RA pdf - صباح الربيعي

RHEUMATOID ARTHRITIS:

IS A CHRONIC SYSTEMIC INFLAMMATORY ARTHRITIS .

CHARACTERIZED BY REMISSION AND EXACERBATION ,

WITH EXTRA ARTICULAR MANIFESTATIONS,

OCCURRING THROUGHOUT THE WORLD IN ALL

ETHNIC GROUPS . FEMALE : MALE RATIO IS 3:1. CAN

EFFECT ANY AGE BUT THE PEAK INCIDENCE OCCUR

WITHIN 4

AND 5

DECADES OF LIFE.

ETIOLOGY :

GENETICS AND ENVIRONMENTAL FACTORS

IMPLICATED CLEARLY IN THE ETIOLOGY AND

PATHOGENESIS OF RA.

GENETIC FACTORS

- CONCORDANCE IN MONOZYGOTIC TWINS IS 12-15% IN

COMPARE WITH 3% IN DIAZYGOTIC TWINS.

- INCREASED FREQUENCY IN 1

–DEGREE RELATIVE OF

PATIENTS.

- IN UP TO 50% OF GENETIC SUSCEPTIBILITY IS DUE GENES IN

HLA REGION.

HLA DR4 IN(50-70%) IN CAUCASIAN PATIENTS COMPARE TO

20-25% IN NORMAL POPULATION.

HLA DR4 ALSO ASSOCIATED WITH PROGRESSIVE AND SEVERE

DISEASE.

NON GENETIC RISK FACTORS:

-INFLUENCE OF SEX HORMONES TWO TO THREE TIMES

ARE LIKELY TO OCCUR IN FEMALES THAN MALES.

- TOBACCO SMOKING IS STRONG RISK FACTOR FOR

ETIOLOGY AND SEVERITY AND REDUCE

RESPONSIVNESS TO DMARDS AND BIOLOGICAL

TREATMENT .

- SUSCEPTIBILITY INCREASE IN POST PARTUM AND

BREAST FEEDING PERIOD.

- ALTHOUGH IT IS THOUGHT THAT RA IS TRIGGERED BY

INFECTIOUS AGENT IN A GENETICALLY SUSCEPTIBLE

HOST , A SPECIFIC PATHOGEN HAS NOT BEEN

IDENTIFIED.

Pathology

* swelling and congestion of synovial membrane

•

Cellular infiltration of synovium

•

CD4 Tcells and Th17 cells play important role in

pathogenesis.

* Effusion of synovial fluid

Hypertrophy of synovial membrane

Lymphoid follicles formed in synovial tissue .B cell

to produce cytokines and autoantibodies RF and

ACPA

Synovial macrophages produce pro inflammatory

cytokines( TNF, IL-1,IL-6 and IL15) these

stimulating fibroblast to cause swelling and more

soft tissue and cartilage damage

ACTIVATION OF OSTEOCLAST AND CHONDROCYTE

AND MORE BONE AND CARTILAGE DESTRUCTION. .

-LYMPH NODE ARE OFTEN HYPERRPERPLASTIC WITH

PRODUCTION OF RF AND ACPA BY PLASMA CELLS.

- INFLAMMATORY GRANULOMATOUS TISSUE (PANUS)

EXTEND UNDER AND OVER ARTICULAR CARTILAGE

LEADING TO CARTILAGE AND BONE EROSION.

- LATER FIBROUS OR EVEN BONY ANKYLOSIS MAY

OCCUR.

-- MUSCLES ATROPHY

CLINICAL FEATURES:

-AFTER A PERIOD OF PRODROMAL SYMPTOMS

- PAIN AND JOINT SWELLING OF SMALL JOINTS OF
HANDS ,WRIST AND FEET (USUALLY SPARING THE
DIP JOINTS) USUALLY IN SYMMETRICAL FASHION
WITH MORNING STIFFNESS MORE THAN ONE HOUR.
THE INFLAMED JOINTS ARE TENDER ON PRESSURE
WITH PAINFUL RESTRICTION OF MOVEMENTS.
LARGE JOINTS INVOLVEMENT AND EXTRA
ARTICULAR MANIFESTATIONS MAY OCCUR.

ONSET:

-INSIDIOUS
-ACUTE
-MIMIC POLYMALAGIA RHEUMATICA
-PALINDROMIC RHEUMATISM

I

IF THE DISEASE IS NOT HALTED EARLY BY DISEASE
MODIFYING ANTI RHEUMATIC DRUGS (DMARD)
RESULTING IN BONE EROSIONS , ARTICULAR
DESTRUCTION , LIGAMENT AND TENDON LAXITY OR
CONTRACTURES CAUSING CHARACTERISTIC
DEFORMITY.

HAND

JOINTS

Swelling of proximal

interphalangeal

(fusiform)
and metacarpophalangeal
joints. The distal
interphalangeal joints are
rarely involved "usually
spared".

Synovitis of the wrist usually

uniform feature of RA,

may lead to limitation of

movement, Dorsal

subluxation of ulnar

styloid is common and

may contribute to

rupture of the 4th and

5th extensor tendon.

Median nerve

entrapment can be

occur.

* Radial deviation at the wrist. Ulnar deviation

of MCP joints.

* Swan neck deformity.
* Boutonniere deformity.
* (Z) deformity of the thumb.
* Triggering of finger may occur due to nodules

formation in flexor tendon sheath.

Knee joint

Is commonly involved

with synovial

hypertrophy, chronic

effusion

Popliteal (Baker's) cyst

,with knee synovitis

and the synovial fluid

communicating to

cyst in valve- like

mechanism

preventing the fluid to

return back to joint

cavity. Rupture of cyst

producing picture

similar to DVT

Characteristic pre-

existing history of joint

problem. Doppler

ultrasound study is

required to establish

the diagnosis.

Cervical spine:

*Atlanto-axial

subluxation

*Spinal cord

compression

Foot & Ankle

Eversion.
Dorsal sub luxation of MTP

joint may result in Cock-

up toe deformity.

Painful burse and

Callosities.

Flat foot due to rupture

of the tibialis

post.tendon.

Hallux valgus.
.

EXTRA ARTICULAR MANIFESTATIONS

OCCUR MAINLY IN LONG-STANDING

SEROPOSITIVE EROSIVE DISEASE.

- WEIGHT LOSS, ANOREXIA, GENERALIZED

OSTEOPOROSIS, WASTING OF MUSCLES DUE TO

SYSTEMIC INFLAMMATION.

CUTANEOUS

AND VASCULAR FEATURES

RHEUMATOID NODULES:
USUALLY OCCUR AT PRESSURE SITE SUCH AS

EXTENSOR SURFACE OF FOREARM , SACRUM,

ACHILLES TENDON.

THE NODULES ARE FIRM NON TENDER . IT

ALMOST EXCLUSIVELY OCCUR IN SEROPOSITIVE

DISEASE.

•

Rheumatoid vasculitis

occur in seropositive patients. vasculitis

ranging from benign nail-fold infarct to wide

spread ulceration and skin necrosis.

Vasculitis of medium size artery can lead to

mesentric, renal, and coronory occlusion.

Ocular features:

*Dry eye
Keratoconjuctivitis Sicca"

secondary sjogren

disease. *Episcleritis

(painless unimpaired sight).

*Scleritis (painful and more

serious sight - threatining).

*Scleromalacia (bilateral

thinning of the sclera).

Corneal melting rare, serious,

associated with vasculitis, if

untreated , it can lead to

perforation

CARDIAC MANIFESTATIONS

OCCUR UP TO 30%USUALLY ASYMPTOMATIC.

SYMPTOMATIC PERICARDIAL EFFUSION AND

CONSTRICTIVE PERICARDITIS ARE RARE.

HEART BLOCK, CARDIOMYOPATHY, CORONARY ARTERY

OCCLUSION OR AORTIC REGURGITATION CAN OCCUR.

ACCELERATED ATHEROSCLEROSIS ALSO OCCUR.

PATIENTS WITH RA HAVE AN INCREASED MORTALITY

WHEN COMPARED WITH AGE-MATCHED CONTROLS,

PRIMARILY DUE CARDIOVASCULAR DISEASE

FURTHERMORE THE NSAIDS AND CORTICOSTEROID

EXACERBATE CARDIAC DISEASES.

Pulmonary features

[Rheumatoid lung]

•Pulmonary fibrosis • Pleural

effusion.

• Rheumatoid nodule

(pulmonary)

Bronchitis and bronhiectasis are

common in RA..

•

Rarly potentially fatal

oblitrative bronchiolitis may

occur .

•

Bacterial infection especially

those on cortico steroid.

•

Pulmonary fibrosis may

caused by methotrxate.

•

Anti TNF therapy associated

with TB reactivation..

NEUROLOGICAL COMPLICATIONS

ENTRAPMENT NEUROPATHY . COMPRESSION

OF MEDIAN NERVE IS COMMON (CARPAL
TUNNEL SYNDROME). ULNAR NERVE
COMPRESSION AND TARSAL TUNNEL
SYNDROME CAN ALSO OCCUR.
- DIFFUSE PERIPHERAL NEUROPATHY AND
MONONUERITIS MULTIPLEX (IN RHEUMATOID
VASCULITIS)
-CERVICAL CORD COMPRESSION AT ATLANTO-
AXIAL JOINT OR SUB AXIAL LEVEL
SUBLUXATION

Hematological features:

-Microcytic iron deficiency anaemia (NSAID-

induced GIT blood loss).

-Normochromic normocytic anaemia,

thrombocytosis in active disease.

Felty's syndrome: constitute of: RA , splenomegaly

and neutropenia, in long standing seropositive at

age between 50-70 ,female>male, associate

with sjogren

disease,lymphadenopathy,thrombocytopenia,

recurrent infection, leg ulcer (vasculitis)

•

Other complications

-Amyloidosis (rare) presented as nephrotic

syndrome

-Generalized or localized

lymphadenopathy. In persistent

lymphadenopathy biopsy indicated

because there is risk of associated

lymphoma in patient in long standing

disease.

-Osteoporosis
-Ante -date or accelerated atherosclerosis
- Infections

Investigations:

The diagnosis of RA usually done on clinical

background.

The lab. Invest. is needed for confirmation of

diagnosis or for monitoring of disease

--Acute phase response. ESR and CRP are elevated and may

be not in isolated joint arthritis ..so normal values don’t
exclude the diagnosis.

--RHEUMATOID FACTOR (RF)AND ANTI CITRULINE
PEPTIDE ANTIBODIES (ACPA) ARE PRESENT IN
ABOUT(70%).
RF HAS LOW DIAGNOSTIC SPECIFICITY. THE
PRINCIPLE USE OF RF IS FOR PROGNOSIS SINCE A
HIGH RF TITER AT PRESENTATION CARRY POOR
PROGNOSIS

(ACPA) ANTIBODIES. IT IS SUPERIOR TO RF TO SUPPORT
DIAGNOSIS OF RA. IT MORE SPECIFIC. IT USUALLY
ASSOCIATED WITH MORE SEVERE, EROSIVE RA.

--INVESTIGATION TO MONITOR DRUG SAFETY:
URINALYSIS, LIVER ENZYME, S. UREA AND CREATININE ,
FULL BLOOD COUNT , CXR.

DISEASE ACTIVITY SCORE :DAS-28

IS FREQUENTLY USED TO ASSESS THE DISEASE ACTIVITY AND
RESPONSE TO TREATMENT AND THE NEED FOR BIOLOGICAL
THERAPY.
TO CALCULATE DAS- 28 :
COUNT THE NUMBER OF TENDER AND SWOLLEN JOINTS IN
UPPER LIMBS AND KNEES
• MEASURE THE ESR
• ASK THE PATIENT TO RATE GLOBAL ACTIVITY OF ARTHRITIS
DURING THE
PAST WEEK USING VISUAL ANALOGUE SCALE (VAS) FROM 0
(NO SYMPTOMS) TO 100 (VERY SEVERE)
• ENTER DATA INTO CALCULATOR OR WORK OUT USING A
SPECIAL FORMULA.

A DAS28 SCORE OF HIGHER THAN 5.1 IS INDICATIVE OF
HIGH DISEASE ACTIVITY, WHEREAS A DAS28 BELOW 3.2
INDICATES LOW DISEASE ACTIVITY. A PATIENT IS
CONSIDERED
TO BE IN REMISSION IF THEY HAVE A DAS28 LOWER THAN
2.6 .

Synovial fluid examination :shows non specific

inflammatory changes.

Radio graphical features:

Plain radiography: Can be normal in early stage of disease

apart from soft tissue swelling

Periarticular osteopenia.
marginal non-proliferative erosions and symmetrical joint

narrowing. Plain x-ray also used to detect atlanto-axial

or subaxial subluxation(in flexion and extension

position) where as the degree of cord compression need

MRI.

-MRI AND ULTRASOUND ARE MORE SENSITIVE IN
DETECTING EARLY EROSIONS AND WHEN UNCERTAINTY OF
SYNOVITIS .(NOT USED ROUTINELY IN CLINICAL OBVIOUS
CASES).

-ULTRA SOUND IS INDICATED IN RUPTURE OF BAKER CYST
TO CONFIRM DIAGNOSIS AND TO EXCLUDE POSSIBILITY OF
DVT AS IN SOME INSTANCES BOTH CAN CO EXIST.

the American College of Rheumatology (ACR), in
collaboration with European League Against Rheumatism
(EULAR), released the updated classification criteria
EULAR/ ACR which depend mainly on the number and
distribution of involved joints, serology, acute phase

reactants, and duration of disease , with goal of

distinguishing newly presenting patients with early
undifferentiated arthritis who had a high probability of
developing persistent or erosive RA.



The ACR/ EULAR criteria



Criterion

Score



Joint affect

 1 large joint                         0
   2-10 large joints                  1
   1-3 small joints                    2
   4-10 small joints                  5

Serology
   Negative RF and ACPA         0
   Low positive RF or ACPA     2
   High positive RF or ACPA     3

   Duration of symptoms
   Less than 6 weeks                0
   More than 6 weeks               1

   Acute phase reactant
   Normal CRP and ESR              0
   Abnormal  CRP or ESR            1
• Patients with 6 or more are

considered to have RA.

Management

goal is disease control and induction of disease

remission

• Patient education
• Multidisciplinary team
• Physical rest and passive exercises.
• Re assessment

Drug Therapy:

• Prompt and early introduction of small molecules

DMARDs and corticosteroid play a central role in

induction of remission.

• The patient should be informed that DMARDs will not

improve symptoms immediately. But in longer term the

symptoms will be under control and joint damaged will

be prevented. If no or partial response to DMARD

therapy this necessities increase the dose or combine

with other DMARD, with progression to biological drugs if

needed.

SOME OF DMARDS ARE CONTRAINDICATED IN PREGNANCY.
REGULAR MONITORING IS NECESSARY TO EXCLUDE SIDE
EFFECT AND TOXICITY (MAINLY HEMATOLOGICAL AND LIVER
TOXICITY) AND TO EVALUATE DRUG EFFICACY.
.
IT NOT REVERSE THE ALREADY PRESENT EROSIONS BUT CAN
STOP OR MODIFY THE DISEASE PROGRESSION .
*THE MOST COMMON DMARD OF CHOICE IS
METHOTREXATE ( MTX).

Disease Modifying Anti-Rheumatic Drugs(DMARDs):

Methotrexate(MTX):
It is considered the main drug of choice or the anchor of
DMARD therapy .
The starting dose is 10-15 mg /week increasing by 2.5 mg
every 2- 4 week until benefit or toxicity. The maximum
dose is 25mg/week.
It can used alone or with other DMARD (combination)
therapy.

benefit appear after 1- 4 months after initiation of drug.

• MAIN EARLY SIDE EFFECT ARE NAUSEA , VOMITING ,

MALAISE IF PERSIST PATIENTS CAN EFFECTIVELY TREATED
BY SUBCUTANEOUS ROUT.
PATIENTS SHOULD ALARM ABOUT DRUG INTERACTION
WITH SULPHONOMIDES.
ALSO PATIENT SHOULD AVOID ALCOHOL WHICH MAY
ENHANCE HEPATOTOXICITY.
REGULAR MONITORING IS ESSENTIAL FOR EARLY
DETECTION OF SERIOUS SIDE EFFECT (HEPATIC OR BONE
MARROW TOXICITY) .
PULMONARY PNEUMONITIS IS RARE SERIOUS SIDE
EFFECT, IF OCCUR THE DRUG SHOULD STOPPED
IMMEDIATELY AND PATIENT TREATED WITH HIGH DOSE
OF STEROID.

Sulfasalazine:

 CAN Taken orally alone, but usually with MTX.
 GIT upset and nausea main side effect.
 Starting dose 500mg/day and increasing gradually to 2-4

gm /day

 Monitoring for hematological and hepatic toxicity

Hydroxychlorquine:

Ususlly used with comnination with other

DMARD(mainly MTX.sulfasalazine.)

Given in dose of 400mg/d.
Retinal damage may occur in long term

treatment.

Visual acuity should tested before treatment and

repeated regularly as treatment is going on.

Leflunomide:

Can be used alone or with other drug.
Given in dose of 10- 20 mg/day.
Usually well tolerated, low marrow toxicity, but

may cause liver dysfunction.

Require regular liver and hematological

monitoring.

Gold, pencillamine, ciclosporine:

 these drugs are occasionally used for RA treatment due

to availability of other drugs with a better risk- benefit
profile.

 Corticosteroid : although it has disease modifying effect, but its

main use are:



Induction

of remission in patients with RA who starting synthetic

DMARD. And tapering till the effect of DMARD appear(

bridge

therapy).



In flare up

of disease while patient already on DMARD therapy.



Flare up during pregnancy



Intraarticular injection of

corticosteroid when one or two joints

with persistent synovitis in spite of generalized well

being and

other joints are remitted ( in this situation possibility of infection

should be excluded)

 Corticosteroid therapy carry many side effects mainly

osteoporosis, which is also main complication of RA even in

absence of steroid therapy.

 DEXA should considered in RA with anti osteoporotic measures

especially for those on steroid of 7.5 mg/day for more than 3

months.

Biological therapies
are reserved for the treatment of patients who
have high disease activity despite having had an adequate
trial of traditional DMARDs.
More effective and cost more greater than synthetic DMARDs.
In UK its used restricted to patient with active RA (DAS28 > 5.1;
when an adequate trial of at least two other
DMARDs (including methotrexate) has dts

1-ANTI-TNF THERAPY:
ETANRECEPT
INFLIXIMAB
ADALIMUMAB
GOLIMUMAB
CERTOLIZUMAB
CAN BE USED AS MONOTHERAPY (ALTHOUGH A
COMBINATION WITH MTX GIVE BETTER RESULTS) .
MTX REDUCED NEUTRALIZING EFFECT OF ANTIBODIES
FORMATION AGAINST ANTI-TNF THERAPY

The main side effects of anti TNF alpha therapy are
increase risk of infection mainly reactivation of
latent T.B and increase risk of malignancy mainly
basal cell carcinoma of skin and increase
progression of cancer in patients with prior tumor.

2- Anti B cell therapy: Rituximab
3- Inhibitor of T- cell activation: (Abatacept).
4- ANTI IL-6( Tocillizumab).
5- Anti IL-1(Anakinra).

now

JAK

(janus kinase inhibitor): tofacitinib and

baricitinib.

• New diagnosis of rheumatoid arthritis
• s

Increase dose over 12 week MTX

• +

• Prednisolone Decrease dose

over 12 weeks

•                                                           DAS 28  <2.6             DAS 28 >2.6
•
•                                      Continue MTX                               Add SSZ + HCQ
•
•                                                                                     DAS 28<2.6            DAS 28 2.6-5.1

DAS 28>5.1

•
• Continue triple therapy Change DMARD or

add low-dose prednisolone Add biologic

Surgery:

in complicated conditions surgical interventions may
required as: synovectomy, tendon repair, arthrodeses,

arthroplasty

General measures:
Patient education about nature of disease, regular
monitoring and periodic disease assessment.
Physical rest, NSAIDs and analgesia.
Joint protection , splinting, regular active and gentle
passive exercise to preserve joint function prevent
muscle atrophy and joint contracture.
Hospitalization needed in multiple joint injection ,
splinting, joint injections.

*Prognosis:

the following factors at presentation are associated with

poor prognosis:

1- higher base line disability.
2- insidious onset.
3- female gender.
4- positive Rheumatoid factor , anti-ccp(ACPA) and nodule

formation, smoking

5- positive family history of severe RA.
6- involvement of MTP.
7- disease duration of over three months.
8- presence of extra-articular                             manifestations.

RA during pregnancy: most patients with
RA go into remission during pregnancy.
methotrexate should be discontinued for at least 3 months
and leflunomide discontinued for at least 24 months
before trying to conceive.
Paracetamol: the oral analgesic of choice during
pregnancy.
Oral NSAIDs and selective COX-2 inhibitors: can be used
after implantation to 20 weeks’ gestation.
Corticosteroids: may be used to control disease flares; the
following
maternal risks as hypertension, glucose intolerance
and osteoporosis should be considered.

DMARDs that may be used: sulfasalazine,

hydroxychloroquine, azathioprine if required to control
inflammation.
DMARDs that must be avoided: methotrexate,
leflunomide, cyclophosphamide, mycophenolate ,gold .

Biological therapies: safety during pregnancy is currently
unclear. Theoretical risk is immunosuppression of neonate.

Breastfeedin

methotrexate, leflunomide,
cyclophosphamide, are contraindicated.