Rheumatoid Arthritis

Rheumatoid arthritis is an autoimmune

disease, where immune system reacts against
our self-antigens produces tissue damage by
producing autoantibodies, inflammatory
mediators and proteins. It mainly affects the
joints (the synovium is the main target) but
also having extra-articular manifestations.
Prevalence
The prevalence of RA is approximately
0.8–1.0% in Europe and the Indian
subcontinent, with a female-to-male ratio of
3:1.
The prevalence is lower in South-east Asia
(0.4%). The highest prevalence in the world
is in Pima Indians (5%).
Pathophysiology

RA is a complex disease having both genetic and

environmental components in pathophysiology.
Genetic because there is higher concordance of RA
in monozygotic (12–15%) compared with dizygotic
twins (3%), and an increased frequency of disease in
first-degree relatives of patients.
Studies have detected nearly 100 genetic loci that are
associated with the risk of developing RA.
Pathophysiology
The strongest association is with variants in the HLA
region and there are also non-HLA loci lie within or
close to genes involved in regulating the immune
response.
RA occurs when an environmental stimulus, such as
infection, triggers autoimmunity in a genetically
susceptible host by modifying host proteins through
processes like citrullination so that they become
immunogenic.
Pathophysiology
No single specific pathogen has been identified as a
cause. An important environmental risk factor is
cigarette smoking, which is also associated with more
severe disease and reduced responsiveness to
treatment.
Remission may occur during pregnancy and
sometimes RA first presents post-partum. This is
likely to be due to suppression of the immune
response during pregnancy but hormonal changes
may also play a role.
Pathophysiology
Inflammatory versus non-inflammatory arthritis
Inflammatory joint disease
• Rheumatoid Arthritis
• Seronegative spondyloarthropathies, eg
Psoriatic arthritis, reactive arthritis and enteropathic arthritis.
• Polymyalgia rheumatica: in older patients.
• Crystal arthritis, eg gout.
• Connective tissue diseases, eg Systemic lupus erythematosus
Non-inflammatory/mechanical arthritis
• Osteoarthritis (OA).
• Fibromyalgia/chronic widespread pain.
• Soft-tissue rheumatism.
Clinical features
Presentations:
• Chronic insidious onset:
o Over weeks to months,
o Starting with fatigue, anorexia and vague
musculoskeletal symptoms.
o Typical presentation is with pain, joint swelling and
stiffness
o Affecting the small joints of the hands, feet and wrists
in a symmetrical fashion.
o Large joint involvement, extraarticular features are
also, present.
Clinical features
Presentations:
 Acute onset:
oLess frequent,
oIt appears over a week or two, and rarely over a
few days.
oAppears with severe early morning stiffness,
polyarthritis and pitting oedema.
oOccurs more commonly in old age.
 Polymyalgia Rheumatica like: proximal muscle stiffness
mimicking polymyalgia rheumatica.
Clinical features
Presentations:
 Palindromic:
oRelapsing and remitting episodes of pain, stiffness and
swelling that last for only a few hours or days.
oFeatures with complete resolution in between, attacks
such as self-limiting swelling of a knee.
oExtra-articular onset is recognized.
Clinical features
Presentations:
Acute synovitis of an involved joint leads to pain, swelling,
stiffness and loss of function.

Chronic active disease leads to joint damage and the

characteristic deformities of RA.

Examination typically reveals swelling and tenderness of the

affected joints. Erythema is unusual and its presence
suggests coexistent sepsis.
Clinical features
Presentations:
Deformities:
• Ulnar deviation of the fingers, ‘swan neck’ deformity, the
boutonnière or ‘button hole’ deformity, and a Z deformity
of the thumb.
• Dorsal subluxation of the ulna at the distal radio-ulnar joint
may occur and contribute to rupture of the fourth and fifth
extensor tendons.
• Triggering of fingers may occur because of nodules in the
flexor tendon sheaths.
Clinical features
Deformities
• Subluxation of the MTP joints of the feet may result in ‘cock-
up’ toe deformities, causing pain on weight-bearing on the
exposed MTP heads and the development of secondary
adventitious bursae and callosities.
• In the hindfoot, a ‘valgus deformity’ of the calcaneus with loss
of the longitudinal arch (flat foot) due to rupture of the tibialis
posterior tendon.
• Popliteal (Baker’s) cysts may occur in patients with knee
synovitis, and rupture may be induced by knee flexion, leading
to calf pain and swelling that may mimic a deep venous
thrombosis (DVT).
Clinical features
Systemic features
Anorexia, weight loss and fatigue may occur throughout the
disease course.

Extra-articular features:
Extra-articular features are most common in patients with
long-standing seropositive erosive disease but may
occasionally occur at presentation, especially in men.
Most are due to serositis, granuloma and nodule formation
or vasculitis.
Clinical features
Nodules:
Rheumatoid nodules occur almost exclusively in RF- or ACPA-
positive patients, usually in extensor tendons.
They are frequently asymptomatic but some may be complicated by
ulceration and secondary infection.
Vasculitis:
This is uncommon but may occur in seropositive patients. The
presentation is with systemic symptoms, such as fatigue and fever and
nail-fold infarcts.

Rarely, cutaneous ulceration, skin necrosis and mesenteric, renal or

coronary artery occlusion may occur.
Clinical features
Extra-articular features
Eye
Episcleritis, scleritis, keratoconjunctivitis sicca and
Scleromalacia perforans
Skin
Rheumatoid nodules, Vasculitis (palpable purpura),
Palmar erythema and Pyoderma gangrenosum
Haematological:
Anaemia, Splenomegaly, Felty’s syndrome,
Lymphadenopathy and Cryoglobulinaemia
Clinical features
Extra-articular features
Respiratory
Pleurisy with effusion, Pulmonary fibrosis and Caplan’s
syndrome
Cardiovascular
Raynaud’s phenomenon, Pericarditis, Myocarditis,
Cardiac nodules and mitral valve disease
Neurological
Carpal tunnel syndrome, Peripheral neuropathy,
Mononeuritis multiplex and Cervical myelopathy.
Other complications
• Amyloidosis, rare but usually presents with nephrotic
syndrome.
• Microcytic anaemia, normocytic anaemia with
thrombocytosis occurs in patients with active disease.
• Felty’s syndrome is a rare complication of seropositive
RA in which splenomegaly occurs in combination with
neutropenia and thrombocytopenia.
• Localized or generalized lymphadenopathy
• Osteoporosis is a common complication and muscle-
wasting may occur as the result of systemic
inflammation and reduced activity.
Investigations
The diagnosis of RA is essentially clinical but investigations
are useful in confirming the diagnosis and assessing disease
activity.
• ESR and CRP
• Tests for ACPA: Positive in about 70% of cases and are
highly specific of RA.
• Test for RF: Positive in about 70% of cases, most of whom
also test positive for ACPA. RF is less specific than ACPA,
however, and positive tests can occur in other diseases.
• Ultrasound examination and MRI
• Plain X-rays: Periarticular osteoporosis and marginal joint
erosions may be observed with more advanced disease.
DAS28 is widely used to assess disease activity, response
to treatment and need for biological therapy.
Management
The treatment goal is to suppress inflammation, control
symptoms and prevent joint damage.
This involves a combination of pharmacological and non-
pharmacological therapies.

Pharmacological therapy:
DMARD therapy should be introduced in all patients as this
improves outcome.
Management
• On first diagnosis, prednisolone and methotrexate should
be started
• If the patient fails to respond adequately or toxicity occurs,
then an additional DMARD is combined with MTX.
• Themost common combination is triple therapy is:
methotrexate, sulfasalazine and hydroxychloroquine
• Other DMARDs can be substituted or added, along with
a low-dose glucocorticoid such as prednisolone (5–10 mg
daily) if the patient fails to respond fully.
Management
• Ifdisease activity remains high (DAS28 > 5.1) despite
triple therapy, it is usual to progress to biologic therapy.
• The most commonly used first-line biologics in RA are
TNF inhibitors.
• When the patient has been stabilized on biologic treatment
for 12 months or more, a reduction in dose should be
considered, since it is possible to reduce the dose in up to
50% of patients without loss of therapeutic effect.
Disease-modifying anti-rheumatic drugs (DMARDs)

Methotrexate, sulfasalazine, hydroxychloroquine, gold,

ciclosporin, leflunomide, penicillamine; they delay disease
progression and reduce subsequent disability, and should be
introduced early in disease.

In the first 2 years, provided satisfactory and sustained

control, step-down combination therapy may be considered
cautiously, although it may not maintain long-term benefit.
After 2 years, if stable, drugs and doses may be cautiously
withdrawn, but with prompt return of drugs if there are flare-
ups.
Glucocorticoids

Short-term treatment with glucocorticoids helps manage

flares in people with recent-onset or established disease by
rapidly decreasing inflammation.
Biological agents
Rationale:
Rheumatoid synovitis contains predominantly T lymphocytes (CD4+ T-
helper type 1), macrophages and fibroblasts with secretion of pro-
inflammatory cytokines (interleukin-1 (IL-1), IL-6 and tumor necrosis factor
(TNF)-α) and metalloproteinases, which mediate tissue damage.

• TNF-α mediates proliferative and inflammatory aspects

• IL-1 mediates cartilage destruction and bone erosion
• IL-6 mediates many actions of TNF-α and IL-1 but also recruits B
cells.
Most T-helper type 1 cells are memory cells but some mediate B-cell help,
enhancing local auto-antibody formation.

Plasma cells secreting rheumatoid factor are also present.

Biological agents
• Three monoclonal antibody antagonists to TNF-α are
available: Adalimumab, Etanercept and Infliximab
• Rituximab, a B-cell-targeted treatment acting on
• Abatacept inhibits the co-stimulatory signal for T-cell
activation.
• Anakinra

The JAK inhibitors tofacitinib and baricitinib have efficacy

in patients who fail to respond adequately to other DMARDs
and provide an alternative to biologic therapies.
RA is a chronic disease and flares can occur even in patients
who are established on DMARD and biologic therapy.
Transient flares can be dealt with by intra-articular
glucocorticoid injections or a short course of oral
glucocorticoids, but if a sustained flare occurs, a change in
systemic DMARD and/or biologic therapy may need to be
considered.
Non-pharmacological therapy

Physical and occupational therapy play important roles and

it is vital for all patients to be assessed by an occupational
therapist and physiotherapist and the appropriate advice and
treatment provided.