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Rheumatoid Arthritis: Classification of Ra
Rheumatoid Arthritis: Classification of Ra
RHEUMATOID ARTHRITIS
DEFINITION
The course of disease is highly variable, ranging from mild cases with non-
erosive, even sometimes spontaneously remitting disease, to severe, rapidly
progressive and destructive RA. Recent analysis of genetic risk factors,
autoantibody responses and therapeutic studies suggests, however, that clinical
RA might consist of pathogenetically distinct subgroups, and that different
treatment strategies should be applied to patients within these groups.
CLASSIFICATION OF RA
1. Auto antibodies:
ACPA positive RA
ACPA negative RA
RF positive RA
RF negative RA (better prognosis, better survival, less extra-articular
manifestations)
2. The onset
Very early RA
Early RA
Chronic RA
EPIDEMIOLOGY
PATHOGENESIS
1. Genetic factors
The most relevant genetic factor is the shared epitope. Is found in HLA class II
molecules on chromosomal location 6p21.3. Several HLA-DRB1 molecules
(*0101, *0102,*0401, *0404, *0405, *0408, *1001 and *1402) share a common
amino acid sequence at position 70-74 in the third hypervariable region of the
DRβ1-chain. This sequence consists of glutamineleucine-arginine-alanine-
alanine (QKRAA), QRRAA or RRRAA. The shared epitope is implicated in the
binding of a putative arthritogenic peptide. The amino acids at position 70 and
71 flanking positions 72-74 (RAA) seem to modulate the T cell response, thus
influencing the risk conferred by the shared epitope to the development of RA.
Infections:
Mycobacteria,
Epstein-Barr Virus,
Parvovirus B19 etc.
Smoking confers an increased risk for the development of RA (ACPA positive RA,
and a more severe evolution of RA). Smoking induces an anti-citrullin specific
immune response by inducing apoptosis and subsequently citrullination in
alveolar cells.
Coffee consumption is associated with ACPA positive RA.
CLINICAL MANIFESTATIONS
B symptoms:
low grade fever
fatigue (loss of energy)
weight loss
Common symptoms:
pain (typical - small joints involvement)
small joints swelling
stiffness (morning and after resting stiffness that lasts more than 30
minutes)
Other symptoms:
extra-articular manifestations (pleuritis, pericarditis etc.)
Joints involvement:
symmetrical
mono, oligoarthritis – less common
poliarthritis – more common
joints first involved - swelling of the proximal interphalangeal
(PIP) joints, the metacarpophalangeal (MCP) joints, the wrists and the
metatarsophalangeal (MTP) joints
the DIP joints are not usually part of the clinical tableau (differential
diagnose with psoriatic arthritis)
Common deformities of the joints:
Fusiform swelling (spindle shape fingers) – synovitis of PIP joints
Swan-neck deformity – contraction of the flexors of the MCPs, the flexor
contraction of the MCP joint, hyperextension of PIP, flexion of DIP joint
Boutonniere deformity – flexion of the PIP, hyperextension of the DIP
joints
Ulnar deviation of fingers
subluxations of MCPs
“Piano key” ulnar head secondary to destruction of the ulnar collateral
ligament
Claw/hammer toe – inflammation of the MTP joints with subluxation of
the metatarsal heads.
The dorsal and the lumbar spine are not usually involved in RA.
Thirty to fifty patients with RA are complaining of the cervical spine. The C1-C2
is the most commonly involved level. The pattern of the cervical spine
involvement is:
C1-C2 subluxation - (atlantoaxial) subluxation
anterior subluxation is caused by synovial proliferation around the
odontoid process and the C1 arch, thus leading to the rupture of the alar
and transverse ligaments. It is more than 3 mm between the arch of C1
and the odontoid of C2. The risk of spinal cord compression is when the
anterior atlanto-odontoid interval is more than 9mm or the posterior
atlanto-odontoid interval is less than 14 mm.
vertical subluxation - is the result of collapse of the lateral articulations
between C1-C2. The odontoid impinge the brainstem.
lateral
posterior
C1-2 impactions – destructions between the occipitoatlantal and atlantoaxial
joints.
Subaxial involvement – the C2-C3, C3-C4 facets and intervertebral disks are
involved.
Tenosynovitis, bursitis and carpal tunnel syndrome may be the first
manifestations of RA.
Extraarticular manifestations in RA
Pulmonary manifestations
a. Pleural disease – pleural effusion, pleurisy
Pleural effusion is characterized by:
cellular exudates
high protein levels
high lactate dehydrogenase levels
low glucose levels
low ph (infections)
b. Nodules
Its can be solitary or multiple. Its can resolve spontaneously or cavitate.
Caplan’s syndrome equals coil miners with RA and pulmonary rheumathoid
nodules.
c. Interstitial pulmonary fibrosis (IPF) – fibrosing alveolitis
Is characterized by dyspnea, Velcro rales and primary fibrosis (lower lobes). A
rapid progression of IPF is called Hamman-Rich syndrome.
d. Bronchiolitis obliterans (BO) – Attention to the side effects of
Penicilamine!!! Patients are complaining of dyspnea. It can be visualized
hyperinflated chest x-rays and small airways obstruction on pulmonary
function test.
e. Bronchiolitis obliterans with organizing pneumonia (BOOP)
f. Nonspecific interstitial pneumonitis (NSIP)
Cardiac manifestations
a. Pericarditis – can lead to pain, tamponade (rare), constriction
(uncommon)
b. Nodules – valvular problems, conduction abnormalities
c. Coronary arteritis – myocardial infarction
d. Myocarditis – congestive heart failure
Ocular manifestations
a. episcleritis
b. scleritis
c. retinal nodules
d. choroid nodules
Dermatologic manifestations
a. vasculitis
Types of vasculitis in RA:
Leukocytoclastic vasculitis (inflammation of postcapillary venules)–
palpable purpura
Small arteriolar vasculitis – infarcts of digit pulp + distal sensorial
neuropathy (vasculitis of vasa nervorum)
Medium vessel vasculitis – livedo reticularis, visceral arteritis +
mononeuritis multiplex
Pioderma gangrenosum
b. subcutaneous nodules
c. palmar erythema
Neuromuscular manifestations
a. mononeuritis multiplex
b. peripheral neuropathy
c. entrapment neuropathy – median nerve (carpal tunnel), posterior tibial
nerve (tarsal tunnel), ulnar nerve (cubital tunnel), radial nerve –
interosseous branch
Hematologic manifestations
a. Felty’s syndrome – splenomegaly, leukopenia
b. Lymphomas
c. Large granular lymphocyte syndrome
Others
Sjögren’s syndrome
Amyloidosis – AA associated amyloidosis – poor controlled RA – nephrotic
syndrome
Miscellaneous manifestations:
Palindromic rheumatism – affects the large joints, lasts a few hours, days and
remits spontaneously.
RS3PE syndrome – acute severe onset of symmetrical synovitis of the small
joints of the hands, wrists and flexors sheats plus pitting edema of the dorsum of
the hand (“boxing glove” hand). Ussually affects 70 years old Caucasian males. All
patients are RF negative.
LABORATORY FINDINGS
1. Inflammatory markers
ESR (erythrocyte sedimentation rate) elevated
CRP (C-reactive protein) elevated
2. Antibodies
RF (rheumatoid factor) – is a series of antibodies that recognize
the Fc portion of an IgG molecule as it’s antigen. Isotypes of RF:
IgG, IgA, IgM, IgE.
anti - CCP antibodies
ANA (antinuclear antibodies)
3. thrombocytosis – active disease
4. leucocytosis – active disease
5. low levels of hemoglobin - anemia
6. serum iron – low levels – acute phase reaction
7. ferritin – high levels – acute phase reaction
8. serum albumin – low levels – negative acute phase reactant
9. Synovial fluid is characterized by:
inflammatory pattern
WBC (white blood cells) 5000-50.000/mm3
> 50% of PMN’s
elevated protein level
low glucose level
negative cultures
no crystals
IMAGISTIC FINDINGS
Ultrasound in RA
It is an extension of the clinical exam. It can show the synovitis of the involved
joints, erosions (at an early stage of the disease) and tendinitis/tenosynovitis.
MRI can depict the erosions of the wrist and fingers earlier than ultrasound. The
marrow edema shown in MRI is not a patognomonic sign in RA. It reveals only a
site of inflammation.
CLASSIFICATION CRITERIA
A. Joint involvement
1 large joint 0
2 to 10 large joints 1
1 to 3 small joints (with or without involvement of large joints) 2
4 to10 small joints (with or without involvement of large joints) 3
>10 joints (at least 1 small joint) 5
D. Duration of symptoms
< 6 weeks 0
≥ 6 weeks 1
DIFFERENTIAL DIAGNOSES
DISEASE ASSESSMENT
The activity of the disease can be quantified by different indexes. The most
common used are:
Disease Activity Score - DAS 28 consists of: 28-swollen joint counts (28-SJC)
and 28-tender joint counts (28-TJC) in addition to patient global assessments of
disease activity on a visual analogue scale (VAS) and erythrocyte sedimentation
rate (ESR) or CRP (C reactive protein).
Simplified Disease Activity Index (SDAI) includes 28-SJC and 28-TJC, patient
and investigator global assessments of disease activity on a VAS and C-reactive
protein (CRP).
Clinical Disease Activity Index (CDAI) is the SDAI without the lab assessment.
PROGNOSTIC MARKERS
The known predictors of structural damage are: RF, anti-CCP antibodies, acute
phase reactants, the erosive disease.
The mortality predictors are: extraarticular manifestations, comorbidities, age,
physical status, education, RF.
The major cause of death among RA patients is cardiovascular and
cerebrovascular diseases. Male sex and age at disease onset have been found to
predict both the occurrence of cardiovascular events and death. Alongside with
the cardiovascular events an increased moratlity is due to disease activity, age,
level of education, comorbidities and corticotherapy.
TREATMENT
Contraindication:
Obstructive biliary disease
Liver disease
Viral hepatitis
Severe immunodeficiency
Rifampicin treatment
Side effects:
Diarrhoea
Alopecia
Rash
Leucopenia
Hepatotoxicity
Hypertention
teratogenic/fetal death
Side effects
Gastrointestinal
Central nervous system toxicity – headache; dizziness
4-5% rash
myelosuppresion !!!
fever + rash+ abnormal liver function – viral illness
Retinal toxicity :
HCQ > 6.5 mg/kg/w
CQ > 3mg/kg/w
More than 10 years of treatment
Impaired renal or liver function
Age > 60 years old
Obesity
Macular degeneration
History – previously antimalarial drugs
Rarely – myopathy (HCQ)
Side effects
Hypertrichosis
Tremor
Gum hyperplasia
Hypertension
Dose related with the loss of renal function
Dose: 2.5 mg/kgc –increased with 0.5-0.75 mg/kgc
6. Other DMARDS
Azathioprine (Imuran)
Immunossupresor
Mielossupresion
Risk of lymphoma, non-melanoma skin cancer
Hepatotoxicity
D-Penicillamin
Tetracycline derivates – inhibits metalloproteinase activity involved in
joint destruction
Adjunctive therapy in early RA
a. Anti TNFα
1. INFLIXIMABUM (REMICADE)
It is a human murine chimeric antibody.
Dose: 3 mg/kgc PEV 0-2-6-8 weeks afterwards increasing the dose (if not LDA
or remmission) till 10mg/kgc.
2. ETANERCEP (ENBREL)
It is a recombinant TNFα receptor fused to a human Fc molecule creating a TNFα
binding agent.
Dose: 50mg sc weekly.
3. ADALIMUMABUM (HUMIRA)
It is a human antiTNFα antibody.
Dose: 40mg sc bimonthly.
4. GOLIMUMABUM (SIMPONI) similar with Infliximab but it is given once
monthly sc.
5. CERTOLIZUMABUM (CYMZIA) is a humanised pegylate antiTNFα antibody.
Dose:
2, 4 week 400mg (2x200mg)
400mg monthly .
B. RITUXIMAB (MABTHERA) is a monoclonal chimeric (huminised and murine
sequences) anti CD20 antibody.
C. TOCILIZUMAB (RoActemra) is an inhibitor of IL 6 receptor.
Dose: 4mg/kgc lunar PEV
D. ANAKINRA is a recombinant Il 1 antagonist.
E. ABATACEPT (ORENCIA) is a soluble recombinant fully human protein that
comprises the extracellular domain of CTLA4 and the Fc portion of the IgG1
molecule that has been modified to prevent complement activation.
Glucocorticosteroids
Prednisolone – the most used
Dexamethasone
Pleiotropic effects:
Immunosupressive effects
Anti-inflammatory effects
Rapid and effective mode of action
Adm.: per os, PEV (pulse therapy), ia – thumb rule (no > 4 adm. at the
same joint/year; metilprednisolone, triamcinolone + derivates)
NSAIDS + COXIBS
Pathophysiological mechanisms
Nociceptive pain:
Inflammation
OA
Non-nociceptive pain due to sensitization:
Secondary fibromyalgia
Neuropathic pain:
Carpian tunnel syndrome
EULAR evaluation:
Gastrointestinal
Cardiovascular
Renal
References:
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Group, 2009, 824: 61-91
2. West S., Rheumatology Secrets, 14: 117-128, Hanley and Belfus, 2002,
695: 117-127
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van Venrooij,W.J. 1998. Citrulline is an essential constituent of antigenic
determinants recognized by rheumatoid arthritis-specific autoantibodies.
J.Clin.Invest 101:273-281.
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Vincent,C., Simon,M., Senshu,T., Masson-Bessiere,C., Jolivet-Reynaud,C. et
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