Rheumatoid arthritis is a chronic inflammatory disease that affects the joints, causing pain, stiffness, and swelling. It can also impact other body systems. While the exact cause is unknown, genetics and environmental factors are believed to play a role. Common symptoms include joint deformities, fatigue, and anemia. Diagnosis involves evaluating symptoms, physical exam findings, blood tests, and x-rays. Treatment focuses on reducing inflammation and joint damage through medications like DMARDs, NSAIDs, and corticosteroids. The goals are to relieve symptoms, improve function, and prevent disability. Care requires a multidisciplinary approach including medication management, exercise, and lifestyle changes.

1. RHEUMATOID ARTHRITIS
• Rheumatoid arthritis (RA) is one of the most
common chronic inflammatory conditions,
affecting the population aetiology affecting both
articular tissue and extra-articular organs.
• There is a wide range of extra-articular features.
The disease is progressive and results in pain,
stiffness and swelling of joints which can lead to
significant morbidity and increased mortality

2. EXTRA-ARTICULAR FEATURES OF RHEUMATOID ARTHIRITS
COMMON UNCOMMON
Anaemia
Nodules (subcutaneous)
Muscle wasting
Dry eyes
Depression
Osteoporosis
Episcleritis
Carpal tunnel syndrome
Leg ulcers
Lymphadenopathy
Nailfold vasculitis
Pleural and pericardial effusions
Fibrosing alveolitis
Pericarditis
Scleritis
Systemic vasculitis
Mitral value and conduction defects
Nodules (lungs, eyes, heart)
Felty’s syndrome (seropositive rheumatoid arthritis,
splenomegaly and neutropenia, incidence <1%)

3. EPIDEMOLOGY
• Approximately 1% of the adult population
worldwide is affected by rheumatoid arthritis.
• The prevalence of rheumatoid arthritis
increases with age in both sexes with nearly
5% of women and 2% of men over 55 years of
age affected.
• The peak age of incidence is around 55-64
years in women and 65-75 years in men.

4. AETIOLOGY
• The cause of rheumatoid arthritis remains unclear. It is postulated that a genetically
susceptible host is exposed to an unknown pathogen (antigen) and this interaction gives rise
to a persistent immunological response.
• Whether the initiating agent is an infection, a self-antigen or an environmental factor
remains unproven.
• This model makes the assumption that the host’s immune human leucocytes antigen (HLA)
response genes, immunoglobulin genes and T-cell receptor genes have an impact later in the
chain of pathological events during stage II of the disease. The initial stage I, in this complex
model, involves synovial tissue injury.
• The most definite genetic association with rheumatoid arthritis is with HLA alleles. The HLA-
DR4 allele is associated with development and severity of rheumatoid arthritis.
• In American whites, 60-70% of rheumatoid arthritis patients are positive for HLA-DR4. This
seems to be particularly important in severe forms of the disease. The frequency of HLA-DR4
among Dutch patients with severe extra-articular disease is greater than 90%.

5. • Epstein-Barr virus has been lined to rheumatoid arthritis for many
years.
• Of patients with rheumatoid arthritis, 80% have a circulating
antibody directed against antigens specific for Epstein-Barr virus,
and the autoantibody response in rheumatoid arthritis enhances
the response to these antigens.
• Parvoviruses (small DNA viruses that cause disease in many
species), particularly B19, have been linked to rheumatoid arthritis.
Mycobacteria have also been linked to rheumatoid arthritis because
these bacteria express heat shock proteins (HSPs).
• A potential hypothesis is that antibodies and T-cell exist that
recognize epitopes shared by the HSPs of both the infectious agents
and host cells. This would facilitate cross reactivity of lymphocytes
with host cells, triggering an immunological reaction

6. pathophysiology
• Chronic inflammation of the synovial tissue lining
the joint capsule results in the proliferation of this
tissue.
• The inflamed, proliferating synovium
characteristic of rheumatoid arthritis is called
pannus.
• This pannus invades the cartilage and eventually
the bone surface, producing erosions of bone and
cartilage and leading to destruction of the joint.
• The factors that initiate the inflammatory process
are unknown.

7.  The proinflammatory cytokines tumor necrosis factor (TNF),
interleukin (IL)-1 and IL-6 are key substances in the initiation
and continuance of rheumatoid inflammation
• The processed antigen is recognized by major histocompatibility complex proteins on
the lymphocyte, which activates it to stimulate the production of T and B cells.
• Lymphocytes may be either B cells (derived from bone marrow) or T cells (derived from
thymus tissue).
• T cells may be either CD4+ (T-helper) or CD8+ (cytotoxic or killer) T cells. There are two
subtypes of T-helper cells, TH1, which promote inflammation by producing interferon-γ,
tumor necrosis factor, and interleukin-2, and TH2, which produce the antiinflammatory
cytokines IL-4, IL-5 and IL-10.
• CD8+ killer T cells have a regulatory effect on the immune process by suppressing
activity of CD4+ cells through release of antiinflammatory cytokines and promoting
apoptosis (cell death).
• Activated T cells produce cytotoxins, which are directly toxic to tissues, and cytokines,
which stimulate further activation of inflammatory processes and attract cells to areas
of inflammation. Macrophages are stimulated to release prostaglandins and cytotoxins.
• The released inflammatory mediators causes the erosion of synovial tissue and cartilage
destruction.

8. CLINICAL MANIFESTATIONS
CRITERIA FOR DIAGNOSIS OF RHEUMATOID ARTHRITIS
CRITERIA COMMENT
1.Morning stiffness During lasting >1hr for >6 weeks
2. Arthritis of at least three joint areas Soft tissue swelling or exudation for >6 weeks
3.Arthritis of hand joints Swelling in wrist, metacarpophalangeal joints or proximal interphalangeal joints
lasting >6 weeks
4.Symmetrical arthritis Symmetrical involvement of same joint areas on both sides of body lasting >6
weeks
5.Rheumatoid nodules Subcutaneous nodules as observed by physician
6.Serum rheumatoid factor Abnormal level of serum rheumatoid factor assessed by a method positive in
less than 5% of control subjects
7.Radiographic changes Typical changes seen an anteroposterior films of wrist and hands
Presence of four or more of the above criteria indicates that the patient has rheumatoid arthritis.

10. Sc nodules

11. Investigations
• The diagnosis of rheumatoid arthritis is made on presenting signs,
symptoms and some biochemical investigations.
• The most useful of these are the inflammatory markers, for
example erythrocyte sedimentation rare (ESR), C-reactive protein
(CRP) and plasma viscosity (PV), rheumatoid factor (RF) and
antinuclear antibodies (ANA).
• Note: A raised inflammatory marker simply confirms the presence
of an inflammatory condition and occurs in many disease states. A
normal inflammatory marker, however, does not preclude active
disease.
• Although these markers are not specific to rheumatoid arthritis
they may be used to assess response to drug treatment as they are
usually raised when the disease is active.

12. • Rheumatoid factors are autoantibodies are mostly
IgM type which is present in75-80% of patients with
rheumatoid arthritis (seropositive disease) and 5% of
normal subjects.
• Extra-articular features of rheumatoid arthritis are
much more common in the patients with a high titre
for RF.
• Antinuclear antibodies are investigated to rule out the
possibility of other connective tissue disorders such as
systemic lupus erythematosus (SLE). Antinuclear
antibodies are raised in 80% of patients with SLE, and
about 20% of patients with rheumatoid arthritis.

13. • Radiographs, mainly of the hands and feet, have been used to
establish the diagnosis of rheumatoid arthritis and to follow its
progression.
• Erosions can be seen at the joint margins and loss of joint space due
to erosion of cartilage and bone may be identified.
• In severe long standing disease the dominant features include
magnetic resonance imaging (MRI) and ultrasound (US) is being
increasingly used to detect inflammatory activity.
• Erosions traditionally detected on X-ray will not be apparent in the
early stages of the disease. Early diagnosis and treatment of
inflammation are important to limit joint damage and so MRI and
US are used to detect early changes in rheumatoid arthritis patients
(Keen & Emey 2005).

14. GOALS OF TREATMENT
• Decrease pain and inflammation
• Prevent joint destruction
• Improve joint function
• Maintain normal life style

15. Non-pharmacological treatment
• Physiotherapy
• Heat, cold and electrotherapy
• Occupational therapy
• Surgical treatment(knee replacement/ hip
replacement)

16. Pharmacological treatment
• NSAIDS
• DMARDS
• Corticosteroids
• Cytokine inhibitors

17. • FLOW CHART IN DIPIRO

18. Non-Steroidal anti-inflammatories
(NSAIDS) / Coxibs for symptom
control
NSAIDS should seldom be used as monotherapy for RA
because
1) Only Reduce pain and swelling by inhibiting COX
2) Do not alter course of the disease.
Note: they should be used in combination with DMARDS

19. CHOICE OF NSAIDS
• Based on 12 controlled epidemiological studies
Ibuprofen has the lower risk of gastrointestinal complications
and azapropazone highest
• Drug relative risk
• Ibuprofen 1.0
• Diclofenac 2.3
• Naproxen 7.0
• Indomethacin 8.0
• Piroxicam 9.0
• Azapropazone 11.7

20. • In patients with high risk of gastrointestinal toxicity, first line choice
of analgesic would be paracetamol.
• If anti-inflammatory effect is required, then either ibuprofen or
diclofenac is preferred In addition to PPI, or misoprostol.
• Patient response:
• Patient response to NSAIDS is highly variable
• It is estimated that 60% patients will respond to any one NSAID.
• If patient does not respond it may be necessary to try several other
NSADIS before the most appropriate agent is found.
• It is recommended that drug should be changed after one week of
non response if analgesic action is required or 3 weeks if anti
infammatoryaction is required.

21. Adverse effects
• Gastrointestinal complications like abdominal
pain, diarrhoea (minor effects), duodenal and
gastric uclers( major effects).
• Renal impairment,
• Angio-edema,
• Hepaptic dysfunction,
• Heamatological abnoramalities
• And bronchospasm.

22. Drug interactions
Affected drug Drug causing
effect
Effect produced
Oral anticoagulants NSAIDS Aspirin enhances hypothrombinaemic
effect
All NSAIDS increase risk of GI bleeding,
anti platelet action
Hypotensive agents NSAIDS Decreased hypotensive effect
Diuretics NSAIDS Decreased diuretic effect
Potassium- sparing drugs,
e.g. ACE inhibitors,
Potassium- sparing
diuretics
Indomethaci
n
hyperkalaemia
Lithium Most NSAIDS Increased lithium toxicity
Methotrexate NSAIDS Increased methotrexate toxicity
Most NSAIDS Probenicid Incresaed NSAID concentration

23. Notes:
• Use of cox-2 selective inhibitors with PPI or misoprostol has
no use.
• cox-2 selective inhibitors are less used evethough they have
lower GI complications. Because they are contrindicated in
IHD, CVD, PAD, and CHF.
• But non-selective inhibitors are not known to cause increased
cariovascular toxicity

24. Dosage Regimens for Nonsteroidal Antiinflammatory
Drugs
Drug Dosage Dosing schedule
Aspirin 2.6-5.6g Four times daily
diclofenac 150-200mg Three times to four
times daily
Ibuprofen 1.2-3.2g Three times to four
times daily
Indomethacin 50-200mg Two times to four
times daily

25. Disease Modifying Anti-rheumatic
Agents
• Drugs that actually alter the disease course .
• Should be used as soon as diagnosis is made.
• Appearance of benefit delayed for weeks to
months. Initial benefit can take 4-16 weeks, with
response to treatment usually expected within 4-6
months.
• NSAIDS must be continued with them until true
remission is achieved.

26. How to select DMARDS
• The selection is based on the adverse effects
profile and efficacy profile.
• In practice, initial treatment of RA is generally
with a single agent. If satisfactory response is not
achieved after a 3-6 month trial with
monotherapy, then combination treatment s
usually given.
• The popularly used combination is methotrexate
and sulfasalazine(5 years continuous rate)

27. DMARDs

28. Popular combinations
• Methotrexate + sulfasalazine
• Methotrexate + hydroxychloroquine
• Methotrexate + leflunomide
• Ciclosporine + hydroxychloroquine
• Ciclosporine + Methotrexate
• Note: if any of this combination is not
working, then cytokine inhibitors are given

29. • Sulfasalazine:
• Has high continuous rate and low rate of serious
adverse effects
• Used in mild to moderate RA
• Monitoring requirements are less required
• Dose: initially 500 mg OD
increasing in weekly steps of 500mg to 3g daily
AE: Reversible male infertility, bone marrow
suppression, hepatitis
MONITORING PARAMETERS: FBC AND LFT

30. Methotrexate:
It has high continuous rate and low incidence of AE.
Is used in moderate to severe disease
Has rapid onset of action of 4-6 weeks
Is easy to administer as a single weekly dose and response rate is 40-50%.
Dose: 5-25mg once weekly(on the same day each week)
Dose should be reduced in renal impairment patients.
DI: alcohol
AE: bone marrow suppression, hepatitis, stomatitis, pneumonitis.
MONITORING PARAMETERS: FBC AND LFT
CI: pregnancy, peptic ulcer disease, liver disease
Note: nausea and stomatitis can be managed by the addition of folic acid
which should be omitted on the day methotrexate is administered.

31. Sodium aurothiomalate(gold inj):
Is very agent in the treatment of RA
However its is limited due to side effect profile.
Precaution:
Patient must be checked for proteinurea. If
significant protein is detected, the gold therapy
should be withheld.
Auranofin(oral gold):
Less toxic and less effective.
It is now seldom used.
Adverse effects are similar to gold inj.
Diarrhoea caused by oral gold can be managed by
high fiber diet.

32. Cyclosporin:
• Patients who have failed to respond to conventional therapy, may
respond to cyclosporin therapy.
• Patient should have normal BP and creatinin level before this drug
therapy is given because it causes HTN and nephrotoxicity
• Other side effects are hirsutism, tremor and gum hyperplasia.
Hydrroxychloroquine:
• Least toxic and least effective
Dose: 400 to 800mg/day
AE: GI toxicity, retinopathy
Leflunomide:
Has both anti-inflammatory and immunomodulatory properties
Has rapid onset of action of 4 weeks.
MOA: inhibits the synthesis of DNA and RNA in immune response cells,
particularly activated T-cells.it also inhibits the production of
proinflammatory cytokines TNF-α and IL-1.

33. Dosage, side effects and monitoring guidelines for
DMARDS
Drug Dose schedule Averse effetcs Monitoring
Sulfasalazine initially 500 mg OD
increasing in
weekly steps of
500mg to 1g Bd
Reversible male
infertility, bone
marrow suppression,
hepatitis
FBC and LFTs
fortnightly for 2
months then monthly
for 4 months then 3
monthly
Methotrexate 5-25mg once weekly bone marrow
suppression, hepatitis,
stomatitis,
pneumonitis
FBC and LFTs
fortnightly for 2
months then monthly
for 4 months then 3
monthly
Ciclosporine 2.5 mg/ kg per day HTN, renal
impairment,
hirsutism, tremor and
gum hyperplasia.
FBC, LFT BP,
CREATININE LEVELS
Hydroxychlotoquine 200mg twice daily up
to 3 months, then OD
Skin pigmentation,
retinopathy, psychosis
Fundoscopy,
perimetry yearly

34. corticosteroids
• Supress cytokines and produce rapid improvement in symptoms and signs
• Slowdown the radiographic changes
• These are used to provide temporary relief until DMARDS become active.
• Prednisolone is given orally
• Dose: 10mg orally
• Intra-articular administration (methyl prednisolone or triamsinolone)can
effectively relieve pain, increase mobility and reduce deformity in one or
more joints
• The dose is dependent upon the joint size, with methylprednisolne acetate
40-80mg or trimsinolone acetonide 20-40mg appropriate for lager joints
such as knee.
• Once the injection is given, the next dose is given at interval of 1-5 weeks .

35. BIOLOGICS IN RA
• Cytokines such as TNF-α ,IL-1,IL-10 etc. are key
mediators of immune function in RA and have
been major targets of therapeutic manipulations
in RA.
• Of the various cytokines,TNF-α has attaracted
maximum attention.
• Various biologicals approved in RA are:-
1) Anti TNF agents : Infliximab Etanercept Adalimumab
2) IL-1 receptor antagonist : Anakinra
3) IL-6 receptor antagonist : Tocilizumab
4) Anti CD20 antibody : Rituximab
5) T cell costimulatory inhibitor : Abatacept

36. 25 mg s/c twice a
wk
May be given with
MTX or as
monotherapy.
Injection site
reaction,URTI ,
reactivation of
TB,development of
ANA,exacerbation of
demyelenating
disease.

37. Agent Usual
dose/route
Side effects
.
Anakinra 100 mg s/c once
daily
May be given with
MTX or as
monotherapy.
Injection site
pain,infections,
neutropenia
Active infections
Contraindications
(Anti-IL-1)

38. Lifestyle Modifications
1. Quit smoking: According to Dr. Edward Skol, a rheumatologist with
Scripps Health, environmental factors such as smoking can sometimes
trigger the development of rheumatoid arthritis.
2. Use dietary supplements: Fish oils and omega-3a can help control the
inflammatory process of the disease, said Dr. Gregg Middleton, an
associate clinical professor of rheumatology and orthopedics at
the University of California, San Diego.
3. Lose weight: Dr. Natasha Conley, director of osteopathy at Kaiser
Permanente, said it’s common sense that less pressure on the weight-
bearing joints will ease discomfort for those with rheumatoid arthritis.
4. Perform low-impact exercises: Swimming, yoga, aerobics and other
exercises that are easy on the joints can help keep the body properly
stretched while not placing too much pressure on the body, said Skol.
5. Follow an anti-inflammatory diet: “A healthy diet is a good thing, even
though the relationship between specific foods (and rheumatoid
arthritis) are not linked,” Conley said. She stated that such foods would
include fruits, vegetables and fish.