2. RHEUMATOID ARTHRITIS(RA)
Is a complex systemic
inflammatory condition
manifesting initially as symmetric
swollen and tender joints of the
hands and/or feet.
It results from complex
interaction b/n genes and env’t,
leading to a breakdown of
immune tolerance and synovial
inflammation in a characteristic
symmetric pattern.
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3. EPIDEMIOLOGY
•RA is estimated to have a
prevalence of 1%
•It can occur at any age
•3 females to 1 males
•Increasing age (peak onset 35–50
years of age)
• Current tobacco smoking
• Family Hx of RA
• Stress may influence RA onset
and disease activity
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4. AETIOLOGY
The cause of RA remains unknown.
• Variations between ethnic groups in susceptibility
to RA,
• Heterogeneity of disease course
• variations in clinical, radiological and laboratory
findings within groups
Strongly suggest that multiple factors,
both environmental and genetic,
influence onset and progression of
RA.
From an immunological point of view
RA is considered an autoimmune
disease
Factors contributing to RA development
• Genetic variations
• autoantibodies
• cellular immune responses
• hormones & gene-environment interactions
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5. PATHOPHYSIOLOGY(1)
Chronic inflammation of the synovial
tissue lining the joint capsule results
in the proliferation of this tissue which
invades the cartilage and eventually
the bone surface;
The ability of the immune
system to differentiate between
self and non-self is lost and
attacks synovial and other
connective tissues
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6. PATHOPHYSIOLOGY (2)
Rheumatoid arthritis is characterised by
the infiltration of a variety of inflammatory
cells into the joint.
The synovial membrane becomes highly
vascularised and hypertrophied, creating
a so called pannus formation.
There is proliferation of synovial fibroblasts
and an increase in the number of
inflammatory cells present within the joint.
Erosion of bone and cartilage destruction of the joint.
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7. PATHOPHYSIOLOGY (3)
The inflammatory cells involved include
T-cells (CD4) B-cells, macrophages and
plasma cells.
Cytokines cause the synovium to release
proteolytic enzymes, results in
destruction of bone and cartilage.
Key cytokines involved in rheumatoid
arthritis include Tumour necrosis factor
(TNF)-α, interleukin-1, interleukin- 6
and granulocyte macrophage colony-
stimulating factor (GM-CSF).
End results of the chronic inflammation
• Loss of cartilage results in loss of the
joint space.
• Formation of scar tissue leads to loss
of joint motion or bony fusion (known
as ankylosis).
• Tendon contracture leads to chronic
deformity
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8. PATHOPHYSIOLOGY (4)
Rheumatoid Factor
Are antibodies directed against the Fc
portion of immunoglobulin G (IgG)
Anti Citrullinated Peptide antibody
The autoantibody most likely directly
related to RA-pathogenesis, targets
proteins containing the atypical amino-
acid citrullin.
Active citrullination has been detected in
RA synovium, whereas citrullinated
proteins are absent from healthy joints
Genetic factors
Contribute 53-65% of the risk of developing
this disease.
Most of genetic risks are associated with the
ACPA-positive subgroup of RA patients
Environmental Risk Factors
some environmental factors may have specific
effects directly related to RA-pathogenesis
whereas others might have non-specific effects
promoting inflammation in general
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9. CLINICAL PRESENTATION AND Dx. (1)
Symptoms
Nonspecific systemic symptoms : fatigue, weakness,
anorexia, & diffuse musculoskeletal pain.
Pain in involved joints and prolonged morning joint
stiffness.
Signs
The metacarpophalangeal (MCP), proximal
interphalangeal (PIP), metatarsophalangeal (MTP),
and wrist joints are involved frequently.
• Joint involvement is usually symmetric.
• Limited joint function.
• Swan neck and/or boutonniere deformities may be
present
• Signs of joint inflammation (tenderness,
warmth, swelling, and erythema).
• Low-grade fever
Extraarticular manifestations
• Skin: Subcutaneous nodules
• Ocular: Keratoconjunctivitis sicca, scleritis
• Pulmonary: Interstitial fibrosis, pleuritis,
• Vasculitis: leukocytoclastic vasculitis
• Neurologic: Peripheral neuropathy
• Hematologic: Anemia, thrombocytosis
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10. CLINICAL PRESENTATION AND Dx. (2)
Laboratory Tests
•Rheumatoid factor +ve
The test is -ve in up to 30% of patients
•Elevated ESR
ESR: > 20 mm/hour in men
> 30 mm/hour in women
•Elevated C-reactive protein
CRP> 0.7 mg/dL
•CBC:
Slight elevation in WBC, slight anemia
thrombocytosis
•Anticitrullinated protein Abs +ve
Other Diagnostic Tests
• Synovial fluid analysis:
Straw colored, slightly cloudy, WBC
5–25 × 103/mm3 (109/L),
no bacterial growth if cultured
• Joint x-rays: To establish baseline
and evaluate joint damage
• MRI: May detect erosions earlier in
the course of disease than x-rays
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11. TREATMENT (1)
Desired outcomes
1. Reduce or eliminate pain
2. Protect articular structures
3. Control systemic complications
4. Prevent loss of joint function
5. Improve/maintain quality of life.
Non- Pharmacologic Treatment
Rest : Reduces Pain and stress on joints
Occupational therapy
Physical therapy
Use of assistive devices
Weight reduction
Surgery (Tenosynovectomy, tendon repair,
and joint replacements)
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12. TREATMENT (2)
Pharmacologic therapy
Non-steroidal anti-inflammatory drugs
Glucocorticoids,
DMARDs
Should be started within the first 3
months of symptom onset for better
outcome
Biologic response modifiers (BRM)
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Data
adapted
from
ACR/EULAR
2010
Classification
Criteria
for
Rheumatoid
Arthritis
TOTAL: 6 or greater indicates definite RA
13. TREATMENT (3)
NSAIDs
Provide analgesic and anti-inflammatory
benefits for joint pain and swelling.
Associated with an increased risk of GI
ulcers or hemorrhage, fluid retention,
exacerbation of existing hypertension,
and decreased renal function in certain
patient populations
Do not prevent joint damage or
change the underlying disease.
Proton pump inhibitor or histamine-2
receptor blocker or misoprostol co-
administered with NSAIDs as a
prophylaxis for highly risk group of
patient
NSAIDs and DMARDs have steroid-
sparing properties that permit
reductions of corticosteroid doses.
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14. TREATMENT (4)
Glucocorticoids
Used in RA for their anti-inflammatory
and immune suppressive properties
Mechanisms
Interfere with antigen presentation to T lymphocytes,
Inhibit prostaglandin and leukotriene synthesis
Inhibit neutrophil and monocyte superoxide radical
generation.
Low-dose glucocorticoid treatment
(prednisone ≤10 mg/day) effectively
reduces inflammation through inhibition
of cytokines and inflammatory mediators
and prevents disease progression.
Oral corticosteroids can be used in several ways.
oUsed in bridging therapy,
ocontinuous low-dose therapy
oshort-term high-dose bursts to control
flares
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15. TREATMENT (5)
Disease Modifying Anti Rheumatic Drugs
Are the mainstay of RA
treatment because they modify
the disease process and prevent
or reduce joint damage
Selection depends on
ΘDisease severity
ΘPatient characteristics
i.e. Comorbidities, likelihood of adherence
ΘCost
ΘClinician experience with the
medication
Methotrexate
It exerts its anti-inflammatory effect by
Inhibition purine biosynthesis
Inhibiting the production of certain cytokines.
Administered 7.5mg once per week within the 3
month of diagnosis until the patient has symptomatic
improvement or a maximum dose of 20 mg/week is
reached
Concomitant folic acid is given routinely to reduce
the risk of folate-depleting reactions induced by
methotrexate therapy eg, stomatitis, diarrhea, nausea,
alopecia, myelosuppression, and elevations in liver
function tests
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16. TREATMENT (6)
Serious adverse reactions include pulmonary
fibrosis and hepatotoxicity
If monotherapy does not produce complete
resolution of symptoms, methotrexate may be
used in combination with other DMARDs
methotrexate plus cyclosporine,
methotrexate plus hydroxychloroquine and/or
sulfasalazine,
methotrexate plus leflunomide, and
methotrexate plus infliximab or etanercept
Hydroxychloroquine and Sulfas
Hydroxychloroquine acts by stabilizing lysosomes
and decrease chemotaxis
Sulfasalazine, a prodrug, is cleaved by bacteria in the
colon into sulfapyridine and 5-aminosalicylic acid.
Sulfapyridine moiety is responsible for the agent’s
antirheumatic properties
If patients do not respond to methotrexate
monotherapy, adding one of these agents may
provide the benefit necessary to reduce symptoms
satisfactorily alazine
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17. TREATMENT (7)
The onset of action of hydroxychloroquine may
be delayed up to 6 weeks, and for sulphasalazine
antirheumatic effects should be seen in 2 months.
Hydroxychloroquine may cause retinal toxicity,
and patients must have their eyes examined at
least annually.
Starting sulfasalazine at low doses and titrating
slowly will minimize the nausea and abdominal
discomfort caused by the drug.
Leflunomide
Acts by inhibiting dihydroorotate dehydrogenase
An enzyme with in the mitochondria that supplies T-
lymphocytes with the necessary components to respond to
cytokine stimulation.
Begins with a loading dose (100 mg for 3 days) followed
by a maintenance dose (20 mg/day)
Undergoes enterohepatic circulation, the drug takes many
months to cleared from circulation
If therapy requires abrupt discontinuation (e.g. due to
toxicity or pregnancy), administering cholestyramine will
accelerate removal of leflunomide from the body
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18. TREATMENT (8)
Biologic Response Modifiers
Biologic response modifiers (BRMs) are
indicated in patients who have failed an
adequate trial of DMARD therapy.
They have no toxicity that requires
laboratory monitoring
Etanercept, Infliximab Anakinra , Abatacept
Rituximab
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Refference
• Pharmacotherapy principles & practice 5TH EDITION
• Dipiro pharmacotherapy handbook ninth edition
The systemic inflammation of RA leads to joint destruction, disability, and premature death. Juvenile idiopathic arthritis (JIA) is the most common form of arthritis in children.
Both linkage and association studies have established that the human leukocyte antigen (HLA)-DRB1 gene is the major genetic susceptibility locus for rheumatoid arthritis (RA). Interpretation of early studies of HLA associations in RA has been complicated by evolving changes in nomenclature and methods of HLA typing . Originally, HLA typing was achieved with immunological reagents.
It appears that individual major stressful life events do not play a significant role. Instead, chronic presence of minor stressors (daily hassles, work and relationship stress, financial pressures) may affect the immune response and RA disease activity.
Gender- Women before the menopause are affected three times more often than men with an equal sex incidence thereafter suggesting an aetiological role for sex hormones.’
Familial -There is an increased incidence in those with a family history of RA.
Genetic factors - Human leucocyte antigen (HLA)-DR4 and HLA-DRB1* 0404/0401 confer susceptibility to RA and are associated with development of more severe erosive disease
Genetic factors contribute 53-65% of the risk of developing this disease.
RF, present mostly as IgM-RF, but detectable in subgroups of patients also as IgG- and IgA-RF,
RF are thought to form immune complexes activating complement in the joint, which in turn leads to increased vascular permeability and the release of chemotactic factors recruiting immune-competent effector cells to the joint
Genetic Risk Factors
Comparisons between concordance rates in monozygotic twins in several populations indicate that approximately 50% of the variation in prevalence of RA is caused by genetic factors
Abs= antibody
Hydroxycholorquine and sulfasalazine are relatively inexpensive compared with the new biologic agents.
