Rheum A To Logy

Rheumatology

Unprotected copy By: Dr.JKR [email protected]

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

Summary of Arthritic Disease

26

Basics of Immunology Immune Mechanisms of Disease Immunogenetics and Disease

2

Clinical Approach to Arthritis

26

Common Medications

27

Summary Key Questions

28

References

30

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

15

17

Seronegative Rheumatic Diseases . ... .18 Ankylosing Spondylitis (AS) Reactive Arthritis (ReA) Psoriatic Arthritis (PsA) Inflammatory Bowel Disease (IBD) Undifferentiated Spondylopathy Crystal-induced Arthropathies Gout Pseudogout (Chondrocalcinosis) Synovial Fluid Analysis

22

Non-Articular Rheumatism Polymyalgia Rheumatica Fibromyalgia

24

Toronto Notes 2008

Rheumatology RHI

Dr.JKR

Toronto Notes 2008

Basic Anatomy ReviewlBasics of Immunology

RH2 Rheumatology

Basic Anatomy Review erosion Bursa Synovial

Cartilage

membrane

destruction

~ Synovitis

Synovial

fluid

Tendon

CartjlageU-roi;:::~:=:;~J

Cartilage particle

Osteophyte

Loss of joint space

Cartilage destruction

Degenerative Joint

Normal Joint

Effusion

~_.iUjOintspace

narrowing

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

Rheumatology RH3

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 (mononuclear phagocytes, Bcells, others)

Recognized by CD4+ (helper) Tlymphocytes

III

Complement components

In plasma

Chemotaxis, opsonization, lysis of bacteria and cells

Table 2. HLA-Associated Rheumatic Disease HLAType

Associated Conditions

Comments

827

Ankylosing spondylitis Reactive arthritis Psoriatic arthritis IBD arthropathy (spine)

In AS, relative risk = 70-90 In reactive arthritis, relative risk = 40 Psoriatic also associated with B38

DR4, DR1

Rheumatoid arthritis

93% of patients

DR3

Sjogren's syndrome SLE Rheumatoid arthritis

DR3 associated with many non-rheumatic conditions (Celiac disease, Type 1 DM, Graves' disease, Chronic active hepatitis)

Differential Diagnoses of Common Presentations

o

Table 3. Differential Diagnosis of Joint Pain Monoarticular Infectious (see Infectious Diseases, 10221 Bacterial Mycobacterial Fungal Viral Crystal-induced Gout CPPD Hydroxyapatite Hemarthrosis Trauma/fracture Anticoagulants Bleeding diatheses Neoplasm Inflammatory Seropositive ICTD) Seronegative Degenerative

Non-articular • Musculoskeletal Tendonitis Bursitis Strain FibromyalgialPMR • Neurological involvement Spinal stenosis/spondylolisthesis Degenerative disc disease Cauda equina syndrome Neoplasm Thoracic outlet syndrome • Vascular Intermittent claudication

Polyarticular • Infectious Lyme disease Bacterial endocarditis Septicemia Gonococcus Viral!EBV, parvovlrusi • Post-inlectious Rheumatic fever Reactive arthritis Enteric infections • Inflammatory Seropositive (CTD) Seronegative

~'

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

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 • Ankylosing spondylitis • Rheumatoid arthritis • Polymyalgia rheumatica • Osteoarthritis

Oligoarthritis • Seronegative disorders • Psoriatic arthritis • Reactive arthritis • Infectious arthritis • Crystal-induced arthritis

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

• Psoriatic arthritis • Tophaceous gout

Dr.JKR

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)

RH4 Rheumatology

Differential Diagnoses of Common PresentationslDegenerative Arthritis: Osteoarthritis

Table 5. Seropositive vs. Seronegative Rheumatic Diseases Seropositive Demographics

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.

Toronto Notes 2008

Seronegative M>F

Peripheral Arthritis

Symmetrical Small and large joints DIP less involved

Usually larger joints, lower extremities (psoriatic arthritis may be the exception) Dactylitis Enthesitis DIP in Psoriatic arthritis

Pelvic/Axial Disease

No (except for C-spinel

Yes

Enthesopathy

No

Yes

Extra-Articular

Nodules Vasculitis Sicca Raynaud's phenomenon

Iritis 1= Anterior Uveitisl Oral ulcers GI 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 • • • • • • •

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

Symptoms

Signs

joint pain with motion; relieved with rest short duration of stiffness «1/2 hr) after immobility joint instability/buckling loss of function joint locking due to "joint mouse" (bone or cartilage fragment)

joint line tenderness; stress pain bony enlargement at affected joints malalignment/deformity (angulation) limited ROM 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

• 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)

Table 7. Features of Seropositive Arthropathies Systemic Lupus Erythematosus

Scleroderma

Dermatomyositis

History

Multisy~emic

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

Heliotrope rash [eyelidsl, Gonron's papules, macular erythema and poikiloderma Ishoulders, ned< and che~l, proximal muscle weakness ± pain

AM~iffness[>lhrl

EftusedJoints Tenosynovtis Nodules Bone-on-bone crepitus

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

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

Rasn, proximal muscle weakness

Non-specific

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

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

Increased ESR Increased platelets Decreased Hb NormalWBC

Possible increased ESR Normal platelets Decreased Hb NormalWBC

Specific

RF +ve in -80%

ANA tve in 9B% Anti-SM tve in 30% Anti-
ANA +VB in ,90% Anti-topoisomerase 1 Idiffusel Anti-centromere lusually in CREST. see sidebarl

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

Mild inflammation with +ve ANA

Not specfic

Not specific

± pulmonary fibrosis

±esophageal dysmotility

± esophageal dysmotility

± inter~itiallung

Physical Examination

Laboratory

Synovial Fluid

Inflammation leukocytoSis [>10,0001

Radiographs

Demineralization Nondewuctivelnonerosive Symmetridconcentric joint ± osteoporosis, osteopenla space narrowing ± sofl tissue swelling Erosions of subchondral bone Absence of bone repair

:!:calcinosis

Dr.JKR

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 osteoar1hri-

Clinical Features Rheumatoid Arthritis

disease rash, photosensitivity, Raynaud's, alopecia, cardiac and pulmonary serosnis, CNS symptoms, glomerulonephritis

'1.,

lis of the knee IN Engl JMed2002;347~1-81

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

Symmetrical Po~anhritis Ismail joint involvementl

Rheumatology RH5

disease

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/Ir There 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

RH6 Rheumatology

Toronto Notes 2008

Seropositive Rheumatic Diseases: Connective Tissue Disorders

Rheumatoid Arthritis (RA)

--'''--

o

,,

....

Definition

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

Common Presentation • Morning stiffness >30 min. improving with use • Symmetric joint involvement • Initially involves small joints of hands and feet • Constitutional symptoms

....

...J

,,

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

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

• 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

• • • • • • • • •

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

• 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

~

Figure 4. Common sites of joint involvement in RA Osteoprotegerin ligand

I r

i

Activation of complement

cascade

~

Accumulation of PMNs; inflammatory symptoms

B- and T-cell accumulation in

~putrophil

recruitment

inflammatory

Release of elastase + protease

~

Osteoclastogenesis

Pannus fonnation

Matrix

\

~

mediators

I t

metalloproteinasps

I

Degradation of peptidoglycan of cartilage

~

~

Proliferation of synovial

rblaslS ",~

~

rOVium

Release of

Promotes inflammation

In!a':'ion 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 • 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 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

ClaW~To.e

~ .~

HammerToe

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

Figure 6. Joint deformities

I

Vasculitis episcleritis, scleritis periungual infarction cutaneous ulcers palpable purpura peripheral neuropathy • sensory: stocking-glove • mononeuritis multiplex

Lymphocytic infiltrate rheumatoid nodules pulmonary fibrosis pleural effusion/pleuritis pulmonary nodules peri-/myocarditis, valvular disease Hashimoto's thyroiditis Sjogren's syndrome Felty's syndrome hepatosplenomegaly

Figure 7. EAF of RA

Treatment • goals of therafY • contro disease activity • relieve pain and stiffness maintain function and lifestyle • prevent or control joint damage key is early diagnosis and early intervention with disease modifying anti-rheumatic drugs (DMARDs)

Dr.JKR

... ' ~

9)--------------,

Poor prognostic features of RA include young age of onset, high RF titer, elevat· ed ESR, activity of >20 joints, and presenceofEAF.

... '9~ · } - - - - - - - - - - - , Common Syndromes in RA 1. Sjogren's syndrome (sicca complex dry eyes and mouth) 2. Caplan's syndrome (multiple pulmonary nodules and pneumoconiosis) 3. Felty's syndrome (arthritis, splenomegaly, neutropenia)

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" w-.g illiIinab, CIIlllbiledwilh bIckfound peliInII wiIh rl1elIIIIlIIid arMs trIIlIn,

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 infu-

sions 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 inftilinab 3mii\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 (Arava TM) • 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

Systemic Lu

Seropositive Rheumatic Diseases: Connective Tissue Disorders

_

Rheumatology

RH~

hematosus (SLE)

..... . . £ -

-_..::-_----

Definition • chronic inflammatory multisystem disease of un1.nown etiology, characterized by production of autoantibodies and diverse clinical mamfestations

.:'

Diagnostic Criteria of SLE:

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 Discoid rash Photosensitivity Oral/nasal ulcers Arthritis Serositis Neurologic disorder

Classic "butterfly rash; sparing of nasolabial folds, no scarring May cause scarring due to invasion of basement membrane Skin rash in reaction to sunlight Usually painless Symmetric, involving <2 small or large peripheral joints, non-erosive Pleuritis or pericarditis Seizures or psychosis

MD SOAP BRAIN Malar rash Discoid rash Serositis Oral ulcers ANA Photosensitivity

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Blood Renal Arthritis Immune Neurologic

,

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

Laboratory Renal disorder Hematologic disorder Immunologic disorder

Antinuclear antibody lANA)

Proteinuria 1>0,5 g/day or 3+1 Cellular casts IRBC, Hb, granular, tubular, mixedl Hemolytic anemia, leukopenia, lymphopenia, thromboctyopenia Anti-dsDNA Ab, anti-Sm Ab Antiphospholipid antibodies based on the finding of serum anticardiolipin Ab, lupus anticoagulant, or false positive VDRL Most sensitive test (98%)

Note: "4, 7, 11" rule • 4 out 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

gnvironment Stress. viruses. sun Genetic Hormonal

+

HLA~

T-cell,

'(

Drug,

Form
Cytotoxic Ab

+

Auto-Ab

~

Immune complexes

Cell damage/death

+

Jnl1ammatiuTI

Figure 8. Multifactorial etiology of SLE

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, weigh 1 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)

Dr.JKR

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

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 • serologic hallmark is high titer ANA detected by immunofluorescence • ANA has high sensitivity (98%) and therefore is a useful screening test, but poor 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

Consider septic arthritis and avascular necrosis in patients with SLE and joint pain.

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

Seropositive Rheumatic Diseases: Connective Tissue Disorders

Toronto Notes 2008

• 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) • mostly children and young adults

\ / Morphea • hard oval patches on the skin

Linear 'Iine of thickened skin

(systemic sclerosis) ~ ~ 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 • pulmonary hypertension common • early visceral • CREST (see RH5) involvement (renal, pulmonary fibrosis)

Figure 9. Forms of Scleroderma

Dr.JKR

Rheumatology RHll

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Manifestations of APS Thromboembolic events Recurrent fetal loss Thrombocytopenia

RH12 Rheumatology

Seropositive Rheumatic Diseases: Connective Tissue Disorders

Toronto Notes 2008

Signs and Symptoms Table 10. Clinical Manifestations of Scleroderma

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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 Due to vasospasm following cold exposure or emotional stress 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

Scleroderma is the most common cause of secondary Raynaud's phenomenon.

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 H 2 -receptor antagonists • small bowd bacterial overgrowth: broad-spectrum antibiotics (tetracycline, metrunidazole) • Raynaud's: vasodilators (CCBs, local NTG cream, systemic PGE 2 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 1. Progressive symmetric proximal muscle weakness 2. Elevated muscle enzymes 3. EMG changes 4. Muscle biopsy 5. Typical rash of dermatomyositis

Description Typical involvement of shoulders and hips Increased CK, aldolase, LOH, AST, ALT Short polyphasic motor units, high frequency repetitive discharge, insertional irritability Segmental fibre necrosis, basophilic regeneration, perivascular inflammation and atrophy 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

Dr.JKR

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

Seropositive Rheumatic Diseases: Connective Tissue Disorders

RH14 Rheumatology

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

o

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

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

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 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)

Oral

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

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 Connective Tissue 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 Small vessel • Non·ANCA·associated Predominantly cutaneous vasculitis Henoch·Schiinleln purpura (see Pediatrics, P941

Characteristic Features ·immune complexes ·also known as hypersensitivity~eukocytoclastic vasculitis · vascular deposition of IgA causing systemic vasculitis (skin, GI, renall, seen most frequently in childhood, usually self·limiting condition

Essential cryoglobulinemic vasculitis • ANCA-associated Wegener's granulomatosis Ic-ANCA >p-ANCA) Churg-Strauss syndrome

150% ANCA positive) Microscopic polyangiitis

170% ANCA positive, usually p-ANCA) Medium-sized vessel Polyarteritis nodosa Kawasaki's lsee Pediatrics, P941 Large vessel Giant celi arteritis (temporal arteritis) Takayasu's arteritis Other Vasculitides Buerger's disease

Behcets disease Vasculitis mimicry

-granulomatous inflammation of vessels of respiratory tract and kidneys, most common in middle age, most present initially with symptoms of URTI -granulomatous inflammation of vessels with hypereosinophilia and eosinophilic tissue infiltration, sometimes associated With p-ANCA or c-ANCA · other manifestations include coronary arterhis, myocarditis and neuropathy -pauci'lmmune necrotizing vasculitis, affecting kidneys Inecrotizing glomerulonephritis), lungs (capillaritis and alveolar hemorrhage), skin -any age [average 40-50'sl, unknown etiology in most cases ·segmental non-granulomatous necrotizing inflammation -Tlymphocyte response and granuloma formation -Tlymphocyte response and granuloma fomnation -over 50 years of age, more common in women, inflammation predominantly of the aorta and those arteries originating from it · "pulseless disease; increased ESR, fever, night sweats, chronic inflammation, most often the aorta and its branches, usually young adults of Asian descent, F>M

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

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Churg·Strauss Triad • Allergic rhinitis and asthma • Eosinophilic infiltrative disease resembling pneumonia • Systemic vasculitis

Seropositive Rheumatic Diseases: Vasculitides

RH16 Rheumatology

Toronto Notes 2008

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

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Wegener's Granulomatosis SMALL VESSEL ANCA-ASSOCIATED VASCULITIS

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Classic Features: • necrotizing granulomatous vasculitis of lower and upper respiratory tract • focal segmental glomerulonephritis

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

Polyarteritis Nodosa (PAN)

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_

Rheumatology RH17

[. o

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

'" ~, ~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

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

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

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

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)

Dr.JKR

Medical Emergency

Untreated, GCA can lead to permanent 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, hypoalbuminemia, anemia, muhiple myeloma, bacterial infections, malignancy. ESR (and CRPI is insensitive for PM/DM, AS, PSS, SLE, viral infections.

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% Sjogren's 50% SLE 20%

<5%

Autoantibodies IIgM >IgG >IgAI directed against Fe domain of IgG 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% MCTD95% Sjogren's 70-90% CREST 80%

<5% other CTDs

Antibodies against nuclear components IDNA, RNA, histones, centromere) 1:40 dilution found in 5-30% of the normal population 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% SLE 10%

0%

Usually occurs with anti-Ro

Antiphosphollpid antibodies (LAC, ACLAI

APS SLE 31-40%

<5%

By definition present in APS 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% Idiopathic SLE >50%

0% 0%

Antl-RNP

MCTD

0%

By definition present in MCTD; present in many other CTD

Anti-centromere Anti-topoisomerase I (formerly ScI-701

CREST> 80% PSS 26-76%

0% 0%

Specific for CREST variant of PSS

c-ANCA

Active Wegener's >90%

0%

Specific and sensitive

p-ANCA

Wegener's 10%, other vasculitis

0%

Nonspecific and poor sensitivity Ifound in ulcerative colitis, polyarteritis nodosa, microscopic polyangiitis, Churg-Strauss, rapidly progressive glomerulonephritisl

Anti-Mi-1

Dermatomyositis 15-10%

Specific but not sensitive

Antibodies against RBCs, WBCs, or platelets

SLE

Perform direct Coomb's test Test hemoglobin, reticulocyte, leukocyte and platelet count, antiplatelet Abs

Sero_negative Rheumatic Diseases Table 15. A Comparison of the Spondyloarthropathies Feature M:F Age onset

20's

Peripheral arthritis Distribution Sacroiliitis Dactylitis Enthesitis Skin lesions

25% Axial, LE 100% Uncommon Common Rare Nil specific

PsA 1:1 35-45 96% Any 40% 35% Common 100% Psoriasis

Uveitis Urethritis Aortic Regurgitation

30% Rare Occasional 90%

Occasional Occasional Rare 40%

HLA-B27

AS 5:1

Dr.JKR

ReA 8:1

20% Common Occasional

20's

90% LE 80% Common Common Common Keratoderma

80%

IBD 1:1 any Common LE 20%

Uncommon Less Common Occasional Pyoderma, Erythema Nodosum Rare Rare Occasional 30%

Toronto Notes 2008

Seronegative Rheumatic Diseases

Rheumatology

RH19

Ankylosing Spondylitis (AS)

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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)

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)

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 Past History

Inflammatory

Mechanical ±

++

Acute

+ Insidious

Family History Onset Age (years)

15-90

<40

Sleep Disturbance

±

++

Morning Stiffness

<30 minutes

>1 hour

Worse

+ Better

Rest

Better

Worse

Radiation of Pain

Anatomic (L5-S1)

Diffuse (thoracic, buttock)

Sensory Symptoms

+

Motor Symptoms

+

Involvement of Other Systems Exercise

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

Dr.JKR

....

'~

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

Consider AS in the differential for causes of aortic regurgitation.

Toronto Notes 2008

Seronegative Rheumatic Diseases

RH20 Rheumatology

• 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 • • • •

o

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)

",' ,

•. l - - - - - - - - - - - ,

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

",' ,

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

•. l - - - - - - - - - - - ,

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

• 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

o

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

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

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

Dr.JKR

'"

,,

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

Both ankylosing spondylitis and IBD-arthritis feature symmetric sacroiliitis.

Crystal-Induced Arthropathies

RH22 Rheumatology

Toronto Notes 2008

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

• 1st MTP • ankle • knee

"0

u

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.

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

"" Precipitants of Gout Drugs are FACT: Furosemide Aspirin/Alcohol Cytotoxic drugs Thiazide diuretics Foods are SALTS: Shellfish Anchovies Liver and Kidney Turkey Sardines

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 Rheumatology RIm

• 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

• • • •

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

Figure 12. Common sites of involvement in CPPD

o

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 Age

M.F Older

Distribution Radiology

M>F Middle-aged males Post-menopausal females Acute Negative birefringence, needle-shaped Fi rst MTp, foot "Holes in bones"

Treatment

Indomethacin, colchicine, allopurinol

Onset of disease Crystal type

Acute/insidious Positive birefringence, rhomboid-shaped Knee, wrist, polyarticular Chondrocalcinosis OA (knee, wrist, 2nd and 3rd MCP) NSAIDs

Synovial Fluid Analysis • synovial fluid is an ultrafiltrate of plasma plus hyaluronate; it lubricates joint surfaces and nourishes articular cartilage

Three Most Important Tests 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

Dr.JKR

""

',

.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

Toronto Notes 2008

Crystal-Induced Arthropathies/Septic ArthritisINon-Articular Rheumatism

RH24 Rheumatology

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

Infectious

Colour

Opaque

Sanguinous

Clear

Clear

Opaque

Hemorrhagic

Viscosity

High Idue to hyaluronate)

High

Low

Low

Variable

WBClmm'

<200

<2,000

>2,000

>50,000

Variable

%PMN

<25%

<25%

>25%

>50%

Variable

Trauma Osteoarthritis Neuropathy Hypertrophic· arthropathy

Seropositives Septic arthritis Seronegatives Crystal arthropathies

Examples

Trauma Hemophilia CPPD

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

[

Polymyalgia Rheumatica (PMR)

_ _- ' ' - -

Definition ....

',

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

PMR Criterie 1. Age over 50 2. Bilateral aching/morning stiffness>1 month 3. ESR over 40 mm/hr 4. Prompt response to low-dose corticosteroids

• 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

.J

Toronto Notes 2008

Non-Articular Rheumatism

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

trapezius supraspinatus

Occiput: at suboccipital muscle insertion

Low cervical, C5-C7 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

Gluteal, upper outer quadrants

Greater trochanter: posterior to trochanteric prominence Knee, at medial fat pad

Figure 13.Tender Point Sites

Dr.JKR

Rheumatology RH25

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 Characteristic Features

Classification Degenerative Osteoarthritis (OA)

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

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

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

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

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

Seronegative rheumatic diseases

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

Ankylosing spondylitis (AS) Reactive arthritis Psoriatic arthritis Inflammatory bowel disease (lBO)

Crystal-induced

Remitting, recurring pattern Mono or oligoarthritis Tophi Renal involvement

Gout (monosodium urate) Pseudogout (calcium pyrophosphate dihydrate) Hydroxyapatite deposition disease

Septic/infectious

Acute monoarthritis or migratory polyarthritis Constitutional symptoms

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

Periarticular structures affected Trigger points

Clinical Approach to Arthritis Approach to Making a Decision

I

I Inflammatory

_J

Articular

I

Degenerative

I

I

Seropositive Seronegative Crystal Septic

Prim
I Non-Articular

I

II

Localized

Generalized

I

I

II

Bursitis Tendinitis Capsulitis

Fibromyalgia PMR

II

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

Dr.JKR

I

I

Toronto Notes 2008

Common Medications

Rheumatology RH27

Common Medications Table 21. Common Medications for Osteoarthritis Class

NSAIDs

COX-2 Inhibitors

Generic Drug Name

Trade Name

Dosing

Indications

acetaminophen

Tylenol™

500 mg tid

1st line

2nd line

Arth rate C™ Naprosyn™, Aleve™ MoblCOX™

325-975 mg qid 200-600 mg tid 25-50 mg tid 50-200 mg tid 125-500 mg bid 7.5-15 mg 00

GI bleed Renal impairment Allergy to ASA, NSAIDs Pregnancy IT3)

Nausea, tinnitus, vertigo, rash, dyspepsia, GI bleed, PUD, hepatitis, renal failure, HTN, nephrotic syndrome

Celebrex'M

200 mg 00

High risk for GI bleed: age>65 hx of GI bleed, PUD

Renal impairment Sulfa allergy (celecoxib) Cardiovascular disease

Delayed ulcer healing Renal/hepatic impairment Rash

ECASA ibuprofen diclofenac diclofenac/misoprostol naproxen meloxicam celecoxib

AdviiTMMotrin™

Volta~enTM

Contraindications

Adverse Effects Hepatotoxicity Overdose>10 g Potentiates Warfarin

D1!ler treatments

Comments

Combination analgesics (acetaminophen + codeine)

Enhanced short term effect compared to acetaminophen alone 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

COMMONLY USED hydroxychloroqulne $

Plaquenil'M

400-600 mg 00 initially Retinal disease, G6PD deficiency 200-400 mg 00 maintenance

GI symptoms, macular damage, neuromyopathy, skin rash

sulfasalazine $

Salazopyrim™ Azulfidine™ (US)

1000 mg bid

Sulfa/ASA allergy, kidney disease, G6PD deficiency

GI symptoms, headache, leukopenia, rash

methotrexate $

Rheumatrex'M FolexiMexate'M

qweekly 7.5-25 mg PO/IM/SC

Bone marrow suppression, liver disease, significant lung disease, immunodeficiency, pregnancy, EtOH abuse

Urticaria, GI symptoms, tubular necrosis, myelosuppression, cirrhosis, pneumonitis, oral ulcers

gold !injectable) $

Solganal'M Myocrysine'M

weekly or monthly injections lBO, kidney/liver disease

NOT COMMONLY USED cyclosporine $$

Contraindications

Adverse Effects

Rash, mouth soreness/ulcers, proteinuria, marrow suppression

Kidney/liver disease, infection, hypertension

Bleeding, hypertension, decreased renal function, hair growth, tremors

gold (oral! $

lBO, kidney/liver disease

Diarrhea, rash, stomatitis

azathioprine $

Kidney~iver

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 hematologic/kidney disease

Rash, loss of taste/appetite, GI symptoms, nephritic syndrome

NEWER DMARDs (Biologicals)

disease

MECHANISM OF ACTION Inhibits pyrimidine synthesis and has antiproliferative activity

leflunomide $$$

Arava™

10-20 mg PO 00

etanercept $$$

Enbrer M

25 mg biweekly or 50 mg weekly SC mjectlons

FUSion protem ofTNF receptor and Fc portion of IgG Decreases number of active joints by 50% from baseline after 6 months

infliximab $$$

Remicade'M

3-5 mg/kg IV q Bweeks

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, 2weeks apart

Causes B cell depletion, binds to CD20

$$$

Dr.JKR

Toronto Notes 2008

Summary Key Questions

RH28 Rheumatology

Summary Key Questions Answers

QUestions

1.

List 6signs of osteoarthritis on physical examination.

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

2.

What are 4radiological hallmarks of OA?

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

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?

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.

4.

What percentage of patients with RA are rheumatoid factor positive?

60-80%

5.

Name 5poor prognostic features of RA

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

6.

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

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

7.

Which antibody is most sensitive for the diagnosis of SLE?

ANA 198% sensitivel

8.

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

Hydralazine, isoniazid, procainamide, chlorpromazine and methyldopa

9.

Listthe three commonest manifestations of APS.

Thromboembolic events, recurrent spontaneous abortions, thrombocytopenia

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

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.

11.

il iil iii) ivl vi

List the 5diagnostic criteria for polymyositis/dermatomyositis.

progressive symmetric proximal muscle weakness elevated muscle enzymes (CK, aldolase, LoH, AST, All) EMG changes muscle biopsy typical rash of dermatomyositis (required for the diagnosis of oMI

Definite PM/OM if fulfill 4criteria; probable if fulfill 3criteria; possible if fulfill 2criteria 12.

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

Dry eyes, dry mouth, and inflammatory arthritis.

13.

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

Non-Hodgkin's lymphoma.

Dr.JKR

Toronto ;'\Totes 2008

Summary Key Questions

Questions

Answers

14.

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

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

To diagnose Wegener's aminimum of 2of the above criteria are required. 15.

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

>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

16

List the features for the diagnosis of Giant Cell Arteritis.

il iii iii) ivl

17.

List the differential diagnosis of an elevated ESR.

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

18.

What are the common joints involved in ankylosing spondylitis?

SI, hip, shoulder

19.

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

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

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?

age >50 yrs temporal artery tenderness or decreased pulse ESR >50 abnormal artery on biopsy

GI infec~ons - Shigella, Salmonella, Campy/obacter, Yersinia; GU infections - Chlamydia, Mycoplasma species. il ii) iii) iv) v)

asymmetric oligoarthritis arthrrtis of DIP joints wrth nail changes destructive Imutilansl arthrrtis symmetric polyarthritis sacroilirtis and spondylitis

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

23.

What are the common preciprtants of gout attacks?

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

24.

List 3risk factors for the development of pseudogout.

Old age, advanced OA, and neuropathic joints

25.

What are the common srtes of involvement in pseudogout?

Knee, polyartlcularwrisl. MCP, 1st MTP

26.

What is the differential diagnosis of acute monoarthritis?

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

27.

What are the tender point sites in fibromyalgia?

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

28.

What are the features for the diagnosis of polymalgia rheumatica?

>411, prompt response to low-dose corticosteroids.

Age >50, bilateral aching/morning stiffness for 1month, ESR

Dr.JKR

Rheumatology RH29

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. A comparison of etanercept and methotrexate in patients with early rheumatoid arthri· tis. N Engl 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