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Rheumatoid arthritis (RA) (Complications (Cardiovascular: vasculitis,…
Rheumatoid arthritis (RA)
Chronic inflammatory disease of unknown etiology.
Progressive destruction of synovial joints
with loss of cartilage and bone, damaged temdons and ligaments
Fluctuating clinical course; unpredictable prognosis
Characterized by:
Loss of physical function and worse quality of life
Premature death (increased risk of coronary artery diseases)
clinical course
Type 1 = Self-limited—5% to 20%
Type 2 = Minimally progressive—5% to 20%
Type 3 = Progressive—60% to 90%
Causes of Death in RA: CV diseases, cancer, infections, renal, lung.
Epidemiology
most common inflammatory arthritis
Affects 1% of the population.
more in women
.
age of onset
20-40 yr
Peak age:
45 and 65
years
Pathophysiology
Genetic predisposition: ( monozygotic>dizygotic twins, MHC- HLA-
DR4
/DR1).
Environment (smoking, hormonal, viral)
Autoimmunity & Inflammation
HLA Antigen
Ankylosing Spondylitis B27
Reactive Arthritis B27
Lupus DR3
Rheumatoid Arthritis DR4
Synovial inflammation
Synovitis:
proliferation of synovial lining cells
influx of mononuclear cells
angiogenesis
Pannus:
the component of the inflamed synovium that invades cartilage and bone
Joint effusion:
influx of neutrophils into synovial fluid
cytokine production
Macrophage-derived cytokines: Proinflammatory cytokines: TNF-a, IL-1, IL-6
T cell cytokines: Interleukin-17 > interferon-gamma
Interleukin-6
Induction of Il-6 by TNF explains systemic manifestations of inflammation:
acute phase response
anemia
hypergammaglobulinemia
hypoalbuminemia
Signs and Symptoms
Symmetric joint pain
Swelling of small peripheral joints
Morning joint stiffness of variable duration
diffuse aching
Fatigue, malaise and depression (may come first by weeks or months)
swan neck deformity, boutonnière deformity
hammer toe, mallet toe, claw toe
Joints Involment
Mostly: Wrist, Hand, foot, Knee, Elbow, Shoulder
Less: Cervical spine, Axial spine, Hip
Clinical Evaluation of Joints
Joints are
warm and tender on palpation
.
Swelling
may be soft when as a result of synovitis, fluctuant as a result of an effusion, or bony as a result of malalignment
Muscle
wasting
around the joints
Instability
Loss of range of movement
Forms of RA
Early: Up to 3 month from the onset of symptoms.
Late: More than 3 months from the onset of symptoms – firm diagnosis
Sequence of Articular Involvement in the early phase
Small joints
of hand + wrist (53%)
MTP + ankle joints (21%)
Knees (13%)
Shoulders ( 9%)
treatment
Recommendation:
Treatment should be started as soon as possible
Suppress disease as strongly as possible
Patients with active onset of RA should be treated more aggressively
Pharmacotherapy, Kinesitherapy, Surgical and orthopedic treatment , Psychotherapy, Physiotherapy, Balneotherapy
Surgical Procedures: Synovectomy, Tenosynovectomy, Tendon Surgery, Arthroplasty, Arthrodesis
Pharmacotherapy
NSAIDs
:
all of these drugs involves inhibition of cyclooxygenase (COX) pathway
They do not reduce underlying inflammatory process
Corticosteroids
:
powerful disease-controlling drugs, but they are avoided in the long term because side-effects are inevitable
They increase risk of: osteoporosis, diabetes, hypertension and cataract
May be used in intra-articular injections
Disease Modifying Antirheumatic Drugs (DMARDs)
Methotrexate
:
Target of Activity: Dihydrofolate reductase; folate metabolism
Most common drug for RA
,
Antagonist of folic acid,
Used in low doses in RA treatment,
Sulfosalazine:
Target of Activity: multifactorial, including impairment of lymphocyte function and cytokine synthesis
Weak antagonist of folic acid
Possible allergic reactions
Leflunomide:
Target of Activity: Pyridine synthesis
Inhibits synthesis of RNA and DNA and cell cycle in rapidly dividing cells such as lymphocytes.
Main side effects are: diarrhoea and rash.
Gold: mainly as i.m. injections, less effective as oral preparations, frequent side effects: skin rashes, neutropenia, thrombocytopenia, glomerulonephritis
Antimalarial Drugs:
Hydroxychloroquine is the least toxic but also least effective.
Eye function should be monitored
D-penicillamine: not used due to many side effects such as induction of Lupus erythematodus, myasthenia, Goodpasteure syndrome, myositis
Cyclophosphamide:
in RA with vasculitis
effective in rapidly dividing cells
Main side-effects: myelosuppression, increased sensitivity to infections, urinary bladder bleeding, pneumonia, carcinoma
Cyclosporin A:
block calcineurine and associated signalling mechanism of T-lymphocyte activation
more effective in combination with Methotrexate
Azathioprine:
when other DMARDs have been ineffective
When there are extra-articular manifestations
Side-effects: neutropenia, trombocytopenia and abnormal liver
common features:
Controls or modifies progress of the joint disease
Effective after several month of regular treatment
Action is sustained after withdrawal of treatment
(except sulfasalazine and methotrexate)
Frequent and severe side effects
Time for effect for drugs modifying progress of the disease:
1-3 months – methotrexate, sulfasalazine, leflunomide, azathioprine
2 – 4 months- cyclosporin A
3 – 6 months – gold i.m., Hydroxychloroquine, D-penicillamine
Biologic Disease Modifying Antirheumatic Drugs (bDMARDs)
TNF inhibitors- ( etanercept, infliximab, adalimumab, golimumab, cetrolizumab)
IL-1 inhibition –anakinra
Il-6 inhibition- tocilizumab
T-cell signaling –abatacept
B-cell depletion-rituximab
Tyrosine kinase inhibitors -tofacitinib
Complications:
Serious infections
Opportunistic infections (TB)
Malignancies
Demyelination
Hematologic abnormalities
Administration reactions
Congestive heart failure
Autoantibodies and lupus
Complications
Cardiovascular: vasculitis, pericarditis (most common), Rheumatoid nodules can be found in the myocardium, endocardium and on valves
Rheumatoid nodules
Pulmonary: pulmonary nodules, Serositis causing pleural effusion, interstitial fibrosis, pleuritis, Caplan syndrom (RA coexisting with pneumoconiosis) – large cavitating lung nodules, Obstructive bronchiolitis
Ocular: scleritis, conjunctivitis, Dry corneitis, keratoconjunctivitis sicca and xerostomia (dry eyes and mouth)
Neurologic (peripheral changes): compression neuropathy (carpal or tarsal tunnel syndrome), Peripheral neuropathy (mononeuritis multiplex)
Skin: distal leg ulcers, palmar erythema
Hematologic:
anemia and thrombocytosis, Leukocytes –mostly normal,
Rare: Leukopenia (Felty’s syndrome) leukocytosis (Adult onset Still disease )
-Causes of Anemia in RA:
• Anemia of chronic disease
• Iron defficiency – blood loss caused by NSAIDs
• Suppression of BM function – by sulfasalazine, penicillamine, gold and cytotoxic drugs
• Folate defficiency – caused by sulfasalazine, methotrexate
• Vitamin B12 defficiency – caused by associated pernicious anemia
• Hemolysis – caused by sulfasalazine
• Felty’s syndrome (arthritis, splenomegaly, neutropenia)
Renal/hepatic:
amyloidosis
, Glomerulonephritis, increase liver enzymes
Diagnosis
Methods: Radiological ( X-ray, Densitometry, CT-scan), USG (with power doppler), MRI, LAB., Histopathological)
Radiologic Features:
Early stage: Soft tissue swelling
Intermediate stage: Mild
juxtaarticular osteoporosis
,
Narrowing of joint space and bone erosions
Late stage: Large erosions, anatomic deformities, ankylosis
Laboratory Findings:
RF positive in up to 70%, ANA positive in 30%
Anti-CCP
positive in up to 70%;
specific for RA
90-98 %
Acute phase reactants
(ESR, CRP) increase
Chemistries normal, except slight dec. in albumin, inc. in total protein, and dec. in iron
Urinalysis - rare proteinuria
blood: mild anemia,
thromocytosis
autoantibodies
Rheumatoid factors RF
-
Autoantibody to Fc region of IgG
not specific for RA
May be: IgM, IgG, IgA
Other causes of positive test for RF:
Other connective tissue diseases, Viral infections, Leprosy, Subacute bacterial endocarditis, TB, Sarcoidosis, Mixed essential cryoglobulinemia
Antibodies to citrullinated protein ACPA
Citrullination of proteins occurs in inflamed joints in many forms of arthritis
NOT specific for RA.
Loss of tolerance to citrullinated proteins is
specific
for RA
Detected using synthetic cyclic citrullinated peptides: “anti-CCP antibodies”
(CCP) antibodies: Sencitivity 40-60%, Specifity>95%, Detectable earlier than RF,
Strong correlation between IgM-RF, CCP and erosive diseases
American College of Rheumatology Criteria
At least 4 of the following:
1.Morning stiffness >1 hour
2.Arthritis of >=3 joint areas
3.Arthritis of hand joints
4.Symmetric arthritis
5.Rheumatoid nodules
6.Serum rheumatoid factor
7.Radiographic changes
1,2 &3 Must be present for at least 6 weeks
Assesment of disease activity
Laboratory markers of disease activity:(ESR, CRP, HgB, platels, albumin), not RF,anty-CCP !!!
American College of Rheumatology Response Criteria
Disease Activity score-28 (DAS-28)
Simplified Disease Activity Index ( SDAI)
Clinical Disease Activity Index (CDAI)
DAS28 (DISEASE ACIVITY SCORE):
DAS28 ≤ 3,2 low activity,
DAS28 > 3,2 i ≤ 5,1 mild activity
DAS28 ≥ 5,1 high activity
DD
Psoriatic arthritis or other seronegative spondylarthropathy
Osteoarthritis
Polyarticular gout
Other connective tissue diseases
Calcium pyrophosphate deposition disease
2010 ACR/EULAR Classification Criteria for RA *