Rheumatoid arthritis: Difference between revisions

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{{Infobox_Disease |
{{subpages}}
  Name          = Rheumatoid arthritis |
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  Image          = |
'''Rheumatoid arthritis''' ('''RA''') is traditionally considered a chronic, [[inflammation|inflammatory]] [[autoimmunity|autoimmune disorder]] that causes the [[immune system]] to attack the [[joints]]. It is a disabling and painful [[inflammation|inflammatory]] condition, which can lead to substantial loss of mobility due to pain and joint destruction. RA is a [[systemic disease]], often affecting extra-articular tissues throughout the body including the [[skin]], blood vessels, [[heart]], [[lung]]s, and [[muscle]]s. About 60% of RA patients are unable to work 10 years after the onset of their disease.<ref>[http://www.hopkins-arthritis.som.jhmi.edu/rheumatoid/rheum_clin_pres.html [[Johns Hopkins University]]: Rheumatoid Arthritis]</ref>
  Caption        = |
  DiseasesDB    = 11506 |
  ICD10          = {{ICD10|M|05||m|05}}-{{ICD10|M|06||m|05}} |
  ICD9          = {{ICD9|714}} |
  ICDO          = |
  OMIM          = 180300 |
  MedlinePlus    = 000431 |
  eMedicineSubj  = med |
  eMedicineTopic = 2024 |
  eMedicine_mult = {{eMedicine2|emerg|48}} {{eMedicine2|pmr|124}} |
  MeshID        = D001172 |
}}
 
'''Rheumatoid arthritis''' ('''RA''') is traditionally considered a chronic, [[inflammation|inflammatory]] [[autoimmunity|autoimmune disorder]] that causes the [[immune system]] to attack the [[joints]]. It is a disabling and painful [[inflammation|inflammatory]] condition, which can lead to substantial loss of mobility due to pain and joint destruction. RA is a [[systemic disease]], often affecting extra-articular tissues throughout the body including the [[skin]], [[blood vessel]]s, [[heart]], [[lung]]s, and [[muscle]]s. About 60% of RA patients are unable to work 10 years after the onset of their disease.<ref>[http://www.hopkins-arthritis.som.jhmi.edu/rheumatoid/rheum_clin_pres.html [[Johns Hopkins University]]: Rheumatoid Arthritis]</ref>


Rheumatoid arthritis appears to have been described in paintings more than a century before the first detailed medical description of the condition in 1800 by Landre-Beauvais.<ref>{{cite journal |author= Dequeker J., Rico H.|title=Rheumatoid arthritis-like deformities in an early 16th-century painting of the Flemish-Dutch school |journal= Jama|volume= 268|pages=249-251|year=1992|pmid=1608144|}}</ref>
Rheumatoid arthritis appears to have been described in paintings more than a century before the first detailed medical description of the condition in 1800 by Landre-Beauvais.<ref>{{cite journal |author= Dequeker J., Rico H.|title=Rheumatoid arthritis-like deformities in an early 16th-century painting of the Flemish-Dutch school |journal= Jama|volume= 268|pages=249-251|year=1992|pmid=1608144|}}</ref>
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The name is derived from the Greek. ''Rheumatos'' means "flowing", and this initially gave rise to the term 'rheumatic fever', an illness that can follow throat infections and which includes joint pain. The suffix -''oid'' means "resembling", i.e. resembling rheumatic fever. ''Arthr'' means "joint" and the suffix -''itis'', a "condition involving inflammation". Thus rheumatoid arthritis was a form of joint inflammation that resembled rheumatic fever.  
The name is derived from the Greek. ''Rheumatos'' means "flowing", and this initially gave rise to the term 'rheumatic fever', an illness that can follow throat infections and which includes joint pain. The suffix -''oid'' means "resembling", i.e. resembling rheumatic fever. ''Arthr'' means "joint" and the suffix -''itis'', a "condition involving inflammation". Thus rheumatoid arthritis was a form of joint inflammation that resembled rheumatic fever.  


==Features==
==Signs and symptoms==
===Articular (joints)===
===Articular (joints)===
==== Rheumatoid arthritis and osteoarthritis====
The inflammatory activity leads to erosion and destruction of the joint surface as the pathology progresses, which impairs their range of movement and leads to deformity. The fingers are typically deviated towards the little finger (''[[ulnar deviation]]'') and can assume unnatural shapes. Classical deformities in rheumatoid arthritis are the [[Boutonniere deformity]] (Hyperflexion at the [[proximal interphalangeal joint]] with hyperextension at the [[distal interphalangeal joint]]), [[swan neck deformity]] (Hyperextension at the [[proximal interphalangeal joint]], hyperflexion at the [[distal interphalangeal joint]]). The thumb may develop a "Z-Thumb" deformity with fixed flexion and [[subluxation]] at the [[metacarpophalangeal joint]], and hyperextension at the IP joint.
In contrast to [[osteoarthritis]], rheumatoid arthritis is a chronic, inflammatory, multisystem, autoimmune disorder. It is commonly polyarticular, i.e. it affects many joints. The symptoms that distinguish rheumatoid arthritis from other forms of [[arthritis]] are inflammation and soft-tissue swelling of many joints at the same time ([[polyarthritis]]). The joints are usually affected initially asymmetrically and then in a symmetrical fashion as the disease progresses. The pain generally improves with use of the affected joints, and there is usually stiffness of all joints in the morning that lasts over 1 hour. Thus, the pain of rheumatoid arthritis is usually worse in the morning compared to the classic pain of osteoarthritis where the pain worsens over the day as the joints are used.
 
====Rheumatoid arthritis versus osteoarthritis====
The symptoms that distinguish rheumatoid arthritis from other forms of [[arthritis]] are inflammation and soft-tissue swelling of many joints at the same time ([[polyarthritis]]). The joints are usually affected initially asymmetrically and then in a symmetrical fashion as the disease progresses. The pain generally improves with use of the affected joints, and there is usually stiffness of all joints in the morning that lasts over 1 hour. Thus, the pain of rheumatoid arthritis is usually worse in the morning compared to the classic pain of osteoarthritis where the pain worsens over the day as the joints are used.


Extra-articular manifestations also distinguish this disease from osteoarthritis (hence it is a multisystemic disease). For example, most patients also suffer with [[anemia]], either as a consequence of the disease itself (anaemia of chronic disease) or as a consequence of [[gastrointestinal bleeding]] as a side effect of drugs used in treatment, especially [[NSAID]]s (non-steroidal anti-inflammatory drugs) used for [[analgesia]]. [[Hepatosplenomegaly]] may occur with concurrent leukopaenia ([[Felty's syndrome]]), and lymphocytic infiltration may affect the salivary and lacrimal glands ([[Sjögren's syndrome]]). Pericarditis, pleurisy, alveolitis, scleritis and subcutaneous nodules are other features associated with rheumatoid arthritis.
Extra-articular manifestations also distinguish this disease from osteoarthritis (hence it is a multisystemic disease). For example, most patients also suffer with [[anemia]], either as a consequence of the disease itself (anaemia of chronic disease) or as a consequence of [[gastrointestinal bleeding]] as a side effect of drugs used in treatment, especially [[NSAID]]s (non-steroidal anti-inflammatory drugs) used for [[analgesia]]. [[Hepatosplenomegaly]] may occur with concurrent leukopaenia ([[Felty's syndrome]]), and lymphocytic infiltration may affect the salivary and lacrimal glands ([[Sjögren's syndrome]]). Pericarditis, pleurisy, alveolitis, scleritis and subcutaneous nodules are other features associated with rheumatoid arthritis.


====Deformities====
===Cutaneous manifestations===
As the pathology progresses the inflammatory activity leads to erosion and destruction of the joint surface, which impairs their range of movement and leads to deformity. The fingers are typically deviated towards the little finger (''[[ulnar deviation]]'') and can assume unnatural shapes.  Classical deformities in rheumatoid arthritis are the [[Boutonniere deformity]] (Hyperflexion at the [[proximal interphalangeal joint]] with hyperextension at the [[distal interphalangeal joint]]), [[swan neck deformity]] (Hyperextension at the [[proximal interphalangeal joint]], hyperflexion at the [[distal interphalangeal joint]]).  The thumb may develop a "Z-Thumb" deformity with fixed flexion and [[subluxation]] at the [[metacarpophalangeal joint]], and hyperextension at the IP joint.
The most prominent cutaneous manifestations of rheumatoid arthritis are rheumatoid nodules and vasculitis.


====Cutaneous manifestations====
====Vasculitis====
# The cutaneous (strictly speaking subcutaneous) feature most characteristic of rheumatoid arthritis is the rheumatoid nodule. The initial pathologic process in nodule formation is unknown but is thought to be related to small-vessel inflammation. The mature lesion is defined by an area of central necrosis surrounded by palisading macrophages and fibroblasts and a cuff of cellular connective tissue and chronic inflammatory cells. The typical rheumatoid nodule may be a few [[millimetre]]s to a few [[centimetre]]s in diameter and is usually found over bony prominences, such as the olecranon, the calcaneum at the Achilles tendon insertion, the metacarpophalangeal joints, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF titer and severe erosive arthritis. They can rarely occur throughout the body in internal organs.
Rheumatoid arthritis is associated with a variety of forms of vasculitis. A benign form occurs as microinfarcts around the nailfolds. More severe forms include livedo reticularis, which is a network (reticulum) of erythematous to purplish discoloration of the skin due to the presence of an obliterative cutaneous capillaropathy. (This rash is also otherwise associated with the antiphospholipid-antibody syndrome, a hypercoagulable state linked to antiphospholipid antibodies and characterized by recurrent vascular thrombosis and second trimester miscarriages.
# Rheumatoid arthritis is associated with a variety of forms of vasculitis. A benign form occurs as microinfarcts around the nailfolds. More severe forms include livedo reticularis, which is a network (reticulum) of erythematous to purplish discoloration of the skin due to the presence of an obliterative cutaneous capillaropathy. (This rash is also otherwise associated with the antiphospholipid-antibody syndrome, a hypercoagulable state linked to antiphospholipid antibodies and characterized by recurrent vascular thrombosis and second trimester miscarriages.  


Rheumatoid arthritis is rarely associated with pyoderma gangrenosum, a necrotizing, ulcerative, noninfectious neutrophilic dermatosis. Sweet's syndrome, a neutrophilic dermatosis usually associated with myeloproliferative disorders, viral infections, and drug reactions, also occurs in rheumatoid arthritis (6). Other complications include [[erythema nodosum]], lobular panniculitis, atrophy of digital skin, [[palmar erythema]], diffuse thinning (rice paper skin), and skin fragility.
====Other cutaneous manifestations====
Rheumatoid arthritis is rarely associated with pyoderma gangrenosum, a necrotizing, ulcerative, noninfectious neutrophilic dermatosis. Other complications include [[erythema nodosum]], lobular panniculitis, atrophy of digital skin, [[palmar erythema]], diffuse thinning of the skin (rice paper skin), and skin fragility.


===Extra-articular (elsewhere)===
===Rheumatoid nodules===
The cutaneous (strictly speaking subcutaneous) feature most characteristic of rheumatoid arthritis is the rheumatoid nodule. The initial pathologic process in nodule formation is unknown but is thought to be related to small-vessel inflammation. The mature lesion is defined by an area of central necrosis surrounded by palisading macrophages and fibroblasts and a cuff of cellular connective tissue and chronic inflamed cells. The typical rheumatoid nodule may be a few [[millimetre]]s to a few [[centimetre]]s in diameter and is usually found over bony prominences, such as the olecranon, the calcaneum at the Achilles tendon insertion, the metacarpophalangeal joints, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF titer and severe erosive arthritis. They can rarely occur throughout the body in internal organs.


;Pulmonary: The [[lungs]] may become involved as a part of the primary disease process or as a consequence of therapy. [[Fibrosis]] may occur spontaneously or as a consequence of therapy (for example [[methotrexate]]). [[Caplan's nodules]] are found as are [[pulmonary effusion]]s.
===Other===
;Pulmonary: The [[lungs]] may become involved as a part of the primary disease process or as a consequence of therapy. If such is the case, [[fibrosis]] may occur spontaneously or as a consequence of therapy (for example [[methotrexate]]). In addition, [[Caplan's nodules]] are found as are [[pulmonary effusion]]s.


;Renal: [[Amyloidosis]] can occur.
;Renal: [[Amyloidosis]] in the kidney can occur.


;Cardiovascular: Possible complications that may arise include: pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis. The risk of cardiovascular, specifically myocardial infarction (heart attack) or congestive heart failure are greater in individuals with RA. Over 1/3 of deaths of people with RA are directly attributable to cardiovascular death.
;Cardiovascular: Possible complications that may arise include: pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis. The risk of cardiovascular, specifically myocardial infarction (heart attack) or congestive heart failure are greater in individuals with RA. Over 1/3 of deaths of people with RA are directly attributable to cardiovascular death.


;Ocular: Keratoconjunctivitis sicca (dry eyes), [[scleritis]], [[episcleritis]] and [[scleromalacia]].
;Ocular: Keratoconjunctivitis sicca (dry eyes), [[scleritis]], [[episcleritis]] and [[scleromalacia]] are possible complications of rheumatoid arthritis.
 
;Gastrointestinal: [[Felty syndrome]], [[anemia]]


;Neurological: Peripheral neuropathy and [[mononeuritis multiplex]] may occur. The most common  problem is carpal tunnel syndrome due to compression of the median nerve by swelling around the wrist.  [[Atlanto-axial subluxation]] can occur, owing to erosion of the odontoid process and or/transverse ligaments in the cervical spine's connection to the skull. Such an erosion (>3mm) can give rise to vertebrae slipping over one another and compressing the spinal cord. At first the patient experiences clumsiness but without due care this can progress to [[quadriplegia]].
;Neurological: Peripheral neuropathy and [[mononeuritis multiplex]] may occur. The most common  problem is carpal tunnel syndrome due to compression of the median nerve by swelling around the wrist.  [[Atlanto-axial subluxation]] can occur, owing to erosion of the odontoid process and or/transverse ligaments in the cervical spine's connection to the skull. Such an erosion (>3mm) can give rise to vertebrae slipping over one another and compressing the spinal cord. At first the patient experiences clumsiness but without due care this can progress to [[quadriplegia]].
;Vasculitis: [[Vasculitis]] in rheumatoid arthritis is common. It is typically presents as vasculitic nailfold infarcts.


;Osteoporosis: [[Osteoporosis]] classically occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines.
;Osteoporosis: [[Osteoporosis]] classically occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines.
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The [[incidence (epidemiology)|incidence]] of RA is in the region of 3 cases per 10,000 population per annum. Onset is uncommon under the age of 15 and from then on the incidence rises with age until the age of 80. The [[prevalence]] rate is 1%, with women affected three to five times as often as men. It is 4 times more common in smokers than non-smokers. Some [[Indigenous peoples of the Americas|Native American]] groups have higher prevalence rates (5-6%) and black persons from the [[Caribbean]] region have lower prevalence rates. First-degree relatives prevalence rate is 2-3% and disease concordance in [[Twin#Identical twins|monozygotic twins]] is approximately 15-20%.
The [[incidence (epidemiology)|incidence]] of RA is in the region of 3 cases per 10,000 population per annum. Onset is uncommon under the age of 15 and from then on the incidence rises with age until the age of 80. The [[prevalence]] rate is 1%, with women affected three to five times as often as men. It is 4 times more common in smokers than non-smokers. Some [[Indigenous peoples of the Americas|Native American]] groups have higher prevalence rates (5-6%) and black persons from the [[Caribbean]] region have lower prevalence rates. First-degree relatives prevalence rate is 2-3% and disease concordance in [[Twin#Identical twins|monozygotic twins]] is approximately 15-20%.


It is strongly associated with the inherited tissue type [[Major histocompatibility complex]] (MHC) antigen [[Human leukocyte antigen|HLA]]-DR4 (most specifically DR0401 and 0404) — hence family history is an important risk factor.
It is strongly associated with the inherited tissue type [[Major histocompatibility complex]] (MHC) antigen [[Human leukocyte antigen|HLA]]-DR4 (most specifically DR0401<ref>[http://rheumatology.oxfordjournals.org/cgi/reprint/kel011v1.pdf Oxfordjournals - kel011v1]</ref> and 0404) — hence family history is an important risk factor.


==Diagnosis==
==Diagnosis==
===Diagnostic criteria===
===Diagnostic criteria===
The [[American College of Rheumatology]] has defined ([[1987]]) the following criteria for the classification of rheumatoid arthritis:<!--
The [[American College of Rheumatology]] revised [http://www.rheumatology.org/practice/clinical/classification/ra/ra_2010.asp diagnostic criteria] in 2010.<ref>Aletaha D  et al. 2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum  2010 Sep; 62:2569. {{doi|10.1002/art.27584}} http://pubmed.gov/20872595</ref> [http://www.ncbi.nlm.nih.gov/pubmed/3358796?dopt=Abstract Original criteria] were previously published in 1987:<ref>{{cite journal | author = Arnett F, Edworthy S, Bloch D, McShane D, Fries J, Cooper N, Healey L, Kaplan S, Liang M, Luthra H | title = The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. | journal = Arthritis Rheum | volume = 31 | issue = 3 | pages = 315-24 | year = 1988 | PMID = 3358796 | url=http://www.rheumatology.org/publications/classification/ra/ra.asp?aud=mem}}</ref>  
  --><ref>{{cite journal | author = Arnett F, Edworthy S, Bloch D, McShane D, Fries J, Cooper N, Healey L, Kaplan S, Liang M, Luthra H | title = The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. | journal = Arthritis Rheum | volume = 31 | issue = 3 | pages = 315-24 | year = 1988 | id = PMID 3358796 | url=http://www.rheumatology.org/publications/classification/ra/ra.asp?aud=mem}}</ref>  
 
* Morning stiffness of >1 hour most mornings for at least 6 weeks.
<!--* Morning stiffness of >1 hour most mornings for at least 6 weeks.
* Arthritis and soft-tissue swelling of >3 of 14 joints/joint groups
* Arthritis and soft-tissue swelling of >3 of 14 joints/joint groups
* Arthritis of hand joints
* Arthritis of hand joints
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At least four criteria have to be met for classification as RA.
At least four criteria have to be met for classification as RA.


It is important to note that these criteria are not intended for the diagnosis of patients for routine clinical care.  They were primarily intended to categorise patients, for research.  For example: one of the criteria is the presence of bone erosion on X-Ray.  Prevention of bone erosion is one of the main aims of treatment because it is generally irreversible.  To wait until all of the ACR criteria for rheumatoid arthritis are met is therefore likely to result in a worse outcome for the patient.  Most patients and rheumatologists would agree that it would be better to treat the patient as early as possible and prevent bone erosion from occurring, even if this means treating patients who don't fulfill the ACR criteria.  The ACR criteria are, however, very useful for categorising patients with established rheumatoid arthritis, for example for epidemiological purposes.
It is important to note that these criteria are not intended for the diagnosis of patients for routine clinical care.  They were primarily intended to categorise patients, for research.  For example: one of the criteria is the presence of bone erosion on X-Ray.  Prevention of bone erosion is one of the main aims of treatment because it is generally irreversible.  To wait until all of the ACR criteria for rheumatoid arthritis are met is therefore likely to result in a worse outcome for the patient.  Most patients and rheumatologists would agree that it would be better to treat the patient as early as possible and prevent bone erosion from occurring, even if this means treating patients who don't fulfill the ACR criteria.  The ACR criteria are, however, very useful for categorising patients with established rheumatoid arthritis, for example for epidemiological purposes.-->


===Blood tests===
===Blood tests===
When RA is being clinically suspected, [[immunology|immunological]] studies are required, such as [[rheumatoid factor]] (RF, a specific [[antibody]]).<!--
When RA is suspected, [[immunologic test]]s of the patient's blood are required.
  --><ref>{{cite web | title=Rheumatoid Factor | url=http://www.labtestsonline.org/understanding/analytes/rheumatoid/test.html | work=Lab Tests Online | publisher=American Association for Clinical Chemistry | date=September 30, 2006 | accessdate=2006-10-28}}</ref>
 
A negative RF does not rule out RA; rather, the arthritis is called ''[[seronegative]]''. During the first year of illness, rheumatoid factor is frequently negative. 80% of patients eventually convert to seropositive status. RF is also seen in other illnesses, like [[Sjögren's syndrome]], and in approximately 10% of the healthy population, therefore the test is not very specific.
====Rheumatoid factor====
The [[rheumatoid factor]] (RF) blood test is a blood test for an [[autoantibody]] against [[gamma-chain immunoglobulin]]s and may help diagnose RA.<ref>{{cite web | title=Rheumatoid Factor | url=http://www.labtestsonline.org/understanding/analytes/rheumatoid/test.html | work=Lab Tests Online | publisher=American Association for Clinical Chemistry | date=September 30, 2006 | accessdate=2006-10-28}}</ref> [[Meta-analysis|Meta-analyses]] of the accuracy of the rheumatoid factor found:<ref name="pmid17548411">{{cite journal |author=Nishimura K, Sugiyama D, Kogata Y, ''et al'' |title=Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis |journal=Ann. Intern. Med. |volume=146 |issue=11 |pages=797–808 |year=2007 |pmid=17548411 |doi= |issn=}}</ref>
* [[sensitivity (tests)|sensitivity]] 69%
* [[specificity (tests)|specificity]] 85%


Because of this low [[Specificity (tests)|specificity]], a new serological test has been developed in recent years, which tests for the presence of so called [[anti-citrullinated protein]] antibodies (ACPA). Like RF, this test can detect approximately 80% of all RA patients, but is rarely positive in non-RA patients, giving it a specificity of around 98%. In addition, ACP antibodies can be often detected in early stages of the disease, or even before disease onset. Currently, most common test for ACP antibodies is the anti-CCP ([[cyclic citrullinated peptide]]) test. <!--
Thus, a negative RF does not rule out RA.  
  --><ref>{{cite web | title=CCP (Cyclic Citrullinated Peptide antibody) | url=http://www.labtestsonline.org/understanding/analytes/ccp/test.html | work=Lab Tests Online | publisher=American Association for Clinical Chemistry | date=January 15, 2005 | accessdate=2006-10-28}}</ref>


Also, several other [[blood test]]s are usually done to allow for other causes of arthritis, such as [[lupus erythematosus]]. The [[erythrocyte sedimentation rate]] (ESR), [[C-reactive protein]],<!--
====Anti-cyclic citrullinated peptide (anti-CCP) antibody====
  --><ref>{{cite web | title=C-Reactive Protein | url=http://www.labtestsonline.org/understanding/analytes/crp/test.html| work=Lab Tests Online | publisher=American Association for Clinical Chemistry | date=September 3, 2004 | accessdate=2006-10-28}}</ref>
Because of the low [[Specificity (tests)|specificity]] of the RF, a new test is for the presence of Anti–citrullinated peptide antibodies (ACPA). These antibodies include anti-cyclic citrullinated peptide (anti-CCP) antibodies.<ref>{{cite web | title=CCP (Cyclic Citrullinated Peptide antibody) | url=http://www.labtestsonline.org/understanding/analytes/ccp/test.html | work=Lab Tests Online | publisher=American Association for Clinical Chemistry | date=January 15, 2005 | accessdate=2006-10-28}}</ref> A [[meta-analysis]] of the accuracy of the anti-CCP found:<ref name="pmid17548411">{{cite journal |author=Nishimura K, Sugiyama D, Kogata Y, ''et al'' |title=Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis |journal=Ann. Intern. Med. |volume=146 |issue=11 |pages=797–808 |year=2007 |pmid=17548411 |doi= |issn=}}</ref><ref  name="doi10.1059/0003-4819-152-7-201004060-00010">{{Cite journal
[[full blood count]], [[renal function]], [[liver enzyme]]s and other immunological tests (e.g. [[antinuclear antibody]]/ANA)<!--
| doi =  10.1059/0003-4819-152-7-201004060-00010
  --><ref>{{cite web | title=ANA (Antinuclear Antibody) | url=http://www.labtestsonline.org/understanding/analytes/ana/test.html | work=Lab Tests Online | publisher=American Association for Clinical Chemistry | date=December 13, 2004 | accessdate=2006-10-28}}</ref>
| volume = 152
are all performed at this stage. [[Ferritin]] can reveal [[hemochromatosis]], which can mimic RA.
| issue = 7
| pages =  456-464
| last = Whiting
| first =  Penny F.
| coauthors = Nynke Smidt, Jonathan A.C.  Sterne, Roger Harbord, Anya Burton, Margaret Burke, Rebecca Beynon, Yoav  Ben-Shlomo, John Axford, Paul Dieppe
| title = Systematic Review: Accuracy of Anti–Citrullinated Peptide Antibodies for  Diagnosing Rheumatoid Arthritis
| journal = Annals of Internal Medicine
| accessdate =  2010-04-06
| date = 2010-04-06
| url = http://www.annals.org/content/152/7/456.abstract
}}</ref>
* [[sensitivity (tests)|sensitivity]] 67%<ref  name="pmid17548411"/> to 57%<ref name="doi10.1059/0003-4819-152-7-201004060-00010"/>
* [[specificity (tests)|specificity]] 95%<ref  name="pmid17548411"/> to 96%<ref name="doi10.1059/0003-4819-152-7-201004060-00010"/>


==Pathophysiology==
==Pathophysiology==
===Causes===
===Causes===
The cause of RA is still unknown to this day, but has long been suspected to be infectious. It could be due to food allergies or external organisms. ''[[Mycoplasma]]'', ''[[Erysipelothrix]]'', [[Epstein-Barr virus]], [[parvovirus|parvovirus B19]] and [[rubella]] have been suspected but never supported in epidemiological studies. As in other autoimmune diseases, the "mistaken identity" theory suggests that an offending organism causes an immune response that leaves behind antibodies that are specific to that organism. The antibodies are not specific enough, though. They begin an immune attack against, in this case, the [[synovium]], because some molecule in the synovium "looks like" a molecule on the offending organism that created the initial immune reaction - this phenomenon is called [[molecular mimicry]].  
The cause of RA is not known. Once triggered, the immune response causes inflammation of the synovium, leading to edema, vasodilation and infiltration by activated T-cells (mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). Early and intermediate molecular mediators of inflammation include [[tumor necrosis factor alpha]] (TNF-α), [[interleukin]]s [[IL-1]], [[Interleukin 6|IL-6]], [[IL-8]] and [[IL-15]], [[transforming growth factor]] beta, [[fibroblast growth factor]] and [[platelet-derived growth factor]]. Synovial macrophages and dentritic cells function as antigen presenting cells by expressing MHC class II molecules, leading to the production of immunoglobins, rheumatoid factors of the IgG and IgM class and complement components by B-Lymphocytes. The disease progresses in concert with formation of granulation tissue at the edges of the synovial lining ([[pannus]]) with extensive angiogenesis and production of enzymes that cause tissue damage.  Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues.


But physical and emotional effects, stress and improper diet could play a role in the disease. Some research suggests that alcohol consumption lowers the risk of developing the disease. In addition, a Swedish study found that the risk decreased as the consumption of alcohol increased from light to moderate levels. <ref> Turesson, Carl. Increased Alcohol Intake Associated with Decreased Risk of Developing Rheumatoid Arthritis. (Abstract) Paper presented at the annual European Congress of Rheumatology. Barcelona, Spain. June 13-16, 2007. European League Against Rheumatism, June 15, 2007; Myllykangas-Lusojarvi, R., Aho, K., Kautiainen, H., and Hakala, M. Reduced incidence of alcohol related deaths in subjects with rheumatoid arthritis. ''Annals of Rheumatoid Diseases'', 2000, ''59'', 75-76; Voight, L., ''et al''. Smoking, obesity, alcohol consumption and the risk of rheumatoid arthritis. ''Epidemiology'', 1994, ''5'', 525-532 </ref>
====Environmental factors====
The risk decreased as the consumption of alcohol increased from light to moderate levels. <ref> Turesson, Carl. Increased Alcohol Intake Associated with Decreased Risk of Developing Rheumatoid Arthritis. (Abstract) Paper presented at the annual European Congress of Rheumatology. Barcelona, Spain. June 13-16, 2007. European League Against Rheumatism, June 15, 2007; Myllykangas-Lusojarvi, R., Aho, K., Kautiainen, H., and Hakala, M. Reduced incidence of alcohol related deaths in subjects with rheumatoid arthritis. ''Annals of Rheumatoid Diseases'', 2000, ''59'', 75-76; Voight, L., ''et al''. Smoking, obesity, alcohol consumption and the risk of rheumatoid arthritis. ''Epidemiology'', 1994, ''5'', 525-532 </ref>


It is suspected that susceptibility to rheumatoid arthritis is an inherited trait.<ref name="medicinenet">{{cite web | title=Rheumatoid Arthritis Causes, Diagnosis, Information, Symptoms, and Treatment on MedicineNet.com | url=http://www.medicinenet.com/script/main/art.asp?articlekey=466&pf=3&page=1 | publisher=MedicineNet.com | date=October 16, 2006 | accessdate=2007-02-27 }}</ref>
====Inheritance and molecular basis====
Autoimmune diseases require that the affected individual have a defect in the ability to distinguish foreign molecules from the body's own. There are markers on many cells that confer this self-identifying feature. However, some classes of markers allow for RA to happen. The [[major histocompatibility complex]] encodes the cell-surface proteins known as the [[human leukocyte antigens]] (HLAs) that are responsible for self-identification. In some populations, some HLA genotypes are associated with RA. Among anglo patients with RA, 70% express HLA-DR4, compared to 28% of patients without RA.<ref name="pmid12069565">{{cite journal |author=Smith JB, Haynes MK |title=Rheumatoid arthritis--a molecular understanding |journal=Ann. Intern. Med. |volume=136 |issue=12 |pages=908–22 |year=2002 |pmid=12069565 |doi= |issn=|url=http://www.annals.org/cgi/content/full/136/12/908}}</ref> In Native Americans, a similar association occurs with HLA-DR9.<ref name="pmid12069565"/>


Autoimmune diseases require that the affected individual have a defect in the ability to distinguish foreign molecules from the body's own. There are markers on many cells that confer this self-identifying feature. However, some classes of markers allow for RA to happen. 90% of patients with RA have the cluster of markers known as the HLA-DR4/DR1 cluster, whereas only 40% of unaffected [[Scientific control|controls]] do. Thus, in theory, RA requires susceptibility to the disease through genetic endowment with specific markers '''and''' an infectious event that triggers an autoimmune response.
Genes outside of the HLA region are also associated with RA. A [[single-nucleotide polymorphism]] (SNP) of the STAT4 gene is associated with both rheumatoid arthritis and [[systemic lupus erythematosus]] (SLE).<ref name="pmid17804842">{{cite journal |author=Remmers EF, Plenge RM, Lee AT, ''et al'' |title=STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus |journal=N. Engl. J. Med. |volume=357 |issue=10 |pages=977–86 |year=2007 |pmid=17804842 |doi=10.1056/NEJMoa073003 |issn=}}</ref>


Once triggered, the immune response causes inflammation of the synovium, leading to edema, vasodilation and infiltration by activated T-cells (mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). Early and intermediate molecular mediators of inflammation include [[tumor necrosis factor alpha]] (TNF-α), [[interleukin]]s [[IL-1]], [[Interleukin 6|IL-6]], [[IL-8]] and [[IL-15]], [[transforming growth factor]] beta, [[fibroblast growth factor]] and [[platelet-derived growth factor]]. Synovial macrophages and dentritic cells function as antigen presenting cells by expressing MHC class II molecules, leading to the production of immunoglobins, rheumatoid factors of the IgG and IgM class and complement components by B-Lymphocytes.  The disease progresses in concert with formation of granulation tissue at the edges of the synovial lining ([[pannus]]) with extensive angiogenesis and production of enzymes that cause tissue damage.  Modern pharmacological treatments of RA target these mediators. Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues.
====The role of infections====
Various infections have been suspected of contributing to RA. Examples are ''[[Mycoplasma]]''<ref name="pmid3369750">{{cite journal |author=Clark HW, Coker-Vann MR, Bailey JS, Brown TM |title=Detection of mycoplasmal antigens in immune complexes from rheumatoid arthritis synovial fluids |journal=Annals of allergy |volume=60 |issue=5 |pages=394–8 |year=1988 |pmid=3369750 |doi= |issn=}}</ref>, ''[[Erysipelothrix]]'', [[Epstein-Barr virus]], [[Parvovirus B19]] and [[rubella]] have been suspected but never supported in epidemiological studies. Although tetracycline antibiotics have been used to treat RA, these antibiotics may have nonspecific immunomodulator effects.<ref name="pmid14510338">{{cite journal |author=Reeta KH, Mediratta PK, Mahajan P, Sharma KK |title=Effect of minocycline and tetracycline on immunological responses in experimental animals |journal=Indian journal of medical sciences |volume=56 |issue=11 |pages=553–9 |year=2002 |pmid=14510338 |doi= |issn=}}</ref>


====Bacteria/antibiotic hypothesis====
==Treatment==
[[Thomas McPherson Brown]] along with other researchers and patient groups believe that it can be demonstrated that RA is caused by a bacterial infection, in particular mycoplasma that localizes to joints.<ref>[http://www.roadback.org/ www.roadback.org] - patient group</ref>
 
Thomas McPherson Brown used [[tetracycline antibiotics]] to treat rheumatoid arthritis, and concluded that improvement in symptoms was evidence that the antibiotic must be killing a bacterium that caused the arthritis.  The tetracycline antibiotics that he used, however also ''"exhibit [[immunomodulator]]y properties, which may contribute significantly to their beneficial effects in rheumatoid arthritis"''.<ref>{{cite journal | author = Reeta K, Mediratta P, Mahajan P, Sharma K | title = Effect of minocycline and tetracycline on immunological responses in experimental animals. | journal = Indian J Med Sci | volume = 56 | issue = 11 | pages = 553-9 | year = 2002 | id = PMID 14510338}}</ref>  In other words, the same drug can both kill bacteria and suppress the immune system, and the latter may be responsible for its benefits in rheumatoid arthritis.  That said, there are thousands of documented cases of remission of RA and other related auto-immune diseases using antibiotics on file at the National Hospital in Washington, D.C., where Dr. Brown practiced, and many other reports from rheumatologists worldwide that judicious use of [[minocycline]], sometimes combined with [[clindamycin]], along with diet change, nutritional supplements, and vigorous exercise, and various other immune-strengthening alternative therapies, such as [[acupuncture]], hyperbaric oxygen, and infra-red sauna, can retard or remit the disease.  Tumor necrosis factor inhibitors are a class of drugs that markedly reduce resistance to certain types of bacterial infection (including the mycobacteria that were hypothesised to be to blame for rheumatoid arthritis by McPherson Brown). They are, however very effective in treating RA.  In fact, they are one of the most effective treatments for rheumatoid arthritis in widespread use.  If rheumatoid arthritis were caused by bacteria, we would expect the disease to worsen, not improve, when tumour necrosis factor inhibitors are used, contrary to what is widely observed.  The bacteria/antibiotic hypothesis therefore has very little support amongst the majority of rheumatologists and researchers, but is seen by a small number of integrative physicians and caregivers as part of the web of factors that produce the disease. Several large, long-term studies in the last ten years, both in the United States and Europe, have convinced these integrative healers that antibiotics have an important role to play in the armamentarium of weapons against RA, and an evolved form of the antibiotic protocol originally devised by Dr. Brown at the National Hospital has now been officially sanctioned as a DMARD (disease-modifying anti-rheumatic drug) by the AMA and recognized by the Arthritis Foundation.
 
Rheumatoid arthritis, ankylosing spondylitis, systemic and discoid lupus, Sjogren's disease, celiac disease, dermatitis herpetiformis, Crohn's disease, ulcerative colitis and scleritis have been associated with the genetic porphyrias.  Lupus, transient and sustained autoantibody production have been reported with both neurovisceral and cutaneous porphyrias since the early 1950s.


Physicians should be on high alert for porphyrias in families with autoimmune diseases since porphyrinogenic drugs can lead to acute porphyria attacks and further medical complications. Pericarditis, syndrome of inappropriate antidiuretic hormone, focal and systemic neuropathy, and pancreatitis have been reported with the highly drug sensitive porphyrias.
There is no known cure for rheumatoid arthritis. However, many different types of treatment can be used to alleviate symptoms. [[Pharmacology|Pharmacological]] treatment of RA can be divided into [[disease-modifying antirheumatic drug]]s (DMARDs), [[anti-inflammatory]] agents and [[analgesic]]s.<ref name="pmid16738955">{{cite journal | author = O'Dell J | title = Therapeutic strategies for rheumatoid arthritis. | journal = N Engl J Med | volume = 350 | issue = 25 | pages = 2591-602 | year = 2004 | id = PMID 15201416}}</ref><ref>{{cite journal | author = Hasler P | title = Biological therapies directed against cells in autoimmune disease. | journal = Springer Semin Immunopathol | volume = 27 | issue = 4 | pages = 443-56 | year = 2006 | month=Jun | id = PMID 16738955}}</ref>


Testing should be appropriate for all neurovisceral and cutaneous porphyrias. The urine screening test used to detect acute neurovisceral porphyria attacks is an unreliable test and inappropriate for hereditary coproporphyria, variegate porphyria and children.
Treating to specific goals or targets may be most effective.<ref name="pmid20237123">{{cite journal| author=Schoels M, Knevel R, Aletaha D, Bijlsma JW, Breedveld FC, Boumpas DT et al.| title=Evidence for treating rheumatoid arthritis to target: results of a systematic literature search. | journal=Ann Rheum Dis | year= 2010 | volume= 69 | issue= 4 | pages= 638-43 | pmid=20237123
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=20237123 | doi=10.1136/ard.2009.123976 }} </ref>


==Treatment==
===Clinical practice guidelines===
Clinical practice guidelines by the American College of Rheumatology recommend [[leflunomide]] or [[methotrexate]] as options for initial treatment.<ref>Saag KG et al. (2008) [http://www.rheumatology.org/publications/guidelines/recommendations.asp?aud=prs 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis]. Arthritis & Rheumatism</ref>


There is no known cure for rheumatoid arthritis. However, many different types of treatment can be used to alleviate symptoms.
===Systematic reviews===
Systematic reviews of treatments suggests that [[etanercept]] best balances effectiveness and [[drug toxicity]].<ref name="pmid19884297">{{cite journal| author=Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA et al.| title=A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. | journal=CMAJ | year= 2009 | volume= 181 | issue= 11 | pages= 787-96 | pmid=19884297
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=19884297 | doi=10.1503/cmaj.091391 | pmc=PMC2780484 }} <!--Formatted by http://sumsearch.uthscsa.edu/cite/--></ref><ref name="pmid19821440">{{cite journal| author=Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA et al.| title=Biologics for rheumatoid arthritis: an overview of Cochrane reviews. | journal=Cochrane Database Syst Rev | year= 2009 | volume=  | issue= 4 | pages= CD007848 | pmid=19821440
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=19821440 | doi=10.1002/14651858.CD007848.pub2 }} <!--Formatted by http://sumsearch.uthscsa.edu/cite/--></ref>


Historic treatments for this condition have included: [[gold]] salts, [[RICE]], [[acupuncture]], [[apple]] diet, [[nutmeg]], some light exercise every now and then, [[nettle]]s, [[bee]] venom, prayer, [[copper]] bracelets, [[rhubarb]] diet, rest, extractions of teeth, [[fasting]], [[honey]], [[vitamin]]s, [[insulin]], [[magnet]]s, and electric convulsion therapy ([[ECT]]).<ref>[http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1639217&blobtype=pdf [[NIH]]: History of the treatment of rheumatoid arthritis]</ref> [[Cortisone]] therapy has offered relief to many patients in the past, but its long-term effects have been deemed undesirable.<ref>[http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1520676 [[NIH]]: Results of Long-Continued Cortisone Administration in Rheumatoid Arthritis]</ref>
===Disease modifying anti-rheumatic agents===
The term '''Disease Modifying Anti-Rheumatic Agent''' or '''Disease Modifying Anti-Rheumatic Drug (DMARD)''' refers to agents that show evidence of processes thought to underlie the disease, such as a raised erythrocyte sedimentation rate, reduced haemoglobin level, raised rheumatoid factor level and more recently, raised C-reactive protein level. "Agent" became more preferred than "drug" to be more inclusive of the various biological treatments.  


[[Pharmacology|Pharmacological]] treatment of RA can be divided into [[disease-modifying antirheumatic drug]]s (DMARDs), [[anti-inflammatory]] agents and [[analgesic]]s.<ref>{{cite journal | author = O'Dell J | title = Therapeutic strategies for rheumatoid arthritis. | journal = N Engl J Med | volume = 350 | issue = 25 | pages = 2591-602 | year = 2004 | id = PMID 15201416}}</ref><ref>{{cite journal | author = Hasler P | title = Biological therapies directed against cells in autoimmune disease. | journal = Springer Semin Immunopathol | volume = 27 | issue = 4 | pages = 443-56 | year = 2006 | month=Jun | id = PMID 16738955}}</ref> DMARDs have been found to produce durable remissions and delay or halt disease progression. In particular they prevent bone and joint damage from occurring secondary to the uncontrolled inflammation.  This is important as such damage is usually irreversible.  Anti-inflammatories and analgesics improve pain and stiffness but do not prevent joint damage or slow the disease progression.
More recently, the working definition is an agent that reduces the rate of damage to bone and cartilage.  For other areas of medicine, [[disease-modifying treatment]] is coming into use for drugs that can stop or reverse a progressive disease.


====Rationale for early use====
There is an increasing recognition amongst rheumatologists that permanent damage to the joints occurs at a very early stage in the disease.  In the past the strategy used was to start with just an anti-inflammatory drug, and assess progression clinically and using X-rays.  If there was evidence that joint damage was starting to occur then a more potent DMARD would be prescribed.  Tools such as ultrasound and MRI are more sensitive methods of imaging the joints and have demonstrated that joint damage occurs much earlier and in more patients than was previously thought.  Patients with normal X-rays will often have erosions detectable by ultrasound that X ray could not demonstrate.
There is an increasing recognition amongst rheumatologists that permanent damage to the joints occurs at a very early stage in the disease.  In the past the strategy used was to start with just an anti-inflammatory drug, and assess progression clinically and using X-rays.  If there was evidence that joint damage was starting to occur then a more potent DMARD would be prescribed.  Tools such as ultrasound and MRI are more sensitive methods of imaging the joints and have demonstrated that joint damage occurs much earlier and in more patients than was previously thought.  Patients with normal X-rays will often have erosions detectable by ultrasound that X ray could not demonstrate.


Light exercise may be beneficial for improving blood circulation to joints and thereby allowing white blood cells to get to the area requiring treatment.
Using DMARDs early reduces structural joint damage.  In the early stage of the disease, the joints are increasingly infiltrated by cells of the immune system that signal to one another and are thought to set up self-perpetuating chronic inflammation.  Interrupting this process as early as possible with an effective DMARD (such as methotrexate) appears to improve the outcome from the RA for years afterwards.  Delaying therapy for as little as a few months after the onset of symptoms can result in worse outcomes in the long term..<ref name="pmid16190499">{{cite journal | author = Vital E, Emery P | title = Advances in the treatment of early rheumatoid arthritis. | journal = Am Fam Physician | volume = 72 | issue = 6 | pages = 1002, 1004 | year = 2005 | month=Sep 15 | id = PMID 16190499 | url=http://www.aafp.org/afp/20050915/editorials.html}}</ref>
 
There may be other reasons why starting DMARDs early is beneficial as well as prevention of structural joint damage.  In the early stage of the disease, the joints are increasingly infiltrated by cells of the immune system that signal to one another and are thought to set up self-perpetuating chronic inflammation.  Interrupting this process as early as possible with an effective DMARD (such as methotrexate) appears to improve the outcome from the RA for years afterwards.  Delaying therapy for as little as a few months after the onset of symptoms can result in worse outcomes in the long term. There is therefore considerable interest in establishing the most effective therapy in patients with early arthritis, when they are most responsive to therapy and have the most to gain.<ref>{{cite journal | author = Vital E, Emery P | title = Advances in the treatment of early rheumatoid arthritis. | journal = Am Fam Physician | volume = 72 | issue = 6 | pages = 1002, 1004 | year = 2005 | month=Sep 15 | id = PMID 16190499 | url=http://www.aafp.org/afp/20050915/editorials.html}}</ref>
 
For certain patients shown to be unresponsive to or intolerant of DMARDs, the [[Prosorba column]] blood filtering device appeared promising after the FDA approved it for treatment of RA in 1999 <ref> Fresenius HemoCare, Inc., "New Hope for Rheumatoid Arthritis Patients," press release, September 17, 1999. Dr. [[Gerónimo Lluberas]] is quoted as saying, "It offers a bright new promise to those that are otherwise unresponsive to this dreadful disease." Also see arthritis.about.com [http://arthritis.about.com/od/arthqa/f/prosorba.htm] </ref>. The Prosorba column employs protein A covalently bound to an inert silica matrix. The protein A binds immunoglobulin G (IgG) and circulating immune complexes (CIC). This blocks antigens responsible for autoimmune joint deterioration. [http://www.freseniushc.com/product/prosorba_column.html]


Treatment also includes rest and physical activity. Regular exercise is important for maintaining joint mobility and making the joint muscles stronger. Swimming is especially good, as it allows for exercise with a minimum of stress on the joints. Heat and cold applications are modalities that can ease symptoms before and after exercise. Pain in the joints is sometimes alleviated by oral [[acetaminophen]] (paracetamol). Other areas of the body, such as the eyes and lining of the heart, are treated individually.  However, there is no diet that has been shown to alleviate rheumatoid arthritis, although fish oil may have anti-inflammatory effects.<ref name="medicinenet" />
====Types of DMARDS====
Many rheumatologists consider methotrexate to be the most important and useful DMARD, largely because of lower rates of stopping the drug through toxicity; however, a systematic review was not able to conclude that any one or combination of DMARDs was preferable.<ref name="pmid18025440">{{cite journal |author=Donahue KE, Gartlehner G, Jonas DE, ''et al'' |title=Systematic review: comparative effectiveness and harms of disease-modifying medications for rheumatoid arthritis |journal=Ann. Intern. Med. |volume=148 |issue=2 |pages=124–34 |year=2008 |pmid=18025440 |doi=}}</ref>


===Disease modifying anti-rheumatic drugs (DMARDs)===
DMARDs can be further subdivided into traditional small molecular mass drugs synthesised chemically and newer 'biological' agents produced through genetic engineering.  
The term Disease Modifying Anti-Rheumatic Agent was originally introduced to indicate a drug that reduced evidence of processes thought to underly the disease, such as a raised erythrocyte sedimentation rate, reduced haemoglobin level, raised rheumatoid factor level and more recently, raised C-reactive protein level. More recently, the term has been used to indicate a drug that reduces the rate of damage to bone and cartilage. DMARDs can be further subdivided into traditional small molecular mass drugs synthesised chemically and newer 'biological' agents produced through genetic engineering.  


=====Small molecular mass drugs=====
Traditional small molecular mass drugs:
Traditional small molecular mass drugs:
*[[azathioprine]]
*[[azathioprine]]
*[[ciclosporin]] (cyclosporine A)
*[[ciclosporin]] (cyclosporine A)
*[[D-penicillamine]]
*[[D-penicillamine]]
*[[gold salts]]
*[[gold drugs]]
*[[chloroquine]])
*[[hydroxychloroquine]]
*[[hydroxychloroquine]]
*[[leflunomide]]
*[[leflunomide]]
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The most important and most common adverse events relate to [[liver]] and [[bone marrow]] toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds, D-penicillamine), renal toxicity (cyclosporine A, parenteral gold salts, D-penicillamine), pneumonitis (MTX), allergic [[skin]] reactions (gold compounds, SSZ), autoimmunity (D-penicillamine, SSZ, minocycline) and infections (azathioprine, cyclosporine A). Hydroxychloroquine may cause ocular toxicity, although this is rare, and because hydroxychloroquine does not affect the bone marrow or liver it is often considered to be the DMARD with the least toxicity.  Unfortunately hydroxychloroquine is not very potent, and for most patients hydroxychloroquine alone is insufficient to control symptoms.
The most important and most common adverse events relate to [[liver]] and [[bone marrow]] toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds, D-penicillamine), renal toxicity (cyclosporine A, parenteral gold salts, D-penicillamine), pneumonitis (MTX), allergic [[skin]] reactions (gold compounds, SSZ), autoimmunity (D-penicillamine, SSZ, minocycline) and infections (azathioprine, cyclosporine A). Hydroxychloroquine may cause ocular toxicity, although this is rare, and because hydroxychloroquine does not affect the bone marrow or liver it is often considered to be the DMARD with the least toxicity.  Unfortunately hydroxychloroquine is not very potent, and for most patients hydroxychloroquine alone is insufficient to control symptoms.


Many rheumatologists consider methotrexate to be the most important and useful DMARD, largely because of lower rates of stopping the drug through toxicity.   Nevertheless, methotrexate is often considered by patients and even other doctors as a very "toxic" drug.  This reputation is not entirely justified, and at times can result in patients being denied the most effective treatment for their arthritis.  Although methotrexate does indeed have the potential to suppress the bone marrow or cause hepatitis, these effects can be monitored using regular blood tests, and the drug withdrawn at an early stage if the tests are abnormal, before any serious harm is done (typically the blood tests return to normal after stopping the drug). In clinical trials in which patients with RA were treated with one of a range of different DMARDs, patients who were prescribed methotrexate were those who stayed on their medication the longest (the others stopped theirs because of either side-effects or failure of the drug to control the arthritis).  Lastly, methotrexate is often preferred by rheumatologists because if it does not control arthritis on its own then it works well in combination with many other drugs, especially the biological agents.  Other DMARDs may not be as effective or safe in combination with biological agents.
=====Biological agents=====
Systematic reviews have compared available biological agents.<ref name="pmid20950126">{{cite journal| author=Kristensen L, Jakobsen A, Bartels E, Geborek P, Bliddal H, Saxne T et al.| title=The number needed to treat for second-generation biologics when treating established rheumatoid arthritis: a systematic quantitative review of randomized controlled trials. | journal=Scand J Rheumatol | year= 2010 | volume=  | issue=  | pages=  | pmid=20950126 | doi=10.3109/03009742.2010.491834 | pmc= | url= }} </ref><ref name="pmid20447957">{{cite journal| author=Nam JL, Winthrop KL, van Vollenhoven RF, Pavelka K, Valesini G, Hensor EM et al.| title=Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. | journal=Ann Rheum Dis | year= 2010 | volume= 69 | issue= 6 | pages= 976-86 | pmid=20447957 | doi=10.1136/ard.2009.126573 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20447957  }} </ref> Biological agents include:
* [[Cytokine]] inhibors
** [[Tumor necrosis factor-alpha]] (TNFα) [[cytokine]] inhibitors<ref name="pmid17099951">{{cite journal| author=Dentener MA, Wouters EF| title=Tumor necrosis factor inhibitors for rheumatoid arthritis. | journal=N Engl J Med | year= 2006 | volume= 355 | issue= 19 | pages= 2047-8; author reply 2048 | pmid=17099951 | doi= | pmc= | url= }} </ref>
*** [[Certolizumab]] is a [[antibody]]
*** [[Etanercept]] (Enbrel) is a [[recombinant fusion protein]]
*** [[Golimumab]] is a [[antibody]]
*** [[Infliximab]] (Remicade) is a chimeric [[antibody]]
*** [[Adalimumab]] (Humira) is a monoclonal [[antibody]]
** [[Interleukin]]-1 [[cytokine]] blockers
*** [[Anakinra]]. Anakinra is currently not recommended by [[National Institute for Health and Clinical Excellence]].<ref name="NICE79">National  Collaborating Centre for Chronic Conditions. [http://www.guideline.gov/content.aspx?id=14310 Rheumatoid arthritis: the management of rheumatoid arthritis in adults]. London (UK): National  Institute for Health and Clinical Excellence (NICE); 2009 Feb. 35 p. (NICE clinical guideline; no. 79).</ref>
** [[Interleukin]]-6
*** [[Tocilizumab]]
* [[Lymphocyte]] inhibitors
** [[B-lymphocyte]] inhibitor
*** [[Rituximab]] (Rituxan) is an [[antibody]] to the [[CD20 antigen]]<ref name="pmid15201414">{{cite journal| author=Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR et al.| title=Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. | journal=N Engl J Med | year= 2004 | volume= 350 | issue= 25 | pages= 2572-81 | pmid=15201414 | doi=10.1056/NEJMoa032534 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15201414 }} </ref>
** T-[[lymphocyte]] inhibitor
*** [[Abatacept]] (Orencia) is a [[recombinant fusion protein]] to the CD152 antigen (cytotoxic T-lymphocyte antigen 4 or CTLA-4)<ref name="pmid16785475">{{cite journal| author=Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C et al.| title=Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. | journal=Ann Intern Med | year= 2006 | volume= 144 | issue= 12 | pages= 865-76 | pmid=16785475 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16785475 }} </ref><ref name="pmid16162882">{{cite journal| author=Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J et al.| title=Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 11 | pages= 1114-23 | pmid=16162882 | doi=10.1056/NEJMoa050524 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16162882 }} </ref>


====Biological agents====
===Anti-inflammatory drugs===
Biological agents include:
*tumor necrosis factor alpha (TNFα) blockers - [[etanercept]] (Enbrel), [[infliximab]] (Remicade), [[adalimumab]] (Humira)
*[[interleukin]]-1 blockers - [[anakinra]]
*anti-[[B cell]] (CD20) [[antibody]] - [[rituximab]] (Rituxan)<ref>{{cite journal | author = Edwards J, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close D, Stevens R, Shaw T | title = Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. | journal = N Engl J Med | volume = 350 | issue = 25 | pages = 2572-81 | year = 2004 | id = PMID 15201414}}</ref>
*blockers of T cell activation - [[abatacept]] (Orencia)
 
===Anti-inflammatory agents and analgesics===
Anti-inflammatory agents include:
Anti-inflammatory agents include:
*[[glucocorticoids]]
*[[glucocorticoids]]
*[[Non-steroidal anti-inflammatory drug]] (NSAIDs, most also act as analgesics)
*[[Non-steroidal anti-inflammatory drug]] (NSAIDs, most also act as analgesics)


===Analgesics===
Analgesics include:
Analgesics include:
*[[acetaminophen]] (Paracetamol outside US)
*[[acetaminophen]] (Paracetamol outside US)
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*[[lidocaine]] topical
*[[lidocaine]] topical


==Research==
===Non-drug treatments===
===Pain relief===
Other therapies are [[weight loss]], [[occupational therapy]], [[podiatry]], [[physiotherapy]], [[joint injection]]s, and special tools to improve hard movements (e.g. special tin-openers).
Recent research indicates that [[cytokines]], a group of chemicals that are produced by various cells in the body, may be responsible for generating the response of chronic [[Pain and nociception|pain]] associated with Rheumatoid Arthritis. Medications that affect the release of cytokines or block the action of cytokines may reduce the response of chronic pain. Various anti-cytokine medications are now being used to treat painful disease states such as Rheumatoid Arthritis, and [[Crohn's Disease]]. In addition, research using the anti-cytokine medication, [[Thalidomide]], is being evaluated for its effect in treating chronic pain associated with [[Arachnoiditis]]. Food (vegetables) with higher water content should be avoided.{{Fact|date=July 2007}}
 
Severely affected joints may require [[joint replacement]] surgery, such as knee replacement.
 
===Historical treatments===
Historical treatments for this condition have included: [[gold]] salts, [[RICE]], [[acupuncture]], [[Apple (fruit)|apple]] diet, [[nutmeg]], some light exercise every now and then, [[nettle]]s, [[bee]] venom, prayer, [[copper]] bracelets, [[rhubarb|rhubarb diet]] , rest, extractions of teeth, [[fasting]], [[honey]], [[vitamin]]s, [[insulin]], [[magnet]]s, and electric convulsion therapy ([[ECT]]).<ref name="pmid177148">{{cite journal |author=Hart FD |title=History of the treatment of rheumatoid arthritis |journal=British medical journal |volume=1 |issue=6012 |pages=763–5 |year=1976 |pmid=177148 |doi= |issn=}}</ref> [[Cortisone]] therapy has offered relief to many patients in the past, but its long-term effects have been deemed undesirable.<ref name="pmid14848703">{{cite journal |author=BOLAND EW, HEADLEY NE |title=Results of long-continued cortisone administration in rheumatoid arthritis |journal=California medicine |volume=74 |issue=6 |pages=416–23 |year=1951 |pmid=14848703 |doi= |issn=}}</ref>
 
===Investigational treatments===
====Anti-cytokines====
Recent research indicates that [[cytokines]], a group of chemicals that are produced by various cells in the body, may be responsible for generating the response of chronic [[pain]] associated with Rheumatoid Arthritis. Medications that affect the release of cytokines or block the action of cytokines may reduce the response of chronic pain. [[Thalidomide]], is being evaluated for its effect in treating chronic pain associated with [[Arachnoiditis]].


===Specific desensitization===
====Specific desensitization====
An experimental treatment known as [[enzyme potentiated desensitization]] (EPD) is now under development for the treatment of rheumatoid arthritis and other [[autoimmune diseases]].  EPD uses dilutions of allergen (in this case type 2 [[collagen]]) and an enzyme, [[β-glucuronidase]], to which T-regulatory lymphocytes respond by favouring desensitization, rather than sensitization.  Initial results are encouraging <ref>[http://www.epidyme.com/ra.html EPD treatment of rheumatoid arthritis proof of concept results on Epidyme website] use of EPD to treat autoimmune diseases.</ref> but the treatment is still at an early stage of development.
An experimental treatment known as [[enzyme potentiated desensitization]] (EPD) is now under development for the treatment of rheumatoid arthritis and other [[autoimmune diseases]].  EPD uses dilutions of allergen (in this case type 2 [[collagen]]) and an enzyme, [[β-glucuronidase]], to which T-regulatory lymphocytes respond by favouring desensitization, rather than sensitization.  Initial results are encouraging <ref>[http://www.epidyme.com/ra.html EPD treatment of rheumatoid arthritis proof of concept results on Epidyme website] use of EPD to treat autoimmune diseases.</ref> but the treatment is still at an early stage of development.


===Other therapies===
====Other====
Other therapies are [[weight loss]], [[occupational therapy]], [[podiatry]], [[physiotherapy]], [[joint injection]]s, and special tools to improve hard movements (e.g. special tin-openers).
For certain patients shown to be unresponsive to or intolerant of DMARDs, the [[Prosorba column]] blood filtering device appeared promising after the FDA approved it for treatment of RA in 1999 <ref> Fresenius HemoCare, Inc., "New Hope for Rheumatoid Arthritis Patients," press release, September 17, 1999. Dr. [[Gerónimo Lluberas]] is quoted as saying, "It offers a bright new promise to those that are otherwise unresponsive to this dreadful disease." Also see arthritis.about.com [http://arthritis.about.com/od/arthqa/f/prosorba.htm] </ref>. The Prosorba column employs protein A covalently bound to an inert silica matrix. The protein A binds immunoglobulin G (IgG) and circulating immune complexes (CIC). This blocks antigens responsible for autoimmune joint deterioration. [http://www.freseniushc.com/product/prosorba_column.html]
 
Severely affected joints may require [[joint replacement]] surgery, such as knee replacement.


==Prognosis==
==Prognosis==
Line 194: Line 214:


===Mortality===
===Mortality===
Estimates of the life-shortening effect of RA vary; most sources cite a lifespan reduction of 5 to 10 years; the [[National Institutes of Health]] has estimated a lifespan reduction of 10 to 20 years.<ref>[www.nih.gov/about/researchresultsforthepublic/arthritis.pdf Rheumatoid arthritis prognosis]</ref> According to the [[UK]]'s National Rheumatoid Arthritis Society, "Young age at onset, long disease duration, the concurrent presence of other health problems (called co-morbidity), and characteristics of severe RA – such as poor functional ability or overall health status, a lot of joint damage on x-rays, the need for hospitalisation or involvement of organs other than the joints – have been shown to associate with higher mortality".<ref>[http://www.rheumatoid.org.uk/article.php?article_id=112 Excess mortality in rheumatoid arthritis]</ref> Positive responses to treatment may indicate a better prognosis. A 2005 study by the [[Mayo Clinic]] noted that RA patients suffer a doubled risk of heart disease,<ref>[http://www.mayoclinic.org/news2005-rst/2654.html The second largest contributor of mortality is cerebrovascular disease. Increased risk of heart disease in rheumatoid arthritis patients]</ref> independent of other risk factors such as [[diabetes]], alcohol abuse, and elevated [[cholesterol]], blood pressure and [[body mass index]]. The mechanism by which RA causes this increased risk remains unknown; the presence of chronic inflammation has been proposed as a contributing factor.<ref>[http://www.hopkins-arthritis.org/news-archive/2002/cardiac.html Cardiac disease in rheumatoid arthritis]</ref>
Estimates of the life-shortening effect of RA vary; most sources cite a lifespan reduction of 5 to 10 years; the [[National Institutes of Health]] has estimated a lifespan reduction of 10 to 20 years.<ref>[www.nih.gov/about/researchresultsforthepublic/arthritis.pdf Rheumatoid arthritis prognosis]</ref> According to the [[United Kingdom|UK]]'s National Rheumatoid Arthritis Society, "Young age at onset, long disease duration, the concurrent presence of other health problems (called co-morbidity), and characteristics of severe RA – such as poor functional ability or overall health status, a lot of joint damage on x-rays, the need for hospitalisation or involvement of organs other than the joints – have been shown to associate with higher mortality".<ref>[http://www.rheumatoid.org.uk/article.php?article_id=112 Excess mortality in rheumatoid arthritis]</ref> Positive responses to treatment may indicate a better prognosis. A 2005 study by the [[Mayo Clinic]] noted that RA patients suffer a doubled risk of heart disease,<ref>[http://www.mayoclinic.org/news2005-rst/2654.html The second largest contributor of mortality is cerebrovascular disease. Increased risk of heart disease in rheumatoid arthritis patients]</ref> independent of other risk factors such as [[diabetes]], alcohol abuse, and elevated [[cholesterol]], blood pressure and [[body mass index]]. The mechanism by which RA causes this increased risk remains unknown; the presence of chronic inflammation has been proposed as a contributing factor.<ref>[http://www.hopkins-arthritis.org/news-archive/2002/cardiac.html Cardiac disease in rheumatoid arthritis]</ref>


==History==
==History==
To delineate the history of rheumatoid arthritis a researcher must rely on scanty and ambiguous data from old medical literature and buried skeletons.  The current consensus is too speculative for the taste of some scholars.  Nevertheless a tentative best guess has emerged.
To delineate the history of rheumatoid arthritis a researcher must rely on scanty and ambiguous data from old medical literature and buried skeletons.  The current consensus is too speculative for the taste of some scholars.  Nevertheless a tentative best guess has emerged.


The first known traces of arthritis date back at least as far as [[4500 BC]]. A text dated [[123 AD]] first describes [[symptom]]s very similar to rheumatoid arthritis. It was noted in skeletal remains of [[Indigenous peoples of the Americas|Native Americans]] found in [[Tennessee]].<ref>http://mcclungmuseum.utk.edu/research/renotes/rn-05txt.htm Tennessee Origins of Rheumatoid Arthritis</ref> In the Old World the disease is vanishingly rare before the 1600s.<ref>http://www.arc.org.uk/newsviews/arctdy/104/bones.htm
The first known traces of arthritis date back at least as far as [[4500 BC]]. A text dated [[123 AD]] first describes [[symptom]]s very similar to rheumatoid arthritis. It was noted in skeletal remains of [[Indigenous peoples of the Americas|Native Americans]] found in [[Tennessee (U.S. state)|Tennessee]].<ref>http://mcclungmuseum.utk.edu/research/renotes/rn-05txt.htm Tennessee Origins of Rheumatoid Arthritis</ref> In the Old World the disease is vanishingly rare before the 1600s.<ref>http://www.arc.org.uk/newsviews/arctdy/104/bones.htm
  Bones of Contention</ref> and on this basis investigators believe it spread across the Atlantic during the [[Age of Exploration]]. In [[1859]] the disease acquired its current name.
  Bones of Contention</ref> and on this basis investigators believe it spread across the Atlantic during the [[Age of Exploration]]. In 1859 the disease acquired its current name.


A fascinating anomaly has been noticed from investigation of Precolumbian bones.  The bones from the Tennessee site show no signs of tuberculosis even though it was  prevalent at the time throughout the Americas.<ref>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14528501&dopt=Abstract Unified theory of the origins of erosive arthritis: conditioning as a protective/directing mechanism?</ref>Jim Mobley, at Pfizer, has discovered a historical pattern of epidemics of tuberculosis followed by a surge in the number of rheumatoid arthritis cases a few generations later.<ref>http://media.www.michigandaily.com/media/storage/paper851/news/2005/02/01/News/Scientist.Finds.Surprising.Links.Between.Arthritis.And.Tuberculosis-1428389.shtml?sourcedomain=www.michigandaily.com&MIIHost=media.collegepublisher.com  Scientist finds surprising links between arthritis and tuberculosis</ref> Mobley attributes the spikes in arthritis to selective pressure caused by tuberculosis. A hypervigilant immune system is protective against tuberculosis at the cost of an increased risk of autoimmune disease.
A fascinating anomaly has been noticed from investigation of Precolumbian bones.  The bones from the Tennessee site show no signs of tuberculosis even though it was  prevalent at the time throughout the Americas.<ref>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14528501&dopt=Abstract Unified theory of the origins of erosive arthritis: conditioning as a protective/directing mechanism?</ref>Jim Mobley, at Pfizer, has discovered a historical pattern of epidemics of tuberculosis followed by a surge in the number of rheumatoid arthritis cases a few generations later.<ref>http://media.www.michigandaily.com/media/storage/paper851/news/2005/02/01/News/Scientist.Finds.Surprising.Links.Between.Arthritis.And.Tuberculosis-1428389.shtml?sourcedomain=www.michigandaily.com&MIIHost=media.collegepublisher.com  Scientist finds surprising links between arthritis and tuberculosis</ref> Mobley attributes the spikes in arthritis to selective pressure caused by tuberculosis. A hypervigilant immune system is protective against tuberculosis at the cost of an increased risk of autoimmune disease.
Line 206: Line 226:
The art of [[Peter Paul Rubens]] may depict the effects of rheumatoid arthritis, for it is presumed that he used his own hands as a model.  In his later paintings, his rendered hands show increasing deformity consistent with the symptoms of the disease.<ref>[http://jama.ama-assn.org/cgi/content/abstract/245/5/483 JAMA article - Rubens and the question of antiquity of rheumatoid arthritis]</ref><ref>http://japan.medscape.com/viewarticle/538251 Did RA travel from New World to Old? The Rubens connection</ref>
The art of [[Peter Paul Rubens]] may depict the effects of rheumatoid arthritis, for it is presumed that he used his own hands as a model.  In his later paintings, his rendered hands show increasing deformity consistent with the symptoms of the disease.<ref>[http://jama.ama-assn.org/cgi/content/abstract/245/5/483 JAMA article - Rubens and the question of antiquity of rheumatoid arthritis]</ref><ref>http://japan.medscape.com/viewarticle/538251 Did RA travel from New World to Old? The Rubens connection</ref>


==List of notable people with rheumatoid arthritis==


*[[Kathleen Turner]]
*[[Aida Turturro]]<ref>http://findarticles.com/p/articles/mi_pwwi/is_200308/ai_mark654573218</ref>
*[[Peter Paul Rubens]]
*[[Barry Gibb]]<ref>http://www.beegees-world.com/archives7.html</ref>
*[[Lucille Ball]]
*[[Christiaan Barnard]]
*[[Pierre-Auguste Renoir]]
*[[Billy Bowden]]
*[[Max Clifford]]
*[[Hitesh Dhalawat]]


==References==
==References==
Line 223: Line 232:
<references/>
<references/>
</div>
</div>
==External links==
*[http://logikbase.com/website/techprofile.cfm?licid=596 Use of Jellyfish Collagen (Type II) in the Treatment of Rheumatoid Arthritis]
* {{cite web | title=Rheumatoid Arthritis | url=http://www.arthritis.org/conditions/DiseaseCenter/RA/default.asp | publisher=Arthritis Foundation}}
* {{cite web | title=Rheumatoid Arthritis | url=http://www.arc.org.uk/arthinfo/patpubs/6033/6033.asp | publisher=Arthritis Research Campaign}}
* {{cite web | author=Charles Weber | title=History of rheumatoid arthritis | url= http://charles_w.tripod.com/arthritis2.html}}
*[http://www.antibodypatterns.com/ana.php ANA]
* {{cite web | title=Living with Rheumatoid Arthritis | url=http://mediapedia.wikidot.com/living-with-rheumatoid-arthritis | publisher=NLM | accessdate=2007-04-01}} video
*[http://www.arthritis.ca/programs%20and%20resources/news%20magazine/1989/vector/default.asp?s=1 The Vector Theory]
*[http://www.biomedcode.com BioMedCode Animal Models for Rheumatoid Arthritis (TNF<sup>ΔARE</sup>)]

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Rheumatoid arthritis (RA) is traditionally considered a chronic, inflammatory autoimmune disorder that causes the immune system to attack the joints. It is a disabling and painful inflammatory condition, which can lead to substantial loss of mobility due to pain and joint destruction. RA is a systemic disease, often affecting extra-articular tissues throughout the body including the skin, blood vessels, heart, lungs, and muscles. About 60% of RA patients are unable to work 10 years after the onset of their disease.[1]

Rheumatoid arthritis appears to have been described in paintings more than a century before the first detailed medical description of the condition in 1800 by Landre-Beauvais.[2]

Etymology

The name is derived from the Greek. Rheumatos means "flowing", and this initially gave rise to the term 'rheumatic fever', an illness that can follow throat infections and which includes joint pain. The suffix -oid means "resembling", i.e. resembling rheumatic fever. Arthr means "joint" and the suffix -itis, a "condition involving inflammation". Thus rheumatoid arthritis was a form of joint inflammation that resembled rheumatic fever.

Signs and symptoms

Articular (joints)

The inflammatory activity leads to erosion and destruction of the joint surface as the pathology progresses, which impairs their range of movement and leads to deformity. The fingers are typically deviated towards the little finger (ulnar deviation) and can assume unnatural shapes. Classical deformities in rheumatoid arthritis are the Boutonniere deformity (Hyperflexion at the proximal interphalangeal joint with hyperextension at the distal interphalangeal joint), swan neck deformity (Hyperextension at the proximal interphalangeal joint, hyperflexion at the distal interphalangeal joint). The thumb may develop a "Z-Thumb" deformity with fixed flexion and subluxation at the metacarpophalangeal joint, and hyperextension at the IP joint.

Rheumatoid arthritis versus osteoarthritis

The symptoms that distinguish rheumatoid arthritis from other forms of arthritis are inflammation and soft-tissue swelling of many joints at the same time (polyarthritis). The joints are usually affected initially asymmetrically and then in a symmetrical fashion as the disease progresses. The pain generally improves with use of the affected joints, and there is usually stiffness of all joints in the morning that lasts over 1 hour. Thus, the pain of rheumatoid arthritis is usually worse in the morning compared to the classic pain of osteoarthritis where the pain worsens over the day as the joints are used.

Extra-articular manifestations also distinguish this disease from osteoarthritis (hence it is a multisystemic disease). For example, most patients also suffer with anemia, either as a consequence of the disease itself (anaemia of chronic disease) or as a consequence of gastrointestinal bleeding as a side effect of drugs used in treatment, especially NSAIDs (non-steroidal anti-inflammatory drugs) used for analgesia. Hepatosplenomegaly may occur with concurrent leukopaenia (Felty's syndrome), and lymphocytic infiltration may affect the salivary and lacrimal glands (Sjögren's syndrome). Pericarditis, pleurisy, alveolitis, scleritis and subcutaneous nodules are other features associated with rheumatoid arthritis.

Cutaneous manifestations

The most prominent cutaneous manifestations of rheumatoid arthritis are rheumatoid nodules and vasculitis.

Vasculitis

Rheumatoid arthritis is associated with a variety of forms of vasculitis. A benign form occurs as microinfarcts around the nailfolds. More severe forms include livedo reticularis, which is a network (reticulum) of erythematous to purplish discoloration of the skin due to the presence of an obliterative cutaneous capillaropathy. (This rash is also otherwise associated with the antiphospholipid-antibody syndrome, a hypercoagulable state linked to antiphospholipid antibodies and characterized by recurrent vascular thrombosis and second trimester miscarriages.

Other cutaneous manifestations

Rheumatoid arthritis is rarely associated with pyoderma gangrenosum, a necrotizing, ulcerative, noninfectious neutrophilic dermatosis. Other complications include erythema nodosum, lobular panniculitis, atrophy of digital skin, palmar erythema, diffuse thinning of the skin (rice paper skin), and skin fragility.

Rheumatoid nodules

The cutaneous (strictly speaking subcutaneous) feature most characteristic of rheumatoid arthritis is the rheumatoid nodule. The initial pathologic process in nodule formation is unknown but is thought to be related to small-vessel inflammation. The mature lesion is defined by an area of central necrosis surrounded by palisading macrophages and fibroblasts and a cuff of cellular connective tissue and chronic inflamed cells. The typical rheumatoid nodule may be a few millimetres to a few centimetres in diameter and is usually found over bony prominences, such as the olecranon, the calcaneum at the Achilles tendon insertion, the metacarpophalangeal joints, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF titer and severe erosive arthritis. They can rarely occur throughout the body in internal organs.

Other

Pulmonary
The lungs may become involved as a part of the primary disease process or as a consequence of therapy. If such is the case, fibrosis may occur spontaneously or as a consequence of therapy (for example methotrexate). In addition, Caplan's nodules are found as are pulmonary effusions.
Renal
Amyloidosis in the kidney can occur.
Cardiovascular
Possible complications that may arise include: pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis. The risk of cardiovascular, specifically myocardial infarction (heart attack) or congestive heart failure are greater in individuals with RA. Over 1/3 of deaths of people with RA are directly attributable to cardiovascular death.
Ocular
Keratoconjunctivitis sicca (dry eyes), scleritis, episcleritis and scleromalacia are possible complications of rheumatoid arthritis.
Neurological
Peripheral neuropathy and mononeuritis multiplex may occur. The most common problem is carpal tunnel syndrome due to compression of the median nerve by swelling around the wrist. Atlanto-axial subluxation can occur, owing to erosion of the odontoid process and or/transverse ligaments in the cervical spine's connection to the skull. Such an erosion (>3mm) can give rise to vertebrae slipping over one another and compressing the spinal cord. At first the patient experiences clumsiness but without due care this can progress to quadriplegia.
Osteoporosis
Osteoporosis classically occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines.
Lymphoma
The incidence of lymphoma is increased in RA as it is in most autoimmune conditions.

Epidemiology

The incidence of RA is in the region of 3 cases per 10,000 population per annum. Onset is uncommon under the age of 15 and from then on the incidence rises with age until the age of 80. The prevalence rate is 1%, with women affected three to five times as often as men. It is 4 times more common in smokers than non-smokers. Some Native American groups have higher prevalence rates (5-6%) and black persons from the Caribbean region have lower prevalence rates. First-degree relatives prevalence rate is 2-3% and disease concordance in monozygotic twins is approximately 15-20%.

It is strongly associated with the inherited tissue type Major histocompatibility complex (MHC) antigen HLA-DR4 (most specifically DR0401[3] and 0404) — hence family history is an important risk factor.

Diagnosis

Diagnostic criteria

The American College of Rheumatology revised diagnostic criteria in 2010.[4] Original criteria were previously published in 1987:[5]


Blood tests

When RA is suspected, immunologic tests of the patient's blood are required.

Rheumatoid factor

The rheumatoid factor (RF) blood test is a blood test for an autoantibody against gamma-chain immunoglobulins and may help diagnose RA.[6] Meta-analyses of the accuracy of the rheumatoid factor found:[7]

Thus, a negative RF does not rule out RA.

Anti-cyclic citrullinated peptide (anti-CCP) antibody

Because of the low specificity of the RF, a new test is for the presence of Anti–citrullinated peptide antibodies (ACPA). These antibodies include anti-cyclic citrullinated peptide (anti-CCP) antibodies.[8] A meta-analysis of the accuracy of the anti-CCP found:[7][9]

Pathophysiology

Causes

The cause of RA is not known. Once triggered, the immune response causes inflammation of the synovium, leading to edema, vasodilation and infiltration by activated T-cells (mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). Early and intermediate molecular mediators of inflammation include tumor necrosis factor alpha (TNF-α), interleukins IL-1, IL-6, IL-8 and IL-15, transforming growth factor beta, fibroblast growth factor and platelet-derived growth factor. Synovial macrophages and dentritic cells function as antigen presenting cells by expressing MHC class II molecules, leading to the production of immunoglobins, rheumatoid factors of the IgG and IgM class and complement components by B-Lymphocytes. The disease progresses in concert with formation of granulation tissue at the edges of the synovial lining (pannus) with extensive angiogenesis and production of enzymes that cause tissue damage. Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues.

Environmental factors

The risk decreased as the consumption of alcohol increased from light to moderate levels. [10]

Inheritance and molecular basis

Autoimmune diseases require that the affected individual have a defect in the ability to distinguish foreign molecules from the body's own. There are markers on many cells that confer this self-identifying feature. However, some classes of markers allow for RA to happen. The major histocompatibility complex encodes the cell-surface proteins known as the human leukocyte antigens (HLAs) that are responsible for self-identification. In some populations, some HLA genotypes are associated with RA. Among anglo patients with RA, 70% express HLA-DR4, compared to 28% of patients without RA.[11] In Native Americans, a similar association occurs with HLA-DR9.[11]

Genes outside of the HLA region are also associated with RA. A single-nucleotide polymorphism (SNP) of the STAT4 gene is associated with both rheumatoid arthritis and systemic lupus erythematosus (SLE).[12]

The role of infections

Various infections have been suspected of contributing to RA. Examples are Mycoplasma[13], Erysipelothrix, Epstein-Barr virus, Parvovirus B19 and rubella have been suspected but never supported in epidemiological studies. Although tetracycline antibiotics have been used to treat RA, these antibiotics may have nonspecific immunomodulator effects.[14]

Treatment

There is no known cure for rheumatoid arthritis. However, many different types of treatment can be used to alleviate symptoms. Pharmacological treatment of RA can be divided into disease-modifying antirheumatic drugs (DMARDs), anti-inflammatory agents and analgesics.[15][16]

Treating to specific goals or targets may be most effective.[17]

Clinical practice guidelines

Clinical practice guidelines by the American College of Rheumatology recommend leflunomide or methotrexate as options for initial treatment.[18]

Systematic reviews

Systematic reviews of treatments suggests that etanercept best balances effectiveness and drug toxicity.[19][20]

Disease modifying anti-rheumatic agents

The term Disease Modifying Anti-Rheumatic Agent or Disease Modifying Anti-Rheumatic Drug (DMARD) refers to agents that show evidence of processes thought to underlie the disease, such as a raised erythrocyte sedimentation rate, reduced haemoglobin level, raised rheumatoid factor level and more recently, raised C-reactive protein level. "Agent" became more preferred than "drug" to be more inclusive of the various biological treatments.

More recently, the working definition is an agent that reduces the rate of damage to bone and cartilage. For other areas of medicine, disease-modifying treatment is coming into use for drugs that can stop or reverse a progressive disease.

Rationale for early use

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

Using DMARDs early reduces structural joint damage. In the early stage of the disease, the joints are increasingly infiltrated by cells of the immune system that signal to one another and are thought to set up self-perpetuating chronic inflammation. Interrupting this process as early as possible with an effective DMARD (such as methotrexate) appears to improve the outcome from the RA for years afterwards. Delaying therapy for as little as a few months after the onset of symptoms can result in worse outcomes in the long term..[21]

Types of DMARDS

Many rheumatologists consider methotrexate to be the most important and useful DMARD, largely because of lower rates of stopping the drug through toxicity; however, a systematic review was not able to conclude that any one or combination of DMARDs was preferable.[22]

DMARDs can be further subdivided into traditional small molecular mass drugs synthesised chemically and newer 'biological' agents produced through genetic engineering.

Small molecular mass drugs

Traditional small molecular mass drugs:

The most important and most common adverse events relate to liver and bone marrow toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds, D-penicillamine), renal toxicity (cyclosporine A, parenteral gold salts, D-penicillamine), pneumonitis (MTX), allergic skin reactions (gold compounds, SSZ), autoimmunity (D-penicillamine, SSZ, minocycline) and infections (azathioprine, cyclosporine A). Hydroxychloroquine may cause ocular toxicity, although this is rare, and because hydroxychloroquine does not affect the bone marrow or liver it is often considered to be the DMARD with the least toxicity. Unfortunately hydroxychloroquine is not very potent, and for most patients hydroxychloroquine alone is insufficient to control symptoms.

Biological agents

Systematic reviews have compared available biological agents.[23][24] Biological agents include:

Anti-inflammatory drugs

Anti-inflammatory agents include:

Analgesics

Analgesics include:

Non-drug treatments

Other therapies are weight loss, occupational therapy, podiatry, physiotherapy, joint injections, and special tools to improve hard movements (e.g. special tin-openers).

Severely affected joints may require joint replacement surgery, such as knee replacement.

Historical treatments

Historical treatments for this condition have included: gold salts, RICE, acupuncture, apple diet, nutmeg, some light exercise every now and then, nettles, bee venom, prayer, copper bracelets, rhubarb diet , rest, extractions of teeth, fasting, honey, vitamins, insulin, magnets, and electric convulsion therapy (ECT).[30] Cortisone therapy has offered relief to many patients in the past, but its long-term effects have been deemed undesirable.[31]

Investigational treatments

Anti-cytokines

Recent research indicates that cytokines, a group of chemicals that are produced by various cells in the body, may be responsible for generating the response of chronic pain associated with Rheumatoid Arthritis. Medications that affect the release of cytokines or block the action of cytokines may reduce the response of chronic pain. Thalidomide, is being evaluated for its effect in treating chronic pain associated with Arachnoiditis.

Specific desensitization

An experimental treatment known as enzyme potentiated desensitization (EPD) is now under development for the treatment of rheumatoid arthritis and other autoimmune diseases. EPD uses dilutions of allergen (in this case type 2 collagen) and an enzyme, β-glucuronidase, to which T-regulatory lymphocytes respond by favouring desensitization, rather than sensitization. Initial results are encouraging [32] but the treatment is still at an early stage of development.

Other

For certain patients shown to be unresponsive to or intolerant of DMARDs, the Prosorba column blood filtering device appeared promising after the FDA approved it for treatment of RA in 1999 [33]. The Prosorba column employs protein A covalently bound to an inert silica matrix. The protein A binds immunoglobulin G (IgG) and circulating immune complexes (CIC). This blocks antigens responsible for autoimmune joint deterioration. [2]

Prognosis

The course of the disease varies greatly from patient to patient. Some patients have mild short-term symptoms, but in most the disease is progressive for life. Around 20%-30% will have subcutaneous nodules (known as rheumatoid nodules); this is associated with a poor prognosis.

Disability

  • Daily living activities are impaired in most patients.
  • After 5 years of disease, approximately 33% of patients will not be working
  • After 10 years, approximately half will have substantial functional disability.

Prognostic factors

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

Mortality

Estimates of the life-shortening effect of RA vary; most sources cite a lifespan reduction of 5 to 10 years; the National Institutes of Health has estimated a lifespan reduction of 10 to 20 years.[34] According to the UK's National Rheumatoid Arthritis Society, "Young age at onset, long disease duration, the concurrent presence of other health problems (called co-morbidity), and characteristics of severe RA – such as poor functional ability or overall health status, a lot of joint damage on x-rays, the need for hospitalisation or involvement of organs other than the joints – have been shown to associate with higher mortality".[35] Positive responses to treatment may indicate a better prognosis. A 2005 study by the Mayo Clinic noted that RA patients suffer a doubled risk of heart disease,[36] independent of other risk factors such as diabetes, alcohol abuse, and elevated cholesterol, blood pressure and body mass index. The mechanism by which RA causes this increased risk remains unknown; the presence of chronic inflammation has been proposed as a contributing factor.[37]

History

To delineate the history of rheumatoid arthritis a researcher must rely on scanty and ambiguous data from old medical literature and buried skeletons. The current consensus is too speculative for the taste of some scholars. Nevertheless a tentative best guess has emerged.

The first known traces of arthritis date back at least as far as 4500 BC. A text dated 123 AD first describes symptoms very similar to rheumatoid arthritis. It was noted in skeletal remains of Native Americans found in Tennessee.[38] In the Old World the disease is vanishingly rare before the 1600s.[39] and on this basis investigators believe it spread across the Atlantic during the Age of Exploration. In 1859 the disease acquired its current name.

A fascinating anomaly has been noticed from investigation of Precolumbian bones. The bones from the Tennessee site show no signs of tuberculosis even though it was prevalent at the time throughout the Americas.[40]Jim Mobley, at Pfizer, has discovered a historical pattern of epidemics of tuberculosis followed by a surge in the number of rheumatoid arthritis cases a few generations later.[41] Mobley attributes the spikes in arthritis to selective pressure caused by tuberculosis. A hypervigilant immune system is protective against tuberculosis at the cost of an increased risk of autoimmune disease.

The art of Peter Paul Rubens may depict the effects of rheumatoid arthritis, for it is presumed that he used his own hands as a model. In his later paintings, his rendered hands show increasing deformity consistent with the symptoms of the disease.[42][43]


References

  1. ↑ Johns Hopkins University: Rheumatoid Arthritis
  2. ↑ Dequeker J., Rico H. (1992). "Rheumatoid arthritis-like deformities in an early 16th-century painting of the Flemish-Dutch school". Jama 268: 249-251. PMID 1608144.
  3. ↑ Oxfordjournals - kel011v1
  4. ↑ Aletaha D et al. 2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010 Sep; 62:2569. DOI:10.1002/art.27584 http://pubmed.gov/20872595
  5. ↑ Arnett F, Edworthy S, Bloch D, McShane D, Fries J, Cooper N, Healey L, Kaplan S, Liang M, Luthra H (1988). "The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.". Arthritis Rheum 31 (3): 315-24.
  6. ↑ Rheumatoid Factor. Lab Tests Online. American Association for Clinical Chemistry (September 30, 2006). Retrieved on 2006-10-28.
  7. ↑ 7.0 7.1 7.2 7.3 Nishimura K, Sugiyama D, Kogata Y, et al (2007). "Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis". Ann. Intern. Med. 146 (11): 797–808. PMID 17548411. [e]
  8. ↑ CCP (Cyclic Citrullinated Peptide antibody). Lab Tests Online. American Association for Clinical Chemistry (January 15, 2005). Retrieved on 2006-10-28.
  9. ↑ 9.0 9.1 9.2 Whiting, Penny F.; Nynke Smidt, Jonathan A.C. Sterne, Roger Harbord, Anya Burton, Margaret Burke, Rebecca Beynon, Yoav Ben-Shlomo, John Axford, Paul Dieppe (2010-04-06). "Systematic Review: Accuracy of Anti–Citrullinated Peptide Antibodies for Diagnosing Rheumatoid Arthritis". Annals of Internal Medicine 152 (7): 456-464. DOI:10.1059/0003-4819-152-7-201004060-00010. Retrieved on 2010-04-06. Research Blogging.
  10. ↑ Turesson, Carl. Increased Alcohol Intake Associated with Decreased Risk of Developing Rheumatoid Arthritis. (Abstract) Paper presented at the annual European Congress of Rheumatology. Barcelona, Spain. June 13-16, 2007. European League Against Rheumatism, June 15, 2007; Myllykangas-Lusojarvi, R., Aho, K., Kautiainen, H., and Hakala, M. Reduced incidence of alcohol related deaths in subjects with rheumatoid arthritis. Annals of Rheumatoid Diseases, 2000, 59, 75-76; Voight, L., et al. Smoking, obesity, alcohol consumption and the risk of rheumatoid arthritis. Epidemiology, 1994, 5, 525-532
  11. ↑ 11.0 11.1 Smith JB, Haynes MK (2002). "Rheumatoid arthritis--a molecular understanding". Ann. Intern. Med. 136 (12): 908–22. PMID 12069565. [e]
  12. ↑ Remmers EF, Plenge RM, Lee AT, et al (2007). "STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus". N. Engl. J. Med. 357 (10): 977–86. DOI:10.1056/NEJMoa073003. PMID 17804842. Research Blogging.
  13. ↑ Clark HW, Coker-Vann MR, Bailey JS, Brown TM (1988). "Detection of mycoplasmal antigens in immune complexes from rheumatoid arthritis synovial fluids". Annals of allergy 60 (5): 394–8. PMID 3369750. [e]
  14. ↑ Reeta KH, Mediratta PK, Mahajan P, Sharma KK (2002). "Effect of minocycline and tetracycline on immunological responses in experimental animals". Indian journal of medical sciences 56 (11): 553–9. PMID 14510338. [e]
  15. ↑ O'Dell J (2004). "Therapeutic strategies for rheumatoid arthritis.". N Engl J Med 350 (25): 2591-602. PMID 15201416.
  16. ↑ Hasler P (Jun 2006). "Biological therapies directed against cells in autoimmune disease.". Springer Semin Immunopathol 27 (4): 443-56. PMID 16738955.
  17. ↑ Schoels M, Knevel R, Aletaha D, Bijlsma JW, Breedveld FC, Boumpas DT et al. (2010). "Evidence for treating rheumatoid arthritis to target: results of a systematic literature search.". Ann Rheum Dis 69 (4): 638-43. DOI:10.1136/ard.2009.123976. PMID 20237123. Research Blogging.
  18. ↑ Saag KG et al. (2008) 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis. Arthritis & Rheumatism
  19. ↑ Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA et al. (2009). "A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview.". CMAJ 181 (11): 787-96. DOI:10.1503/cmaj.091391. PMID 19884297. PMC PMC2780484. Research Blogging.
  20. ↑ Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA et al. (2009). "Biologics for rheumatoid arthritis: an overview of Cochrane reviews.". Cochrane Database Syst Rev (4): CD007848. DOI:10.1002/14651858.CD007848.pub2. PMID 19821440. Research Blogging.
  21. ↑ Vital E, Emery P (Sep 15 2005). "Advances in the treatment of early rheumatoid arthritis.". Am Fam Physician 72 (6): 1002, 1004. PMID 16190499.
  22. ↑ Donahue KE, Gartlehner G, Jonas DE, et al (2008). "Systematic review: comparative effectiveness and harms of disease-modifying medications for rheumatoid arthritis". Ann. Intern. Med. 148 (2): 124–34. PMID 18025440. [e]
  23. ↑ Kristensen L, Jakobsen A, Bartels E, Geborek P, Bliddal H, Saxne T et al. (2010). "The number needed to treat for second-generation biologics when treating established rheumatoid arthritis: a systematic quantitative review of randomized controlled trials.". Scand J Rheumatol. DOI:10.3109/03009742.2010.491834. PMID 20950126. Research Blogging.
  24. ↑ Nam JL, Winthrop KL, van Vollenhoven RF, Pavelka K, Valesini G, Hensor EM et al. (2010). "Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA.". Ann Rheum Dis 69 (6): 976-86. DOI:10.1136/ard.2009.126573. PMID 20447957. Research Blogging.
  25. ↑ Dentener MA, Wouters EF (2006). "Tumor necrosis factor inhibitors for rheumatoid arthritis.". N Engl J Med 355 (19): 2047-8; author reply 2048. PMID 17099951. [e]
  26. ↑ National Collaborating Centre for Chronic Conditions. Rheumatoid arthritis: the management of rheumatoid arthritis in adults. London (UK): National Institute for Health and Clinical Excellence (NICE); 2009 Feb. 35 p. (NICE clinical guideline; no. 79).
  27. ↑ Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR et al. (2004). "Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.". N Engl J Med 350 (25): 2572-81. DOI:10.1056/NEJMoa032534. PMID 15201414. Research Blogging.
  28. ↑ Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C et al. (2006). "Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial.". Ann Intern Med 144 (12): 865-76. PMID 16785475. [e]
  29. ↑ Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J et al. (2005). "Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition.". N Engl J Med 353 (11): 1114-23. DOI:10.1056/NEJMoa050524. PMID 16162882. Research Blogging.
  30. ↑ Hart FD (1976). "History of the treatment of rheumatoid arthritis". British medical journal 1 (6012): 763–5. PMID 177148. [e]
  31. ↑ BOLAND EW, HEADLEY NE (1951). "Results of long-continued cortisone administration in rheumatoid arthritis". California medicine 74 (6): 416–23. PMID 14848703. [e]
  32. ↑ EPD treatment of rheumatoid arthritis proof of concept results on Epidyme website use of EPD to treat autoimmune diseases.
  33. ↑ Fresenius HemoCare, Inc., "New Hope for Rheumatoid Arthritis Patients," press release, September 17, 1999. Dr. Gerónimo Lluberas is quoted as saying, "It offers a bright new promise to those that are otherwise unresponsive to this dreadful disease." Also see arthritis.about.com [1]
  34. ↑ [www.nih.gov/about/researchresultsforthepublic/arthritis.pdf Rheumatoid arthritis prognosis]
  35. ↑ Excess mortality in rheumatoid arthritis
  36. ↑ The second largest contributor of mortality is cerebrovascular disease. Increased risk of heart disease in rheumatoid arthritis patients
  37. ↑ Cardiac disease in rheumatoid arthritis
  38. ↑ http://mcclungmuseum.utk.edu/research/renotes/rn-05txt.htm Tennessee Origins of Rheumatoid Arthritis
  39. ↑ http://www.arc.org.uk/newsviews/arctdy/104/bones.htm Bones of Contention
  40. ↑ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14528501&dopt=Abstract Unified theory of the origins of erosive arthritis: conditioning as a protective/directing mechanism?
  41. ↑ http://media.www.michigandaily.com/media/storage/paper851/news/2005/02/01/News/Scientist.Finds.Surprising.Links.Between.Arthritis.And.Tuberculosis-1428389.shtml?sourcedomain=www.michigandaily.com&MIIHost=media.collegepublisher.com Scientist finds surprising links between arthritis and tuberculosis
  42. ↑ JAMA article - Rubens and the question of antiquity of rheumatoid arthritis
  43. ↑ http://japan.medscape.com/viewarticle/538251 Did RA travel from New World to Old? The Rubens connection
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