Rheumatoid polyarthritis

Prof.Univ.Dr.Corina Zorilă
• According to the World Health Organization, rheumatic
disease is the most frequently reported cause of illness
in adults.
• 150 million people in Europe suffer from acute or
chronic rheumatic disease during life.
• Under the generic name of rheumatic diseases are
covered more than 100 different diseases that cause
pain, swelling and limited mobility.
• With increasing life expectancy is predictable that it will
be an increase also in these diseases.
Definition
 Rheumatoid polyarthritis (RP) is a
major collagenosis
 Rheumatoid arthritis (RA) is an
inflammatory disorder of connective
tissue with predominant synovium
affection, causing severe joint
damage, which is accompanied by
numerous immune abnormalities
and systemic manifestations.
Definition
 Rheumatoid arthritis (RA) is a chronic
systemic inflammatory disease whose
hallmark feature is a persistent symmetric
polyarthritis (synovitis) that affects the hands
and feet . Any joint lined by a synovial
membrane may be involved, however, and
extra-articular involvement of organs such as
the skin, heart, lungs, and eyes can be
significant.
Incidence / Prevalence: 0.3 -2.1%.
It occurs in about 1% of the general
population, which means that in our
country there are more than 200,000
patients with this suffering.
Dominance of age, the more often 35-40
years.
Children - 4-6years and 12-14.
Domination Sex: Women Men 3/1.
Heredity: increased familial aggregation.
Etiology
 The cause of rheumatoid polyarthritis (RP)
remains unknown.
 Multiple pathogenic theories have been conveyed,
such as :
 infectious theory: disease is caused by an
unknown infectious agents including
mycoplasmas, Epstein-Barr virus (EBV),
cytomegalovirus virus, parvovirus, rubella virus,
but there are compelling evidence for this
purpose.
 Most recently has been demonstrated similarities
between certain Gram-negative bacteria and
products of EBV, which may act as super-
antigens, but their role remains uncertain.
Genetic theory
 In the Genetic studies RP is linked to the major
histocompatibility complex (MHC) class. II.

 Genes associated with RP are DRB1 * 0401 and

DRB1 * 0404.
 The greater susceptibility to RP have individuals
who are carriers of both genes DRB1 * 0401 and
DRB1 * 0404.
 Some forms of RP are associated with other
genes such as DRB1 * 01 - * 1001 - * 1402.

 Patients with RA and DR4 gene are likely to

develop more severe forms of the disease, with
more joint erosions.
Immunological theory
 RP is characterized by an increased
titre of type II anticolagen
antibodies.
 IgG and IgM antibodies are fixed on
the joint cartilage, activates
lymphocytes and other
inflammatory mediators, which will
ultimately lead to synovial lesions.
Immunological theory
 The main function of HLA class II
molecules is to present antigenic
peptides to CD4 + T cells.
suggesting that the RP is due to
unidentified artrogenic antigen.
 The antigen may be endogenous or
exogenous, such as viral protein or
endogenous protein.
 It is assumed that the clinical
manifestations are an exuberant immune
response in people with certain features
as the disease association certifies some
histocompatibility antigens.
 Risk factors - genetic, immunological
factors, hormonal factors, psychological
factors, environmental factors.
 In the pathogenesis of rheumatoid arthritis is
difficult to define a rigorous sequence of events
due to process complexity.
 Schematically, the distinguished three
evolutionary points: synovitis, cartilage
destruction and fibrosis.
 Initially there is an injury to the endothelial cells,
causing swelling and infiltration of mononuclear
cells (lymphocytes and T memory lymphocytes
(CD4)). B lymphocytes are last synovial
mononuclear infiltrate occurring, what explains
that in the beginning most cases of rheumatoid
arthritis are seronegative (rheumatoid factor not
present)
 Simultaneously angiogenesis=neovasculaisation
process is triggered, a process essential for the
maintenance of the disease.
 Factors that induce neovascularization are
determined largely by the local ischemia (micro
thrombosis, vascular compression via joint
exudate, etc.), which employs factors such as
VEGF (Vascular endothelial Growth Factor) IL-8,
FGF (Fibroblast Growth Factor), TNF - (tumoral
necrosis factor).
Morphopathology
 The synovial membranes from
patients is characterized by
hyperplasia, hypervascularization
and inflammatory cell infiltration,
particularly of CD4 + T, which is the
principal immune response
orchestrator.
Morphopathology
 Most important local effect of synovitis
progression process is performed by
multiplying infiltrative-proliferative
synovial cells and lymphocytes and
plasma cells by recruitment of new
lymphocytes from the bloodstream.
 Hypertrophied synovial tissue, ample
vascularized is called articular pannus . It
invades the periphery joint, lesions first
appearing at the junction of bone with the
cartilage.
Morphopathology
 In late evolution of suffering, acute
phenomena disappear and form a
fibrous tissue due to excessive
activity of fibroblasts in stimulating
macrophages.
 Limited joint movements are
becoming more important, leading
to semi ankylosis or complete
ankylosis.
 Rheumatoid nodules are the result
of a process of vasculitis that occurs
especially when circulating immune
complexes are present at high titers
Rheumatoid nodules
Pathogenesis
 In the synovial fluid is found rheumatoid factor (RF),
secreted by synovial lymphocytes formed in 80% of
IgM and rarely IgG and IgA.
 It has the properties of IgG antibody to structural
abnormalities (glycosylation deficiency), IgG coupled
with an antigen or to the IgG aggregates.
 This will form immune complexes, which by
complement fixation become vulnerable to
phagocytosis performed by polymorphonuclear,
macrophages and synovial cells type A.
 Phagocytic leukocytes that forms these immune
complexes are referred as ”ragocites”.
 Complement serum is low in the synovial fluid.
 The precise pathogenic role of rheumatic factor is not
known but may be related to complement activation by
immune complex formation.
The role of cytokines
 Monocytes, macrophages, fibroblasts and LT
release numerous cytokines when stimulated
 Il 1, IL 6 and TNF are key cytokines that promote
inflammation in RA.
 TNF is a potent cytokine
 TNF is an autocrine stimulator as an inducer of
other inflammatory cytokines such as IL 1, IL 6,
IL 8 and GM CSF (granulocyte-monocyte colony-
stimulating factor).
 TNF also promotes inflammation by stimulating
fibroblasts to express adhesion molecules.
Classification
Clinical and anatomical feature:
- Simetrical polyarthritis;
- Extra-articular manifestations;
- Special syndromes S. Felty (RP +
splenomegaly + neutropenia);
- Rheumatoid arthritis in combination with:
deforming osteoarthrosis, diffuse diseases
of connective tissue

- Juvenile arthritis (including Styll's disease)

Immunological feature:
• RP seropositive;
• RP seronegative
Signs and symptoms
 Insidious onset of nonspecific signs: fatigue, loss of
appetite, weight loss, myalgia, low-grade fever.

 After a few weeks, months, follows:

 - Morning stiffness in small joints in adjacent tissues;
 - Arthritis in 3 or more joint areas;
 - Swelling of the metacarpophalangeal joints
symmetrically (MCF), interphalangeal (IF) or fist;
 - Subcutaneous rheumatoid nodules;
 Catching joint is symmetrical and centripetal!
 - Periarticular lesions (tenosynovitis, bursitis, synovial
cysts);
Signs and symptoms
 The characteristic feature in hand is proximal
interphalangeal joint synovitis and meta carpo
phalangial(MCP) Deformity is present after a year
of evolution (as in M, the "buttonhole" ulnar
deviation)
 Synovitis of the elbow - the joint effusion
extension movement is more limited. Late and
rarely cause major erosion of cartilage.
 The knees are commonly affected, beginning
effusion and synovitis were then proliferative.
Cartilage and bone erosions are however delayed
and less intense.
Signs and symptoms
In a number of patients (15-20% of the
systemic) is acute onset of high fever,
chills,
 Rheumatoid rash,
 Polyneuropathy,
 Organ damage,
 Vasculitis,
 Lymphadenopathy,
 Splenomegaly,
 Pleural efusion.
Laboratory investigations
There are no specific tests for the diagnosis
of AR .
In order to assess the degree of
inflammation are used:
 Acute phase reactant (CRP, serum
protein electrophoresis)
 Rheumatoid factor,
 Antinuclear antibodies (ANA),
 Seric Complement,
 Synovial fluid analysis, assessment of
HLA.
Extra-articular manifestations
 impaired reticuloendothelial system:
splenomegaly, lymphadenopathy
 the lungs :pleural effusion, rheumatoid
nodules
  heart :pericarditis, affecting small
vessels=coronaritis
 eyes: episcleritis, keratitis band, uveitis
 nervous system =polyneuritis
 amyloidosis
 In the RP we have changes in blood:
 Increased ESR and acute phase
reactants: fibrinogen, C-reactive protein,
alfa2-globulin, haptoglobin.
 Discrete or moderate hyper gamma
globulins.
 Immunological markers:
 rheumatoid factor
 perinuclear antibodies
 Anti keratin antibodies
 Serum complement is usually normal,
although it may vary.
 Perinuclear and anti keratin antibodies
are more specific for PR than RF (IgM)
and was observed to occur early in
serum.
 Other more recently described antibody
are ACP antibodies and anti-GPI
antibodies
 ACPA =anticitrullinated protein
antibody
 anti-GPI, GPI is a ubiquitous antigen,
usually belonging to the Krebs cycle.
ACPA antibodies
 ACPA were put in evidence in the serum
of patients with RA seems that these
antibodies may occur with years before
clinical signs of arthritis, they are
detectable by ELISA
 ACPA and positive serology (latex or
Waaler-Rose test) as well as the presence
of an inflammatory syndrome or type
alleles DRB1 forms the RP with reserved
prognosis.
In the synovial fluid
 Diagnostic procedures - arthroscopy, synovial biopsy,
joint puncture.
 usually opaque liquid with a variable number of
leukocytes (50.000-60.000/mm3) that the majority
(75%) were polymorphonuclear. Between them there
are some cells called ”ragocite”
 Rheumatoid factor (RF) is present, secreted by synovial
lymphocytes (80% IgM and rarely IgG and IgA).
 immune complexes are elevated, which by complement
fixation become vulnerable to phagocytosis performed
by polymorphonuclear, macrophages and synovial cells
type A.
 Phagocytic leukocytes that forms these immune
complexes are referred as ”ragocite”
Other investigations
 wrist, hands radiographs,
  electrocardiogram,
 ophthalmologic examination by slit
lamp
Radiographic signs
 Juxta-articular osteoporosis

 Joint erosions

 Joint space narrowing

 In advanced stages: subluxations,

ankylosis
Staging (after Steinbrocker)
 Stage I - osteoporosis;
 Stage II - osteoporosis + joint
space narrowing (unique erosion);
 Stage III - Stage II + multiple
erosions;
 Stage IV - Stage III + bone
ankylosis
 Clinical and Functional
Classification:
Class I: unaltered capacity to perform all
daily activities.
Class II: daily activities can be made but
with pain and reduced joint mobility.
Class III: the ability to care for himself.
Class IV: immobilization in bed or
wheelchair and incapable of self-care.
Positive diagnosis ARA essential
diagnostic criteria (1987)

- Morning stiffness for at least an hour, lasting even

under the most favorable> 6 weeks.
- Arthritis in at least 3 or more joint areas installed in>
6 weeks.
- Swelling (arthritis) symmetric> 6 weeks.
- Swelling (arthritis) of the proximal interphalangeal or
metacarpophalangeal joints or fists> 6 weeks.
- Subcutaneous rheumatoid nodules (20-30%).
- A positive rheumatoid factor.
Typical radiographic changes (at least juxta-articular
osteoporosis and erosions in wrists, joint space
narrowing).
For diagnosis requires at least 4 criteria to be present.
EULAR Criteria
 In the new criteria set, classification as "definite RA" is
based
 on the confirmed presence of synovitis in at least 1 joint,
 absence of an alternative diagnosis that better explains the
synovitis, and
 achievement of a total score of 6 or greater (of a possible
10) from the individual scores in 4 domains:
 number and site of involved joints (score range 0-5),
 serologic abnormality (score range 0-3),
 elevated acute-phase response (score range 0-1),
 and symptom duration (2 levels; range 0-1).
Differential Diagnosis
 Seronegative spondyloarthropathies,
 Diffuse diseases of connective tissue
 Rheumatic fever,
 Attack of gout,
 Pseudogout,
  Fibromyalgia,
 Chronic degenerative rheumatism
(osteoarthritis)
 Endocarditis.
Complications
 Felty's syndrome,
 Caplan syndrome,
 Reye syndrome or DIC (JRA - the systemic)
 subluxations and dislocations,
 compression neuropathies (carpal canal
syndrome, cubital syndrome)
 contractures and ankylosis,
 amyloidosis,
 downturn stature
 in case of damages to eyes - decreased vision up
to blindness.
Prognosis, evolution
 Prognosis in RA is reserved
 Disability in the first 10 years of
disease rate (50%),
 Remission after a long period of
treatment,
 Early mortality - 15-30%,
 Progressive evolution - 70%
 Slowly progressive -15%
Poor prognostic factors
 ► Persistently moderate or high disease
activity despite conventional synthetic
DMARD (csDMARD) therapy according to
composite measures including joint counts
► High acute phase reactant levels
 ► High swollen joint count
 ► Presence of RF and/or ACPA, especially
at high levels
 ► Presence of early erosions
 ► Failure of two or more csDMARDs Low-
dose glucocorticoids
Clinical Forms
 Juvenile rheumatoid arthritis;
 In some people after the age of 70 years
appears acute arthritis, symmetrical wrist,
accompanied by pronounced edema of
the soft tissue (boxing glove)resistance to
therapy with NSAIDs,but positive after
systemic glucocorticosteroids.
 Rheumatoid factor is usually negative.
Treatment
 General measures - stopping pain,
reducing inflammation, protecting
the bone and articular structures,
maintaining joint function, control of
systemic manifestations.
 Diet - diet contributes to shaping
the immune system, restrictions fat,
vitamins and minerals
Treatment
 SMARD =Anti inflammatory
medication :
 NSAIDs ,
 corticosteroids
 DMARDS
 Gold salts could have therapeutic
effect especially when administered
early in the disease (Tauredon)
 DMARD( DMARDs, disease-modifying
antirheumatic drugs) nomenclature:

csDMARDs : methotrexate, leflunomide, sulfasalazine,

hydroxychloroquine
Targeted synthetic DMARDs: baricitinib, tofacitinib,
upadacitinib
Biological DMARD
 TNFi: adalimumab, certolizumab, etanercept, golimumab,
infliximab;
 IL6Ri: sarilumab, tocilizumab;

 Costimulation-i: abatacept;
 anti-B cell (CD20): rituximab
 Biosimilar DMARDs (currently for: adalimumab,
etanercept, infliximab, rituximab)

Cs= CONVENTIONAL SINTETIC

TNF-alpha blockers
 Advanced biological treatments to combat rheumatoid
arthritis, such as infliximab (Remicade) are "enemies“
of TNF - alpha or "blocking factors".
 Infliximab blocks TNF - alpha, which help control the
inflammation process
 Infliximab works fast
 Many patients begin to feel the effect of therapy in
approximately two weeks. Both patients with
moderate, and those severe affected by rheumatoid
arthritis, they made ​a 2-hour IV infusion, used in
combination with methotrexate.
 adalimumab 40-80mg/s/sc 4s
 etanercept
Monoclonal antibodies anti-interleukin-
6 receptor

Tocilizumab was superior in terms of

prevention of bone erosion as it was
seen in simple bone radiography.
Antagonists of IL-1 receptor
 Anakinra- Used alone or in combination with DMARDs
other than tumor necrosis factor (TNF) blocking agents
(e.g., adalimumab, etanercept, infliximab) for the
management of signs and symptoms of rheumatoid
arthritis and to inhibit progression of structural damage
associated with the disease in adults with moderately to
severely active disease who have had an inadequate
response to therapy with one or more DMARDs.
 Concomitant use of TNF blocking agents (e.g.,
adalimumab, etanercept, infliximab) not recommended.1
 Increased incidence of serious infections and lack of
additional clinical benefit with combined anakinra and
etanercept therapy
 Recommandations EULAR
 12 recommendations :
 1) inflammatory joint disease is characterized by the presence
of swelling, pain and stiffness. Patients with more than one
affected joint must be addressed and seen by a rheumatologist
if possible before six weeks of evolution.
 2) Clinical examination is the method of choice and , in
doubtful cases , we can help echo - Doppler and MRI for
detecting synovitis .
 3 ) There should be other inflammatory joint diseases as RA by
clinical examination and blood tests to minimum blood count,
urinalysis , transaminases and research antinuclear antibodies.
Depending on the case , you can also ask Lyme serology ,
parvovirus , hepatitis B and C , chest radiograph
 4) All patients should be counted the number of tender and
swollen joints , erythrocyte sedimentation rate , C-reactive
protein (CRP), the rheumatoid factor and anti -CCP antibodies
and radiological erosions . All these elements are correlated
with radiographic progression

5 ) Patients at risk of developing persistent or erosive inflammatory joint
disease should be treated by a treatment delayed action even if they do
not meet the criteria of an inflammatory rheumatic disease defined . This
recommendation is justified by the frequent occurrence of erosions in the
first 2 years of evolution and possible treatments delayed action
preventive action

 6) Informing the patient about his illness and treatment is important and
should develop education and the ability to maintain professional activity
programs

 7) Non-steroidal anti- inflammatory drugs (NSAIDs ) should be considered

as symptomatic after evaluation of the gastrointestinal condition, renal
and cardiovascular .

 8) corticosteroids to less than 10 mg / d of prednisone, which reduces pain

and swelling dose , should also be considered in combination with
treatments delayed action. She is also credited for preventive action on
the progression of radiographic damage . Local corticosteroid injections
can provide an improvement. The long- term low-dose corticosteroids is
not known .
 9) Methotrexate is the touchstone of
therapy and should be used first in patients
at risk of developing persistent disease.
 It can also be used sulfasalazine or
leflunomide. Methotrexate has proven
efficacy on the progression of radiological
damage and may also be associated with
other treatments (sulfasalazine,
biotherapy)
 10) The goal of treatment is to achieve remission. Regular
monitoring of disease activity and side effects should guide
treatment decisions. Intensive interventions early in the
course can improve the prognosis in the longer term including
radiological progression.
 11) Non-pharmacological interventions (non-dynamic
exercises, occupational therapy, hydrotherapy) can be used
as adjuvant therapy.
 12) monitoring disease activity includes the number of tender
and swollen joints, physician assessment and patient,
erythrocyte sedimentation rate (ESR) and CRP every 3
months and that of the X-ray structural damage every 6 to 12
months during the first year. Treatment should be tailored to
achieve remission.
S
Ankylosing spondylitis(AS)
 The disease is more common in
men
 93% shows an immunological
marker HLA B27 *
 The average age of diagnosis is 24
to 25 years
 There is usually an average delay of
eight years between the onset of
symptoms and diagnosis.
Reactive arthritis

Definition
Reactive arthritis (ReA) is a systemic
disease preceded by an infection of the
joint located at the distance within which
occurs nonsuppurative inflammation of
the synovial membrane and articular
cavity with not detection of infectious
agents.
Belonges to the group of seronegative
spondylarthropathys.
 Signs and symptoms
 Initially diarrheal disease or urogenital, then, after a latent period
occurs:
 - Asymmetric oligo-or polyarthritis (often large joints of the lower
limb).
 - Acute sacroiliac.
 - Spondylartritis.
 - Periarticular lesions: enthesitis, bursitis, tendonitis, aponevrositis.
 - Swelling of the big toe of the foot similar to gout.
 - Swelling of the fingers transsagital looking like "sausages".
 - Skin and mucosal lesions (balanitis, palmoplantar keratoderma,
stomatitis, gingivitis, glossitis, alopetie).
 - Ocular (conjunctivitis, iridocyclitis, uveitis rarely).
 - Urogenital diseases (urethritis, prostatitis, cystitis, salpingo-
oophoritis, cervicitis, vulvovaginitis).
 - Damage to the digestive tract (colitis, hepatomegaly)
 damage to the heart (arrhythmias,
aortitis, pericarditis).
 - lymphadenopathy
 One third of the patients exhibit
Reiter triad (arthritis + urethritis +
conjunctivitis).
 Primary infection may develop
asymptomatic or in milder forms.
Reactive artritis
 Causes - most often - infection with
Chlamydia, Ureaplasma, Yersinia,
Shigella, Salmonella,
Campylobacter, Clostridium, Borel
Neisseria HIV.
 Risk factors - genetic, immune
factors, immunosuppressive
therapy, bowel dismicrobism,
chronic diseases, allergy.
 Features : - Primary, chronically or recurrent.
 Clinical and morphological feature:
 - Musculoskeletal: mono-, oligo-, rheumatoid,
sacroiliac, spondyloarthritis, enthesopathy, bursitis,
achilo tendonitis;
 - Urogenital organs: urethritis, prostatitis, cystitis,
colpitis, salpingo-oophoritis, cervicitis;
 - Camera eye: conjunctivitis, iridocyclitis, uveitis rarely.
 Radiological feature:
 - Arthritis: stage I, II, III, IV (after Steinbrocker);
 - Heel spurs;
 - Unilateral sacroiliac (stage I, II);
 - Spondyl Arthritis (sindesmofites, asymmetric
intervertebral ankylosis).
Laboratory investigations
 Blood test
 Microscopic and bacteriological examination of
secretions from the urethra, the cervix, morning
urine, synovial fluid,
 Stool (most often not significant)
 Indicators phase reactant (CRP, serum protein
electrophoresis), rheumatoid factor titer
Antistreptolysine (ASO),
 Antinuclear antibodies,
 Complement system, serological antibodies
 Specific HIV examination, determination of HLA.
 Laboratory
 Accelerated ESR, CRP, fibrinogen
 leukocytosis, thrombocytosis, anemia
o identify the causative agent in urethral, cervix,
vagina, urine, feces,
o stool (most often insignificant specific antibodies in
diagnostic titers (titer evolution has diagnostic value
only)
o synovial fluid: 50% neutrophils - 60%, 20%
macrophage - 30%, phagocyte - positive HLA-B 27
(70-90% of cases).
Other investigations
 vaginal examination.
 digital rectal examination for
prostate pathology.
 recto-, sigmo-, ileo-colitis
colonoscopy to define and assess
the degree of injuries.
 rectal mucosa biopsy (in unclear
cases).