cs;slf;f k;

fPy; thA tsp moy; fPy; thA kUj;Jtk; o cs;kUe;J o ntsp kUe;J rpwg;G kUj;Jtk; Rheumatoid Arthritis pathophysiology Pathogenesis Clinical Features Criteria for diagnosis Complications Investigations Management

RHEUMATOID ARTHRITIS Rheumatoid arthritis (RA) is an autoimmune disease that results in a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attac s fle!ible (synovial) "oints# It can be a disabling and painful condition, $hich can lead to substantial loss of functioning and mobility if not ade%uately treated# &he process involves an inflammatory response of the capsule around the "oints (synovium) secondary to s$elling (turgescence) of synovial cells, e!cess synovial fluid, and the development of fibrous tissue (pannus) in the synovium# &he pathology of the disease process often leads to the destruction of articular cartilage and an ylosis (fusion) of the "oints# RA can also produce diffuse inflammation in the lungs, the membrane around the heart (pericardium), the membranes of the lung (pleura), and $hite of the eye (sclera), and also nodular lesions, most common in subcutaneous tissue# Although the cause of RA is un no$n, autoimmunity plays a big part, and RA is a systemic autoimmune disease# It is a clinical diagnosis made on the basis of symptoms, physical e!am, radiographs ('(rays) and labs#)*+ &reatments are pharmacological and non(pharmacological# ,on(

pharmacological treatment includes physical therapy, orthoses, occupational therapy and nutritional therapy but these don-t stop the progression of "oint destruction# Analgesia (pain illers) and anti(inflammatory drugs, including steroids, suppress symptoms, but don-t stop the progression of "oint destruction either# .isease(modifying antirheumatic drugs (.MAR.s) slo$

or halt the progress of the disease# &he ne$er biologics are .MAR.s#)*+ &he evidence for complementary and alternative medicine (CAM) treatments for RA related pain is $ea ,)/+ $ith the lac of high %uality evidence leading to the conclusions that their use is currently not supported by the evidence# )0+ Patients should inform their health care provider of any CAM treatments and continue ta ing traditional treatments#)1+ About 2#34 of the 5nited 6tates adult population has RA, $omen t$o to three times as often as men# )7+ 8nset is most fre%uent during middle age, but people of any age can be affected#)3+ &he name is based on the term 9rheumatic fever9, an illness $hich includes "oint pain and is derived from the :ree $ord -rheuma (nom.), -rheumatos (gen.) (9flo$, current9)# &he suffi! ( oid (9resembling9) gives the translation as joint inflammation that resembles rheumatic fe er# &he first recogni;ed description of RA $as made in *<22 by .r# Augustin =acob >andr?(@eauvais (*AA/B*<12) of Paris#)A+ Signs and symptoms RA primarily affects "oints, ho$ever it also affects other organs in *7B/74 of individuals#)<+ It can be difficult to determine $hether disease manifestations are directly caused by the rheumatoid process itself, or from side effects of the medications used to treat it B for e!ample, lung fibrosis from methotre!ate or osteoporosis from corticosteroids#

Joints

A diagram sho$ing ho$ rheumatoid arthritis affects a "oint Arthritis of "oints involves inflammation of the synovial membrane# =oints become s$ollen, tender and $arm, and stiffness limits their movement# Cith time, multiple "oints are affected (it is a polyarthritis)# Most commonly involved are the small "oints of the hands, feet and cervical spine, but larger "oints li e the shoulder and nee can also be involved# surface causing deformity and loss of function#)*+ RA typically manifests $ith signs of inflammation, $ith the affected "oints being s$ollen, $arm, painful and stiff, particularly early in the morning on
)D+ E*2<D

6ynovitis can

lead to tethering of tissue $ith loss of movement and erosion of the "oint

$a ing or follo$ing prolonged inactivity# Increased stiffness early in the morning is often a prominent feature of the disease and typically lasts for more than an hour# :entle movements may relieve symptoms in early stages of the disease# &hese signs help distinguish rheumatoid from non( inflammatory problems of the "oints, often referred to as osteoarthritis or 9$ear(and(tear9 arthritis# In arthritis of non(inflammatory causes, signs of inflammation and early morning stiffness are less prominent $ith stiffness typically less than * hour, and movements induce pain caused by mechanical arthritis#)*2+ In RA, the "oints are often affected in a fairly symmetrical fashion, although this is not specific, and the initial presentation may be asymmetrical#)D+ E*2<D As the pathology progresses the inflammatory activity leads to tendon tethering and erosion and destruction of the "oint surface, $hich impairs range of movement and leads to deformity# &he fingers may suffer from almost any deformity depending on $hich "oints are most involved# 6pecific deformities, $hich also occur in osteoarthritis, include ulnar deviation, boutonniere deformity, s$an nec deformity and 9F(thumb#9 9F(thumb9 or 9F(deformity9 consists of hypere!tension of the interphalangeal "oint, fi!ed fle!ion and sublu!ation of the metacarpophalangeal "oint and gives a 9F9 appearance to the thumb#
)D+ E*2<D

&he hammer toe deformity may be seen# In

the $orst case, "oints are no$n as arthritis mutilans due to the mutilating nature of the deformities#)citation needed+ Skin &he rheumatoid nodule, $hich is sometimes cutaneous, is the feature most characteristic of RA# It is a type of inflammatory reaction no$n to

pathologists as a 9necroti;ing granuloma9# &he initial pathologic process in nodule formation is un no$n but may be essentially the same as the synovitis, since similar structural features occur in both# &he nodule has a central area of fibrinoid necrosis that may be fissured and $hich corresponds to the fibrin(rich necrotic material found in and around an affected synovial space# 6urrounding the necrosis is a layer of palisading macrophages and fibroblasts, corresponding to the intimal layer in synovium and a cuff of connective tissue containing clusters of lymphocytes and plasma cells, corresponding to the subintimal ;one in synovitis# &he typical rheumatoid nodule may be a fe$ millimetres to a fe$ centimetres in diameter and is usually found over bony prominences, such as the olecranon, the calcaneal tuberosity, the metacarpophalangeal "oint, or other areas that sustain repeated mechanical stress# ,odules are associated $ith a positive RF (rheumatoid factor) titer and severe erosive arthritis# Rarely, these can occur in internal organs or at diverse sites on the body# 6everal forms of asculitis occur in RA# A benign form occurs as (reticulum) of erythematous to purplish

microinfarcts around the nailfolds# More severe forms include livedo reticularis, $hich is a net$or capillaropathy# 8ther, rather rare, s in associated symptoms include pyoderma discoloration of the s in caused by the presence of an obliterative cutaneous

gangrenosum, 6$eet-s syndrome, drug reactions, erythema nodosum, lobe panniculitis, atrophy of finger s in, palmar erythema, diffuse thinning (rice paper s in), and s in fragility (often $orsened by corticosteroid use)#

Lungs Fibrosis of the lungs is a recogni;ed response to rheumatoid disease# It is also a rare but $ell recogni;ed conse%uence of therapy (for e!ample $ith methotre!ate and leflunomide)# Caplan-s syndrome describes lung nodules in individuals $ith RA and additional e!posure to coal dust# Pleural effusions are also associated $ith RA# Another complication of RA is Rheumatoid >ung .isease# It is estimated that about one %uarter of Americans $ith RA develop Rheumatoid >ung .isease#)**+ Kidneys Renal amyloidosis can occur as a conse%uence of chronic inflammation# )*/+ RA may affect the idney glomerulus directly through a vasculopathy or a mesangial infiltrate but this is less $ell documented (though this is not surprising, considering immune comple!(mediated hypersensitivities are no$n for pathogenic deposition of immune comple!es in organs $here blood is filtered at high pressure to form other fluids, such as urine and synovial fluid)*0+)# &reatment $ith Penicillamine and gold salts are recogni;ed causes of membranous nephropathy# Heart and !ood "esse!s People $ith RA are more prone to atherosclerosis, and ris of myocardial infarction (heart attac ) and stro e is mar edly increased#)*1+)*7+ 8ther possible complications that may arise includeE pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis#)*3+ Many people $ith RA do not e!perience the same chest pain that others feel $hen they have angina or myocardial infarction# &o reduce cardiovascular ris , it is crucial to maintain

optimal control of the inflammation caused by RA ($hich may be involved in causing the cardiovascular ris ), and to use e!ercise and medications appropriately to reduce other cardiovascular ris factors such as blood lipids and blood pressure# .octors $ho treat RA patients should be sensitive to cardiovascular ris $hen prescribing anti(inflammatory medications, and may $ant to consider prescribing routine use of lo$ doses of aspirin if the gastrointestinal effects are tolerable#)*3+ Other 8cular &he eye is directly affected in the form of episcleritis $hich $hen severe can very rarely progress to perforating scleromalacia# Rather more common is the indirect effect of eratocon"unctivitis sicca, $hich is a dryness of eyes and mouth caused by lymphocyte infiltration of lacrimal and salivary glands# Chen severe, dryness of the cornea can lead to eratitis and loss of vision# Preventive treatment of severe dryness $ith measures such as nasolacrimal duct bloc age is important# Gepatic Cyto ine production in "oints andHor hepatic (liver) Iupffer cells leads to increased activity of hepatocytes $ith increased production of acute(phase proteins, such as C(reactive protein, and increased release of en;ymes such as al aline phosphatase into the blood# In Felty-s syndrome, Iupffer cell activation is so mar ed that the resulting increase in hepatocyte activity is associated $ith nodular hyperplasia of the liver, $hich may be palpably enlarged# Although Iupffer cells are $ithin the hepatic parenchyma, they are separate from

hepatocytes# As a result there is little or no microscopic evidence of hepatitis (immune(mediated destruction of hepatocytes)# Gepatic involvement in RA is essentially asymptomatic# Gematological Anemia is by far the most common abnormality of the blood cells $hich can be caused by a variety of mechanisms# &he chronic inflammation caused by RA leads to raised hepcidin levels, leading to anemia of chronic disease $here iron is poorly absorbed and also se%uestered into macrophages# RA may also cause a $arm autoimmune hemolytic anemia#)*A+ &he red cells are of normal si;e and colour (normocytic and normochromic)# A lo$ $hite blood cell count (neutropenia) usually only occurs in patients $ith Felty-s syndrome $ith an enlarged liver and spleen# &he mechanism of neutropenia is comple!# An increased platelet count (thrombocytosis) occurs $hen inflammation is uncontrolled# ,eurological Peripheral neuropathy and mononeuritis multiple! may occur# &he most common problem is carpal tunnel syndrome caused by compression of the median nerve by s$elling around the $rist# Atlanto(a!ial sublu!ation can occur, o$ing to erosion of the odontoid process andHor transverse ligaments in the cervical spine-s connection to the s ull# 6uch an erosion (J0mm) can give rise to vertebrae slipping over one another and compressing the spinal cord# Clumsiness is initially e!perienced, but $ithout due care this can progress to %uadriplegia#

Constitutional symptoms Constitutional symptoms including fatigue, lo$ grade fever, malaise, morning stiffness, loss of appetite and loss of $eight are common systemic manifestations seen in patients $ith active RA# 8steoporosis >ocal osteoporosis occurs in RA around inflamed "oints# It is postulated to be partially caused by inflammatory cyto ines# More general osteoporosis is probably contributed to by immobility, systemic cyto ine effects, local cyto ine release in bone marro$ and corticosteroid therapy# >ymphoma &he incidence of lymphoma is increased in RA, although it is still uncommon#)*<+)*D+ #auses RA is a form of autoimmunity, the causes of $hich are still not completely no$n# It is a systemic ($hole body) disorder principally affecting synovial tissues# &here is no evidence that physical and emotional effects or stress could be a trigger for the disease# &he many negative findings suggest that either the trigger varies, or that it might in fact be a chance event inherent $ith the immune response)/2+ Galf of the ris for RA is believed to be genetic# )/*+ It is strongly associated $ith the inherited tissue type ma"or histocompatibility comple! (MGC) antigen G>A(.R1 (most specifically .R212* and 2121), and the genes P&P,// and PA.I1Khence family history is an important ris factor# )//+)/0+ Inheriting the P&P,// gene has been sho$n to double a person-s

susceptibility to RA# PA.I1 has been identified as a ma"or ris factor in people of Asian descent, but not in those of Luropean descent# )/1+ First( degree relatives prevalence rate is /B04 and disease genetic concordance in mono;ygotic t$ins is appro!imately *7B/24#)/7+)/3+ 6mo ing is the most significant non(genetic ris
)/*+

$ith RA being up to

three times more common in smo ers than non(smo ers, particularly in men, heavy smo ers, and those $ho are rheumatoid factor positive#)/A+ Modest alcohol consumption may be protective#)/<+ Lpidemiological studies have confirmed a potential association bet$een RA and t$o herpesvirus infectionsELpstein(@arr virus (L@M) and Guman Gerpes Mirus 3 (GGM(3)#)/D+ Individuals $ith RA are more li ely to e!hibit an abnormal immune response to L@M and have high levels of anti(L@M antibodies#)02+ Mitamin . deficiency is common in those $ith RA and may be causally associated#)0*+ 6ome trials have found a decreased ris for RA $ith vitamin . supplementation $hile others have not#)0*+ $athophysio!ogy &he ey pieces of evidence relating to pathogenesis areE
*# A genetic lin $ith G>A(.R1 and related allotypes of MGC Class II

and the & cell(associated protein P&P,//#

/# An undeniable lin

to the pathogenesis of vascular disease of many

types, including the possibility of a strong causal connection to rheumatoid vasculitis, a typical feature of this condition#)0/+

0# A remar able deceleration of disease progression in many cases by

bloc ade of the cyto ine &,F (alpha)#

1# A similar dramatic response in many cases to depletion of @

lymphocytes, but no comparable response to depletion of & lymphocytes# 7# A more or less random pattern of $hether and $hen predisposed individuals are affected#
3# &he presence of autoantibodies to Ig:Fc,

no$n as rheumatoid

factors (RF), and antibodies to citrullinated peptides (ACPA)# &hese data suggest that the disease involves abnormal @ cellB& cell interaction, $ith presentation of antigens by @ cells to & cells via G>A(.R eliciting & cell help and conse%uent production of RF and ACPA# Inflammation is then driven either by @ cell or & cell products stimulating release of &,F and other cyto ines# &he process may be facilitated by an effect of smo ing on citrullination but the stochastic (random) epidemiology suggests that the rate limiting step in genesis of disease in predisposed individuals may be an inherent stochastic process $ithin the immune response such as immunoglobulin or & cell receptor gene recombination and mutation# (6ee entry under autoimmunity for general mechanisms#) If &,F release is stimulated by @ cell products in the form of RF or ACPA (containing immune comple!es, through activation of immunoglobulin Fc receptors, then RA can be seen as a form of &ype III hypersensitivity#)00+)01+ If &,F release is stimulated by & cell products such as interleu in(*A it might be considered closer to type IM hypersensitivity although this terminology may be getting some$hat dated and unhelpful#)07+ &he debate on the relative roles of immune comple!es and & cell products in inflammation in RA has

continued for 02 years# &here is little doubt that both @ and & cells are essential to the disease# Go$ever, there is good evidence for neither cell being necessary at the site of inflammation# &his tends to favour immune comple!es (based on antibody synthesised else$here) as the initiators, even if not the sole perpetuators of inflammation# Moreover, $or by &hurlings and others in Paul(Peter &a -s group and also by Arthur Iavanagh-s group suggest that if any immune cells are relevant locally they are the plasma cells, $hich derive from @ cells and produce in bul the antibodies selected at the @ cell stage#)citation needed+ Although &,F appears to be the dominant, other cyto ines (chemical mediators) are li ely to be involved in inflammation in RA# @loc ade of &,F does not benefit all patients or all tissues (lung disease and nodules may get $orse)# @loc ade of I>(*, I>(*7 and I>(3 also have beneficial effects and I>(*A may be important# Constitutional symptoms such as fever, malaise, loss of appetite and $eight loss are also caused by cyto ines released into the blood stream# As $ith most autoimmune diseases, it is important to distinguish bet$een the cause(s) that trigger the process, and those that may permit it to persist and progress# #!ini%a! &eatures A norma! immune response &he factors that allo$ an abnormal immune response, once initiated, to become permanent and chronic, are becoming more clearly understood# &he genetic association $ith G>A(.R1, as $ell as the ne$ly discovered

associations $ith the gene P&P,// and $ith t$o additional genes,)03+ all implicate altered thresholds in regulation of the adaptive immune response# It has also become clear from recent studies that these genetic factors may interact $ith the most clearly defined environmental ris factor for RA, namely cigarette smo ing)/A+)0A+ 8ther environmental factors also appear to modulate the ris of ac%uiring RA, and hormonal factors in the individual may e!plain some features of the disease, such as the higher occurrence in $omen, the not(infre%uent onset after child(birth, and the (slight) modulation of disease ris by hormonal medications# L!actly ho$ altered regulatory thresholds allo$ the triggering of a specific autoimmune response remains uncertain# Go$ever, one possibility is that negative feedbac mechanisms that normally maintain tolerance of self are overta en by aberrant positive feedbac mechanisms for certain antigens such as Ig: Fc (bound by RF) and citrullinated fibrinogen (bound by ACPA) (see entry on autoimmunity)# 8nce the abnormal immune response has become established ($hich may ta e several years before any symptoms occur), plasma cells derived from @ lymphocytes produce rheumatoid factors and ACPA of the Ig: and IgM classes in large %uantities# &hese are not deposited in the $ay that they are in systemic lupus# Rather, they activate macrophages through Fc receptor and complement binding, $hich seems to play an important role in the intense inflammatory response present in RA#)0<+ &his contributes to inflammation of the synovium, in terms of edema, vasodilation and infiltration by activated &(cells (mainly C.1 in nodular aggregates and C.< in diffuse infiltrates)# 6ynovial macrophages and dendritic cells further function as antigen presenting cells by e!pressing MGC class II molecules, leading to an

established local immune reaction in the tissue# &he disease progresses in concert $ith formation of granulation tissue at the edges of the synovial lining (pannus) $ith e!tensive angiogenesis and production of en;ymes that cause tissue damage# Modern pharmacological treatments of RA target these mediators# 8nce the inflammatory reaction is established, the synovium thic ens, the cartilage and the underlying bone begins to disintegrate and evidence of "oint destruction accrues# Diagnosis Imaging

'(ray of the hand in rheumatoid arthritis#

Appearance of synovial fluid from a "oint $ith inflammatory arthritis#

6igns of destruction and inflammation on ultrasonography and magnetic resonance imaging in the second metacarpophalangeal "oint in established RA# &hin arro$s indicate an erosive changeN thic arro$s indicate synovitis# 5ltrasonography (left side of image) in the (a) longitudinal and (b) the transverse planes sho$s both signs of destruction and inflammation# A!ial

&*($eighted magnetic resonance images $ere obtained (c) before and (d) after contrast administration, also demonstrating synovitis# Additionally, a coronal &*($eighted magnetic resonance image (e) before contrast administration visuali;es the same bone erosion as sho$n in panels c and d# '(rays of the hands and feet are generally performed in people $ith a polyarthritis# In RA, there may be no changes in the early stages of the disease, or the !(ray may demonstrate "u!ta(articular osteopenia, soft tissue s$elling and loss of "oint space# As the disease advances, there may be bony erosions and sublu!ation# '(rays of other "oints may be ta en if symptoms of pain or s$elling occur in those "oints# 8ther medical imaging techni%ues such as magnetic resonance imaging (MRI) and ultrasound are also used in RA#)citation needed+ &here have been technical advances in ultrasonography# Gigh(fre%uency transducers (*2 MG; or higher) have improved the spatial resolution of ultrasound imagesN these images can depict /24 more erosions than conventional radiography# Also, color .oppler and po$er .oppler ultrasound, $hich sho$ vascular signals of active synovitis depending on the degree of inflammation, are useful in assessing synovial inflammation# &his is important, since in the early stages of RA, the synovium is primarily affected, and synovitis seems to be the best predictive mar er of future "oint damage#)0D+ '!ood tests Chen RA is clinically suspected, immunological studies are re%uired, such as testing for the presence of rheumatoid factor (RF, a non(specific

antibody)#)12+ A negative RF does not rule out RAN rather, the arthritis is called seronegati e# &his is the case in about *74 of patients# )1*+ .uring the first year of illness, rheumatoid factor is more li ely to be negative $ith some individuals converting to seropositive status over time# RF is also seen in other illnesses, for e!ample 6"Ogren-s syndrome, Gepatitis C, chronic infections and in appro!imately *24 of the healthy population, therefore the test is not very specific# @ecause of this lo$ specificity, ne$ serological tests have been developed, $hich test for the presence of the anti(citrullinated protein antibodies (ACPAs) or anti(CCP# >i e RF, these tests are positive in only a proportion (3A4) of all RA cases, but are rarely positive if RA is not present, giving it a specificity of around D74#)1*+ As $ith RF, there is evidence for ACPAs being present in many cases even before onset of clinical disease#)citation needed+ &he most common tests for ACPAs are the anti(CCP (cyclic citrullinated peptide) test and the Anti(MCM assay (antibodies against mutated citrullinated Mimentin)# Recently a serological point(of(care test (P8C&) for the early detection of RA has been developed# &his assay combines the detection of rheumatoid factor and anti(MCM for diagnosis of RA and sho$s a sensitivity of A/4 and specificity of DD#A4#)1/+)10+ Also, several other blood tests are usually done to allo$ for other causes of arthritis, such as lupus erythematosus# &he erythrocyte sedimentation rate (L6R), C(reactive protein, full blood count, renal function, liver en;ymes and other immunological tests (e#g#, antinuclear antibodyHA,A) are all performed at this stage# Llevated ferritin levels can reveal hemochromatosis,

a mimic of RA, or be a sign of 6till-s disease, a seronegative, usually "uvenile, variant of rheumatoid arthritis#)citation needed+ #riteria (or diagnosis In /2*2 the !"#" $%& ' ()*$& &heumatoid $rthritis %lassification %riteria $ere introduced#)11+ &hese ne$ classification criteria overruled the 9old9 ACR criteria of *D<A and are adapted for early RA diagnosis# &he 9ne$9 classification criteria, "ointly published by the American College of Rheumatology (ACR) and the Luropean >eague Against Rheumatism (L5>AR) establish a point value bet$een 2 and *2# Lvery patient $ith a point total of 3 or higher is une%uivocally classified as an RA patient, provided he has synovitis in at least one "oint and given that there is no other diagnosis better e!plaining the synovitis# Four areas are covered in the diagnosisE)11+

"oint involvement, designating the metacarpophalangeal "oints, pro!imal interphalangeal "oints, the interphalangeal "oint of the thumb, second through fifth metatarsophalangeal "oint and $rist as small joints, and shoulders, elbo$s, hip "oints, nees, and an les as large jointsE
o o o

Involvement of * large "oint gives 2 points Involvement of /B*2 large "oints gives * point Involvement of *B0 small "oints ($ith or $ithout involvement of large "oints) gives / points Involvement of 1B*2 small "oints ($ith or $ithout involvement of large "oints) gives 0 points

Involvement of more than *2 "oints ($ith involvement of at least * small "oint) gives 7 points

serological parameters B including the rheumatoid factor as $ell as ACPA B 9ACPA9 stands for 9anti(citrullinated protein antibody9E
o o o

,egative RF and negative ACPA gives 2 points >o$(positive RF or lo$(positive ACPA gives / points Gigh(positive RF or high(positive ACPA gives 0 points

acute phase reactantsE * point for elevated erythrocyte sedimentation rate, L6R, or elevated CRP value (c(reactive protein) duration of arthritisE * point for symptoms lasting si! $ee s or longer

&he ne$ criteria accommodate to the gro$ing understanding of RA and the improvements in diagnosing RA and disease treatment# In the 9ne$9 criteria serology and autoimmune diagnostics carries ma"or $eight, as ACPA detection is appropriate to diagnose the disease in an early state, before "oints destructions occur# .estruction of the "oints vie$ed in radiological images $as a significant point of the ACR criteria from *D<A# )17+ &his criterion no longer is regarded to be relevant, as this is "ust the type of damage that treatment is meant to avoid# &he criteria are not intended for the diagnosis for routine clinical careN they $ere primarily intended to categori;e research (classification criteria)# In clinical practice, the follo$ing criteria applyE)citation needed+

t$o or more s$ollen "oints morning stiffness lasting more than one hour for at least si! $ee s the detection of rheumatoid factors or autoantibodies against ACPA such as autoantibodies to mutated citrullinated vimentin can confirm

the suspicion of RA# A negative autoantibody result does not e!clude a diagnosis of RA# Di((erentia! diagnoses 6everal other medical conditions can resemble RA, and usually need to be distinguished from it at the time of diagnosisE)13+)1A+

Crystal induced arthritis (gout, and pseudogout) B usually involves particular "oints ( nee, M&P*, heels) and can be distinguished $ith aspiration of "oint fluid if in doubt# Redness, asymmetric distribution of affected "oints, pain occurs at night and the starting pain is less than an hour $ith gout# 8steoarthritis B distinguished $ith '(rays of the affected "oints and blood tests, age (mostly older patients), starting pain less than an hour, a(symmetric distribution of affected "oints and pain $orsens $hen using "oint for longer periods# 6ystemic lupus erythematosus (6>L) B distinguished by specific clinical symptoms and blood tests (antibodies against double(stranded .,A) 8ne of the several types of psoriatic arthritis resembles RA B nail changes and s in symptoms distinguish bet$een them >yme disease causes erosive arthritis and may closely resemble RA B it may be distinguished by blood test in endemic areas Reactive arthritis (previously Reiter-s disease) B asymmetrically involves heel, sacroiliac "oints, and large "oints of the leg# It is usually associated $ith urethritis, con"unctivitis, iritis, painless buccal ulcers, and eratoderma blennorrhagica#

An ylosing spondylitis B this involves the spine, although a RA(li e symmetrical small("oint polyarthritis may occur in the conte!t of this condition# Gepatitis C B RA(li e symmetrical small("oint polyarthritis may occur in the conte!t of this condition# Gepatitis C may also induce Rheumatoid Factor auto(antibodies

Rarer causes that usually behave differently but may cause "oint painsE)13+

6arcoidosis, amyloidosis, and Chipple-s disease can also resemble RA# Gemochromatosis may cause hand "oint arthritis# Acute rheumatic fever can be differentiated from RA by a migratory pattern of "oint involvement and evidence of antecedent streptococcal infection# @acterial arthritis (such as streptococcus) is usually asymmetric, $hile RA usually involves both sides of the body symmetrically# :onococcal arthritis (another bacterial arthritis) is also initially migratory and can involve tendons around the $rists and an les#

Monitoring progression &he progression of RA can be follo$ed using scores such as +isease $cti it, -core of !. joints (.A6/<)# It is $idely used as an indicator of RA disease activity and response to treatment, but is not al$ays a reliable indicator of treatment effect#)1<+ &he "oints included in .A6/< are (bilaterally)E pro!imal interphalangeal "oints (*2 "oints), metacarpophalangeal "oints (*2), $rists (/), elbo$s (/), shoulders (/) and

nees (/)# Chen loo ing at these "oints, both the number of "oints $ith tenderness upon touching (TE)*+) and s$elling (S,*+) are counted# In addition, the erythrocyte sedimentation rate (ESR) is measured# Also, the patient ma es a sub"ective assessment (SA) of disease activity during the preceding A days on a scale bet$een 2 and *22, $here 2 is 9no activity9 and *22 is 9highest activity possible9# Cith these parameters, .A6/< is calculated asE)1D+

From this, the disease activity of the patient can be classified as follo$sE)1D+ #urrent DAS*+ P 0#/ J 0#/ but P 7#* J 7#* Inactive Moderate Mery active DAS*+ de%rease (rom initia! "a!ue J *#/ J 2#3 but P *#/ Moderate :ood improvement improvement Moderate Moderate improvement Moderate improvement improvement ,o improvement

P 2#3 ,o improvement ,o improvement ,o improvement

Management &here is no cure for RA, but treatments can improve symptoms and slo$ the progress of the disease# .isease(modifying treatment has the best results $hen it is started early and aggressively#)72+ &he goals of treatment are to minimi;e symptoms such as pain and s$elling, to prevent bone deformity (for e!ample, bone erosions visible in '(rays), and to maintain day(to(day functioning#)7*+ &his can often be achieved using t$o main classes of medicationsE analgesics such as ,6AI.s, and disease(

modifying antirheumatic drugs (.MAR.s)#)7/+ RA should generally be treated $ith at least one specific anti(rheumatic medication# )72+ &he use of ben;odia;epines (such as dia;epam) to treat the pain is not recommended as it does not appear to help and is associated $ith ris s# )70+ Analgesics, other than ,6AI.s, offer lesser, but some benefit $ith respect to pain# )/*+ $hilst not causing the same level of gastrointestinal irritation# Li(esty!e Regular e!ercise is recommended as both safe and useful to maintain muscles strength and overall physical function#)71+ It is uncertain if specific dietary measures have an effect#)77+ Disease modi(ying agents .isease(modifying antirheumatic drugs (.MAR.) are the primary treatment for RA#)/*+ &hey are a diverse collection of drugs, grouped by use and convention# &hey have been found to improve symptoms, decrease "oint damage, and improve overall functional abilities# )/*+ &hey should be started very early in the disease as $hen they result in disease remission in appro!imately half of people and improved outcomes overall#)73+ &he most commonly used agent is methotre!ate $ith other fre%uently used agents including sulfasala;ine and leflunomide# 6odium aurothiomalate (:old) and cyclosporin are less commonly used due to more common adverse effects# Agents may be used in combinations#)/*+ Methotre!ate is the most important and useful .MAR. and is usually the first treatment#)7*+)7/+)7A+ Adverse effects should be monitored regularly $ith

to!icity including gastrointestinal, hematologic, pulmonary, and hepatic#)7A+ 6ide effects such as nausea, vomiting or abdominal pain can be reduced by ta ing folic acid#)7<+ &he most common undesirable affect is that it increases liver en;ymes in almost *74 of people#)7A+ It is thus recommended that those $ho consistently demonstrate abnormal levels of liver en;ymes or have a history of liver disease or alcohol use undergo liver biopsies# )7D+ Methotre!ate is also considered a teratogenic and as such, it is recommended $omen of childbearing age should use contraceptives to avoid pregnancy and to discontinue its use if pregnancy is planned#)7*+)7A+ @iological agents should generally only be used if methotre!ate and other conventional agents are not effective after a trial of three months# )32+ &hese agents includeE tumor necrosis factor alpha (&,FQ) bloc ers)/*+ such as infli!imabN interleu in * bloc ers such as ana inra, monoclonal antibodies against @ cells such as ritu!imab,)3*+ & cell costimulation bloc er such as abatacept among others# &hey are often used in combination $ith either methotre!ate or leflunomide#)/*+ &,F bloc ers and methotre!ate appear to have similar effectiveness $hen used alone and better results are obtained $hen used together# &,F bloc ers appear to have e%uivalent effectiveness $ith etanercept appearing to be the safest#)3/+ Abatacept appears effective for RA $ith /24 more people improving $ith treatment than $ithout#)30+ &here ho$ever is a lac of evidence to distinguish bet$een the biologics available for RA#)31+ Issues $ith the biologics include their high cost and association $ith infections including tuberculosis#)/*+

Anti-in(!ammatory agents ,6AI.s reduce both pain and stiffness in those $ith RA#)/*+ :enerally they appear to have no effect on people-s long term disease course and thus are no longer first line agents#)/*+)37+ ,6AI.s should be used $ith caution in those $ith gastrointestinal, cardiovascular, or idney problems#)33+)3A+)3<+ C8'(/ inhibitors, such as celeco!ib, and ,6AI.s are e%ually effective#)3D+ &hey have a similar gastrointestinal ris as an ,6AI.s plus a proton pump inhibitor#)A2+ In the elderly there is less gastrointestinal intolerance to celeco!ib than to ,6AI.s alone#)A*+ &here ho$ever is an increased ris of myocardial infarction $ith C8'(/ inhibitors#)3D+ Anti(ulcer medications are not recommended routinely but only in those high ris of gastrointestinal problems#)A/+ :lucocorticoids can be used in the short term for flare(ups, $hile $aiting for slo$(onset drugs to ta e effect#)/*+ In"ection of glucocorticoids into individual "oints is also effective#)/*+ Chile long(term use reduces "oint damage it also results in osteoporosis and susceptibility to infections, and thus is not recommended#)/*+ Surgery In early phases of the disease, an arthroscopic or open synovectomy may be performed# It consists of the removal of the inflamed synovia and prevents a %uic destruction of the affected "oints# 6everely affected "oints may re%uire "oint replacement surgery, such as physiotherapy is al$ays necessary# nee replacement#)/*+ Postoperatively,

A!ternati"e medi%ine &here has been an increasing interest in the use of complementary and alternative medicine interventions for the treatment of pain in rheumatoid arthritis# Chile there have been multiple studies sho$ing beneficial effects in RA on a $ide variety of CAM modalities, these studies are often affected by publication bias and are generally not high %uality evidence such as randomi;ed controlled trials (RC&s), ma ing definitive conclusions difficult to reach#)/+ &he ,ational Center for Complementary and Alternative Medicine has concluded, 9In general, there is not enough scientific evidence to prove that any complementary health approaches are beneficial for RA, and there are safety concerns about some of them# 6ome mind and body practices and dietary supplements may help people $ith RA manage their symptoms and therefore may be beneficial additions to conventional RA treatments, but there is not enough evidence to dra$ conclusions#9 )1+ A systematic revie$ of CAM modalities (e!cluding fish oil) found 9&he ma"or limitation in revie$ing the evidence for CAMs is the paucity of RC&s in the area# &he available evidence does not support their current use in the management of RA#9)0+ 8ne revie$ suggests that of the various alternative medicine treatments evaluated, only acupuncture, bee venom acupuncture, herbal remedies, dietary omega(0 fatty acids, and pulsed electromagnetic field therapy have been studied $ith RC&s and sho$ promise in treating the pain of RA, though no definitive conclusions could be reached#)/+ Dietary supp!ements

&he American College of Rheumatology states that no herbal medicines have health claims supported by high %uality evidence and thus they do not recommend their use#)A0+ &here is no scientific basis to suggest that herbal supplements advertised as 9natural9 are safer for use than conventional medications as both are chemicals# Gerbal medications, although labelled 9natural9, may be to!ic or fatal if consumed# )A0+ 6ome evidence supports omega(0 fatty acids and gamma(linolenic acid in RA# )A1+ &he benefit from omega(0 appears modest but consistent,)A7+ though the current evidence is not strong enough to determine that supplementation $ith omega(0 polyunsaturated fatty acids (found in fish oil) is an effective treatment for RA#)A3+ :amma(linolenic acid, $hich may reduce pain, tender "oint count and stiffness, is generally safe#)AA+ &he follo$ing sho$ promise as treatments for RA, based on preliminary studiesE bos$ellic acid,)A<+ curcumin,)AD+ .evil-s cla$,)<2+)<*+ Luonymus alatus,
)</+

and &hunder god vine (/ri0ter,gium 1ilfordii)#)<0+

Gerbal supplements can often have significant side effects, and can interact $ith prescription medications being ta en at the same time# &hese ris s are often e!acerbated by the false general belief by patients that herbal supplements are al$ays safe and the hesitancy by patients in reporting the use of herbal supplements to physicians#)/+ ,CCAM has noted that, 9In particular, the herb thunder god vine (&ripterygium $ilfordii) can have serious side effects#9)1+ Manua! therapies

&he evidence for acupuncture is inconclusive)<1+ $ith it appearing to be e%uivalent to sham acupuncture#)<7+ $re"ention &here is no no$n prevention for the contraction# Reduction of ris factors and aggressive treatment after diagnosis are recommended actions#)<3+ $rognosis &he course of the disease varies greatly# 6ome people have mild short(term symptoms, but in most the disease is progressive for life# Around /24B024 $ill have subcutaneous nodules ( no$n as rheumatoid nodules)N this is associated $ith a poor prognosis# $rognosti% (a%tors Poor prognostic factors include persistent synovitis, early erosive disease, e!tra(articular findings (including subcutaneous rheumatoid nodules), positive serum RF findings, positive serum anti(CCP autoantibodies, carriership of G>A(.R1 96hared Lpitope9 alleles, family history of RA, poor functional status, socioeconomic factors, elevated acute phase response (erythrocyte sedimentation rate )L6R+, C(reactive protein )CRP+), and increased clinical severity# Morta!ity RA is no$n to reduce the lifespan of patients by any$here from three to */ years#)7*+ A ne$ line of research does, ho$ever, sho$ that the use of ne$ biologic drug therapies e!tend the lifespan of patients $ith RA and reduce

the ris

and progression of atherosclerosis# )<A+ According to the 5I-s

,ational Rheumatoid Arthritis 6ociety, 9Roung age at onset, long disease duration, the concurrent presence of other health problems (called co( morbidity), and characteristics of severe RAKsuch as poor functional ability or overall health status, a lot of "oint damage on !(rays, the need for hospitalisation or involvement of organs other than the "ointsKhave been sho$n to associate $ith higher mortality9#)<<+ Positive responses to treatment may indicate a better prognosis# A /227 study by the Mayo Clinic noted that RA sufferers suffer a doubled ris of heart disease, )<D+ independent of other ris factors such as diabetes, alcohol abuse, and elevated cholesterol, blood pressure and body mass inde!# &he mechanism by $hich RA causes this increased ris remains un no$nN the presence of chronic inflammation has been proposed as a contributing factor#)D2+ Epidemio!ogy .isability(ad"usted life year for RA per *22,222 inhabitants in /221#)D*+ no data S12 12B72 72B32 32BA2 A2B<2 <2BD2 RA affects bet$een 2#7 and *4 of adults in the developed $orld $ith bet$een 7 and 72 per *22,222 people ne$ly developing the condition each year#)/*+ In /2*2 it resulted in about 1D,222 deaths globally#)D/+ D2B*22 *22B**2 **2B*/2 */2B*02 *02B*12 J*12

8nset is uncommon under the age of *7 and from then on the incidence rises $ith age until the age of <2# Comen are affected three to five times as often as men# 6ome ,ative American groups have higher prevalence rates (7B34) and people from the Caribbean region have lo$er prevalence rates# &he age at $hich the disease most commonly starts is in $omen bet$een 12 and 72 years of age, and for men some$hat later# )D0+ RA is a chronic disease, and although rarely, a spontaneous remission may occur, the natural course is almost invariably one of persistent symptoms, $a!ing and $aning in intensity, and a progressive deterioration of "oint structures leading to deformations and disability#

History &he first no$n traces of arthritis date bac at least as far as 1722 @C# A te!t dated */0 A. first describes symptoms very similar to RA# It $as noted in s eletal remains of ,ative Americans found in &ennessee#)D1+ In the 8ld Corld, the disease is vanishingly rare before the *Ath century# )D7+ and on this basis investigators believe it spread across the Atlantic during the Age of L!ploration# In *<7D the disease ac%uired its current name# An anomaly has been noticed from investigation of Pre(Columbian bones# &he bones from the &ennessee site sho$ no signs of tuberculosis even though it $as prevalent at the time throughout the Americas# )D3+ =im Mobley, at Pfi;er, has discovered a historical pattern of epidemics of tuberculosis follo$ed by a surge in the number of RA cases a fe$ generations later# )DA+ Mobley attributes the spi es in arthritis to selective pressure caused by tuberculosis# A hypervigilant immune system is protective against tuberculosis at the cost of an increased ris of autoimmune disease# &he art of Peter Paul Rubens may possibly depict the effects of RA# In his later paintings, his rendered hands sho$, in the opinion of some physicians, increasing deformity consistent $ith the symptoms of the disease# )D<+)DD+ RA appears to some to have been depicted in *3th(century paintings#)*22+ Go$ever, it is generally recognised in art historical circles that the painting of hands in the *3th and *Ath century follo$ed certain stylised conventions, most clearly seen in the Mannerist movement# It $as conventional, for instance to sho$ the upheld right hand of Christ in $hat no$ appears a

deformed posture# &hese conventions are easily misinterpreted as portrayals of disease# &hey are much too $idespread for this to be plausible# &he first recogni;ed description of RA $as in *<22 by the French physician .r Augustin =acob >andr?(@eauvais (*AA/B*<12) $ho $as based in the famed 6alpTtriUre Gospital in Paris#)A+ &he name 9rheumatoid arthritis9 itself $as coined in *<7D by @ritish rheumatologist .r Alfred @aring :arrod#)*2*+ Gistoric treatments for RA have also includedE rest, ice, compression and elevation, apple diet, nutmeg, some light e!ercise every no$ and then, nettles, bee venom, copper bracelets, rhubarb diet, e!tractions of teeth, fasting, honey, vitamins, insulin, magnets, and electroconvulsive therapy (LC&)#)*2/+ Most of these have either had no effect at all, or their effects have been modest and transient, $hile not being generali;able# )citation
needed+

&he

Prosorba column blood filtering device (removing Ig:) $as approved by the F.A in *DDD for treatment of RA)*20+ Go$ever it $as discontinued at the end of /223#)*21+