Rheumatoid Arthritis.

Rheumatoid Arthritis

Introduction Epidemiology/genetics Pathogenesis Clinical Features
Laboratory Manifestations Diagnosis Management considerations and therapy

Rheumatoid arthritis Chronic, systemic inflammatory disease
Unknown etiology Persistent inflammatory synovitis Synovial inflammation (pannus) cartilage destruction, bone erosion with subsequent deformity Peripheral joints in symmetric fashion Extra-articular manifestations also occur -Chronic, systemic, inflammatory disorder of unknown etiology characterized by diathrodial joint involvement. Primary site of pathology is the synovium of joints. The synovium becomes inflammed and proliferates forming a pannus that invades bone, cartilage and ligament and leads to damage and deformities. - RF + and extra-articular manifestations commonly accompany the joint disease but arthritis represent the major manifestations

Epidemiology 2.5 million Americans (~1%), 165 million worldwide
Females > males 3:1; all races Peak age onset: 4th-5th decade 80% develop between ages 35-50yrs Prevalence increases with age Chippewa and Pima Indians: 5.3%, Asia: China 0.3% and Japan 0.6%, Rural South Africa: 0.1% RA has a 3:1 to 5:1 female predominance less than age 60, in patients above 60 ratio becomes more even

Genetics Strongly associated with HLA-DR4
DRB1*0401/0404  severe and erosive disease “Shared epitope” on 3rd hypervariable region of HLA-DRB1 + HLA-DR4 seen in 20-30% of general population Other factors involved for disease to develop -HLA class II: HLA-DR4 - The DRB1*0401/0404 alleles code for specific amino acid sequences in the antigen binding cleft of the HLA-DR molecule. Controls the trimolecular interaction: t cell receptor, peptide and MHC molecule Susceptibility gene or “shared epitope” postulated on the 3rd hypervariable region of HLA-DRB1. DRB1*0401/0404 are associated with severe and erosive disease  increased risk of developing the disease but also more likely to develop; DRB*0101 milder and seronegative disease Gene dosage  patients inheriting 2 genes vs 1: increased severity of erosive disease and higher risk of extra-articular manifestations

Genetics T lymphocytes recognizing antigens in synovial tissue
T cells, macrophages + fibroblasts produce pro-inflammatory cytokines Play a key role in synovitis and tissue destruction Pro-inflammatory cytokines: TNF alpha, IL-1 and IL-6 Pro-inflammatory cytokines that enhance synovial proliferation and stimulate secretion of matrix degrading metalloproteinases. Monozygotic twins is 30-50% and diazygotic twins 2-3%. Risk to unaffected siblings for developing RA (if one sibling has RA) is 5-10times that of general population.

Pathophysiological Role of Cytokines + Other Mediators and Inhibitors in RA
Figure 1. Pathophysiological Role of Cytokines and Other Mediators and Their Inhibitors in RA: -In the current model of the pathogenesis of RA, an infective agent or other stimulus binds to receptors on dendritic cells, activating the innate immune system. Dendritic cells migrate into lymph nodes, presenting antigen to T cells, which are activated by the dual signal of antigen presentation and costimulation through CD28. -Activated T cells proliferate and migrate into the joint. In the synovial tissue, T cells produce interferon-{gamma} and other proinflammatory cytokines that stimulate macrophages and fibroblasts as well as chondrocytes, osteoclasts, and B cells. Activated macrophages and fibroblasts release a variety of cytokines, including TNF-{alpha}. TNF-{alpha} is a central component in the cascade of cytokines, stimulating the production of additional inflammatory mediators and the further recruitment of immune and inflammatory cells into the joint. -Infliximab and adalimumab are monoclonal anti-TNF-{alpha} antibodies that bind to TNF-{alpha} with high affinity and prevent it from binding to its receptors. Etanercept is a fusion protein consisting of two p75 TNF receptors that are linked to the Fc portion of human IgG1. It also binds to TNF-{alpha} and prevents it from interacting with its receptors on cell surfaces. - Activated T-cells release cytokines including IL-2 IFN-, TNF-, IL-3 and TNF-. TNF-, plays a key role in the pathology of rheumatoid arthritis. TNF- stimulates the macrophages, which produce TNF-, IL-1 and IL-6. TNF- is also a potent stimulator of IL-1, IL-6, and IL-8, which stimulate chondrocytes, osteoclasts and fibroblasts that release metalloproteinases (e.g., MMP-1 and MMP-3), ultimately leading to the erosion of bone and cartilage. 1-3 TNF- is at the apex of the inflammatory cascade promoting downstream mediators that lead to bone erosion and inflammation in RA.1,4 Blocking TNF- inhibits the production of IL-1, IL-6, and IL-8 and may have a more global effect versus blocking other cytokines further down the cascade. (Feldmann M. Development of anti-TNF therapy for rheumatoid arthritis. Nature Review. 2002). Pannus erodes cartilage, bone, ligament and tendons : Scott D and Kingsley G. N Engl J Med 2006;355:

Risk Factors For Aggressive RA
HLA-DR4, High titer RF and + CCP ab Early radiographic erosions Constitutional symptoms Insidious onset Early appearance of rheumatoid nodules - Low grade fever, anorexia, weight loss, fatigue

Disease onset Insidious: Most common presentation Abrupt:
Small peripheral joints: MCPs, PIPs, wrists Abrupt: Acute polyarthritis  Intense pain, swelling + limitation Slow monoarticular: Knees/shoulders  progresses to small joints Usually presents insidiously Prodromal syndrome: malaise, weight loss and vague periarticular pain and stiffness can be seen Slow monoarticular: shoulders/knees. Spreads within weeks to small peripheral joint additively Less common, the onset is acute, triggered by a stressful situation, infection, trauma or in the peripartum period

Overview: Joint Involvement
TMJ: % C-spine: % Shoulder: % SC Joints : ? Elbow: 40-50% Wrist: 80-90% Hand: MCP 90-95% PIP % Hips: % Knees: % Ankles: % Foot : MTP 50-90% PIP %

Clinical features Symmetric inflammatory synovitis (palpable swelling) of small peripheral joints Tenderness to palpation and ROM Symptoms last > 6 weeks Useful indicator of disease activity Morning stiffness > 1˚  improves with activity Inflammatory synovitis: peripheral synovial swelling with tenderness on palpation and on ROM; swelling other than bony proliferation and it may be peri-articular and intra-articular Symptoms lasting 6 weeks  duration is a useful indicator of the activity of the disease Morning stiffness > 1 hr ( unlike OA which morning stiffness is < 30 minutes) may recur especially after strenuous activity

Clinical features Symmetric polyarticular joint involvement (>3 joints) Small joint arthropathy: MCPs, PIPs, wrists, MTPs Knees, ankles and shoulders Typically spares: thoracolumbar spine + DIP joints Entrapment syndromes also commonly occur Carpal tunnel and tarsal tunnel Symmetric and polyarticular: buzzwords for RA and SLE as well as systemic sclerosis and psoriasis; hemochromatosis affects 2nd and 3rd MCPs but is asymmteric Knee is the most common single joint involved in RA - DIP disease more common than appreciated (never 1st finding and usually in RF+) - Flipper/boxing glove – massive hand swelling and pitting edema (acute onset) - Flail thumb – synovitis destroys collateral ligaments, trying to pinch pushes the terminal phalanx away so patients start to pinch against the prox phalanx - Duckbill – like swan neck of thumb due to 1st CMC disease

- Examination of the hands is important, because the features they exhibit are frequently a reflection of the patient’s overall disease. - Symmetric swelling of PIPs, MCPs and wrists. - The swelling of the PIPs may be fusiform as in this pic

- With MCP involvement, the development of volar subluxation and ulnar drift is characteristic.

Boutonniere Deformity
Boutonniere: flexion of the PIP joint and hyperextension of the DIP joint the lateral bands of the joint move volarly, destroying the extensor balance; the lat bands become the flexors of the joint and the extension of the joint is concentrated on the DIP region

Swan neck deformity www.medscape.com
Swan neck: hyperextension of PIP and flexion of DIP main extensor forces focus on the base of the proximal phalanx and the lat bands sublux dorsally; early on the deformity may be reversible, later on may become more difficult and the bands may have to snap in order to flex; finally the lat bands may become fixed

Foot abnormalities Foot deformities: Most common are hallux valgus and hammertoes Cock-up toes occur due to subluxation of the MTP heads

Tenosynovitis - Extensor tendon rupture: The 4/5th digits can’t extend due to tendon rupture; contributing factors: 1. Tensosynovitis of the extensor tendons and dorsal subluxation of the ulna in relation to the distal radius “Tuck Sign” - extending the fingers will accentuate the swelling, as the swelling occurs below the extensor retinaculum - Picture: Rheumatoid arthritis: extensor tendon rupture The fourth and fifth fingers cannot be extended because the extensor tendons to these digits have ruptured. Surgical exploration confirmed the rupture. Contributing factors included tenosynovitis of the extensor tendons and dorsal subluxation of the ulna in relation to the distal end of the radius.

- Ulnar subluxation and rheumatoid nodules

Baker’s cyst Swelling posterior knee
Ruptured popliteal cyst swelling of calf (pseudo-phlebitis) Mimics DVT “Crescent sign” - Frequency 5-50% - Baker cysts are not uncommon and can be caused by virtually any cause of joint swelling (arthritis). The excess joint fluid (synovial fluid) bulges to the back of the knee to form the Baker cyst. The most common type of arthritis associated with Baker cysts is osteoarthritis, also called degenerative arthritis. Baker cysts can occur in children with juvenile arthritis of the knee. Baker cysts also can result from cartilage tears (such as a torn meniscus), rheumatoid arthritis, and other knee problems - A Baker cyst may cause no symptoms or be associated with knee pain and/or tightness behind the knee, especially when the knee is extended or fully flexed. Baker cysts are usually visible as a bulge behind the knee that is particularly noticeable on standing and when compared to the opposite uninvolved knee. They are generally soft and minimally tender. Baker cysts can become complicated by protrusion of fluid down the leg between the muscles of the calf (dissection). The cyst can rupture, leaking fluid down the inner leg to sometimes cause the appearance of a painless bruise on the inner ankle. Baker cyst dissection and rupture are frequently associated with swelling of the leg and can mimic phlebitis of the leg. A ruptured Baker cyst typically causes rapid-onset swelling of the leg. Picture 1: Rheumatoid arthritis: popliteal cyst. This patient with longstanding rheumatoid arthritis involving multiple joints had popliteal pain bilaterally and developed pronounced swelling with pain along the posteromedial portion of the right leg. The swelling results from a ruptured popliteal cyst (Baker's cyst) that has dissected into the calf muscles. The patient also had marked redness and tenderness in the calf and a positive Homans' sign. The diagnosis was confirmed by arthrography. -Picture 2: A 48-year-old female with rheumatoid arthritis developed a ruptured popliteal cyst which resulted in swelling and ecchymosis of the lower extremity. Pooling of blood at the ankle and foot produces the classic “crescent sign.”

Axial disease

Axial Disease Anterior alantoaxial subluxation of C1-2 common
≥ 3 mm separation between odontoid and atlas Recurrent HA, tingling in UE, unexplained dizziness Susceptible to trauma with endotracheal intubation Must get pre-op X-rays of neck (lateral flexion/extension) Symptomatic cervical myelopathy  spinal fusion - AAS: can cause scary clunking sensation, due to synovitis and laxity of ligaments holding odontoid to the atlas Space between odontoid process and arch of atlas 3mm or less, >3mm call AAS; can exceed 10mm (free space lost and cord at risk) Cervical subluxation can occur at any level; apophyseal erosions can occur with instability Erosions – of dens or of apophyseal joints in occipitoatlantal area (odontoid can move into foramen magnum, sudden death with trauma or vomiting), can also cause VBI ** RARE May describe HA that starts at base of skull and radiates to the scalp. Other non-specific sx such as tingling of the arms, unexplained dizziness. Sx fusion is not needed for asymptomatic C1-C2 subluxation even if is > 5mm. Spinal fusion is reserved for patients with myelopathy. Very susceptible to trauma associated to normal endotracheal intubation and therefore may present with post op syncope, lightheadness, nystagmus and any of the various types of sensory/motor focal deficits. SI joints: AS and RA can coexist, mostly in men. Mostly in late disease, erosions and osteopenia noted.

C Spine X-ray

Extra-articular manifestations
40% of patients Increased frequency: +RF, +CCP ab, HLA-DR1 +DR4 Environmental factors such as smoking Life expectancy loss of 18 yrs 5x mortality risk

Systemic Extra-Articular Manifestations
Organ System Systemic Extra-Articular Manifestations General Fever, LAD, weight loss and fatigue Bone Osteopenia and osteoporosis Cardiovascular CAD, MI, pericarditis, myocarditis, coronary vasculitis, nodules on the valves Dermatologic Palmar erythema, subcutaneous nodules, vasculitis Hematologic Anemia, thrombocytosis, Felty’s syndrome, LGL, NHL Neuromuscular Entrapment neuropathy, peripheral neuropathy, mononeuritis multiplex Ocular Keratoconjunctivits sicca, scleritis, episcleritis, peripheral ulcerative keratitis Other Sjogrens syndrome, amyloidosis, vasculitis Pulmonary Pleural Effusion, pleuritis, nodules, ILD, bronchiolitis obliterans, Study from Turesson: Turesson C. Ann Rheum Dis 2007;66:59-64. Objective : to study antibodies to CCP and RF in patients with active, severe extra-articular RA compared to controls without ExRA -- 35 with severe ExRA were studied and 70 patients with RA but no extra-articular manifestations. Bottom line: RF was strongly associated with severe ExRA manifestations in patients with RA and a similar but weaker association exist for anti-CCP antibodies. This suggest a role for RF and anti-CCP ab in the pathogenesis of ExRA.

Rheumatoid nodules 20-40%of SPRA patients
Reflects level of RA disease activity Develops on pressure areas Risk factors: +RF, subchondral cysts, Methotrexate(MTX) Regarded as most characteristic extra-articular manifestation of RA. Rare in seronegative patients -Increased risk of developing severe extra-articular manifestations when they occur early in disease. - Occurs on pressure areas such as: elbows, occipital scalp, finger joints, proximal ulna, ischial and sacral prominences, achilles tendon

Rheumatoid nodules Single/multiple nodules
Interfere with function/ulcerate Regress with DMARDS MTX may result in ↑ nodulosis Usually painless but may interfere with function and ulcerate Rheumatoid nodules associated with MTX will be a rapid onset (regress with d/c) also is seen with: 0401 [positive, RF positive pts) Men May have higher incidence of concurrent vasculitis HCQ may have a protective effect

Rheumatoid nodules May involve internal organs Sites of movement:
Pulmonary parenchyma/pleura Pericardium/myocardium Heart valves Vocal cords - Nodules may occur in internal organ, particularly at sites of movement. - Like surface nodules, they are asymptomatic unless interfering with function, so their exact incidence is unknown. Individual organ involvement is discussed later. -Pulmonary nodules: common, but less frequent than pleurisy; upper > lower lobes; may be solitary or multiple - Variable clinical course (persist unchanged), resolve spontaneously and can cavitate

Caplan’s syndrome Pulmonary nodulosis + pneumoconiosis
Exposure to inorganic dusts (coal, asbestos, silca) Similar to simple rheumatoid nodules Modified tissue response to inhaled dusts May lead to progressive massive fibrosis (PMF) - Caplan’s syndrome is pneumoconiosis and RA are synergistic. They produce a violent fibroblastic reaction with obliterative granulomatous fibrosis. It has become rare as environmental health protection improves (ie respirators). - Rapid development of multiple peripheral basilar nodules in association with mild airway obstruction. - Nodules in Caplan’s syndrome are surrounded by pigment cells. - No effective treatment, but prognosis is good.

Interstitial lung disease
Most common lung manifestation ↑ mesenchymal reactivity  fibrosis PE: fine, diffuse dry rales; low DLCO CXR: Reticular/reticulonodular pattern  honeycombing Interstitial lung disease (ILD) is the most common manifestation of rheumatoid lung disease. Increased risk with smoking. - The increase reactivity of mesenchymal cell in RA is believed to be the cause of pulmonary fibrosis in this disease. Physical exam findings are of fine, diffuse dry rales. - Rheumatoid arthritis associated interstitial lung disease (RA-ILD) is usually similar to idiopathic pulmonary fibrosis (IPF, also called cryptogenic fibrosing alveolitis (CFA)) in terms of its clinical presentation, pathology, disease spectrum, and pathogenesis [2-4]. However, a wide spectrum of findings may be present on lung biopsy in patients with RA-ILD; these changes can generally be classified histologically as a form of idiopathic interstitial pneumonia (IIP).

Interstitial lung disease
Wide spectrum of findings on lung biopsy Histologic finding  idiopathic interstitial pneumonia (IIP) Tx: “ground-glass” on HRCT  good response to tx High dose steroids, imuran and cytoxan

Pleurisy/pleural disease
Inflamed pleura  thicken, calcify + forming adhesions Pleural fluid reveals: Low glucose (< 30mg/dl) High protein (>4 g/dl) and LDH Low complement (CH50 ) Cellular infiltrates (mononuclear) Improves with treatment of RA Rarely, the inflamed pleural membrane becomes thickened enough to interfere with lung expansion requiring pleurectomy. Pleural adhesions frequently form during resolution and may calcify. Occasionally, large effusions require drainage. Examination of the pleural fluid reveals exudative effusion with: RF (+) Suggest local production Immune complexes High protein >4g/dl Complement consumption Low glucose mg/dl. Impair glucose transport into the pleural space thought to be due to thickening of the pleura. Mononuclear cellular infiltrate – / mm3 The above characteristic are concerning for malignancy, infection and TB which must be ruled out.

Hematologic involvement
Mild hypochromic normocytic anemia Thrombocytosis Lymphadenopathy Felty’s syndrome Large granular lymphocyte syndrome “Pseudo-Felty Syndrome

Felty’s syndrome Classic triad: RA, neutropenia, splenomegaly
Risk factors: RF+, nodular RA and +HLADR4 Manifestations: Non-healing leg ulcers Infections PMNs < 1000/mm3 Common cause of death Mnemonic: What is Felty’s: The ANSwer = arthritis, neutropenia and splenomegaly The leukopenia is typically an isolated neutropenia and mild (although it can be severe). Platelets are rarely reduced. They can have a severe hypochromic anemia due to increased spleen or liver uptake. - The spleen is usually massive and occasionally tender (splenic infarct). 1/3 of patients have a normal spleen and many RA pateint can have an enlarge spleen (diffuse lymphoid hyperplasia). ? Specificity. - Interesting, liver nodular regenerative hyperplasia with increased fibrosis occurs in Felty’s but not RA. - Neutropenia due to bone marrow abnormalities rather than the spleen, so splenectomy may only be temporarily useful. Most patients are women, >50yrs, high ESR, +ANA (anti-histone Ab), ANCA (against lactoferrin) are found in 75% of FS pts. Bacterial infections are common and are the cause of most deaths associated with this syndrome RF: PMNs < 1000; skin ulcers, GC use, hypocomplementemia, high levels of immue complexes www. knol.google.com

Felty’s syndrome Treatment: DMARDs  Methotrexate Splenectomy
TNFi  no studies in actual treatment of Felty’s Steroids improve neutropenia but ↑ risk of infection - Tx for FS directed against neutropenia. - Most require no additional tx for cytopenia, but DMARDs (gold and MTX usually drugs of choice) often used to improve cytopenia, cutaneous vasculitis, and may decrease risk for infection - Splenectomy may be indicated for recurrent serious infections resistant to DMARDs

Large granular Lymphocyte syndrome
Variant of Felty’s Peripheral blood or bone marrow  LGL cells Circulating LGLs, neutropenia, frequent infections, splenomegaly 3-14%  leukemia unlike Felty’s. No splenectomy! - Many circulating LGL, neutropenia, splenomegaly and frequent infections. Are probably cytotoxic T cells or NK cells. Unlike Felty’s- 3-14% of pts with LGL syndrome progress to leukemia; exacerbations, rather than improvement, frequently follows splenectomy. Immunophenotyping: surface markers not typically seen with Felty’s: CD2, CD3, CD8, CD 16, CD 57 Picture: Peripheral blood smear from a patient with T-Cell large granular lymphocytes leukemia shows four large granular lymphocytes, abundant cytoplasm containing azurophilic granules, and a round to oval nucleus.

Ocular Involvement Keratoconjunctivitis sicca Episcleritis Scleritis
Local or diffuse Scleritis Scleromalacia perforans Choroid and retinal nodules -Keratoconjunctivitis sicca: Seen in 10-35% of patients. Often a Sjogren’s overlap. Sx: Dry eyes, burning sensation, gritty sensation of FB, mucoid discharge. Often symptomatic treatment. -Episcleritis: correlates with disease activity; simple or nodular, affects the limbus. Lesions may or may not be painful. No discharge. In episcleritis, the eye becomes red within minutes. Episcleritis appears most frequently close to the limbus over the anterior sclera. Gritty discomfort is common but pain is not. The lesion may be transient or persistent. Unlike conjunctivitis, episcleritis results in no discharge other than tearing in response to the gritty discomfort. Loss of vision does not occur as a direct result of the episcleritis, but keratitis or cataract development can cause visual loss. Scleritis: serious, sight threatening condition; ~5% of patients and occurs b/l in 70% of patients. Anterior segment common but may involve entire eye. Red, painful eye without discharge. Scleritis is rarer and potentially more serious problems. Scleritis cause severe ocular pain and a dark red discoloration. No discharge is present. Depending on the intensity, scleritis can be localized, superficial or generalized with or without granulomatous resorption of the sclera down to the uveal layer. When this complication occurs it is known as scleromalacia perforans. Scleromalacia perforans – slow progressive asymptomatic nodular destruction of the sclera. Tx: GC, cytoxan, cyclosporine, imuran, biologics. Picture: Rheumatoid arthritis: scleromalacia perforans, herniation This eye demonstrates marked scleral thinning and adjacent scleral and conjunctival injection. The darker pigmented uveal tissue has herniated through the softened sclera, and perforation is imminent. Note the nonconcentric pupil.

Rheumatoid vasculitis
< 1% of RA pts Risk factors: High titer RF & long standing, severe disease (> 10yrs) Male gender Smoking Prior DMARD use Hypocomplemetemia Circulating cryoglobins -Often severe RA, increased frequency with HLA-DRB1 *0401 - More common in men than in woman - Smoking which is also a risk factor for development of RA in the general population is associated with an increased risk of vasculitis among patients with RA - Given the observed interaction between smoking and HLA-DRB1 alleles as risk factors of RA smoking may have immunomodulatory effects with impact on rheumatoid In a community based cohort of patients with Ra from Olmsted county, Minnesota the 30 yr incidence of vasculitis was 3.6% ** There is a genetic pre-disposition toward developing RA, as HLA-DRB1 shared epitope genotypes are strongly associated with extra-articular manifestations, including rheumatoid vasculitis. Pathophysiology: Proposed mechanism include Autoab targeting of the vessel Deposition of IC (small vessel inflammation + organ damage) Local Ag driven cellular immune response Wide spectrum of vessel size involvement: venules + small arterioles (LCV) and medium vessels similar to PAN

Rheumatoid vasculitis
Clinical presentations: Cutaneous ulcerations Mononeuritis multiplex Foot/wrist drop Palpable purpura Distal arteritis Visceral arteritis: Heart, lungs, bowel, spleen, kidneys - Distal arteritis can range from nail fold infarcts to gangrene of finger tips  Digital infarcts shown. Clinical presentation ranges from frequent nail edge lesions, splinter hemorrhages to peripheral gangrene (uncommon). - Cutaneous ulcerations can resemble pyoderma gangrenosum or complicated by infections Neurovascular disease can lead to mild distal sensory neuropathy or a severe sensorimotor neuropathy such as mononeuritis multiplex. May also have rheumatoid pachymeningitis which is rare and confined to dura and pia mater. Patients with systemic rheumatoid vasculitis may develop mononeuritis multiplex however most cases of peripheral neuropathy in patients with RA is not due to vasculitis but rather to conditions such as local nerve compression and diabetes. Rheumatoid pachymeningitis: elevated levels of IgG (including IgM and IgG RF’s and low-molecular weight IgM) and immune complexes are found in the CSF. Visceral arteritis which is identical to necrotizing polyarteritis and can involve peripheral nerves, bowel, lungs, heart, spleen and other organs. Intestinal involvement can begin as minor abdominal pain that can progress to severe pain, a quiet tender belly on exam, and bowel infarction. Pauci immune GN may also occur in RA. IC deposition in the arteries and capillaries and pauci-immune lesions in medium sized arteries and renal and glomerulae. Palpable purpura is rarely found in untreated RA, and when present, is usually linked to anti-rheumatic therapy. - Picture 1: Rheumatoid arthritis: vasculitis with small infarcts, fingers These splinter hemorrhages and necrotic areas at the fingertips and around the nails were caused by vasculitis and occlusion of terminal arteries resulting in subsequent skin infarction. These changes can be found in several connective tissue diseases including rheumatoid arthritis, systemic lupus erythematosus, and polyarteritis nodosa. Picture 2: Rheumatoid arthritis: vasculitis and gangrene, fingers. Atrophy and gangrene are present on the tip of the middle finger. Less extensive necrotic lesions appear at the ends of the fourth and fifth fingers. These digital infarcts are caused by inflammatory occlusion of small arteries. Similar lesions may occur in polyarteritis, other connective tissue diseases, embolic illnesses, diabetes mellitus, and other conditions.

Course of RA Intermittent (15-20%) Long clinical remission (10%)
Progressive disease (65-70%)

Risk factors for increased morbidity/mortality
Social factors: Early age at diagnosis ↓ socioeconomic status Psychosocial stress Low HAQ scores Physical factors: Extra-articular features Erosions on x-ray ↑RF + ↑ESR/CRP Duration of disease Disability at diagnosis > 20 swollen joints

Morbidity/Mortality in ra
Median life expectancy decreased by 3-18 yrs Mortality rates higher with extra-articular manifestions and women ~50% stop working within 5-10ys of diagnosis ~80% disabled to some degree after 20 yrs Cardiac involvement: pericarditis, myocarditis, endocarditis, atherosclerosis; may also have granulomatous proliferation or vasculitis; often clinically asymptomatic. Echocardiogram useful in evaluation of even clinically asymptomatic patients. - Pericarditis: most frequent cardiac manifestation. Incidence varies 30-50% in pts per echo/post-mortem. < 10% clinically evident. RF+ and concurrent active arthritis. Histology: pericardial fluid with RF and IC as well as decreased complement. “Bread and butter pericarditis” fibrinoid necrosis. Tx: outcome favorable. Rare complication of serious complications such as constrictive pericarditis (males) and cardiac tamponade. Treat with NSAIDs and steroids which are effective but steroids do not prevent recurrence. Pericardiectomy for recurrent episodes. Endocarditis: Valvulitis most common histologic lesion (aortic > mitral > tricuspid). It can involve the valve in 5% and cause acute perforation which can cause emergency surgery. Infective endocarditis very rare. Atherosclerosis: Increased risk compared with general population (RR ). Tx monitor BP, anti-hypertensive tx, minimize NSAIDs, diet /exercise. ASA/statins, cessation of smoking. Anti-TNFs: stage 3-4 may promote heart failure and decreased compliance while controlling inflammation and plaque formation. DMARDS: Mtx along with folic acid.

Morbidity/Mortality in ra
Infection: 70% more likely to have infection Don’t forget septic arthritis in RA patients  arthocentesis NH lymphoma: 2-5 fold increased risk CAD: 3x the risk of sudden death/MI Cerebrovascular diseases: 70% more likely to have a stroke

Laboratory manifestations
No lab test is specific for RA RF + Anti-CCP + (anti-cyclic citrullinated peptide antibody) Increased ESR/CRP ANA + (25% of patients) Anemia +thrombocytosis -ANA: other serologies are usually negative; more severe disease with worse prognosis when +ANA

Rheumatoid factor Usually IgM Ab recognizes Fc portion of IgG molecule
70% RF+ at onset, 85% overall in first 2 years High titer  severe disease, extra-articular manifestations, increased mortality Normal 1-4%, 10-25% + over age 70

Mnemonic for +RF CHronic:
CH: Chronic diseases  liver/pulmonary/sarcoidosis R: Rheumatoid arthritis O: Other CTDS (SLE, SS, MCTD) N: Neoplasms (XRT, chemotherapy) I: Infections (SBE, HIV, Hepatitis B+C, TB, Parvovirus B19) C: Cryoglobinemia

Anti-CCP Autoantibody directed at cyclic citrullinated peptide
Sensitivity 65-70%, specificity (95%) RF and CCP ab combination  specificity 99.5% Detectable in early RA May antedate onset of inflammatory disease Predictor of aggressive + erosive disease Amino acids formed by post-translational modification of arginine Thus, with specificity, it is very helpful in distinguishing patients who have (+)RF with another disease process – i.e., Hep C It is not 100% specific – other processes (i.e., TB) can have (+)CCP CCP typical negative in Hepatitis C CCP not useful in predicting extra-articular disease and not useful in longitudinal monitoring of disease

1987 ACR classification criteria for RA
Must have 4 of 7 criteria: Morning stiffness at least 1 ˚ Swelling in 3 or more joints Swelling of MCP, PIP or wrist joints Symmetric joint swelling Radiographic erosions or periarticular osteopenia SQ rheumatoid nodules Positive RF At least 6 weeks - MCP: %, wrist 80-90%, PIP 65-90%, MTP 50-90%

Differential Diagnosis for RA
Comments Connective tissue diseases SLE, Systemic sclerosis, Sjogren’s Hemochromatosis 2nd /3rd MCP joints, distinctly asymmetric Check iron studies and skin changes Infectious endocarditis R/o murmurs, high fever and IVDA Polyarticular gout Joints often erythematous, rarely coexists with RA PMR Unlike PMR, RA rarely presents with proximal extremity pain Sarcoidosis Granulomas likely, as are hypercalcemia and chest X-ray findings common Seronegative spondyloarthopathy Tends to be more asymmteric than RA and typically involves the spine. Still’s disease Fever, leukocytosis, sore throat, liver dysfunction and salmon colored rash Viral arthritis Parvovirus B19, hepatitis B and C

Parvovirus B19 Symmetrical polyarthritis of peripheral small joints
May resemble RA as well as SLE More common in adults (60%) > children (5-10%) Daycare worker or mother of small children Check B19 IgM antibodies or viral B19 DNA Self limited  but may require further treatment Single stranded DNA virus discovered in 1975 Clinical experiment in human volunteers –caused viremia 6 days after inoculation without IgG antinodies. Developed IgM antibodies by the 2nd week of inoculation. Onset of IgM ab was associated with clinical illness of rash, arthralgias, and arthritis. In some patients: neutropenia, lymphopenia, and thrombocytopenia. In children, rash is common and appears as a bright red “ slapped cheek”. Joint symptoms are rare in children 5-10%, in adults rash is rare and joint symptoms more common and occur in up to 60%. Rapid onset of symmetrical ployarthritis in peripheral joints, primarily of hands and wrists. Typically, self limited but symptoms may persist for months to even years No long term joint damage occurs. Sx likely 2/2 IC deposition and a non-specific inflammatory response Dx: definitive dx is detection of B19 IgM antibodies or viral B19 DNA. IgM antibodies occur early, increasing in about one month but are often undetectable in 2-3 months. Viral B19 DNA by PCR may persists. IgG persists for years and perhaps for life. Thus IgG has little diagnostic value and is found in 50% of healthy adult population. The clinical presentation may resemble RA, JIA especially in patients whom don’t present with typical HPV exanthem and who have a clinical course of > 2 months. Many patients meet ACR criteria and even have low to moderate RF titers. May mimic SLE  may present with rash, fever, myalgia, arthopathy, cytopenias, hypocomplementemia and a +ANA. Tx: some patients may require plaquenil.

Work-up for an inflammatory arthritis
CBC, CMP, UA, RF/CCP, ESR/CRP Uric acid, HIV, chronic hepatitis, Parvovirus B19 IgM, TSH, ANA, PPD X-rays: bilateral hands/feet + chest X-ray Arthrocentesis: Inflammatory  WBC 5,000-50,000 (N 60-80%) - Radiographs higher yield with chronic symptoms

Importance of early diagnosis
RA is progressive Structural damage occurs within first 2-3 years of disease 70% have radiographic damage with in first 3 years MRI reveals erosions earlier in disease Early aggressive treatment  slows progression +disability

Radiographs Rheumatoid arthritis: hands, advanced deformity (radiograph) The metacarpophalangeal joints demonstrate marked narrowing, subluxation, and ulnar deviation. Erosions are seen in the metacarpal heads. The proximal interphalangeal joints are narrowed, but there is no reactive bone change. Demineralization is present in bones adjacent to the metacarpophalangeal and proximal interphalangeal joints. The carpal spaces are narrowed, and erosions are present in the carpal bones and ulnar styloid processes.

Radiographic features
A: abnormal alignment B: bones C: cartilage D: deformity E: erosions S: soft tissue swelling -Hand radiographs: 1st change is soft tissue swelling then juxta-articular osteopenia, erosions of “bare areas” such as radial/MCP heads Joint space loss – late findings Diffuse osteopenia and deformities

Joint space narrowing, periarticular osteopenia and erosions
-Periarticular osteopenia: The distribution of osteopenia is due in large part to the hyperaemia in bone, stimulated by the synovial disease. Joint space narrowing: Uniform narrowing of joint space due to loss of articular cartilage without significant erosions. Also see ulnar drift Picture: Rheumatoid arthritis: hand, progressive metacarpophalangeal erosion (radiographs) Progressive changes can be seen in this metacarpophalangeal joint, beginning with (A) soft-tissue swelling, but with intact underlying cortex and no erosions. This is followed by (B) thinning of the radial side of the cortex with minimal disturbance of underlying trabeculae and minimal joint space narrowing. A marginal erosion (C) appears on the radial aspect of the metacarpal head. There is loss of bone substance and joint space narrowing.

Marginal erosions Figure 1: Marginal erosions. (A) Erosions (arrows) occurring at the bare area of bone at a metacarpophalangeal joint. (B) Diagram showing erosions (arrows) at bare area of bone in relation to articular cartilage (arrowheads) and synovium. Figure 2: Rheumatoid arthritis: metatarsal erosion (radiograph). A dorsoplantar projection of the forefoot shows soft-tissue swelling, osteopenia, and narrowing of the metatarsophalangeal joints. There are large erosions of the fourth and fifth metatarsal heads and adjacent phalanges.

RA treatment Step up or step down approach  achieve remission
Treat early disease aggressively and alleviate pain Maintain function for essential daily activities Maximize quality of life Slow progression/rate of joint damage - With the earlier introduction of DMARD therapy, many rheumatologists have suggested the simultaneous use of different DMARDs. Different strategies (Figure 1) favor a step-up (sequential addition of new DMARDs to existing treatment), a step-down (initial use of multiple DMARDs with subsequent withdrawal once remission is achieved) or a parallel approach (simultaneous use of two or more DMARDs); however, there is no consensus regarding either the most effective strategy, or the combination of DMARDs for the treatment of RA.

Overview of RA treatment
Patient education Modify CAD RF and Stop smoking !!! NSAIDs + low dose corticosteroids Disease modifying agents (DMARDs) Biologics Physical/occupational therapy Surgery for structural joint damage

Keys to Optimizing the Outcome of Treatment
Table 2. Keys to Optimizing the Outcome of Treatment. - Step-up approach – in which DMARDs are added in sequential fashion until s/s of RA controlled. Also step-down method (induction therapy) based on early intensive therapy which may alter the natural history of the disease. - “I was involved in rheumatology when the traditional pyramid was developed in the early 1960s. Basically, the pyramid started out with self-management: education, appropriate rest, balanced with exercise and the use of nonsteroidal antiinflammatory drugs (NSAIDs) -- perhaps low-dose steroids and analgesic agents. We felt our approach at that time was much safer than going on to the stronger drugs such as immunosuppressants, gold-based drugs, or antibiotics, all of which we had back then. If all else failed, we would go on to what were considered experimental drugs and procedures at the time. The orthopedic surgeons continuously bailed us out of trouble, and intra-articular corticosteroids were used as needed to control individual joint disease. - But I think all of us have adopted early and aggressive intervention as our mode of therapy over the past 10 years. We know that damage occurs extremely early. We know it's progressive. One of the major messages emerging in the past few years is that damage and symptoms do not correlate in this disease. - - Early intervention leads to better outcomes, and aggressive, particularly combination, therapy is more effective. - The treatment of RA has changed considerably within the past decade, moving from a conservative approach designed to control clinical symptoms to a more aggressive approach designed to limit joint destruction. Instead of delaying treatment with DMARDs, such as methotrexate, sulphasalazine and hydroxychloroquine, these drugs are being used increasingly in the treatment of early stage disease as well as in more aggressive combination regimens. This evolution in patient management recognizes that the side-effects associated with RA—severe functional declines, joint destruction, work disability, comorbid diseases and premature mortality—are generally considerably greater than the side-effects associated with DMARDs and corticosteroids [1, 2]. Despite the toxicities of these medications, the natural history of RA suggests that the risks of using these drugs is much lower than the risks associated with insufficient treatment. Within the first 2 yr of disease, many patients have radiographic evidence of substantial bone erosions, but, more importantly, radiographic progression of disease occurs in almost all patients time [3–6]. In most patients with serious RA, progression of bone erosions is best described by a first-order model in which approximately 50% of detectable radiographic damage occurs during the first 5 yr of disease [7]. By providing only symptomatic treatment of early-stage disease, the processes inherent to radiographic progression remain unchecked. In the conservative approach to RA treatment, extensive joint damage is often present by the time DMARDs and corticosteroids are finally introduced. - Conversely, by introducing these medications, as well as the newly developed biological therapies, in early-stage disease, it may be possible to limit or slow damage within the joint. O'Dell J. N Engl J Med 2004;350:

NSAID therapy Pros Cons Controls inflammation Improves mobility, ROM
↓ pain/swelling Improves mobility, ROM Improve quality of life Low cost Does not modify disease progression GI toxicity Renal complications CNS toxicity Helpful in the first few weeks of symptoms. Provide partial relief of pain and stiffness Don’t modify disease progression GI: ulcerations, perforations and hemorrhage with 1.5% of patients admitted for related GI problems. Cox2: appear to increase the CV adverse events

Corticosteroid therapy
Pros Cons Anti-inflammatory + immunosuppressive effects Bridge to initiation of DMARD therapy Dose of < 10 mg/day CSI used for joint flares Disease progression? Tapering + discontinuation difficult Skin thinning, Cushingoid appearance, cataracts Steroid induced osteopenia/osteoporosis -Potent suppressors of the inflammatory response in RA ? Decrease progression of RA radiographically Low dose prednisone (< 10 mg). May substitute for NSAIDs. Used as bridge therapy (dose of mg po daily) SE: thinning of skin, cataracts, osteoporosis, HTN, HLP All patients should receive supplemental calcium/vitamin D as well as consideration for bisphosphonates

Disease modifying anti-rheumatic Drugs
Slows disease progression Decreases radiographic progression Improves functional disability Decreases pain + interferes with inflammatory processes

Methotrexate Pros Cons Gold standard DMARD Improves survival
Proven efficacy and durability in moderate to severe RA Used in combination with other DMARDs Labs q 2 months Bone marrow suppression Alopecia, stomatitis Lung + liver toxicity Contraindicated: pregnancy, pre-existing renal + liver disease (hepatitis) MTX: is an anti-folate agent with anti-inflammatory properties. Used as initial DMARD of choice for RA regardless of prognosis. Used in combination with other medications such as HCQ, sulfasalazine as well as biologics. Demonstrated efficacy and durability with long term track record of acceptable toxicity and low cost. -Significantly lowers mortality (mortalitiy hazard ratio of 0.4). Improvement in 6 weeks. Dose of mg po q week. Administer with folic acid to reduce SE. SE: - Pre-existing liver (alcohol use) and renal disease are contraindications. - Hypersensitivity pneumonitis: Occurs in ~2% of RA patients taking MTX. Presentation: Non-productive cough, progressive dyspnea and decreased exercise tolerance, Low grade fever; PE: tachypnea, hypoxemia and bibasilar rales; CXR: Combined alveolar and interstitial pattern; dx: Blood and sputum cultures are negative. BAL  r/o infection. Lymphocytic alveolar infiltrate and peripheral eosinophilia favor MTX lung injury Tx: Discontinue MTX (permanently)  Parenteral CS and respiratory support may be needed

Leflunomide (Arava) Pros Cons Early onset of action (~4 weeks)
Targets autoimmune lymphocytes  anti-inflammatory Effective for moderate/severe RA Black box warning: Hepatotoxicity HTN, alopecia GI side effects  diarrhea, weight loss Contraindicated: severe liver disease, pregnancy - MOA: Blockade of pyrimidine synthesis pathways has anti-proliferative effects. Complementary with MTX. Highly protein bound with half life of days. Use as alternative to MTX SE: Most common is hepatic. 5 % with elevated transaminases (generally less than twice the upper limit of normal). Combination of leflunomide and MTX may be associated with a high risk of hepatotoxic effects. Other common SE: Weight loss, diarrhea, HTN and reversible alopecia. Pregnancy and fertility: causes fetal death and is teratogenic

Other DMARDs Hydroxycloroquine (HCQ) aka plaquenil Sulfasalazine (SSZ)
Ocular toxicity (eye examination every year) Sulfasalazine (SSZ) Reversible oligospermia Minocycline Cyclosporine Gold

Combination therapy Does not increase toxicity significantly
Long term outcome more favorable Superior efficacy to monotherapy Combinations: MTX/SSZ/HCQ MTX and biologics

Biologic Therapies Figure 1. Inflammation in the Rheumatoid Joint.
Figure 1. Inflammation in the Rheumatoid Joint. The identity of the inciting antigen is not known, but it most likely drives lymphocyte proliferation, which contributes to the production of the rheumatoid-factor autoantibody. The fixation of complement amplifies the destructive cascade, attracting additional inflammatory cells and resulting in the production of cytokines and enzymes. These, in turn, mediate tissue damage, including cartilage loss and bone erosion. Likely sites of action of the major drugs described in this article are shown. C denotes serum complement protein, and C* activated serum complement protein.

Anti-tumor necrosis factor therapy
FDA approved: Infliximab (Remicaide)  IV infusion Given with MTX to reduce human anti-chimeric ab (HACAs) Adalimumab (Humira) Etanercept (Enbrel) Certoluzimab pegol (Cimzia) Golimumab (Simponi) -Infliximab (chimeric protein made from human and mouse components) and adalimumab (SQ q 2 weeks) are monoclonal ab; enbrel is a soluble TNF receptor ( SQ q week) -Infliximab IV infusion q 6-8 weeks. Should be given with MTX to minimize anti-chimeric ab (HACAs) that are thought to be responsible for SE. Can cause significant hepatotoxicity.

Anti-tnf summary Rapid onset of action with improvement in symptoms
Disability and quality of life Inhibition of radiographic progression Sustained efficacy of at least 5 years Class effect 1st line therapy with MTX for high disease activity

Safety data for TNF Serious infections (opportunistic fungal, TB)
Infusion, injection reactions Malignancy potential Neurologic/demyelinating disease Autoab (ANA + DS DNA) and lupus like syndrome CHF worsening, new onset -1/54 infection risk (abx, hospitalization) -1/150 malignancy risk  routine cancer screening

Other Biologics Anakinra (Kineret) Abatacept (Orencia)
IL-1 receptor antagonist Rituximab (Rituxan) Chimeric monoclonal IgG1 anti-CD20 antibody B lymphocyte depletion Abatacept (Orencia) CTLA-4Ig Support or abrogate activation of T-cells Tocilizumab (Actemra) Humanized monoclonal antibody against IL-6 receptor Abatacept (Orencia): Fusion protein composed of Ig fused to the extracellular domain of CTLA-4 selective costimulation modulator as it inhibits the costimulation of T cells Clinical Use: Moderate to severe RA refractory to DMARDS and TNF inhibitors Dosing: IV infusion based on weight at 0,2 and 4 wks then q 4 weeks Kremer et al, evaluated 652 patients who were inadequate responders to MTX and compared abatacept vs Abatacept + MTX. ACR 20 at 1 yr was 73.1% in abatacept and MTX Side Effects: infection, infusion site reactions Rituximab: A chimeric monoclonal ab against CD 20 Acts through complement and antibody mediated cytotoxicity as well as induction of apoptosis Clinical Use: Moderate to severe RA with inadequate response to one or more TNF antagonists Dosing: 1000mg IV q 2 weeks x 2 doses In the Reflex study, demonstrated a single course of rituximab and MTX significant improved symptoms in 24 weeks in patients who failed to respond to 1 or more TNF inhibitors Anikinra (Kineret): Recombiant form of human IL-1 receptor antagonist Targets the type IL-1 receptor expressed in many tissues Clinical use: Pt with no response or are unable to tolerate MTX, leflunomide or TNF inhibitors Alone or in combination with MTX has been more effective than placebo Short ½ life of 6 hrs daily administration is more effective than injections given weekly Renal clearance and should be avoided in renal failure Side Effects: skin irritation, myelosupression, and increased risk of infection Toclizumab: January 11, 2010 ( UPDATED January 13, 2010 ) — The US Food and Drug Administration (FDA) has approved tocilizumab intravenous infusion (Actemra, Roche) for the once-monthly treatment of moderately to severely active rheumatoid arthritis (RA) in adults who have had an inadequate response to 1 or more tumor necrosis factor antagonist therapies. The first-in-class interleukin 6 receptor–inhibiting monoclonal antibody is the ninth biologic agent approved for the treatment of RA and may be used alone or in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARDS). It is expected to be available in the United States the week of January 18, 2010.

Initiating Biologic therapy
Basic labs: CBC, CMP PPD (TB screen) or quantiferon gold Chronic hepatitis panel and HIV Routine health screening and vaccinations: Flu and PNA No live vaccines after initiation of therapy Ensure routine cancer screening UTD -Routine cancer screening -PPD: + for LTBI place on INH therapy for at least 1 month

Conclusions Recognize and treat RA early
RA is progressive  disability Newer agents and aggressive therapy offers great hope for the future of most patients

Any questions???

Bibliography Feldmann M. Development of anti-TNF therapy for rheumatoid arthritis. Nature Review. 2002; 2: Turesson C, et al. Extra-articular disease manifestations in rheumatoid arthritis: incidence of trends and risk factors over 46 years. Ann Rheum Dis 2003; 62: Turesson C, et al. Rheumatoid factor and antibodies to cyclic citullinated peptides are associated with severe extra-articular manifestations in rheumatoid arthritis. Ann Rheum Dis 2007; 66:59-64. Turesson C, Matteson E. Vasculitis in Rheaumatoid Arthritis. Current Opinion in Rheumatology. Feb 2009. Levesque M. Systemic Extra-articular manifestations of rheumatoid arthritis. Medscape 2008.

Bibliography Scott et al. Tumor Necrosis Factor Inhibitors for Rheumatoid arthritis. N Engl J Med 2006; 355: Olson et al. New Drugs for Rheumatoid Arthritis. N Engl J Med 2004; 350: Odell, J. Therapeutic Strategies for Rheumatoid Arthritis. N Engl J Med 2004; 350: Harris E, et al. Overview of the systemic and nonarticular manifestations of rheumatoid arthritis. Uptodate June 09. Odell JR et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 1996; 334:

Activated T-cells release cytokines including IL-2 IFN-, TNF-, IL-3 and TNF-. TNF- , plays a key role in the pathology of rheumatoid arthritis. TNF- stimulates the macrophages, which produce TNF-, IL-1 and IL-6. TNF- is also a potent stimulator of IL-1, IL-6, and IL-8, which stimulate chondrocytes, osteoclasts and fibroblasts that release metalloproteinases (e.g., MMP-1 and MMP-3), ultimately leading to the erosion of bone and cartilage. 1-3 TNF- is at the apex of the inflammatory cascade promoting downstream mediators that lead to bone erosion and inflammation in RA.1,4 Blocking TNF- inhibits the production of IL-1, IL-6, and IL-8 and may have a more global effect versus blocking other cytokines further down the cascade. Feldmann M. Development of anti-TNF therapy for rheumatoid arthritis. Nature Review. 2002; 2: Feldmen M. Nature Reviews 2002; 2:

Inflammation in the Rheumatoid Joint
Figure 1. Inflammation in the Rheumatoid Joint. The identity of the inciting antigen is not known, but it most likely drives lymphocyte proliferation, which contributes to the production of the rheumatoid-factor autoantibody. The fixation of complement amplifies the destructive cascade, attracting additional inflammatory cells and resulting in the production of cytokines and enzymes. These, in turn, mediate tissue damage, including cartilage loss and bone erosion. Likely sites of action of the major drugs described in this article are shown. C denotes serum complement protein, and C* activated serum complement protein. Olsen N and Stein C. N Engl J Med 2004;350:

Rheumatoid Arthritis.

Similar presentations

Presentation on theme: "Rheumatoid Arthritis."— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Rheumatoid Arthritis.

Similar presentations

Presentation on theme: "Rheumatoid Arthritis."— Presentation transcript:

Similar presentations

About project

Feedback