Rheumatology

Unprotected copy By: Dr.JKR

Jkr336@hotmail.com

Dr.JKR

RH Rheumatology

Justine Cohen, Amanda Mayo and Julia Warden, chapter editors Lawrence Aoun and Sam Silver, associate editors Jeremy Adams, EBM editor Dr. Heather McDonald-Blumer and Dr. Dana Jerome, staff editors

Basic Anatomy Review 2

Basics of Immunology 2 Immune Mechanisms of Disease Immunogenetics and Disease

Differential Diagnoses of Common .....3 Presentations

Degenerative Arthritis: Osteoarthritis ..4

Seropositive Rheumatic Diseases: Connective Tissue Disorders 5 Rheumatoid Arthritis (RA)� Systemic Lupus Erythematosus (SLE)� Antiphospholipid Antibody Syndrome (APS)� Scleroderma/Progressive Systemic Sclerosis� (PSS)� Idiopathic Inflammatory Myopathy� Sjogren's Syndrome� Mixed Connective Tissue Disease/Overlap� Syndrome (MCTD)�

Seropositive Rheumatic Diseases: Vasculitides 15 Predominantly Cutaneous Vasculitis� Wegener's Granulomatosis� Polyarteritis Nodosa (PAN)� Giant Cell Arteritis (Temporal Arteritis)�

Seropositive Rheumatic Diseases: Investigations 17

Seronegative Rheumatic Diseases . ... .18� Ankylosing Spondylitis (AS)� Reactive Arthritis (ReA)� Psoriatic Arthritis (PsA)� Inflammatory Bowel Disease (IBD)� Undifferentiated Spondylopathy�

Crystal-induced Arthropathies 22 Gout Pseudogout (Chondrocalcinosis) Synovial Fluid Analysis

Non-Articular Rheumatism 24 Polymyalgia Rheumatica Fibromyalgia

Summary of Arthritic Disease 26

Clinical Approach to Arthritis 26

Common Medications 27

Summary Key Questions 28

References 30

Toronto Notes 2008 Rheumatology RHI

Dr.JKR

RH2 Rheumatology Basic Anatomy ReviewlBasics of Immunology� Toronto Notes 2008

Basic Anatomy Review

erosion Bursa

Synovial Cartilage membrane destruction

~ SynovitisSynovial fluid

Tendon Cartilage EffusionCartjlageU-roi;:::~:=:;~J particleOsteophyte

Loss of ~_.iUjOintspaceCartilage joint spacedestruction� narrowing

Normal Joint Degenerative Joint Infiammatory Joint

©Frances Yeunq 200S; revised by Desmond Ballance 2006

Figure 1. Structure of normal, degenerative and inflammatory joint

Basics of Immunology

Immune Mechanisms of Disease------"------­•� fundamental principles of pathogenesis of autoimmune diseases

• disease results from a failure to discriminate between self and non-self • autoreactive T cell is a common effector of many of these diseases • certain HLA haplotypes are associated with increased susceptibility to disease

(see Table 2) • activated immune system against self --+ cell damage/destruction --+ altered

cell function •� mechanisms of immunologically mediated disorders (4 types of immune reactions):

i.� anaphylactic (type I) •� formation of IgE -. release of mediators from basophils/mast cells

• diffuse inflammation •� e.g. asthma, allergic rhinitis, anaphylaxis

ii. cytotoxic (type II) •� formation of antibody -> deposit and bind to Ag on cell surface --+

phagocytosis or lysis of target cell •� e.g. autoimmune hemolytic anemia, Goodpasture's syndrome, Graves'

disease, pernicious anemia iii. immune complex (type III)

•� Ag-Ab complexes form --> activate complement --+ attracts inflammatory cells anet release of cytokines

•� e.g. SLE, PAN, post-streptococcal glomerulonephritis iv. cell-mediated/delayed hypersensitivity (type IV)

•� st'nsitized T cells' release of cytokines and T-cell mediated cytotoxicity •� e.g. contact dermatitis

Immunogenetics and Disease •� cell surface molecules called human leukocyte antigen (HLA) or major�

histocompatibility complex (MHC) playa role in mediating immune reactions� •� discrete domains of hypervariability within MHC molecules appear to represent�

"susceptibility determinants"� •� there are three classes of MHC; the gt'nes encoding them are on chromosome 6

Dr.JKR

Toronto Notes 2008 Basics of Immunology/Difterential Diagnoses of Common Presentations

Table 1. Classes of Major Histocompatibility Complexes (MHCs)

MHC Class Types� Location Function

HLA-A, -B, -C All cells� Recognized by CD8+ (cytotoxic) Tlymphocytes

II HLA-Dp, -DO, -DR� Antigen presenting cells Recognized by CD4+ (helper)� (mononuclear phagocytes, Bcells, others) Tlymphocytes�

III� Complement In plasma Chemotaxis, opsonization,� components lysis of bacteria and cells�

Table 2. HLA-Associated Rheumatic Disease

HLAType� Associated Conditions Comments

827� Ankylosing spondylitis In AS, relative risk =70-90� Reactive arthritis In reactive arthritis, relative risk = 40� Psoriatic arthritis Psoriatic also associated with B38� IBD arthropathy (spine)�

DR4, DR1� Rheumatoid arthritis 93% of patients

DR3� Sjogren's syndrome DR3 associated with many non-rheumatic conditions SLE (Celiac disease, Type 1 DM, Graves' disease, Rheumatoid arthritis Chronic active hepatitis)

Differential Diagnoses of Common� Presentations� Table 3. Differential Diagnosis of Joint Pain

Monoarticular Polyarticular Non-articular� Infectious (see Infectious Diseases, 10221 • Infectious • Musculoskeletal� Bacterial Lyme disease Tendonitis� Mycobacterial Bacterial endocarditis Bursitis� Fungal Septicemia Strain� Viral Gonococcus FibromyalgialPMR� Crystal-induced Viral!EBV, parvovlrusi • Neurological involvement�

Gout • Post-inlectious Spinal stenosis/spondylolisthesis CPPD Rheumatic fever Degenerative disc disease Hydroxyapatite Reactive arthritis Cauda equina syndrome

Hemarthrosis Enteric infections Neoplasm� Trauma/fracture • Inflammatory Thoracic outlet syndrome� Anticoagulants Seropositive (CTD) • Vascular� Bleeding diatheses Seronegative Intermittent claudication�

Neoplasm Inflammatory� Seropositive ICTD)� Seronegative�

Degenerative

Patterns of Joint Involvement • symmetrical vs. asymmetrical • small vs. large • mono V5. oligo vs. polyarticular • axial V5. peripheral

Table 4. Differential Diagnosis of Joint Pain: Patterns of Joint Involvement

Symmetrical� Asymmetrical

Large Joint Polyarthritis� Oligoarthritis • Ankylosing spondylitis� • Seronegative disorders • Rheumatoid arthritis� • Psoriatic arthritis • Polymyalgia rheumatica� • Reactive arthritis • Osteoarthritis� • Infectious arthritis

• Crystal-induced arthritis

Small Joint Polyarthritis • Seropositive disorders (RF+, ANA+) • Psoriatic arthritis • Psoriatic arthritis� • Tophaceous gout

Rheumatology RH3

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~'

Joint Pain Causes SOFTER TISSUE

Sepsis� OA� Fracture� Tendon/muscle� Epiphyseal� Referred�

Tumour� Ischemia� Seropositive arthritides� Seronegative arthritides� Urate (gout)/other crystal� Extra-articular rheumatism� (polymyalgia/fibromyalgial�

Septic Arthritis is a Medical Emergency! Consider empiric antibiotic treatment until septic arthritis is excluded by history, physical exam and synovial fluid analysis. (see Infectious Diseases, ID22)

Dr.JKR

RH4 Rheumatology Differential Diagnoses of Common PresentationslDegenerative Arthritis: Osteoarthritis Toronto Notes 2008

G1ucoumine therapy fvr treating osteoarthritis (TowheedTE, Maxwell K,AnastassiadesTP, et al. Cochrane Dat1Jbase ofSystemic Reviews 2005, Issue 2. Art. No.: COO02946. DOl: 10,1002114651858. COOO2946. pub21 Study: Meta·analysis of 20 RCTs1n=27501 examining the efficacy of glucosamine on OA. Resultl: Overall analysis of 15 RCTs favoured glucosamine over placebo for total reduction in pain (measured by avariety of methodsl. Significant differences between glucosamine and placebo were also observed when compared to Levesque Index scores. Only the gluoosamine containing Rotta prepara1ion was found to be significant No significant differenoes in I'vUMAC lin pain, stiffness and function subscalesl were found between glucosamine and ~acebo when on~ studies with adequate allocation concealment were included.There was evidence to suggest that glucosamine may ~ow the radiolog~ progression of OA at 3years. Glucosamine had an excellent safety profile. Conclusion: Glucosamine appears helpful for pain when all studies (low quality and older studiesl are included. However, when on~ the higher quality studies are included, there is no longer adifference between gluoosamine and placebo. Glucosamine was very well tolerated with low toxicity. Rotta prepara1ion of glucosamine may be of some benefit.

MelHnaIysis: Chondroitin flIr osteoarthritis 01 tlle knee and hip (Annals of Intemal Medicine, 17 April, 2001 Volume 146(81:~1 Study: Meta-analysis of 20 RCTsIn=3Il46l examining the efficacy of chondroitin on OA. Results: The analysis of this review was hampered by ~gnificant trial heterogeneity. Tria~ with poor methodology (small numbers, inadequate randomization concealment no intention to treat analysisl showed larger effect sizes in lavour of glucosamine than more recent lna~.l'ihen the authors analyzed on~ the newer and more robust trials, an effect~ze of-o.3 (095%: -0.13 to 0.071 was generated.� Conclusion: There ~ high quality evidence to suggest� there is no difference between chondroitin and placebo.� Chondroitin should be disregarded from routine use in� clinical practice.�

• hand (DIP, PIP, 1st CMC)

• hip • knee • 1st MTP • L-spine (L4-L5, L5-S1) • C-spine •� uncommon: ankle, shoulder,

elbow, MCp, rest of wrist

Figure 2. Common sites of involvement in OA

Table 5. Seropositive vs. Seronegative Rheumatic Diseases Seropositive Seronegative

Demographics M>F

Peripheral Arthritis� Symmetrical Usually larger joints, lower extremities Small and large joints (psoriatic arthritis may be the exception) DIP less involved Dactylitis

Enthesitis DIP in Psoriatic arthritis

Pelvic/Axial Disease� No (except for C-spinel Yes

Enthesopathy� No Yes

Extra-Articular� Nodules Iritis 1= Anterior Uveitisl Vasculitis Oral ulcers Sicca GI Raynaud's phenomenon GU

Dermatological features

Extra-Articular Features •� consider skin and appendages, eyes, lungs, cardiac, pulmonary, CI, CU, neurologic,

psychiatriC

Degenerative Arthritis: Osteoarthritis Definition •� primary (idiopathic)

•� most common, of unknown etiology •� secondary

• post-traumatic or mechanical •� post-inflammatory (e.g. RA) or post-infectious

heritable skeletal disorders (e.g. scoliosis) endocrine disorders (e.g. acromegaly, hyperparathyroidism, hypothyroidism) metabolic disorders (e.g. gout, pseudogout, hemochromatosis, Wilson's disease, ochronosis)

•� neuropathic (also known as Charcot joints) •� atypical joint trauma due to loss of proprioceptive senses (e.g. diabetes,

syphilis) avascular necrosis (e.g. fracture, steroids, alcohol, gout, sickle cell)

• other (e.g. congenital malformation)

Etiology and Pathophysiology •� abnormal physical forces lead to altered joint function and damage •� primary event is deterioration of articular cartilage due to local biomechanical factors

and release of proteolytic and collagenolytic enzymes •� OA develops when cartilage catabolism> synthesis • loss of proteoglycans and water exposes underlying bone

•� abnormalloca1 bone metabolism further damages joint •� synovitis is secondary to cartilage damage therefore may see small effusions in OA

Epidemiology •� most common arthropathy (12% of age 25-74) •� increased prevalence with increasing age (35% of 3D-year olds, 85% of 8D-year olds)

Risk Factors •� genetic predisposition, advanced age, obesity (for knee OA), female, trauma

Signs and Symptoms •� signs and symptoms localized to affected joints (not a systemic disease) •� pain is often insidious, gradually progressive, with intermittent flare-ups and

remissions

Table 6. Signs and Symptoms of OA Symptoms� Signs

joint pain with motion; relieved with rest joint line tenderness; stress pain short duration of stiffness «1/2 hr) after immobility bony enlargement at affected joints joint instability/buckling malalignment/deformity (angulation) loss of function limited ROM joint locking due to "joint mouse" (bone or cartilage fragment) periarticular muscle atrophy

crepitus on passive ROM inflammation mild if present

Joint Involvement •� any joint can be affected especially knee, hip, hand, spine (shoulder, elbow, wrist and

ankle are less common)

Dr.JKR

Toronto Notes 2008 Degenerative Arthritis: Osteoarthritis/Seropositive Rheumatic Diseases: Connective Tissue Disorders Rheumatology RH5

•� hand • DIP (Heberden's nodes = osteophytes ~) enlargement of joints) • PIP (Bouchard's nodes) (see Figure 3)�

CMC (usually thumb squaring)� MCP is usually spared (except the 1st MCP)�

•� hip • dull or sharp pain in trochanter, groin, anterior thigh, or knee�

internal rotation and abduction are lost first� •� knee

• narrowing of one compartment of the knee is the rule, medial> lateral • standing x-rays must be done (not supine)

•� foot •� common in first MTP

•� lumbar spine • very common especially L4-LS, L5-S1 • degeneration of intervertebral discs with possible disc herniation and facet joint

degeneration •� reactive bone growth can contribute to neurological impingement (e.g. sciatica,

neurogenic claudication) or listhesis (slippage) •� cervical spine

• commonly presents with neck pain, especially in lower cervical area

Investigations •� blood work

• normal CBC and ESR • negative RF and ANA

•� synovial fluid --) non-inflammatory (see Table 19, RH24) •� radiology (4 hallmark findings, see sidebar)

Treatment •� presently no treatment alters the natural history of OA •� non-pharmacological therapy

• weight loss (minimum 5-10 Ibs.loss) • rest/low-impact exercise • physiotherapY' with heat, massage, exercise programs� • occupational therapy --) aids, spfmts, cane, walKer, bracing�

•� medical therapy • NSAIDs, acetaminophen (see Common Medications, RH27) • hyaluronic joint injections (Hyalgan™, Synvise™, etc.)

•� surgical treatment • joint debridement, osteotomy, total and/or partial joint replacement, fusion

Table 7. Features of Seropositive Arthropathies Clinical Features Rheumatoid Arthritis

History

Physical Examination

Laboratory

Non-specific

Specific

Synovial Fluid

Radiographs

Symmetrical Po~anhritis Ismail joint involvementl AM~iffness[>lhrl

EftusedJoints Tenosynovtis Nodules Bone-on-bone crepitus

Increased ESR in 50·60% Increased platelets Decreased Hb Decreased WBC {Felty'sl

RF +ve in -80%

Inflammation leukocytoSis [>10,0001

Demineralization Symmetridconcentric joint space narrowing Erosions of subchondral bone Absence of bone repair

Systemic Lupus Erythematosus

Multisy~emic disease rash, photosensitivity, Raynaud's, alopecia,

cardiac and pulmonary serosnis, CNS symptoms, glomerulonephritis

Confirm historical findings Itypically smalilointsi� ±effused joints Ican be minimal. look for� soft tissue swellingl�

Increased ESR� Decreased platelets� Decreased Hb lautOimmunel� Decreased WBC !leukopenia, Iymphopenial�

ANA tve in 9B%� Anti-SM tve in 30%� Anti-<lsDNA +ve in 50·70%� Decreased C3, C4, total hemolytic complement� False positive VORL lin lupus subtypes)� Increased PTT lin lupus subtypes; e,g. antiphospholipid Abl�

Mild inflammation with +ve ANA�

Nondewuctivelnonerosive� ±osteoporosis, osteopenla� ±sofl tissue swelling�

Scleroderma

Raynaud's, stiffness of fingers, skin tightness, heanburnJdysphagia pulmonary hypenension, renal dysfunction

S~n tightness on dorsum of hand, facial skin tightening, telangiectasia, calcinosis, non-effused joint

Increased ESR Increased platelets Decreased Hb NormalWBC

ANA +VB in ,90% Anti-topoisomerase 1 Idiffusel Anti-centromere lusually in CREST. see sidebarl

Not specfic

±pulmonary fibrosis ±esophageal dysmotility :!:calcinosis

Dermatomyositis

Heliotrope rash [eyelidsl, Gonron's papules, macular erythema and poikiloderma Ishoulders, ned< and che~l,

proximal muscle weakness ±pain

Rasn, proximal muscle weakness

Possible increased ESR Normal platelets Decreased Hb NormalWBC

CPK elevated in 80% ANA +Ve in 33% anti-Jo-1,anti-Mi·2 Muscle biopsy -key for diagnosis EMG MRI

Not specific

±esophageal dysmotility ± inter~itiallung disease

'1., OA of MCP joints can be seen in hemochromatosis or chondrocalcinosis.

Bouchard's node

Heberden's� node�

Figure 3. Bouchard's and� Heberden's nodes�

AcoolmIed trial martl1rosCOtJic ~ry for osteoar1hri­lis of the knee IN Engl JMed2002;347~1-81

Sludy. Randomized, double-blind, placebo·controlled trial with follow up of2years. Plli8ms:l80 patients s75 years (mean age 52yrs,!ll% male, 60% whnel with o~eoartflritis of tile knee and at least moderate knee pain despne maximal medical tiler· apy. 1nIlIIwnIion: Patients were randomiled to receive arthroscopic debridemen~ artflroscopic lavage, or placeoo surgery Is~n inci~ons and ~mulated debride­mentwithout insertion of tile artflroscopel. Prin8Iy 0uIt0me: Sell reponed scores on pain and function scales, and an objective test of wal~ng and stair climbing. IIesu/IrThere was no difference between groups in pain relief at any time point in 2years of follow up. Similarly, tflere was no difference between groups in sell·reported function at any time. In fac~ objective scores for walking and ~air climbing were signfficantly worse in the debridement group tflan in the placebo group at 2weeks and one year po~·op, and there was a trend toward poorer scores at 2years, although this resullwas notstatistical~ signfficant Coocllsioos: Seft reponed pain and functional out· comes were equivalent in patients receiving artflroscopy arM! sham surgery for osteoartflritis of the knee, Furthermore, objective measures of function favoured tile placebo group.

'" , ,•.l------------.

The Radiographic Hallmarks of OA 1.� joint space narrowing 2.� subchondral sclerosis 3.� subchondral cyst formation 4.� osteophytes

'" ' ,.)-------------, CREST Syndrome Calcinosis -calcium deposits on skin Raynaud's phenomenon Esophageal dysfunction - acid reflux Sclerodactyly - tightening of skin Telangiectasia - superficial dilated blood vessels

Dr.JKR

RH6 Rheumatology

o

.... , ,.l------------,

Common Presentation •� Morning stiffness >30 min. improving

with use • Symmetric joint involvement •� Initially involves small joints of hands

and feet • Constitutional symptoms

.... , ,.l------------,

Criteria are 91·94% sensitive and 89% specific for RA.

• PIP • MCP • wrist. not 1st CMC • elbow • shoulder • knee • ankle • MTP • C-spine

Figure 4. Common sites of joint involvement in RA

Seropositive Rheumatic Diseases: Connective Tissue Disorders� Toronto Notes 2008

--'''--� ...JRheumatoid Arthritis (RA)Definition •� chronic, symmetric, erosive synovitis of peripheral joints (i.e. wrists, Mcr joints, and

MTP joints) •� characterized by a number of extra-articular features

Table 8. Diagnostic Criteria: RA diagnosed if 4 or more of the following 7 criteria present (American Rheumatism Association, 1987)

Criteria� Definition

1. Morning stiffness� Joint stiffness>1hour for >6 weeks

2.� Arthritis of three or more joint areas At least 3active joints for >6 weeks; commonly involved� joints are PIp, MCp, wrist. elbow, knee, ankle, MTP�

3. Arthritis of hand joints� At least one active joint in wrist, MCP or PIP for >6 weeks

4. Symmetric arthritis� Bilateral involvement of PIp, MCp, or MTP for >6 weeks

5.� Rheumatoid nodules Subcutaneous nodules over bony prominences, extensor� surfaces or in juxta·articular regions�

6. Serum RF� Found in 60-80% of RA patients

7.� Radiographic changes Erosions or periarticular osteopenia, likely to see earliest� changes at ulnar styloid, 2nd and 3rd MCP and PIP joints�

Etiology and Pathophysiology •� autoimmune disorder, unknown etiology •� hallmark of RA is hypertrophy of the synovial membrane

• outgrowth of activated rheumatoid synovium (pannus) into and over the articular surtace results in destruction of articular cartilage and subchondral bone

•� two theories dttempt to explain chronic remissions and exacerbations seen in RA •� sequestered Ag

•� during inflammation, immune complexes (lCs) are deposited at cartilagt'-bone junction, which is an avascular area --+ rcs remain free of reticulo-endothelial system but are released as further cartilage breaks down --+ triggers cascade

• molecular mimicry •� cartilage damage --> altered configuration of cartilage resembles

offending agent --+ triggers cascade

Unknown Ag(s)

~ Antigen presenting cell

~

Osteoprotegerin ligand

I r i

~ Activation of complement B- and T-cell ~putrophil Promotes Proliferation Osteoclastogenesis cascade accumulation recruitment inflammation of synovial I

in rOVium ~ rblaslS ",~ t~ Accumulation of PMNs; Release of Release of Pannus fonnation Matrix inflammatory symptoms inflammatory elastase + protease \ metalloproteinasps

mediators ~ I

Degradation of In!a':'ion of cartilage peptidoglycan / of cartilage ~~ I CartIIace and bone destruction .....----------'

Figure 5. Proposed Pathogenesis of RA

Dr.JKR

Toronto Notes 2008� Seropositive Rheumatic Diseases: Connective Tissue Disorders Rheumatology RH7

Epidemiology • incidence 0.6-2.9 per 1,000 population/yr, prevalence 1% of adult population •� F:M = 3:1; age of onset 20-40 yrs • genetic predisposition: HLA-DR4/DRI association (93% of patients have

either HLA type)

Signs and Symptoms •� variable course of exacerbations and remissions •� morning stiffness >1 hr, improves with use, aggravated by rest • symmetric joint involvement (see Figure 4) •� signs of disease activity: synovitis (assessed by tender and swollen joint count),

elevated serum markers of inflammation such as ESR or CRP, decreased grip strength, increased pain

•� signs of mechanical joint damage: loss of motion, crepitus, instability, deformity •� constitutional symptoms: profound fatigue; rarely myalgia or weight loss •� extra-articular features (see Figure 7) and radiographic damage • limitation of function and decrease in global functional status

Classification of Global Functional Status in RA (American College of Rheumatology, 1991) •� Class I: able to perform usual ADLs (self-care, vocational, avocational) •� Class II: able to perform self-care and vocational activities, restriction of

avocational activities •� Class III: able to perform self-care, restriction of vocational and avocational activities •� Class IV: limited in ability to perform self-care, vocational, avocational activities

Complications of Chronic Synovitis •� joint deformities (see Figure 6)

•� swan neck deformity, boutonniere deformity • ulnar deviation of MCP; radial deviation of wrist joint ClaW~To.e•� hammer toe, mallet toe, claw toe • flexion contractures

•� atlanto-axial and subaxial subluxation ~ • neurological impingement (long tract signs)� .~ • difficult intubation

• limited shoulder mobility, C-spine instability, spontaneous tears of the rotator cuff� HammerToe leading to chronic spasm

•� tenosynovitis ---> may cause rupture of tendons •� Carpal Tunnel Syndrome •� ruptured Baker's cyst (outpouching of synoviurn behind the knee); presentation

similar to acute thrombophlebitis •� anemia of chronic disease •� decreased functional capacity and early mortality

Extra-Articular Features (EAF) •� classified in terms of the underlying process: either vasculitis or a lymphocytic infiltrate

Extra-Articular Features I� Figure 6. Joint deformities

Vasculitis� Lymphocytic infiltrate ... ' ~ episcleritis, scleritis rheumatoid nodules� 9)--------------,

periungual infarction pulmonary fibrosis Poor prognostic features of RA includecutaneous ulcers pleural effusion/pleuritis young age of onset, high RF titer, elevat·palpable purpura� pulmonary nodules ed ESR, activity of >20 joints, and pres­peripheral neuropathy� peri-/myocarditis, valvular disease enceofEAF.

•� sensory: stocking-glove Hashimoto's thyroiditis •� mononeuritis multiplex Sjogren's syndrome�

Felty's syndrome� hepatosplenomegaly� ... ' ~

9·}-----------,Figure 7. EAF of RA

Common Syndromes in RATreatment 1. Sjogren's syndrome (sicca complex ­•� goals of therafY

dry eyes and mouth)• contro disease activity 2. Caplan's syndrome (multiple• relieve pain and stiffness

maintain function and lifestyle pulmonary nodules and •� prevent or control joint damage pneumoconiosis)

key is early diagnosis and early intervention with disease modifying 3. Felty's syndrome (arthritis, anti-rheumatic drugs (DMARDs) splenomegaly, neutropenia)

Dr.JKR

RH8 Rheumatology

ea.n- rlT..-Str8lIgies i1 EJIt1� hIIlIlDidArll1rilis� (Ann Intern MIld20 March 2007:146(61) Slud(.RCT of 5(1 patiants comparing 4different treatment strategies for early rheumatoid arthritis. hrIrwliliIr Group 1: SequellliaJ Monotl1erapy witI1 traditional DMARDs Group 2: Step-Up Combination Therapy Group 3: Initial Cllmbination Therapy witI1 pred­nisone (11qJ dosel Group 4: Initial Combination Therapyl'lith inftiximab IIlIruk Patients in groups 3and 4responded faster and had signifu:antly greater overall change in phys­ical function scoras after the first year of treatment By end of the second year, groups 1and 2had echieved asimilar response to groups 3and 4. Groups 3and 4also showed signifu:antly less radio­logic progression of their disease over 2years than groups 1and 2. There WIlre no signifu:ant differ­ences in tDxicity levels belween the 4groups. CciIII:ilrilIIIlnitiai combination therapy witI1 pred­nisone or inftiximab results in faster response rates. Whether faster initial response rates leads to better Iong~enn disease outcomes is not yet studied.

.... ' ~ .l-------------,

Only DMARDs (not analgesics or NSAIDsI� a~er the course of RA!�

1111"williIinab, CIIlllbiledwilh bIckfound trIIlIn,-.g peliInIIwiIh rl1elIIIIlIIid arMs� n lIlilUI COlIIIItidiliIIISTAIlII� IAnhritis Rheum 2lXE;54:11lMi1 _Randomized, placebiH:ontrolied muJticentre trial 1'IIiIJIr;11Mpa1ients lmean age 52yrs, 110% femalel wiIfJ active moderate to severe rheumato~ arthritis despite treatment I'fith methotrexate. ~Pa1ientswere randonlaed to receive infu­sions of ~acebo, infIiximab dosed at3 m¢g, Of inftix­imab dosed at 10 ffi9\g at 0, ~ 6, and 14 weBb, in addi­tion to mel!lolrexate tflerapy. I'riw(IUeomc Incidence of serious infection wilfJin 22 weeks of randomization. "'Compared I'fith the placebo group, the relative risk of devellJIling serious inleclion was 1.0 195%CI 03· 11, P~.9951 in patienls receiving intiximab at 3m¢g and l' \95%CI1.H9, P=6.0131 in patienls receiving inflixinab at 10 n¢g.ln addilion,31% of patients receiving ilftiximab at 3111(l1kg and 32% of patients receMng infl~imab at 10m!i\g were able to achieve remission at 22 WIleks compll'ed wiIfJ on~ 14% of those receiving ~acebo (PdlJXII, NNT=5I. CIJrxaD:Therapy I'fith inftilinab3mii\g does not signific.lntJr increase the risk of serious infection in patients I'fith active moderate III severe rheumatoid antnis already receiving methotrexate. HOWBVeI, ther· apyl'fith infIiximab 10 ~ does s~nlficantJr increase the risk of serious infection in tflis population.

Seropositive Rheumatic Diseases: Connective Tissue Disorders� Toronto Notes 2008

A) Education, occupational therapy, physiotherapy, vocational coun­selling • therapeutic exercise program (isometrics and active ROM exercise during flares,

aquatic/aerobic/strengthening exercise between flares), assistive devices and patient education

• patients may need job modification, time off work or change in occupation • The Arthritis Society (Canada) and Arthritis Foundation (U.s.) provide resources

and programs

B) Medical • NSAIDs, DMARDs and steroids are the mainstay of pharmacological therapy

1. Reduction of Inflammation and Pain • NSAIDS

• individualize according to efficacy and tolerability • contraindicated or cautioned in some patients

• analgesics • add acetaminophen ± opioid pm for synergistic pain control

• corticosteroids • local

•� intra-articular injections to control symptoms in a specific joint • eye drops for eye involvement

• systemic (prednisone) •� low dose (5-10 mg/day) useful for (a) short term to improve

symptoms if NSAIDs ineffective, (b) to bridge gap until DMARD takes effect or (c) for refractory disease

•� moderate to high dose (20-60+ mg/day) for cardiopulmonary disease •� high dose (1 mg/kglday) for vasculitis •� do baseline DEXA bone density scan and start bisphosphonate,

calcium, and vitamin 0 therapy if using corticosteroids >3 months at >7.5 mg/day

• side effects: osteoporosis, avascular necrosis (AVN), hypertension, cataracts, glaucoma, peptic ulcer disease (PUD), susceptibility to infection, hypokalemia, hyperglycemia, hyperlipidemia, weight gain, acne

• cautions/contraindications: active infection, osteoporosis, hypertension, gastric ulcer, diabetes, TB

2. Disease Modifying Antirheumatic Drugs (DMARDs) • combination DMARDs are the standard of care •� start DMARDs within 3 months of diagnosis to decrease disease

progression and symptoms and signs • DMARDs reduce or prevent joint damage, and are associated with better

long-term disability index • delayed onset of action (may take 8-12 weeks) •� many DMARDs have potential toxicities that require periodic monitoring •� if repetitive flares, progressive joint damage, or ongoing disease activity after

3 months of maximal therapy . • change or add other D'MARDs •� mild and early stages:

• hydroxych1oroquine or sulfasalazine monotherapy preferred • moderate to severe disease (especially if unfavourable prognostic factors):

• methotrexate is the gold standard • single regimen with methotrexate or leflunomide (AravaTM) • combination therapy: methotrexate + sulfasalazine + hydroxychloroquine;

methotrexate + cyClosporine; methotrexate + leflunomide • biological DMARDs: indicated if persistent disease activity (see Common

Medications, RH27)

C) Surgical Therapy • synovectomy: debridement and/or removal of inflamed synovium from

individual joints (surgical or radioactive) • joint replacement (hip, shoulder, knee) • joint fusion (wrist, thumb, ankle, C-spine) • reconstruction (tendon repair) • surgery indicated for muftiplc DMARD failure, unacceptable pain, or structural

joint damage

Dr.JKR

Toronto !IIotes 2008� Seropositive Rheumatic Diseases: Connective Tissue Disorders

Systemic Lu hematosus (SLE) _� ..... ..£- -_..::-_---­

Definition •� chronic inflammatory multisystem disease of un1.nown etiology, characterized by�

production of autoantibodies and diverse clinical mamfestations�

Table 9. Diagnostic Criteria of SLE: 4 or more of 11 must be present serially or� simultaneously (American College of Rheumatology, 1997 update)�

Criteria� Description

Clinical Malar rash Classic "butterfly rash; sparing of nasolabial folds, no scarring� Discoid rash May cause scarring due to invasion of basement membrane� Photosensitivity Skin rash in reaction to sunlight� Oral/nasal ulcers Usually painless� Arthritis Symmetric, involving <2 small or large peripheral joints, non-erosive� Serositis Pleuritis or pericarditis� Neurologic disorder Seizures or psychosis�

Laboratory Renal disorder� Proteinuria 1>0,5 g/day or 3+1

Cellular casts IRBC, Hb, granular, tubular, mixedl� Hematologic disorder Hemolytic anemia, leukopenia, lymphopenia, thromboctyopenia� Immunologic disorder Anti-dsDNA Ab, anti-Sm Ab�

Antiphospholipid antibodies based on the finding of serum anticardiolipin Ab, lupus anticoagulant, or false positive VDRL

Antinuclear antibody lANA) Most sensitive test (98%)

Note: "4, 7, 11" rule •4out of 11 criteria (4 lab, 7 clinical) for diagnosis

Etiology and Pathophysiology •� disorder characterized by autoantibodies causing multi-organ inflammation •� peripheral polyarthritis with symmetric involwment of small and large joints

Proposed Etiology •� genetics

• common assoLiation with HLA-B8/-DR3; -10% have positive family history •� estrogen

• prepubertal and postmenopausal women have similar incidence to men •� men with SLE have higher concentrahon of estrogemc metabolites

•� infection • viral (nonspecific stimulant of immw1e response)

•� drugs • anticonvulsants (phenytoin) • antihypertensives (hydralazine) • antiarrhythmics (procainamide) • isoniazid (INH) • anti-histone antibodies are commonly seen in drug-induced lupus • oral contraceptive pills associated with exacerbation

Epidemiology •� prevalence: 0.05% overall •� F:M = 10:1; age of onset in reproductive years, 13-40 •� more common and severe in African-Americans and Asians • bimodal mortality pattern

• early (within 2 years) • active SLE, active nephritis, infection secondary to steroid use

• late (>10 years) •� inactive SLE, inactive nephritis, atherosclerosis partly secondary to

long-term steroids and partially due to chronic inflammation

Signs and Symptoms •� characterized by periods of exacerbation and remission •� systemic

• fever, malaise, fatigue, lymphadenopathy, weigh1 loss •� vascular

• Raynaud's phenomenon (see sidebar), thrombosis, vasculitis, livedo reticularis (mottled discolouration of skin due to narrowing of blood vessels, characteristic lacy or net-like appearance)

Rheumatology RH~

.:'

Diagnostic Criteria of SLE: MD SOAP BRAIN Malar rash Blood Discoid rash Renal Serositis Arthritis Oral ulcers Immune ANA Neurologic Photosensitivity

.... ~ , .1-----------,

Radiographically, unlike RA, the arthritis of SLE is non-erosive,

gnvironment� Stress. viruses. sun�

Genetic + Hormonal�

HLA~ T-cell, '( Drug,

Form<ttion of / Auto-Ab ~

Cytotoxic Ab Immune complexes

+ + Cell damage/death Jnl1ammatiuTI

Figure 8. Multifactorial etiology of SLE

Raynaud's Phenomenon Vasospastic disorder characteristically causil\g discolouratiol\ of fil\gers and toes (white7blue7red), Classic triggers: cold and emotional stress,

Dr.JKR

RHIO Rheumatology Seropositive Rheumatic Diseases: Connective Tissue Disorders� Toronto Notes 2008

•� dennatologic • maculopapular rash, photosensitivity, panniculitis (inflammation of

subcutaneous fat and muscle tissue), alopecia (hair loss), urticaria, purpura, oral, nasal, genital ulcers

•� ophthalmic • conjunctivitis, episcleritis, keratoconjunctivitis, cytoid bodies (cotton wool

exudates on fundoscopy = infarction of nerve cell layer of retina) •� gastrointestinal

• pancreatitis, lupus enteropathy, hepatitis, hepatomegaly •� pulmonary

• interstitial lung disease, pulmonary hypertension, PE, alveolar hemorrhage, pleuritis

•� musculoskeletal • arthralgias, arthritis, avascular necrosis, myositis

•� neurologic • depression, personality disorder, cerebritis, transverse myelitis, seizures,

headache, peripheral neuropathy

Investigations Consider septic arthritis and avas­ • serologic hallmark is high titer ANA detected by immunofluorescence cular necrosis in patients with SLE • ANA has high sensitivity (98%) and therefore is a useful screening test, but poor and joint pain. specificity

•� anti-dsDNA Ab (dett'cted by Crithidia test, Farr radioimmunoassay) and anti-Sm Ab are specific for SLE (95-99%)

•� a drop in anti-dsDNA titer and normalization of serum complement (C3, C4) are useful to monitor response to treatment in patients who are clinically and serologically concordant

•� lupus anticoagulant may cause clotting abnormalities and increased PTI

Treatment •� goals of therapy:

•� treat early using the mildest form possible, then slowly withdraw therapy •� if high doses of steroids necessary for long-term control, use steroid-sparing

agents too, then taper if possible •� symptomatic treatment tailored to organ system involved and severity of disease •� patient education: use topical sunscreen, avoid UV light and estrogens •� NSAIDs ± gastroprotective agents for arthritis, pleurisy, pericarditis •� antimalarials for dermatologic and MSK manifestations, constitutional symptoms

(hydroxychloroquine if no serious internal organ involvement --> improves long tenn control, prevents flares)

•� topical steroids for rash •� systemic steroids for prevention of end organ damage secondary to inflammation • bisphosphonates, calcium, vitamin D to combat osteoporosis •� steroid-sparing: azathioprine, cyclophosphamide, methotrexate, mycophenolate • high-dose oral prednisone/IV methylprednisolone, IV cyclophosphamide for serious

organ involvement (e.g. cerebritis or SLE nephritis) • all medications used to treat SLE require periodic monitoring for potential toxicities

[ Antiphospholipid Antibody Syndrome (APS) Definition •� multisystem vasculopathy manifested by recurrent thromboembolic events,

spontaneous abortions and thrombocytopenia •� circulating antiphospholipid autoAbs (anticardiolipin Ab and lUpus anticoagulant)

interfere with coagulation cascade •� primary vs. secondary

• secondary APS develops in SLE, other connective tissue diseases, malignancy, drugs (hydralazine, procainamide, phenytoin, interferon, quinidine), infections (HIV, TB, hepatitis C, infectious mononucleosis)

•� catastrophic APS • fatal condition with sepsis, ARDS (acute respiratory distress syndrome),

MODS (multi-organ dysfunction syndrome), TIP (thrombotic thrombocytopenic purpura)

Signs and Symptoms •� primary manifestation is venous or arterial thrombosis

•� venous thrombosis --+ DVT, PE, renal and retinal vein thrombosis • arterial thrombosis --+ ~troke(TlA, multi-infarct dementia, Ml,

valvular incompetencE', limb ischemia

Dr.JKR

Toronto Notes 2008� Seropositive Rheumatic Diseases: Connective Tissue Disorders Rheumatology RHll

•� recurrent spontaneous abortions including first and second trimester fetal loss, premature birth at <34 wks gestational age

•� hematologic abnormalities • thrombocytopenia, hemolytic anemia, neutropenia

•� skin • livedo reticularis, purpura, leg ulcers, and gangrene

Investigations •� serology

• diagnosis: lupus anticoagulant, or anticardiolipin (IgG or IgM) antibody positive on 2 occasions, at least 12 weeks apart

Treatment •� thrombosis

• lifelong anticoagulation with warfarin ---> target INR 2.5-3.5 •� recurrent fetal loss

•� aspirin, heparin, ± steroids •� catastrophic APS

• high-dose steroids, anticoagulation, cyclophosphamide, plasmapheresis

SclerodermalProgressive Systemic ·Sclerosis (PSS}

Definition •� a non-inflammatory disorder characterized by widespread small vessel vasculopathy

and fibrosis, which occurs in the setting of immune system activation and autoimmunity

Diagnosis •� diagnostic criteria: 1 major or ~ minor criteria

• major criterion: proximal scleroderma • minor criteria: sclerodactyly, digital pitting scars or loss of substance from finger

pads, bibasilar pulmonary fibrosis •� serology

• anti-topoisomerase 1: specific but not sensitive for systemic sclerosis • anti-centromere favours diagnosis of CREST variant (limited systemic sclerosis)

Etiology and Pathophysiology •� idiopathic vasculopathy (not vasculitis) leading to atrophy and fibrosis of tissues

•� intimal proliferation and media mucinous degeneration ---> progressive obliteration of vessel lumen ---> fibrotic tissue

• resembles malignant hypertension

Epidemiology •� F:M = 3-4:1, peaking in 5th and 6th decades •� associated with HLA-DRI •� associated environmental exposure (silica, epoxy resins, toxic oil, aromatic

hydrocarbons, polyvinyl chloride)

SCLERODERMA

Localized~ ~Generalized (no involvement of internal organs)� (systemic sclerosis) • mostly children and young adults ~ ~

Limited systemic sclerosis Diffuse systemic sclerosis • skin sclerosis restricted to •widespread skin

hands, face, neck disease (proximal to wrist, / \ • 3rd to 4th decade can involve trunk), tendons

Morphea Linear • pulmonary hypertension common • early visceral • hard oval patches 'Iine of thickened • CREST (see RH5) involvement (renal, pulmonary

on the skin skin fibrosis)

Figure 9. Forms of Scleroderma

.... ' ,~}------------,

Manifestations of APS Thromboembolic events� Recurrent fetal loss� Thrombocytopenia�

Dr.JKR

RH12 Rheumatology Seropositive Rheumatic Diseases: Connective Tissue Disorders� Toronto Notes 2008

Signs and Symptoms

Table 10. Clinical Manifestations of Scleroderma

System� Features

Dermatologic� Initial phase characterized by painless non·pitting edema Progressive bilateral swelling of fingers, hands and feet leading to skin tightening Characteristic face: mask·like facies with tight lip, beak nose, radial perioral furrows Atrophy, ulcerations, hypo/hyperpigmentation, telangiectasias, calcinosis, periungual erythema, pruritus

..... ' ~ Vascular Episodes (minutes to hours) of well·demarcated blanching and/or cyanosis of digits followed by.)------------, erythema (Raynaud's phenomenon), tingling and pain�

Scleroderma is the most common cause Due to vasospasm following cold exposure or emotional stress� of secondary Raynaud's phenomenon. If severe, can result in infarction of tissue at fingertips"" digital pitting scars, frank gangrene or�

autoamputation of the fingers or toes

Gastrointestinal (N90%)� GI tract becomes arigid tube leading to decreased motility Distal esophageal hypomotility t dysphagia Loss of lower esophageal sphincter function'" GERD, ulcerations, strictures Small bowel hypomotility"; bacterial overgrowth, diarrhea, bloating, cramps, malabsorption, weight loss Large bowel hypomotility..., pathognomonic radiographic finding on barium stUdy is large bowel wide mouth diverticuli

Renal� Mild proteinuria, creatinine elevation and/or hypertension are common 'Scleroderma renal crisis" (10·15%) may lead to malignant arterial hypertension, oliguria and microangiopathic hemolytic anemia

Pulmonary� Interstitial fibrosis, pulmonary HTN, pleurisy, and pleural effusions

Cardiac� Left ventricular dysfunction, pericarditis, pericardial effusion, arrhythmias

Musculoskeletal� Polyarthralgias "; polyarthritis affecting both small and large joints Subcutaneous calcifications (calcinosisl "Resorption of distal tufts" (radiological finding) Proximal weakness 2° to disuse, atrophy, low grade myopathy

Endocrine� Hypothyroidism common

Treatment •� patient education about precautionary measures (e.g. avoid cold) • expectant treatment with methotrexate/cyclosporine (little evidence in the literature) •� symptomatic treatment

• gastroesophageal reflux disease (GERD): PPls are first line, then H2-receptor antagonists

• small bowd bacterial overgrowth: broad-spectrum antibiotics (tetracycline, metrunidazole)

• Raynaud's: vasodilators (CCBs, local NTG cream, systemic PGE2 inhibitors) •� renal disease: ACE inhibitors • myositis, pericarditis: steroids • pulmonary hypertension (BTN): bosentan (Tracleer™), epoprostenol (Flolan™),

sildenafil (Viagra™, in trials)

Idiopathic Inflammatory Myopathy •� autoimmune diseases characterized by proximal limb and neck weakness, may be

associated with muscle pain •� autoantibodies: ANA, anti-Jo-l (DM), anti-Mi-2, other myositis-specific antibodies •� classification

• adult polymyositis (PM)/dermatomyositis (DM) • juvenile DM (usually with vasculitis) • PM/DM associated with malignancy • PM/DM associated with connective tissue disease • inclusion body myositis (IBM)

Dr.JKR

Toronto Notes 2008� Seropositive Rheumatic Diseases: Connective Tissue Disorders Rheumatology RH13

POLYMYOSITIS (PM)IDERMATOMYOSITIS (OM)

Definition •� a number of conditions in which muscle becomes damaged by a non-suppurative

lymphocytic inflammatory process •� PM: inflammation of muscles, DM: inflammation of muscles and skin

Diagnosis •� definite PM/DM if 4 criteria fulfilled •� probable if fulfill 3 criteria •� possible if fulfill 2 criteria

Table 11. Diagnostic criteria for PMlDM

Criteria� Description

1. Progressive symmetric proximal muscle weakness� Typical involvement of shoulders and hips 2. Elevated muscle enzymes� Increased CK, aldolase, LOH, AST, ALT 3.� EMG changes Short polyphasic motor units, high frequency repetitive

discharge, insertional irritability 4.� Muscle biopsy Segmental fibre necrosis, basophilic regeneration,

perivascular inflammation and atrophy 5. Typical rash of dermatomyositis� Required for diagnosis of OM

Etiology and Pathophysiology •� PM is CD8 cell-mediated muscle necrosis, found in adults •� OM is B-cell and C04 immune complex-mediated perifasicular vasculitis

Signs and Symptoms •� progressive symmetrical proximal muscle weakness (shoulder and hip) developing

over weeks to months •� early symptom is difficulty lifting head off pillow •� dermatological

• OM has characteristic dermatological features, found in children and adults, F>M

•� Gottron's papules -� pink-violaceous, flat-topped papules overlying the dorsal surface of

the interphalangeal joints •� Gottron's sign

- erythematous smooth or scaly patches over the dorsal IP, MCP, elbows, knees, or medial malleoli

•� heliotrope (purple) rash over the eyelids; usually with edema •� "shawl sign"

- erythematous rash over neck, upper chest, and shoulders •� cardiac

• dysrhythmias, congestive heart failure, conduction defect, ventricular hypertrophy, pericarditis

•� gastrointestinal • oropharyngeal and lower esophageal dysphagia, reflux

•� pulmonary • weakness of respiratory muscles, intrinsic lung pathology, aspiration

Treatment •� physical therapy •� medical

• high dose corticosteroid (1-2 mglkglday) and slow taper • immunosuppressive agents (azathioprine, methotrexate, cyclophosphamide,

cyclosporine) • intravenous immunoglobulin for OM

•� malignancy surveillance • detailed history and physical (breast, pelvic and rectal exam) •� CXR, abdominal and pelvic ultrasound, stool occult blood, Pap test,

mammogram

Prognosis •� DMIPM Associated with Malignancy

• increased risk of malignancy: age >50, DM>PM, normal CK,� refractory disease�

•� 2.4-6.5 fold increased risk of underlying malignancy usually in interna] organs

..... ' ,~I--------------,

Signs of OM Gottron's papules and Gottron's� sign are pathognomonic of OM� (occur in 70% of patients).�

Dr.JKR

RH14 Rheumatology

o

.... ' ,.1-----------,

ClusicTriad� (Idantifiea 93'10 of Sjiigren'.� patientsl� • Dry eyes • Dry mouth (dysphagia, xerostomial •� Arthritis {small joint, asymmetrical,�

nonerosivel�

.... '.,.)--------------, Patients with Sjogren's syndrome are at� higher risk of non·Hodgkin's lymphoma.�

Seropositive Rheumatic Diseases: Connective Tissue Disorders� Toronto Notes 2008

•� Inclusion Body Myositis • age >50, M>F, slowly progressive, vacuoles in cells on biopsy • suspect when patient unresponsive to treatment • distal as well as proximal muscle weakness •� muscle biOpsy positive for inclusion bodies

Sjogren's Syndrome Definition •� autoimmune condition characterized by dry eyes (keratoconjunctivitis sicca) and dry

mouth (xerostomia), caused by lymphocytic infiltration of salivary and lacrimal glands •� primary and secondary form (i.e. associated with RA, SLE, DM, and HIV) •� incidence estimated at 4/100,000 people •� 90% of cases are among females •� mean age of diagnosis is 40-60 yrs

Diagnosis (SSASSS) •� Symptoms of dry eyes •� Signs of dry eye - Schirmh test (to assess tear flow) or slit lamp exam with Rose

Bengal stain •� Autoantibodies anti-Ro, anti-La, ANA, RF •� Symptoms of dry mouth •� Signs of dry mouth - Sialography •� Salivary gland biopsy: gold standard

Note: Need 4 of the above criteria, one of which must be either autoantibodies or salivary gland biopsy (sensitivity 95% - European Community Criteria)

Etiology and Pathophysiology •� may evolve into systemic disorder and may lead to diminished exocrine gland activity

in respiratory tract and skin

Signs and Symptoms •� systemic manifestations:

• arthralgias, arthritis, subclinical diffuse interstitial lung disease, renal disease, palpable purpura, systemic vasculitis

•� results in "sicca complex": dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia)

Complications •� xerotrachea resulting in chronic dry cough •� Staphylococcus blepharitis: most common complication •� autoimmune thyroid dysfunction in 45% of patients •� vascular involvement leads to peripheral neuropahy (most common systemic

complication) •� glomerulonephritis •� lymphoma

Table 12. Signs and Symptoms of Sicca

Location� Manifestation

Ocular� Burning/dry/painful eye relieved by tears� Foreign body sensation (worse in evening)� Blepharitis�

Oral� Dry mouth - difficulty swallowing food without drinking Rapidly progressive caries (secondary to decreased saliva volume and its antibacterial factors) Erythema of hard palate and oral mucosa Oral candidiasis, angular cheilitis (inflammation and fissuring at the commissures of the mouth)

Treatment •� good dental hygiene •� artificial tears or surgical punctal occlusion for xerophthalmia •� adequate hydration for xerostomia •� topical nystatin or dotrimazole x 4-6 weeks for oral candidiasis •� hydroxychloroquine, corticosteroids, immunosuppressive agents for severe systemic

involvement •� agents that stimulate salivary flow (e.g. pilocarpine)

Dr.JKR

------

Toronto Notes 2008 Seropositive Rheumatic Diseases: Connective Tissue DisordersNasculitides Rheumatology RH15

Mixed ConnectiveTissue Disease (MCTD) I Overlap Syndrome •� syndrome with features of 2 different CTD are present (e.g. SLE, PSS, PM) with

presence of anti-RNP Ab (see Table 14, RBI8) •� common symptoms: Raynaud's phenomenon, swollen fingers •� prognosis

•� 50-60% will evolve into SLE • 40% will evolve into scleroderma� • only 10% will remain as MCTD for the rest of their lives�

Seropositive Rheumatic Diseases: Vasculitides VASCULITIS •� inflammation and subsequent necrosis of blood vessels with resulting tissue ischemia or

infarction •� any organ system can be involved •� keys to diagnosis

• clinical suspicion: suspect in cases of unexplained multiple organ ischemia or� systemic illness with no evidence of malignancy or infection�

• labs non-specific: anemia, increased Wile and ESR, abnormal urinalysis • biopsy if tissue accessible • angiography if tissue inaccessible

•� treatment generally entails corticosteroids and/or immunosuppressives

Table 13. Classification of Vasculitis and Characteristic Features Classification� Characteristic Features

Small vessel • Non·ANCA·associated · immune complexes

Predominantly cutaneous vasculitis ·also known as hypersensitivity~eukocytoclastic vasculitis Henoch·Schiinleln purpura (see Pediatrics, P941 · vascular deposition of IgA causing systemic vasculitis (skin, GI, renall, seen

most frequently in childhood, usually self·limiting condition ,� ' ,Essential cryoglobulinemic vasculitis� ~.)------------,

• ANCA-associated Churg·Strauss Triad Wegener's granulomatosis Ic-ANCA >p-ANCA) -granulomatous inflammation of vessels of respiratory tract and kidneys, • Allergic rhinitis and asthma

most common in middle age, most present initially with symptoms of URTI • Eosinophilic infiltrative diseaseChurg-Strauss syndrome -granulomatous inflammation of vessels with hypereosinophilia and resembling pneumonia150% ANCA positive)� eosinophilic tissue infiltration, sometimes associated With p-ANCA or c-ANCA

• Systemic vasculitis · other manifestations include coronary arterhis, myocarditis and neuropathy� Microscopic polyangiitis -pauci'lmmune necrotizing vasculitis, affecting kidneys Inecrotizing� 170% ANCA positive, usually p-ANCA) glomerulonephritis), lungs (capillaritis and alveolar hemorrhage), skin�

Medium-sized vessel Polyarteritis nodosa -any age [average 40-50'sl, unknown etiology in most cases

· segmental non-granulomatous necrotizing inflammation Kawasaki's lsee Pediatrics, P941 -Tlymphocyte response and granuloma formation

Large vessel -Tlymphocyte response and granuloma fomnation Giant celi arteritis (temporal arteritis) -over 50 years of age, more common in women, inflammation predominantly of the aorta and

those arteries originating from it Takayasu's arteritis · "pulseless disease; increased ESR, fever, night sweats, chronic inflammation, most often

the aorta and its branches, usually young adults of Asian descent, F>M

Other Vasculitides Buerger's disease · also known as thromboangiitis obliterans, inflammation secondary to pathological clotting,

affects small and medium-sized vessels of distal extremities, most important etiologic factor is cigarette smokmg, mnst common in Asian males, may lead to distal claudication and gangrene

Behcets disease -pathology: leukoclastic vasculitis, multisystem disorder presenting with ocular involvement, recurrent oral and genital ulceration, venous thrombosis, skin and jOint involvement

Vasculitis mimicry ·cholesterol emboli, atrial myxoma

Predominantly Cutaneous Vasculitis SMALL VESSEL NON-ANCA ASSOCIATED VASCULITIS •� subdivided into

• drug-induced vasculitis •� serum sickness reaction • vasculitis associated with other underlying primary diseases

Dr.JKR

RH16 Rheumatology Seropositive Rheumatic Diseases: Vasculitides� Toronto Notes 2008

o

.... '� ,9'\-------------,

Classic Features: • necrotizing granulomatous vasculitis�

of lower and upper respiratory tract� • focal segmental glomerulonephritis

Etiology and Pathophysiology •� cutaneous vasculitis following:

•� drug exposure (allopurinol, gold, sulfonamides, penicillin, phenytoin) • viral or bacterial infection • idiopathic causes

•� small vessels involved (post-capillary vessels most frequently) •� usually causes a leukocytoclastic vasculitis = debris from neutrophils around vessels •� sometimes due to cryoglobulins which precipitate in cold temperatures

Signs and Symptoms •� palpable purpura ± vesicles and ulceration, urticaria, macules, papules, bullae,

subcutaneous nodules

Investigations •� vascular involvement (both arteriole and venule) established by skin biopsy

Treatment •� stop possible offending drug •� usually self-limiting •� corticosteroids ± immunosuppressive agents

Wegener's Granulomatosis SMALL VESSEL ANCA-ASSOCIATED VASCULITIS

Definition •� granulomatous inflammation of vessels that may affect the upper airways (rhinitis,

sinusitis), lungs (pulmonary nodules, infiltrates), and kidneys (glomerulonephritis, renal failure)

•� highly associated with cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) •� incidence 5 per 100,000; more common in Northern latitudes

Diagnosis •� diagnosis with 2 of 4 criteria (American College of Rheumatology, 1990)

1.� nasal or oral inflammation, ulcers, epistaxis 2.� abnormal findings on CXR, including nodules, cavitations 3.� urinary sediment (protein, RBC casts) 4.� biopsy of involved tissue: lungs show granulomas, and kidneys show necrotizing

segmental glomerulonephritis

Etiology and Pathophysiology •� transformation from inflammatory prodrome (serous otitis media and sinusitis) to

full-blown vasculitic syndrome

Signs and Symptoms •� systemic

• malaise, fever, weakness, weight loss •� ENT

• sinusitis or rhinitis, nasoseptal perforation, saddle nose deformity, extension into the orbit with proptosis, hearing loss

•� pulmonary • cough, hemoptysis, tracheobronchial erosion, pneumonitis, lung nodules,

infiltrations, cavitary lesions •� renal

• segmental necrotizing glomerulonephritis (vasculitis rarely seen) • other

• joint, skin, eye complaints, vasculitic neuropathy

Investigations •� other tests include

• specific: ANCA (c-ANCA > p-ANCA) • renal or lung biopsy • general: anemia, leukocytosis, elevated ESR

•� possible decline in c-ANCA and ESR used to monitor response to treatment in some patients

Treatment •� prednisone 1 mg/kg for 6-12 months ± cyclophosphamide 2 mg/kglday PO for

3-6 months followed by high dose methotrexate (20-25 mg porsc weekly) •� consider biologic agents (infliximab, rituximab, IVIg) and plasmapheresis in systemic

disease resistant to corticosteroids plus cyclophosphamide

Dr.JKR

Toronto Notes 2008 Seropositive Rheumatic Diseases: Vasculitides/Seropositive Rheumatic Diseases: Investigations Rheumatology RH17

Polyarteritis Nodosa (PAN)� _.e...-. ~

MEDIUM VESSEL VASCULITIS

Definition •� pauci-immune necrotizing vasculitis of medium to small vessles, without associated

glomerulonephritis or pulmonary capillaritis (as seen in microscopic polyangiitis) •� incidence 0.7 per 100,000; affects inviduals between 40-60 yrs; M:F = 2:1

Etiology and Pathophysiology •� focal panmural necrotizing inflammatory lesions in small and medium-sized arteries •� thrombosis, aneurysm or dilatation at lesion site may occur •� healed lesions show proliferation of fibrous tissue and endothelial cells that may lead

to luminal occlusion

Diagnosis •� diagnosis with >3 of 10 criteria (American Collegue of Rheumatology, 1990)

•� weight loss >4 kg •� myalgias, weakness or leg tenderness •� levido reticularis (mottled reticular pattern over skin) •� neuropathy •� testicular pain or tenderness •� diastolic BP >90 mmHg •� elevated Cr or BUN •� hepatitis B positive •� arteriographic abnormality (commonly aneurysms) •� biopsy of artery showing presence of granulocytes or macronuclear leukocytes

in the artery wall

Treatment •� prednisone 1 mglkglday ± cyclophosphamide 2 mglkglday PO •� :!: anti-viral therapy to enhance clearance of HBV

Giant Cell Arteritis (Temporal Arteritis) LARGE VESSEL VASCULITIS

Signs and Symptoms •� temporal headaches ± scalp tenderness due to inflammation of involved portion of the

temporal or occipital arteries •� sudden, painless loss of vision and/or diplopia due to narrowing of the ophthalmic or

posterior ciliary arteries •� tongue and jaw claudication (pain in muscles of mastication on chewing) •� polymyalgia rheumatica (proximal myalgia, constitutional symptoms, elevated ESR)

occurs in 30% of patients •� aortic arch syndrome (involvement of subclavian and brachial branches of aorta result

in pulseless disease), aortic aneurysm ± rupture

Investigations •� diagnosis made by clinical suspicion, increased ESR, increased CRP, temporal artery

biopsy within 14 days of starting steroids, angiography

Treatment •� if suspect GCA, immediately start high dose prednisone 1 mglkg in divided doses

tapering prednisone as symptoms resolve; highly effective in treatment and in prevention of blindness and other vascular complications

•� ASA 325 mg tid

• Bloodwork, Urinalysis, Synovial fluid analysis •� general: CBC, BUN, creatinine •� acute phase reactants: complement (C3 and C4), fibrinogen, CRP, ferritin, albumin •� ESR (erythrocyte sedimentation rate) increases with the increase of acute phase

reactants, and chronically, with increase in gamma globulins •� C3, C4 often decrease in active SLE •� urinalysis to detect disease complications (proteinuria, active sediment) •� serology: autoantibodies (Table 14, RH18) •� synovial fluid analysis (Table 19, RH24) •� radiology (plain film, CT, MRI, ultrasound, bone densitometry, angiography,�

bone scan)�

[. o

'" ~ ~ ,1-----------,

There is an association between� hepatitis Bsurface antigen� (HBsAg) positivity and PAN.�

'" ~ ~ ,.l-----------,

Consider PAN in a non-diabetic� patient with mononeuritis multiplex.�

Medical Emergency Untreated, GCA can lead to per­�manent blindness in 20-25%!�

GCA CRITERIA Age >50, new headache, temporal artery tenderness or decreased pulse, ESR over 50, and abnormal artery biopsy. Presence of 3or more criteria yields sensitivity of 94%, specificity of 91%.

'" ~ ~ ,}------------,

Differential Diagnosis of Elevated ESR Rheumatoid arthritis, PMR, GCA, hypoal­�buminemia, anemia, muhiple myeloma,� bacterial infections, malignancy. ESR� (and CRPI is insensitive for PM/DM, AS,� PSS, SLE, viral infections.�

Dr.JKR

RH18 Rheumatology Seropositive Rheumatic Diseases: Vasculitides/Seronegative Rheumatic Diseases Toronto Notes 2008

Table 14. Autoantibodies and Their Prevalence in Rheumatic Diseases

Autoantibody� Disease Normal Comments

RF� RA80% <5% Autoantibodies IIgM >IgG >IgAI directed against Fe Sjogren's 50% domain of IgG SLE 20% 10-10% over age 65

Present in most seropositive diseases Levels correlate with disease severity in RA Non-specific; may be present in IE, tuberculosis, hep Cinfections, silicosis, sarcoidosis

ANA� SLE 98% <5% Antibodies against nuclear components MCTD95% other CTDs IDNA, RNA, histones, centromere) Sjogren's 70-90% 1:40 dilution found in 5-30% of the normal population CREST 80% Sensitive but not specific for SLE

4 patterns: 11 Rim pattern in SLE 21 Homogenous (diffuse) pattern in SLE, RA, drug-induced lupus 31 Speckled pattern in SLE, PSS, RA, MCTD, Sjogren's, scleroderma 4) Nucleolar pattern in scleroderma

Anti-dsDNA SLE 50-70% 0%� Specific for SLE Levels correlate with disease activity

Anti-Sm� SLE <30% 0% Specific but not sensitive for SLE

Anti-Ro ISSAI Sjogren's 40-95% 05%� Subacute cutaneous SLE and mothers of babies with neonatal lupus SLE 25%

Anti-La (SSBI� Sjogren's 40% 0% Usually occurs with anti-Ro SLE 10%

Antiphosphollpid APS <5% By definition present in APS antibodies (LAC, ACLAI SLE 31-40% Only small subset of SLE patients develop clinical syndrome of APS

If positive will get afalse positive VDRL test

Anti-histone� Drug-induced SLE >90% 0% Idiopathic SLE >50% 0%

Antl-RNP� MCTD 0% By definition present in MCTD; present in many other CTD

Anti-centromere CREST> 80% 0% Specific for CREST variant of PSS Anti-topoisomerase I PSS 26-76% 0% (formerly ScI-701

c-ANCA� Active Wegener's >90% 0% Specific and sensitive

p-ANCA Wegener's 10%, 0% Nonspecific and poor sensitivity Ifound in ulcerative colitis, other vasculitis polyarteritis nodosa, microscopic polyangiitis, Churg-Strauss, rapidly

progressive glomerulonephritisl

Anti-Mi-1� Dermatomyositis 15-10% Specific but not sensitive

Antibodies against SLE Perform direct Coomb's test RBCs, WBCs, or Test hemoglobin, reticulocyte, platelets leukocyte and platelet count, antiplatelet Abs

Sero_negative Rheumatic Diseases

Table 15. A Comparison of the Spondyloarthropathies Feature AS PsA ReA IBD M:F 5:1 1:1 8:1 1:1 Age onset 20's 35-45 20's any Peripheral arthritis 25% 96% 90% Common Distribution Axial, LE Any LE LE Sacroiliitis 100% 40% 80% 20% Dactylitis Uncommon 35% Common Uncommon Enthesitis Common Common Common Less Common Skin lesions Rare 100% Common Occasional

Nil specific Psoriasis Keratoderma Pyoderma, Erythema Nodosum

Uveitis 30% Occasional 20% Rare Urethritis Rare Occasional Common Rare Aortic Regurgitation Occasional Rare Occasional Occasional HLA-B27 90% 40% 80% 30%

Dr.JKR

Toronto Notes 2008� Seronegative Rheumatic Diseases

Ankylosing Spondylitis (AS) ---"-------~--~

Definition •� inflammatory arthritis involving the sacroiliac joints and vertebrae •� prototype of the spondyloarthropathies

Etiology and Pathophysiology •� enthesitis (inflammation of ligament at site of attachment to bone) •� inflammation leads to osteopenia, then erosion, then ossification

Epidemiology •� prevalence 0.2% of general population •� M:F =5:1; females have milder disease •� 95% of patients have HLA-B27 (9% HLA-B27 positive in general population)

Signs and Symptoms •� axial

•� mid and lower back stiffness, pain at rest, persistent buttock pain, painful sacroiliac joint (Faber's test) (see Table 16)

• postural changes: increased thoracic kyphosis, decreased lumbar lordosis, forward protrusion of cervical spine, increased occiput-to-wall distance

• spinal restriction: lumbar, thoracic, cervical spine in flexion, extension rotation, decreased Schober's test

• decreased chest wall expansion (normal >5 cm at T4) •� peripheral

• asymmetrical large joint peripheral arthritis, most often involving lower limb •� extra-articular manifestations�

• ophthalmic: acute anterior uveitis (25-30% patients)� • cardiac: aortitis, aortic regurgitation, pericarditis, conduction disturbances, heart

failure (rare) • renal: amyloidosis and IgA nephropathy • respiratory: apical fibrosis (rare) • neurologic: cauda equina syndrome (rare)

Investigations •� x-ray of SI joint: "pseudowidening" of joint due to erosion with joint sclerosis -> bony

fusion (late), symmetric sacroiliitis •� x-ray of spine: appearance of "squaring of edges" from erosion and sclerosis on comers

of vertebral bodies leading to ossification of outer fibres of annulus fibrosis (bridging syndesmophytes), this produces a "bamboo spine" radiographically

Table 16. Types of Back Pain

Parameter Mechanical� Inflammatory Past History ±� ++ Family History� +

Onset Acute� Insidious

Age (years) 15-90� <40

Sleep Disturbance ±� ++ Morning Stiffness <30 minutes� >1 hour

Involvement of Other Systems� +

Exercise Worse� Better

Rest Better� Worse

Radiation of Pain Anatomic (L5-S1) Diffuse (thoracic, buttock)

Sensory Symptoms +

Motor Symptoms +

Treatment •� conservative/non-pharmacologic

• heat • prevent fusion in poor posture and disability by: exercise (e.g. swimming),

postural and deep breathing exercises, outpatient PT, smoking cessation

Rheumatology RH19

• SI • spondylitis • hip • shoulder

Figure 10. Common sites of involvement of AS

... Extra-articular Manifestations� of Ankylosing Spondylitis� (6 As):� Atlanto-axial subluxation� Anterior uveitis� Apical lung fibrosis� Aortic incompetence� Amyloidosis (kidneys)� Autoimmune bowel disease (UC)�

.... ' ~ .}-----------,

Consider AS in the differential for� causes of aortic regurgitation.�

Dr.JKR

RH20 Rheumatology Seronegative Rheumatic Diseases� Toronto Notes 2008

o

",' ,•.l-----------,

The triad of arthritis, conjunctivitis,� and urethritis is 99% specific (but� 51% sensitive) for ReA.�

",' ,•.l-----------,

Look for genetic predisposition� (HLA-B271 and infection.�

•� medical •� NSAIDs: do not alter natural history •� DMARDs for peripheral arthritis (sulfasalazine, methotrexate) •� Biologics for axial involvement •� manage extra-articular manifestations

•� surgical • hip replacement, vertebral osteotomy for marked deformity

I.

Prognosis •� spontaneous remissions and relapses are common and can occur at any age •� function may be excellent despite spinal deformity •� favorable prognosis if female and age of onset >40 •� early onst:'t with hip disease may lead to severe disability; may require arthroplasty

Reactive Arthritis Definition •� a generic term for a sterile arthritis following an infection (e.g. rheumatic fever, post

viral arthritis etc.) •� when capitalized i.e. Reactive Arthritis (ReA), it refers to one of the seronegative

spondyloarthropathies in which patients have a peripheral arthritis (of greater than 1 month duration) accompanied by one or more extra-articular manifestations, that appears shortly after certain infections of the CI or CD tracts (see below)

Etiology •� onset following an infectious episode either involving the CI or CD tract

• Cl: Shigella, Salmonella, Campylobaeter, Yersinia species • CD: Chlamydia (isolated in 16-44% of ReA cases), Mycoplasma species

•� acute pattern of clinical course •� 1-4 weeks post-infection • lasts weeks to years with 1/3 chronic� • often recurring� • spinal involvement persists

Epidemiology •� in HLA-B27 patients, axial> peripheral involvement •� M>F

Signs and Symptoms •� musculoskeletal

• peripheral arthritis, asymmetric pattern, spondylitis (thick and skipped syndesmophytes), Achilles tendinitis, plantar fasci.itis, dactylitis ("sausage digits")

• ophthalmic • iritis (anterior uveitis), conjunctivitis

•� dermatologic • keratoderma blenorrhagicum (hyperkeratotic skin lesions on palms and soles)

and balanitis circinata (small, shallow, painless ulcers of glans penis and urethral meatus) are diagnostic

•� gastrointestinal • oral ulcers, diarrhea

•� urethritis and cervicitis • sterile Lultures; presence not related to site of initiating infection

Investigations •� diagnosis is clinical plus laboratory •� lab findings: normocytic, normochromic anemia and leukocytosis •� cultures are sterile •� HLA-B27 positive

Treatment •� appropriate antibiotics if thert:' is documented infection •� NSAIDs, physical therapy, home exercise •� local therapy

• joint protection • intra-articular steroid injection • topical steroid for ocular involvement

•� systemic therapy • corticosteroids, sulfasalazine, methotrexate (for peripheral joint involvement

only) • TNF inhibitors for spinal inflammation

Dr.JKR

Toronto Notes 2008� Seronegative Rheumatic Diseases Rheumatology RH21

Psoriatic Arthritis Etiology and Pathophysiology •� unclear but many genetic, immunologic and somt:' environmental factors involved

(e.g. psoriatic plaque flora, particularly Group A Streptococcus, and trauma)

Epidemiology •� psoriasis affects 1% of population •� arthropathy in 10% of patients with psoriasis •� 15-20% of patients will develop joint disease before skin lesions appear

Signs and Symptoms •� dermatolgic

• well-demarcated erythematous plaques with silvery scale • nail involvement includes pitting, transverse or longitudinal ridging,

discolouration, subungual hyperkeratosis, onycholysis, and oil drops •� musculoskeletal

• 5 general pattems •� asymmetric oligoarthritis (most common -70%) •� arthritis of DIP joints with nail changes •� destructive (mutilans) arthritis (5%) •� symmetric polyarthritis (similar to RA) • sacroiliitis and spondylitis (usually older, male patients)

• ophthalmic • conjunctivitis, iritis (uveitis)

•� cardiac and respiratory (late findings) • aortic insufficiency • apical lung fibrosis

•� neurologic • cauda equina syndrome

•� radiologic • floating syndesmophytes • pencil and cup arpearance at IP joints� • osteolysis, periostitis�

Treatment •� treat skin disease (e.g. steroid cream, salicylic .md/or retinoic acid, tar, UV light) •� first-line is NSAlDs; if they fail to reduce synovitis and pain then use intra-articular steroids •� persistent or severe disease with erosive arthritis --> DMARDs, biologic therapies •� spinal disease -+ biologic therapies

Inflammatory Bowel Disease (lBD) -------~~-~

(see Gastroenterology. G20) •� manifestations of ulcerative colitis and Crahn's disease include peripheral arthritis

(large joint, asymmetrical), spondylitis, and hypertrophic osteoarthropathy •� arthralgia, myalgia, osteoporosis and aseptic necrosis of bone 2° to steroid treatment of

bowel inflammation •� NSAIDs should be used cautiously as they may exacerbate bowel disease

Table 17. Comparing Features of Spondylitis vs. Peripheral Arthritis in IBD

Parameter Spondylitis Peripheral Arthritis

HLA-B27 association yes no

gender� M>F M=F

onset before IBD yes no

parallels IBD course no yes

type of IBD UC = Crohn's Crohn's

Undifferentiated Spondyloarthropathy •� does not meet criteria for any of the well defined spondyloarthropathies •� generally good prognosis and responds well to NSAIDs

o

'" ' ,,}-------------, Check "hidden" areas for psoriatic� lesions (ears, hair line, umbilicus,� anal c1ett, nailsl.�

'" , ,,'\-------------,

Both ankylosing spondylitis and� IBD-arthritis feature symmetric� sacroiliitis.�

Dr.JKR

RH22 Rheumatology Crystal-Induced Arthropathies� Toronto Notes 2008

• 1st MTP "0 u

• ankle • knee

Figure 11. Common sites of involvement in gout (asymmetric joint involvement)

'- ~ ,.:r-----------,

An acute gout attack may mimic� cellulitis. However, joint mobility� is preserved in cellulitis.�

"" Precipitants of Gout

Drugs are FACT: Furosemide� Aspirin/Alcohol� Cytotoxic drugs� Thiazide diuretics�

Foods are SALTS: Shellfish� Anchovies� Liver and Kidney� Turkey� Sardines�

Crystal-Induced Arthropathies

Gout Definition •� derangement in purine metabolism resulting in hyperuricemia, monosodium urate

crystal deposits in tissues (tophi), synovium (microtophi)

Etiology and Pathogenesis •� sources of uric add: diet and endogenous •� synthesis

• hypoxanthine --> xanthine -. uric acid • both steps catalyzed by xanthine oxidase

Hyperuricemia •� primary or genetic

•� mostly due to idiopathic renal underexcretion (90%) • also idiopathic overproduction or abnormal enzyme production/function

•� secondary • dietary excess • underexcretion (>90%) - renal failure, drugs, systemic conditions� • overproduction «10%) - increased nucleic acid turnover states�

•� majority of people with hyperuricemia do not have gout, and normal or low uric acid levels do not rule out gout

•� common precipitants: EtOH, dit'lary excess, dehydration (e.g. thiazide and loop diuretics), trauma, illness, surgery

• other associated conditions: hypertension, obesity, diabetes, starvation

Epidemiology •� most common in males >45 years old •� extremely ran:' in premenopausal female

Signs and Symptoms •� recurrent episodes of acute arthritis •� acute gouty arthritis

• painful, usually involving lower extremities (e.g. first MTP joint = "podagra") • joint mobility may be limited • attack will subside on its own within several days to weeks and mayor may

not recur •� tophi

•� urate deposits in cartilage, tendons, bursae, soft tissues, and synovial membranes •� common sites: first MTP, ear helix, olecranon bursae, tendon insertions

(common in Achilles tendon) •� kidney

• gouty nephropathy • uric acid calculi

Investigations •� joint aspirate: >90% of joint aspirates show crystals of monosodium urate (see Table 19,

RH24) (negatively birefringent) •� differential diagnosis includes pseudogout, trauma, sepsis, OA

Treatment

Alacute gout •� NSAIDs: high dose, then taper as symptoms improve •� corticosteroids: intra-articular, oral or intra-muscular (if renal or Gl disease and/or

if NSAIDs contraindicated or tail) •� colchicine within first 24 hours but effectiveness limited by narrow therapeutic range •� allopurinol can worsen an acute attack (therefore do not start during acute flare)

B) chronic gout •� not the same as treahnent of acute gout •� conservative

• avoid foods with high purine content (e.g. visceral meats, sardines, shellfish, beans, peas), avoid drugs with hyperuricemic effects (e.g. pyrazinamide, ethambutol, thiazide, alcohol)

Dr.JKR

-------------------------------------------Toronto Notes 2008� Crystal-Induced Arthropathies

•� medical • antihyperuricemic drugs: decrease uric acid production (allopurinol and

feboxostat inhibit xanthine oxidase) • uricosuric drugs (probenecid, sulfinpyrazone): use if failure on or intolerant to

allopurinol; do not use in renal failure •� prophylaxis prior to starting antihyperurkemic drugs (colchicine/low-dose NSAID) •� in renal disease secondary to hyperuricemia, use low-dose allopurinol and monitor�

creatinine�

Pseudogout (Chondrocalcinosis) Etiology and Pathophysiology •� acute inflammatory arthritis due to phagocytosis of IgG-coated calcium pyrophosphate

dihydrate (CPPD) crystals by neutrophils and subsequent release of inflammatory mediators within joint space

Epidemiology •� more frequently polyarticular and slower in onset in comparison to gout, lasts up to�

3 weeks but is self-limited� •� risk factors: old age, advanced OA, neuropathic joints •� other associated conditions: hypE'rparathyroidism, hypothyroidism, hypomagnesemia,

hypophosphatemia (low ALP), diabetes, hemochromatosis

Signs and Symptoms •� affects knees, wrist, MCP joints, hips, shoulders, elbows, ankles, big toe •� may present as chronic arthritis with acute exacerbations •� 5% will mimic rheumatoid arthritis (symmetrical polyarticular pattern with morning

stiffness and constitutional symptoms) •� may be triggered by dehydration, acute illness, surgery, trauma •� 50% of the patients will develop degenerative joint changes

Investigations •� must aspirate joint to rule out septic arthritis, gout •� crystals of CPPD: present in 60% of patients and often only a few crystals •� x-rays show chondrocalcinosis: punctate radiodensities in fibrocartilaginous structures

(e.g. knee menisci) or linear radiodensities in hyaline articular cartilage •� chondrocalcinosis seen in 75% of pseudogout •� differential diagnosis includes gout, trauma, sepsis, RA

Treatment • joint aspiration, rest, and protection •� l\SAIDs - also used for maintenance therapy •� prophylactic colchicine PO (controversial) •� intra-articular steroids to relieve intlarnmation

Table 18. Gout vs. Pseudogout

Parameter Gout� Pseudogout Gender M>F� M.F Age Middle-aged males Older

Post-menopausal females� Onset of disease Acute Acute/insidious� Crystal type Negative birefringence, Positive birefringence,�

needle-shaped rhomboid-shaped� Distribution Fi rst MTp, foot Knee, wrist, polyarticular� Radiology "Holes in bones" Chondrocalcinosis�

OA (knee, wrist, 2nd and 3rd MCP)� Treatment Indomethacin, colchicine, allopurinol NSAIDs�

Synovial Fluid Analysis •� synovial fluid is an ultrafiltrate of plasma plus hyaluronate; it lubricates joint surfaces

and nourishes articular cartilage

Three Most ImportantTests of Synovial Fluid (TheThree Cs) 1. Cell count and differential 2. Culture and Gram stain (bacteria, mycobactE'ria, fungi) 3. Crystal examination (microscopy with polarized lignt)

•� gout (monosodium urate) -. needle-shaped, negatively birefringent (yellow) • pseudogout (calcium pyrophosphate dihydrate)� --> rhomboid-sfiapeet

positively birefringent (blue) •� protein, LDH, glucose less helpful

Rheumatology RIm

• knee • polyarticular wrist • hand (MCP) • foot (1st MTP)

Figure 12. Common sites of involvement in CPPD

o

"" ' ,.1-----------,

Differential Diagnosis of Acute Monoarthritis • septic arthritis�

(see Infectious Diseases, 1022)� • gout • pseudogout • trauma • hemarthrosis� • osteonecrosis� • osteoarthritis� ·tumour� • systemic inflammatory disease • polyarthritis presenting with�

monoarticular symptoms�

Dr.JKR

RH24 Rheumatology Crystal-Induced Arthropathies/Septic ArthritisINon-Articular Rheumatism Toronto Notes 2008

[

.... ' ,.}------------,

PMR Criterie 1. Age over 50 2.� Bilateral aching/morning�

stiffness>1month� 3. ESR over 40 mm/hr 4.� Prompt response to low-dose�

corticosteroids�

Table 19. Synovial Fluid Analysis Parameter Normal Non-Inflammatory Inflammatory Infectious Hemorrhagic

Colour Clear Clear Opaque Opaque Sanguinous

Viscosity� High Idue to High Low Low Variable hyaluronate)

WBClmm'� <200 <2,000 >2,000 >50,000 Variable

%PMN� <25% <25% >25% >50% Variable

Examples� Trauma Seropositives Septic arthritis Trauma Osteoarthritis Seronegatives Hemophilia Neuropathy Crystal arthropathies CPPD Hypertrophic· arthropathy

Non-Articular Rheumatism •� disorders that plimarily affect soft tissues or periarticular structures •� includes bursitis, tendinitis, tenosynovitis, fibromyalgia (fibrositis) and polymyalgia

rheumatica

Polymyalgia Rheumatica (PMR)__-''--� .J

Definition •� characterized by profound pain and stiffness of the proximal extremities (girdle area) •� closely related to giant cell arteritis (15% of patients with PMR develop GCA)

Diagnosis •� age >50 years •� more than two affected muscle groups •� at least a one month duration •� increased ESR •� rapid and lasting response to corticosteroids •� must rule out infection, RA, SLE, PAN, polymyositis, malignancy, and giant cell

arteritis

Epidemiology •� incidence 50 per 100,000 per year in those over age 50 •� age of onset typically >50, F:M = 2:1

Signs and Symptoms •� constitutional symptoms prominent (fever, weight loss, malaise) •� morning stiffness of symmetrical proximal muscles (neck, hip and shoulder girdles,

thighs) •� physical examination reveals tender muscles but no weakness or atrophy •� laboratory investigations often reveal anemia, elevated ESR, CRP and platelets;

normal CK

Treatment • goal of therapy: symptom relief •� start with steroid dose of 15-20 mg PO daily •� taper slowly over 2-year period monitoring ESR and symptoms closely •� treat relapses aggressively (50% relapse rate)

Dr.JKR

Toronto Notes 2008� Non-Articular Rheumatism Rheumatology RH25

Fibromyalgia-"""-------------------------' Definition •� chronic, widespread pain with characteristic tender points

Diagnosis •� history of widespread pain for at least 3 months in four quadrants of body •� pain in 11 of 18 tender points with approximate force of 4 kg by digital palpation •� must rule out numerous other causes (e.g. polymyositis, polymyalgia rheumatica,

thyroid disorders, sleep apnea), although presence of second clinical disorder does not exclude the diagnosis of fibromyalgia

Epidemiology •� F:M=3:1 •� primarily ages 25 to 45, some adolescents • prevalence of 2-5% in general population, higher in rheumatology patients • overlaps with chronic fatigue syndrome and myofascial pain syndrome •� strong association with psychiatric illness

Investigations •� laboratory investigations typically normal unless underlying illness present •� workup includes: TSH, ESR, laboratory sleep assessment

Signs and Symptoms •� widespread aching, stiffness and reproducible tender points (see Figure 13) •� fatigue •� sleep disturbance: non-restorative sleep, difficulty falling asleep, and frequent

wakening •� symptoms aggravated by physical activity, poor sleep, emotional stress •� patient feels that joints are diffusely swollen although joint examination is normal •� neurologic symptoms of hyperalgesia, paresthesias •� associated with irritable bowel or bladder syndrome, migraines, tension headaches,

obesity, depression, and anxiety

Treatment •� conservative

•� education - disease is benign, non-deforming and does not progress • exercise program (walking, aquatic exercises) •� support back and neck: neck support while sleeping, abdominal muscle

strengthening exercises •� stress reduction; psychiatric treatment when necessary • biofeedback, meditation, acupuncture, physiotherapy may be helpful

•� medical •� low dose tricyclic antidepressant (e.g. amitriptyline)

•� for sleep restoration •� select those with lower anticholinergic side effects

• NSAIDs if pain interferes with sleep

Paired tender points

Occiput: at suboccipital muscle insertion "- ""') occiput

trapezius Low cervical, C5-C7"-:.~! . supraspinatus napezius, midpoint of upper border

Supraspinatus: above scapular spine near medial border )

Second lib: 2nd costochondral junction

Lateral epicondyle, 2 em below this point

/"-+--1- lateral epicondyle Gluteal, upper outer quadrants

gluteal Greater trochanter: posterior to trochanteric prominence

Knee, at medial fat pad

Figure 13.Tender Point Sites

Dr.JKR

RH26 Rheumatology Summary of Arthritic Diseases/Clinical Approach to Arthritis Toronto Notes 2008

Summary of Arthritic Diseases

Table 20. Classification of Arthritis and Characteristic Features

Classification

Degenerative Osteoarthritis (OA)

Seropositive rheumatic diseases

1. Connective Tissue Disease Rheumatoid Arthritis (RA)� Systemic lupus erythematosus (SLE)� Antiphospholipid antibody syndrome (APS)� Scleroderma/progressive systemic sclerosis (PSS)� Polymyositis (PMY)ldermatomyositis (OMY)� Mixed connective tissue disease (MCTO)� Sjogren's syndrome�

2. Vasculitides Polyarteritis nodosa (PAN)� Microscopic polyangiitis� Wegener's granulomatosis� Predominantly cutaneous vasculitis� Giant cell arteritis (GCA)�

Seronegative rheumatic diseases Ankylosing spondylitis (AS)� Reactive arthritis� Psoriatic arthritis� Inflammatory bowel disease (lBO)�

Crystal-induced Gout (monosodium urate)� Pseudogout (calcium pyrophosphate dihydrate)� Hydroxyapatite deposition disease�

Septic/infectious

Non-Articular Localized (bursitis, capsulitis, tendinitis, myositis) Generalized (fibromyalgia, polymyalgia rheumatica)

Characteristic Features

Insidious onset Older age (>50 years old) Negative serology

Positive serology Constitutional symptoms Skin nodules, ulcers, rash Raynaud's phenomenon Vascular involvement Renal involvement Neurological involvement Sicca syndrome

see Table 15 Medium vessel disease Small vessel disease, ANCA associated Small vessel disease, ANCA associated Small vessel disease, non-ANCA associated Large vessel disease

Axial skeleton involvement Anterior uveitis, conjunctivitis, urethritis Enthesitis, sacroiliitis, dactylitis, urethritis Psoriasis, keratoderma, E. nodosum Family history and HLA-B27 association

Remitting, recurring pattern Mono or oligoarthritis Tophi Renal involvement

Acute monoarthritis or migratory polyarthritis Constitutional symptoms

Periarticular structures affected Trigger points

Clinical Approach to Arthritis

Approach to Making a Decision I I

Articular Non-ArticularI _J I I Inflammatory Degenerative Localized Generalized

I II I I I I

Seropositive BursitisPrim<lry FibromyalgiaSeronegative TendinitisII�Secondary PMRCrystal CapsulitisSeptic II

Figure 14. Clinical Evaluation of Arthritis: Approach to Making a Diagnosis With permission of Dr,Arthur A.M.Bookman

I

Dr.JKR

Toronto Notes 2008� Common Medications Rheumatology RH27

Common Medications Table 21. Common Medications for Osteoarthritis Class� Generic Drug Name Trade Name Dosing Indications Contraindications Adverse Effects

acetaminophen Tylenol™ 500 mg tid 1st line� Hepatotoxicity Overdose>10 g Potentiates Warfarin

NSAIDs� ECASA 325-975 mg qid 2nd line GI bleed Nausea, tinnitus, vertigo, rash, ibuprofen AdviiTMMotrin™ 200-600 mg tid Renal impairment dyspepsia, GI bleed, PUD, diclofenac Volta~enTM 25-50 mg tid Allergy to ASA, NSAIDs hepatitis, renal failure, HTN, diclofenac/misoprostol Arth rate C™ 50-200 mg tid Pregnancy IT3) nephrotic syndrome naproxen Naprosyn™, Aleve™ 125-500 mg bid meloxicam MoblCOX™ 7.5-15 mg 00

COX-2 celecoxib Celebrex'M 200 mg 00 High risk for Renal impairment Delayed ulcer healing Inhibitors GI bleed: age>65 Sulfa allergy (celecoxib) Renal/hepatic impairment

hx of GI bleed, PUD Cardiovascular disease Rash

D1!ler treatments� Comments

Combination analgesics Enhanced short term effect compared to acetaminophen alone (acetaminophen + codeine) More adverse effects: sedation, constipation, nausea, GI upset

Intra-articular corticosteroid injection� Short-term (weeks··months) decrease in pain and improvement in function Do not inject >3-4 times/year in the same joint

Intra-articular hyaluronan q6months� Modest decrease in pH in Used for mild-mode. ate OA Precaution With chicken/egg allergy

Topical NSAIDs� 1.5% vvt/wt topical diclofenac (Pennsaid) May use for patients who fail acetaminophen treatment and who wish to avoid systemic therapy

Capsaicin cream� Moderate decrease in pain

Glucosamine sulfate/chondroitin� Limited clinical studies No regulation by Health Canada

Table 22. DMARDs Used in the Treatment of Rheumatoid Arthritis Genetic Drug Name Trade Name Dosing Contraindications Adverse Effects

COMMONLY USED hydroxychloroqulne Plaquenil'M 400-600 mg 00 initially Retinal disease, G6PD deficiency GI symptoms, macular damage, neuromyopathy, skin rash $ 200-400 mg 00 maintenance

sulfasalazine Salazopyrim™ 1000 mg bid Sulfa/ASA allergy, kidney disease, GI symptoms, headache, leukopenia, rash $ Azulfidine™ (US) G6PD deficiency

methotrexate Rheumatrex'M qweekly Bone marrow suppression, Urticaria, GI symptoms, tubular necrosis, $ FolexiMexate'M 7.5-25 mg PO/IM/SC liver disease, significant lung disease, myelosuppression, cirrhosis, pneumonitis, oral ulcers

immunodeficiency, pregnancy, EtOH abuse

gold !injectable) Solganal'M weekly or monthly injections lBO, kidney/liver disease Rash, mouth soreness/ulcers, proteinuria, $ Myocrysine'M marrow suppression

NOT COMMONLY USED

cyclosporine Kidney/liver disease, Bleeding, hypertension, decreased renal $$ infection, hypertension function, hair growth, tremors

gold (oral!� lBO, kidney/liver disease Diarrhea, rash, stomatitis $

azathioprine Kidney~iver disease Pancytopenia, biliary stasis, rash, hair $ loss, vomtting, diarrhea

cyclophosphamide Kidney/liver disease Cardiotoxicity, GI symptoms, hemorrhagic cystitis, $ nephrotoxictty, bone marrow suppression, sterility

penicillamine Penicillin allergy Rash, loss of taste/appetite, GI symptoms, $ hematologic/kidney disease nephritic syndrome

NEWER DMARDs (Biologicals)� MECHANISM OF ACTION

leflunomide Arava™ 10-20 mg PO 00 Inhibits pyrimidine synthesis and has antiproliferative activity $$$

etanercept EnbrerM 25 mg biweekly FUSion protem ofTNF receptor and Fc portion of IgG $$$ or 50 mg weekly Decreases number of active joints by 50% from baseline after 6months

SC mjectlons

infliximab Remicade'M 3-5 mg/kg IV qBweeks Chimerrc mouse/human monoclonal Ab against TNFa $$$ Rapidly reduces number of swollen joints

anakinra Kineret™ 100 mg SC DO Interleukin-l receptor antagonist $$$ Reduce joint activity and x-ray progression

adalimumab Humira™ 40 mg SC q 2weeks Monoclonal antl-TNFa antibody $$$

abatacept Ofenc\a™ IV infusion Costimulation modulator of Tcell activation $$$

rttuximab Rituxan™ 2IV infUSions, Causes B cell depletion, binds to CD20 $$$ 2weeks apart

Dr.JKR

RH28 Rheumatology Summary Key Questions� Toronto Notes 2008

Summary Key Questions� QUestions

1.� List 6signs of osteoarthritis on physical examination.

2.� What are 4radiological hallmarks of OA?

3.� List the diagnostic criteria for RA as outlined by the American College of Rheumatology. How'many of these criteria are required for the diagnosis of RA?

4.� What percentage of patients with RA are rheumatoid factor positive?

5.� Name 5poor prognostic features of RA

6.� List the diagnostic criteria for SLE. How many of these criteria are required for the diagnosis of SLE?

7.� Which antibody is most sensitive for the diagnosis of SLE?

8.� List five major pharmacologic agents that are associated with drug-induced lupus.

9.� Listthe three commonest manifestations of APS.

10.� What are the features of scleroderma renal crisis and what percentage of patients with scleroderma are at risk of developing renal crisis?

11.� List the 5diagnostic criteria for polymyositis/dermatomyositis.

12.� List the features of the classic triad of Sjiigren's disease.

13.� What type of malignancy are patients with Sjogren's at greatest risk of developing?

Answers

Joint line tenderness, bony enlargement at affected joints, malalignmenVjoint deformity, limited ROM, periarticular muscle atrophy, and crepitus on ROM.

Joint space narrowing, subchondral sclerosis, intraosseous cyst formation, and osteophytes.

il morning stiffness>1hr iiI arthritis of >3 joints iiil arthritis of hand joints ivl symmetric arthritis v) rheumatoid nodules vii serum RF viii radiographic changes including erosions or periarticular

osteopenia

4or more of these criteria for more than 6weeks are required to make the diagnosis of RA.

60-80%

Young age at onset, high RF titers, elevated ESR, >20 active joints, and the presence of extra-articular features.

il malar rash iil discoid rash iiil photosensitivity iv) oral/nasal ulcers vi arthritis vii serositis (pleuritis or pericarditisl vii) neurologic disorder Iseizures or psychosisI viiil renal disorders Iproteinuria or cellular castsl ixl hematological disorder Ii.e., hemolytic anemial xl immunological disorder Ii.e., anti-dsONA Ab, anti-Sm Abl xii ANA

ANA 198% sensitivel

Hydralazine, isoniazid, procainamide, chlorpromazine and methyldopa

Thromboembolic events, recurrent spontaneous abortions, thrombocytopenia

Malignant arterial hypertension (> 150/90 mmHgl.1'Cr, oliguria, and microangiopathic hemolytic anemia, 10-15% of scleroderma patients are at risk of developing scleroderma renal crisis.

il progressive symmetric proximal muscle weakness iil elevated muscle enzymes (CK, aldolase, LoH, AST, All) iii) EMG changes ivl muscle biopsy vi typical rash of dermatomyositis (required for the

diagnosis of oMI

Definite PM/OM if fulfill 4criteria; probable if fulfill 3criteria; possible if fulfill 2criteria

Dry eyes, dry mouth, and inflammatory arthritis.

Non-Hodgkin's lymphoma.

Dr.JKR

Toronto ;'\Totes 2008� Summary Key Questions Rheumatology RH29

Questions� Answers

14.� List the diagnostic crrteria for Wegener's granulomatosis. How may of these criteria are required for the diagnosis of Wegener's granulomatosis?

15.� List the diagnostic criteria for polyarteritis nodosa. How many of the criteria are required for the diagnosis of PAN?

16� List the features for the diagnosis of Giant Cell Arteritis.

17.� List the differential diagnosis of an elevated ESR.

18.� What are the common joints involved in ankylosing spondylitis?

19.� What percentage of patients with ankylosing spondylitis are HlA-B27 positive? What is the prevalence of HlA-B27 in the general population?

20.� What GI and GU infections precede the development of Reactive Arthritis?

21.� List the 5general MSK patterns of psoriatic arthritis.

22.� What are the common sites of involvement in gout and what is the pattern of joint involvement?

23.� What are the common preciprtants of gout attacks?

24.� List 3risk factors for the development of pseudogout.

25.� What are the common srtes of involvement in pseudogout?

26.� What is the differential diagnosis of acute monoarthritis?

27.� What are the tender point sites in fibromyalgia?

28.� What are the features for the diagnosis of polymalgia rheumatica?

i) nasal or oral inflammation, ulcers, epistaxis iil abnormal CXR findings including nodules, cavitations iii) urinary sedimentlprotein, RBC castsl ivl biopsy of involved tissue: lung tissue shows granulomas;

renal tissue shows necrotizing segmental granulomatosis

To diagnose Wegener's aminimum of 2of the above criteria are required.

>3 out of 10 required: il weight loss >4 kg iii myalgias, weakness, or leg tenderness iiil livedo re~cularis

ivl neuropathy vi testicular pain or tenderness VI) diastolic BP >90 mmHg viii tCr or BUN viiil Hepatitis Bvirus ix) arteriographlc abnormalrty xl biopsy or artery showing presence of granulocytes

or mononuclear leukocytes in the arterial wall

il age >50 yrs iii temporal artery tenderness or decreased pulse iii) ESR >50 ivl abnormal artery on biopsy

RA, PMR, GCA, hypoalbuminemia, anemia, multiple myeloma, bacterial mfecllOns, malignancy.

SI, hip, shoulder

95% of patients with AS are HlA-B27 positive. 9% of the general population is HlA-B27 positive.

GI infec~ons - Shigella, Salmonella, Campy/obacter, Yersinia; GU infections - Chlamydia, Mycoplasma species.

il asymmetric oligoarthritis ii) arthrrtis of DIP joints wrth nail changes iii) destructive Imutilansl arthrrtis iv) symmetric polyarthritis v) sacroilirtis and spondylitis

1st MTP, ankle, knee. The pattern of joint involvement is asymmetrical.

Alcohol, dietary excess, dehydration, thiazide and loop diure~cs, trauma, illness, and surgery

Old age, advanced OA, and neuropathic joints

Knee, polyartlcularwrisl. MCP, 1st MTP

Septic arthritis, gout, pseudogoul. trauma, hemarthrosis, osteonecrosis, osteoarthritis, tumor, systemic inflammatory disease, polyarthrrtis presenting with monoarticular symptoms

Occiput, trapezius, supraspinatus, low cervical, second rib, lateral epicondyle, gluteal, greater trochanter, medial fat pad of knee.

Age >50, bilateral aching/morning stiffness for 1month, ESR >411, prompt response to low-dose corticosteroids.

Dr.JKR

RH30 Rheumatology References Toronto Notes 2008

References�

ACR Subcommittee on Rheumatoid Arthritis Guidelines, 2002. Guidelines for the Management of Rheumatoid Arthritis: 2002 Update, Arthritis & Rheumatism 46121:328·346. ACR, Guidelines for Referral and Management of Systemic Lupus Erythematosus in Adults· 9199, ACR. Guidelines for the Medical Management of Osteoarthritis of the Hip - 11/95. ACR. Guidelines for the Medical Management of Osteoarthritis of the Knee - 11195.� Bathon JM, Martin RW, Fleischmann RM, et al. Acomparison of etanercept and methotrexate in patients with early rheumatoid arthri·� tis. NEngl J Med 2000;343:1586-93. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. The VIGOR Study Group, N EnglJ Med2000;343:1520·28.� Bookman AM. Clinical Evaluation of Arthritis. University ofToronto Foundations of Medical Practice Lecture. 2006.� Brater DC, Harris C, Redfern JS, Gertz BJ. Renal effects of COX-2-selective inhibitors. Amer J Nephrology 2001 ;21111:1·15.� Kremer, JM. Rational use of new and existing disease-modifying agents in rheumatoid arthritis, Ann Intern Med2001:134: 695-706.� Smetana, GW and Shmerling RH, Does this patient have temporal arteritis? JAMA 2002; 287:92-101� CMAJ Clinical Basics Rheumatology Series.� Brady OH, Masri BA, Garbuz OS, Duncan CPO 10. Joint replacement of the hip and knee· when to refer and what to expect. CMAJ� 2000;163110): 1285·91� Cibere J. 4. Acute monoarthritis. CMAJ 2000;162(11!:1577-83.� Clark BM 9. Physical & occupational therapy in the management of arthritis. CMAJ 2000;163(8!:999·1005.� Ensworth S. lis it arthritis? CMAJ2000;16217):1011·6,� Huang SHK. 7. Basics of therapy. CMAJ 2000;16314!:417-23� Klippel JH, Weyand CM, and Wortmann RL. Primer on Rheumatic Diseases, 11th ed. Arthritis Foundation, 1997.� Klinkhoff A. 5. Diagnosis and management of inflammatory polyarthritis. CMAJ 2000;162113):1833-38,� Lacaille D. 8. Advanced therapy. CMAJ 2000;163(6):721-8.� Musculoskeletal Injury; (OPOT!, Queen's Printer of Ontario, June 2000. www.opot.org� Ontano MusculoskeletalTherapeutics Review Panel. OntarioTreatment Guidelines for Osteoarthritis, Rheumatoid Arthritis, and Acute� Price GE, 6. Localized therapy, CMAJ 2000;163121:176-83,� Puttick MPE. 11 Evaluation of the patient with pain all over, CMAJ 2001;164121:223-27.� Reid G, Esdaile JM, 3. Getting the most out of radiology. CMAJ 2000;16219):1318-25.� Shojania K, 2, What laboratory tests are needed? CMAJ 2000;16218):1157·63.� Taunton JE, Wilkinson M, 14. Diagnosis and management of anterior knee pain. CMAJ 2001;164111):1595-601 Tsang I. 12. Pain in the neck. CMAJ 2001;164(8):1182·7. Wade, J.P. 15. Osteoporosis. CMAJ 2001;165(1!:45·50, Wing PC, 13. Minimizing disability in patients with low-back pain. CMAJ2001;164!191:1459·68,

Dr.JKR