Rheumatoid Arthritis
• RA is a chronic inflammatory joint disease with multisystem involvement.
• Females are affected three times more often than males (3: 1).
• Onset is usually during fourth and fifth decades of life.
• Factors producing RA include infectious trigger, genetic predisposition and autoimmune
response. The role of genetic influences in the aetiology of RA is marked by association
with HLA-DR4 in 70% of patients.
Clinical features
Onset
• Insidious onset with fatigue, anorexia, weakness and vague musculoskeletal symptoms.
• Acute onset with rapid development of polyarthritis accompanied by constitutional symptoms
including fever, lymphadenopathy and splenomegaly.
• Palindromic onset where recurrent acute episodes of joint pain and stiffness occur in individual joints
lasting only a few hours or days.
Articular manifestations
● Joint involvement is usually symmetric. It is characterised by pain, swelling, tenderness
and painful limitation of movements.
● The MCP and PIP of the hands, wrists, knees, and the MTP and PIP of the feet are the most
common joints involved.
● Generalised stiffness may occur but "morning stiffness" lasting more than l hour is a
characteristic feature.
Hands and Wrist
Swelling of the proximal, but not the distal interphalangeal joints results in "spindling" of the fingers.
• Hyperextension of the proximal interphalangeal joints with flexion of the distal interphalangeal joints results in
"swan-neck" deformity.
• Flexion of the proximal interphalangeal joints and extension of the distal interphalangeal joints result in
"boutonniere" or buttonhole deformity.
• Hyperextension of the first interphalangeal joint and flexion of the first metacarpophalangeal joint with a
consequent loss of thumb mobility and pinch can occur.
• Extensor tendon rheumatoid granulomata and tendon rupture result in "dropped finger".
• Radial deviation of the wrist with ulnar deviation of the digits often with palmar subluxation of the proximal
phalanges results in the "Z" deformity.
• Wrist synovitis with median nerve entrapment can result in carpal tunnel syndrome.
• Whole of hand may be swollen in very acute cases with pitting oedema over dorsum giving rise to the
"boxing glove" appearance
Foot and ankle
Swelling of the metatarsophalangeal joints results in "broadening" of the forefoot.
• Lateral deviation and dorsal subluxation of the toes.
• Plantar subluxation of the metatarsal heads.
• Eversion at the hindfoot (subtalar joint).
• Hallus valgus deformity
Other joints
Flexion contractures of elbows, wrists, knees and hips.
• Shoulder joint involvement can occur as glenohumeral arthritis, rotator cuff fraying and
rupture.
• Cervical spine involvement can result in atlanto-axial subluxation with progressive
spastic quadriparesis.
• Cricoarytenoid joint involvement results in hoarseness of voice and stridor.
• Pain and swelling behind the knee can result from extension of inflamed synovium into
the popliteal space (popliteal cyst or Baker's cyst).
Extra articular manifestations
Rheumatoid Nodules
• These develop in 25% of persons with RA. They are firm, round masses felt in the subcutaneous
tissues-e.g. the olecranon bursa, the proximal ulna, the Achilles tendon and the occiput.
Visceral structures like heart, lungs and pleura may also be involved.
• Rheumatoid nodules are clinical predictors of more severe arthritis, seropositivity, joint erosions
and rheumatoid vasculitis.
Rheumatoid vasculitis
These manifestations are seen in patients with a high titre of circulating rheumatoid factor.
Vasculitis results in the following manifestations:
• Polyneuropathy and mononeuritis multiplex.
• Cutaneous ulcerations, palpable purpurae and distal gangrene.
• Visceral infarction resulting in stroke, acute myocardial infarction and mesenteric arteritis.
Pleuropulmonary Manifestations
• Pleural involvement results in effusion with low levels of pleural fluid glucose (less
than 10 mg/dL).
• Pulmonary involvement resulting in interstitial fibrosis.
• Caplan's syndrome-multiple nodules and interstitial lung disease due to pneumoconiosis.
Cardiovascular Manifestations
• Pericarditis and chronic constrictive pericarditis.
• Premature atherosclerosis (an important cause of increased morbidity and mortality).
• Valvular involvement.
• Conduction defects
Neurological Manifestations
• Nerve entrapment syndromes--e.g. carpal and tarsal tunnel syndromes.
• Spinal compression due to atlanto-axial subluxation.
• Peripheral neuropathies.
Ophthalmological Manifestations
• Scleritis, episcleritis and scleromalacia perforans.
• Sicca complex, comprising keratoconjunctivitis sicca, xerostomia and salivary gland
enlargement.
• Glaucoma.
Osteoporosis
• Osteoporosis secondary to rheumatoid involvement is very common. It may be aggravated
by corticosteroid therapy and immobilisation
Felty’s syndrome
Felty's syndrome refers to the constellation of neutropenia, splenomegaly and RA. It is considered an extra-
articular
manifestation of RA.
• It is seen in patients with long-standing, chronic, seropositive RA.
• It has a poor prognosis, with an increased mortality due to a higher incidence of severe infection.
Clinical Features (In Addition to Features of RA)
• Most often, rheumatoid arthritis is present for several years before neutropenia and splenomegaly become
apparent.
• Splenomegaly.
• Lymphadenopathy.
• Skin pigmentation.
• Weight Joss.
• Keratoconjunctivitis sicca.
• Subcutaneous rheumatoid nodules.
• Vasculitis resulting in mononeuritis multiplex and necrotising skin lesions.
• Recurrent infections and chronic leg ulcers.
• Carpal tunnel syndrome.
Laboratory Abnormalities
• Neutropenia <1500/mm3, anaemia and thrombocytopenia.
• High titres of rheumatoid factor.
• Increased levels of circulating immune complexes (CIC).
Treatment
• Treatment of underlying RA.
• Immunosuppressive agents particularly methotrexate and azathioprine are beneficial.
• In patients with life-threatening or refractory bacterial infection, G-CSF may be given to rapidly reverse
neutropenia.
Splenectomy is indicated in:
• Recurrent or serious infections.
• Severe ulcers.
• Severe and persistent granulocytopenia ( <500 mm3)
despite DMARD therapy for rheumatoid arthritis.
• Severe anaemia due to hypersplenism.
Haematological Manifestations
• Normocytic normochromic anaemia.
• Thrombocytosis.
• Eosinophilia and mild leucocytosis
Diagnosis -EULAR criteria/ American College of Rheumatology criteria
Features Score
A.Joint involvement
1 large joint 0
2-10 large joints 1
1-3 small joints (with or without involvement of large joints) 2
4-10 small joints (with or without involvement of large joints) 3
>10 joints (at least 1 small joint) 5
B.Serology (at least one test result is needed for classification)
Negative RF and negative anti-citrullinated protein antibodies (ACPA) 0
Low-positive RF or low-positive ACPA 2
High-positive RF or high-positive ACPA 3
C.Acute-phase reactants (at least one test result is needed for classification)
Normal CRP and normal ESR 0
Abnormal CRP or abnormal ESR 1
D.Duration of symptoms
<6 weeks 0
more than or equal to 6 weeks 1
Score more than or equal to 6/10 is needed to classify as RA
Investigations
• Markers of acute inflammation-raised ESR, anaemia, thrombocytosis, increased levels of acute phase proteins [e.g.
C-reactive protein (CRP)] and increased plasma viscosity.
• Rheumatoid factor.(RF)
• Anti-citrullinated protein antibodies (ACPA), usually detected by anticyclic citrullinated peptide (CCP) antibodies.
• Radiographs of the affected joints may be useful. The characteristic radiological changes are symmetrical pattern of
involvement, juxta-articular osteoporosis, soft tissue swelling, bone erosions and joint space narrowing.
• Ultrasonography and MRI have greater sensitivity than plain radiographs for the detection of soft tissue synovitis
before
joint damage.
• Rarely, synovial fluid analysis, synovial biopsy and arthroscopy are required. The synovial fluid contains 2000-50,000
leucocytes/µL with no crystals or organism.
Management
Rest and splinting of the joints should be instituted in the acute stage of illness.
• Active and passive physiotherapy helps in mobilisation and prevention of contractures.
Analgesics
• Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line drugs used in the
management of RA. They act by suppression of inflammation. None of the NSAIDs has
been shown to be more effective than aspirin in the treatment of RA.
DMARDs
• Disease modifying antirheumatic drugs (DMARDs) are indicated in most cases. The traditionally used DMARDs
are:
• Hydroxychloroquine.
• Oral gold (auranofin).
• Parenteral (intramuscular) gold.
• D-penicillarnine.
• Sulphasalazine.
• Methotrexate.
• Leflunornide.
• Most patients should be started on a combination of DMARDs and analgesics in the early course of disease.
• DMARDs reduce inflammation and prevent damage to joints, bones and ligaments.
• These agents take 3-4 months before their full effect.
Methotrexate
Currently, methotrexate is the drug of choice for RA. It may be given alone or in combination with
hydroxychloroquine
(hydroxychloroquine alone may not be effective in halting the progression of disease).
• The usual starting dose is 7.5-10 mg/week orally. If a positive response does not occur within 4-8 weeks, and there
has
been no toxicity, the dose should be increased by 2.5-5 mg/week each month to 20-25 mg/week before considering
the
treatment a failure.
• To improve the efficacy of MTX at dosages of 20-25 mg weekly, a change to subcutaneous administration should
be considered.
• Folic acid is given in a dose of 5 mg once a week, on the day following methotrexate dose. It reduces some
adverse events
(gastrointestinal intolerance, stomatitis, hepatotoxicity, hyperhomocysteinaernia, and alopecia) associated with
methotrexate
Other DMARDs
If the patient does not respond to methotrexate, the options include gold or D-penicillamine,
sulphasalazine or leflunornide.
• A combination of methotrexate and leflunomide may be more effective than either drug alone.
• Leflunomide is a pyrimidine antagonist that blocks the enzyme dihydroorotate dehydrogenase,
thereby blocking the synthesis of DNA. It has an efficacy similar to that of methotrexate. It can be
used either alone or in combination with methotrexate. Dose is 10-20 mg/day.
Biologicals
Biological response modifiers are the agents that block specific immune factors leading to RA
● Anti-TNF-a inhibitors include monoclonal antibodies (infliximab, adalimumab, golimumab
and certolizumab) and a soluble receptor fusion protein (etanercept).
● Rituximab (anti-CD20 antibody that blocks CD20 present on B cells)
● Tocilizumab (a monoclonal antibody that binds to IL-6 receptors)
● Abatacept (T-cell receptor CTLA4 that down regulates T cells)
● Anakinra(IL-1 receptor blocker)
• Usually given along with methotrexate or other conventional DMARD
Infliximab
A chimeric IgG 1 monoclonal antibody (a chimera of human constant and mouse variable regions).
• Binds to TNF-a and TNF-13 and lyses TNF-producing cells to neutralise their activity.
• Initial dose 3 mg/kg is given intravenously over 2 hours.
• Same dose repeated at 2 and 6 weeks, and then every 8 weeks.
• Dose can be increased to 10 mg/kg or infusion interval can be shortened, if an adequate response is not attained.
• Patient monitored for any side effects during and I hour after infusion.
• Side effects include pruritus, influenza-like symptoms, headache and hypotension. Occasionally, serum sickness
can
develop 1-2 weeks after infusion.
• Reactivation of tuberculosis can occur. Other important side effects include soft tissue and joint infections,
fungal
infections and demyelination.
Etanercept
• A soluble dimeric fusion protein consisting of soluble human p75-TNF receptor and Fe portion of
human IgG 1.
• It blocks the TNF receptor.
• Dose is 25 mg subcutaneously twice a week.
• Injection site reactions in the form of redness and swelling can occur.
Adalimumab
• A humanised IgG 1 monoclonal antibody (fully human constant and variable regions)
lmmunosuppressants
• Immunosuppressants are used as third-line drugs for disease that recurs or does not
respond to second-line agents.
They inhibit the immune system and have potentially serious side effects. These include
cyclophosphamide and azathioprine. However, in acute vasculitis causing serious organ
involvement intravenous cyclophosphamide may be lifesaving.
Corticosteroids
• Corticosteroid therapy is reserved for selected indications. Intra-articular corticosteroid
injections are useful in the acute stage. Prednisolone is administered orally. The indications of
systemic corticosteroid therapy are:
• Active synovitis in many joints, in spite of good conservative regimen of antirheumatic
therapy and physiotherapy. In such cases, low-dose glucocorticoids should be considered in
addition to DMARDs.
• Incapacitating constitutional symptoms such as fever and weight loss, neuropathy and
rheumatoid vasculitis.
Surgical therapy
Surgical therapy is useful in maintenance of joint function, and prevention and correction
of deformities. Various modalities include reconstructive hand surgery, arthroplasties, total
joint replacements, tenosynovectomy and open or close synovectomy.
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