RHEUMATOID

ARTHRITIS
Presenter : Dr.Shirish kumar ,2nd yr PG
Moderator : Dr.Karunakar , MD .
Asst. professor , Dept of Medicine
KMC/MGMH.

INTRODUCTION :
➤ It’s a CHRONIC inflammatory disease of UNKNOWN ETIOLOGY.
➤ Affects 0.5-1% of adult population worldwide .
➤ Female to Male ratio 2-3:1
➤ It’s a most common form of INFLAMMATORY ARTHRITIS.
➤ SYMMETRIC POLYARTHRITIS
➤ Persistently active RA articular cartilage and bone destruction

Functional disability
ETIOLOGY OF RA :
GENETIC RISK FACTORS :
▪ Alleles which confer the greatest risk fo RA are located within MHC CLASS II locus.
▪ Variations in HLA-DRB1 which encodes for class II MHC carries high risk of RA .
▪ Single nucleotide polymorphisms in PTPN22 ( Protein Tyrosine Phosphatase non–receptor 22 ) . These protein
encodes lymphoid tyrosine phsphatase , a protein that regulates T and B cell function .
▪ Polymorphisms in PADI4 ( Peptidyl arginine deaminase type IV ) , PADI4 encodes an enzyme involved in
conversion of arginine to citrulline and is postulated to play a role in the development of antibodies to citrullinated
antigens .
▪ Polymorphisms in APOM ( apolipoprotein M )

ENVIRONMENTAL RISK FACTORS :

▪ Cigarette smoking .
▪ Infections like – EBV , Mycoplasma , Mycobacteria , Parvovirus B19 , Retroviruses etc..
▪ Periodontitis caused by the oral microbiome porphyromonas gingivalis .

PATHOGENESIS OF RA :
➤ The pathogenic mechanisms of synovial inflammation are likely to result from complex
interplay of genetic,environmental and immunologic factors that produces
dysregulation of the immune system and a breakdown in self tolerance .

➤ The pathogenesis of RA is build upon the concept that self-reactive T cells drive the
chronic inflammatory response .

➤ Cytokines , chemokines,antibodies , and endogenous danger signals bind to

receptors on the surface of immune cells and stimulate a cascade of intracellular
signalling events that amplify the inflammatory response .
 CLINICAL CLASSIFICATION OF RA :
➤ Circulating autoantibodies primarily RHEUMATOID FACTOR (RF) , Anti-
citrullinated protein antibodies ( ACPA ) , Anti-carbamylated antibodies & anti-
peptidylglargine deaminase 4 antibodies( anti-PAD4) can be detected in serum before
RA symptom onset often by many years .
1) PRECLINICAL RA :
✓ The period of autoimmunity preceding the initial articular signs and symptoms of
disease has been termed PRECLINICAL RA .
✓ There is presence of subclinical inflammation that is reflected by ↑CRP and other pro-
inflammatory cytokines and chemokines .
✓ Inflammation during these preclinical RA is seen in LUNGS ( bronchiectasis ) , oral
(periodontitis ) or intestinal mucosa .

2) CLINICAL RA: / CLINICAL FEATURES OF RA :

➤ Age of incidence = Peak at 25-55 yrs
Plateau till 75 yrs and then decreases .
➤ Inflammation of joints , tendons and bursae will lead to symptoms of RA.
➤ EARLY MORNING JOINT STIFFNESS
( lasts for more than 1 hour and then eases with physical activity)
➤ Earliest involved joints - SMALL JOINTS OF HAND AND FEET
➤ WRIST , MCP(metacarpophalangeal), PIP(proximal interphalangeal joint) are
more frequently involved.
➤ SYMMETRIC involvement.
➤ monoarticular (or) Oligoarticular (≤4) ( or ) Polyarticular (>5).
➤ FLEXOR TENDON TENOSYNOVITIS :
~ frequent hallmark of RA.
~ Decreases range of motion and grip strength
~ leads to “Trigger fingers.”
➤ Progressive destruction of joints and soft tissues will lead to IRREVERSIBLE
DEFORMITIES.
➤ SWAN NECK DEFORMITY : Hyperextension of PIP + Flexion of DIP .
➤ BOUTONNIERE DEFORMITY : Flexion of PIP + Hyperextension of DIP .
➤ ULNAR DEVIATION : Subluxation of MCP joints with subluxation or partial destruction of
proximal phalanx to volar side .
➤ Z - LINE DEFORMITY : Subluxation of 1st MCP joint with Hyperextension of 1st
interphalangeal joint.
➤ PIANO KEY MOVEMENT OF ULNAR STYLOID : Subluxation of Ulna secondary to
inflammation of ulnar styloid and tenosynovitis of the extensor carpi ulnaris.
➤ PES PLANO VALGUS ( Flat foot ) : due to chronic inflammation of ankle and mid tarsal
regions
➤ Atlantoaxial involvement of C-SPINE :
~Very rare ( <10%)
~Progressive instability of C1 on C2
~may cause Cervical compressive myelopathy in rare cases.
➤ Temporomandibular joint :
~ commonly involved
~ Radiographic abnormalities will be seen but no significant symptoms
( or ) functional impairment.
➤ CONSTITUTIONAL SYMPTOMS : Weight loss
Fever ( if > 38.3°C ,suspect systemic vasculitis or inf
Fatigue
Malaise
Depression
Cachexia ( in severe cases ) .
EXTRA-ARTICULAR MANIFESTATIONS OF RA :
- Seen in 40% patients.
- can be seen even prior to onset of arthritis .
- seen in pt’s with H/o SMOKING , EARLY ONSET OF SIGNIFICANT PHYSICAL
DISABILITY, H/o RA factor + or anti-CCP + .
1) SUBCUTANEOUS NODULES:
- in 30-40% pt’s.
- FIRM , NON - TENDER , adherent to Periosteum/tendons or bursae .
- Commonly seen in areas subjected to repeated trauma or irritation
i..e.. Forearms , sacral prominences and Achille’s Tendon .
- may occur in LUNG , PLEURA, PERICARDIUM and PERITONEUM .
- usually BENIGN , Infection , ulceration and gangrene may occur .
2. SJOGREN’s SYNDROME :
( Secondary Sjögren’s syndrome )
Keratoconjunctivitis sicca (Dry eyes ) or Xerostomia(Dry mouth).
+
another CTD like RA .
3) PULMONARY :
a ) PLEURITIS ( m/c ) — Pleuritic chest pain
Dyspnea
Pleural friction rub
EXUDATIVE pleural effusion.
b ) INTERSTITIAL LUNG DISEASE :
seen in 12% patients .
associated with cigarette smoking .
Dry cough and progressive dyspnea .
HRCT CHEST: infiltrative opacification in pheriphery of both lungs .
m/c types of ILD in RA :
UIP ( Usual interstitial pneumonia )
&
NSIP ( Non-specific interstitial pneumonia ).
 UIP - progressive scarring of lungs - HONEY COMB
APPEARENCE in pheripheries & lower portions of lungs .
NSIP - Symmetric B/L GGO’s with fine reticulations with volume
loss and Traction bronchiectasis .
Pulmonary function testing : RESTRICTIVE PATTERN
( ↓ TLC and ↓ DLCO )
ILD secondary to RA responds more to
IMMUNOSUPPRESSIVE THERAPHY than Idiopathic ILD .
C ) PULMONARY NODULES : Solitary or Multiple .
D ) CAPLAN SYNDROME : Pulmonary nodules + Pneumoconiasis + RA
E ) others : Respiratory bronchiolitis & Bronchiectasis - rarely seen .
 4) CARDIAC INVOLVEMENT:
• m/c involved : PERICARDIUM ( in 50% pts )
• INCREASED INCIDENCE OF CAD and ATHEROSCLEROSIS .
Risk of CCF is 2 fold high .
Presence of increased serum inflammatory markers -
increases risk of CVS disease.
M/c/c of death in RA is CARDIOVASCULAR DISEASE .
Rheumatoid nodules may be seen in Heart muscles .
MR is the m/c valvular abnormality in RA .
It occurs at higher frequency than general population .

CARDIOMYOPATHY 2° to necrotising or granulomatous

myocarditis or CAD or Diastolic dysfunction.
➤ 5) VASCULITIS :
✦ Occur in LONG STANDING DISEASE , RA + / anti -CCP + /
Hypocomplimentemia .
✦ seen in < 1% patients .
✦ Cutaneous signs : Petechiae , purpura , Digital infarcts , Gangrene
Livedo reticularis .
Large , painful , lower limb ulcers
( VASCULITIC ULCERS )

Responds well to
IMMUNOSUPPRESSIVE THERAPHY
& SKIN GRAFTING .
✦ Sensorimotor polyneuropathies
✦ Mononeuritis multiplex .
6) HEMATOLOGIC :
✦ Normocytic,normochromic ANEMIA .

✦ ↑ Platelet count ( as an Acute Phase reactant . )

✦ FELTY’s SYNDROME :

Nodular RA

Spleenomegaly Neutropenia

✦ T cell large granular lymphocytic leukemia ( T-LGL ) :

- seen in early stages of RA .
- chronic indolent clinal growth → Neutropenia
Spleenomegaly .
7) LYMPHOMA : - 2-4 fold increased risk of lymphoma
- M/c type encountered : Diffuse Large B-Cell Lymphoma .

8) OSTEOPOROSIS : - seen in 20-30% pts .

- inflammatory mileu of joint spills over into rest of the body
and promotes generalised bone loss by activating
osteoclasts .
- Chronic use of glucocorticoids & disability related
immobility also contributes to osteoporosis .
- Hip fractures are more common .

9) HYPOANDROGENISM :
- Men and postmenopausal women with RA →

 - chronic use of Glucocorticoid theraphy → inhibition of FSH and LH

secretion from pituitary .

contributes to Hypoadrogenism .
- decreased testosterone → osteoporosis
- Men with Hypoadrogenism should be considered for
ANDROGEN REPLACEMENT THERAPY.

10) OTHERS : Cervical myelopathy

Pyoderma gangrenousum.
Membranous Nephropathy
2° Amyloidosis
Keratoconjunctivitis sicca , Episcleritis , Scleritis
Periodontitis .
DIAGNOSIS OF RA :
➤ ACR - EULAR CRITERIA :
Signs and symptoms of Chronic inflamm. Arthritis

DIAGNOSIS
OF RA

Lab investigations Radiography

Score ≥ 6 is definite for RA .

LAB INVESTIGATIONS :
↑ CRP and ESR ( Non-Specific ) .
1) Serum IgM RA Factor :

75-80% + in RA .
( Negative disease does not exclude the disease ) .
Seen in 1-5% of Normal population .
Seen in other CTD’s : 1° Sjogrens , SLE ,
Type 2 essential cryoglobulinemia .
SABE , HEP B , HEP C .
2) SERUM anti - CCP antibodies ( cyclic citrullinated peptide ) :
Same sensitivity as RA Factor .
Specificity = 95%
If positive it predicts a worst prognosis .
Positive test in the setting of Early inflamm. arthritis is useful
in distinguishing RA from other forms of arthritis .
➤ 3) SYNOVIAL FLUID ANALYSIS :
reflects acute inflamm. state ( WBC = 5000 - 50,000/μL )

( WBC < 2000/μL in non- inflammatory arthritis like Osteoarthritis. )

mostly done to confirm inflamm. arthritis and to exclude Infection (or)
Crystal induced arthritis like Gout & Pseudogout .
➤ 4) JOINT IMAGING :
PLAIN X-RAY : PERIARTICULAR OSTEOPENIA . ( Classic finding ) .
( Lateral aspect of 5th MTP joint targeted first . )
other findings : Soft tissue swelling , Symmetric joint space
loss , Subchondral erosions .

advanced RA → Severe destruction , Joint subluxation and

collapse .
ULTRASOUND : USG + Power Color Doppler → Better than Plain X-ray
MRI : Greatest sensitivity for detecting SYNOVITIS , JOINT EFFUSIONS ,
Early Bone and Bone marrow changes.
BONE MARROW EDEMA → Early sign of Inflamm. Joint disease .
INDEX USED TO MEASURE RHEUMATOID ARTHRITIS DISEASE ACTIVITY:
TREATMENT OF RA :
1. DMARD’s ( Disease Modifying Anti-Rheumatic Drugs :

These are the drugs which has the ability to

change the course of RA (for the better).

These are the drugs which has the ability to

slow or prevent the structural progression
of RA.
 CONVENTIONAL DMARD’s
Delayed onset of action ~ 6-12 weeks .

METHOTREXATE ( MTX ) : → DMARD of choice and is the anchor drug for

most of combination therapies .
→ Stimulates adenosine release from cells ,
producing anti-inflammatory effect

LEFLUNOMIDE : → Similar efficacy that of MTX .

→ can be used as Monotheraphy or in
combination with MTX .
→ inhibitor of Pyrimidine synthesis .
HYDROXYCHLOROQUINE :
→ used for Early , mild disease ( or )
as an adjunctive theraphy in combination
with other DMARD’s .
→ Not a True DMARD ( does not delay the
radiological progression of the disease ) .

SULFASALAZINE : → Slows down radiological progression .

MINOCYCLINE , GOLD SALTS , PENICILLAMINE , AZATHIOPRENE AND

CYCLOSPORINE .

GLUCOCORTICOIDS.
TOFACITINIB : ( Targetted Synthetic DMARD )

→ Small molecule inhibitor that inhibits JAK 1 and JAK 3

→ Oral drug 5mg BD or 11mg daily .
→ used as Monotheraphy or in combination with MTX .
→ adverse effects : ↑ risk of infection , ↑LFT ,↑creatinine , Neutropenia ,
Dyslipidemia , URTI , diarrhoea , headache ,
Nasopharyngitis .
 BIOLOGICAL DMARD’s

Protein therapeutics designed mostly to target cytokines and cell

surface molecules .

INFLIXIMAB
TNF α INHIBITORS :
ADALIMUMAB → reduces signs and symptoms of RA , slows the radiologic
GOLIMUMAB
progression of joint damage , improves physical function
CERTOLIZUMAB
ETANERCEPT
and quality of life .
→ usually used in combination with background MTX therapy.
→ avoided in pt’s with : Active infection / Hypersensitivity /
Chronic Hep B or CCF .
→ ↑risk of infections - Bacterial , fungal , Reactivation of Latent TB.
→ All patients are screened for Latent TB prior to initiation of
TNF - α therapy with PPD skin test + IFN-γ release assay.
ANAKINRA ( IL -1 RECEPTOR ANTAGONST ) :

→ Limited use in RA
→ Do not combine with TNF -α therapy due to ↑ risk of infections .
→ 100mg SQ Daily.
ABATACEPT :
→ inhibits co-stimulation of T-cells by blocking CD28 - CD80/86
interactions.
→ inhibit function of Antigen presenting cell by reverse signalling through
CD80 and CD86
→ used in combination with MTX or another DMARD like Leflunomide .
→ Reduces disease activity , slows radiological progression of damage &
improve functional disability .
→ ↑risk of infections .
→ 500-1000mg iv at 0,2,4weeks and then every 4 weeks OR 125mg SQ
weekly.
RITUXIMAB : (ANTI CD-20 MAb.)

→ works by depleting B-cells thereby decreasing inflamm. response .

→ used for REFRACTORY RA in combination with MTX .
→ effective for seropositive pts more than seronegative pts .
→ side effects : Infusion reactions ,↑risk of infections
Progressive multifocal leukoencephaloapthy ( PML )
→ 1000mg iv for 2days ( day 0 and day 14 ) may repeat every 24weeks or
more . Premedicate with methylpred 100mg to decrease infusionreactions.

TOCILIZUMAB : (IL-6 receptor antagonist )

Pro inflammatory cytokine .

→ Monotheraphy or in combination with MTX and other DMARD’s .
→ side effects : Neutropenia ,↑risk of infections , thrombocytopenia
↑LDL cholesterol
→ 4-8mg/kg IV monthly or 162mg SQ every alternate week .
 NSAID’s:
2. → anti-inflammatory and analgesic
( Non-selective inhibition of COX -1 and COX -2 )
→ Used as an adjunctive theraphy for symptoms management .
→ NSAID’s should be rarely used without concomitant use of
DMARD’s .

→ Side effects : Gastritis , Peptic ulcer , Renal dysfunction .

GLUCOCORTICOIDS :
3.
→ initially administered in Low to Moderate doses to achieve rapid
control before the onset of fully effective DMARD theraphy which
takes several weeks or even months .
→ 1-2 weeks of burst of Glucocorticoids are prescribed for management of
acute disease flares .
→ Chronic administration of Low doses ( 5-10mg/day ) of prednisone is
prescribed to control disease in pts with inadequate response to DMARD’s .

→ High dose Glucocorticoids are necessary for treatment of

severe extraarticular manifestations of RA like ILD .
→ Intraarticular injection of Triamcinolone acetonide is given if
pt has one or few inflammed joints . it allows rapid control of
inflammation .
→ Side effects : 1. OSTEOPOROSIS ( long term complication)

Bisphosphonates .
Teriparatide .
Denosumab .

2. ↑Risk of peptic ulcer when used along with

NSAID’s .
➤ Treatment of Extraarticular manifestations in RA :
Treatment of underlying RA improves extraarticular manifestations .
Aggressive treatment of early disease can potentially prevent their
occurrence in the first place .
RA - ILD :

High dose corticosteroids + adjunctive immunosuppressive agents

[ Azathioprene / MMF / Rituximab ]

Leflunomide and MTX → PULMONARY TOXICITY.

APPROACH TO A PATIENT WITH RA :
DIAGNOSED RA

Start with METHOTREXATE

no response or inadequate response within 3-6 months .

COMBINATION THERAPY

ORAL TRIPLE THERAPHY : MTX + Sulfasalazine + Hydroxychloroquine

Methotrexate and Leflunomide .

Methotrexate + Biological ( Eg : TNF α inhibitor )

COMBINATION THERAPHY ALWAYS OUTPERFORMS MONOTHERAPHY

 DMARD-
Naive
Established
RA .

Moderate or
Low disease
High disease
activity
activity

DMARD DMARD
Monotheraphy Monotheraphy

Moderate or
High disease
activity

Combination conventional DMARDs or

TNF inhibitor ± MTX or
Non-TNF Biologic DMARD ± MTX or
Tofacitinib ± MTX

PREGNANCY AND RA :
75% of pts symptoms improve during pregnancy then FLARES after delivery

Treated with Low doses of Prednisone .

HYDROXYCHLOROQUINE and SULFASALAZINE are safest DMARD’s in pregnancy .
Methotrexate and Leflunomide contraindicated due to Teratogenicity .
Biological DMARD’s are also avoided in pregnancy.
ELDERLY AND RA :
1/3rd of pts of RA are > 60yrs of age .
Conventional DMARD’s and Biologic DMARD’s are equally effective & safe in younger and
older adults .
↑Risk of infections and there is decline in Renal function normally as age ↑↑ . So risk of renal side
effects with NSAID’s and DMARD’s i..e… MTX ↑ in elderly .
MTX not prescribed if serum creatinine is >2mg/dL as most of it is cleared by kidney .
REFERENCES :
HARRISON’s PRINCIPLES OF INTERNAL MEDICINE 20th Ed .
KELLY’s TEXTBOOK OF RHEUMATOLOGY 11th Ed.