Rheumatoid arthritis
Overview
 
Rheumatoid arthritis is a chronic, systemic
Systemic disease
Life-threatening disease redirects here.A systemic disease is one that affects a number of organs and tissues, or affects the body as a whole. Although most medical conditions will eventually involve multiple organs in advanced stage Life-threatening disease redirects here.A systemic disease is one...

 inflammatory disorder
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium
Synovium
Synovial membrane is the soft tissue found between the articular capsule and the joint cavity of synovial joints....

 (synovitis) secondary to hyperplasia
Hyperplasia
Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....

 of synovial cells, excess synovial fluid, and the development of pannus
Pannus
Pannus is a medical term for an abnormal layer of fibrovascular tissue or granulation tissue. Common sites for pannus formation include over the cornea, over a joint surface , or on a prosthetic heart valve...

 in the synovium. The pathology of the disease process often leads to the destruction of articular cartilage and ankylosis
Ankylosis
Ankylosis or anchylosis is a stiffness of a joint due to abnormal adhesion and rigidity of the bones of the joint, which may be the result of injury or disease. The rigidity may be complete or partial and may be due to inflammation of the tendinous or muscular structures outside the joint or of...

 of the joints.
Encyclopedia
Rheumatoid arthritis is a chronic, systemic
Systemic disease
Life-threatening disease redirects here.A systemic disease is one that affects a number of organs and tissues, or affects the body as a whole. Although most medical conditions will eventually involve multiple organs in advanced stage Life-threatening disease redirects here.A systemic disease is one...

 inflammatory disorder
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium
Synovium
Synovial membrane is the soft tissue found between the articular capsule and the joint cavity of synovial joints....

 (synovitis) secondary to hyperplasia
Hyperplasia
Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....

 of synovial cells, excess synovial fluid, and the development of pannus
Pannus
Pannus is a medical term for an abnormal layer of fibrovascular tissue or granulation tissue. Common sites for pannus formation include over the cornea, over a joint surface , or on a prosthetic heart valve...

 in the synovium. The pathology of the disease process often leads to the destruction of articular cartilage and ankylosis
Ankylosis
Ankylosis or anchylosis is a stiffness of a joint due to abnormal adhesion and rigidity of the bones of the joint, which may be the result of injury or disease. The rigidity may be complete or partial and may be due to inflammation of the tendinous or muscular structures outside the joint or of...

 of the joints. Rheumatoid arthritis can also produce diffuse inflammation in the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...

s, pericardium
Pericardium
The pericardium is a double-walled sac that contains the heart and the roots of the great vessels.-Layers:...

, pleura, and sclera
Sclera
The sclera , also known as the white or white of the eye, is the opaque , fibrous, protective, outer layer of the eye containing collagen and elastic fiber. In the development of the embryo, the sclera is derived from the neural crest...

, and also nodular lesions, most common in subcutaneous tissue
Subcutaneous tissue
The hypodermis, also called the hypoderm, subcutaneous tissue, or superficial fascia is the lowermost layer of the integumentary system in vertebrates. Types of cells that are found in the hypodermis are fibroblasts, adipose cells, and macrophages...

. Although the cause of rheumatoid arthritis is unknown, autoimmunity
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...

 plays a pivotal role in both its chronicity and progression, and RA is considered a systemic autoimmune disease.

About 1% of the world's population is afflicted by rheumatoid arthritis, women three times more often than men. Onset is most frequent between the ages of 40 and 50, but people of any age can be affected. It can be a disabling and pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

ful condition, which can lead to substantial loss of functioning and mobility if not adequately treated. It is a clinical diagnosis made on the basis of symptoms, physical exam, radiographs (X-rays
Medical imaging
Medical imaging is the technique and process used to create images of the human body for clinical purposes or medical science...

) and labs, although the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) publish diagnostic guidelines. Diagnosis and long-term management are typically performed by a rheumatologist
Rheumatology
Rheumatology is a sub-specialty in internal medicine and pediatrics, devoted to diagnosis and therapy of rheumatic diseases. Clinicians who specialize in rheumatology are called rheumatologists...

, an expert in joint, muscle and bone diseases.

Various treatments are available. Non-pharmacological treatment includes physical therapy
Physical therapy
Physical therapy , often abbreviated PT, is a health care profession. Physical therapy is concerned with identifying and maximizing quality of life and movement potential within the spheres of promotion, prevention, diagnosis, treatment/intervention,and rehabilitation...

, orthoses, occupational therapy
Occupational therapy
Occupational therapy is a discipline that aims to promote health by enabling people to perform meaningful and purposeful activities. Occupational therapists work with individuals who suffer from a mentally, physically, developmentally, and/or emotionally disabling condition by utilizing treatments...

 and nutritional therapy but do not stop progression of joint destruction. Analgesia (painkillers) and anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....

 drugs, including steroids
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...

, are used to suppress the symptoms, while disease-modifying antirheumatic drug
Disease-modifying antirheumatic drug
Disease-modifying antirheumatic drugs is a category of otherwise unrelated drugs defined by their use in rheumatoid arthritis to slow down disease progression...

s (DMARDs) are required to inhibit or halt the underlying immune process and prevent long-term damage. In recent times, the newer group of biologics
Biologics
A biologic is a medicinal product such as a vaccine, blood or blood component, allergenic, somatic cell, gene therapy, tissue, recombinant therapeutic protein, or living cells that are used as therapeutics to treat diseases...

 has increased treatment options.

The name is based on the term "rheumatic fever
Rheumatic fever
Rheumatic fever is an inflammatory disease that occurs following a Streptococcus pyogenes infection, such as strep throat or scarlet fever. Believed to be caused by antibody cross-reactivity that can involve the heart, joints, skin, and brain, the illness typically develops two to three weeks after...

", an illness which includes joint pain and is derived from the Greek word ῥεύμα-rheuma (nom.), ῥεύματος-rheumatos (gen.) ("flow, current"). The suffix -oid ("resembling") gives the translation as joint inflammation that resembles rheumatic fever. The first recognized description of rheumatoid arthritis was made in 1800 by Dr. Augustin Jacob Landré-Beauvais
Augustin Jacob Landré-Beauvais
Augustin Jacob Landré-Beauvais was a French surgeon best known for his description of rheumatoid arthritis. Born in Orléans, he studied under Pierre-Joseph Desault and Marie François Xavier Bichat in Paris, and then from 1792 under Jean Louis Petit in Lyon. In 1796 he obtained an internship at the...

 (1772–1840) of Paris.

Signs and symptoms

While rheumatoid arthritis primarily affects joints, problems involving other organs of the body are known to occur. Extra-articular ("outside the joints") manifestations other than anemia (which is very common) are clinically evident in about 15–25% of individuals with rheumatoid arthritis. It can be difficult to determine whether disease manifestations are directly caused by the rheumatoid process itself, or from side effects of the medications commonly used to treat it – for example, lung fibrosis from methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...

 or osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

 from corticosteroids.

Joints

The arthritis of joints known as synovitis
Synovitis
Synovitis is the medical term for inflammation of the synovial membrane. This membrane lines joints which possess cavities, known as synovial joints. The condition is usually painful, particularly when the joint is moved. The joint usually swells due to synovial fluid collection.Synovitis may...

 is inflammation of the synovial membrane that lines joints and tendon sheaths. Joints become swollen, tender and warm, and stiffness limits their movement. With time RA nearly always affects multiple joints (it is a polyarthritis
Polyarthritis
Polyarthritis is any type of arthritis which involves 5 or more joints simultaneously. It is usually associated with autoimmune conditions.Polyarthritis may be experienced at any age and is not gender specific.-Causes:...

), most commonly small joints of the hand
Hand
A hand is a prehensile, multi-fingered extremity located at the end of an arm or forelimb of primates such as humans, chimpanzees, monkeys, and lemurs...

s, feet
Foot
The foot is an anatomical structure found in many vertebrates. It is the terminal portion of a limb which bears weight and allows locomotion. In many animals with feet, the foot is a separate organ at the terminal part of the leg made up of one or more segments or bones, generally including claws...

 and cervical spine, but larger joints like the shoulder and knee can also be involved. Synovitis can lead to tethering of tissue with loss of movement and erosion of the joint surface causing deformity and loss of function.

Rheumatoid arthritis typically manifests with signs of inflammation, with the affected joints being swollen, warm, painful and stiff, particularly early in the morning on waking or following prolonged inactivity. Increased stiffness early in the morning is often a prominent feature of the disease and typically lasts for more than an hour. Gentle movements may relieve symptoms in early stages of the disease. These signs help distinguish rheumatoid from non-inflammatory problems of the joints, often referred to as osteoarthritis
Osteoarthritis
Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...

 or "wear-and-tear" arthritis. In arthritis of non-inflammatory causes, signs of inflammation and early morning stiffness are less prominent with stiffness typically less than 1 hour, and movements induce pain caused by mechanical arthritis. In RA, the joints are often affected in a fairly symmetrical fashion, although this is not specific, and the initial presentation may be asymmetrical.

As the pathology progresses the inflammatory activity leads to tendon tethering and erosion and destruction of the joint surface, which impairs range of movement and leads to deformity. The fingers may suffer from almost any deformity depending on which joints are most involved. Medical students are taught to learn names for specific deformities, such as ulnar deviation
Ulnar deviation
Ulnar deviation, also known as ulnar drift, is a hand deformity in which the swelling of the metacarpophalangeal joints causes the fingers to become displaced, tending towards the little finger. Its name comes from the displacement toward the ulna...

, boutonniere deformity
Boutonniere deformity
Boutonniere deformity is a deformed position of the fingers or toes, in which the joint nearest the knuckle is permanently bent toward the palm while the furthest joint is bent back away...

, swan neck deformity
Swan neck deformity
Swan neck deformity is a deformed position of the finger, in which the joint closest to the fingertip is permanently bent toward the palm while the nearest joint to the palm is bent away from it...

 and "Z-thumb," but these are of no more significance to diagnosis or disability than other variants, since they occur in osteoarthritis as well. "Z-thumb" or "Z-deformity" consists of hyperextension of the interphalangeal joint, fixed flexion and subluxation of the metacarpophalangeal joint and gives a "Z" appearance to the thumb.

Skin

The rheumatoid nodule
Rheumatoid nodule
A rheumatoid nodule is a local swelling or tissue lump, usually rather firm to touch, like an unripe fruit, which occurs almost exclusively in association with rheumatoid arthritis. Very rarely rheumatoid nodules occur as 'rheumatoid nodulosis' in the absence of arthritis...

, which is often subcutaneous, is the cutaneous feature most characteristic of rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

. The initial
Initial
In a written or published work, an initial is a letter at the beginning of a work, a chapter, or a paragraph that is larger than the rest of the text. The word is derived from the Latin initialis, which means standing at the beginning...

 pathologic process in nodule formation is unknown but may be essentially the same as the synovitis, since similar structural features occur in both. The nodule has a central area of fibrinoid necrosis
Fibrinoid necrosis
Fibrinoid necrosis is a form of necrosis, or tissue death, in which there is accumulation of amorphous, basic, proteinaceous material in the tissue matrix with a staining pattern reminiscent of fibrin. It is associated with conditions such as immune vasculitis Fibrinoid necrosis is a form of...

 that may be fissured and which corresponds to the fibrin-rich necrotic material found in and around an affected synovial space. Surrounding the necrosis is a layer of palisading macrophages and fibroblasts, corresponding to the intimal layer in synovium and a cuff of connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...

 containing clusters of lymphocytes and plasma cells, corresponding to the subintimal zone in synovitis. The typical rheumatoid nodule may be a few millimetres to a few centimetres in diameter and is usually found over bony prominences, such as the olecranon
Olecranon
The olecranon is a large, thick, curved bony eminence of the forearm that projects behind the elbow.It is situated at the upper end of the ulna, one of the two bones in the forearm...

, the calcaneal tuberosity, the metacarpophalangeal joint, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF (rheumatoid factor) titer and severe erosive arthritis. Rarely, these can occur in internal organs or at diverse sites on the body.

Several forms of vasculitis
Vasculitis
Vasculitis refers to a heterogeneous group of disorders that are characterized by inflammatory destruction of blood vessels. Both arteries and veins are affected. Lymphangitis is sometimes considered a type of vasculitis...

occur in rheumatoid arthritis. A benign form occurs as microinfarcts around the nailfolds. More severe forms include livedo reticularis, which is a network (reticulum) of erythematous to purplish discoloration of the skin caused by the presence of an obliterative cutaneous capillaropathy.

Other, rather rare, skin associated symptoms include:
  • pyoderma gangrenosum
    Pyoderma gangrenosum
    Pyoderma gangrenosum is a disease that causes tissue to become necrotic, causing deep ulcers that usually occur on the legs. When they occur, they can lead to chronic wounds. Ulcers usually initially look like small bug bites or papules, and they progress to larger ulcers. Though the wounds...

    , a necrotizing, ulcerative, noninfectious neutrophilic dermatosis.
  • Sweet's syndrome, a neutrophilic dermatosis usually associated with myeloproliferative disorders
  • drug reactions
  • erythema nodosum
    Erythema nodosum
    Erythema nodosum is an inflammation of the fat cells under the skin characterized by tender red nodules or lumps that are usually seen on both shins...

  • lobular panniculitis
    Panniculitis
    Panniculitis is a group of diseases whose hallmark is inflammation of subcutaneous adipose tissue...

  • atrophy
    Atrophy
    Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...

     of digital skin
  • palmar erythema
    Palmar erythema
    Palmar erythema is reddening of the palms at the thenar and hypothenar eminences.-Causes:It is associated with various physiological as well as pathological changes, the principal one of which is portal hypertension. It is also seen in patients with liver dysfunction, such as chronic liver disease...

  • diffuse thinning (rice paper skin), and skin fragility (often worsened by corticosteroid use).


Lungs

Fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...

 of the lungs is a recognized response to rheumatoid disease. It is also a rare but well recognized consequence of therapy (for example with methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...

 and leflunomide
Leflunomide
Leflunomide is a medication of the DMARD type, used in active moderate to severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor.-Basic chemical, pharmacological, and marketing data:...

). Caplan's syndrome
Caplan's syndrome
Caplan's syndrome is a combination of rheumatoid arthritis and pneumoconiosis that manifests as intrapulmonary nodules, which appear homogenous and well-defined on chest X-ray.. The syndrome is named after Dr...

 describes lung nodules in individuals with rheumatoid arthritis and additional exposure to coal
Coal
Coal is a combustible black or brownish-black sedimentary rock usually occurring in rock strata in layers or veins called coal beds or coal seams. The harder forms, such as anthracite coal, can be regarded as metamorphic rock because of later exposure to elevated temperature and pressure...

 dust. Pleural effusion
Pleural effusion
Pleural effusion is excess fluid that accumulates between the two pleural layers, the fluid-filled space that surrounds the lungs. Excessive amounts of such fluid can impair breathing by limiting the expansion of the lungs during ventilation.-Pathophysiology:...

s are also associated with rheumatoid arthritis. Another complication of RA is Rheumatoid Lung Disease
Rheumatoid Lung Disease
Rheumatoid Lung Disease, also called Rheumatoid Lung is a disease of the lung associated with rheumatoid arthritis. It is estimated that about one quarter of people with rheumatoid arthritis develop Rheumatoid Lung Disease.-Symptoms:...

. It is estimated that about one quarter of Americans with RA develop Rheumatoid Lung Disease.

Kidneys

Renal amyloidosis
Amyloidosis
In medicine, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid proteins, which are abnormally deposited in organs and/or tissues and cause harm. A protein is described as being amyloid if, due to an alteration in its secondary structure, it...

 can occur as a consequence of chronic inflammation. Rheumatoid arthritis may affect the kidney glomerulus directly through a vasculopathy or a mesangial infiltrate but this is less well documented (though this is not surprising, considering immune complex-mediated hypersensitivities are known for pathogenic deposition of immune complexes in organs where blood is filtered at high pressure to form other fluids, such as urine and synovial fluid). Treatment with Penicillamine
Penicillamine
Penicillamine is a pharmaceutical of the chelator class. It is sold under the trade names of Cuprimine and Depen. The pharmaceutical form is D-penicillamine, as L-penicillamine is toxic...

 and gold salts
Gold salts
Gold salts describe ionic chemical compounds of gold. The term, which is a misnomer, has evolved into a synonym for the gold compounds used in medicine...

 are recognized causes of membranous nephropathy.

Heart and blood vessels

People with rheumatoid arthritis are more prone to atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...

, and risk of myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

 (heart attack) and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...

 is markedly increased.
Other possible complications that may arise include: pericarditis
Pericarditis
Pericarditis is an inflammation of the pericardium . A characteristic chest pain is often present.The causes of pericarditis are varied, including viral infections of the pericardium, idiopathic causes, uremic pericarditis, bacterial infections of the precardium Pericarditis is an inflammation of...

, endocarditis
Endocarditis
Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves . Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or even on intracardiac devices...

, left ventricular failure, valvulitis and fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...

. Many people with rheumatoid arthritis do not experience the same chest pain that others feel when they have angina or myocardial infarction. To reduce cardiovascular risk, it is crucial to maintain optimal control of the inflammation caused by rheumatoid arthritis (which may be involved in causing the cardiovascular risk), and to use exercise and medications appropriately to reduce other cardiovascular risk factors such as blood lipids and blood pressure. Doctors who treat rheumatoid arthritis patients should be sensitive to cardiovascular risk when prescribing anti-inflammatory medications, and may want to consider prescribing routine use of low doses of aspirin if the gastrointestinal effects are tolerable.

Other

Ocular: The eye is directly affected in the form of episcleritis which when severe can very rarely progress to perforating scleromalacia. Rather more common is the indirect effect of keratoconjunctivitis sicca
Keratoconjunctivitis sicca
Keratoconjunctivitis sicca , also called keratitis sicca, xerophthalmia or dry eye syndrome is an eye disease caused by eye dryness, which, in turn, is caused by either decreased tear production or increased tear film evaporation. It is found in humans and some animals...

, which is a dryness of eyes and mouth caused by lymphocyte infiltration of lacrimal
Lacrimal gland
The lacrimal glands are paired almond-shaped glands, one for each eye, that secrete the aqueous layer of the tear film. They are situated in the upper, outer portion of each orbit, in the lacrimal fossa of the orbit formed by the frontal bone. Inflammation of the lacrimal glands is called...

 and salivary gland
Salivary gland
The salivary glands in mammals are exocrine glands, glands with ducts, that produce saliva. They also secrete amylase, an enzyme that breaks down starch into maltose...

s. When severe, dryness of the cornea can lead to keratitis and loss of vision. Preventive treatment of severe dryness with measures such as nasolacrimal duct
Nasolacrimal duct
The nasolacrimal duct carries tears from the lacrimal sac into the nasal cavity. Excess tears flow through nasolacrimal duct which drains into the inferior nasal meatus...

 occlusion is important.

Hepatic: Cytokine production in joints and/or hepatic Kupffer cells leads to increased activity of hepatocytes with increased production of acute-phase proteins, such as C-reactive protein, and increased release of enzymes such as alkaline phosphatase into the blood. In Felty's syndrome
Felty's syndrome
Felty's syndrome, also called Felty syndrome, is characterized by the combination of rheumatoid arthritis, splenomegaly and neutropenia.-Symptoms:The symptoms of Felty's syndrome are similar to those of rheumatoid arthritis....

, Kuppfer cell activation is so marked that the resulting increase in hepatocyte activity is associated with nodular hyperplasia of the liver, which may be palpably enlarged. Although Kupffer cells are within the hepatic parenchyma, they are separate from hepatocytes. As a result there is little or no microscopic evidence of hepatitis (immune-mediated destruction of hepatocytes). Hepatic involvement in RA is essentially asymptomatic.

Hematological: Anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...

 is by far the most common abnormality of the blood cells. Rheumatoid arthritis may cause a warm autoimmune hemolytic anemia
Warm autoimmune hemolytic anemia
Warm Antibody Autoimmune Hemolytic Anemia is the most common of the autoimmune hemolytic diseases. About half of the cases are idiopathic, with the other half attributable to a predisposing condition or medications being taken.-Pathophysiology:...

. The red cells are of normal size and colour (normocytic and normochromic). A low white blood cell count (neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...

) usually only occurs in patients with Felty's syndrome
Felty's syndrome
Felty's syndrome, also called Felty syndrome, is characterized by the combination of rheumatoid arthritis, splenomegaly and neutropenia.-Symptoms:The symptoms of Felty's syndrome are similar to those of rheumatoid arthritis....

 with an enlarged liver and spleen. The mechanism of neutropenia is complex. An increased platelet count (thrombocytosis
Thrombocytosis
Thrombocytosis is the presence of high platelet counts in the blood, and can be either primary or reactive...

) occurs when inflammation is uncontrolled, as does the anemia.

Neurological: Peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....

 and mononeuritis multiplex may occur. The most common problem is carpal tunnel syndrome
Carpal tunnel syndrome
Carpal Tunnel Syndrome is an entrapment idiopathic median neuropathy, causing paresthesia, pain, and other symptoms in the distribution of the median nerve due to its compression at the wrist in the carpal tunnel. The pathophysiology is not completely understood but can be considered compression...

 caused by compression of the median nerve by swelling around the wrist. Atlanto-axial subluxation can occur, owing to erosion of the odontoid process and or/transverse ligaments in the cervical spine's connection to the skull. Such an erosion (>3mm) can give rise to vertebrae slipping over one another and compressing the spinal cord. Clumsiness is initially experienced, but without due care this can progress to quadriplegia
Quadriplegia
Tetraplegia, also known as quadriplegia, is paralysis caused by illness or injury to a human that results in the partial or total loss of use of all their limbs and torso; paraplegia is similar but does not affect the arms...

.

Constitutional symptoms: Constitutional symptoms
Constitutional symptoms
Constitutional symptoms refers to a group of symptoms that can affect many different systems of the body.Examples include Weight loss, fevers, fatigue, and malaise.Other examples include chills, night sweats, and decreased appetite....

 including fatigue, low grade fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

, malaise
Malaise
Malaise is a feeling of general discomfort or uneasiness, of being "out of sorts", often the first indication of an infection or other disease. Malaise is often defined in medicinal research as a "general feeling of being unwell"...

, morning stiffness, loss of appetite and loss of weight are common systemic manifestations seen in patients with active rheumatoid arthritis.

Osteoporosis: Local osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

 occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines. More general osteoporosis is probably contributed to by immobility, systemic cytokine effects, local cytokine release in bone marrow and corticosteroid therapy.

Lymphoma: The incidence of lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...

 is increased in RA, although it is still uncommon.

Imaging

X-ray
X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...

s of the hands and feet are generally performed in people with a polyarthritis. In rheumatoid arthritis, there may be no changes in the early stages of the disease, or the x-ray may demonstrate juxta-articular osteopenia, soft tissue swelling and loss of joint space. As the disease advances, there may be bony erosions and subluxation. X-rays of other joints may be taken if symptoms of pain or swelling occur in those joints.

Other medical imaging techniques such as magnetic resonance imaging (MRI) and ultrasound are also used in rheumatoid arthritis.

There have been technical advances in ultrasonography. High-frequency transducers (10 MHz or higher) have improved the spatial resolution of ultrasound images; these images can depict 20% more erosions than conventional radiography. Also, color Doppler and power Doppler ultrasound, which show vascular signals of active synovitis depending on the degree of inflammation, are useful in assessing synovial inflammation. This is important, since in the early stages of rheumatoid arthritis, the synovium is primarily affected, and synovitis seems to be the best predictive marker of future joint damage.

Blood tests

When RA is clinically suspected, immunological
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...

 studies are required, such as testing for the presence of rheumatoid factor
Rheumatoid factor
Rheumatoid factor is an autoantibody most relevant in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG. RF and IgG join to form immune complexes that contribute to the disease process...

 (RF, a non-specific antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

). A negative RF does not rule out RA; rather, the arthritis is called seronegative. This is the case in about 15% of patients. During the first year of illness, rheumatoid factor is more likely to be negative with some individuals converting to seropositive status over time. RF is also seen in other illnesses, for example Sjögren's syndrome
Sjögren's syndrome
Sjögren's syndrome , also known as "Mikulicz disease" and "Sicca syndrome", is a systemic autoimmune disease in which immune cells attack and destroy the exocrine glands that produce tears and saliva....

, Hepatitis C, chronic infections and in approximately 10% of the healthy population, therefore the test is not very specific.

Because of this low specificity, new serological tests have been developed, which test for the presence of the anti-citrullinated protein antibodies (ACPAs) or anti-CCP. Like RF, these tests are positive in only a proportion (67%) of all RA cases, but are rarely positive if RA is not present, giving it a specificity of around 95%. As with RF, there is evidence for ACPAs being present in many cases even before onset of clinical disease.

The most common tests for ACPAs are the anti-CCP (cyclic citrullinated peptide) test and the Anti-MCV
Mutated citrullinated Vimentin
Detection of autoantibodies against mutated citrullinated vimentin is part of RA diagnostics , especially in sera negative for rheumatoid factor . Anti-MCV antibodies are member of ACPA family, a group of the so called antibodies to citrullinated protein/peptide antigens.Rheumatoid arthritis is an...

 assay (antibodies against mutated citrullinated Vimentin). Recently a serological point-of-care test (POCT) for the early detection of RA has been developed. This assay combines the detection of rheumatoid factor and anti-MCV for diagnosis of rheumatoid arthritis and shows a sensitivity of 72% and specificity of 99.7%.

Also, several other blood tests are usually done to allow for other causes of arthritis, such as lupus erythematosus
Lupus erythematosus
Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...

. The erythrocyte sedimentation rate
Erythrocyte sedimentation rate
The erythrocyte sedimentation rate , also called a sedimentation rate or Biernacki Reaction, is the rate at which red blood cells sediment in a period of 1 hour...

 (ESR), C-reactive protein
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...

, full blood count, renal function
Renal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...

, liver enzymes and other immunological tests (e.g., antinuclear antibody/ANA) are all performed at this stage. Elevated ferritin
Ferritin
Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...

 levels can reveal hemochromatosis, a mimic RA, or be a sign of , a seronegative, usually juvenile, variant of rheumatoid.

Criteria

In 2010 the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria were introduced. These new classification criteria overruled the "old" ACR criteria of 1987 and are adapted for early RA diagnosis. The "new" classification criteria, jointly published by the American College of Rheumatology
American College of Rheumatology
The American College of Rheumatology is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy and practice support that foster excellence in the care of people with arthritis and rheumatic and...

 (ACR) and the European League Against Rheumatism
European League Against Rheumatism
The is an international organisation in the field of rheumatology. The society publishes a medical journal, the Annals of the Rheumatic Diseases, and organises an annual scientific meeting, the Annual European Congress of Rheumatology....

 (EULAR) establish a point value between 0 and 10. Every patient with a point total of 6 or higher is unequivocally classified as an RA patient, provided he has synovitis in at least one joint and given that there is no other diagnosis better explaining the synovitis. Four areas are covered in the diagnosis:
  • joint involvement, designating the metacarpophalangeal joint
    Metacarpophalangeal joint
    The metacarpophalangeal joints are of the condyloid kind, formed by the reception of the rounded heads of the metacarpal bones into shallow cavities on the proximal ends of the first phalanges, with the exception of that of the thumb, which presents more of the characters of a ginglymoid joint...

    s, proximal interphalangeal joints, the interphalangeal joint
    Interphalangeal joint
    Interphalangeal joint may refer to:*Interphalangeal articulations of hand*Interphalangeal articulations of foot...

     of the thumb, second through third metatarsophalangeal joint and wrist
    Wrist
    In human anatomy, the wrist is variously defined as 1) the carpus or carpal bones, the complex of eight bones forming the proximal skeletal segment of the hand;...

     as small joints, and elbow
    Elbow
    The human elbow is the region surrounding the elbow-joint—the ginglymus or hinge joint in the middle of the arm. Three bones form the elbow joint: the humerus of the upper arm, and the paired radius and ulna of the forearm....

    s, hip joints and knee
    Knee
    The knee joint joins the thigh with the leg and consists of two articulations: one between the fibula and tibia, and one between the femur and patella. It is the largest joint in the human body and is very complicated. The knee is a mobile trocho-ginglymus , which permits flexion and extension as...

    s as large joints:
    • Involvement of 1 large joint gives 0 points
    • Involvement of 2-10 large joints gives 1 point
    • Involvement of 1-3 small joints (with or without involvement of large joints) gives 2 points
    • Involvement of4-10 small joints (with or without involvement of large joints) gives 3 points
    • Involvement of more than 10 joints (with involvement of at least 1 small joint) gives 5 points
  • serological parameters – including the rheumatoid factor
    Rheumatoid factor
    Rheumatoid factor is an autoantibody most relevant in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG. RF and IgG join to form immune complexes that contribute to the disease process...

     as well as ACPA
    Anti-citrullinated protein antibody
    Anti-citrullinated protein antibodies or anti-cyclic citrullinated protein antibodies are autoantibodies that are frequently detected in the blood of rheumatoid arthritis patients...

     – "ACPA" stands for "anti-citrullinated protein antibody":
    • Negative RF and negative ACPA gives 0 points
    • Low-positive RF or low-positive ACPA gives 2 points
    • High-positive RF or high-positive ACPA gives 3 points
  • acute phase reactants: 1 point for elevated erythrocyte sedimentation rate, ESR
    Erythrocyte sedimentation rate
    The erythrocyte sedimentation rate , also called a sedimentation rate or Biernacki Reaction, is the rate at which red blood cells sediment in a period of 1 hour...

    , or elevated CRP
    C-reactive protein
    C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...

     value (c-reactive protein)
  • duration of arthritis
    Arthritis
    Arthritis is a form of joint disorder that involves inflammation of one or more joints....

    : 1 point for symptoms lasting six weeks or longer


The new criteria accommodate to the growing understanding of rheumatoid arthritis and the improvements in diagnosing RA and disease treatment. In the "new" criteria serology and autoimmune diagnostics
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...

 carries major weight, as ACPA detection is appropriate to diagnose the disease in an early state, before joints destructions occur. Destruction of the joints viewed in radiological images was a significant point of the ACR criteria from 1987. This criterion no longer is regarded to be relevant, as this is just the type of damage that treatment is meant to avoid.

The criteria are not intended for the diagnosis for routine clinical care; they were primarily intended to categorize research (classification criteria). In clinical practice, the following criteria apply:
  • two or more swollen joints
  • morning stiffness lasting more than one hour for at least six weeks
  • the detection of rheumatoid factor
    Rheumatoid factor
    Rheumatoid factor is an autoantibody most relevant in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG. RF and IgG join to form immune complexes that contribute to the disease process...

    s or autoantibodies
    Autoantibody
    An autoantibody is an antibody manufactured by the immune system that is directed against one or more of the individual's own proteins. It is derived from the Greek "auto" which means "self", "anti" which means "against" and "body"...

     against ACPA
    Anti-citrullinated protein antibody
    Anti-citrullinated protein antibodies or anti-cyclic citrullinated protein antibodies are autoantibodies that are frequently detected in the blood of rheumatoid arthritis patients...

     such as autoantibodies to mutated citrullinated vimentin can confirm the suspicion of rheumatoid arthritis. A negative autoantibody result does not exclude a diagnosis of RA.

Differential diagnoses

Several other medical conditions can resemble RA, and usually need to be distinguished from it at the time of diagnosis:
  • Crystal induced arthritis (gout
    Gout
    Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...

    , and pseudogout) – usually involves particular joints (knee, MTP1, heels) and can be distinguished with aspiration of joint fluid if in doubt. Redness (RA doesn't have redness at the joints), asymmetric distribution of affected joints, pain occurs at night and the starting pain is less than an hour with gout.
  • Osteoarthritis
    Osteoarthritis
    Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...

     – distinguished with X-ray
    X-ray
    X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...

    s of the affected joints and blood tests, age (mostly older patients), starting pain less than an hour, a-symmetric distribution of affected joints and pain worsens when using joint for longer periods.
  • Systemic lupus erythematosus
    Systemic lupus erythematosus
    Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...

     (SLE) – distinguished by specific clinical symptoms and blood tests (antibodies against double-stranded DNA)
  • One of the several types of psoriatic arthritis
    Psoriatic arthritis
    Psoriatic arthritis is a type of inflammatory arthritis that, according to the National Psoriasis Foundation, will develop in up to 30 percent of people who have the chronic skin condition psoriasis...

     resembles RA – nail changes and skin symptoms distinguish between them
  • Lyme disease
    Lyme disease
    Lyme disease, or Lyme borreliosis, is an emerging infectious disease caused by at least three species of bacteria belonging to the genus Borrelia. Borrelia burgdorferi sensu stricto is the main cause of Lyme disease in the United States, whereas Borrelia afzelii and Borrelia garinii cause most...

     causes erosive arthritis and may closely resemble RA – it may be distinguished by blood test in endemic areas
  • Reactive arthritis
    Reactive arthritis
    Reactive arthritis , is classified as an autoimmune condition that develops in response to an infection in another part of the body. Coming into contact with bacteria and developing an infection can trigger the disease. Reiter's syndrome has symptoms similar to various other conditions collectively...

     (previously Reiter's disease) – asymmetrically involves heel, sacroiliac joints, and large joints of the leg. It is usually associated with urethritis
    Urethritis
    Urethritis is inflammation of the urethra. The most common symptom is painful or difficult urination.-Causes:The disease is classified as either gonococcal urethritis, caused by Neisseria gonorrhoeae, or non-gonococcal urethritis , most commonly caused by Chlamydia trachomatis...

    , conjunctivitis
    Conjunctivitis
    Conjunctivitis refers to inflammation of the conjunctiva...

    , iritis
    Iritis
    Iritis is a form of anterior uveitis and refers to the inflammation of the iris of the eye.-Types:There are two main types of iritis: acute and chronic. They differ in numerous ways....

    , painless buccal ulcers, and keratoderma blennorrhagica
    Keratoderma blennorrhagica
    Keratoderma blennorrhagica are skin lesions commonly found on the palms and soles but which may spread to the scrotum, scalp and trunk also, and which resemble psoriasis....

    .
  • Ankylosing spondylitis
    Ankylosing spondylitis
    Ankylosing spondylitis , previously known as Bekhterev's disease, Bekhterev syndrome, and Marie-Strümpell disease is a chronic inflammatory disease of the axial skeleton with variable involvement of peripheral joints and nonarticular structures...

     – this involves the spine and is usually diagnosed in males, although a RA-like symmetrical small-joint polyarthritis may occur in the context of this condition.
  • Hepatitis C
    Hepatitis C
    Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...

     – RA-like symmetrical small-joint polyarthritis may occur in the context of this condition. Hepatitis C may also induce Rheumatoid Factor auto-antibodies


Rarer causes that usually behave differently but may cause joint pains:
  • Sarcoidosis
    Sarcoidosis
    Sarcoidosis , also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells form as nodules in multiple organs. The cause of sarcoidosis is unknown...

    , amyloidosis, and Whipple's disease
    Whipple's disease
    Whipple's disease is a rare, systemic infectious disease caused by the bacterium Tropheryma whipplei. First described by George Hoyt Whipple in 1907 and commonly considered a gastrointestinal disorder, Whipple's disease primarily causes malabsorption but may affect any part of the body including...

     can also resemble RA.
  • Hemochromatosis may cause hand joint arthritis.
  • Acute rheumatic fever can be differentiated from RA by a migratory pattern of joint involvement and evidence of antecedent streptococcal infection. Bacterial arthritis (such as streptococcus) is usually asymmetric, while RA usually involves both sides of the body symmetrically.
  • Gonococcal arthritis (another bacterial arthritis) is also initially migratory and can involve tendons around the wrists and ankles.

Monitoring progression

The progression of rheumatoid arthritis can be followed using scores such as Disease Activity Score of 28 joints . It is widely used as an indicator of RA disease activity and response to treatment, but is not always a reliable indicator of treatment effect. The joints included in DAS28 are (bilateral
Bilateral
Bilateral may refer to any concept including two sides, in particular:*Bilateralism, the political and cultural relations between two states*Bilateral symmetry, symmetry between two sides of an organism...

ly): proximal interphalangeal joints (10 joints), metacarpophalangeal joint
Metacarpophalangeal joint
The metacarpophalangeal joints are of the condyloid kind, formed by the reception of the rounded heads of the metacarpal bones into shallow cavities on the proximal ends of the first phalanges, with the exception of that of the thumb, which presents more of the characters of a ginglymoid joint...

s (10), wrist
Wrist
In human anatomy, the wrist is variously defined as 1) the carpus or carpal bones, the complex of eight bones forming the proximal skeletal segment of the hand;...

s (2), elbow
Elbow
The human elbow is the region surrounding the elbow-joint—the ginglymus or hinge joint in the middle of the arm. Three bones form the elbow joint: the humerus of the upper arm, and the paired radius and ulna of the forearm....

s (2), shoulder
Shoulder
The human shoulder is made up of three bones: the clavicle , the scapula , and the humerus as well as associated muscles, ligaments and tendons. The articulations between the bones of the shoulder make up the shoulder joints. The major joint of the shoulder is the glenohumeral joint, which...

s (2) and knee
Knee
The knee joint joins the thigh with the leg and consists of two articulations: one between the fibula and tibia, and one between the femur and patella. It is the largest joint in the human body and is very complicated. The knee is a mobile trocho-ginglymus , which permits flexion and extension as...

s (2). When looking at these joints, both the number of joints with tenderness upon touching (TEN28) and swelling (SW28) are counted. In addition, the erythrocyte sedimentation rate
Erythrocyte sedimentation rate
The erythrocyte sedimentation rate , also called a sedimentation rate or Biernacki Reaction, is the rate at which red blood cells sediment in a period of 1 hour...

 (ESR) is measured. Also, the patient makes a subjective assessment (SA) of disease activity during the preceding 7 days on a scale between 0 and 100, where 0 is "no activity" and 100 is "highest activity possible". With these parameters, DAS28 is calculated as:


From this, the disease activity of the patient can be classified as follows:
Current
DAS28
| DAS28 difference from initial value
> 1.2 > 0.6 but ≤ 1.2 ≤ 0.6
≤ 3.2 Inactive Good improvement Moderate improvement No improvement
> 3.2 but ≤ 5.1 Moderate Moderate improvement Moderate improvement No improvement
> 5.1 Very active Moderate improvement No improvement No improvement

Pathophysiology and causes

Rheumatoid arthritis is a form of autoimmunity, the causes
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....

 of which are still incompletely known. It is a systemic (whole body) disorder principally affecting synovial tissues.

The key pieces of evidence relating to pathogenesis are:

1. A genetic link with HLA-DR4
HLA-DR4
HLA-DR4 is a HLA-DR serotype that recognizes the DRB1*04 gene products. The DR4 serogroup is large and has a number ofmoderate frequency alleles spread over large regions of the world.-Serology:The serological identification of DR4 is good...

 and related allotypes of MHC Class II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....

 and the T cell-associated protein PTPN22
PTPN22
Protein tyrosine phosphatase, non-receptor type 22 , also known as PTPN22, is a protein that in humans is encoded by the PTPN22 gene. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms...

.

2. A undeniable link with cigarette smoking and the pathogenesis of rheumatoid vasculitis, a typical feature of this condition.

3. A remarkable deceleration of disease progression in many cases by blockade of the cytokine TNF
Tumor necrosis factors
Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...

 (alpha).

4. A similar dramatic response in many cases to depletion of B lymphocytes, but no comparable response to depletion of T lymphocytes.

5. A more or less random pattern of whether and when predisposed individuals are affected.

6. The presence of autoantibodies to IgGFc, known as rheumatoid factor
Rheumatoid factor
Rheumatoid factor is an autoantibody most relevant in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG. RF and IgG join to form immune complexes that contribute to the disease process...

s (RF), and antibodies to citrullinated peptide
Anti-citrullinated protein antibody
Anti-citrullinated protein antibodies or anti-cyclic citrullinated protein antibodies are autoantibodies that are frequently detected in the blood of rheumatoid arthritis patients...

s (ACPA).

These data suggest that the disease involves abnormal B cell–T cell interaction, with presentation of antigens by B cells to T cells via HLA-DR eliciting T cell help and consequent production of RF and ACPA. Inflammation is then driven either by B cell or T cell products stimulating release of TNF and other cytokines. The process may be facilitated by an effect of smoking on citrullination
Citrullination
Citrullination or deimination is the term used for the post-translational modification of the amino acid arginine in a protein into the amino acid citrulline. This reaction, shown below, is performed by enzymes called peptidylarginine deiminases...

 but the stochastic (random) epidemiology suggests that the rate limiting step in genesis of disease in predisposed individuals may be an inherent stochastic process within the immune response such as immunoglobulin or T cell receptor gene recombination and mutation. (See entry under autoimmunity
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...

 for general mechanisms.)

If TNF release is stimulated by B cell products in the form of RF or ACPA -containing immune complexes, through activation of immunoglobulin Fc receptor
Fc receptor
An Fc receptor is a protein found on the surface of certain cells - including natural killer cells, macrophages, neutrophils, and mast cells - that contribute to the protective functions of the immune system....

s, then RA can be seen as a form of Type III hypersensitivity
Type III hypersensitivity
Type III hypersensitivity occurs when antigens and antibodies are present in roughly equal amounts, causing extensive cross-linking.-Presentation:...

.

If TNF release is stimulated by T cell products such as interleukin-17 it might be considered closer to type IV hypersensitivity
Type IV hypersensitivity
Type IV hypersensitivity is often called delayed type hypersensitivity as the reaction takes two to three days to develop. Unlike the other types, it is not antibody mediated but rather is a type of cell-mediated response....

 although this terminology may be getting somewhat dated and unhelpful.
The debate on the relative roles of immune complexes and T cell products in inflammation in RA has continued for 30 years. There is little doubt that both B and T cells are essential to the disease. However, there is good evidence for neither cell being necessary at the site of inflammation. This tends to favour immune complexes (based on antibody synthesised elsewhere) as the initiators, even if not the sole perpetuators of inflammation. Moreover, work by Thurlings and others in Paul-Peter Tak's group and also by Arthur Kavanagh's group suggest that if any immune cells are relevant locally they are the plasma cells, which derive from B cells and produce in bulk the antibodies selected at the B cell stage.

Although TNF appears to be the dominant, other cytokines (chemical mediators) are likely to be involved in inflammation in RA. Blockade of TNF does not benefit all patients or all tissues (lung disease and nodules may get worse). Blockade of IL-1, IL-15
Interleukin 15
Interleukin 15 is a cytokine with structural similarity to IL-2. Like IL-2, IL-15 binds to and signals through the IL-2/IL-15 beta chain and the common gamma chain . IL-15 is secreted by mononuclear phagocytes following infection by virus...

 and IL-6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...

 also have beneficial effects and IL-17
Interleukin 17
Interleukin-17 is the founding member of a group of cytokines called the IL-17 family. IL-17A, was originally identified as a transcript from a rodent T-cell hybridoma by Rouvier et al. in 1993...

 may be important. Constitutional symptoms such as fever, malaise, loss of appetite and weight loss are also caused by cytokines released in to the blood stream.

As with most autoimmune diseases, it is important to distinguish between the cause(s) that trigger the process, and those that may permit it to persist and progress.

Possible infectious triggers

It has long been suspected that certain infections could be triggers for this disease. The "mistaken identity" theory suggests that an infection triggers an immune response, leaving behind antibodies that should be specific to that organism. The antibodies are not sufficiently specific, though, and set off an immune attack against part of the host. Because the normal host molecule "looks like" a molecule on the offending organism that triggered the initial immune reaction—this phenomenon is called molecular mimicry
Molecular mimicry
Molecular mimicry is defined as the theoretical possibility that sequence similarities between foreign and self-peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides...

. Some infectious organisms suspected of triggering rheumatoid arthritis include Mycoplasma
Mycoplasma
Mycoplasma refers to a genus of bacteria that lack a cell wall. Without a cell wall, they are unaffected by many common antibiotics such as penicillin or other beta-lactam antibiotics that target cell wall synthesis. They can be parasitic or saprotrophic. Several species are pathogenic in humans,...

, Erysipelothrix, parvovirus B19
Parvovirus
Parvovirus, often truncated to "parvo", is both the common name in English casually applied to all the viruses in the Parvoviridae taxonomic family, and also the taxonomic name of the Parvovirus genus within the Parvoviridae family...

 and rubella
Rubella
Rubella, commonly known as German measles, is a disease caused by the rubella virus. The name "rubella" is derived from the Latin, meaning little red. Rubella is also known as German measles because the disease was first described by German physicians in the mid-eighteenth century. This disease is...

, but these associations have never been supported in epidemiological studies. Nor has convincing evidence been presented for other types of triggers such as food allergies.

Epidemiological studies have confirmed a potential association between RA and two herpesvirus infections: Epstein-Barr virus
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...

 (EBV) and Human Herpes Virus 6
Human Herpesvirus Six
Human herpesvirus 6 is one of the eight known viruses that are members of the human herpesvirus family. The Human herpesvirus 6 is a virus within the Betaherpesvirinae subfamily of the genus, Roseoloviruses. There are seven other types of viruses in this family. HHV-6 has two known variants:...

 (HHV-6).
Individuals with RA are more likely to exhibit an abnormal immune response to the Epstein-Barr virus.

The allele HLA-DRB1*0404 is associated with low frequencies of T cells specific for the EBV glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...

 110 and predisposes one to develop RA.

Psychological factors

There is no evidence that physical and emotional effects or stress could be a trigger for the disease. The many negative findings suggest that either the trigger varies, or that it might in fact be a chance event inherent with the immune response, as suggested by Edwards et al.

Continued abnormal immune response

The factors that allow an abnormal immune response, once initiated, to become permanent and chronic, are becoming more clearly understood. The genetic association with HLA-DR4, as well as the newly discovered associations with the gene PTPN22
PTPN22
Protein tyrosine phosphatase, non-receptor type 22 , also known as PTPN22, is a protein that in humans is encoded by the PTPN22 gene. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms...

 and with two additional genes, all implicate altered thresholds in regulation of the adaptive immune response. It has also become clear from recent studies that these genetic factors may interact with the most clearly defined environmental risk factor for rheumatoid arthritis, namely cigarette smoking
Other environmental factors also appear to modulate the risk of acquiring RA, and hormonal factors in the individual may explain some features of the disease, such as the higher occurrence in women, the not-infrequent onset after child-birth, and the (slight) modulation of disease risk by hormonal medications. Exactly how altered regulatory thresholds allow the triggering of a specific autoimmune response remains uncertain. However, one possibility is that negative feedback mechanisms that normally maintain tolerance of self are overtaken by aberrant positive feedback mechanisms for certain antigens such as IgG Fc (bound by RF) and citrullinated fibrinogen (bound by ACPA) (see entry on autoimmunity
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...

).

Once the abnormal immune response has become established (which may take several years before any symptoms occur), plasma cells derived from B lymphocytes produce rheumatoid factors and ACPA of the IgG and IgM classes in large quantities. These are not deposited in the way that they are in systemic lupus. Rather, they appear to activate macrophages through Fc receptor and perhaps complement binding. This can contribute to inflammation of the synovium, in terms of edema, vasodilation and infiltration by activated T-cells (mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). Synovial macrophages and dendritic cells further function as antigen presenting cells by expressing MHC class II molecules, leading to an established local immune reaction in the tissue. The disease progresses in concert with formation of granulation tissue at the edges of the synovial lining (pannus
Pannus
Pannus is a medical term for an abnormal layer of fibrovascular tissue or granulation tissue. Common sites for pannus formation include over the cornea, over a joint surface , or on a prosthetic heart valve...

) with extensive angiogenesis and production of enzymes that cause tissue damage. Modern pharmacological treatments of RA target these mediators. Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues.

Role of vitamin D

The discovery of the vitamin D receptor (VDR) in the cells of the immune system and the fact that activated dendritic cells produce the vitamin D hormone suggested that vitamin D could have immunoregulatory properties. VDR, a member of the nuclear hormone receptor superfamily, was identified in mononuclear cells, dendritic cells, antigen-presenting cells, and activated T-B lymphocytes. In synthesis, the most evident effects of the D-hormone on the immune system seem to be in the downregulation of the Th1-driven autoimmunity. Low serum levels of vitamin D3 might be partially related, among other factors, to prolonged daily darkness (reduced activation of the pre vitamin D by the ultra violet B sunlight), different genetic background (i.e. vitamin D receptor polymorphism) and nutritional factors, and explain the latitude-related prevalence of autoimmune diseases such as rheumatoid arthritis (RA), by considering the potential immunosuppressive roles of vitamin D. 25(OH)D3 plasma levels have been found inversely correlated at least with the RA disease activity showing a circannual rhythm (more severe in winter). Recently, greater intake of vitamin D was associated with a lower risk of RA, as well as a significant clinical improvement was strongly correlated with the immunomodulating potential in vitamin D-treated RA patients.

In patients with rheumatoid arthritis measuring vitamin D levels seems particularly pertinent as deficiency is highly prevalent in the group. Vitamin D is already known to be important in preventing osteoporosis and fracture falls, which are also common in RA. It is too early to tell whether administering vitamin D directly affects disease activity.

Treatment

There is no known cure for rheumatoid arthritis, but many different types of treatment can alleviate symptoms and/or modify the disease process. Recommendations of the American College of Rheumatology (ACR), published in 2008, followed a trend in supporting earlier, more aggressive treatment of RA, and reflected heightened expectations of treatment effectiveness, including remission or substantial alleviation of symptoms for a rising percentage of patients.

The goal of treatment is twofold: alleviating the current symptoms, and preventing the future destruction of the joints with the resulting handicap if the disease is left unchecked. These two goals may not always coincide: while pain relievers may achieve the first goal, they do not have any impact on the long-term consequences. For these reasons, the ACR recommends that RA should generally be treated with at least one specific anti-rheumatic medication, also named DMARD (see below), to which other medications may be added depending on how long a person has had RA, how active the disease is, and prognostic factors (such as X-ray evidence of bone erosion; elevation of blood factors such as Rheumatoid factor
Rheumatoid factor
Rheumatoid factor is an autoantibody most relevant in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG. RF and IgG join to form immune complexes that contribute to the disease process...

, anti-cyclic citrullinated peptide
Anti-citrullinated protein antibody
Anti-citrullinated protein antibodies or anti-cyclic citrullinated protein antibodies are autoantibodies that are frequently detected in the blood of rheumatoid arthritis patients...

, C-reactive protein
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...

, and erythrocyte sedimentation rate
Erythrocyte sedimentation rate
The erythrocyte sedimentation rate , also called a sedimentation rate or Biernacki Reaction, is the rate at which red blood cells sediment in a period of 1 hour...

; age and gender; physical functioning; and smoking, for example).

Cortisone
Cortisone
Cortisone is a steroid hormone. It is one of the main hormones released by the adrenal gland in response to stress. In chemical structure, it is a corticosteroid closely related to corticosterone. It is used to treat a variety of ailments and can be administered intravenously, orally,...

 therapy has offered relief in the past, but its long-term effects have been deemed undesirable. However, cortisone injections can be valuable adjuncts to a long-term treatment plan, and using low dosages of daily cortisone (e.g., prednisone or prednisolone, 5–7.5 mg daily) can also have an important benefit if added to a proper specific anti-rheumatic treatment.

Pharmacological
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...

 treatment of RA can be divided into disease-modifying antirheumatic drugs (DMARDs), anti-inflammatory agents and analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

s.
Treatment also includes rest and physical activity.

Disease modifying anti-rheumatic drugs (DMARDs)

The term Disease-modifying anti-rheumatic drug (DMARD) originally meant a drug that affects biological measures such as ESR and haemoglobin and autoantibody levels, but is now usually used to mean a drug that reduces the rate of damage to bone and cartilage. DMARDs have been found both to produce durable symptomatic remissions and to delay or halt progression. This is important as such damage is usually irreversible. Anti-inflammatories and analgesics improve pain and stiffness but do not prevent joint damage or slow the disease progression.

There is an increasing recognition among rheumatologists that permanent damage to the joints occurs at a very early stage in the disease. In the past it was common to start with just an anti-inflammatory drug, and assess progression clinically and using X-rays. If there was evidence that joint damage was starting to occur then a more potent DMARD would be prescribed. Ultrasound and MRI are more sensitive methods of imaging the joints and have demonstrated that joint damage occurs much earlier and in more sufferers than was previously thought. People with normal X-rays will often have erosions detectable by ultrasound that X ray could not demonstrate. The aim now is to treat before damage occurs.

There may be other reasons why starting DMARDs early is beneficial as well as prevention of structural joint damage. From the earliest stages of the disease, the joints are infiltrated by cells of the immune system that signal to one another in ways that may involve a variety of positive feedback loops (it has long been observed that a single corticosteroid injection may abort synovitis in a particular joint for long periods). Interrupting this process as early as possible with an effective DMARD (such as methotrexate) appears to improve the outcome from the RA for years afterwards. Delaying therapy for as little as a few months after the onset of symptoms can result in worse outcomes in the long term. There is therefore considerable interest in establishing the most effective therapy with early arthritis, when they are most responsive to therapy and have the most to gain.

Disease-modifying anti-rheumatic drugs have been used in the treatment of rheumatic arthritis for a long time now. Over 90% of rheumatologists now use combination therapy
Combination therapy
Combination therapy or polytherapy is the use of more than one medication or other therapy. In contrast, monotherapy is any therapy which is taken by itself....

 of multiple disease modifying drugs for rheumatoid arthritis as it has become apparent that using combination of these drugs does not increase their relative toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...

 profiles. Common combinations of DMARDs include methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...

 – hydroxychloroquine
Hydroxychloroquine
Hydroxychloroquine is an antimalarial drug, sold under the trade names Plaquenil,Axemal, Dolquine, and Quensyl, also used to reduce inflammation in the treatment of rheumatoid arthritis and lupus...

, methotrexate – sulfasalazine, sulfasalazine – hydroxychloroquine, and methotrexate – hydroxychloroquine – sulfasalazine.

In order to be effective, disease-modifying anti-rheumatic drugs must be administered before the deformities appear or the erosive disease occurs. Usually, Rheumatologists do not wait for the fulfillment of the criteria for classification of RA as published by the American College of Rheumatology
American College of Rheumatology
The American College of Rheumatology is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy and practice support that foster excellence in the care of people with arthritis and rheumatic and...

 (ACR) and start treatment with this type of drugs if the pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

 and synovitis
Synovitis
Synovitis is the medical term for inflammation of the synovial membrane. This membrane lines joints which possess cavities, known as synovial joints. The condition is usually painful, particularly when the joint is moved. The joint usually swells due to synovial fluid collection.Synovitis may...

 persist and the function is compromised.

Traditional small molecular mass drugs

Chemically synthesised DMARDs:
  • azathioprine
    Azathioprine
    Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...

  • ciclosporin
    Ciclosporin
    Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...

     (cyclosporine A)
  • D-penicillamine
  • gold salts
    Gold salts
    Gold salts describe ionic chemical compounds of gold. The term, which is a misnomer, has evolved into a synonym for the gold compounds used in medicine...

  • hydroxychloroquine
    Hydroxychloroquine
    Hydroxychloroquine is an antimalarial drug, sold under the trade names Plaquenil,Axemal, Dolquine, and Quensyl, also used to reduce inflammation in the treatment of rheumatoid arthritis and lupus...

  • leflunomide
    Leflunomide
    Leflunomide is a medication of the DMARD type, used in active moderate to severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor.-Basic chemical, pharmacological, and marketing data:...

  • methotrexate (MTX)
    Methotrexate
    Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...

  • minocycline
    Minocycline
    Minocycline is a broad-spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bacteriostatic antibiotic, classified as a long-acting type...

  • sulfasalazine (SSZ)



Cytotoxic drugs:
  • Cyclophosphamide
    Cyclophosphamide
    Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....



The most important and most common adverse events relate to liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

 and bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...

 toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds, D-penicillamine), renal toxicity (cyclosporine A, parenteral gold salts, D-penicillamine), pneumonitis (MTX), allergic skin reactions (gold compounds, SSZ), autoimmunity (D-penicillamine, SSZ, minocycline) and infections (azathioprine, cyclosporine A).

Hydroxychloroquine may cause ocular toxicity, although this is rare, and because hydroxychloroquine does not affect the bone marrow or liver it is often considered to be the DMARD with the least toxicity. Unfortunately hydroxychloroquine is not very potent, and is usually insufficient to control symptoms on its own.

Methotrexate is considered by many rheumatologists to be the most important and useful DMARD, largely because of lower drop-out rates for reasons of toxicity. Nevertheless, methotrexate is often considered as a very 'toxic' drug. This reputation is not entirely justified, and at times can result in people being denied the most effective treatment for their arthritis. Although methotrexate does have the potential to suppress bone marrow or cause hepatitis, these effects can be monitored using regular blood tests, and the drug withdrawn at an early stage if the tests are abnormal before any serious harm is done (typically the blood tests return to normal after stopping the drug). In clinical trials, where one of a range of different DMARDs were used, people who were prescribed methotrexate stayed on their medication the longest (the others stopped because of either side-effects or failure of the drug to control the arthritis). Methotrexate is often preferred by rheumatologists because if it does not control arthritis on its own then it works well in combination with many other drugs, especially the biological agents. Other DMARDs may not be as effective or as safe in combination with biological agents.

Sulphasalazine : Although it appears to be a highly efficient drug in the treatment of rheumatoid arthritis, sulphasalazine may cause side effects that can range in severity from mild to serious. Mild side effects that may arise from treatment with sulphasalazine include nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

 and skin rash. Generally, nausea that appears as a result of treatment with this DMARD occurs in the first days of treatment and then it tends to diminish to disappearance. To avoid nausea, specialists recommend starting with low doses and then gradually increasing them until the usual dosage is achieved. Skin rash has been reported in nearly 5% of the patients and it may present pruritus. Rare side effects include Stevens–Johnson syndrome and reduced fertility
Fertility
Fertility is the natural capability of producing offsprings. As a measure, "fertility rate" is the number of children born per couple, person or population. Fertility differs from fecundity, which is defined as the potential for reproduction...

 due to reversible oligospermia
Oligospermia
Oligospermia, also oligozoospermia, refers to semen with a low concentration of sperm and is a common finding in male infertility. Often semen with a decreased sperm concentration may also show significant abnormalities in sperm morphology and motility...

. Severe side effects that can appear from therapy with sulphasalazine, though rare, are aplastic anemia
Aplastic anemia
Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and anemia...

 and neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...

 which may result in the death
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....

 of the patient
Patient
A patient is any recipient of healthcare services. The patient is most often ill or injured and in need of treatment by a physician, advanced practice registered nurse, veterinarian, or other health care provider....

. The latter is estimated to have occurred in approximately 2% of the patients but death and further complications were avoided by removing the drug from the patient's therapy. Also, according to WHO
Who
Who may refer to:* Who , an English-language pronoun* who , a Unix command* Who?, one of the Five Ws in journalism- Art and entertainment :* Who? , a 1958 novel by Algis Budrys...

, there have been approximately 700 of patients in whom this medicine caused blood dyscrasis. Leukopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....

 has also been reported in therapies with sulphasalazine, but in very rare cases.

Anti-malarials
Antimalarial drug
Antimalarial medications, also known as antimalarials, are designed to prevent or cure malaria. Such drugs may be used for some or all of the following:* Treatment of malaria in individuals with suspected or confirmed infection...

 such as chloroquine
Chloroquine
Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...

 and hydroxychloroquine
Hydroxychloroquine
Hydroxychloroquine is an antimalarial drug, sold under the trade names Plaquenil,Axemal, Dolquine, and Quensyl, also used to reduce inflammation in the treatment of rheumatoid arthritis and lupus...

 have been used to treat rheumatoid arthritis. It has been pointed out, through clinical studies, that chloroquine has a higher toxicity compared to hydroxychloroquine. Although hydroxyxhloroquine appears to be more efficient in treating rheumatoid arthritis than placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...

, it is also inferior to sulphasalazine, especially in what concerns preventing the joint damage that is caused by the disease. As most drugs, anti-malarials may also produce side effects. Mild side effects from hydroxychloroquine include nausea and skin rash. More serious, bone marrow suppression
Bone marrow suppression
Bone marrow suppression or myelotoxicity or myelosuppression, is the decrease in cells responsible for providing immunity, carrying oxygen, and those responsible for normal blood clotting is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine...

 may occur, though rare. Also, aplastic anemia and agranulocytosis
Agranulocytosis
Granulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...

 can develop as a result of anti-malarial therapy and may potentially cause the death of the patient. A much more worrisome side effect from treatment with anti-malarials is the damage that these drugs seem to be causing to the cornea
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...

 and retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...

. Recent studies have however shown that if the dosage of hydroxychloroquine given to the patients does not exceed 6.5 mg/kg, the risks of developing ocular complications are minimal.

Gold
Gold
Gold is a chemical element with the symbol Au and an atomic number of 79. Gold is a dense, soft, shiny, malleable and ductile metal. Pure gold has a bright yellow color and luster traditionally considered attractive, which it maintains without oxidizing in air or water. Chemically, gold is a...

 compounds are also options in treating this type of disease. Specialists agree that injectable gold is much more effective in the treatment of rheumatoid arthritis than auranofin
Auranofin
Auranofin is a gold complex classified by the World Health Organization as an antirheumatic agent.It has the brand name Ridaura.-Use in HIV infection:...

. Yet, this type of drug has been shown to be more efficient than placebo and even though its level of toxicity is quite low, auranofin seems to be causing more side effects than any other type of DMARD. Auranofin is therefore not considered efficient in the treatment of rheumatoid arthritis because of its poor results and because it is intolerable for most patients. Sodium aurothiomalate (Myocrisin) on the other hand is another type of gold compound that is injected and which appears to be as efficient as sulphasalazine, d-penicillamine and methotrexate. Given that there is not enough proof that gold compounds are indeed efficient in preventing the progression of erosions and the high toxicity of these drugs, they are usually not included in the treatment plan for rheumatoid arthritis.

A Cochrane systematic review has determined that Abatacept
Abatacept
Abatacept is a fusion protein composed of an immunoglobulin fused to the extracellular domain of CTLA-4, a molecule capable of binding B7. Abatacept is a selective costimulation modulator as it inhibits the costimulation of T cells...

 was an effective treatment for rheumatoid arthritis. Against placebo, it was found to increase mobility and make patients twice as likely to achieve a 50% improvement in symptoms. However Cochrane has called for more studies to be conducted, given the lack of evidence to distinguish between the biologics available for rheumatoid arthritis.

Biological agents

Biological agents (biologics) include:
  • tumor necrosis factor alpha (TNFα) blockers – etanercept
    Etanercept
    Etanercept is a drug that treats autoimmune diseases by interfering with the tumor necrosis factor by acting as a TNF inhibitor. Pfizer describes in a SEC filing that the drug is used to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis...

     (Enbrel), infliximab
    Infliximab
    Infliximab is a monoclonal antibody against tumour necrosis factor alpha . It is used to treat autoimmune diseases. Remicade is marketed by Janssen Biotech, Inc...

     (Remicade), adalimumab
    Adalimumab
    Adalimumab is the third TNF inhibitor, after infliximab and etanercept, to be approved in the United States. Like infliximab and etanercept, adalimumab binds to TNFα, preventing it from activating TNF receptors; adalimumab was constructed from a fully human monoclonal antibody, while infliximab...

     (Humira), certolizumab pegol
    Certolizumab pegol
    Certolizumab pegol is a therapeutic monoclonal antibody produced by UCB for the treatment of Crohn's disease and rheumatoid arthritis.-Method of action:...

     (Cimzia), golimumab
    Golimumab
    Golimumab is a human monoclonal antibody which is used as an immunosuppressive drug and marketed under the brand name Simponi. Golimumab targets tumor necrosis factor alpha , a pro-inflammatory molecule and hence is a TNF inhibitor....

     (Simponi)
  • Interleukin 1 (IL-1) blockers – anakinra
    Anakinra
    Anakinra is a drug used to treat rheumatoid arthritis.-Mechanism:Anakinra is an interleukin-1 receptor antagonist...

     (Kineret)
  • monoclonal antibodies against B cell
    B cell
    B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...

    s – rituximab
    Rituximab
    Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...

     (Rituxan)
  • T cell
    T cell
    T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...

     costimulation blocker – abatacept
    Abatacept
    Abatacept is a fusion protein composed of an immunoglobulin fused to the extracellular domain of CTLA-4, a molecule capable of binding B7. Abatacept is a selective costimulation modulator as it inhibits the costimulation of T cells...

     (Orencia)
  • Interleukin 6 (IL-6) blocker
    Anti-IL-6
    Anti-interleukin-6 agents are a recent class of therapeutics.Interleukin-6 is relevant to many inflammatory diseases and many cancers. Hence anti-IL-6 agents have been sought....

    s – tocilizumab
    Tocilizumab
    Tocilizumab is an immunosuppressive drug, mainly for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis, a severe form of RA in children. It is a humanized monoclonal antibody against the interleukin-6 receptor...

     (an anti-IL-6 receptor antibody) (RoActemra, Actemra)

Anti-inflammatory agents and analgesics

Anti-inflammatory agents include:
  • glucocorticoids
  • Non-steroidal anti-inflammatory drug
    Non-steroidal anti-inflammatory drug
    Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...

     (NSAIDs, most also act as analgesics)


Analgesics include:
  • paracetamol
    Paracetamol
    Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...

     (acetaminophen in US and Canada)
  • opiates
  • diproqualone
    Diproqualone
    Diproqualone is an analogue of methaqualone developed in the 1980s and marketed mainly in France and some other European countries. It has sedative, anxiolytic, antihistamine and analgesic properties, and is used primarily for the treatment of inflammatory pain associated with osteoarthritis and...

  • lidocaine
    Lidocaine
    Lidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...

     topical


Historic treatments for RA have also included: rest, ice, compression and elevation
RICE (medicine)
RICE is a treatment method for soft tissue injury which is an acronym for Rest, Ice, Compression and Elevation. When used appropriately, recovery duration is usually shortened and discomfort minimized....

, apple
Apple
The apple is the pomaceous fruit of the apple tree, species Malus domestica in the rose family . It is one of the most widely cultivated tree fruits, and the most widely known of the many members of genus Malus that are used by humans. Apple grow on small, deciduous trees that blossom in the spring...

 diet, nutmeg
Nutmeg
The nutmeg tree is any of several species of trees in genus Myristica. The most important commercial species is Myristica fragrans, an evergreen tree indigenous to the Banda Islands in the Moluccas of Indonesia...

, some light exercise every now and then, nettle
Nettle
Nettles constitute between 24 and 39 species of flowering plants of the genus Urtica in the family Urticaceae, with a cosmopolitan though mainly temperate distribution. They are mostly herbaceous perennial plants, but some are annual and a few are shrubby...

s, bee
Bee
Bees are flying insects closely related to wasps and ants, and are known for their role in pollination and for producing honey and beeswax. Bees are a monophyletic lineage within the superfamily Apoidea, presently classified by the unranked taxon name Anthophila...

 venom, copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...

 bracelets, rhubarb diet
Rhubarb diet
The rhubarb diet is a fad diet, originating in the Huangdi Neijing, which is gaining popularity in Western Europe. It entails substituting boiled rhubarb and dairy products for two meals daily. The laxative effect of rhubarb may aid weight loss. Advocates claim that rhubarb increases the effect of...

, extractions of teeth, fasting
Fasting
Fasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. An absolute fast is normally defined as abstinence from all food and liquid for a defined period, usually a single day , or several days. Other fasts may be only partially restrictive,...

, honey
Honey
Honey is a sweet food made by bees using nectar from flowers. The variety produced by honey bees is the one most commonly referred to and is the type of honey collected by beekeepers and consumed by humans...

, vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...

s, insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

, magnet
Magnet
A magnet is a material or object that produces a magnetic field. This magnetic field is invisible but is responsible for the most notable property of a magnet: a force that pulls on other ferromagnetic materials, such as iron, and attracts or repels other magnets.A permanent magnet is an object...

s, and electroconvulsive therapy
Electroconvulsive therapy
Electroconvulsive therapy , formerly known as electroshock, is a psychiatric treatment in which seizures are electrically induced in anesthetized patients for therapeutic effect. Its mode of action is unknown...

 (ECT). Most of these have either had no effect at all, or their effects have been modest and transient, while not being generalizable.

NSAIDs used in the treatment of RA include ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....

, naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...

, meloxicam
Meloxicam
Meloxicam is a nonsteroidal anti-inflammatory drug with analgesic and fever reducer effects. It is a derivative of oxicam, closely related to piroxicam, and falls in the enolic acid group of NSAIDs...

, etodolac
Etodolac
Etodolac: Etodolac belongs to a class of drugs called nonsteroidal anti-inflammatory drugs . Other members of this class include aspirin, ibuprofen , naproxen , indomethacin , nabumetone and numerous others. These drugs are used for the management of mild to moderate pain, fever, and inflammation...

, nabumetone
Nabumetone
Nabumetone is a non-steroidal anti-inflammatory drug , the only 1-naphthaleneacetic acid derivative. Nabumetone has been developed by Beecham...

, sulindac
Sulindac
Sulindac is a non-steroidal anti-inflammatory drug of the arylalkanoic acid class that is marketed in the UK & U.S. by Merck as Clinoril.-Uses:...

, tolementin, choline magnesium salicylate, diclofenac
Diclofenac
Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....

, diflusinal, indomethicin, Ketoprofen
Ketoprofen
Ketoprofen, 2--propionic acid is one of the propionic acid class of non-steroidal anti-inflammatory drug with analgesic and antipyretic effects...

, Oxaprozin
Oxaprozin
Oxaprozin, also known as Oxaprozinum, is a non-steroidal anti-inflammatory drug , used to relieve the inflammation, swelling, stiffness, and joint pain associated with osteoarthritis and rheumatoid arthritis. Chemically, it is a propionic acid derivative. It is available in 600 mg tablets...

, and piroxicam
Piroxicam
Piroxicam is a non-steroidal anti-inflammatory drug of the oxicam class used to relieve the symptoms of rheumatoid and osteoarthritis, primary dysmenorrhoea, postoperative pain; and act as an analgesic, especially where there is an inflammatory component...

.

Cortisone
Cortisone
Cortisone is a steroid hormone. It is one of the main hormones released by the adrenal gland in response to stress. In chemical structure, it is a corticosteroid closely related to corticosterone. It is used to treat a variety of ailments and can be administered intravenously, orally,...

 therapy became a controversial medical solution because even though it can provide great relief, there are some questions as to the usefulness of the procedure over a long period of time.

Surgery

In early phases of the disease, an arthroscopic or open synovectomy
Synovectomy
Synovectomy is the surgical removal of a part of the synovial membrane of a synovial joint.-Indications:It is one of the treatment options for certain diseases involving the synovium like:* Severe rheumatoid arthritis or juvenile idiopathic arthritis...

 may be performed. It consists of the removal of the inflammed synovia and prevents a quick destruction of the affected joints. In older patients, the yttrium synovectomy may be performed. It is successful in approximately half of patients. The surgery is mostly done on knee, elbow, shoulder, ankle or tarsal joints. It has to be performed before the destruction of the cartilage. Severely affected joints may require joint replacement
Joint replacement
Replacement arthroplasty [from Greek arthron, joint, limb, articulate, + -plassein, to form, mould, forge, feign, make an image of], or joint replacement surgery, is a procedure of orthopedic surgery in which the arthritic or dysfunctional joint surface is replaced with an orthopaedic prosthesis...

 surgery, such as knee replacement. Postoperatively, physiotherapy is always necessary.

Other therapies

Regular exercise is important for maintaining joint mobility and making the joint muscles stronger. A Cochrane Review of studies determined that exercise programs designed to improve strength and stamina were safe and led to moderate benefits for RA sufferers.

Other therapies are weight loss
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...

, orthoses, occupational therapy, podiatry
Podiatry
Podiatry is a branch of medicine devoted to the study, diagnosis, and treatment of disorders of the foot, ankle, and lower leg. The term podiatry came into use first in the early 20th century United States, where it now denotes a Doctor of Podiatric Medicine , a specialist who is qualified by their...

, physiotherapy, immunoadsorption therapy, joint injection
Joint injection
In medicine, a joint injection is a procedure used in the treatment of inflammatory joint conditions, such as rheumatoid arthritis, psoriatic arthritis, gout, tendinitis, bursitis and occasionally osteoarthritis...

s, and special tools to improve hand movements (e.g., special tin-openers).

Ayurveda
Ayurveda
Ayurveda or ayurvedic medicine is a system of traditional medicine native to India and a form of alternative medicine. In Sanskrit, words , meaning "longevity", and , meaning "knowledge" or "science". The earliest literature on Indian medical practice appeared during the Vedic period in India,...

, mostly in southern India, is another source of treatment, and while it is popular in India there are no studies to show that it benefits patients with RA.

One survey in the United Kingdom between 1998 and 2002 found that arthritis, in its various forms, was among the five most common reasons for the medicinal use of cannabis.
The Prosorba column
Prosorba column
The Prosorba Column is a Plasma filtering device used to treat severe cases of Rheumatoid Arthritis or Psoriatic Arthritis. Its active element is Protein A bonded to a diatomaceous earth/clay bead...

 blood filtering device (removing IgG) was approved by the FDA in 1999 for treatment of RA However it was discontinued at the end of 2006.

The effectiveness of treating RA with acupuncture is inconclusive, and "more rigorous research seems to be warranted" according to one study.

One study of 873 patients with RA found that those who drank some alcohol (none drank more than 10 units of alcohol a week) had reduced severity of symptoms compared to those who drank no alcohol. However a spokeswoman for the Arthritis Research UK (who co-funded the study) warned that some RA treatments, like methotrexate, could damage the liver when taken with large amounts of alcohol.
Experimental chemicals capable to lower secretion of inflammatory cytokines linked to arthritis include Dimethyl sulphoxide and dimethyl sulphone (Kloesch et al., Life Sciences Volume 89, Issues 13-14). However, it is important to safeguard liver against potential toxicity (Brayton, Cornell Vet.,76:61).

Prognosis

The course of the disease varies greatly. Some people have mild short-term symptoms, but in most the disease is progressive for life. Around 20%–30% will have subcutaneous nodules (known as rheumatoid nodule
Rheumatoid nodule
A rheumatoid nodule is a local swelling or tissue lump, usually rather firm to touch, like an unripe fruit, which occurs almost exclusively in association with rheumatoid arthritis. Very rarely rheumatoid nodules occur as 'rheumatoid nodulosis' in the absence of arthritis...

s); this is associated with a poor prognosis.

Prognostic factors

Poor prognostic factors include persistent synovitis, early erosive disease,extra-articular findings (including subcutaneous rheumatoid nodules), positive serum RF findings, positive serum anti-CCP autoantibodies, carriership of HLA-DR4 "Shared Epitope" alleles, family history of RA, poor functional status, socioeconomic factors, elevated acute phase response (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]), and increased clinical severity.

Mortality

Estimates of the life-shortening effect of RA vary; most sources cite a lifespan reduction of 5 to 10 years. According to the UK's National Rheumatoid Arthritis Society, "Young age at onset, long disease duration, the concurrent presence of other health problems (called co-morbidity), and characteristics of severe RA—such as poor functional ability or overall health status, a lot of joint damage on x-rays, the need for hospitalisation or involvement of organs other than the joints—have been shown to associate with higher mortality". Positive responses to treatment may indicate a better prognosis. A 2005 study by the Mayo Clinic
Mayo Clinic
Mayo Clinic is a not-for-profit medical practice and medical research group specializing in treating difficult patients . Patients are referred to Mayo Clinic from across the U.S. and the world, and it is known for innovative and effective treatments. Mayo Clinic is known for being at the top of...

 noted that RA sufferers suffer a doubled risk of heart disease, independent of other risk factors such as diabetes, alcohol abuse, and elevated cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

, blood pressure and body mass index
Body mass index
The body mass index , or Quetelet index, is a heuristic proxy for human body fat based on an individual's weight and height. BMI does not actually measure the percentage of body fat. It was invented between 1830 and 1850 by the Belgian polymath Adolphe Quetelet during the course of developing...

. The mechanism by which RA causes this increased risk remains unknown; the presence of chronic inflammation has been proposed as a contributing factor.

Epidemiology

The incidence
Incidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...

 of RA is in the region of 3 cases per 10,000 population per annum. Onset is uncommon under the age of 15 and from then on the incidence rises with age until the age of 80. The prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...

 rate is 1%, with women affected three to five times as often as men. It is up to three times more common in smokers than non-smokers, particularly in men, heavy smokers, and those who are rheumatoid factor positive. A study in 2010 found that those who drank modest amounts of alcohol regularly were four times less likely to get rheumatoid arthritis than those who never drank.
Some Native American
Indigenous peoples of the Americas
The indigenous peoples of the Americas are the pre-Columbian inhabitants of North and South America, their descendants and other ethnic groups who are identified with those peoples. Indigenous peoples are known in Canada as Aboriginal peoples, and in the United States as Native Americans...

 groups have higher prevalence rates (5–6%) and people from the Caribbean
Caribbean
The Caribbean is a crescent-shaped group of islands more than 2,000 miles long separating the Gulf of Mexico and the Caribbean Sea, to the west and south, from the Atlantic Ocean, to the east and north...

 region have lower prevalence rates. First-degree relatives prevalence rate is 2–3% and disease genetic concordance in monozygotic twins is approximately 15–20%.

It is strongly associated with the inherited tissue type Major histocompatibility complex
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...

 (MHC) antigen HLA
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...

-DR4 (most specifically DR0401 and 0404)—hence family history is an important risk factor.

The risk of first developing the disease (the disease incidence
Incidence
Incidence may refer to:* Incidence , a measure of the risk of developing some new condition within a specified period of time* Incidence , the binary relations describing how subsets meet...

) appears to be greatest for women between 40 and 50 years of age, and for men somewhat later. RA is a chronic disease, and although rarely, a spontaneous remission may occur, the natural course is almost invariably one of persistent symptoms, waxing and waning in intensity, and a progressive deterioration of joint structures leading to deformations and disability.

History

The first known traces of arthritis date back at least as far as 4500 BC. A text dated 123 AD first describes symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...

s very similar to rheumatoid arthritis. It was noted in skeletal remains of Native Americans found in Tennessee
Tennessee
Tennessee is a U.S. state located in the Southeastern United States. It has a population of 6,346,105, making it the nation's 17th-largest state by population, and covers , making it the 36th-largest by total land area...

. In the Old World the disease is vanishingly rare before the 1600s. and on this basis investigators believe it spread across the Atlantic during the Age of Exploration. In 1859 the disease acquired its current name.

An anomaly has been noticed from investigation of Precolumbian bones. The bones from the Tennessee site show no signs of tuberculosis even though it was prevalent at the time throughout the Americas. Jim Mobley, at Pfizer, has discovered a historical pattern of epidemics of tuberculosis followed by a surge in the number of rheumatoid arthritis cases a few generations later. Mobley attributes the spikes in arthritis to selective pressure caused by tuberculosis. A hypervigilant immune system is protective against tuberculosis at the cost of an increased risk of autoimmune disease.

The art of Peter Paul Rubens may possibly depict the effects of rheumatoid arthritis. In his later paintings, his rendered hands show, in the opinion of some physicians, increasing deformity consistent with the symptoms of the disease. Rheumatoid arthritis appears to some to have been depicted in 16th century paintings. However, it is generally recognised in art historical circles that the painting of hands in the sixteenth and seventeenth century followed certain stylised conventions, most clearly seen in the Mannerist movement. It was conventional, for instance to show the upheld right hand of Christ in what now appears a deformed posture. These conventions are easily misinterpreted as portrayals of disease. They are much too widespread for this to be plausible.

The first recognized description of rheumatoid arthritis was in 1800 by the French physician Dr Augustin Jacob Landré-Beauvais (1772–1840) who was based in the famed Salpêtrière Hospital
Pitié-Salpêtrière Hospital
The Pitié-Salpêtrière Hospital is a teaching hospital located in Paris, France. Part of the Assistance publique - Hôpitaux de Paris, it is one of Europe's largest hospitals...

 in Paris. The name "rheumatoid arthritis" itself was coined in 1859 by British rheumatologist Dr Alfred Baring Garrod
Alfred Baring Garrod
Sir Alfred Baring Garrod FRS was an English physician.He was born in Ipswich, the son of Robert and Sarah Garrod.He initially apprenticed at Ipswich Hospital, and later moved to University College Hospital, where he earned his medical doctorate in 1843. Afterwards he was an assistant at West...

.

Notable cases

  • Christiaan Barnard
    Christiaan Barnard
    Christiaan Neethling Barnard was a South African cardiac surgeon who performed the world's first successful human-to-human heart transplant.- Early life :...

    , the first surgeon to perform a human-to-human heart transplant had to retire owing to the condition. He also wrote a book on living with arthritis.
  • Billy Bowden
    Billy Bowden
    Brent Fraser "Billy" Bowden is an international cricket umpire from New Zealand. He was a player until he began to suffer from rheumatoid arthritis and took up umpiring...

    , international cricket umpire who had to retire from active play because of rheumatoid arthritis.
  • James Coburn
    James Coburn
    James Harrison Coburn III was an American film and television actor. Coburn appeared in nearly 70 films and made over 100 television appearances during his 45-year career, and played a wide range of roles and won an Academy Award for his supporting role as Glen Whitehouse in Affliction.A capable,...

     claimed to have healed the condition using pills containing a sulfur-containing compound on his return to acting.
  • Raoul Dufy
    Raoul Dufy
    Raoul Dufy[p] was a French Fauvist painter. He developed a colorful, decorative style that became fashionable for designs of ceramics and textiles, as well as decorative schemes for public buildings. He is noted for scenes of open-air social events...

    , French artist (1877–1953), continued to paint despite RA and was one of the first patients ever treated with cortisone, in a Boston hospital.
  • Jamie Farr
    Jamie Farr
    Jamie Farr is an American television, film, and theater actor. He is best known for having played the role of cross-dressing Corporal Maxwell Q. Klinger in the television sitcom M*A*S*H.-Early life:...

    , American actor, famous for his role as Max Klinger on the 1970s television
    Television
    Television is a telecommunication medium for transmitting and receiving moving images that can be monochrome or colored, with accompanying sound...

     series M*A*S*H.
  • Melvin Franklin
    Melvin Franklin
    David Melvin English better known by the stage name Melvin Franklin, was an American bass singer. Franklin is best known for his role as a member of Motown singing group The Temptations from 1960 to 1994....

    , bass singer of the Temptations. He treated RA with cortisone shots so he could perform.
  • Dorothy Hodgkin, Nobel prize winning scientist, developed severe deforming rheumatoid arthritis at age 28. In spite of this she continued her career and developed X-ray crystallography
    X-ray crystallography
    X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...

    , which underpins much of the information known about rheumatoid arthritis. She also discovered the structure of insulin
    Insulin
    Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

     and enabled the discovery of the genetic code
    Genetic code
    The genetic code is the set of rules by which information encoded in genetic material is translated into proteins by living cells....

    .
  • Matt Iseman
    Matt Iseman
    Matthew C. "Matt" Iseman is an American comedian, actor, and television host, who began his career as a physician.- Early life and medical career :...

    , licensed physician and professional comedian, and host of Style Network's Clean House.
  • Sandy Koufax
    Sandy Koufax
    Sanford "Sandy" Koufax is a former left-handed baseball pitcher who played his entire 12-year Major League Baseball career for the Brooklyn/Los Angeles Dodgers...

    , an American Hall-of-Fame baseball pitcher who played from 1955 to 1966 for the Los Angeles Dodgers.
  • Erik Lindbergh
    Erik Lindbergh
    Erik Lindbergh is an aviator, a promoter of space tourism, and an artist. Grandson of pioneering aviator Charles Lindbergh, who was the first person to fly non-stop between New York and Paris in 1927, in 2002 Erik honored the 75th anniversary of his grandfather's historic flight by retracing the...

    , aviator and member of the X-Prize administration. Erik has been a spokesman for the arthritis drug Enbrel, as a result of his success with the treatment.
  • Bob Mortimer
    Bob Mortimer
    Robert "Bob" Renwick Mortimer is an English comedian and actor, who is best known for his double act with Vic Reeves...

     British comedian and actor.
  • Auguste Renoir, impressionist painter, whose later 'softer' style might have reflected in some way his severe disability.
  • Kathleen Turner
    Kathleen Turner
    Mary Kathleen Turner is an American actress. She came to fame during the 1980s, after roles in the Hollywood films Body Heat, Peggy Sue Got Married, Romancing the Stone, The War of the Roses, Who Framed Roger Rabbit and Prizzi's Honor...

     and Aida Turturro
    Aida Turturro
    Aida Turturro is an American actress probably best known for playing Janice Soprano, sister of New Jersey mob boss Tony Soprano, on the HBO TV series The Sopranos .-Personal life:...

     have worked to raise public awareness of the condition

See also

  • Adult-onset Still's disease
    Adult-onset Still's disease
    Adult-onset Still's disease is a rare form of inflammatory arthritis that was characterized by EG Bywaters in 1971. The underlying cause is unknown. It usually presents with high spiking fevers, joint and muscle pains, a salmon colored rash and other symptoms of systemic inflammation.- History...

  • Juvenile idiopathic arthritis
    Juvenile idiopathic arthritis
    Juvenile idiopathic arthritis is the most common form of persistent arthritis in children. JIA is a subset of arthritis seen in childhood, which may be transient and...

  • Synovitis
    Synovitis
    Synovitis is the medical term for inflammation of the synovial membrane. This membrane lines joints which possess cavities, known as synovial joints. The condition is usually painful, particularly when the joint is moved. The joint usually swells due to synovial fluid collection.Synovitis may...

  • Biologics
    Biologics
    A biologic is a medicinal product such as a vaccine, blood or blood component, allergenic, somatic cell, gene therapy, tissue, recombinant therapeutic protein, or living cells that are used as therapeutics to treat diseases...

  • Arthritis Care
    Arthritis Care
    Arthritis Care is the UK's largest charity dedicated to supporting people with arthritis . It is a user led organisation which means people with arthritis are at the heart of its work – they form its membership, are involved in its activities and are well represented on its staff and board of...

  • Psoriasis
    Psoriasis
    Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...

  • Arthritis
    Arthritis
    Arthritis is a form of joint disorder that involves inflammation of one or more joints....

  • Rheumatoid factor
    Rheumatoid factor
    Rheumatoid factor is an autoantibody most relevant in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG. RF and IgG join to form immune complexes that contribute to the disease process...

  • Inflammation
    Inflammation
    Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...



External links

NRAS – National Rheumatoid Arthritis Society
The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
x
OK