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Polyarthrite rhumatoïde / Rheumatoid arthritis RA

Polyarthrite rhumatoïde

La polyarthrite rhumatoïde (PR) est la cause la plus fréquente des polyarthrites chroniques.

Elle est caractérisée par une atteinte articulaire souvent bilatérale et symétrique, évoluant par poussées vers la déformation et la destruction des articulations atteintes.

Le diagnostic peut en être malaisé au début de son évolution, en raison de l'absence de signe clinique spécifique, du caractère inconstant des signes biologiques, et du retard d'apparition des érosions articulaires radiologiques.

Sommaire

Synonymes

  • polyarthrite chronique évolutive (PCE) (F. Costes et J. Forestier, 1929), polyarthrite rhumatismalearthrite rhumatoïdearthrodynie (Cullen), goutte asthénique primitive (Landré-Beauvais), polyarthrite chronique déformante ou p.c. inflammatoire ou p.c. rhumatismale (De sèze et Ryckewaert) ou p.c. symétrique progressive (Bezançon et M.P.Weil), rhumatisme chronique déformant (Teissier et Roque) ou rh. ch. progressif généralisé ou rh. ch. progressif infectieux (Weissenbach et Françon) ou rh. articulaire chronique progressif (Charcot, 1853)
  • Anglais : rheumatoid arthritis

Épidémiologie

La polyarthrite rhumatoïde est le plus fréquent des rhumatismes inflammatoires de l'adulte.

On évalue sa prévalence entre 0,3 et 0,8 % selon les pays. En France, elle est située à 0,4 %1.

Il existe une nette prédominance féminine avec un sex-ratio de 3/1, mais cette différence semble s'atténuer avec l'âge.

Le pic de fréquence se situe autour de la quarantaine, cependant la maladie peut débuter à tout âge y compris chez l'enfant (cf. arthrites juvéniles idiopathiques).

Il existe certains facteurs de risque environnementaux, dont le tabagisme, le surpoids2, l'exposition à la poussière de silice3.

Causes

La polyarthrite rhumatoïde est une maladie auto-immune d'origine inconnue.

Elle met en jeu des facteurs hormonaux, environnementaux (infections…), sur terrain génétique prédisposé, la part de ce dernier dépasse vraisemblablement les 50%4.

Les arguments pour une prédisposition génétique sont l'agrégation familiale de cas de polyarthrite rhumatoïde et la présence chez les sujets atteints des allèles HLA DR1 et DR4 dans 60 % des cas. La présence d'une mutation sur le gène PTPN22 qui code une tyrosine phosphatase double également le risque de développer la maladie qui est parfois plus grave5. Une mutation du gène TRAF1–C5 situé sur le chromosome 9 est également corrélé avec une forme plus grave de la polyarthrite rhumatoïde (avec présence d'anticorps anti-CCP : cyclic citrullinated peptide)6.

Les mécanismes immunologiques effecteurs sont multiples :

  • stimulation des lymphocytes T CD4+,
  • stimulation des lymphocytes B et différentiation en plasmocytes, responsables entre autres de sécrétion de facteurs rhumatoïdes et autres auto-anticorps
  • sécrétion de cytokines pro-inflammatoires intra-articulaire, principalement le TNFalpha, à l'origine des synovites et des érosions articulaires.

Signes cliniques au début

Différents degrés de déformations des doigts dans l'arthrite rhumatoide.

La maladie débute généralement par une polyarthrite, c'est-à-dire l'inflammation de quatre articulations ou plus, caractérisée par des douleurs d'horaire inflammatoire (réveils nocturnes, dérouillage matinal de durée supérieure à 30 minutes), une raideur articulaire et un gonflement appelé synovite.

Il existe peu de signes spécifiques pour différencier la polyarthrite rhumatoïde des autres causes de polyarthrite (cf. diagnostics différentiels). Cependant, certaines caractéristiques cliniques sont évocatrices :

  • L'évolution progressive et insidieuse : subaiguë, c'est-à-dire évoluant depuis plus de 2 semaines, ou surtout chronique évoluant depuis plus de 3 mois ;
  • Le siège des synovites aux petites articulations : poignets et chevilles et surtout mains et pieds au niveau des interphalangiennes proximales (ou IPP, entre 1re et 2e phalanges) et articulations métacarpo-phalangiennes (ou MCP, entre le métacarpien et la 1re phalange). Toutes les articulations peuvent cependant être atteintes en cours d'évolution : genoux, coudes, épaules, hanches, articulations temporo-mandibulaires… En revanche, les interphalangiennes distales (entre les 2e et 3e phalanges) et les sacro-iliaques sont toujours respectées. Le rachis est également épargné, à l'exception du rachis cervical.
  • La topographie en général bilatérale et symétrique.
  • L'intensité des signes inflammatoires locaux : tuméfaction chaude et douloureuse donnant l'aspect classique de "doigts en fuseaux" ;
  • La coexistence de ténosynovites (inflammation des tendons musculaires) ;
  • L'association possible à des nodosités cutanées appelées nodules rhumatoïdes. Localisés sur la face d'extension des coudes des doigts ou sur le tendon d'Achille, ils sont très spécifiques de la polyarthrite rhumatoîde mais inconstants et tardifs.

Examens biologiques

Il existe généralement un syndrome inflammatoire lorsque la maladie est en poussée, se traduisant par une augmentation de la vitesse de sédimentation et de la protéine C réactive. Il peut s'accompagner d'une hyperleucocytose à prédominance de polynucléaires neutrophiles et d'une anémie inflammatoire non spécifiques.

Les examens immunologiques dans le sérum peuvent retrouver :

  • un facteur rhumatoïde, détecté par les réactions de latex, Waaler-Rose, ou par des techniques plus modernes comme l'ELISA ou la néphélométrie. Le facteur rhumatoïde est une immunoglobuline (d'isotype M, G ou A) dirigée contre le fragment constant d'une autre immunoglobuline d'isotype G. Test sensible puisque présent dans 80% des polyarthrites rhumatoïdes, le dosage du facteur rhumatoïde présente l'inconvénient d'une faible spécificité (environ 50%) avec une fréquente positivité dans un grand nombre d'autres maladies. De plus, le test est fréquemment négatif en début d'évolution et ne se positive qu'au cours de la première année d'évolution.
  • des anticorps anti-CCP (cyclic citrullinated peptide) : présents dans seulement environ 60% des cas mais très spécifiques de la maladie (environ 95%)7. Il est d'ailleurs possible que les polyarthrites rhumatoïdes ne comportant pas ce type d'anticorps soient une forme différente de la maladie, le tabagisme, par exemple, influançant négativement les porteurs et restant sans effet chez les non-porteurs8.
  • rarement, des Anticorps antinucléaires à faible taux (30%).

La ponction articulaire retrouve plus de 1 000 leucocytes par millimètre cube, confirmant le caractère inflammatoire de l'épanchement. Elle n'a pas cependant pas d'intérêt pour le diagnostic sauf en cas de doute sur une polyarthrite de cause infectieuse (recherche de germe dans le liquide articulaire) ou microcristalline (recherche de cristaux d'urate de sodium dans la goutte, de pyrophosphate de calcium dans la chondrocalcinose).

Examens radiologiques

Le bilan radiographique initial minimal comporte des clichés des mains/poignets et des avant-pieds de face et de trois-quarts, des clichés de l'ensemble des articulations douloureuses et une radiographie pulmonaire.

Au cours de l'évolution, la surveillance des destructions doit comporter un bilan radiographique tous les six mois pendant les deux premières années, puis tous les ans à tous les deux ans. Un cliché dynamique du rachis cervical en flexion forcée doit être réalisé régulièrement afin de dépister les complications cervicales de la maladie.

Les signes radiologiques :

  • Ils sont discrets au début : déminéralisations osseuses périarticulaires, se traduisant par une hypertransparence osseuse autour des articulations, signe non spécifique présent dans l'ensemble des rhumatismes inflammatoires. Il existe un épaississement des parties molles périarticulaires.
  • Plus tard apparaîtront les destructions articulaires caractéristiques de la polyarthrite rhumatoïde : pincement de l'interligne articulaire, microgéodes (sortes de "trous" dans l'os sous-chondral) et érosions osseuses. L'érosion de la tête du 5e métatarsien, visible sur une radiographie des avant-pieds, constitue classiquement la destruction articulaire la plus précoce et est d'un grand intérêt diagnostique.
  • L'aboutissement des lésions est la destruction articulaire complète correspondant aux déformations observées à l'examen au bout de plusieurs années d'évolution : subluxations des métacarpo-phalangiennes et des interphalangiennes, flessum des coudes et genoux, ankyloses notamment du carpe (=poignet) etc...

Évolution

Évolution articulaire

Le plus souvent, l'évolution, qui s'étale sur des dizaines d'années, se fait par poussées, entrecoupées de rémissions de rythme et de durée imprévisibles. Au cours des poussées, la plupart des articulations sont gonflées et douloureuses, associées à des signes généraux (fièvre modérée ou fébrilcule, asthénie) et fréquemment d'un syndrome inflammatoire biologique. Le suivi de l'activité de la maladie peut se faire à l'aide de différents scores. Le plus utilisé en pratique clinique est le « DAS 28 », calculé à partir de quatre paramètres : l'indice articulaire ( nombre d 'articulations douloureuses - sauf pieds chevilles et hanches non comptabilisées ), l'indice synovial (nombre d 'articulations gonflées - sauf pieds chevilles et hanches), activité de la maladie évaluée sur une échelle de 0 à 100 par le patient, et vitesse de sédimentation.

Après plusieurs années d'évolution apparaissent les déformations caractéristiques, secondaires à la destruction articulaire et à l'atteinte tendineuse :

  • aux poignets : subluxation antérieure de la main, subluxation postérieure de la tête cubitale « en touche de piano » pouvant conduire à la rupture du tendon extenseur du 5e doigt.
  • aux mains : déformations des doigts en maillet (flexion de l'interphalangienne distale), en col de cygne (flexion de l'interphalangienne distale et hyperextension de l'interphalangienne proximale), ou en boutonnière (hyperextension de l'interphalangienne distale et flexion de l'interphalangienne proximale) ; déformation du pouce en Z ; fréquent« coup de vent cubital » des doigts (déviation latérale des doigts) ; aspect des mains « en dos de chameau » (gonflement des rangées des métacarpo phalangiennes et carpiennes et atrophie des muscles interosseux)
  • aux coudes et genoux : flessum irréductible ;
  • aux pieds : orteils « en marteau » ou en griffe, coup de vent péronier (déviation latérale des orteils), hallux valgus (déviation interne du 1er orteil) et quintus varus (déviation interne du 5e orteil) aboutissant à un avant-pied triangulaire, affaissement de la voûte plantaire ;
  • enraidissement des hanches et des épaules ;
  • sur le rachis cervical : atteinte tardive, comportant en particulier une possible subluxation atloïdo-axoidienne qui concerne les deux premières vertèbres et peut conduire à une compression de la moelle épinière cervicale en l'absence de traitement.
  • ruptures tendineuses compliquant l'évolution des ténosynovites.

Dans les polyarthrites très évoluées, les poussées inflammatoires ont tendance à devenir moins fréquentes. On assiste alors à l'extinction progressive de la maladie. À ce stade, les douleurs sont plus fréquemment d'horaire mécanique (prédominance le soir et aux mouvements, absence de dérouillage articulaire matinal) liées aux destructions articulaires.

La polyarthrite rhumatoïde est une affection d'évolution et de gravité très hétérogènes. Le retentissement fonctionnel, socioprofessionnel, psychologique peut être considérable. Schématiquement on considère que 30% sont d'évolution relativement bénigne, 50% intermédiaires et 20% sévères. La définition de la sévérité n'est cependant pas consensuelle actuellement.

Actuellement, on rattache la gravité d'une polyarthrite rhumatoïde à l'altération de la qualité de vie qu'elle entraîne, évaluée par le score HAQ (Health Assessment Questionnaire) et à l'importance des destructions articulaires.

Évolution extra-articulaire

D'autres atteintes portant sur des organes extra-articulaires sont possibles : poumons, cœur, système nerveux périphérique, "syndrome sec" avec l'œil sec et bouche sèche (syndrome de Gougerot-Sjögren).

Traitement

La stratégie thérapeutique comporte plusieurs volets

Traitement symptomatique

Il permet le soulagement des symptômes. Il peut comporter le repos simple lors des poussées, les traitements antalgiques classiques, les anti-inflammatoires non stéroïdiens, les corticostéroïdes à faible dose, inférieure à 10 mg/jour pour en limiter les effets secondaires. Dans les poussées très inflammatoires polysynoviales, un ou plusieurs bolus peuvent être réalisées pour soulager rapidement le patient en attendant l'efficacité d'un nouveau traitement de fond.

Traitements de fond

Ils sont aussi appelés " DMARD" (disease modifying anti-rheumatic drugs) visant à contrôler les manifestations inflammatoires cliniques de la maladie, et à freiner son évolution destructrice. Leur efficacité est en général retardée (un à trois mois), suspensive (reprise d'activité à l'arrêt), et malheureusement inconstante, et épuisable obligeant à changer de molécule. Ils doivent donc être constamment adaptés à l'activité inflammatoire et à la sévérité de la maladie .

Principales molécules

Pratiquement abandonnés en raison d'une tolérance médiocre, ce sont les sels d'or et la D-pénicillamine.

Utilisé dans les polyarthrites peu actives et non érosives ou dans les polyarthrites inclassées, ce sont les antipaludéens de synthèse comme l'hydroxychloroquine (Plaquénil). Il possède une efficacité clinique mais ne prévient pas les destructions.

Le méthotrexate est utilisé en première intention à la dose de 10 à 20 mg/ semaine, par voie orale, sous-cutanée ou intra-musculaire. D'autres molécules sont également employées : léflunomide (Arava) ; sulfasalazine, (Salazopyrine). L'association de ces molécules (en particulier, salazopyrine + méthotrexate +/- hydroxyplaquenil) pourrait en améliorer l'efficacité ; cependant, cette idée reste discutée.

Dans les formes sévères, certains immunosuppresseurs comme l'azathioprine (Imurel), la ciclosporine (NeoralSandimmum) peuvent être employés.

Réservées aux formes sévères d'emblée, ou en cas d'échec ou d'échappement aux traitements précédents sont les biothérapies :

  • les anti-TNF alpha : infliximab (Remicade) en perfusions de 3 à 5 mg/kg toutes les 8 semaines, Etanercept (Enbrel) en sous-cutanée, adalimumab (Humira) en sous-cutanée. Leur efficacité clinique et radiologique est souvent spectaculaire, au prix d'effets secondaires de gravité variable, principalement infectieux (en particulier tuberculose mais aussi autres infections bactériennes et virus). L'initiation du traitement, de prescription hospitalière, comporte une recherche systématique de foyer infectieux et notamment d'une tuberculose latente. Ces molécules sont principalement associées à un autre traitement de fond (méthotrexate, léflunomide…) afin de prévenir l'apparition d'anticorps anti-antiTNFalpha, qui favoriseraient les résistances et les allergies au traitement, mais elles peuvent également être utilisées en monothérapie.
  • Un inhibiteur du CTLA4 : l'abatacept commercialisé sous le nom d'Orancia® est approuvé en France, dans la prise en charge des polyarthrites réfractaires aux anti TNF, il s'administre sous forme de perfusions mensuelles à la dose de 8 mg/ kg en une vingtaine de minutes, en association au méthotrexate.
  • les antagonistes du récepteur de l'interleukine-1 : anakinra (Kineret), peu utilisés en raison d'une efficacité médiocre.
  • un anti-CD20rituximab (Mabthera), après échec des anti-TNF alpha est également disponible, il est utilisé en association avec des perfusions de corticoides, deux perfusions à 15 jours d'intervalles, puis une perfusion tous les 6 mois, et a un effet de déplétion des lymphocytes B sur au moins six mois.
  • un inhibiteur de l'interleukine-6 : le tocilizumab (RoActemra), approuvé en France en décembre 2009, indiqué dans les échecs au méthotrexate en perfusion intra-veineuse toutes les 4 semaines, à la posologie de 8 mg/kg.
  • en cours d'évaluation : deux nouveaux anti-TNF alpha, le golimumab et le certolizumab pegol; d'autres anti CD 20 Ocrelizumab, et des inhibiteurs des MAP kinases.

Outre les molécules, les stratégies d'utilisations des traitements semblent également très importantes pour obtenir une rémission, plusieurs études comme TICORA, Fin RaCo, et BEST notamment suggèrent que l'utilisation précoces d'une combinaison de traitement de fond à bonne dose et tôt dans l'histoire de la maladie donnait plus de rémission, et permet plus souvent l'arrêt des anti TNF, que dans les suites d'une initiation tardive. De plus la mesure du DAS tous les trois mois avec un Seuil à 2,4 constitue un élément décisionnel important dans l'obtention d'une rémission.

Traitements locaux

Les infiltrations intra-articulaires de dérivés corticoïdes sont à visée symptomatique, dans le cas d'une ou de quelques articulations gonflées malgré une maladie peu active par ailleurs.

La synoviorthèse isotopique (injection intra-articulaire d'isotopes radioactifs) ou chimique (injection d'acide osmique), consistent en la destruction de la synoviale d'une articulation restant inflammatoire malgré les infiltrations de corticoïdes.

La chirurgie a certaines indications : synovectomie d'une petite articulation inflammatoire malgré les mesures précédentes, ténosynovectomie ; au stade tardif de destruction articulaire : correction d'une déformation invalidante ou douloureuse (arthrodèse du poignet ou de l'arrière pied…), ou arthroplastie qui concerne principalement les grosses articulations  : hanches, genoux, épaules, plus rarement poignets et métacarpophalangiennes ; réparation d'une rupture tendineuse.

Rééducation

La physiothérapie permet de diminuer la douleur et l'inflammation lors des poussées inflammatoires.

La kinésithérapie, les règles d'hygiène de vie, l'éducation gestuelle et les exercices posturaux sont d'un appoint non négligeable.

L'ergothérapie consiste en la confection d'attelles de repos (portées pendant la nuit) et orthèses qui s'opposent aux attitudes vicieuses et aux déformations articulaires. Elle permet l'aide à la réadaptation du patient dans son environnement habituel.

Traitement non conventionnel

Des extraits d'une plante médicinale, Tripterygium wilfordii, pourraient avoir, dans certains cas, une efficacité au moins équivalente à celle de la sulfasalazine9.

Autres mesures

L'information concernant la maladie, individuellement et au sein de groupes de patients, reste indispensable. Elle peut être associée à une orientation vers des associations de malades.

En France, les soins sont pris en charge à 100% au titre de l'ALD 30 dans les formes severes.

Diagnostic différentiel

TABLEAU DES PRINCIPALES POLYARTHRITES
CLASSEMENTPENSER D'ABORD ÀPUIS À
Polyarthrites bactériennesSepticémie
Endocardite
Gonocoque
Brucellose
Maladie de Lyme
Tuberculose
Polyarthrites viralesHépatite B et C
Parvovirus B19
Oreillonsrubéole
mononucléose infectieuse,
cytomégalovirus (CMV)
VIH
Polyarthrites "post-infectieuses"Arthrites réactionnelles (post ChlamydiaeShigellaYersiniaCampylobacter…)RAA (rhumatisme articulaire aigu)
Rhumatisme post-streptococcique
Polyarthrites "métaboliques"goutte
Chondrocalcinose
Hématochromatose
Maladie de Wilson
Rhumatismes inflammatoiresPolyarthrite rhumatoïde
Spondylarthropathies périphériques (dont rhumatisme psoriasique)
Rhumatisme palindromique
Syndrome RS3PE
Polyarthrite paranéoplasique
Maladies auto-immunesLupus systémique]
Syndrome de Gougerot-Sjögren
Autres connectivites
Vascularites
Sarcoïdose


Voir aussi

Star of life3.svgPolyarthrite rhumatoïde
CIM-10:M05-M06


Liens externes

http://fr.wikipedia.org/wiki/Polyarthrite_rhumatoïde

Rheumatoid arthritis

Rheumatoid arthritis
Classification and external resources

A diagram showing how rheumatoid arthritis affects a joint
ICD-10M05.-M06.
ICD-9714
OMIM180300
DiseasesDB11506
MedlinePlus000431
eMedicinemed/2024emerg/48pmr/124
MeSHD001172

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks the joints producing an inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints. Rheumatoid arthritis can also produce diffuse inflammation in the lungspericardiumpleura, and sclera, and also nodular lesions, most common in subcutaneous tissue under the skin. Although the cause of rheumatoid arthritis is unknown, autoimmunity plays a pivotal role in its chronicity and progression.

About 1% of the world's population is afflicted by rheumatoid arthritis, women three times more often than men. Onset is most frequent between the ages of 40 and 50, but people of any age can be affected. It can be a disabling and painful condition, which can lead to substantial loss of functioning and mobility. It is diagnosed chiefly on symptoms and signs, but also with blood tests (especially a test called rheumatoid factor) and X-rays. Diagnosis and long-term management are typically performed by a rheumatologist, an expert in the diseases of joints and connective tissues.[1]

Various treatments are available. Non-pharmacological treatment includes physical therapy, orthoses and occupational therapyAnalgesia (painkillers) and anti-inflammatory drugs, includingsteroids, are used to suppress the symptoms, while disease-modifying antirheumatic drugs (DMARDs) are often required to inhibit or halt the underlying immune process and prevent long-term damage. In recent times, the newer group of biologics has increased treatment options.[1]

The name is based on the term "rheumatic fever", an illness which includes joint pain and is derived from the Greek word rheumatos ("flowing"). The suffix -oid ("resembling") gives the translation as joint inflammation that resembles rheumatic fever. The first recognized description of rheumatoid arthritis was made in 1800 by Dr Augustin Jacob Landré-Beauvais (1772–1840) of Paris.[2]

Contents

Signs and symptoms

While rheumatoid arthritis primarily affects joints, problems involving other organs of the body are known to occur. Extra-articular ("outside the joints") manifestations other than anemia (which is very common) are clinically evident in about 15-25% of individuals with rheumatoid arthritis.[3] It can be difficult to determine whether disease manifestations are directly caused by the rheumatoid process itself, or from side effects of the medications commonly used to treat it - for example, lung fibrosis from methotrexate or osteoporosis from corticosteroids.

Joints

The arthritis of joints known as synovitis is inflammation of the synovial membrane that lines joints and tendon sheaths. Joints become swollen, tender and warm, and stiffness limits their movement. With time RA nearly always affects multiple joints (it is a polyarthritis), most commonly small joints of the handsfeet and cervical spine, but larger joints like the shoulder and knee can also be involved. Synovitis can lead to tethering of tissue with loss of movement and erosion of the joint surface causing deformity and loss of function.[1]

Rheumatoid arthritis typically manifests with signs of inflammation, with the affected joints being swollen, warm, painful and stiff, particularly early in the morning on waking or following prolonged inactivity. Increased stiffness early in the morning is often a prominent feature of the disease and may last for more than an hour. Gentle movements may relieve symptoms in early stages of the disease. These signs help distinguish rheumatoid from non-inflammatory problems of the joints, often referred to as osteoarthritis or "wear-and-tear" arthritis. In arthritis of non-inflammatory causes, signs of inflammation and early morning stiffness are absent, and movements induce pain caused by the wear-and-tear.[4] In RA, the joints are often affected in a fairly symmetrical fashion, although this is not specific, and the initial presentation may be asymmetrical.

Hands affected by RA

As the pathology progresses the inflammatory activity leads to tendon tethering and erosion and destruction of the joint surface, which impairs range of movement and leads to deformity. The fingers may suffer from almost any deformity depending on which joints are most involved. Medical students are taught to learn names for specific deformities, such as ulnar deviationboutonniere deformityswan neck deformity and "Z-thumb," but these are of no more significance to diagnosis or disability than other variants.

Skin

The rheumatoid nodule, which is often subcutaneous, is the feature most characteristic of rheumatoid arthritis. The initial pathologic process in nodule formation is unknown but may be essentially the same as the synovitis, since similar structural features occur in both. The nodule has a central area of fibrinoid necrosis that may be fissured and which corresponds to the fibrin-rich necrotic material found in and around an affected synovial space. Surrounding the necrosis is a layer of palisading macrophages and fibroblasts, corresponding to the intimal layer in synovium and a cuff of connective tissue containing clusters of lymphocytes and plasma cells, corresponding to the subintimal zone in synovitis. The typical rheumatoid nodule may be a few millimetres to a few centimetres in diameter and is usually found over bony prominences, such as the olecranon, the calcaneal tuberosity, the metacarpophalangeal joint, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF (rheumatoid factor) titer and severe erosive arthritis. Rarely, these can occur in internal organs or at diverse sites on the body.

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

Other, rather rare, skin associated symptoms include:

Lungs

Fibrosis of the lungs is a recognised response to rheumatoid disease. It is also a rare but well recognised consequence of therapy (for example with methotrexate and leflunomide). Caplan's syndrome describes lung nodules in individuals with rheumatoid arthritis and additional exposure to coal dust. Pleural effusions are also associated with rheumatoid arthritis.

Kidneys

Renal amyloidosis can occur as a consequence of chronic inflammation.[5] Rheumatoid arthritis may affect the kidney glomerulus directly through a vasculopathy or a mesangial infiltrate but this is less well documented. Treatment with Penicillamine and gold salts are recognized causes of membranous nephropathy.

Heart and blood vessels

People with rheumatoid arthritis are more prone to atherosclerosis, and risk of myocardial infarction (heart attack) and stroke is markedly increased.[6][7] Other possible complications that may arise include: pericarditisendocarditis, left ventricular failure, valvulitis andfibrosis.[8] Many people with rheumatoid arthritis do not experience the same chest pain that others feel when they have angina or myocardial infarction. To reduce cardiovascular risk, it is crucial to maintain optimal control of the inflammation caused by rheumatoid arthritis (which may be involved in causing the cardiovascular risk), and to use exercise and medications appropriately to reduce other cardiovascular risk factors such as blood lipids and blood pressure. Doctors who treat rheumatoid arthritis patients should be sensitive to cardiovascular risk when prescribing anti-inflammatory medications, and may want to consider prescribing routine use of low doses of aspirin if the gastrointestinal effects are tolerable.[8]

Other

Ocular
The eye is directly affected in the form of episcleritis which when severe can very rarely progress to perforating scleromalacia. Rather more common is the indirect effect of keratoconjunctivitis sicca, which is a dryness of eyes and mouth caused by lymphocyte infiltration of lachrymal and salivary glands. When severe, dryness of the cornea can lead to keratitis and loss of vision. Preventive treatment of severe dryness with measures such as nasolacrimal duct occlusion is important.
Hepatic
Cytokine production in joints and/or hepatic Kupffer cells leads to increased activity of hepatocytes with increased production of acute-phase proteins, such as C-reactive protein, and increased release of enzymes such as alkaline phosphatase into the blood. InFelty's syndrome, Kuppfer cell activation is so marked that the resulting increase in hepatocyte activity is associated with nodular hyperplasia of the liver, which may be palpably enlarged. Because Kuppfer cells are not within the liver parenchyma, there is little or no evidence of hepatitis. Hepatic involvement in RA is essentially asymptomatic.
Hematological
Anemia is by far the most common abnormality of the blood cells. The red cells are of normal size and colour (normocytic). A low white blood cell count (neutropenia) usually only occurs in patients with Felty's syndrome with an enlarged liver and spleen. The mechanism of neutropenia is complex. An increased platelet count (thrombocytosis) occurs when inflammation is uncontrolled, as does the anemia.
Neurological
Peripheral neuropathy and mononeuritis multiplex may occur. The most common problem is carpal tunnel syndrome caused by compression of the median nerve by swelling around the wrist. Atlanto-axial subluxation can occur, owing to erosion of the odontoid process and or/transverse ligaments in the cervical spine's connection to the skull. Such an erosion (>3mm) can give rise to vertebrae slipping over one another and compressing the spinal cord. Clumsiness is initially experienced, but without due care this can progress to quadriplegia.
Constitutional symptoms
Constitutional symptoms including fatigue, low grade fevermalaisemorning stiffnessloss of appetite and loss of weight are common systemic manifestations seen in patients with active rheumatoid arthritis.
Osteoporosis
Local osteoporosis occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines. More general osteoporosis is probably contributed to by immobility, systemic cytokine effects, local cytokine release in bone marrow and corticosteroid therapy.
Lymphoma
The incidence of lymphoma is increased in RA, although it is still uncommon.[citation needed]

Diagnosis

Imaging

X-ray of the hand in rheumatoid arthritis.
Appearance of synovial fluid from a joint with inflammatory arthritis.
Signs of destruction and inflammation on ultrasonography and magnetic resonance imaging in the secondmetacarpophalangeal joint in established rheumatoid arthritis. Thin arrows indicate an erosive change; thick arrows indicate synovitis. Ultrasonography (left side of image) in the (a) longitudinal and (b) the transverse planes shows both signs of destruction and inflammation. Axial T1-weighted magnetic resonance images were obtained (c) before and (d) after contrast administration, also demonstrating synovitis. Additionally, a coronal T1-weighted magnetic resonance image (e) before contrast administration visualizes the same bone erosion as shown in panels c and d.

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

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

Blood tests

When RA is clinically suspected, immunological studies are required, such as testing for the presence of rheumatoid factor (RF, a specific antibody).[9] A negative RF does not rule out RA; rather, the arthritis is calledseronegative. This is the case in about 15% of patients.[10] During the first year of illness, rheumatoid factor is more likely to be negative with some individuals converting to seropositive status over time. RF is also seen in other illnesses, for example Sjögren's syndrome, and in approximately 10% of the healthy population, therefore the test is not very specific.

Because of this low specificity, new serological test have been developed, which tests for the presence of so called anti-citrullinated protein antibodies (ACPAs). Like RF, these tests are positive in only a proportion (67%) of all RA cases, but are rarely positive if RA is not present, giving it a specificity of around 95%.[10] As with RF, there is evidence for ACPAs being present in many cases even before onset of clinical disease.[citation needed]

The most common tests for ACPAs are the anti-CCP (cyclic citrullinated peptide) test and the Anti-MCV assay (antibodies against mutated citrullinated Vimentin). Recently a serological point-of-care test (POCT) for the early detection of RA has been developed. This assay combines the detection of rheumatoid factor and anti-MCV for diagnosis of rheumatoid arthritis and shows a sensitivity of 72% and specificity of 99.7%.[11][12]

Also, several other blood tests are usually done to allow for other causes of arthritis, such as lupus erythematosus. The erythrocyte sedimentation rate (ESR), C-reactive proteinfull blood countrenal functionliver enzymes and other immunological tests (e.g. antinuclear antibody/ANA) are all performed at this stage. Elevated ferritin levels can reveal hemochromatosis, a mimic RA, or be a sign of Still's disease, a seronegative, usually juvenile, variant of rheumatoid.[citation needed]

Diagnostic criteria

The American College of Rheumatology has defined (1987) the following criteria for the classification of rheumatoid arthritis:[13]

  • Morning stiffness of >1 hour most mornings for at least 6 weeks.
  • Arthritis and soft-tissue swelling of >3 of 14 joints/joint groups, present for at least 6 weeks
  • Arthritis of hand joints, present for at least 6 weeks
  • Symmetric arthritis, present for at least 6 weeks
  • Subcutaneous nodules in specific places
  • Rheumatoid factor at a level above the 95th percentile
  • Radiological changes suggestive of joint erosion

At least four criteria have to be met for classification as RA. These criteria are not intended for the diagnosis for routine clinical care; they were primarily intended to categorize 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 may sometimes result in a worse outcome. Most sufferers and rheumatologists would agree that it would be better to treat the condition as early as possible and prevent bone erosion from occurring, even if this means treating people who don't fulfill the ACR criteria. The ACR criteria are, however, very useful for categorising established rheumatoid arthritis, for example for epidemiological purposes.[citation needed]

Differential diagnosis

Several other medical conditions can resemble RA, and usually need to be distinguished from it at the time of diagnosis:[14]

  • Crystal induced arthritis (gout, and pseudogout) - usually involves particular joints and can be distinguished with aspiration of joint fluid if in doubt
  • Osteoarthritis - distinguished with X-rays of the affected joints and blood tests
  • Systemic lupus erythematosus (SLE) - distinguished by specific clinical symptoms and blood tests (antibodies against double-stranded DNA)
  • One of the several types of psoriatic arthritis resembles RA - nail changes and skin symptoms distinguish between them
  • Lyme disease causes erosive arthritis and may closely resemble RA - it may be distinguished by blood test in endemic areas
  • Reactive arthritis (previously Reiter's disease) - asymmetrically involves heel, sacroiliac joints, and large joints of the leg. It is usually associated with urethritisconjunctivitisiritis, painless buccal ulcers, and keratoderma blennorrhagica.
  • Ankylosing spondylitis - this involves the spine and is usually diagnosed in males, although a RA-like symmetrical small-joint polyarthritis may occur in the context of this condition.

Rarer causes that usually behave differently but may cause joint pains:[14]

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

Etiology

Rheumatoid arthritis is a form of autoimmunity, the causes of which are still incompletely known. It is a systemic (whole body) disorder principally affecting synovial tissues.

Pathophysiology

The key pieces of evidence relating to pathogenesis are:

1. A genetic link with HLA-DR4 and related allotypes of MHC Class II and the T cell-associated protein PTPN22.

2. A link with cigarette smoking that appears to be causal.[citation needed]

3. A dramatic response in many cases to blockade of the cytokine TNF (alpha).

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

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

6. The presence of autoantibodies to IgGFc, known as rheumatoid factors (RF), and antibodies to citrullinated peptides (ACPA).

These data suggest that the disease involves abnormal B cell - T cell interaction, with presentation of antigens by B cells to T cells via HLA-DR eliciting T cell help and consequent production of RF and ACPA. Inflammation is then driven either by B cell or T cell products stimulating release of TNF and other cytokines. The process may be facilitated by an effect of smoking on citrullination but the stochastic (random) epidemiology suggests that the rate limiting step in genesis of disease in predisposed individuals may be an inherent stochastic process within the immune response such as immunoglobulin or T cell receptor gene recombination and mutation. (See entry under autoimmunity for general mechanisms.)

If TNF release is stimulated by B cell products in the form of RF or ACPA - containing immune complexes, through activation of immunoglobulin Fc receptors, then RA can be seen as a form of Type III hypersensitivity.[15] [16] If TNF release is stimulated by T cell products such as interleukin-17 it might be considered closer to type IV hypersensitivity although this terminology may be getting somewhat dated and unhelpful.[17] The debate on the relative roles of immune complexes and T cell products in inflammation in RA has continued for 30 years. There is little doubt that both B and T cells are essential to the disease. However, there is good evidence for neither cell being necessary at the site of inflammation. This tends to favour immune complexes (based on antibody synthesised elsewhere) as the initiators, even if not the sole perpetuators of inflammation. Moreover, work by Thurlings and others in Paul-Peter Tak's group and also by Arthur Kavanagh's group suggest that if any immune cells are relevant locally they are the plasma cells, which derive from B cells and produce in bulk the antibodies selected at the B cell stage.[citation needed]

Although TNF appears to be the dominant, other cytokines (chemical mediators) are likely to be involved in inflammation in RA. Blockade of TNF does not benefit all patients or all tissues (lung disease and nodules may get worse). Blockade of IL-1, IL-15 and IL-6also have beneficial effects and IL-17 may be important. Constitutional symptoms such as fever, malaise, loss of appetite and weight loss are also caused by cytokines released in to the blood stream.

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

Possible infectious triggers

It has long been suspected that certain infections could be triggers for this disease. The "mistaken identity" theory suggests that an infection triggers an immune response, leaving behind antibodies that should be specific to that organism. The antibodies are not sufficiently specific, though, and set off an immune attack against part of the host. Because the normal host molecule "looks like" a molecule on the offending organism that triggered the initial immune reaction - this phenomenon is called molecular mimicry. Some infectious organisms suspected of triggering rheumatoid arthritis include MycoplasmaErysipelothrixparvovirus B19 and rubellabut these associations have never been supported in epidemiological studies. Nor has convincing evidence been presented for other types of triggers such as food allergies.

Epidemiological studies have confirmed a potential association between RA and two herpesvirus infections: Epstein-Barr virus (EBV) and Human Herpes Virus 6 (HHV-6).[18] Individuals with RA are more likely to exhibit an abnormal immune response to the Epstein-Barr virus.[19] [20] The allele HLA-DRB1*0404 is associated with low frequencies of T cells specific for the EBV glycoprotein 110 and predisposes one to develop RA.[21]

Psychological factors

There is no evidence that physical and emotional effects, stress could be a trigger for the disease. The many negative findings suggest that either the trigger varies, or that it might in fact be a chance event inherent with the immune response, as suggested by Edwards et al.[22].

Continued abnormal immune response

The factors that allow an abnormal immune response, once initiated, to become permanent and chronic, are becoming more clearly understood. The genetic association with HLA-DR4, as well as the newly discovered associations with the gene PTPN22 and with two additional genes[23] , all implicate altered thresholds in regulation of the adaptive immune response. It has also become clear from recent studies that these genetic factors may interact with the most clearly defined environmental risk factor for rheumatoid arthritis, namely cigarette smoking[24] Other environmental factors also appear to modulate the risk of acquiring RA, and hormonal factors in the individual may explain some features of the disease, such as the higher occurrence in women, the not-infrequent onset after child-birth, and the (slight) modulation of disease risk by hormonal medications. Exactly how altered regulatory thresholds allow the triggering of a specific autoimmune response remains uncertain. However, one possibility is that negative feedback mechanisms that normally maintain tolerance of self are overtaken by aberrant positive feedback mechanisms for certain antigens such as IgG Fc (bound by RF) and citrullinated fibrinogen (bound by ACPA) (see entry on autoimmunity).

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

Treatment

There is no known cure for rheumatoid arthritis, but many different types of treatment can alleviate symptoms and/or modify the disease process. Recommendations of the American College of Rheumatology (ACR), published in 2008, followed a trend in supporting earlier, more aggressive treatment of RA, and reflected heightened expectations of treatment effectiveness, including remission or substantial alleviation of symptoms for a rising percentage of patients.[25]

The goal of treatment is two-fold: alleviating the current symptoms, and preventing the future destruction of the joints with the resulting handicap if the disease is left unchecked. These two goals may not always coincide: while pain relievers may achieve the first goal, they do not have any impact on the long-term consequences. For these reasons, the ACR recommends that RA should generally be treated with at least one specific anti-rheumatic medication, also named DMARD (see below), to which other medications may be added depending on how long a person has had RA, how active the disease is, and prognostic factors (such as X-ray evidence of bone erosion; elevation of blood factors such as Rheumatoid factoranti-cyclic citrullinated peptideC-reactive protein, and erythrocyte sedimentation rate; age and gender; physical functioning; and smoking, for example). [25]

Cortisone therapy has offered relief in the past, but its long-term effects have been deemed undesirable.[26]. However, cortisone injections can be valuable adjuncts to a long-term treatment plan, and using low dosages of daily cortisone (e.g., prednisone or prednisolone, 5-7.5 mg daily) can also have an important benefit if added to a proper specific anti-rheumatic treatment.[citation needed]

Pharmacological treatment of RA can be divided into disease-modifying antirheumatic drugs (DMARDs), anti-inflammatory agents and analgesics.[27][28] Treatment also includes rest and physical activity.

Disease modifying anti-rheumatic drugs (DMARDs)

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

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

There may be other reasons why starting DMARDs early is beneficial as well as prevention of structural joint damage. From the earliest stages of the disease, the joints are infiltrated by cells of the immune system that signal to one another in ways that may involve a variety of positive feedback loops (it has long been observed that a single corticosteroid injection may abort synovitis in a particular joint for long periods). Interrupting this process as early as possible with an effective DMARD (such as methotrexate) appears to improve the outcome from the RA for years afterwards. Delaying therapy for as little as a few months after the onset of symptoms can result in worse outcomes in the long term. There is therefore considerable interest in establishing the most effective therapy with early arthritis, when they are most responsive to therapy and have the most to gain.[29]

Traditional small molecular mass drugs

Chemically synthesised DMARDs:

Cytotoxic 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 is usually insufficient to control symptoms on its own.[citation needed]

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

Biological agents

Biological agents (biologics) are produced through genetic engineering, and include:

As of December 2007 Numerous biologics are in clinical trials (e.g. OcrelizumabOfatumumab).[34]

Anti-inflammatory agents and analgesics

Anti-inflammatory agents include:

Analgesics include:

Historic treatments for RA have also included: rest, ice , compression and elevationacupunctureapple diet, nutmeg, some light exercise every now and then, nettlesbee venom, copper bracelets, rhubarb diet, extractions of teeth, fastinghoneyvitaminsinsulin,magnets, and electroconvulsive therapy (ECT).[35]. Most of these have either had no effect at all, or their effects have been modest and transient, while not being generalizable.

Other therapies

Other therapies are weight lossorthoses, occupational therapy, podiatryphysiotherapyimmunoadsorption therapyjoint injections, and special tools to improve hard movements (e.g. special tin-openers). Regular exercise is important for maintaining joint mobility and making the joint muscles stronger.

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

A survey in the United Kingdom between 1998 and 2002 found that arthritis, in its various forms, was among the five most common reasons for the medicinal use of cannabis.[36]

The Prosorba column blood filtering device (removing IgG) was approved by the FDA in 1999 for treatment of RA[37] However it was discontinued at the end of 2006.[38]

The effectiveness of treating RA with acupuncture is inconclusive, and "more rigorous research seems to be warranted" according to one study.[39]

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

Prognosis

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

Disability

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

Prognostic factors

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

Mortality

Estimates of the life-shortening effect of RA vary; most sources cite a lifespan reduction of 5 to 10 years. According to the UK's National Rheumatoid Arthritis Society, "Young age at onset, long disease duration, the concurrent presence of other health problems (called co-morbidity), and characteristics of severe RA – such as poor functional ability or overall health status, a lot of joint damage on x-rays, the need for hospitalisation or involvement of organs other than the joints – have been shown to associate with higher mortality".[40]Positive responses to treatment may indicate a better prognosis. A 2005 study by the Mayo Clinic noted that RA sufferers suffer a doubled risk of heart disease,[41] 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.[42]

Epidemiology

Disability-adjusted life year for rheumatoid arthritis per 100,000 inhabitants in 2004.[43]
     no data     less than 40     40-50     50-60     60-70     70-80     80-90     90-100     100-110     110-120     120-130     130-140     more than 140

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 people from the Caribbean region have lower prevalence rates. First-degree relatives prevalence rate is 2-3% and disease genetic concordance in monozygotic twins is approximately 15-20%.[citation needed]

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

Rheumatoid arthritis affects women three times more often than men, and it can first develop at any age. The risk of first developing the disease (the disease incidence) appears to be greatest for women between 40 and 50 years of age, and for men somewhat later.[44] RA is a chronic disease, and although rarely, a spontaneous remission may occur, the natural course is almost invariably one of persistent symptoms, waxing and waning in intensity, and a progressive deterioration of joint structures leading to deformations and disability.

History

The first known traces of arthritis date back at least as far as 4500 BC. A text dated 123 AD first describes symptoms very similar to rheumatoid arthritis. It was noted in skeletal remains of Native Americans found inTennessee.[45] In the Old World the disease is vanishingly rare before the 1600s.[46] and on this basis investigators believe it spread across the Atlantic during the Age of Exploration. In 1859 the disease acquired its current name.

An anomaly has been noticed from investigation of Precolumbian bones. The bones from the Tennessee site show no signs of tuberculosis even though it was prevalent at the time throughout the Americas.[47] 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.[48] Mobley attributes the spikes in arthritis to selective pressure caused by tuberculosis. A hypervigilant immune system is protective against tuberculosis at the cost of an increased risk of autoimmune disease.

The art of Peter Paul Rubens may possibly depict the effects of rheumatoid arthritis. In his later paintings, his rendered hands show, in the opinion of some physicians, increasing deformity consistent with the symptoms of the disease.[49][50] Rheumatoid arthritis appears to some to have been depicted in 16th century paintings.[51] However, it is generally recognised in art historical circles that the painting of hands in the sixteenth and seventeenth century followed certain stylised conventions, most clearly seen in the Mannerist movement. It was conventional, for instance to show the upheld right hand of Christ in what now appears a deformed posture. These conventions are easily misinterpreted as portrayals of disease. They are much too widespread for this to be plausible.

The first recognized description of rheumatoid arthritis was in 1800 by the French physician Dr Augustin Jacob Landré-Beauvais (1772–1840) who was based in the famed Salpêtrière Hospital in Paris.[2] The name "rheumatoid arthritis" itself was coined in 1859 by British rheumatologist Dr Alfred Baring Garrod.[52]

Notable cases

  • Dorothy Hodgkin, Nobel prize winning scientist, developed severe deforming rheumatoid arthritis at age 28. In spite of this she continued her career and developed X-ray crystallography, which underpins much of the information known about rheumatoid arthritis. She also discovered the structure of insulin and enabled the discovery of the genetic code.
  • Auguste Renoir, impressionist painter, whose later 'softer' style might have reflected in some way his severe disability.
  • Christiaan Barnard, the first surgeon to perform a human-to-human heart transplant had to retire owing to the condition. He also wrote a book on living with arthritis.
  • James Coburn claimed to have healed the condition using pills containing a sulfur-containing compound on his return to acting.
  • Erik Lindbergh, aviator and member of the X-Prize administration. Erik has been a spokesman for the arthritis drug Enbrel, as a result of his success with the treatment.[53]
  • Bob Mortimer British comedian and actor.[54]
  • Kathleen Turner and Aida Turturro have worked to raise public awareness of the condition[55]
  • Billy Bowden, international cricket umpire who had to retire from active play because of rheumatoid arhtirits.
  • Melvin Franklin, bass singer of the Temptations. He treated RA with cortisone shots so he could perform.
  • Jamie Farr, American actor, famous for his role as Max Klinger on the 1970s television series M*A*S*H.
  • Gabi Rojas, An American dancer, She appeared on So You Think You Can Dance Season 5 making the top 54 in Vegas.
  • Sandy Koufax, An American Hall-of-Fame baseball pitcher who played from 1955 to 1966 for the Los Angeles Dodgers.

See also

External links

http://en.wikipedia.org/wiki/Rheumatoid_arthritis
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