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Rheumatoid arthritis – diagnosis, pathology, features and treatment

Rheumatoid arthritis is a chronic immune-inflammatory disease which affects peripheral joints in a symmetrical manner producing inflammatory changes, with cartilage destruction, bony erosions and resultant bone deformities and systemic manifestations which occur in a fair percentage of cases.

The prevalence of the disease is worldwide and approximately one percent of the population is affected. Its maximum incidence is around 4th decade and it increase with advancing age. Women are involved approximately three times more than men (4.9: 1.8). This sex difference decreases with advancing age. The elderly may present with atypical features.

Etiology

Rheumatoid arthritis is an autoimmune disease where both genetic and environmental factors play important role along with infection. Auto immune etiology is considered because of presence of auto antibodies. The nature of antigen is unknown but it could be of bacterial or viral origin.

Cytokine profiles from T cell clones suggest a bias towards Th2 cytokines. Cytokines like IL-4, IL- 6 and gammon IFN are released by the activated CD4 + T cells. These stimulate the production of antibody producing plasma cells which produce antibodies against Fc fragment of IgG termed the rheumatoid factor. Rheumatoid factor then forms immune complexes with IgG.

Genetic predisposition is evident by the development of RA in approximately four times the expected rate in first degree relatives of patients with sero positive disease. An association between HLADR4 has been found in Blacks, Latin Americans. Whites and HLA – DRI among Israeli Jews and Indians. Different subtypes of HLA-DR4 predominate in different ethnic groups. Thus HLA DW4, DW14 and DW15 are associated with the development of rheumatoid arthritis.

Besides genetic factors, environmental factors like climate and urbanization have important role to play in the etiology of disease. In addition bacteria and viruses (Epstein-Barr, retroviruses) have also been incriminated in the etiology of disease.

Pathology

The pathology in RA is inflammatory. The synovial tissue around the joint becomes inflamed and edematous. There is fibrin deposition and granular tissue extends inwards as a ring of ‘PANNUS’ covering which eventually replaces the articular cartilage.

There is infiltration of synovium with macrophages lymphocytes and plasma cells. As the disease progresses, there is synovial cell hyperplasia with fibrosis and synovial infiltrate shows abundance of CD4 + T helper cells.

The characteristics histologic lesion in RA is rheumatoid nodule which is characterized by central area of necrosis, surrounded by radially arranged cellular area consisting of fibroblasts and strands of collagen. This is surrounded by cellular infiltrate comprising of lymphocytes and plasma cells. Focal necrotizing arthritis is the starting point of rheumatoid nodule.

Much of the acute proliferative and long term destructive changes seen in Rheumatoid arthritis result from an imbalance between pro- and anti- inflammatory cytokins produced by the immune system.

Clinical features

Rheumatoid arthritis begins insidiously and is preceded by constitutional symptoms ranging from months to years prior to the onset of articular symptoms. Prodromal symptoms include weakness and fatigue, loss of weight, anemia, tingling and numbness in hands and Raynaud’s-like phenomenon.

When specific symptoms appear the characteristic features include pain, swelling and stiffness of the joints especially of the hands and feet. If the disease is not arrested of this stage, the lesion progresses to ankylosis and deformity of joints.

The onset is often monorticular in 25% of cases while more than one joint is involved in 40-50% of cases. Females are affected more as compared to males, ratio being 3: 1. Although any joint may be involved but often there is symmetrical involvement of proximal inter phalangeal and metacorpophalengeal joints.

The distal interphalangeal joints are rarely involved. In majority of patients hands are soon or later involved. Deformities appear, and may be in the form of pod shaped swelling of the proximal interphalangeal joint (Fusiform I Sausage finger), Radial deviation at the wrist with ulnar deviation of the fingers (Z deformity) Flyperextension of the proximal interphalangeal joint with flexion at distal inter phalangeal joints (swan neck deformity).

With the progression of the disease, almost all the small joints are involved. Early in the disease, knee joints are involved and so the ankles but toes are often spared. Involvement of metatarsophalangeal joints causes plantar subluxation of the metatarsal heads resulting in deformity called ‘Cock up’ toes. Temporomandibular joint is frequently involved and in some patients may be the earliest manifestation.

Morning stiffness of greater than 1 hour is an invariable feature of arthritis. Synovitis of the joints leading to pain, limitation of movements of the joint and deformities is characteristic in most cases of rheumatoid arthritis. This is especially seen in elbow, wrist, knee and ankle joints. Axial involvement may occur but is limited to upper cervical spine.

Many patients of RA have low body mass and consume less than their recommended daily intakes of calcium and vitamin D. Post-menopausal women with RA are at specific risk of osteoporotic fracture.

Rheumatoid arthritis

Extra-articular manifestations

RA is a systemic disease and involves most of the systems in the body. These occur in those individuals who have high titres of auto immune bodies to rheumatoid component of immuno-globulin G. Constitutional manifestation in the form of anemia, malnourishment and chronic illness are commonly seen. Wasting of muscles may be seen within weeks of onset of RA.

Rheumatic nodules varying in size from pea to walnut appear in 10-20% of cases usually on pen-articular structures subjected to mechanical pressure like olecranon, scapula, Achilles Tendon and the occlput. These are hard, non-painful, mobile and transient. In some they may persist for years.

Pulmonary involvement includes interstitial fibrosis, bronchiolitis pleuropulmonary nodules, pneumonitis and pleural effusion. It varies from small asymptomatic collection to massive pleural effusion.

Cardiac involvement is in the form of valvular disease and condiction defects. Although echocardiographic evidence of pericarditis is seen in 50% of cases yet less than 5% of cases are symptomatic. Chronic constrictive pericarditis may also occur.

Rheumatoid vasculitis involves most of the structures in severe form of disease. It generally is in the form of cutaneous ulceration, digital gangrene, distal sensory neuropathy and mononeuritis multiplex.

Though central nervous system is not involved but neuropathy is known. Between 20-35 per cent patients of rheumatoid arthritis will develop significant atlanto axial subluxation, early in the disease but few develop cord compression.

Eyes are involved in a very small percentage of cases and may be in the form of episcleritis and scleritis. Renal involvement, though rare, but is in the form of secondary amyloidosis. This occurs in patients of rheumatoid arthritis of long standing.

FELTY’S SYNDROME

The triad of rheumatoid arthritis, splenomegaly, neutropenia and occasionally anemia, thrombocytopenia is seen in about 1% of patients of R.A. It is a disease of middle age. Females are predominantly involved. It is characterized by intermittent fever, emaciation weight loss and lymphadenopathy and occurs in patients with advanced erosive disease.

It may develop after regression of joint inflammation. Circulating immune complexes are present and there may be evidence of complement consumption. Bone marrow shows moderate hypercellularily and there is paucity of mature neutrophils. Treatment of feltys syndrome is not satisfactory. These patients have increased susceptibility to infection.

Still’s disease

It is a form of poly arthritis which begins in children usually after the age of 16 and is characterized by fever, poly arthritis lymphadenopathy and splenomegaly. Hepatomegaly may be present in some cases. Pericardial involvement may occur in some.

The disease is often episodic with bilateral symmetrical polyarthritis. The joints are swollen but with less pain and tenderness. Pathological changes are identical to those of rheumatod arthritis.

It is distinguished from Rheumatoid arthritis by negative tests for rheumatoid factor. Spontaneous remissions may occur in latEe number of patients before they reach the age of 20. Treatment is as of rheumatoid arthritis in adults.

Late onset rheumatoid arthritis

Rheumatoid arthritis may begin in elderly after the age of 60. It is relatively a milder disease with a lower incidence of HLADR4 and rheumatoid factor positivity. The onset is often sudden, incidence higher in men as compared to females.

Large joints are mainly involved and there is polyarticular onset. Functional capacity of the joints is markedly effected but there are lesser number of joint erosions. These patients should be aggressively treated with NSAIDS and corticosteroids. Overall out come is good. Prognosis depends on RF and DR4 positivity which indicate poor prognosis.

Laboratory investigations

These help to assess the severity of the disease and its possible outcome. No tests are specific for diagnosing rheumatoid arthritis.

Mild anemia (normocytic normochronic or hypochromic) is present in patients with active or chronic disease. Active cases may show moderate leucocytosis.

ESR is increased in nearly 95 per cent of cases and its values may reach 3-4 times the normal in active cases. It is an important guide about the activity of the disease process and for monitoring the treatment.

Rheumatoid factor is an important immunological test, but its presence does not establish the diagnosis. About 70 percent of R.A. patients carry rheumatoid factor. It can serve as an indicator for prognosis since patients with high titres have more severe disease. The test is not useful as a screening procedure hut in patients with suggestive clinical presentation it may suggest the diagnosis.

Later agglutination test with a cut off value of 80 It/ml is more specific. C-reactive protein (CRP) is usually elevated in rheumatoid arthritis and is useful for assessing activity of disease process.

Antinuclear antibodies (ANA5) and other auto antibodies (anticollagen, anti-keratin, antiperinuclear and anti-rheumatoid arthritis) are found in upto 60% of patients of R.A.

American College of Rheumatology Revised criteria for diagnosis of rheumatoid arthritis (1988).

1. Morning stiffness in and around the joints lasting at least for more than 1 hour.

2. Arthritis of 3 or more of 14 possible joint areas (like left or right proximal interphalangeal joints, Metacarpophalangeal, wrist, elbow, knees, ankle and meta tarso phalangeal joints.

3. At least one area swollen in wrist, metacarpophalangeal or proximal inter phalangeal joint.

4. Simultaneous involvement of the same joint areas on both sides of the body.

5. Rheumatoid nodules on bony prominences, extensor surfaces or juxta articular regions (observed by a physician).

6. Serum rhenmatoid factor.

7. Radiographic changes typical of rheumatoid arthritis (erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints in poster anterior radiographs of hand and wrist.

For the diagnosis of rheumatoid arthritis, at least 4 of these criteria must be satisfied.

Higher titers indicate a more aggressive disease.

Synovial fluid analysis is very valuable and confirms the inflammatory nature of the disease. It is usually slightly cloudy with reduced viscosity and increased protein content with low glucose content. The leukocyte count is in the range of 5000-25000 cells per mm3. Counts above 40,000-50,000 cell indicates super added infection.

Radiographic changes in early stages only show soft tissue swelling and haziness and narrowing of the inter articular space with joint effusion. Moderate degree of osteoporosis at the ends of adjacent bones may be seen. These early changes are commonly seen in second and third metacorpophalangeal joints and the third proximal inter phalangeal joint.

As the disease progresses, the inflammatory tissue destroys the cartilage followed by concentric loss of articular space and maiginal joint erosions. These changes usually follow after months of active disease.

Further on erosion of the central portion of the joint results in joint space narrowing, cyst formation, subluxation of the joint, deformities and fibrous ankylosis. Arthroscopy is helpful in studying changes in the joint as well as for obtaining synovial tissue for histopathology.

Differential diagnosis

Rheumatoid arthritis has to be differentiated from osteoarthritis when both are present in the elderly age group. When R.A. is suspected in middle age group, the differentiation has to be from tuberculosis arthritis, gout gonococcal arthritis and rheumatic fever.

Osteoarthritis is a degenerative disorder commonly seen in 5th and 6th decade where generally big joints are involved. Here there is no swelling of joint and subcutaneous nodules are not present. X-rays of the joint will show lipping of joint margins and examination of joint fluid will show it to be non inflammatory. ESR is not raised.

Rheumatic fever is characterized by preceding history of upper respiratory tract infection, fleeting joint pains and absence of residual joint damage. Gonococcal arthritis is seen in patient with history of contact, and presence of discharge from genitalia.

Tuberculous arthritis is generally mono articular and there are other constitutional symptoms like fever, loss of weight and appetite. Gout presents with typical involvement of big toe with raised levels of uric acid in blood. This should make no problem in differential diagnosis.

Difficulty arises when dealing with rheumatoid type of disorders (para rheumatoid) as in cases of disseminated lupus erythematosis, polyarteritis nodosa, dermatomyositis, scieroderma polymyalgia rheumatica and metabolic disorder (Hemochromatosis).

Malignancies especially of the lung are known to produce Hypertrophic osteoarthropathy (Arthritis, clubbing of fingers). These disorders are differentiated by their clinical picture and skin changes.

Treatment of Rheumatoid arthritis

The principles of therapy are:

1. Relief from pain and spasm

2. Reduction of inflammation of joints

3. Restoration and preservation of functional capacity of joint

4. Prevention of joint destruction and disability

5. Induction of remission

6. Correction of deformities if developed

 Therapeutic modalities shall be

1. Rest and physical therapy

2. Non-steroidal anti-inflammatory drugs (NSAIDs)

3. Disease modifying anti-rheumatic drugs (DMARDs) Is low-acting anti-rheumatic drugs (SAARDs)

Specific anti-rheumatic drugs (SARD5) and immunosuppressives

4. Corticosteroids

Rest and physical activity

Rest both physical and mental is very essential in an acute case. Physical rest ameliorates symptoms and should be individualized. Too much rest and immobilization are not desirable, since it may produce stiffness of the joints.

Exercise should be directed towards maintaining muscle strength and improving range of motion of joints. Low intensity aerobic exercises shall be helpful. If a joint is acutely inflamed, splinting is advised.

Both hot and cold applications (Hydrotherapy) on the inflamed joints have beneficial value. Massage & diathermy also have a role. Swimming can help build muscle power and coordination to reduce fall risk.

In addition care must be taken that the patient takes a well balanced diet. Excess of alcohol and smoking be avoided. If patient is overweight, it is desirable that weight reduction measures are undertakekn.

Drugs

Simple analgesics should be started initially (Paracetamol 500 mg three times a day) and are useful in early stage of Rheumatoid arthritis disease. These may be combined with non-steroidal anti-inflammatory agent (NSAID5).

These include ibuprofen, naproxen, flurbiprofen, indomethacin, oxyphenbutazone, piroxican and diclofenac sodium. These agents block the activity of enzyme cyclooxygenase which effects production of prostaglandins and prostocyclin and thus have analgesic, antipyretic and anti- inflammatory properties.

All these agents have same pharmacodynamic properties but vary considerably in potency and to some extent in duration of action.

Major draw back with NSAIDs are their adverse effects on 0.1. Tract (Gastritis, oesophagitis, peptic ulcei dyspepsia) Liver (Cholestasis, rise in enzymes) skin (Rashes). Hematological (Bone Marrow depression, thrombocytopenia, anaemia) and kidney (Fluid retention, edema).

When administering NSAIDs, select those with minimal risk and their dose should be minimal. Do not administer more than one NSAID at the same time. Patients with a past history of peptic ulcer, and those receiving corticosteroids or anti coagulants co administration of gastro protective agent should be done.

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