Rheumatoid arthritis (RA) is a long-term
autoimmune disorder
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly ...
that primarily affects
joints
A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw- ...
.
[ It typically results in warm, swollen, and ]pain
Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
ful joints.[ Pain and stiffness often worsen following rest.][ Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body.][ The disease may also affect other parts of the body, including skin, eyes, lungs, heart, nerves and blood.][ This may result in a low red blood cell count, inflammation around the lungs, and inflammation around the heart.][ Fever and low energy may also be present.] Often, symptoms come on gradually over weeks to months.[
While the cause of rheumatoid arthritis is not clear, it is believed to involve a combination of genetic and environmental factors.][ The underlying mechanism involves the body's ]immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
attacking the joints.[ This results in inflammation and thickening of the ]joint capsule
In anatomy, a joint capsule or articular capsule is an envelope surrounding a synovial joint.bone
A bone is a Stiffness, rigid Organ (biology), organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red blood cell, red and white blood cells, store minerals, provid ...
and cartilage
Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...
.[ The diagnosis is made mostly on the basis of a person's signs and symptoms.][ ]X-rays
An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 Picometre, picometers to 10 Nanometre, nanometers, corresponding to frequency, ...
and laboratory testing may support a diagnosis or exclude other diseases with similar symptoms.[ Other diseases that may present similarly include ]systemic lupus erythematosus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
, psoriatic arthritis
Psoriatic arthritis is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. Thi ...
, and fibromyalgia
Fibromyalgia (FM) is a medical condition defined by the presence of chronic widespread pain, fatigue, waking unrefreshed, cognitive symptoms, lower abdominal pain or cramps, and depression. Other symptoms include insomnia and a general hyp ...
among others.
The goals of treatment are to reduce pain, decrease inflammation, and improve a person's overall functioning. This may be helped by balancing rest and exercise, the use of splints and braces, or the use of assistive devices. Pain medications
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
, steroids
A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
, and NSAIDs are frequently used to help with symptoms.[ ]Disease-modifying antirheumatic drug
Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroidal ...
s (DMARDs), such as hydroxychloroquine
Hydroxychloroquine, sold under the brand name Plaquenil among others, is a medication used to prevent and treat malaria in areas where malaria remains sensitive to chloroquine. Other uses include treatment of rheumatoid arthritis, lupus, an ...
and methotrexate
Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
, may be used to try to slow the progression of disease.[ Biological DMARDs may be used when disease does not respond to other treatments.] However, they may have a greater rate of adverse effects. Surgery to repair, replace, or fuse
Fuse or FUSE may refer to:
Devices
* Fuse (electrical), a device used in electrical systems to protect against excessive current
** Fuse (automotive), a class of fuses for vehicles
* Fuse (hydraulic), a device used in hydraulic systems to protect ...
joints may help in certain situations.[
RA affects about 24.5 million people as of 2015.] This is between 0.5 and 1% of adults in the developed world
A developed country (or industrialized country, high-income country, more economically developed country (MEDC), advanced country) is a sovereign state that has a high quality of life, developed economy and advanced technological infrastruct ...
with 5 and 50 per 100,000 people newly developing the condition each year. Onset is most frequent during middle age and women are affected 2.5 times as frequently as men.[ It resulted in 38,000 deaths in 2013, up from 28,000 deaths in 1990.] The first recognized description of RA was made in 1800 by Dr. Augustin Jacob Landré-Beauvais
Augustin Jacob Landré-Beauvais (1772–1840) was a French surgeon best known for his description of rheumatoid arthritis. reproduced in Born in Orléans, he studied under Pierre-Joseph Desault and Xavier Bichat in Paris, and then from 1792 under ...
(1772–1840) of Paris.[ reproduced in ] The term ''rheumatoid arthritis'' is based on the Greek for watery and inflamed joints.
Signs and symptoms
RA primarily affects joints
A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw- ...
, but it also affects other organs
In biology, an organ is a collection of tissues joined in a structural unit to serve a common function. In the hierarchy of life, an organ lies between tissue and an organ system. Tissues are formed from same type cells to act together in a f ...
in more than 15–25% of cases. Associated problems include cardiovascular disease, osteoporosis, interstitial lung disease, infection, cancer, feeling tired, depression, mental difficulties, and trouble working.
Joints
Arthritis
Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
of joints involves inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
of the synovial membrane
The synovial membrane (also known as the synovial stratum, synovium or stratum synoviale) is a specialized connective tissue that lines the inner surface of capsules of synovial joints and tendon sheath. It makes direct contact with the fibrous ...
. Joints become swollen, tender and warm, and stiffness limits their movement. With time, multiple joints are affected (polyarthritis
Polyarthritis is any type of arthritis that involves 5 or more joints simultaneously. It is usually associated with autoimmune conditions and may be experienced at any age and is not sex specific.
Causes
Polyarthritis is most often caused by an au ...
). Most commonly involved are the small joints of the hand
A hand is a prehensile, multi-fingered appendage located at the end of the forearm or forelimb of primates such as humans, chimpanzees, monkeys, and lemurs. A few other vertebrates such as the koala (which has two opposable thumbs on each "h ...
s, feet
The foot ( : feet) 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 ...
and cervical spine
In tetrapods, cervical vertebrae (singular: vertebra) are the vertebrae of the neck, immediately below the skull. Truncal vertebrae (divided into thoracic and lumbar vertebrae in mammals) lie caudal (toward the tail) of cervical vertebrae. In sau ...
, but larger joints like the shoulder and knee can also be involved.[ ]Synovitis
Synovitis is the medical term for inflammation of the synovial membrane. This membrane lines joints that possess cavities, known as synovial joints. The condition is usually painful, particularly when the joint is moved. The joint usually swel ...
can lead to tethering
Tethering, or phone-as-modem (PAM) is the sharing of a mobile device's Internet connection with other connected computers. Connection of a mobile device with other devices can be done over wireless LAN (Wi-Fi), over Bluetooth or by physical conne ...
of tissue with loss of movement and erosion of the joint surface causing deformity
A deformity, dysmorphism, or dysmorphic feature is a major abnormality of an organism that makes a part of the body appear or function differently than how it is supposed to.
Causes
Deformity can be caused by a variety of factors:
*Arthritis an ...
and loss of function.[ The ]fibroblast-like synoviocyte
Fibroblast-like synoviocytes (FLS) represent a specialised cell type located inside joints in the synovium. These cells play a crucial role in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis.
Fibroblast-like syno ...
s (FLS), highly specialized mesenchymal cells found in the synovial membrane
The synovial membrane (also known as the synovial stratum, synovium or stratum synoviale) is a specialized connective tissue that lines the inner surface of capsules of synovial joints and tendon sheath. It makes direct contact with the fibrous ...
, have an active and prominent role in these pathogenic processes of the rheumatic joints.
RA 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, such as osteoarthritis
Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...
. In arthritis of non-inflammatory causes, signs of inflammation and early morning stiffness are less prominent.
The pain associated with RA is induced at the site of inflammation and classified as nociceptive
Nociception (also nocioception, from Latin ''nocere'' 'to harm or hurt') is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an org ...
as opposed to neuropathic
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or o ...
. 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
A deformity, dysmorphism, or dysmorphic feature is a major abnormality of an organism that makes a part of the body appear or function differently than how it is supposed to.
Causes
Deformity can be caused by a variety of factors:
*Arthritis an ...
. The fingers may develop almost any deformity
A deformity, dysmorphism, or dysmorphic feature is a major abnormality of an organism that makes a part of the body appear or function differently than how it is supposed to.
Causes
Deformity can be caused by a variety of factors:
*Arthritis an ...
depending on which joints are most involved. Specific deformities
A deformity, dysmorphism, or dysmorphic feature is a major abnormality of an organism that makes a part of the body appear or function differently than how it is supposed to.
Causes
Deformity can be caused by a variety of factors:
*Arthritis an ...
, which also occur in osteoarthritis
Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...
, include ulnar deviation
Ulnar deviation, also known as ulnar drift, is a hand deformity in which the swelling of the metacarpophalangeal joints (the big knuckles at the base of the fingers) causes the fingers to become displaced, tending towards the little finger. Its na ...
, boutonniere deformity
Boutonniere deformity is a deformed position of the fingers or toes, in which the joint nearest the knuckle (the proximal interphalangeal joint, or PIP) is permanently bent toward the palm while the farthest joint (the distal interphalangeal joi ...
(also "buttonhole deformity", flexion
Motion, the process of movement, is described using specific anatomical terms. Motion includes movement of organs, joints, limbs, and specific sections of the body. The terminology used describes this motion according to its direction relative ...
of proximal interphalangeal joint and extension of distal interphalangeal joint of the hand), 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 ( DIP flexion with PIP hyperextension). It is commo ...
(hyperextension at proximal interphalangeal joint and flexion at distal interphalangeal joint) and "Z-thumb." "Z-thumb" or "Z-deformity" consists of hyperextension
Motion, the process of movement, is described using specific anatomical terms. Motion includes movement of organs, joints, limbs, and specific sections of the body. The terminology used describes this motion according to its direction relative ...
of the interphalangeal joint, fixed flexion and subluxation
A subluxation is an incomplete or partial dislocation of a joint or organ.
According to the World Health Organization (WHO), a subluxation is a "significant structural displacement", and is therefore always visible on static imaging studies, suc ...
of the metacarpophalangeal joint
The metacarpophalangeal joints (MCP) are situated between the metacarpal bones and the proximal phalanges of the fingers. These joints are of the condyloid kind, formed by the reception of the rounded heads of the metacarpal bones into shallow cav ...
and gives a "Z" appearance to the thumb. The hammer toe
A hammer toe or contracted toe is a deformity of the muscles and ligaments of the proximal interphalangeal joint of the second, third, fourth, or fifth toe causing it to be bent, resembling a hammer. In the early stage a flexible hammertoe is ...
deformity
A deformity, dysmorphism, or dysmorphic feature is a major abnormality of an organism that makes a part of the body appear or function differently than how it is supposed to.
Causes
Deformity can be caused by a variety of factors:
*Arthritis an ...
may be seen. In the worst case, joints are known as arthritis mutilans
Arthritis mutilans is a rare medical condition involving severe inflammation damaging the joints of the hands and feet, and resulting in deformation and problems with moving the affected areas; it can also affect the spine. As an uncommon arthropat ...
due to the mutilating nature of the deformities.
Skin
The rheumatoid nodule
A rheumatoid nodule is a lump of tissue, or an area of swelling, that appear on the exterior of the skin usually around the olecranon (tip of the elbow) or the interphalangeal joints (finger knuckles), but can appear in other areas. There are fou ...
, which is sometimes in the skin, is the most common non-joint feature and occurs in 30% of people who have RA. It is a type of inflammatory reaction known to pathologists as a "necrotizing
Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
granuloma
A granuloma is an aggregation of macrophages that forms in response to chronic inflammation. This occurs when the immune system attempts to isolate foreign substances that it is otherwise unable to eliminate. Such substances include infectious ...
". The initial
In a written or published work, an initial capital, also referred to as a drop capital or simply an initial cap, initial, initcapital, initcap or init or a drop cap or drop, is a letter at the beginning of a word, a chapter, or a paragraph that ...
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 is a specific pattern of irreversible, uncontrolled cell death that occurs when antigen-antibody complexes are deposited in the walls of blood vessels along with fibrin. It is common in the immune-mediated vasculitides which a ...
that may be fissured and which corresponds to the fibrin
Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with platele ...
-rich necrotic material found in and around an affected synovial space. Surrounding the necrosis is a layer of palisading macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
and fibroblasts
A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...
, corresponding to the intimal layer in synovium and a cuff of connective tissue
Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...
containing clusters of lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
s and plasma cell
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...
s, 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 elbow
The elbow is the region between the arm and the forearm that surrounds the elbow joint. The elbow includes prominent landmarks such as the olecranon, the cubital fossa (also called the chelidon, or the elbow pit), and the lateral and the media ...
, the heel
The heel is the prominence at the posterior end of the foot. It is based on the projection of one bone, the calcaneus or heel bone, behind the articulation of the bones of the lower Human leg, leg.
Structure
To distribute the compressive for ...
, the knuckles, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF ( rheumatoid factor) titer
Titer (American English) or titre (British English) is a way of expressing concentration. Titer testing employs serial dilution to obtain approximate quantitative information from an analytical procedure that inherently only evaluates as positiv ...
, ACPA, and severe erosive arthritis. Rarely, these can occur in internal organs or at diverse sites on the body.
Several forms of vasculitis
Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily caused b ...
occur in RA, but are mostly seen with long-standing and untreated disease. The most common presentation is due to involvement of small- and medium-sized vessels. Rheumatoid vasculitis can thus commonly present with skin ulceration and vasculitic nerve infarction known as mononeuritis multiplex
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
.
Other, rather rare, skin associated symptoms include pyoderma gangrenosum
Pyoderma gangrenosum is a rare, inflammatory skin disease where painful pustules or nodules become ulcers that progressively grow. Pyoderma gangrenosum is not infectious.
Treatments may include corticosteroids, ciclosporin, infliximab, or cana ...
, Sweet's syndrome
Sweet syndrome (SS), or acute febrile neutrophilic dermatosis, is a skin disease characterized by the sudden onset of fever, an elevated white blood cell count, and tender, red, well-demarcated papules and plaques that show dense infiltrates by ...
, drug reactions, erythema nodosum
Erythema nodosum (EN) is an inflammatory condition characterized by inflammation of the fat cells under the skin, resulting in tender red nodules or lumps that are usually seen on both shins. It can be caused by a variety of conditions, and typi ...
, lobe panniculitis
Panniculitis is a group of diseases whose hallmark is inflammation of subcutaneous adipose tissue (the fatty layer under the skin – panniculus adiposus). Symptoms include tender skin nodules, and systemic signs such as weight loss and fatigu ...
, atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...
of finger skin, palmar erythema
Palmar erythema is reddening of the palms at the thenar and hypothenar eminences.James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. .
Causes
It is associated with va ...
, and skin fragility (often worsened by corticosteroid use).
Diffuse alopecia areata
Alopecia areata, also known as spot baldness, is a condition in which hair is lost from some or all areas of the body. Often, it results in a few bald spots on the scalp, each about the size of a coin. Psychological stress and illness are po ...
(Diffuse AA) occurs more commonly in people with rheumatoid arthritis. RA is also seen more often in those with relatives who have AA.
Lungs
Lung fibrosis
Pulmonary fibrosis is a condition in which the lungs become scarred over time. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Complications may include pulmonary hypertension, respiratory failu ...
is a recognized complication of rheumatoid arthritis. It is also a rare but well-recognized consequence of therapy (for example with methotrexate
Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
and leflunomide
Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug ( DMARD), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibi ...
). Caplan's syndrome describes lung nodules in individuals with RA and additional exposure to coal
Coal is a combustible black or brownish-black sedimentary rock, formed as rock strata called coal seams. Coal is mostly carbon with variable amounts of other elements, chiefly hydrogen, sulfur, oxygen, and nitrogen.
Coal is formed when dea ...
dust. Exudative
An exudate is a fluid emitted by an organism through pores or a wound, a process known as exuding or exudation.
''Exudate'' is derived from ''exude'' 'to ooze' from Latin ''exsūdāre'' 'to (ooze out) sweat' (''ex-'' 'out' and ''sūdāre'' 'to ...
pleural effusion
A pleural effusion is accumulation of excessive fluid in the pleural space, the potential space that surrounds each lung.
Under normal conditions, pleural fluid is secreted by the parietal pleural capillaries at a rate of 0.6 millilitre per kilog ...
s are also associated with RA.
Heart and blood vessels
People with RA are more prone to atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
, and risk of myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
(heart attack) and stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
is markedly increased.
Other possible complications that may arise include: pericarditis
Pericarditis is inflammation of the pericardium, the fibrous sac surrounding the heart. Symptoms typically include sudden onset of sharp chest pain, which may also be felt in the shoulders, neck, or back. The pain is typically less severe when sit ...
, 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 the ...
, left ventricular failure, valvulitis and fibrosis
Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
. Many people with RA 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
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
caused by RA (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 people with RA 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.
Blood
Anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
is by far the most common abnormality of the blood cells which can be caused by a variety of mechanisms. The chronic inflammation caused by RA leads to raised hepcidin
Hepcidin is a protein that in humans is encoded by the ''HAMP'' gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals.
During conditions in which the hepcidin level is abnormally high, such as inflammation, se ...
levels, leading to anemia of chronic disease
Anemia of chronic disease (ACD) or anemia of chronic inflammation is a form of anemia seen in chronic infection, chronic immune activation, and malignancy. These conditions all produce elevation of interleukin-6, which stimulates hepcidin product ...
where iron is poorly absorbed and also sequestered into macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
. The red cells are of normal size and color (normocytic and normochromic). A low white blood cell count usually only occurs in people with Felty's syndrome Felty's syndrome (FS), also called Felty syndrome, is rare autoimmune disease characterized by the triad of rheumatoid arthritis, enlargement of the spleen and low neutrophil count. The condition is more common in those aged 50–70 years, specifi ...
with an enlarged liver and spleen. The mechanism of neutropenia is complex. An increased platelet count occurs when inflammation is uncontrolled.
Other
The role of the circadian clock in rheumatoid arthritis suggests a correlation between an early morning rise in circulating levels of pro-inflammatory cytokines, such as interleukin-6
Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene.
In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smooth ...
and painful morning joint stiffness.
Kidneys
Renal amyloidosis
Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight ...
can occur as a consequence of untreated chronic inflammation. Treatment with penicillamine
Penicillamine, sold under the brand name of Cuprimine among others, is a medication primarily used for the treatment of Wilson's disease. It is also used for people with kidney stones who have high urine cystine levels, rheumatoid arthritis, ...
or gold salts
Gold-containing drugs are pharmaceuticals that contain gold. Sometimes these species are referred to as "gold salts". "Chrysotherapy" and "aurotherapy" are the applications of gold compounds to medicine. Research on the medicinal effects of g ...
such as sodium aurothiomalate
Sodium aurothiomalate ( INN, known in the United States as gold sodium thiomalate) is a gold compound that is used for its immunosuppressive anti-rheumatic effects. Along with an orally-administered gold salt, auranofin, it is one of only two ...
are recognized causes of membranous nephropathy
Membranous glomerulonephritis (MGN) is a slowly progressive disease of the kidney affecting mostly people between ages of 30 and 50 years, usually white people (i.e., those of European, Middle Eastern, or North African ancestry.).
It is the seco ...
.
Eyes
The eye can be directly affected in the form of episcleritis
Episcleritis is a benign, self-limiting inflammatory disease affecting part of the eye called the episclera. The episclera is a thin layer of tissue that lies between the conjunctiva and the connective tissue layer that forms the white of the e ...
or scleritis
Scleritis is a serious inflammatory disease that affects the white outer coating of the eye, known as the sclera. The disease is often contracted through association with other diseases of the body, such as granulomatosis with polyangiitis or ...
, which when severe can very rarely progress to perforating scleromalacia. Rather more common is the indirect effect of keratoconjunctivitis sicca
Dry eye syndrome (DES), also known as keratoconjunctivitis sicca (KCS), is the condition of having dry eyes. Other associated symptoms include irritation, redness, discharge, and easily fatigued eyes. Blurred vision may also occur. Symptoms range ...
, which is a dryness of eyes and mouth caused by lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
infiltration of lacrimal and salivary gland
The salivary glands in mammals are exocrine glands that produce saliva through a system of ducts. Humans have three paired major salivary glands (parotid, submandibular, and sublingual), as well as hundreds of minor salivary glands. Salivary gla ...
s. When severe, dryness of the cornea can lead to keratitis
Keratitis is a condition in which the eye's cornea, the clear dome on the front surface of the eye, becomes inflamed. The condition is often marked by moderate to intense pain and usually involves any of the following symptoms: pain, impaired e ...
and loss of vision as well as being painful. Preventive treatment of severe dryness with measures such as nasolacrimal duct
The nasolacrimal duct (also called the tear duct) carries tears from the lacrimal sac of the eye into the nasal cavity. The duct begins in the eye socket between the maxillary and lacrimal bones, from where it passes downwards and backwards. The ...
blockage is important.
Liver
Liver problems in people with rheumatoid arthritis may be due to the underlying disease process or as a result of the medications used to treat the disease. A coexisting autoimmune liver disease, such as primary biliary cirrhosis
Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build ...
or autoimmune hepatitis
Autoimmune hepatitis, formerly known as lupoid hepatitis, plasma cell hepatitis, or autoimmune chronic active hepatitis, is a chronic, autoimmune disease of the liver that occurs when the body's immune system attacks liver cells, causing the liv ...
may also cause problems.
Neurological
Peripheral neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
and mononeuritis multiplex
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
may occur. The most common problem is carpal tunnel syndrome
Carpal tunnel syndrome (CTS) is the collection of symptoms and signs associated with median neuropathy at the carpal tunnel. Most CTS is related to idiopathic compression of the median nerve as it travels through the wrist at the carpal tunn ...
caused by compression of the median nerve by swelling around the wrist. Rheumatoid disease of the spine can lead to myelopathy
Myelopathy describes any neurologic deficit related to the spinal cord. The most common form of myelopathy in humans, ''Spinal cord compression, cervical spondylotic myelopathy (CSM)'', also called ''degenerative cervical myelopathy'', results fro ...
. Atlanto-axial subluxation
A subluxation is an incomplete or partial dislocation of a joint or organ.
According to the World Health Organization (WHO), a subluxation is a "significant structural displacement", and is therefore always visible on static imaging studies, suc ...
can occur, owing to erosion of the odontoid process
In anatomy, the axis (from Latin ''axis'', "axle") or epistropheus is the second cervical vertebra (C2) of the spine, immediately inferior to the atlas, upon which the head rests.
The axis' defining feature is its strong odontoid process (bon ...
and/or transverse ligament A transverse ligament is a ligament on a transverse plane, orthogonal to the anteroposterior or oral-aboral axiscan of the body.
In human anatomy, examples are:
* Flexor retinaculum of the hand or transverse carpal ligament (ligamentum carpi tra ...
s in the cervical spine
In tetrapods, cervical vertebrae (singular: vertebra) are the vertebrae of the neck, immediately below the skull. Truncal vertebrae (divided into thoracic and lumbar vertebrae in mammals) lie caudal (toward the tail) of cervical vertebrae. In sau ...
's connection to the skull. Such an erosion (>3mm) can give rise to vertebrae
The spinal column, a defining synapomorphy shared by nearly all vertebrates,Hagfish are believed to have secondarily lost their spinal column is a moderately flexible series of vertebrae (singular vertebra), each constituting a characteristic i ...
slipping over one another and compressing the spinal cord. Clumsiness is initially experienced, but without due care, this can progress to quadriplegia or even death.
Constitutional symptoms
Constitutional symptoms
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
including fatigue
Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
, low grade fever
Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...
, malaise
As a medical term, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. The word has existed in French since at least the 12th century.
The term is often used ...
, morning stiffness, loss of appetite
Anorexia is a medical term for a loss of appetite. While the term in non-scientific publications is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while others i ...
and loss of weight are common systemic manifestations seen in people with active RA.
Bones
Local osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
. More general osteoporosis is probably contributed to by immobility, systemic cytokine effects, local cytokine release in bone marrow and corticosteroid therapy.
Cancer
The incidence of lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...
is increased, although it is uncommon and associated with the chronic inflammation, not the treatment of RA. The risk of non-melanoma skin cancer
Skin cancers are cancers that arise from the skin. They are due to the development of abnormal cells that have the ability to invade or spread to other parts of the body. There are three main types of skin cancers: basal-cell skin cancer (BCC ...
is increased in people with RA compared to the general population, an association possibly due to the use of immunosuppression
Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...
agents for treating RA.
Teeth
Periodontitis
Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main cau ...
and tooth loss are common in people with rheumatoid arthritis.
Risk factors
RA is a systemic (whole body) autoimmune disease. Some genetic and environmental factors affect the risk for RA.
Genetic
Worldwide, RA affects approximately 1% of the adult population and occurs one in 1000 children. Studies show RA primarily affects individuals between the ages of 40–60 years and is seen more commonly in females. A family history of RA increases the risk around three to five times; as of 2016, it was estimated that genetics may account for between 40 and 65% of cases of seropositive RA, but only around 20% for seronegative RA.[ RA is strongly associated with genes of the inherited tissue type ]major histocompatibility complex
The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are calle ...
(MHC) antigen. HLA-DR4
HLA-DR4 (DR4) is an HLA- DR serotype that recognizes the DRB1*04 gene products. The DR4 serogroup is large and has a number of
moderate frequency alleles spread over large regions of the world.
Serology
The serological identification of DR4 is ...
is the major genetic factor implicated – the relative importance varies across ethnic groups.
Genome-wide association studies
In genomics, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an observational study of a genome-wide set of genetic variants in different individuals to see if any varian ...
examining single-nucleotide polymorphism
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently lar ...
s have found around one hundred alleles associated with RA risk. Risk alleles within the HLA (particularly HLA-DRB1
HLA class II histocompatibility antigen, DRB1 beta chain is a protein that in humans is encoded by the ''HLA-DRB1'' gene. DRB1 encodes the most prevalent beta subunit of HLA-DR. DRB1 alleles, especially those encoding amino acid sequence changes at ...
) genes harbor more risk than other loci. The HLA encodes proteins which controls recognition of self versus nonself molecules. Other risk loci include genes affecting co-stimulatory immune pathways, for example CD28
CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor ( TCR) can provid ...
and CD40
Cluster of differentiation 40, CD40 is a costimulatory protein found on antigen-presenting cells and is required for their activation. The binding of CD154 ( CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of d ...
, cytokine signaling, lymphocyte receptor activation threshold (e.g., PTPN22), and innate immune activation appear to have less influence than HLA mutations.
Environmental
There are established epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
and environmental risk factors for RA.[ ]Smoking
Smoking is a practice in which a substance is burned and the resulting smoke is typically breathed in to be tasted and absorbed into the bloodstream. Most commonly, the substance used is the dried leaves of the tobacco plant, which have bee ...
is an established risk factor for RA in Caucasian populations, increasing the risk three times compared to non-smokers, particularly in men, heavy smokers, and those who are rheumatoid factor positive.[ Modest alcohol consumption may be protective.
]Silica
Silicon dioxide, also known as silica, is an oxide of silicon with the chemical formula , most commonly found in nature as quartz and in various living organisms. In many parts of the world, silica is the major constituent of sand. Silica is one ...
exposure has been linked to RA.
Vitamin D deficiency
There are claims that patients that have lower vitamin D levels by 8-10 ng/mL are at risk for rheumatoid arthritis.
Negative findings
No infectious agent has been consistently linked with RA and there is no evidence of disease clustering to indicate its infectious cause, but periodontal disease
Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main caus ...
has been consistently associated with RA.[
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.
]
Pathophysiology
RA primarily starts as a state of persistent cellular activation leading to autoimmunity
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...
and immune complex
An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen of ...
es in joints and other organs where it manifests. The clinical manifestations of disease are primarily inflammation of the synovial membrane
The synovial membrane (also known as the synovial stratum, synovium or stratum synoviale) is a specialized connective tissue that lines the inner surface of capsules of synovial joints and tendon sheath. It makes direct contact with the fibrous ...
and joint damage, and the fibroblast-like synoviocytes play a key role in these pathogenic processes.[ Three phases of progression of RA are an initiation phase (due to non-specific inflammation), an amplification phase (due to ]T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
activation), and chronic inflammatory phase, with tissue injury resulting from the cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
, IL–1, TNF-alpha
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
, and IL–6.
Non-specific inflammation
Factors allowing an abnormal immune response, once initiated, become permanent and chronic. These factors are genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
s which change regulation of the adaptive immune response
The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
.[ Genetic factors interact with environmental risk factors for RA, with cigarette smoking as the most clearly defined risk factor.]
Other environmental and hormonal factors may explain higher risks for women, including onset after childbirth and hormonal medications. A possibility for increased susceptibility is that negative feedback mechanisms – which normally maintain tolerance – are overtaken by positive feedback mechanisms for certain antigens, such as IgG Fc bound by rheumatoid factor and citrullinated fibrinogen bound by antibodies to citrullinated peptides (ACPA – Anti–citrullinated protein antibody). A debate on the relative roles of B-cell produced immune complexes and T cell products in inflammation in RA has continued for 30 years, but neither cell is necessary at the site of inflammation, only autoantibodies to IgGFc, known as rheumatoid factors and ACPA, with ACPA having an 80% specificity for diagnosing RA. As with other autoimmune diseases, people with RA have abnormally glycosylated antibodies, which are believed to promote joint inflammation.
Amplification in the synovium
Once the generalized 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 activate macrophages through Fc receptor and complement binding, which is part of the intense inflammation in RA. Binding of an autoreactive antibody to the Fc receptors is mediated through the antibody's N-glycans, which are altered to promote inflammation in people with RA.
This contributes to local inflammation in a joint, specifically the synovium with edema
Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...
, vasodilation
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
and entry of activated T-cells, mainly CD4 in microscopically nodular aggregates and CD8 in microscopically diffuse infiltrates. Synovial macrophages and dendritic cell
Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...
s function as antigen-presenting cell
An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...
s by expressing MHC class II molecules, which establishes the immune reaction in the tissue.
Chronic inflammation
The disease progresses by forming granulation tissue at the edges of the synovial lining, pannus
Pannus is an abnormal layer of fibrovascular tissue or granulation tissue. Common sites for pannus formation include over the cornea, over a joint surface (as seen in rheumatoid arthritis), or on a prosthetic heart valve. Pannus may grow in a t ...
with extensive angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
and enzymes causing tissue damage. The fibroblast-like synoviocytes have a prominent role in these pathogenic processes.[ The synovium thickens, cartilage and underlying bone disintegrate, and the joint deteriorates, with raised ]calprotectin
Calprotectin is a multiprotein complex, complex of the mammalian proteins S100A8 and S100A9. Synonym, Other names for calprotectin include MRP8-MRP14, calgranulin A and B, cystic fibrosis antigen, L1, 60BB antigen, and 27E10 antigen. The proteins e ...
levels serving as a biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
of these events. Importantly inflammatory events are not limited to synovium but it appear to be systemic, evidence suggest that alterations in T helper profile favoring inflammation such as inflammatory IL-17A producing T helper cells and pathogenic Th17 cells are come from both memory and effector compartment in RA patients peripheral blood.
Cytokines and chemokines attract and accumulate immune cells, i.e. activated T- and B cells, monocytes and macrophages from activated fibroblast-like synoviocytes, in the joint space. By signalling through RANKL
Receptor activator of nuclear factor kappa- ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiati ...
and RANK
Rank is the relative position, value, worth, complexity, power, importance, authority, level, etc. of a person or object within a ranking, such as:
Level or position in a hierarchical organization
* Academic rank
* Diplomatic rank
* Hierarchy
* ...
, they eventually trigger osteoclast
An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pro ...
production, which degrades bone tissue. The fibroblast-like synoviocytes that are present in the synovium during rheumatoid arthritis display altered phenotype compared to the cells present in normal tissues. The aggressive phenotype of fibroblast-like synoviocytes in rheumatoid arthritis and the effect these cells have on the microenvironment of the joint can be summarized into hallmarks that distinguish them from healthy fibroblast-like synoviocytes. These hallmark features of fibroblast-like synoviocytes in rheumatoid arthritis are divided into 7 cell-intrinsic hallmarks and 4 cell-extrinsic hallmarks.[ The cell-intrinsic hallmarks are: reduced apoptosis, impaired contact inhibition, increased migratory invasive potential, changed epigenetic landscape, temporal and spatial heterogeneity, genomic instability and mutations, and reprogrammed cellular metabolism. The cell-extrinsic hallmarks of FLS in RA are: promotes osteoclastogenesis and bone erosion, contributes to cartilage degradation, induces synovial angiogenesis, and recruits and stimulates immune cells.][
]
Diagnosis
Imaging
X-ray
An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nb ...
s of the hands and feet are generally performed when many joints affected. In RA, there may be no changes in the early stages of the disease or the x-ray may show osteopenia
Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop osteop ...
near the joint, soft tissue swelling, and a smaller than normal joint space. As the disease advances, there may be bony erosions and subluxation. Other medical imaging techniques such as magnetic resonance imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...
(MRI) and ultrasound are also used in RA.
Technical advances in ultrasonography like high-frequency transducers (10 MHz or higher) have improved the spatial resolution of ultrasound images depicting 20% more erosions than conventional radiography. Color Doppler and power Doppler ultrasound are useful in assessing the degree of synovial inflammation as they can show vascular signals of active synovitis. This is important, since in the early stages of RA, 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, a physician may test for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs measured as anti-CCP antibodies).
The test is positive approximately two thirds of the time, but a negative RF or CCP antibody does not rule out RA, rather, the arthritis is called '' seronegative'', which occurs in approximately a third of people with RA. During the first year of illness, rheumatoid factor is more likely to be negative with some individuals becoming seropositive over time. RF is a non-specific antibody and seen in about 10% of healthy people, in many other chronic infections like hepatitis C
Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, a ...
, and chronic autoimmune diseases such as Sjögren's syndrome and systemic lupus erythematosus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
. Therefore, the test is not specific
Specific may refer to:
* Specificity (disambiguation)
* Specific, a cure or therapy for a specific illness
Law
* Specific deterrence, focussed on an individual
* Specific finding, intermediate verdict used by a jury in determining the fina ...
for RA.
Hence, new serological tests check for anti-citrullinated protein antibodies ACPAs. These tests are again positive in 61–75% of all RA cases, but with a specificity of around 95%. As with RF, ACPAs are many times present before symptoms have started.
The by far most common clinical test for ACPAs is the anti-cyclic citrullinated peptide
Cycle, cycles, or cyclic may refer to:
Anthropology and social sciences
* Cyclic history, a theory of history
* Cyclical theory, a theory of American political history associated with Arthur Schlesinger, Sr.
* Social cycle, various cycles in soc ...
(anti CCP) ELISA. In 2008 a serological point-of-care test
Point-of-care testing (POCT or bedside testing) is defined as medical diagnostic testing at or near the point of care—that is, at the time and place of patient care. This contrasts with the historical pattern in which testing was wholly or most ...
for the early detection of RA combined the detection of RF and anti-MCV with a sensitivity of 72% and specificity of 99.7%.
To improve the diagnostic capture rate in the early detection of patients with RA and to risk stratify these individuals, the rheumatology field continues to seek complementary markers to both RF and anti-CCP. 14-3-3η (YWHAH
14-3-3 protein eta also referred to as 14-3-3η is a protein that in humans is encoded by the ''YWHAH'' gene.
Function
This gene product belongs to the 14-3-3 family of proteins that are normally intracellular in nature and help to mediate si ...
) is one such marker that complements RF and anti-CCP, along with other serological measures like c-reactive protein
C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 ...
. In a systematic review, 14-3-3η has been described as a welcome addition to the rheumatology field. The authors indicate that the serum based 14-3-η marker is additive to the armamentarium of existing tools available to clinicians, and that there is adequate clinical evidence to support its clinical benefits.
Other blood tests are usually done to differentiate from other causes of arthritis, like the erythrocyte sedimentation rate
The erythrocyte sedimentation rate (ESR or sed rate) is the rate at which red blood cells in anticoagulated whole blood descend in a standardized tube over a period of one hour. It is a common hematology test, and is a non-specific measure of ...
(ESR), C-reactive protein
C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 ...
, full blood count
A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cells and plat ...
, kidney function
Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging.
Functions of a healthy kidney include maintaining a person's fluid ...
, liver enzyme
Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin tim ...
s and other immunological tests (e.g., antinuclear antibody/ANA) are all performed at this stage. Elevated ferritin
Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary ' ...
levels can reveal hemochromatosis
Iron overload or hemochromatosis (also spelled ''haemochromatosis'' in British English) indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatos ...
, a mimic of RA, or be a sign of Still's disease, a seronegative, usually juvenile, variant of rheumatoid arthritis.
Classification criteria
In 2010, the ''2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria'' were introduced.
The new criteria are not diagnostic criteria, but are classification criteria to identify disease with a high likelihood of developing a chronic form. However a score of 6 or greater unequivocally classifies a person with a diagnosis of rheumatoid arthritis.
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 The American College of Rheumatology (ACR; until 1985 called American Rheumatism Association) is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy ...
(ACR) and the European League Against Rheumatism
The European Alliance of Associations for Rheumatology (EULAR) formerly the European League Against Rheumatism is a European non-governmental organization which represents the people with arthritis/rheumatism, health professional and scientific so ...
(EULAR) establish a point value between 0 and 10. Four areas are covered in the diagnosis:[
* joint involvement, designating the ]metacarpophalangeal joint
The metacarpophalangeal joints (MCP) are situated between the metacarpal bones and the proximal phalanges of the fingers. These joints are of the condyloid kind, formed by the reception of the rounded heads of the metacarpal bones into shallow cav ...
s, proximal interphalangeal joint
The interphalangeal joints of the hand are the hinge joints between the phalanges of the fingers that provide flexion towards the palm of the hand.
There are two sets in each finger (except in the thumb, which has only one joint):
* "proximal in ...
s, the interphalangeal joint of the thumb, second through fifth metatarsophalangeal joint
The metatarsophalangeal joints (MTP joints), also informally known as toe knuckles, are the joints between the metatarsal bones of the foot and the proximal bones (proximal phalanges) of the toes. They are condyloid joints, meaning that an ellipt ...
and wrist
In human anatomy, the wrist is variously defined as (1) the Carpal bones, carpus or carpal bones, the complex of eight bones forming the proximal skeletal segment of the hand; "The wrist contains eight bones, roughly aligned in two rows, known ...
as ''small joints'', and shoulder
The human shoulder is made up of three bones: the clavicle (collarbone), the scapula (shoulder blade), and the humerus (upper arm bone) as well as associated muscles, ligaments and tendons. The articulations between the bones of the shoulder mak ...
s, elbow
The elbow is the region between the arm and the forearm that surrounds the elbow joint. The elbow includes prominent landmarks such as the olecranon, the cubital fossa (also called the chelidon, or the elbow pit), and the lateral and the media ...
s, hip joint
In vertebrate anatomy, hip (or "coxa"Latin ''coxa'' was used by Celsus in the sense "hip", but by Pliny the Elder in the sense "hip bone" (Diab, p 77) in medical terminology) refers to either an anatomical region or a joint.
The hip region is ...
s, knee
In humans and other primates, the knee joins the thigh with the leg and consists of two joints: one between the femur and tibia (tibiofemoral joint), and one between the femur and patella (patellofemoral joint). It is the largest joint in the hu ...
s, and ankle
The ankle, or the talocrural region, or the jumping bone (informal) is the area where the foot and the leg meet. The ankle includes three joints: the ankle joint proper or talocrural joint, the subtalar joint, and the inferior tibiofibular join ...
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 of 4–10 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 as well as ACPA – "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, or elevated CRP value (c-reactive protein)
* duration of arthritis
Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
: 1 point for symptoms lasting six weeks or longer
The new criteria accommodate to the growing understanding of RA and the improvements in diagnosing RA and disease treatment. In the "new" criteria, serology and autoimmune diagnostics 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.
Differential diagnoses
Several other medical conditions can resemble RA, and need to be distinguished from it at the time of diagnosis:
* Crystal induced arthritis (gout
Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intensit ...
, and pseudogout
Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, also known as pseudogout and pyrophosphate arthropathy, is a rheumatologic disease which is thought to be secondary to abnormal accumulation of calcium pyrophosphate dihydrate crys ...
) – usually involves particular joints (knee, MTP1, heels) and can be distinguished with an aspiration of joint fluid if in doubt. Redness, asymmetric distribution of affected joints, pain occurs at night and the starting pain is less than an hour with gout.
* Osteoarthritis
Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...
– distinguished with X-ray
An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nb ...
s of the affected joints and blood tests, older age, starting pain less than an hour, asymmetric distribution of affected joints and pain worsens when using joint for longer periods.
* Systemic lupus erythematosus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
(SLE) – distinguished by specific clinical symptoms and blood tests (antibodies against double-stranded DNA)
* One of the several types of psoriatic arthritis
Psoriatic arthritis is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. Thi ...
resembles RA – nail changes and skin symptoms distinguish between them
* Lyme disease
Lyme disease, also known as Lyme borreliosis, is a vector-borne disease caused by the ''Borrelia'' bacterium, which is spread by ticks in the genus ''Ixodes''. The most common sign of infection is an expanding red rash, known as erythema migran ...
causes erosive arthritis and may closely resemble RA – it may be distinguished by blood test in endemic areas
* Reactive arthritis
Reactive arthritis, also known as Reiter's syndrome, is a form of inflammatory arthritis that develops in response to an infection in another part of the body (cross-reactivity). Coming into contact with bacteria and developing an infection can ...
– asymmetrically involves heel, sacroiliac
The sacroiliac joint or SI joint (SIJ) is the joint between the sacrum and the ilium bones of the pelvis, which are connected by strong ligaments. In humans, the sacrum supports the spine and is supported in turn by an ilium on each side. The ...
joints and large joints of the leg. It is usually associated with urethritis
Urethritis is the inflammation of the urethra. The most common symptoms include painful or difficult urination and urethral discharge. It is a commonly treatable condition usually caused by infection with bacteria. This bacterial infection is oft ...
, conjunctivitis
Conjunctivitis, also known as pink eye, is inflammation of the conjunctiva, outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may ...
, iritis
Uveitis () is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and ...
, painless buccal ulcers, and keratoderma blennorrhagica.
* Axial spondyloarthritis
Axial spondyloarthritis (also often referred to as axSpA) is a chronic, autoinflammatory disease predominantly affecting the axial skeleton (sacroiliac joints and spine). The best-known member of the axial spondyloarthritis disease family is ankyl ...
(including ankylosing spondylitis
Ankylosing spondylitis (AS) is a type of arthritis characterized by long-term inflammation of the joints of the spine typically where the spine joins the pelvis. Occasionally areas affected may include other joints such as the shoulders or hip ...
) – this involves the spine, although an RA-like symmetrical small-joint polyarthritis may occur in the context of this condition.
* Hepatitis C
Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, a ...
– 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 which usually behave differently but may cause joint pains:[
* ]Sarcoidosis
Sarcoidosis (also known as ''Besnier-Boeck-Schaumann disease'') is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph nodes. Less commonly af ...
, amyloidosis
Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight ...
, and 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 as a gastrointestinal disorder, Whipple's disease primarily causes m ...
can also resemble RA.
* Hemochromatosis
Iron overload or hemochromatosis (also spelled ''haemochromatosis'' in British English) indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatos ...
may cause hand joint arthritis.
* Acute rheumatic fever can be differentiated by a migratory pattern of joint involvement and evidence of antecedent streptococcal
''Streptococcus'' is a genus of gram-positive ' (plural ) or spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales (lactic acid bacteria), in the phylum Bacillota. Cell division in streptococci occur ...
infection.
* Bacterial arthritis (such as by ''Streptococcus
''Streptococcus'' is a genus of gram-positive ' (plural ) or spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales (lactic acid bacteria), in the phylum Bacillota. Cell division in streptococci occurs ...
'') is usually asymmetric, while RA usually involves both sides of the body symmetrically.
* Gonococcal arthritis (a bacterial arthritis) is also initially migratory and can involve tendon
A tendon or sinew is a tough, high-tensile-strength band of dense fibrous connective tissue that connects muscle to bone. It is able to transmit the mechanical forces of muscle contraction to the skeletal system without sacrificing its ability ...
s around the wrists and ankles.
Sometimes arthritis is in an undifferentiated stage (i.e. none of the above criteria is positive), even if synovitis is witnessed and assessed with ultrasound imaging.
Difficult-to-treat
Rheumatoid arthritis (D2T RA) is a specific classification RA by the European League against Rheumatism ( EULAR).
Signs of illness:
# Persistence of signs and symptoms
# Drug resistance
Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, ...
# Does not respond on two or more biological treatments
# Does not respond on anti-rheumatic drugs with different mechanism of action
Factors contributing to difficult-to-treat disease:
# Genetic risk factors
# Environmental factors (diet, smoking, physical activity)
# Overweight and obese
Genetic factors
Genetic factors such as HLA-DR1B1, TRAF1
TNF receptor-associated factor 1 is a protein that in humans is encoded by the ''TRAF1'' gene.
Function
The protein encoded by this gene is a member of the TNF receptor (TNFR) associated factor (TRAF) protein family. TRAF proteins associate wit ...
, PSORS1C1 and microRNA
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...
146a are associated with difficult to treat rheumatoid arthritis, other gene polymorphisms seem to be correlated with response to biologic modifying anti-rheumatic drugs (bDMARDs). Next one is FOXO3A gene region been reported as associated with worst disorder. The minor allele at FOXO3A summon a differential response of monocytes in RA patients. FOXO3A can provide an increase of pro-inflammatory cytokines, including TNFα. Possible gene polymorphism: STAT4, PTPN2, PSORS1C1 and TRAF3IP2 genes had been correlated with response to TNF inhibitors.
HLA-DR1 and HLA-DRB1 gene
The ''HLA''-''DRB1'' gene is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex is the human version of the major histocompatibility complex (MHC). Currently, have been identified at least 2479 different versions of the ''HLA''-''DRB1'' gene. The presence of HLA-DRB1 alleles seems to predict radiographic damage, which may be partially mediated by ACPA development, and also elevated sera inflammatory levels and high swollen joint count. HLA-DR1 is encoded by the most risk allele HLA-DRB1
HLA class II histocompatibility antigen, DRB1 beta chain is a protein that in humans is encoded by the ''HLA-DRB1'' gene. DRB1 encodes the most prevalent beta subunit of HLA-DR. DRB1 alleles, especially those encoding amino acid sequence changes at ...
which share a conserved 5-aminoacid sequence that is correlated with the development of anti-citrullinated protein antibodies. HLA-DRB1 gene have more strong correlation with disease development. Susceptibility to and outcome for rheumatoid arthritis (RA) may associate with particular HLA-DR alleles, but these alleles vary among ethnic groups and geographic areas.
MicroRNAs
MicroRNAs are a factor in the development of that type of disease. MicroRNAs usually operate as a negative regulator of the expression of target proteins and their increased concentration after biologic treatment (bDMARDs) or after anti-rheumatic drugs. Level of miRNA before and after anti-TNFa/DMRADs combination therapy are potential novel biomarkers for predicting and monitoring outcome. For instance, some of them were found significantly upregulated by anti-TNFa/DMRADs combination therapy. For example, miRNA-16-5p, miRNA-23-3p, miRNA125b-5p, miRNA-126-3p, miRNA-146a-5p, miRNA-223-3p. Curious fact is that only responder patients showed an increase in those miRNAs after therapy, and paralleled the reduction of TNFα, interleukin (IL)-6, IL-17, rheumatoid factor (RF), and C-reactive protein (CRP).
Monitoring progression
Many tools can be used to monitor remission in rheumatoid arthritis.
* DAS28: ''Disease Activity Score of 28 joints'' () is widely used as an indicator of RA disease activity and response to treatment. Joints included are ( bilaterally): proximal interphalangeal joint
The interphalangeal joints of the hand are the hinge joints between the phalanges of the fingers that provide flexion towards the palm of the hand.
There are two sets in each finger (except in the thumb, which has only one joint):
* "proximal in ...
s (10 joints), metacarpophalangeal joint
The metacarpophalangeal joints (MCP) are situated between the metacarpal bones and the proximal phalanges of the fingers. These joints are of the condyloid kind, formed by the reception of the rounded heads of the metacarpal bones into shallow cav ...
s (10), wrist
In human anatomy, the wrist is variously defined as (1) the Carpal bones, carpus or carpal bones, the complex of eight bones forming the proximal skeletal segment of the hand; "The wrist contains eight bones, roughly aligned in two rows, known ...
s (2), elbow
The elbow is the region between the arm and the forearm that surrounds the elbow joint. The elbow includes prominent landmarks such as the olecranon, the cubital fossa (also called the chelidon, or the elbow pit), and the lateral and the media ...
s (2), shoulder
The human shoulder is made up of three bones: the clavicle (collarbone), the scapula (shoulder blade), and the humerus (upper arm bone) as well as associated muscles, ligaments and tendons. The articulations between the bones of the shoulder mak ...
s (2) and knee
In humans and other primates, the knee joins the thigh with the leg and consists of two joints: one between the femur and tibia (tibiofemoral joint), and one between the femur and patella (patellofemoral joint). It is the largest joint in the hu ...
s (2). When looking at these joints, both the number of joints with tenderness upon touching (TEN28) and swelling (SW28) are counted. The erythrocyte sedimentation rate
The erythrocyte sedimentation rate (ESR or sed rate) is the rate at which red blood cells in anticoagulated whole blood descend in a standardized tube over a period of one hour. It is a common hematology test, and is a non-specific measure of ...
(ESR) is measured and the affected person 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 affected person can be classified as follows:]
It is not always a reliable indicator of treatment effect. One major limitation is that low-grade synovitis may be missed.
* Other: Other tools to monitor remission in rheumatoid arthritis are: ACR-EULAR Provisional Definition of Remission of Rheumatoid arthritis, Simplified Disease Activity Index and Clinical Disease Activity Index. Some scores do not require input from a healthcare professional and allow self-monitoring by the person, like HAQ-DI.
Prevention
There is no known prevention for the condition other than the reduction of risk factors.
Supplementation
Evidence suggests that increasing vitamin D levels to the range of 40–60 ng/mL could reduce the risk of rheumatoid arthritis.
Management
There is no cure for RA, but treatments can improve symptoms and slow the progress of the disease. Disease-modifying treatment has the best results when it is started early and aggressively. The results of a recent systematic review found that combination therapy with tumor necrosis factor (TNF) and non-TNF biologics plus methotrexate (MTX) resulted in improved disease control, Disease Activity Score (DAS)-defined remission, and functional capacity compared with a single treatment of either methotrexate or a biologic alone.
The goals of treatment are to minimize symptoms such as pain and swelling, to prevent bone deformity (for example, bone erosions visible in X-rays), and to maintain day-to-day functioning. This is primarily addressed with disease-modifying antirheumatic drugs
Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroidal ...
(DMARDs); dosed physical activity; analgesics and physical therapy
Physical therapy (PT), also known as physiotherapy, is one of the allied health professions. It is provided by physical therapists who promote, maintain, or restore health through physical examination, diagnosis, management, prognosis, patient ...
may be used to help manage pain. RA should generally be treated with at least one specific anti-rheumatic medication.[ The use of benzodiazepines (such as ]diazepam
Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, a ...
) to treat the pain is not recommended as it does not appear to help and is associated with risks.
Lifestyle
Regular exercise is recommended as both safe and useful to maintain muscle strength and overall physical function. Physical activity is beneficial for people with rheumatoid arthritis who experience fatigue, although there was little to no evidence to suggest that exercise may have an impact on physical function in the long term, a study found that carefully dosed exercise has shown significant improvements in patients with RA. Moderate effects have been found for aerobic exercises and resistance training on cardiovascular fitness and muscle strength in RA. Furthermore, physical activity had no detrimental side effects like increased disease activity in any exercise dimension. It is uncertain if eating or avoiding specific foods or other specific dietary measures help improve symptoms. Occupational therapy
Occupational therapy (OT) is a global healthcare profession. It involves the use of assessment and intervention to develop, recover, or maintain the meaningful activities, or ''occupations'', of individuals, groups, or communities. The field of ...
has a positive role to play in improving functional ability in people with rheumatoid arthritis. Weak evidence supports the use of wax baths (thermotherapy
Heat therapy, also called thermotherapy, is the use of heat in therapy, such as for pain relief and health. It can take the form of a hot cloth, hot water bottle, ultrasound, heating pad, hydrocollator packs, whirlpool baths, cordless FIR h ...
) to treat arthritis in the hands.
Educational approaches that inform people about tools and strategies available to help them cope with rheumatoid arthritis may improve a person's psychological status and level of depression in the shorter-term. The use of extra-depth shoes and molded insoles may reduce pain during weight-bearing activities such as walking. Insoles may also prevent the progression of bunion
A bunion, also known as hallux valgus, is a deformity of the joint connecting the big toe to the foot. The big toe often bends towards the other toes and the joint becomes red and painful. The onset of bunions is typically gradual. Complicatio ...
s.
Disease-modifying agents
Disease-modifying antirheumatic drugs
Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroidal ...
(DMARDs) are the primary treatment for RA.[ They are a diverse collection of drugs, grouped by use and convention. They have been found to improve symptoms, decrease joint damage, and improve overall functional abilities.][ DMARDs should be started early in the disease as they result in disease remission in approximately half of people and improved outcomes overall.][
The following drugs are considered DMARDs: ]methotrexate
Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
, sulfasalazine
Sulfasalazine, sold under the brand name Azulfidine among others, is a medication used to treat rheumatoid arthritis, ulcerative colitis, and Crohn's disease. It is considered by some to be a first-line treatment in rheumatoid arthritis. It is ...
, leflunomide
Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug ( DMARD), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibi ...
, hydroxychloroquine
Hydroxychloroquine, sold under the brand name Plaquenil among others, is a medication used to prevent and treat malaria in areas where malaria remains sensitive to chloroquine. Other uses include treatment of rheumatoid arthritis, lupus, an ...
, TNF inhibitor
A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ...
s ( certolizumab, adalimumab
Adalimumab, sold under the brand name Humira, among others, is a monoclonal antibody used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurati ...
, infliximab
Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spon ...
and etanercept
Etanercept, sold under the brand name Enbrel among others, is a biologic medical product that is used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF), a soluble inflammatory cytokine, by acting as a TNF inhibitor. It ...
), abatacept
Abatacept, sold under the brand name Orencia, is a medication used to treat autoimmune diseases like rheumatoid arthritis, by interfering with the immune activity of T cells. It is a modified antibody.
Abatacept is a fusion protein composed of ...
, and anakinra
Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. It is a recombinant and slightly modifi ...
. Additionally, rituximab
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in non-geriatric p ...
and tocilizumab
Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, a severe form of arthritis in children, and COVID19. It is a huma ...
are monoclonal antibodies and are also DMARDs.[ Use of tocilizumab is associated with a risk of increased cholesterol levels.
The most commonly used agent is methotrexate with other frequently used agents including sulfasalazine and leflunomide.][ Leflunomide is effective when used from 6–12 months, with similar effectiveness to methotrexate when used for 2 years. Sulfasalazine also appears to be most effective in the short-term treatment of rheumatoid arthritis.
]Hydroxychloroquine
Hydroxychloroquine, sold under the brand name Plaquenil among others, is a medication used to prevent and treat malaria in areas where malaria remains sensitive to chloroquine. Other uses include treatment of rheumatoid arthritis, lupus, an ...
, in addition to its low toxicity profile, is considered effective for treatment of moderate RA treatment.
Agents may be used in combination, however, people may experience greater side effects.[ Methotrexate is the most important and useful DMARD and is usually the first treatment.][DiPiro, Joseph T., Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, and L. Michael Posey (2008) ''Pharmacotherapy: a pathophysiologic approach''. 7th ed. New York: McGraw-Hill, .] A combined approach with methotrexate and biologics improves ACR50, HAQ scores and RA remission rates. Triple therapy consisting of methotrexate, sulfasalazine and hydroxychloroquine may also effectively control disease activity. Adverse effects should be monitored regularly with toxicity including gastrointestinal, hematologic, pulmonary, and hepatic. Side effects such as nausea, vomiting or abdominal pain can be reduced by taking folic acid.
A 2015 Cochrane review found rituximab with methotrexate to be effective in improving symptoms compared to methotrexate alone. Rituximab works by decreasing levels of B-cells (immune cell that is involved in inflammation). People taking rituximab had improved pain, function, reduced disease activity and reduced joint damage based on x-ray images. After 6 months, 21% more people had improvement in their symptoms using rituximab and methotrexate.
Biological agents should generally be used only if methotrexate and other conventional agents are not effective after a trial of three months.[ They are associated with a higher rate of serious infections as compared to other DMARDs. Biological DMARD agents used to treat rheumatoid arthritis include: ]tumor necrosis factor alpha
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
inhibitors (TNF inhibitors) such as infliximab
Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spon ...
; interleukin 1
The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.
Discovery
Discovery of these cytokines began with studies on t ...
blockers such as anakinra
Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. It is a recombinant and slightly modifi ...
, monoclonal antibodies
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ca ...
against B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s such as rituximab
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in non-geriatric p ...
, interleukin 6
Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene.
In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smooth ...
blockers such as tocilizumab, and T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
co-stimulation blockers such as abatacept. They are often used in combination with either methotrexate or leflunomide.[ Biologic monotherapy or ]tofacitinib
Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.
Common side effects include diarrhea, headache, and high blood pressure. Serious side eff ...
with methotrexate may improve ACR50, RA remission rates and function. Abatacept should not be used at the same time as other biologics. In those who are well controlled (low disease activity) on TNF inhibitors, decreasing the dose does not appear to affect overall function. Discontinuation of TNF inhibitors (as opposed to gradually lowering the dose) by people with low disease activity may lead to increased disease activity and may affect remission, damage that is visible on an x-ray, and a person's function. People should be screened for latent tuberculosis
Latent tuberculosis (LTB), also called latent tuberculosis infection (LTBI) is when a person is infected with ''Mycobacterium tuberculosis'', but does not have active tuberculosis. Active tuberculosis can be contagious while latent tuberculosis is ...
before starting any TNF inhibitor
A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ...
therapy to avoid reactivation of tuberculosis.
TNF inhibitors and methotrexate appear to have similar effectiveness when used alone and better results are obtained when used together. Golimumab
Golimumab is a human monoclonal antibody which is used as an immunosuppressive medication and sold under the brand name Simponi. Golimumab targets tumor necrosis factor alpha (TNF-alpha), a pro-inflammatory molecule and hence is a TNF inhibitor. ...
is effective when used with methotraxate. TNF inhibitors may have equivalent effectiveness with etanercept
Etanercept, sold under the brand name Enbrel among others, is a biologic medical product that is used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF), a soluble inflammatory cytokine, by acting as a TNF inhibitor. It ...
appearing to be the safest. Injecting etanercept, in addition to methotrexate twice a week may improve ACR50 and decrease radiographic progression for up to 3 years. Abatacept appears effective for RA with 20% more people improving with treatment than without but long term safety studies are yet unavailable. Adalimumab
Adalimumab, sold under the brand name Humira, among others, is a monoclonal antibody used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurati ...
slows the time for the radiographic progression when used for 52 weeks. However, there is a lack of evidence to distinguish between the biologics available for RA. Issues with the biologics include their high cost and association with infections including tuberculosis
Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in ...
.[ Use of biological agents may reduce fatigue.] The mechanism of how biologics reduce fatigue is unclear.
Gold (sodium aurothiomalate) and cyclosporin
Sodium aurothiomalate
Sodium aurothiomalate ( INN, known in the United States as gold sodium thiomalate) is a gold compound that is used for its immunosuppressive anti-rheumatic effects. Along with an orally-administered gold salt, auranofin, it is one of only two ...
(gold) and cyclosporin
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disea ...
are less commonly used due to more common adverse effects.[ However, cyclosporin was found to be effective in the progressive RA when used up to one year.
]
Anti-inflammatory and analgesic agents
Glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...
s can be used in the short term and at the lowest dose possible for flare-ups and while waiting for slow-onset drugs to take effect.[ Combination of glucocorticoids and conventional therapy has shown a decrease in rate of erosion of bones. Steroids may be injected into affected joints during the initial period of RA, prior to the use of DMARDs or oral steroids.]
Non-NSAID
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
drugs to relieve pain, like paracetamol
Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol.
At a standard dose, paracetamol only slightly decreases body temperature; it is inferior ...
may be used to help relieve the pain symptoms; they do not change the underlying disease.[ The use of paracetamol may be associated with the risk of developing ulcers.]
NSAIDs reduce both pain and stiffness in those with RA but do not affect the underlying disease and appear to have no effect on people's long term disease course and thus are no longer first line agents.[ NSAIDs should be used with caution in those with ]gastrointestinal
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
, cardiovascular
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
, or kidney problems. Rofecoxib was withdrawn from the global market as its long-term use was associated to an increased risk of heart attacks and strokes. Use of methotrexate together with NSAIDs is safe, if adequate monitoring is done. COX-2 inhibitor
COX-2 inhibitors are a type of nonsteroidal anti-inflammatory drug (NSAID) that directly targets cyclooxygenase-2, COX-2, an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration and i ...
s, such as celecoxib
Celecoxib, sold under the brand name Celebrex among others, is a COX-2 inhibitor and nonsteroidal anti-inflammatory drug (NSAID). It is used to treat the pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis, ankyl ...
, and NSAIDs are equally effective. A 2004 Cochrane review found that people preferred NSAIDs over paracetamol. However, it is yet to be clinically determined whether NSAIDs are more effective than paracetamol.
The neuromodulator agents topical capsaicin
Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burning ...
may be reasonable to use in an attempt to reduce pain.[ ]Nefopam
Nefopam, sold under the brand name Acupan among others, is a centrally acting, non-opioid painkilling medication, that is primarily used to treat moderate to severe pain.
Nefopam acts in the brain and spinal cord to relieve pain via novel mecha ...
by mouth and cannabis
''Cannabis'' () is a genus of flowering plants in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized: ''Cannabis sativa'', '' C. indica'', and '' C. ruderalis''. Alternatively ...
are not recommended as of 2012 as the risks of use appear to be greater than the benefits.
Limited evidence suggests the use of weak oral opioids but the adverse effects may outweigh the benefits.
Alternatively, physical therapy has been tested and shown as an effective aid in reducing pain in patients with RA. As most RA is detected early and treated aggressively, physical therapy plays more of a preventative and compensatory role, aiding in pain management alongside regular rheumatic therapy.
Surgery
Especially for affected fingers, hands, and wrists, synovectomy
Synovectomy is a procedure where the synovial tissue surrounding a joint is removed. This procedure is typically recommended to provide relief from a condition in which the synovial membrane or the joint lining becomes inflamed and irritated and i ...
may be needed to prevent pain or tendon rupture when drug treatment has failed. Severely affected joints may require 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 an arthritic or dysfunctional ...
surgery, such as knee replacement. Postoperatively, physiotherapy
Physical therapy (PT), also known as physiotherapy, is one of the allied health professions. It is provided by physical therapists who promote, maintain, or restore health through physical examination, diagnosis, management, prognosis, patient ...
is always necessary.[ There is insufficient evidence to support surgical treatment on arthritic shoulders.
]
Physiotherapy
For people with RA, physiotherapy
Physical therapy (PT), also known as physiotherapy, is one of the allied health professions. It is provided by physical therapists who promote, maintain, or restore health through physical examination, diagnosis, management, prognosis, patient ...
may be used together with medical management.[ This may include cold and ]heat
In thermodynamics, heat is defined as the form of energy crossing the boundary of a thermodynamic system by virtue of a temperature difference across the boundary. A thermodynamic system does not ''contain'' heat. Nevertheless, the term is al ...
application, electronic stimulation, and hydrotherapy
Hydrotherapy, formerly called hydropathy and also called water cure, is a branch of alternative medicine (particularly naturopathy), occupational therapy, and physiotherapy, that involves the use of water for pain relief and treatment. The term ...
. Although medications improve symptoms of RA, muscle function is not regained when disease activity is controlled.
Physiotherapy promotes physical activity. In RA, physical activity like exercise in the appropriate dosage (frequency, intensity, time, type, volume, progression) and physical activity promotion is effective in improving cardiovascular fitness, muscle strength, and maintaining a long term active lifestyle. In the short term, resistance exercises, with or without range of motion exercises, improve self-reported hand functions. Physical activity promotion according to the public health recommendations should be an integral part of standard care for people with RA and other arthritic diseases. Additionally, the combination of physical activities and cryotherapy
Cryotherapy, sometimes known as cold therapy, is the local or general use of low temperatures in medical therapy. Cryotherapy may be used to treat a variety of tissue lesions. The most prominent use of the term refers to the surgical treatment, s ...
show its efficacy on the disease activity and pain relief. The combination of aerobic activity and cryotherapy
Cryotherapy, sometimes known as cold therapy, is the local or general use of low temperatures in medical therapy. Cryotherapy may be used to treat a variety of tissue lesions. The most prominent use of the term refers to the surgical treatment, s ...
may be an innovative therapeutic strategy to improve the aerobic capacity in arthritis patients and consequently reduce their cardiovascular risk while minimizing pain and disease activity.
Compression gloves
Compression gloves are handwear designed to help prevent the occurrence of various medical disorders relating to blood circulation in the wrists and hands. They can be used to treat the symptoms of arthritis
Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
, though the medical benefits may be limited.
Alternative medicine
In general, there is not enough evidence to support any complementary health approaches for RA, with safety concerns for some of them. Some mind and body practices and dietary supplements may help people with symptoms and therefore may be beneficial additions to conventional treatments, but there is not enough evidence to draw conclusions. A systematic review
A systematic review is a Literature review, scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from publ ...
of CAM
Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bin ...
modalities (excluding fish oil) found that " The available evidence does not support their current use in the management of RA.". Studies showing beneficial effects in RA on a wide variety of CAM modalities are often affected by publication bias
In published academic research, publication bias occurs when the outcome of an experiment or research study biases the decision to publish or otherwise distribute it. Publishing only results that show a significant finding disturbs the balance o ...
and are generally not high quality evidence such as randomized controlled trial
A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...
s (RCTs).
A 2005 Cochrane review states that low level laser therapy
Low-level laser therapy (LLLT), cold laser therapy, or photobiomodulation (PBM) is a form of medicine that applies low-level (low-power) lasers or light-emitting diodes (LEDs) to the surface of the body. Whereas high-power lasers are used in la ...
can be tried to improve pain and morning stiffness due to rheumatoid arthritis as there are few side-effects.
There is limited evidence that Tai Chi
Tai chi (), short for Tai chi ch'üan ( zh, s=太极拳, t=太極拳, first=t, p=Tàijíquán, labels=no), sometimes called "shadowboxing", is an neijia, internal Chinese martial art practiced for defense training, health benefits and medita ...
might improve the range of motion of a joint in persons with rheumatoid arthritis. The evidence for acupuncture is inconclusive with it appearing to be equivalent to sham acupuncture.
A Cochrane review in 2002 showed some benefits of the electrical stimulation as a rehabilitation intervention to improve the power of the hand grip and help to resist fatigue. D‐penicillamine may provide similar benefits as DMARDs but it is also highly toxic. Low-quality evidence suggests the use of therapeutic ultrasound on arthritic hands. Potential benefits include increased grip strength, reduced morning stiffness and number of swollen joints. There is tentative evidence of benefit of transcutaneous electrical nerve stimulation
Transcutaneous electrical nerve stimulation (TENS or TNS) is the use of electric current produced by a device to stimulate the nerves for therapeutic purposes. TENS, by definition, covers the complete range of transcutaneously applied currents ...
(TENS) in RA. Acupuncture‐like TENS (AL-TENS) may decrease pain intensity and improve muscle power scores.
Low-quality evidence suggests people with active RA may benefit from assistive technology. This may include less discomfort and difficulty such as when using an eye drop device. Balance training is of unclear benefits.
Dietary supplements
Fatty acids
There has been a growing interest in the role of long-chain omega-3 polyunsaturated fatty acids to reduce inflammation and alleviate the symptoms of RA. Metabolism of omega-3 polyunsaturated fatty acids produces docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which inhibits pro-inflammatory eicosanoids and cytokines (TNF-a, IL-1b and IL-6), decreasing both lymphocyte proliferation and reactive oxygen species. These studies showed evidence for significant clinical improvements on RA in inflammatory status and articular index. Gamma-linolenic acid, an omega-6 fatty acid, may reduce pain, tender joint count and stiffness, and is generally safe. For omega-3 polyunsaturated fatty acids (found in fish oil, flax oil and hemp oil), a meta-analysis reported a favorable effect on pain, although confidence in the effect was considered moderate. The same review reported less inflammation but no difference in joint function. A review examined the effect of marine oil omega-3 fatty acids on pro-inflammatory eicosanoid concentrations; leukotriene4 (LTB4) was lowered in people with rheumatoid arthritis but not in those with non-autoimmune chronic diseases. (LTB4) increases vascular permeabiltity and stimulates other inflammatory substances. A third meta-analysis looked at fish consumption. The result was a weak, non-statistically significant inverse association between fish consumption and RA. A fourth review limited inclusion to trials in which people eat ≥2.7 g/day for more than three months. Use of pain relief medication was decreased, but improvements in tender or swollen joints, morning stiffness and physical function were not changed. Collectively, the current evidence is not strong enough to determine that supplementation with omega-3 fatty acids or regular consumption of fish are effective treatments for rheumatoid arthritis.
Diets
Patients with RA often claim that their symptoms are alleviated by special diets or by simple elimination of certain foods. In contrast, some foods might provoke hypersensitivity responses, which may increase symptoms of RA.
The Dong diet has been suggested for a benefit in RA. This diet is rich in oils, seafood, vegetables, and rice which improve symptoms of RA. It eliminates citrus fruits, chocolate, dairy produce, flour products, alcohol, additives, spices, fizzy drinks, and red meat which are implicated in the aggravation of symptoms.
The Mediterranean diet is a well‐balanced, nutritionally adequate diet that encompasses all the food groups. This diet is rich in fresh fruits and vegetables, whole grains, seafood, nuts and legumes, and olive oil. In contrast, it limits red meat, sugary foods, and dairy, in small portions of yogurt and cheese. The foods in this category parallel the Dong Diet closely and show evidence of overlap. There is beneficial effect in using a Mediterranean diet and Dong diet for a reduction in the number of tender joints, stiffness, and pain.
Vitamins
Adequate Vitamin concentrations may provide an important defence against the increased oxidant stress in patients with RA. Here we look at the effects of vitamins E, C and B on the management of RA.
In general vitamin E deficiency enhances components of the inflammatory response and suppresses components of the immune response. Molecular studies have demonstrated that the formation of the pro-inflammatory prostaglandin E2 is inhibited 95% by aspirin when combined with vitamin E compared to control. This suggests that vitamin E supplementation reduces the need for high dosage of aspirin needed by patients with RA to relieve joint symptoms. This can offer double benefits because lowering the dose of aspirin can also reduce the gastric irritation side effect for patients. Even though there is no evidence of only taking vitamin E supplementation alone, I believe patients with RA should be encouraged to increase their consumption of vitamin E rich cereals, fruit, and vegetables.
Vitamin C is necessary for the growth and development of all body tissues and plays an important role in antioxidant defences. In animal studies biochemical markers of antioxidant defence mechanisms were increased with vitamin C supplementation and infiltration of inflammatory cells into synovial fluid were decreased. From these studies I can conclude that vitamin C supplementation may be more effective for the pain associated with RA however long-term use might aggravate onset of osteoarthritis.
Vitamin B6 and B9 play a role in RA management as well. Studies have shown that low plasma levels of pyridoxal-5-phosphate, the metabolically active form of vitamin B6, have been reported in RA patients, which may be associated with the elevated TNF-a production. Folate supplies are also decreased in RA patients who are taking Methotrexate, an anti-rheumatic drug. We see that folate supplementation can reduce the mucosal and gastrointestinal side effects of low dose Methotrexate in patients with RA. This works in a similar pattern to aspirin and vitamin E supplementation. Therefore, RA patients should be advised to consume dietary sources of vitamin B6 and B9 up to the dietary reference value, until further research is undertaken into the toxicity and effectiveness of large dose supplementation.
Food containing high source of vitamin E to help treat Rheumatoid Arthritis include almonds, avocados, spinach, sunflower seeds and peanut butter. Vitamin C foods include oranges, orange juice, strawberry, broccoli, brussel sprouts and potatoes. Brown rice, barley, and fish contain sources of vitamin B6 and B9. Lastly, Vitamin D can be included in the diet by incorporating tuna, salmon, orange juice and almond Milk into diet.
Minerals
Minerals including fluoride, iron, calcium, and zinc have been studied in the role of RA management. The effects of fluoride supplementation in preventing RA-induced bone loss were examined in a randomized control trial. Results suggest that fluoride therapy may increase vertebral bone mass in RA patients.
Approximately, one-third of cases of anaemia in RA patients may be caused by depletion of iron stores. A major cause for iron deficiency anaemia is the poor dietary intake. Deferioxamine, an iron-chelating agent, which has possible anti-inflammatory properties, causes haemoglobin and serum iron levels to increases. This shows that iron stores are needed within the body and an adequate dietary intake to meet the recommended intakes should be encouraged, even though there is no evidence for additional routine supplementation for patients with RA.
Studies have examined the effect of calcium supplementation on bone mineral density among subjects taking corticosteroids. A study of calcium combined with vitamin D3 in RA patients taking low-dose corticosteroids demonstrated a reduction in bone mineral density loss in both the spine and trochanter, but not the femoral neck. However, no change was seen in BMD with calcium and vitamin D3 supplementation in RA patients not receiving corticosteroids. Therefore, there is little evidence to support calcium and vitamin D supplementation in corticosteroid receiving RA patients.
Lastly, low levels of serum zinc have been reported in patients with RA which may be caused by elevated IL-1b levels. However, Zinc supplementations yield contradictory results and at present do not support a therapeutic use of zinc.
Food containing high source of fluoride to help treat Rheumatoid Arthritis include tomatoes, oranges, bell peppers and grapefruit, which you should eat in moderation. Iron can be incorporated into the diet by eating seafood, spinach, and peas. Moderate amounts of calcium should be included into the diet by having milk, cheese, dairy products, curly kale, okra, bread and fortified flour products such as cereals.
Herbal
The American College of Rheumatology The American College of Rheumatology (ACR; until 1985 called American Rheumatism Association) is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy ...
states that no herbal medicines have health claims supported by high-quality evidence and thus they do not recommend their use.[ There is no scientific basis to suggest that herbal supplements advertised as "natural" are safer for use than conventional medications as both are chemicals. Herbal medications, although labelled "natural", may be toxic or fatal if consumed.]
Due to the false belief that herbal supplements are always safe, there is sometimes a hesitancy to report their use which may increase the risk of adverse reaction.[
The following are under investigation for treatments for RA, based on preliminary promising results (not recommended for clinical use yet): ]boswellic acid
Boswellic acids are a series of pentacyclic terpenoid molecules that are produced by plants in the genus ''Boswellia''. Like many other terpenes, boswellic acids appear in the resin of the plant that exudes them; it is estimated that they mak ...
, curcumin
Curcumin is a bright yellow chemical produced by plants of the ''Curcuma longa'' species. It is the principal curcuminoid of turmeric (''Curcuma longa''), a member of the ginger family, Zingiberaceae. It is sold as a herbal supplement, cosmetic ...
, devil's claw, Euonymus alatus
''Euonymus alatus'', known variously as winged spindle, winged euonymus, or burning bush, is a species of flowering plant in the family Celastraceae, native to central and northern China, Japan, and Korea.
The common name "burning bush" comes fr ...
, and thunder god vine (''Tripterygium wilfordii''). NCCIH
The National Center for Complementary and Integrative Health (NCCIH) is a United States government agency which explores complementary and alternative medicine (CAM). It was initially created in 1991 as the Office of Alternative Medicine (OAM), ...
has noted that, "In particular, the herb thunder god vine (Tripterygium wilfordii) can have serious side effects."[
There is conflicting evidence on the role of ]erythropoiesis
Erythropoiesis (from Greek 'erythro' meaning "red" and 'poiesis' "to make") is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell.
It is stimulated by decrea ...
-stimulating agents for treatment of anemia in persons with rheumatoid arthritis.
Pregnancy
More than 75% of women with rheumatoid arthritis have symptoms improve during pregnancy but might have symptoms worsen after delivery. Methotrexate
Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
and leflunomide
Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug ( DMARD), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibi ...
are teratogenic (harmful to foetus) and not used in pregnancy. It is recommended women of childbearing age should use contraceptives to avoid pregnancy and to discontinue its use if pregnancy is planned. Low dose of prednisolone
Prednisolone is a steroid medication used to treat certain types of allergies, inflammatory conditions, autoimmune disorders, and cancers. Some of these conditions include adrenocortical insufficiency, high blood calcium, rheumatoid arthrit ...
, hydroxychloroquine
Hydroxychloroquine, sold under the brand name Plaquenil among others, is a medication used to prevent and treat malaria in areas where malaria remains sensitive to chloroquine. Other uses include treatment of rheumatoid arthritis, lupus, an ...
and sulfasalazine
Sulfasalazine, sold under the brand name Azulfidine among others, is a medication used to treat rheumatoid arthritis, ulcerative colitis, and Crohn's disease. It is considered by some to be a first-line treatment in rheumatoid arthritis. It is ...
are considered safe in pregnant women with rheumatoid arthritis. Prednisolone should be used with caution as the side effects include infections and fractures.
Vaccinations
People with RA have an increased risk of infections and mortality and recommended vaccinations can reduce these risks. The inactivated influenza vaccine
Influenza vaccines, also known as flu shots, are vaccines that protect against infection by influenza viruses. New versions of the vaccines are developed twice a year, as the influenza virus rapidly changes. While their effectiveness varies fr ...
should be received annually. The pneumococcal vaccine
Pneumococcal vaccines are vaccines against the bacterium '' Streptococcus pneumoniae''. Their use can prevent some cases of pneumonia, meningitis, and sepsis. There are two types of pneumococcal vaccines: conjugate vaccines and polysaccharide v ...
should be administered twice for people under the age 65 and once for those over 65. Lastly, the live-attenuated zoster vaccine
A zoster vaccine is a vaccine that reduces the incidence of herpes zoster (shingles), a disease caused by reactivation of the varicella zoster virus, which is also responsible for chickenpox. Shingles provokes a painful rash with blisters, and ...
should be administered once after the age 60, but is not recommended in people on a tumor necrosis factor alpha
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
blocker.
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 25% will have subcutaneous nodules (known as rheumatoid nodule
A rheumatoid nodule is a lump of tissue, or an area of swelling, that appear on the exterior of the skin usually around the olecranon (tip of the elbow) or the interphalangeal joints (finger knuckles), but can appear in other areas. There are fou ...
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
* Positive serum 14-3-3η (YWHAH
14-3-3 protein eta also referred to as 14-3-3η is a protein that in humans is encoded by the ''YWHAH'' gene.
Function
This gene product belongs to the 14-3-3 family of proteins that are normally intracellular in nature and help to mediate si ...
) levels above 0.5 ng/ml
* Carriership of HLA-DR4 "Shared Epitope" alleles
* Family history of RA
* Poor functional status
* Socioeconomic factors
* Elevated acute phase response (erythrocyte sedimentation rate SR C-reactive protein RP
* Increased clinical severity.
Mortality
RA reduces lifespan on average from three to twelve years. Young age at onset, long disease duration, the presence of other health problems, and characteristics of severe RAsuch 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 jointshave been shown to associate with higher mortality. Positive responses to treatment may indicate a better prognosis. A 2005 study by the Mayo Clinic
The Mayo Clinic () is a nonprofit American academic medical center focused on integrated health care, education, and research. It employs over 4,500 physicians and scientists, along with another 58,400 administrative and allied health staff, ...
noted that individuals with RA have a doubled risk of heart disease, independent of other risk factors such as diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
, excessive alcohol use, and elevated cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
, blood pressure and body mass index
Body mass index (BMI) is a value derived from the mass (weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and he ...
. The mechanism by which RA causes this increased risk remains unknown; the presence of chronic inflammation has been proposed as a contributing factor. It is possible that the use of new biologic drug therapies extend the lifespan of people with RA and reduce the risk and progression of atherosclerosis. This is based on cohort and registry studies, and still remains hypothetical. It is still uncertain whether biologics improve vascular function in RA or not. There was an increase in total cholesterol and HDLc levels and no improvement of the atherogenic index.
Epidemiology
RA affects between 0.5 and 1% of adults in the developed world with between 5 and 50 per 100,000 people newly developing the condition each year.[ In 2010 it resulted in about 49,000 deaths globally.]
Onset is uncommon under the age of 15 and from then on the incidence rises with age until the age of 80. Women are affected three to five times as often as men.
The age at which the disease most commonly starts is in 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 the persistent symptoms, waxing and waning in intensity, and a progressive deterioration of joint structures leading to deformations and disability.
There is an association between periodontitis and rheumatoid arthritis (RA), hypothesised to lead to enhanced generation of RA-related autoantibodies. Oral bacteria that invade the blood may also contribute to chronic inflammatory responses and generation of autoantibodies.
History
The first recognized description of RA in modern medicine was in 1800 by the French physician Dr Augustin Jacob Landré-Beauvais (1772–1840) who was based in the famed Salpêtrière Hospital in Paris.[ The name "rheumatoid arthritis" itself was coined in 1859 by British rheumatologist Dr ]Alfred Baring Garrod
Sir Alfred Baring Garrod (3 May 1819 – 28 December 1907) was an English physician.
Garrod was born in Ipswich, the son of Robert and Sarah (née Ennew) Garrod. He initially apprenticed at Ipswich Hospital, and later moved to University College ...
.
The art of Peter Paul Rubens
Sir Peter Paul Rubens (; ; 28 June 1577 – 30 May 1640) was a Flemish artist and diplomat from the Duchy of Brabant in the Southern Netherlands (modern-day Belgium). He is considered the most influential artist of the Flemish Baroque traditio ...
may possibly depict the effects of RA. In his later paintings, his rendered hands show, in the opinion of some physicians, increasing deformity consistent with the symptoms of the disease. RA appears to some to have been depicted in 16th-century paintings. However, it is generally recognized in art historical circles that the painting of hands in the 16th and 17th century followed certain stylized 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.
Historic (though not necessarily effective) treatments for RA have also included: rest, ice, compression and elevation, apple
An apple is an edible fruit produced by an apple tree (''Malus domestica''). Apple fruit tree, trees are agriculture, cultivated worldwide and are the most widely grown species in the genus ''Malus''. The tree originated in Central Asia, wh ...
diet, nutmeg
Nutmeg is the seed or ground spice of several species of the genus ''Myristica''. ''Myristica fragrans'' (fragrant nutmeg or true nutmeg) is a dark-leaved evergreen tree cultivated for two spices derived from its fruit: nutmeg, from its seed, an ...
, some light exercise every now and then, nettles, bee venom, copper
Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkis ...
bracelets, rhubarb diet, extractions of teeth, fasting
Fasting is the abstention from eating and sometimes drinking. From a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (see " Breakfast"), or to the metabolic state achieved after ...
, honey
Honey is a sweet and viscous substance made by several bees, the best-known of which are honey bees. Honey is made and stored to nourish bee colonies. Bees produce honey by gathering and then refining the sugary secretions of plants (primar ...
, vitamin
A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an Nutrient#Essential nutrients, essential micronutrient that an organism needs in small quantities for the proper functioning of its ...
s, insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
, 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, steel, nickel, ...
s, and electroconvulsive therapy
Electroconvulsive therapy (ECT) is a psychiatry, psychiatric treatment where a generalized seizure (without muscular convulsions) is electrically induced to manage refractory mental disorders.Rudorfer, MV, Henry, ME, Sackeim, HA (2003)"Electroco ...
(ECT).
Etymology
Rheumatoid arthritis 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
Rheumatic fever (RF) is an inflammatory disease that can involve the heart, joints, skin, and brain. The disease typically develops two to four weeks after a streptococcal throat infection. Signs and symptoms include fever, multiple painful jo ...
''. Rhuma which means watery discharge might refer to the fact that the joints are swollen or that the disease may be made worse by wet weather.[
]
Research
Meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
found an association between periodontal disease
Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main caus ...
and RA, but the mechanism of this association remains unclear. Two bacterial species associated with periodontitis are implicated as mediators of protein citrullination in the gums of people with RA.[
]Vitamin D deficiency
Vitamin D deficiency or hypovitaminosis D is a vitamin D level that is below normal. It most commonly occurs in people when they have inadequate exposure to sunlight, particularly sunlight with adequate ultraviolet B rays (UVB). Vitamin D defic ...
is more common in people with rheumatoid arthritis than in the general population. However, whether vitamin D deficiency is a cause or a consequence of the disease remains unclear. One meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
found that vitamin D levels are low in people with rheumatoid arthritis and that vitamin D status correlates inversely with prevalence of rheumatoid arthritis, suggesting that vitamin D deficiency
Vitamin D deficiency or hypovitaminosis D is a vitamin D level that is below normal. It most commonly occurs in people when they have inadequate exposure to sunlight, particularly sunlight with adequate ultraviolet B rays (UVB). Vitamin D defic ...
is associated with susceptibility to rheumatoid arthritis.
The fibroblast-like synoviocytes have a prominent role in the pathogenic processes of the rheumatic joints, and therapies that target these cells are emerging as promising therapeutic tools, raising hope for future applications in rheumatoid arthritis.[
Possible links with intestinal barrier dysfunction are investigated.]
References
External links
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{{DEFAULTSORT:Rheumatoid Arthritis
Rheumatology
Connective tissue diseases
Arthritis
Autoimmune diseases
Disorders of fascia
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Steroid-responsive inflammatory conditions
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