
B Cells
Slide 15 Notes. Rheumatoid Arthritis: Disease Progression
A normal knee joint is illustrated at the top right of the slide. Moving in a counterclockwise direction, the middle panel to the left shows the same joint in an early stage of RA.
Progressive joint damage occurs in unchecked RA. In the early stages of the disease, cartilage destruction begins, and neutrophils, T cells, and B cells are recruited into the synovial cavity.1 The synovial membrane exhibits hyperplasia, and hypertrophic synoviocytes and capillaries are starting to form.
The last panel on the lower right shows a joint with established RA. The greatly thickened, inflamed synovium (pannus) invades and erodes adjacent bone and cartilage.1,2 Activated macrophages, lymphocytes, and fibroblasts and their products stimulate extensive angiogenesis, a central feature in synovial inflammation and pannus formation.1,3 Synovial villi become evident.
Neutrophils
Plasma Cell
Synovial Villi
Extensive
Angiogenesis
Eroded Bone
Pannus
1. Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344:
2. Firestein GS. Etiology and pathogenesis of rheumatoid arthritis. In: Kelley WN, Harris ED Jr, Ruddy S, et al, eds. Textbook of Rheumatology. 5th ed. Philadelphia, PA: WB Saunders; 1997;
3. Tak PP, Bresnihan B. The pathogenesis and prevention of joint damage in rheumatoid arthritis: Advances from synovial biopsy and tissue analysis. Arthritis Rheum. 2000;43:

17. RHEUMATOID ARTHRITIS Cytokine Signaling Pathways Involved in Inflammatory Arthritis
Slide 26 Notes. Cytokine Signaling Pathways Involved in Inflammatory Arthritis
CD4+ T cells might initiate the disease process in RA. Activated by antigens, these cells stimulate monocytes, synovial fibroblasts, and macrophages to produce the key pro-inflammatory cytokines TNF, IL-1, and IL-6 as well as to release matrix metalloproteinases, enzymes that degrade connective tissue matrix.1 TNF and IL-1 also inhibit synovial fibroblasts from producing tissue inhibitors of metalloproteinases.2 These two actions by TNF and IL-1, among others, are believed to result in the joint damage that occurs in RA.1
Activated CD4+ T cells also contribute to joint damage by stimulating the development of osteoclasts by expressing osteoprotegrin ligands (OPGLs) and by stimulating B cells to produce immunoglobulins such as rheumatoid factor.1
Activated macrophages, lymphocytes, and fibroblasts and their products can stimulate angiogenesis, a fact that may account for the increased vascularity of the synovium in rheumatoid joints.1
Other cytokines involved in the complex cellular interactions that occur as part of the inflammatory process include IL-4, IL-10, IL-12, and interferon-g. In addition, CD11 and CD69 cells are involved in the cell-surface signaling that leads to the production of cytokines.1
1. Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344:
2. Shingu M, Nagai Y, Isayama T, Naono T, Nobunaga M, Nagai Y. The effects of cytokines on metalloproteinase inhibitors (TIMP) and collagenase production by human chondrocytes and TIMP production by synovial cells and endothelial cells. Clin Exp Immunol. 1993;94:

18. RHEUMATOID ARTHRITIS Cytokine Signaling Pathways Involved in Inflammatory Arthritis
Slide 26 Notes. Cytokine Signaling Pathways Involved in Inflammatory Arthritis
CD4+ T cells might initiate the disease process in RA. Activated by antigens, these cells stimulate monocytes, synovial fibroblasts, and macrophages to produce the key pro-inflammatory cytokines TNF, IL-1, and IL-6 as well as to release matrix metalloproteinases, enzymes that degrade connective tissue matrix.1 TNF and IL-1 also inhibit synovial fibroblasts from producing tissue inhibitors of metalloproteinases.2 These two actions by TNF and IL-1, among others, are believed to result in the joint damage that occurs in RA.1
Activated CD4+ T cells also contribute to joint damage by stimulating the development of osteoclasts by expressing osteoprotegrin ligands (OPGLs) and by stimulating B cells to produce immunoglobulins such as rheumatoid factor.1
Activated macrophages, lymphocytes, and fibroblasts and their products can stimulate angiogenesis, a fact that may account for the increased vascularity of the synovium in rheumatoid joints.1
Other cytokines involved in the complex cellular interactions that occur as part of the inflammatory process include IL-4, IL-10, IL-12, and interferon-g. In addition, CD11 and CD69 cells are involved in the cell-surface signaling that leads to the production of cytokines.1
1. Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344:
2. Shingu M, Nagai Y, Isayama T, Naono T, Nobunaga M, Nagai Y. The effects of cytokines on metalloproteinase inhibitors (TIMP) and collagenase production by human chondrocytes and TIMP production by synovial cells and endothelial cells. Clin Exp Immunol. 1993;94:

19. RHEUMATOID ARTHRITIS Cytokine Signaling Pathways Involved in Inflammatory Arthritis
Slide 26 Notes. Cytokine Signaling Pathways Involved in Inflammatory Arthritis
CD4+ T cells might initiate the disease process in RA. Activated by antigens, these cells stimulate monocytes, synovial fibroblasts, and macrophages to produce the key pro-inflammatory cytokines TNF, IL-1, and IL-6 as well as to release matrix metalloproteinases, enzymes that degrade connective tissue matrix.1 TNF and IL-1 also inhibit synovial fibroblasts from producing tissue inhibitors of metalloproteinases.2 These two actions by TNF and IL-1, among others, are believed to result in the joint damage that occurs in RA.1
Activated CD4+ T cells also contribute to joint damage by stimulating the development of osteoclasts by expressing osteoprotegrin ligands (OPGLs) and by stimulating B cells to produce immunoglobulins such as rheumatoid factor.1
Activated macrophages, lymphocytes, and fibroblasts and their products can stimulate angiogenesis, a fact that may account for the increased vascularity of the synovium in rheumatoid joints.1
Other cytokines involved in the complex cellular interactions that occur as part of the inflammatory process include IL-4, IL-10, IL-12, and interferon-g. In addition, CD11 and CD69 cells are involved in the cell-surface signaling that leads to the production of cytokines.1
1. Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344:
2. Shingu M, Nagai Y, Isayama T, Naono T, Nobunaga M, Nagai Y. The effects of cytokines on metalloproteinase inhibitors (TIMP) and collagenase production by human chondrocytes and TIMP production by synovial cells and endothelial cells. Clin Exp Immunol. 1993;94:

20. RHEUMATOID ARTHRITIS Articular manifestations - hands
Joints are warm, swollen noticed in superficial joints. Usually symmetrical.
Frequently seen in wrists, MCPs, PIPs & DIPs
Compression of peripheral nerves – carpal tunnel syndrome, ulnar nerve (Guyon’s canal)

21. RHEUMATOID ARTHRITIS Articular manifestations - hands
Tenosynovitis may result in rheumatoid nodules – might interfere with finger flexion.

22. RHEUMATOID ARTHRITIS Presenting Signs and Symptoms
Symmetric joint pain
Swelling of small peripheral joints
Morning joint stiffness of variable duration
Other diffuse aching
Fatigue, malaise, and depression may precede other symptoms by weeks or months
Slide 8 Notes. Rheumatoid Arthritis: Presenting Signs and Symptoms
Typically, pain in the small joints of the hands and feet, together with symmetric swelling, is the first symptom noticed by patients with RA.
The number of affected joints varies greatly, but eventually the disease becomes polyarticular. Although, in principle, any joint can be affected by RA, the distal interphalangeal, sacroiliac, and lumbar spine joints are rarely affected. Extraarticular manifestations of RA include rheumatoid nodules, Sjogren's syndrome, episcleritis and scleritis, interstitial lung disease, pericardial disease, systemic vasculitis, and Felty's syndrome.
Joint stiffness in the morning lasting an hour or more is a characteristic symptom of RA.
Sometimes, nonspecific systemic symptoms, such as fatigue, depression, or low-grade fever, occur weeks or even months before the onset of joint pain and stiffness.
Grassi W et al. Eur J Radiol. 1998;27(suppl 1):S18–S24.
Grassi W, De Angelis R, Lamanna G, Cervini C. The clinical features of rheumatoid arthritis. Eur J Radiol. 1998;27(suppl 1):S18-S24.

23. RHEUMATOID ARTHRITIS Laboratory Findings
Chemistries normal, except slight  in albumin,  total protein, and  iron
Hematologic findings
Mild anemia in 25% to 35% of patients
Normal or slight  in white cell count
Thrombocytosis
eosinophilia
Slide 11 Notes. Rheumatoid Arthritis: Laboratory Findings
The initial laboratory work-up of a patient with suspected or early RA includes a complete blood count, comprehensive metabolic panel, urinalysis, and testing for erythrocyte sedimentation rate (ESR), rheumatoid factor, and antinuclear antibody.1
Up to 80% of patients with RA test positive for rheumatoid factor, but this test is not definitive for RA.2
In up to 80% of patients with RA, especially those who have extraarticular manifestations, the antinuclear antibody (ANA) value is positive.1
Sometime during the disease process, virtually all patients with RA have elevated levels of acute phase reactants (nonspecific indicators of inflammation), including ESR and/or C-reactive proteins (CRP). Persistent elevations of ESR and/or CRP usually are indicators of disease progression.2
Chemistries in RA can indicate a slight decrease in albumin and slight increase in total protein values—signs of a chronic inflammatory process.1 In addition, iron values are also reduced.
Approximately 25% to 35% of patients with RA have mild anemia (ie, hematocrit values between 30% and 34%). The reduced red cell mass may be associated with anemia of chronic disease or with true iron-deficiency anemia secondary to intercurrent blood loss from gastrointestinal bleeding caused by nonsteroidal anti-inflammatory drugs (NSAIDs).
The white-cell count in RA is either normal or slightly elevated as a sign of inflammation. The platelet count also usually is normal, but inflammation may cause thrombocytosis.1
1. Harris ED Jr. Clinical features of rheumatoid arthritis. In: Kelley WN, Harris ED Jr, Ruddy S, et al, eds. Textbook of Rheumatology. 5th ed. Philadelphia, PA: WB Saunders; 1997;
2. Pincus T. Laboratory tests in rheumatic disorders. In: Klippel JH, Dieppe PA, eds. Rheumatology. Vol 1. 2nd ed. London, UK: Mosby; 1998:

24. RHEUMATOID ARTHRITIS Laboratory Findings
Anti-cyclic citrullinated protein (CCP) predicts RA development in patients with polyarthritis. Low sensitivity, high specificity
Rheumatoid factor positive in up to 80% of patients
RF titers correlated with disease severity and extra-articualr manifestations.
Some patients convert from RF/- TO RF/+ (as the disease progresses).
Acute phase reactants (ESR, CRP, PLTs)  in almost all patientsat some point, correlates with synovitis.
Other Acute phase reactants: C3 C4
hypergammaglobulinemia
Slide 11 Notes. Rheumatoid Arthritis: Laboratory Findings
The initial laboratory work-up of a patient with suspected or early RA includes a complete blood count, comprehensive metabolic panel, urinalysis, and testing for erythrocyte sedimentation rate (ESR), rheumatoid factor, and antinuclear antibody.1
Up to 80% of patients with RA test positive for rheumatoid factor, but this test is not definitive for RA.2
In up to 80% of patients with RA, especially those who have extraarticular manifestations, the antinuclear antibody (ANA) value is positive.1
Sometime during the disease process, virtually all patients with RA have elevated levels of acute phase reactants (nonspecific indicators of inflammation), including ESR and/or C-reactive proteins (CRP). Persistent elevations of ESR and/or CRP usually are indicators of disease progression.2
Chemistries in RA can indicate a slight decrease in albumin and slight increase in total protein values—signs of a chronic inflammatory process.1 In addition, iron values are also reduced.
Approximately 25% to 35% of patients with RA have mild anemia (ie, hematocrit values between 30% and 34%). The reduced red cell mass may be associated with anemia of chronic disease or with true iron-deficiency anemia secondary to intercurrent blood loss from gastrointestinal bleeding caused by nonsteroidal anti-inflammatory drugs (NSAIDs).
The white-cell count in RA is either normal or slightly elevated as a sign of inflammation. The platelet count also usually is normal, but inflammation may cause thrombocytosis.1
1. Harris ED Jr. Clinical features of rheumatoid arthritis. In: Kelley WN, Harris ED Jr, Ruddy S, et al, eds. Textbook of Rheumatology. 5th ed. Philadelphia, PA: WB Saunders; 1997;
2. Pincus T. Laboratory tests in rheumatic disorders. In: Klippel JH, Dieppe PA, eds. Rheumatology. Vol 1. 2nd ed. London, UK: Mosby; 1998:

25. RHEUMATOID ARTHRITIS Rheumatoid Factor
Most common autoantibody in RA
Binds to the Fc portion of IgG molecule
Usually an IgM antibody
Less often an IgG or IgA antibody
Detected in 70-80% of RA patients
High titer predicts adverse outcome
Erosive arthritis, vasculitis

26. Rheumatoid Factor Methods of detection
agglutination IgG coated latex beads or erythrocytes
laser nephelometry
indirect immunofluorescence
radioimmuno assay
enzyme-linked immunosorbent assay

27. RHEUMATOID ARTHRITIS Disease associated with +RF
Autoimmune diseases
Infectious diseases (viral, bacterial, parasitic infections
other hyper--globulinemic states
Malignant conditions
Aging (up to 3% of the elderly population

28. RHEUMATOID ARTHRITIS Disease associated with +RF
Autoimmune diseases
rheumatoid arthritis
systemic lupus erythematosus
scleroderma
mixed connective tissue disease
Sjogren’s syndrome

29. RHEUMATOID ARTHRITIS Disease associated with +RF
Viral disease
AIDS
mononucleosis
hepatitis
influenza

30. RHEUMATOID ARTHRITIS Disease associated with +RF
Parasitic infections
trypanosomiasis
malaria
Kala-azar
schistosomiasis
filariasis

31. RHEUMATOID ARTHRITIS Disease associated with +RF
Chronic bacterial infections
tuberculosis
syphilis
leprosy
brucellosis
yaws
salmonellosis
Infective endocarditis

32. RHEUMATOID ARTHRITIS Disease associated with +RF
other hyper--globulinemic states
hyper--globulinemic purpura
Cryoglobulinemia (>90%)
chronic liver disease
Sarcoidosis
Sjogren syndrome
other chronic pulmonary diseases

33. At least 4 of the following criteria Morning stiffness >1 hour
RHEUMATOID ARTHRITIS Diagnosis of Rheumatoid Arthritis American College of Rheumatology Criteria
At least 4 of the following criteria
Morning stiffness >1 hour
Arthritis of 3 joint areas
Arthritis of hand joints
Symmetric arthritis
Rheumatoid nodules
Serum rheumatoid factor
Radiographic changes
Must be present for at least 6 weeks
Slide 13 Notes. Diagnosis of Rheumatoid Arthritis: American College of Rheumatology Criteria
The revised clinical criteria for the diagnosis of rheumatoid arthritis published in 1987 by the American College of Rheumatology are generally accepted today. At least 4 of the following 7 criteria must be present, with the first 4 being present for 6 weeks or more.
Morning stiffness in and around the joints lasting more than 1 hour before maximal improvement.
Physician-observed simultaneous soft tissue swelling (arthritis) or fluid present in 3 or more of 14 joints: right or left proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrist, elbow, knee, ankle, or metatarsophalangeal (MTP).
Soft tissue swelling in at least one area of the wrist; MCP, or PIP joint.
Simultaneous involvement of the same joint areas bilaterally.
Physician-observed rheumatoid nodules over bony prominences, on extensor surfaces, or in juxtaarticular regions.
Abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in <5% of normal controls
Changes typical of RA on posteroanterior hand and wrist radiographs; changes must include erosions or bony decalcification localized in or most marked next to involved joints.
Arnett FC et al. Arthritis Rheum. 1988;31:315–324.
Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:

34. RHEUMATOID ARTHRITIS Radiological Features
Progressive MCP erosion
Thinning of the radial side of the cortex with minimal disturbance of underlying trabeculae and minimal joint space narrowing. A marginal erosion (C) appears on the radial aspect of the metacarpal head. There is loss of bone substance and joint space narrowing.

35. Subcutaneous nodules
Nodules occur in about 20-50% of patients with RA and are usually associated with high titers of rheumatoid factor.
Subcutaneous nodules are also seen in other conditions such as SLE and mixed connective tissue disease.
Methotrexate may enhance development.

36. 2010 Rheumatoid Arthritis Classification Criteria
An American College of Rheumatology/European League Against Rheumatism
Collaborative Initiative
Daniel Aletaha,1 Tuhina Neogi,2 Alan J. Silman,3 Julia Funovits,1 David T. Felson,2
Clifton O. Bingham, III,4 Neal S. Birnbaum,5 Gerd R. Burmester,6 Vivian P. Bykerk,7
Marc D. Cohen,8 Bernard Combe,9 Karen H. Costenbader,10 Maxime Dougados,11
Paul Emery,12 Gianfranco Ferraccioli,13 Johanna M. W. Hazes,14 Kathryn Hobbs,15
Tom W. J. Huizinga,16 Arthur Kavanaugh,17 Jonathan Kay,18 Tore K. Kvien,19 Timothy Laing,20 Philip Mease,21 Henri A. Menard,22 Larry W. Moreland,23 Raymond L. Naden,24 Theodore Pincus,25 Josef S. Smolen,1 Ewa Stanislawska-Biernat,26 Deborah Symmons,27Paul P. Tak,28 Katherine S. Upchurch,18 Jirˇi Vencovsky’,29
Frederick Wolfe,30 and Gillian Hawker31

37. Table 3. The 2010 American College of Rheumatology/European League Against Rheumatism classification. criteria for rheumatoid arthritis Score
Target population (Who should be tested?): Patients who
1) have at least 1 joint with definite clinical synovitis (swelling)*
2) with the synovitis not better explained by another disease†
Classification criteria for RA (score-based algorithm: add score of categories A–D;
a score of 6/10 is needed for classification of a patient as having definite RA)‡
† Differential diagnoses vary among patients with different presentations, but may include conditions such as systemic lupus erythematosus, psoriatic arthritis, and gout. If it is unclear about the relevant differential diagnoses to consider, an expert rheumatologist should be consulted.
‡ Although patients with a score of 6/10 are not classifiable as having RA, their status can be reassessed and the criteria might be fulfilled cumulatively over time.

38. Table 3. The 2010 American College of Rheumatology/European League Against Rheumatism classification. criteria for rheumatoid arthritis Score
A. Joint involvement§
-1 large joint. 0
-large joints 1
-3 small joints (with or without involvement of large joints)# 2
-10 small joints (with or without involvement of large joints) 3
-10 joints (at least 1 small joint)** 5
B. Serology (at least 1 test result is needed for classification)††
-Negative RF and negative ACPA 0
-Low-positive RF or low-positive ACPA 2
-High-positive RF or high-positive ACPA 3
C. Acute-phase reactants (at least 1 test result is needed for classification)‡‡
-Normal CRP and normal ESR 0
-Abnormal CRP or abnormal ESR 1
D. Duration of symptoms§§
-6 weeks 0
-6 weeks 1

39. The criteria are aimed at classification of newly presenting patients
* The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease typical of rheumatoid arthritis (RA) with a history compatible with prior fulfillment of the 2010 criteria should be classified as having RA. Patients with longstanding disease, including those whose disease is inactive (with or without treatment) who, based on retrospectively available data, have previously fulfilled the 2010 criteria should be classified as having RA.

40. § Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment. Categories of joint distribution are classified
according to the location and number of involved joints, with placement into the highest category possible based on the pattern of joint involvement.
. “Large joints” refers to shoulders, elbows, hips, knees, and ankles.
# “Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.
** In this category, at least 1 of the involved joints must be a small joint.

41. RHEUMATOID ARTHRITIS Prognostic factors
Clinical course unpredictable but mostly progressive
Unfavorable prognostic markers
– Male sex – Eosinophilia
– Low socioeconomic status – Elevated ESR or CRP
– Subcutaneous nodules – High RF factor titer
– Systemic signs – Antinuclear antibodies
– Persistent synovitis – Cryoglobulins
– Thrombocytosis – Shared epitope (?)
Disease activity reduced faster and radiographic evidence of joint damage lessened with early diagnosis and treatment
Slide 14 Notes. Rheumatoid Arthritis: Clinical Course
The clinical course of RA is highly variable and difficult to predict. Slow progression of joint symptoms is typical and is interspersed with flares and remissions.1
Unfavorable prognostic markers in RA include male sex, low socioeconomic status, lack of formal education, subcutaneous nodules, systemic manifestations, severe initial clinical disease activity, persistent synovitis, thrombocytosis, eosinophilia, elevated ESR or CRP, high rheumatoid factor titer, antinuclear antibodies, cryoglobulins, circulating immune complexes, elevated C1q levels, complement activation, early erosive changes.1 The presence of shared epitope also may indicate unfavorable prognosis; however, this remains to be confirmed.
Early erosions visible in radiographs are associated with severe disease and rapid progression. A better outcome is likely if RA is diagnosed and treatment is begun before these erosions occur.2 A recent observational study of patients with early RA confirmed that early and continuous treatment with disease modifying antirheumatic drugs (DMARDs) reduces disease activity more rapidly than delayed treatment and results in less radiographic damage after 5 years.3
Albers JMC et al. Ann Rheum Dis. 2001;60:453–458. Grassi W et al. Eur J Radiol. 1998;27(suppl 1):S18–S24.
1. Grassi W, De Angelis R, Lamanna G, Cervini C. The clinical features of rheumatoid arthritis. Eur J Radiol. 1998;27(suppl 1):S18-S24.
2. Kim JM, Weisman MH. When does rheumatoid arthritis begin and why do we need to know? Arthritis Rheum. 2000;43:
3. Albers JMC, Paimela L, Kurki P, et al. Treatment strategy, disease activity, and outcome in four cohorts of patients with early rheumatoid arthritis. Ann Rheum Dis. 2001;60:

42. RHEUMATOID ARTHRITIS Clinical Course of RA
Severity of Arthritis
Years
Type 1 = Self-limited—5% to 20%
Type 2 = Minimally progressive—5% to 20% Type 3 = Progressive—60% to 90%

43. Rheumatoid Arthritis: Typical Course
Damage occurs early in most patients
50% show joint space narrowing or erosions in the first 2 years.
By 10 years, 50% of young working patients are disabled.
Death comes early
Multiple causes
Compared to general population
Women lose 10 years, men lose 4 years

44. TREATMENT OF RHEUMATOID ARTHRITIS Goals of Therapy
Relieve symptoms, including fatigue, pain, swelling, and stiffness
Prevent joint destruction, loss of joint function, deformity, disability, and early death
Preserve quality of life
Achieve clinical remission
Slide 16 Notes. Treatment of Rheumatoid Arthritis: Goals of Therapy
Relief of fatigue and joint pain, swelling, and stiffness is still an essential goal of treatment.
A second goal of treatment is to prevent joint destruction and loss of joint function, which can lead to deformity, disability, and premature death.1 This treatment objective is becoming increasingly important with the realization that early, aggressive treatment of RA using DMARDs can actually prevent the progression of joint damage and bony erosions.
As with any chronic disease causing significant pain and physical disability, preservation of quality of life is essential.
Although a cure for RA has not been discovered, the development of new, highly effective disease-modifying drugs such as DMARDs will enable many patients to achieve clinical remission.3
1. Kremer JM. Rational use of new and existing disease-modifying agents in rheumatoid arthritis. Ann Intern Med. 2001;134:
2. van de Putte LBA, van Gestel AM, van Riel PLCM. Early treatment of rheumatoid arthritis: Rationale, evidence, and implications. Ann Rheum Dis. 1998;57:
3. Möttönen T, Paimela L, Leirisalo-Repo M, Kautiainen H, Ilonen J, Hannonen P. Outcome of patients with early rheumatoid arthritis over a two year period. [Author’s reply.] Ann Rheum Dis. 1999;58:323.

45. TREATMENT OF RHEUMATOID ARTHRITIS General Approach
Start treatment early to prevent joint damage
Institute general therapeutic measures: education, exercise, rest, joint protection, physical therapy
Prescribe medications for symptom relief
Prescribe DMARDs to prevent joint damage and induce remission. Low dose steroids, Biologics
Consider surgery in selected cases
Slide 17 Notes. Treatment of Rheumatoid Arthritis: General Approach
Early treatment of RA is advised to prevent the joint damage that leads to deformity and disability as the disease progresses.1,2
General therapeutic measures include patient education, a balance between exercise and rest, protection of affected joints, and physical and occupational therapy. Education should stress the chronic nature of RA and the importance of weight control, exercise, rest, and proper nutrition. It also should include information about management options during the course of the disease and potential side effects of prescribed medications. Inflamed joints can be splinted to prevent excess movement, and canes and walkers can be used to reduce stress on affected joints.1
NSAIDs and corticosteroids (eg, prednisone) are used to provide symptomatic relief in RA.
DMARDs have the potential to improve long-term outcomes in RA.1,2
In selected patients, surgical intervention often is used to reduce or eliminate pain and restore function in specific joints.2
1. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Guidelines for the management of rheumatoid arthritis. Arthritis Rheum. 1996;39:
2. Kremer JM. Rational use of new and existing disease-modifying agents in rheumatoid arthritis. Ann Intern Med. 2001;134:

46. TREATMENT OF RHEUMATOID ARTHRITIS Measurement of Treatment Effects
Clinical assessment of inflammatory synovitis
Swollen joint count, tender joint count
Laboratory assessment of inflammatory synovitis
Acute phase reactants (eg, ESR, CRP)
Assessment of physical function
Stanford Health Assessment Questionnaire (HAQ)
Short-Form 36 Health Survey (SF-36)
Assessment of structural joint damage
Radiography (ultrasound and magnetic resonance imaging)
Slide 18 Notes. Treatment of Rheumatoid Arthritis: Measurement of Treatment Effects
Thorough assessment of the efficacy of any treatment for RA entails evaluating the extent of inflammatory synovitis and structural joint damage and the degree of physical function. Key laboratory measures of inflammatory activity are the ESR, CRP, and surrogate markers such as fibrinogen values and plasma viscosity.1
A widely accepted means of evaluating the extent of inflammatory synovitis is to count the number of swollen and tender joints.
The Stanford Health Assessment Questionnaire (HAQ) is a widely used measure of physical function.2
Structural joint damage is assessed and monitored using radiography. Ultrasound and magnetic resonance imaging also may have utility in assessing joint structure.3
ACR ad hoc Committee on Clinical Guidelines. Arthritis Rheum. 1996;39:713–722. Grassi W et al. Eur J Radiol. 1998;27(suppl 1):S18–S24.
1. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Guidelines for the management of rheumatoid arthritis. Arthritis Rheum. 1996;39:
2. Grassi W, De Angelis, Lamanna G, Cervini C. The clinical features of rheumatoid arthritis. Eur J Radiol. 1998;27(suppl 1):S18-S24.
3. Van Riel PLCM, van Gestel AM. Clinical outcome measures in rheumatoid arthritis. Ann Rheum Dis. 2000;59 (suppl 1):

47. Improvement in at least 3 of the following 5 measures
TREATMENT OF RHEUMATOID ARTHRITIS ACR Response Criteria ACR20 / ACR50 / ACR70
 20% / 50% / 70% improvement in
Swollen joint count
Tender joint count
Improvement in at least 3 of the following 5 measures
Patient’s global assessment of disease activity
Physicians’ global assessment of disease activity
Patient’s assessment of pain
Acute-phase reactant (ESR, CRP)
Disability (HAQ)
Slide 19 Notes. Treatment of Rheumatoid Arthritis: ACR Response Criteria: ACR20 / ACR50 / ACR70
One widely accepted composite measure of improvement in RA is the American College of Rheumatology (ACR) response criteria.
ACR20 refers to a composite improvement of 20% in swollen joint count, tender joint count (both joint counts based on an assessment of 28 or more joints), and 3 or more of the following measures1:
Patient’s own global assessment of RA disease activity
Physician’s assessment of disease activity
Patient’s own assessment of pain due to RA
Acute-phase reactant (ESR, CRP)
Disability (HAQ)
Following is an example of a patient who has achieved an ACR20 response after a 4-week treatment period:
The number of tender joints is reduced from 28 to 22 (>20% improvement)
The number of swollen joints is reduced from 30 to 24 (20% improvement)
The patient rates how well he is doing (ie, global assessment of RA disease activity) using a 100-mm visual analog scale or a Likert scale; disease activity is reduced by 20 out of 100 mm (20% improvement)
The physician’s assessment of the patient’s current disease activity is decreased by 30 mm out of a 100-mm visual analog scale or a Likert scale (>20% improvement)
The patient assesses his current level of pain using a 100-mm visual analog scale or a Likert scale; his level of pain is reduced by 30 mm (>30% improvement)
There is no change in ESR rate or C-reactive protein level (no improvement)
The patient reports a 15% improvement in scores on the HAQ (<20% improvement)1
This patient satisfied the required 20% improvement in tender joint count and swollen joint count and improved by 20% in 3 of the 5 remaining assessments.1
ACR50 and ACR70 refer to a standard of 50% and 70% improvement in the preceding measures, respectively.2
The ACR response criteria provide a relative measure that refers to the individual patient’s baseline disease activity, with 3 of its 7 criteria assessed by the patient and 4 of 7 assessed by the physician.
Felson DT et al. Arthritis Rheum. 1995;38:727–735.
Felson DT et al. Arthritis Rheum. 1998;41:1564–1570.
1. Felson DT, Anderson JJ, Boers M, et al. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38:
2. Felson DT, Anderson JJ, Lange ML, Wells G, LaValley MP. Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent? Arthritis Rheum. 1998;41:

48. DAS = 0.54 • (RAI) + 0.065 • (sw) + 0.33•Ln(ESR) + 0.0072•GH
TREATMENT OF RHEUMATOID ARTHRITIS Disease Activity Score (DAS) Assessment of Improvement or Response
DAS = 0.54 • (RAI) • (sw) •Ln(ESR) •GH
RAI = number of tender joints (t) calculated using Ritchie Articular Index
Number of swollen joints (sw)
Erythrocyte sedimentation rate (ESR, mm/hour)
General health status (GH) using a 100-mm visual analog scale (VAS)
Slide 20 Notes. Treatment of Rheumatoid Arthritis: Disease Activity Score (DAS): Assessment of Improvement or Response
The disease activity scale (DAS) is a composite index that enables clinicians to assess a patient’s level of disease activity from baseline to follow-up, so that disease progression can be assessed or response to treatment evaluated.
The DAS can be calculated using the equation shown. It includes 4 variables: (1) the Ritchie Articular Index (RAI) (a value determined by the number of tender joints), (2) the number of swollen joints, (3) ESR, and (4) general health (GH) status assessed by the patient using a 100-mm visual analog scale (VAS).
The RAI, with a multiplier of 0.54, is given the most weight in the equation, indicating that the number of tender joints is the greatest determining factor in the DAS.
Using the DAS, a patient is determined to have high disease activity if his or her DAS score is >3.7 and low disease activity if DAS score is 2.4, and is considered to be in remission if DAS score falls below 1.6.
High disease activity >3.7, low disease activity 2.4, remission <1.6
van der Heijde DMFM, van’t Hof MA, van Riel PLCM, et al. Judging disease activity in clinical practice in rheumatoid arthritis: First step in the development of a disease activity score. Ann Rheum Dis.1990;49:

49. TREATMENT OF RHEUMATOID ARTHRITIS EULAR Response Criteria
Decrease in DAS
Present Score
>1.2 >0.6 to 1.2 0.6
Good
DAS  2.4
2.4 < DAS  3.7
DAS > 3.7
Moderate
Slide 21 Notes. Treatment of Rheumatoid Arthritis: EULAR Response Criteria
The European League Against Rheumatism (EULAR) response criteria are based on the Disease Activity Score (DAS) in patients with RA. These criteria were developed by combining changes from baseline and level of disease activity during follow-up.
The EULAR criteria define a “good response” as a >1.2 improvement (ie, decrease) in the DAS from baseline and low disease activity (ie, a DAS score of 2.4) during follow-up.
A “moderate response” is defined as a decrease in the DAS from baseline ranging from >0.6 to 1.2 and either low (DAS 2.4) or moderate (DAS >2.4 but 3.7) disease activity at follow-up. Patients who had an improvement of >1.2 in DAS but who had moderate (DAS >2.4 to 3.7) or high (DAS >3.7) disease activity at follow-up also were considered to have moderate responses.
Patients were considered to be “nonresponders” if they had an improvement in DAS of 0.6, regardless of their disease activity during follow-up (low, moderate, or high). They also were considered to be nonresponders if their disease activity was high (DAS >3.7) during follow-up but their improvement in DAS ranged from >0.6 to 1.2.
The EULAR Response Criteria provide an absolute measure of disease activity improvement as they refer to the absolute measure of DAS.
None
EULAR = European League Against Rheumatism; DAS = Disease activity score.
van Gestel AM et al. Arthritis Rheum. 1996;39:34–40. Copyright © 1996 American College of Rheumatology. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.
van Gestel AM, Prevoo MLL, van ‘t Hof MA, van Rijswijk MH, van de Putte LBA, van Riel PLCM. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism criteria. Arthritis Rheum. 1996;39:34-40.

50. Chronic Inflammation in the Rheumatoid Synovium
Activated T cells
Pannus
Macrophage
& DCs
PMN
B cell
Cytokine
Inflamed
synovial membrane
Bone
Eroding cartilage

51. Chronic Inflammation in the Rheumatoid Synovium
Activated T cells
Pannus
Cyclosporine
Azathioprine
Cyclophosphamide
Macrophage
& DCs
PMN
Anti-signaling
B cell
Cytokine
Rituximab
Inflamed
synovial membrane
Anti-cytokines
Bone
Anti-MMPs
Eroding cartilage

52. Drugs used in RA “Symptomatic” treatment simple analgesics
NSAIDs/ COX inhibitors
(glucocorticoids)

53. Disease modifying agents
Glucocoticoids
Gold
Antimalarials
Sulfasalazine
Methotrexate
Immunosuppressives
Anti-Cytokines
-Halt or prevent joint
damage
-Preserve joint integrity
and function
-Slow acting
-Toxicity problems

54. Biologics Anti-TNF: Infliximab, Etanercept, Humira Anti-IL1b Anti-IL-6
Anti-CD20, rituximab
Anti Jak-Stat signaling
Others

55. TNF osteoclasts synoviocytes chondrocytes joint inflammation cartilage
degradation
bone resorption
pain/joint
inflammation
joint space
narrowing
bone erosion

56. Role of TNFa in RA
Up-regulation of-TNF receptor expression in synoviocytes, chondrocytes and osteoclasts
Induction of secretion of serine proteases (matrix metalloproteinases, MMP’s)
TNFa – modulates angiogenesis
Up-regulation of adhesion molecules (ICAM-1, VCAM etc.)

57. Infliximab (cA2): A Chimeric anti-human TNFa Monoclonal Antibody
V region:A2- A mouse anti-human TNFa monoclonal antibody constant part: A human IgG1-k
cA2 (Infliximab): chimeric (human-mouse) anti-human TNFa neutralizing antibody
Mouse
(Binding site for TNF)
Human (IgG1) 

58. ATTRACT Trial Mean Change in Total Modified Sharp Score
12.6 12 10
*p < vs placebo + MTX 8
Mean change from BL 6 4 2
1.0*
1.1*
1.0*
 0.4*
3 mg/kg
q 8 wk
3 mg/kg
q 4 wk
10 mg/kg
q 8 wk
10 mg/kg
q 4 wk
Placebo
Lipsky.NEMJ 343: 1594,

59. ATTRACT Trial Mean Improvement HAQ (102 Week).6
.5*
.5* .5
.4*
.4* .4
Change in HAQ .3 .2 .2 .1
*p<.001
3 mg/kg
q 8 wk
3 mg/kg
q 4 wk
10 mg/kg
q 8 wk
10 mg/kg
q 4 wk
Placebo
Lipsky.NEMJ 343: 1594,

60. Anti-immunoglobulin antibodies-anti-idiotype, anti-allotype
5-30% after a single dose up to 50% in repeated dosing Allergic reactions, anaphylaxsis
Need for concomitant methotrexate therapy
Infections
Malignancies
Cost $12,000 year

61. Etanercept: A Recombinant sTNF-R:Fc Fusion Protein
Recombinant human TNF-receptor p75-two chains +
Fc of a human IgG1
TNFR:Fc- Etanercept aTNF neutralizing protein

62. ACR Responses Months ACR20 % patients ACR50 ACR70 80 70 60 50 40 30 2010 6 12 18 24 30 36 42
Months
Moreland. Arthritis Rheum

63. Change in Total Sharp Scores and Erosions Over Two Years
Etanercept 25 mg
Methotrexate 20 mg
Total Sharp Scores
Erosions 4 4 * 3 3
Change from baseline (mean) 2 2 * 1 1 6 12 18 24 6 12 18 24
Months
Months
*p = 0.001
*p = 0.001
Genovese. Arthritis Rheum

64. R Fleischmann1, R Burgos-Vargas2, P Ambs3, E Alecock4, J Kremer5
LITHE: Tocilizumab inhibits radiographic progression and improves physical function in rheumatoid arthritis patients at 2 yrs with increasing clinical efficacy over time
R Fleischmann1, R Burgos-Vargas2, P Ambs3, E Alecock4, J Kremer5
1Metroplex Clinical Research Center, Dallas, TX, USA; 2Hospital General de México, Mexico; 3Roche, Basel, Switzerland, 4Roche, Welwyn, UK, 5Albany Medical College, Albany, NY, USA

65. LITHE: Study design Open-label TCZ 8mg/kg Double-blind N=1196
or double-blind
Optional Extension Years 3–5
Double-blind
N=1196
Randomization
1:1:1
TCZ 8 mg/kg + MTX (n=399)
TCZ 4 mg/kg + MTX (n=399)
Open-
label R
All other
DMARDs D/C anti-TNF
washout
Placebo + MTX (n=392)
Day 1
Rescue
1 Year
2 Year
Screening
מחקר ה LITHE נערך על אוכלוסיית נכשלי MTX. המחקר מתוכנן לחמש שנים ובודק את יעילות ובטיחות אקטמרה+MTX, וכן את עיכוב הנזק המפרקי: בשנה הראשונה של המחקר היו שלוש זרועות – פלסבו+MTX, אקטמרה במינון 4 מ"ג/ק"ג + MTX, ואקטמרה במינון 8 מ"ג/ק"ג + MTX עם אפשרות לטיפולי הצלה. המטרה בשנה זו היתה להשוות את היעילות והבטיחות של שלוש זרועות הטיפול השונות.
בשנה השנייה החולים יכלו לעבור לקבל אקטמרה במינון 8מ"ג/ק"ג +MTX או להישאר בטיפול הסמוי שלהם אם השיגו שיפור של יותר מ 70% במספר המפרקים הנפוחים והרגישים לאחר שנה של טיפול.
Rescue 1: Patients who failed to respond to treatment at 16 weeks were offered rescue therapy with tocilizumab (blinded dose)
Rescue 2: Patients who failed to respond to Rescue 1 were offered a second step of tocilizumab rescue therapy at any time between Week 28 and Week 52 (Rescue 2)
Double-blind therapy in Year 2: Patients who responded to treatment at Weeks 48 and 52 (>70% reduction in swollen joint count [SJC] and tender joint count [TJC]) could remain on their blinded therapy

66. Results: Tocilizumab significantly inhibits radiographic progression at 2 years
Placebo + MTX (n=393)
TCZ 4 mg/kg + MTX (n=398)
TCZ 8 mg/kg + MTX (n=398)
p≤0.0025*
1.96
2.0 90
p≤0.0239* 83
1.8 80 75
1.6 70 66
1.4
81% inhibition 60
1.2
Mean change from baseline in GmTSS
Patients without GmTSS progression (%) 50
1.0 40
p≤0.0025*
התוצאות - אקטמרה מעכבת בצורה משמעותית את הנזק המפרקי: לאחר שנתיים טיפול הושג עיכוב של 81% בהתקדמות הנזק המפרקי בקבוצת מטופל האקטמרה לעומת קבוצת הפלסבו. כמו כן בצד הימני של השקופית ניתן לראות שאצל 83% ממטופלי האקטמרה היתה עצירה של התקדמות הנזק המפרקי בזכות הטיפול, מה שמאפשר שמירה על תפקוד תקין לאורך זמן
0.8
0.58
p≤0.0025* 30
0.6
0.37 20
0.4
0.2 10
0.0
GmTSS = Genant-modified total Sharp score Linear extrapolation used for missing data (post-rescue data set to missing) * vs. placebo + MTX
Oral #637

67. Results: DAS28 remission* rates increase over time in MTX-IR patients
TCZ 8 mg/kg + MTX (n=275)
TCZ 8 mg/kg + MTX (n=241) 70 65 60 48 50
Patients (%) 40 30
ומבחינת אחוזי הרמיסיה – כזכור אחד מכל שלושה חולים מגיע להפוגה מהמחלה לאחר חצי שנת טיפול באקטמרה. במחקר ה LITHE – לאחר שנה של טיפול אחוזי הרמיסיה אף עלו והגיעו לכ-50%, כלומר – אחד מכל שני חולים היה בהפוגה מהמחלה. ובמעקב לאורך שנתיים טיפול – 65% מהמטופלים היו ברמיסיה. כלומר – שניים מכל שלושה מטופלים נהנו מהפוגה מהמחלה לאחר שנתיים של טיפול באקטמרה. כך שיעילות אקטמרה אף הולכת וגוברת עם משך זמן הטיפול. 20 10
Week 52
Week 104
*DAS28 <2.6 Last observation carried forward approach used for SJC and TJC for patients who received rescue therapy or withdrew from that time point
Oral #637

68. SAFETY: LONG TERM SAFETY – 2. 4 YEARS SIE
SAFETY: LONG TERM SAFETY – 2.4 YEARS SIE. CV events, lipid profile, liver enzymes
בעדכוני הבטיחות נפרט על שיעור הזיהומים החמורים, ממאירויות, אירועים קרדיווסקולרים, והשפעת אקטמרה על פרופיל הליפידים ואנזימי הכבד לאורך זמן

69. Results: Overall safety profile
All patients receiving ≥1 dose of tocilizumab (n=4,009)
Total treatment exposure (PY)
9,414
Discontinuations due to AEs per 100 PY
5.8
SAEs per 100 PY
14.91
Serious infections per 100 PY
4.7
Deaths per 100 PY
0.53
Deaths from infection per100 PY
0.13
עד פברואר 2009 נצברו מעל 9000 שנות חולה, כאשר שיעור הזיהומים החמורים הינו שיעור נמוך של 4.7 ל-100 שנות חולה. עד כה היו בסה"כ 7 מקרים של ריאקטיבציה של TB. הזיהומים החמורים השכיחים ביותר היו פנומוניה וצלוליטיס, שזהו הפרופיל הבטיחותי המוכר לנו מהטיפולים הביולוגים האחרים.
PY = patient-years SAE = serious adverse event
Oral #1955

70. Summary
ACTEMRA demonstrates high DAS28 remission rate across all patients types
long-term treatment with Actemra is associated with ongoing improvements in the clinical signs and symptoms of RA
Laboratory abnormalities were consistent with the mechanism of action of tocilizumab and could be effectively managed: lipids, cytopenias
The safety profile of Actemra in long-term follow-up was consistent with that seen in 24-week controlled studies
לסיכום:
אקטמרה משיגה שיעורי הפוגה גבוהים בכל אוכלוסיות החולים, כאשר שיעורי ההפוגה ונתוני היעילות האחרים אף הולכים ועולים עם משך הטיפול.
לאקטמרה פרופיל בטיחותי טוב, אשר נשאר עקבי לאורך תקופת המעקב הארוכה. כמו כן השינויים המעבדתיים קרו בחלק קטן מהחולים וניתנים לטיפול באופן אפקטיבי.
Oral #1955