Rheum A To Logy

Rheumatology
Unprotected copy
By: Dr.JKR
Jkr336@hotmail.com
Dr.JKR
RH Rheumatology
Justine Cohen, Amanda Mayo and Julia Warden, chapter editors

Lawrence Aoun and Sam Silver, associate editors
Jeremy Adams, EBM editor
Dr. Heather McDonald-Blumer and Dr. Dana Jerome, staff editors
Basic Anatomy Review 2 Summary of Arthritic Disease 26
Basics of Immunology 2 Clinical Approach to Arthritis 26

Immune Mechanisms of Disease
Immunogenetics and Disease Common Medications 27
Differential Diagnoses of Common ..... 3 Summary Key Questions 28

Presentations
References 30
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)

Vasculitides 15
Predominantly Cutaneous Vasculitis
Wegener's Granulomatosis
Polyarteritis Nodosa (PAN)
Giant Cell Arteritis (Temporal Arteritis)

Investigations 17
Seronegative Rheumatic Diseases . ... .18

Ankylosing Spondylitis (AS)
Reactive Arthritis (ReA)
Psoriatic Arthritis (PsA)
Inflammatory Bowel Disease (IBD)
Undifferentiated Spondylopathy
Crystal-induced Arthropathies 22
Gout
Pseudogout (Chondrocalcinosis)
Synovial Fluid Analysis
Non-Articular Rheumatism 24
Polymyalgia Rheumatica
Fibromyalgia
Toronto Notes 2008 Rheumatology RHI
Dr.JKR
RH2 Rheumatology Basic Anatomy ReviewlBasics of Immunology Toronto Notes 2008
Basic Anatomy Review
erosion
Bursa
Synovial Cartilage
membrane destruction
Synovial
~ Synovitis
fluid
Tendon Cartilage Effusion
CartjlageU-roi;:::~:=:;~J Osteophyte particle
Cartilage
destruction
Loss of
joint space
~_.iUjOintspace
narrowing
Normal Joint Degenerative Joint Infiammatory Joint
©Frances Yeunq 200S; revised by Desmond Ballance 2006
Figure 1. Structure of normal, degenerative and inflammatory joint
Basics of Immunology
Immune Mechanisms of Disease

------"-------
• fundamental principles of pathogenesis of autoimmune diseases
• disease results from a failure to discriminate between self and non-self
• autoreactive T cell is a common effector of many of these diseases
• certain HLA haplotypes are associated with increased susceptibility to disease
(see Table 2)
• activated immune system against self --+ cell damage/destruction --+ altered
cell function
• mechanisms of immunologically mediated disorders (4 types of immune reactions):
i. anaphylactic (type I)
• formation of IgE -. release of mediators from basophils/mast cells
• diffuse inflammation
• e.g. asthma, allergic rhinitis, anaphylaxis
ii. cytotoxic (type II)
• formation of antibody -> deposit and bind to Ag on cell surface --+
phagocytosis or lysis of target cell
• e.g. autoimmune hemolytic anemia, Goodpasture's syndrome, Graves'
disease, pernicious anemia
iii. immune complex (type III)
• Ag-Ab complexes form --> activate complement --+ attracts inflammatory
cells anet release of cytokines
• e.g. SLE, PAN, post-streptococcal glomerulonephritis
iv. cell-mediated/delayed hypersensitivity (type IV)
• st'nsitized T cells' release of cytokines and T-cell mediated cytotoxicity
• e.g. contact dermatitis
Immunogenetics and Disease

• cell surface molecules called human leukocyte antigen (HLA) or major
histocompatibility complex (MHC) playa role in mediating immune reactions
• discrete domains of hypervariability within MHC molecules appear to represent
"susceptibility determinants"
• there are three classes of MHC; the gt'nes encoding them are on chromosome 6
Dr.JKR
Toronto Notes 2008 Basics of Immunology/Difterential Diagnoses of Common Presentations 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 Recognized by CD4+ (helper)

(mononuclear phagocytes, Bcells, others) Tlymphocytes
III Complement In plasma Chemotaxis, opsonization,

components lysis of bacteria and cells
Table 2. HLA-Associated Rheumatic Disease

HLAType Associated Conditions Comments
827 Ankylosing spondylitis In AS, relative risk = 70-90

Reactive arthritis In reactive arthritis, relative risk = 40
Psoriatic arthritis Psoriatic also associated with B38
IBD arthropathy (spine)
DR4, DR1 Rheumatoid arthritis 93% of patients
DR3 Sjogren's syndrome DR3 associated with many non-rheumatic conditions

SLE (Celiac disease, Type 1 DM, Graves' disease,
Rheumatoid arthritis Chronic active hepatitis)
Differential Diagnoses of Common

Presentations o
Table 3. Differential Diagnosis of Joint Pain

Monoarticular Polyarticular Non-articular
~'
Infectious (see Infectious Diseases, 10221 • Infectious • Musculoskeletal
Bacterial Lyme disease Tendonitis Joint Pain Causes
Mycobacterial Bacterial endocarditis Bursitis SOFTER TISSUE
Fungal Septicemia Strain Sepsis
Viral Gonococcus FibromyalgialPMR
OA
Crystal-induced Viral!EBV, parvovlrusi • Neurological involvement
Gout Spinal stenosis/spondylolisthesis Fracture
• Post-inlectious
CPPD Rheumatic fever Degenerative disc disease Tendon/muscle
Hydroxyapatite Reactive arthritis Cauda equina syndrome Epiphyseal
Hemarthrosis Enteric infections Neoplasm Referred
Trauma/fracture • Inflammatory Thoracic outlet syndrome Tumour
Anticoagulants Seropositive (CTD) • Vascular Ischemia
Bleeding diatheses Seronegative Intermittent claudication Seropositive arthritides
Neoplasm Seronegative arthritides
Inflammatory
Urate (gout)/other crystal
Seropositive ICTD)
Extra-articular rheumatism
Seronegative
Degenerative (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 Oligoarthritis
• Ankylosing spondylitis • Seronegative disorders Septic Arthritis is a Medical
• Rheumatoid arthritis • Psoriatic arthritis Emergency! Consider empiric
• Polymyalgia rheumatica • Reactive arthritis antibiotic treatment until septic
• Osteoarthritis • Infectious arthritis
arthritis is excluded by history,
• Crystal-induced arthritis
physical exam and synovial fluid
Small Joint Polyarthritis analysis. (see Infectious Diseases,
• Seropositive disorders (RF+, ANA+) • Psoriatic arthritis ID22)
• Psoriatic arthritis • Tophaceous gout
Dr.JKR
RH4 Rheumatology Differential Diagnoses of Common PresentationslDegenerative Arthritis: Osteoarthritis Toronto Notes 2008
Table 5. Seropositive vs. Seronegative Rheumatic Diseases

Seropositive Seronegative
Demographics M>F
Peripheral Arthritis Symmetrical Usually larger joints, lower extremities
Small and large joints (psoriatic arthritis may be the exception)
DIP less involved Dactylitis
Enthesitis
DIP in Psoriatic arthritis
Pelvic/Axial Disease No (except for C-spinel Yes
Enthesopathy No Yes
Extra-Articular Nodules Iritis 1= Anterior Uveitisl
Vasculitis Oral ulcers
Sicca GI
Raynaud's phenomenon GU
G1ucoumine therapy fvr treating osteoarthritis Dermatological features
(TowheedTE, Maxwell K,AnastassiadesTP, et al.
Cochrane Dat1Jbase ofSystemic Reviews 2005, Issue 2.
Art. No.: COO02946. DOl: 10,1002114651858. COOO2946. Extra-Articular Features
pub21 • consider skin and appendages, eyes, lungs, cardiac, pulmonary, CI, CU, neurologic,
Study: Meta·analysis of 20 RCTs1n=27501 examining
the efficacy of glucosamine on OA. psychiatriC
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 Degenerative Arthritis: Osteoarthritis
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 Definition
pain, stiffness and function subscalesl were found
between glucosamine and ~acebo when on~ studies with
• primary (idiopathic)
adequate allocation concealment were included.There was • most common, of unknown etiology
evidence to suggest that glucosamine may ~ow the • secondary
radiolog~ progression of OA at 3years. Glucosamine had • post-traumatic or mechanical
an excellent safety profile.
Conclusion: Glucosamine appears helpful for pain when • post-inflammatory (e.g. RA) or post-infectious
all studies (low quality and older studiesl are included. heritable skeletal disorders (e.g. scoliosis)
However, when on~ the higher quality studies are endocrine disorders (e.g. acromegaly, hyperparathyroidism, hypothyroidism)
included, there is no longer adifference between metabolic disorders (e.g. gout, pseudogout, hemochromatosis, Wilson's disease,
gluoosamine and placebo. Glucosamine was very well
tolerated with low toxicity. Rotta prepara1ion of ochronosis)
glucosamine may be of some benefit. • neuropathic (also known as Charcot joints)
• atypical joint trauma due to loss of proprioceptive senses (e.g. diabetes,
MelHnaIysis: Chondroitin flIr osteoarthritis 01 tlle syphilis)
knee and hip avascular necrosis (e.g. fracture, steroids, alcohol, gout, sickle cell)
(Annals of Intemal Medicine, 17 April, 2001 Volume
146(81:~1 • other (e.g. congenital malformation)
Study: Meta-analysis of 20 RCTsIn=3Il46l examining the
efficacy of chondroitin on OA. Etiology and Pathophysiology
Results: The analysis of this review was hampered by
~gnificant trial heterogeneity. Tria~ with poor • abnormal physical forces lead to altered joint function and damage
methodology (small numbers, inadequate randomization • primary event is deterioration of articular cartilage due to local biomechanical factors
concealment no intention to treat analysisl showed larger and release of proteolytic and collagenolytic enzymes
effect sizes in lavour of glucosamine than more recent • OA develops when cartilage catabolism> synthesis
lna~.l'ihen the authors analyzed on~ the newer and
more robust trials, an effect~ze of-o.3 (095%: -0.13 to • loss of proteoglycans and water exposes underlying bone
0.071 was generated. • abnormalloca1 bone metabolism further damages joint
Conclusion: There ~ high quality evidence to suggest • synovitis is secondary to cartilage damage therefore may see small effusions in OA
there is no difference between chondroitin and placebo.
Chondroitin should be disregarded from routine use in
clinical practice. Epidemiology
• most common arthropathy (12% of age 25-74)
• increased prevalence with increasing age (35% of 3D-year olds, 85% of 8D-year olds)
Risk Factors
• genetic predisposition, advanced age, obesity (for knee OA), female, trauma
Signs and Symptoms
• signs and symptoms localized to affected joints (not a systemic disease)
• pain is often insidious, gradually progressive, with intermittent flare-ups and
remissions
Table 6. Signs and Symptoms of OA
Symptoms Signs
• hand (DIP, PIP, 1st CMC) joint pain with motion; relieved with rest joint line tenderness; stress pain
short duration of stiffness «1/2 hr) after immobility bony enlargement at affected joints
• hip
• knee joint instability/buckling malalignment/deformity (angulation)
• 1st MTP loss of function limited ROM
• L-spine (L4-L5, L5-S1) joint locking due to "joint mouse" (bone or cartilage fragment) periarticular muscle atrophy
• C-spine crepitus on passive ROM
• uncommon: ankle, shoulder, inflammation mild if present
elbow, MCp, rest of wrist
Joint Involvement
Figure 2. Common sites of
• any joint can be affected especially knee, hip, hand, spine (shoulder, elbow, wrist and
involvement in OA ankle are less common)
Dr.JKR
Toronto Notes 2008 Degenerative Arthritis: Osteoarthritis/Seropositive Rheumatic Diseases: Connective Tissue Disorders Rheumatology RH5
• hand
• DIP (Heberden's nodes = osteophytes ~) enlargement of joints) '1.,
• PIP (Bouchard's nodes) (see Figure 3) OA of MCP joints can be seen in
CMC (usually thumb squaring) hemochromatosis or chondrocalcinosis.
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
Bouchard's node
• 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 Heberden's
• very common especially L4-LS, L5-S1 node
• degeneration of intervertebral discs with possible disc herniation and facet joint
degeneration
• reactive bone growth can contribute to neurological impingement (e.g. sciatica, Figure 3. Bouchard's and
neurogenic claudication) or listhesis (slippage)
• cervical spine Heberden's nodes
• commonly presents with neck pain, especially in lower cervical area
Investigations AcoolmIed trial martl1rosCOtJic ~ry for osteoar1hri-
• blood work lis of the knee
• normal CBC and ESR IN Engl JMed2002;347~1-81
• negative RF and ANA Sludy. Randomized, double-blind, placebo·controlled
• synovial fluid --) non-inflammatory (see Table 19, RH24) trial with follow up of2years.
• radiology (4 hallmark findings, see sidebar) Plli8ms:l80 patients s75 years (mean age 52yrs,!ll%
male, 60% whnel with o~eoartflritis of tile knee and at
Treatment least moderate knee pain despne maximal medical tiler·
• presently no treatment alters the natural history of OA apy.
• non-pharmacological therapy 1nIlIIwnIion: Patients were randomiled to receive
• weight loss (minimum 5-10 Ibs.loss) arthroscopic debridemen~ artflroscopic lavage, or
• rest/low-impact exercise placeoo surgery Is~n inci~ons and ~mulated debride-
• physiotherapY' with heat, massage, exercise programs mentwithout insertion of tile artflroscopel.
• occupational therapy --) aids, spfmts, cane, walKer, bracing Prin8Iy 0uIt0me: Sell reponed scores on pain and
• medical therapy function scales, and an objective test of wal~ng and
• NSAIDs, acetaminophen (see Common Medications, RH27) stair climbing.
• hyaluronic joint injections (Hyalgan™, Synvise™, etc.) IIesu/Ir There was no difference between groups in
• surgical treatment pain relief at any time point in 2years of follow up.
• joint debridement, osteotomy, total and/or partial joint replacement, fusion 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·
Table 7. Features of Seropositive Arthropathies comes were equivalent in patients receiving
artflroscopy arM! sham surgery for osteoartflritis of the
Clinical Features Rheumatoid Arthritis Systemic Lupus Erythematosus Scleroderma Dermatomyositis
knee, Furthermore, objective measures of function
History Symmetrical Multisy~emic disease Raynaud's, stiffness of Heliotrope rash [eyelidsl, favoured tile placebo group.
Po~anhritis Ismail joint rash, photosensitivity, Raynaud's, alopecia, fingers, skin tightness, Gonron's papules, macular
involvementl
AM~iffness[>lhrl
cardiac and pulmonary serosnis, CNS symptoms,
glomerulonephritis
heanburnJdysphagia
pulmonary hypenension,
renal dysfunction
erythema and poikiloderma
Ishoulders, ned< and che~l,
proximal muscle weakness
± pain
'" ,,
•.l - - - - - - - - - - - - .
Physical EftusedJoints Confirm historical findings Itypically smalilointsi S~n tightness on dorsum Rasn, proximal muscle weakness
Examination Tenosynovtis ± effused joints Ican be minimal. look for of hand, facial skin The Radiographic Hallmarks of OA
Nodules soft tissue swellingl tightening, telangiectasia, 1. joint space narrowing
Bone-on-bone crepitus calcinosis, non-effused joint 2. subchondral sclerosis
Laboratory 3. subchondral cyst formation
Non-specific Increased ESR in 50·60% Increased ESR Increased ESR Possible increased ESR 4. osteophytes
Increased platelets Decreased platelets Increased platelets Normal platelets
Decreased Hb Decreased Hb lautOimmunel Decreased Hb Decreased Hb
Decreased WBC {Felty'sl Decreased WBC !leukopenia, Iymphopenial NormalWBC NormalWBC
Specific RF +ve in -80% ANA tve in 9B%
Anti-SM tve in 30%
ANA +VB in ,90%
Anti-topoisomerase 1
CPK elevated in 80%
ANA +Ve in 33%
',
'" . ) - - - - - - - - - - - - - ,
Anti-<lsDNA +ve in 50·70% Idiffusel anti-Jo-1,anti-Mi·2
Decreased C3, C4, total hemolytic complement Anti-centromere Muscle biopsy -key for diagnosis CREST Syndrome
False positive VORL lin lupus subtypes) lusually in CREST. see sidebarl EMG Calcinosis - calcium deposits on skin
Increased PTT lin lupus subtypes; e,g. antiphospholipid Abl MRI Raynaud's phenomenon
Synovial Fluid Inflammation Mild inflammation with +ve ANA Not specfic Not specific Esophageal dysfunction - acid reflux
leukocytoSis [>10,0001 Sclerodactyly - tightening of skin
Radiographs Demineralization Nondewuctivelnonerosive ± pulmonary fibrosis ±esophageal dysmotility Telangiectasia - superficial dilated
Symmetridconcentric joint ± osteoporosis, osteopenla ± esophageal dysmotility ± inter~itiallung disease blood vessels
space narrowing ± sofl tissue swelling :!:calcinosis
Erosions of subchondral bone
Absence of bone repair
Dr.JKR
RH6 Rheumatology Seropositive Rheumatic Diseases: Connective Tissue Disorders Toronto Notes 2008
o
Rheumatoid Arthritis (RA) --'''-- ...J
.... ,,
.l------------,
Definition
• chronic, symmetric, erosive synovitis of peripheral joints (i.e. wrists, Mcr joints, and
MTP joints)
Common Presentation • characterized by a number of extra-articular features
• Morning stiffness >30 min. improving
with use
Table 8. Diagnostic Criteria: RA diagnosed if 4 or more of the following 7 criteria present
• Symmetric joint involvement
(American Rheumatism Association, 1987)
• Initially involves small joints of hands
and feet Criteria Definition
• Constitutional symptoms
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
.... ,,.l------------, 3. Arthritis of hand joints

joints are PIp, MCp, wrist. elbow, knee, ankle, MTP
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
Criteria are 91·94% sensitive and 89%
specific for RA. 5. Rheumatoid nodules Subcutaneous nodules over bony prominences, extensor
surfaces or in juxta·articular regions
6. Serum RF Found in 60-80% of RA patients
7. Radiographic changes Erosions or periarticular osteopenia, likely to see earliest
changes at ulnar styloid, 2nd and 3rd MCP and PIP joints
Etiology and Pathophysiology

• autoimmune disorder, unknown etiology
• hallmark of RA is hypertrophy of the synovial membrane
• outgrowth of activated rheumatoid synovium (pannus) into and over the
articular surtace results in destruction of articular cartilage and subchondral
bone
• two theories dttempt to explain chronic remissions and exacerbations seen in RA
• sequestered Ag
• during inflammation, immune complexes (lCs) are deposited at
cartilagt'-bone junction, which is an avascular area --+ rcs remain free of
reticulo-endothelial system but are released as further cartilage breaks
down --+ triggers cascade
• molecular mimicry
• PIP
• MCP
• cartilage damage --> altered configuration of cartilage resembles
• wrist. not 1st CMC offending agent --+ triggers cascade
• elbow
• shoulder Unknown Ag(s)
•
•
knee
ankle
~
Antigen presenting cell
•
•
MTP
C-spine ~
Figure 4. Common sites of joint
involvement in RA
Osteoprotegerin ligand
I r
i
B- and T-cell ~putrophil Promotes Proliferation

~
Osteoclastogenesis
Activation of complement
cascade accumulation recruitment inflammation of synovial I
rblaslS ",~ t
~
in rOVium ~
Accumulation of PMNs; Release of Release of Pannus fonnation Matrix
inflammatory symptoms inflammatory elastase + protease \ metalloproteinasps
mediators ~ I
~
Degradation of In!a':'ion of cartilage
peptidoglycan /
of cartilage
~ I
CartIIace and bone destruction ..... - - - - - - - - - - '
Figure 5. Proposed Pathogenesis of RA
Dr.JKR
Toronto Notes 2008 Seropositive Rheumatic Diseases: Connective Tissue Disorders Rheumatology RH7
Epidemiology
• incidence 0.6-2.9 per 1,000 population/yr, prevalence 1% of adult population
• F:M = 3:1; age of onset 20-40 yrs
• genetic predisposition: HLA-DR4/DRI association (93% of patients have
either HLA type)
Signs and Symptoms

• variable course of exacerbations and remissions
• morning stiffness >1 hr, improves with use, aggravated by rest
• symmetric joint involvement (see Figure 4)
• signs of disease activity: synovitis (assessed by tender and swollen joint count),
elevated serum markers of inflammation such as ESR or CRP, decreased grip
strength, increased pain
• signs of mechanical joint damage: loss of motion, crepitus, instability, deformity
• constitutional symptoms: profound fatigue; rarely myalgia or weight loss
• extra-articular features (see Figure 7) and radiographic damage
• limitation of function and decrease in global functional status
Classification of Global Functional Status in RA

(American College of Rheumatology, 1991)
• Class I: able to perform usual ADLs (self-care, vocational, avocational)
• Class II: able to perform self-care and vocational activities, restriction of
avocational activities
• Class III: able to perform self-care, restriction of vocational and avocational activities
• Class IV: limited in ability to perform self-care, vocational, avocational activities
Complications of Chronic Synovitis

• joint deformities (see Figure 6)
• swan neck deformity, boutonniere deformity
• ulnar deviation of MCP; radial deviation of wrist joint
ClaW~To.e
~
• hammer toe, mallet toe, claw toe
• flexion contractures
• atlanto-axial and subaxial subluxation
• neurological impingement (long tract signs)
• difficult intubation
.~
• limited shoulder mobility, C-spine instability, spontaneous tears of the rotator cuff HammerToe
leading to chronic spasm
• tenosynovitis ---> may cause rupture of tendons
• Carpal Tunnel Syndrome
• ruptured Baker's cyst (outpouching of synoviurn behind the knee); presentation
similar to acute thrombophlebitis
• anemia of chronic disease
• decreased functional capacity and early mortality
Extra-Articular Features (EAF)

• classified in terms of the underlying process: either vasculitis or a lymphocytic infiltrate
Extra-Articular Features Figure 6. Joint deformities

I
... ' ~
Vasculitis Lymphocytic infiltrate
episcleritis, scleritis rheumatoid nodules 9)--------------,
periungual infarction pulmonary fibrosis
cutaneous ulcers pleural effusion/pleuritis Poor prognostic features of RA include
palpable purpura pulmonary nodules young age of onset, high RF titer, elevat·
ed ESR, activity of >20 joints, and pres-
peripheral neuropathy peri-/myocarditis, valvular disease
enceofEAF.
• sensory: stocking-glove Hashimoto's thyroiditis
• mononeuritis multiplex Sjogren's syndrome
Felty's syndrome
hepatosplenomegaly ... '9~ · } - - - - - - - - - - - ,
Figure 7. EAF of RA
Common Syndromes in RA
Treatment
1. Sjogren's syndrome (sicca complex -
• goals of therafY
• contro disease activity dry eyes and mouth)
• relieve pain and stiffness 2. Caplan's syndrome (multiple
maintain function and lifestyle pulmonary nodules and
• prevent or control joint damage pneumoconiosis)
key is early diagnosis and early intervention with disease modifying 3. Felty's syndrome (arthritis,
anti-rheumatic drugs (DMARDs) splenomegaly, neutropenia)
Dr.JKR
ea.n- rlT..-Str8lIgies i1 EJIt1 A) Education, occupational therapy, physiotherapy, vocational coun-

hIIlIlDidArll1rilis selling
(Ann Intern MIld20 March 2007:146(61) • therapeutic exercise program (isometrics and active ROM exercise during flares,
Slud(.RCT of 5(1 patiants comparing 4different aquatic/aerobic/strengthening exercise between flares), assistive devices and
treatment strategies for early rheumatoid arthritis. patient education
hrIrwliliIr
Group 1: SequellliaJ Monotl1erapy witI1 traditional
• patients may need job modification, time off work or change in occupation
DMARDs • The Arthritis Society (Canada) and Arthritis Foundation (U.s.) provide resources
Group 2: Step-Up Combination Therapy and programs
Group 3: Initial Cllmbination Therapy witI1 pred-
nisone (11qJ dosel B) Medical
Group 4: Initial Combination Therapyl'lith inftiximab • NSAIDs, DMARDs and steroids are the mainstay of pharmacological therapy
IIlIruk Patients in groups 3and 4responded faster
and had signifu:antly greater overall change in phys-
ical function scoras after the first year of treatment
1. Reduction of Inflammation and Pain
By end of the second year, groups 1and 2had • NSAIDS
echieved asimilar response to groups 3and 4. • individualize according to efficacy and tolerability
Groups 3and 4also showed signifu:antly less radio- • contraindicated or cautioned in some patients
logic progression of their disease over 2years than
• analgesics
groups 1and 2. There WIlre no signifu:ant differ-
ences in tDxicity levels belween the 4groups.
• add acetaminophen ± opioid pm for synergistic pain control
CciIII:ilrilIIIlnitiai combination therapy witI1 pred- • corticosteroids
nisone or inftiximab results in faster response rates. • local
Whether faster initial response rates leads to better • intra-articular injections to control symptoms in a specific joint
Iong~enn disease outcomes is not yet studied. • 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
' ~
.... .l-------------, 2. Disease Modifying Antirheumatic Drugs (DMARDs)
• combination DMARDs are the standard of care
Only DMARDs (not analgesics or NSAIDsI • start DMARDs within 3 months of diagnosis to decrease disease
a~er the course of RA! 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)
1111" w-.g
trIIlIn,
illiIinab, CIIlllbiledwilh bIckfound
peliInII wiIh rl1elIIIIlIIid arMs
• many DMARDs have potential toxicities that require periodic monitoring
• if repetitive flares, progressive joint damage, or ongoing disease activity after
n lIlilUI COlIIIItidiliIIISTAIlII 3 months of maximal therapy . • change or add other D'MARDs
IAnhritis Rheum 2lXE;54:11lMi1
_Randomized, placebiH:ontrolied muJticentre trial • mild and early stages:
1'IIiIJIr;11Mpa1ients lmean age 52yrs, 110% femalel • hydroxych1oroquine or sulfasalazine monotherapy preferred
wiIfJ active moderate to severe rheumato~ arthritis • moderate to severe disease (especially if unfavourable prognostic factors):
despite treatment I'fith methotrexate. • methotrexate is the gold standard
~Pa1ientswere randonlaed to receive infu- • single regimen with methotrexate or leflunomide (Arava TM)
sions of ~acebo, infIiximab dosed at3 m¢g, Of inftix-
imab dosed at 10 ffi9\g at 0, ~ 6, and 14 weBb, in addi-
• combination therapy: methotrexate + sulfasalazine + hydroxychloroquine;
tion to mel!lolrexate tflerapy. methotrexate + cyClosporine; methotrexate + leflunomide
I'riw(IUeomc Incidence of serious infection wilfJin • biological DMARDs: indicated if persistent disease activity (see Common
22 weeks of randomization. Medications, RH27)
"'Compared I'fith the placebo group, the relative
risk of devellJIling serious inleclion was 1.0 195%CI 03· C) Surgical Therapy
11, P~.9951 in patienls receiving intiximab at 3m¢g
and l' \95%CI1.H9, P=6.0131 in patienls receiving
• synovectomy: debridement and/or removal of inflamed synovium from
inflixinab at 10 n¢g.ln addilion,31% of patients
individual joints (surgical or radioactive)
receiving ilftiximab at 3111(l1kg and 32% of patients • joint replacement (hip, shoulder, knee)
receMng infl~imab at 10m!i\g were able to achieve • joint fusion (wrist, thumb, ankle, C-spine)
remission at 22 WIleks compll'ed wiIfJ on~ 14% of those • reconstruction (tendon repair)
receiving ~acebo (PdlJXII, NNT=5I. • surgery indicated for muftiplc DMARD failure, unacceptable pain, or structural
CIJrxaD: Therapy I'fith inftilinab 3mii\g does not joint damage
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.
Dr.JKR
Toronto !IIotes 2008 Seropositive Rheumatic Diseases: Connective Tissue Disorders Rheumatology RH~
Systemic Lu _
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 MD SOAP BRAIN
simultaneously (American College of Rheumatology, 1997 update) Malar rash Blood
Discoid rash Renal
Criteria Description Serositis Arthritis
Oral ulcers Immune
Clinical ANA Neurologic
Malar rash Classic "butterfly rash; sparing of nasolabial folds, no scarring Photosensitivity
Discoid rash May cause scarring due to invasion of basement membrane
Photosensitivity
Oral/nasal ulcers
Skin rash in reaction to sunlight
Usually painless
.... ~ ,
.1-----------,
Arthritis Symmetric, involving <2 small or large peripheral joints, non-erosive
Serositis Pleuritis or pericarditis Radiographically, unlike RA, the
Neurologic disorder Seizures or psychosis arthritis of SLE is non-erosive,
Laboratory
Renal disorder Proteinuria 1>0,5 g/day or 3+1
Cellular casts IRBC, Hb, granular, tubular, mixedl
Hematologic disorder Hemolytic anemia, leukopenia, lymphopenia, thromboctyopenia
Immunologic disorder Anti-dsDNA Ab, anti-Sm Ab
Antiphospholipid antibodies based on the finding of serum anticardiolipin Ab,
lupus anticoagulant, or false positive VDRL
Antinuclear antibody lANA) Most sensitive test (98%)
Note: "4, 7, 11" rule • 4 out of 11 criteria (4 lab, 7 clinical) for diagnosis

• 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 gnvironment
Stress. viruses. sun
• prepubertal and postmenopausal women have similar incidence to men Genetic + Hormonal
• men with SLE have higher concentrahon of estrogemc metabolites
HLA~
• infection T-cell, '( Drug,
• viral (nonspecific stimulant of immw1e response)
• drugs
• anticonvulsants (phenytoin) Form<ttion of
• antihypertensives (hydralazine) / Auto-Ab ~
Cytotoxic Ab Immune complexes
• antiarrhythmics (procainamide)
• isoniazid (INH) +
Cell damage/death
+
Jnl1ammatiuTI
• anti-histone antibodies are commonly seen in drug-induced lupus
• oral contraceptive pills associated with exacerbation 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 Raynaud's Phenomenon
• vascular Vasospastic disorder characteristically
• Raynaud's phenomenon (see sidebar), thrombosis, vasculitis, livedo reticularis causil\g discolouratiol\ of fil\gers and
(mottled discolouration of skin due to narrowing of blood vessels, toes (white7blue7red),
characteristic lacy or net-like appearance) Classic triggers: cold and emotional
stress,
Dr.JKR
RHIO Rheumatology Seropositive Rheumatic Diseases: Connective Tissue Disorders Toronto Notes 2008
• dennatologic
• maculopapular rash, photosensitivity, panniculitis (inflammation of
subcutaneous fat and muscle tissue), alopecia (hair loss), urticaria, purpura,
oral, nasal, genital ulcers
• ophthalmic
• conjunctivitis, episcleritis, keratoconjunctivitis, cytoid bodies (cotton wool
exudates on fundoscopy = infarction of nerve cell layer of retina)
• gastrointestinal
• pancreatitis, lupus enteropathy, hepatitis, hepatomegaly
• pulmonary
• interstitial lung disease, pulmonary hypertension, PE, alveolar hemorrhage,
pleuritis
• musculoskeletal
• arthralgias, arthritis, avascular necrosis, myositis
• neurologic
• depression, personality disorder, cerebritis, transverse myelitis, seizures,
headache, peripheral neuropathy
Investigations
Consider septic arthritis and avas- • serologic hallmark is high titer ANA detected by immunofluorescence
cular necrosis in patients with SLE • ANA has high sensitivity (98%) and therefore is a useful screening test, but poor
and joint pain. specificity
• anti-dsDNA Ab (dett'cted by Crithidia test, Farr radioimmunoassay) and anti-Sm Ab
are specific for SLE (95-99%)
• a drop in anti-dsDNA titer and normalization of serum complement (C3, C4) are
useful to monitor response to treatment in patients who are clinically and serologically
concordant
• lupus anticoagulant may cause clotting abnormalities and increased PTI
Treatment
• goals of therapy:
• treat early using the mildest form possible, then slowly withdraw therapy
• if high doses of steroids necessary for long-term control, use steroid-sparing
agents too, then taper if possible
• symptomatic treatment tailored to organ system involved and severity of disease
• patient education: use topical sunscreen, avoid UV light and estrogens
• NSAIDs ± gastroprotective agents for arthritis, pleurisy, pericarditis
• antimalarials for dermatologic and MSK manifestations, constitutional symptoms
(hydroxychloroquine if no serious internal organ involvement --> improves long tenn
control, prevents flares)
• topical steroids for rash
• systemic steroids for prevention of end organ damage secondary to inflammation
• bisphosphonates, calcium, vitamin D to combat osteoporosis
• steroid-sparing: azathioprine, cyclophosphamide, methotrexate, mycophenolate
• high-dose oral prednisone/IV methylprednisolone, IV cyclophosphamide for serious
organ involvement (e.g. cerebritis or SLE nephritis)
• all medications used to treat SLE require periodic monitoring for potential toxicities
[ Antiphospholipid Antibody Syndrome (APS)

Definition
• multisystem vasculopathy manifested by recurrent thromboembolic events,
spontaneous abortions and thrombocytopenia
• circulating antiphospholipid autoAbs (anticardiolipin Ab and lUpus anticoagulant)
interfere with coagulation cascade
• primary vs. secondary
• secondary APS develops in SLE, other connective tissue diseases, malignancy,
drugs (hydralazine, procainamide, phenytoin, interferon, quinidine), infections
(HIV, TB, hepatitis C, infectious mononucleosis)
• catastrophic APS
• fatal condition with sepsis, ARDS (acute respiratory distress syndrome),
MODS (multi-organ dysfunction syndrome), TIP (thrombotic
thrombocytopenic purpura)
Signs and Symptoms

• primary manifestation is venous or arterial thrombosis
• venous thrombosis --+ DVT, PE, renal and retinal vein thrombosis
• arterial thrombosis --+ ~troke(TlA, multi-infarct dementia, Ml,
valvular incompetencE', limb ischemia
Dr.JKR
Toronto Notes 2008 Seropositive Rheumatic Diseases: Connective Tissue Disorders Rheumatology RHll
• recurrent spontaneous abortions including first and second trimester fetal loss, .... ',
~}------------,
premature birth at <34 wks gestational age

Manifestations of APS
• hematologic abnormalities Thromboembolic events
• thrombocytopenia, hemolytic anemia, neutropenia Recurrent fetal loss
• skin Thrombocytopenia
• 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)

• idiopathic vasculopathy (not vasculitis) leading to atrophy and fibrosis of tissues
• intimal proliferation and media mucinous degeneration ---> progressive
obliteration of vessel lumen ---> fibrotic tissue
• resembles malignant hypertension
Epidemiology
• F:M = 3-4:1, peaking in 5th and 6th decades
• associated with HLA-DRI
• associated environmental exposure (silica, epoxy resins, toxic oil, aromatic
hydrocarbons, polyvinyl chloride)
SCLERODERMA
Localized~ ~Generalized
(no involvement of internal organs) (systemic sclerosis)
• mostly children and young adults ~ ~
Limited systemic sclerosis Diffuse systemic sclerosis
• skin sclerosis restricted to • widespread skin
hands, face, neck disease (proximal to wrist,
/ \ • 3rd to 4th decade can involve trunk), tendons
Morphea Linear • pulmonary hypertension common • early visceral
• hard oval patches 'Iine of thickened • CREST (see RH5) involvement (renal, pulmonary
on the skin skin fibrosis)
Figure 9. Forms of Scleroderma
Dr.JKR
Signs and Symptoms
Table 10. Clinical Manifestations of Scleroderma

System Features
Dermatologic Initial phase characterized by painless non·pitting edema

Progressive bilateral swelling of fingers, hands and feet leading to skin tightening
Characteristic face: mask·like facies with tight lip, beak nose, radial perioral furrows
Atrophy, ulcerations, hypo/hyperpigmentation, telangiectasias, calcinosis,
periungual erythema, pruritus
..... ' ~
.)------------,
Vascular Episodes (minutes to hours) of well·demarcated blanching and/or cyanosis of digits followed by
erythema (Raynaud's phenomenon), tingling and pain
Scleroderma is the most common cause Due to vasospasm following cold exposure or emotional stress
of secondary Raynaud's phenomenon. If severe, can result in infarction of tissue at fingertips"" digital pitting scars, frank gangrene or
autoamputation of the fingers or toes
Gastrointestinal (N90%) GI tract becomes arigid tube leading to decreased motility

Distal esophageal hypomotility t dysphagia
Loss of lower esophageal sphincter function'" GERD, ulcerations, strictures
Small bowel hypomotility"; bacterial overgrowth, diarrhea, bloating, cramps, malabsorption,
weight loss
Large bowel hypomotility..., pathognomonic radiographic finding on barium stUdy is large bowel
wide mouth diverticuli
Renal Mild proteinuria, creatinine elevation and/or hypertension are common

'Scleroderma renal crisis" (10·15%) may lead to malignant arterial hypertension, oliguria and
microangiopathic hemolytic anemia
Pulmonary Interstitial fibrosis, pulmonary HTN, pleurisy, and pleural effusions
Cardiac Left ventricular dysfunction, pericarditis, pericardial effusion, arrhythmias
Musculoskeletal Polyarthralgias "; polyarthritis affecting both small and large joints
Subcutaneous calcifications (calcinosisl
"Resorption of distal tufts" (radiological finding)
Proximal weakness 2° to disuse, atrophy, low grade myopathy
Endocrine Hypothyroidism common
Treatment
• patient education about precautionary measures (e.g. avoid cold)
• expectant treatment with methotrexate/cyclosporine (little evidence in the literature)
• symptomatic treatment
• gastroesophageal reflux disease (GERD): PPls are first line, then 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 Description
1. Progressive symmetric proximal muscle weakness Typical involvement of shoulders and hips
2. Elevated muscle enzymes Increased CK, aldolase, LOH, AST, ALT
3. EMG changes Short polyphasic motor units, high frequency repetitive
discharge, insertional irritability
4. Muscle biopsy Segmental fibre necrosis, basophilic regeneration,
perivascular inflammation and atrophy
5. Typical rash of dermatomyositis Required for diagnosis of OM

• 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
..... ',
~I--------------,
• early symptom is difficulty lifting head off pillow

• dermatological Signs of OM
• OM has characteristic dermatological features, found in children and adults, Gottron's papules and Gottron's
F>M sign are pathognomonic of OM
• Gottron's papules (occur in 70% of patients).
- 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
• 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
• 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
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
.... '. ,1 - - - - - - - - - - - , Diagnosis (SSASSS)
• Symptoms of dry eyes
ClusicTriad • Signs of dry eye - Schirmh test (to assess tear flow) or slit lamp exam with Rose
(Idantifiea 93'10 of Sjiigren'. Bengal stain
patientsl • Autoantibodies anti-Ro, anti-La, ANA, RF
• Dry eyes • Symptoms of dry mouth
• Dry mouth (dysphagia, xerostomial • Signs of dry mouth - Sialography
• Arthritis {small joint, asymmetrical, • Salivary gland biopsy: gold standard
nonerosivel
Note: Need 4 of the above criteria, one of which must be either autoantibodies or salivary
gland biopsy (sensitivity 95% - European Community Criteria)

• may evolve into systemic disorder and may lead to diminished exocrine gland activity
in respiratory tract and skin
Signs and Symptoms

• systemic manifestations:
• arthralgias, arthritis, subclinical diffuse interstitial lung disease, renal disease,
palpable purpura, systemic vasculitis
• results in "sicca complex": dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia)
Complications
• xerotrachea resulting in chronic dry cough
• Staphylococcus blepharitis: most common complication
• autoimmune thyroid dysfunction in 45% of patients
• vascular involvement leads to peripheral neuropahy (most common systemic
complication)
• glomerulonephritis
• lymphoma
Table 12. Signs and Symptoms of Sicca

Location Manifestation
Ocular Burning/dry/painful eye relieved by tears
Foreign body sensation (worse in evening)
Blepharitis
Oral Dry mouth - difficulty swallowing food without drinking
Rapidly progressive caries (secondary to decreased saliva volume and its antibacterial factors)
Erythema of hard palate and oral mucosa
Oral candidiasis, angular cheilitis (inflammation and fissuring at the commissures of the mouth)
'.,
Treatment
.... • good dental hygiene
.)--------------, • artificial tears or surgical punctal occlusion for xerophthalmia
Patients with Sjogren's syndrome are at • adequate hydration for xerostomia
higher risk of non·Hodgkin's lymphoma. • 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 Characteristic Features
Small vessel
• Non·ANCA·associated ·immune complexes
Predominantly cutaneous vasculitis ·also known as hypersensitivity~eukocytoclastic vasculitis
Henoch·Schiinleln purpura (see Pediatrics, P941 · vascular deposition of IgA causing systemic vasculitis (skin, GI, renall, seen
Essential cryoglobulinemic vasculitis

most frequently in childhood, usually self·limiting condition
, ',
~.)------------,
• ANCA-associated Churg·Strauss Triad

Wegener's granulomatosis Ic-ANCA >p-ANCA) -granulomatous inflammation of vessels of respiratory tract and kidneys, • Allergic rhinitis and asthma
most common in middle age, most present initially with symptoms of URTI • Eosinophilic infiltrative disease
Churg-Strauss syndrome -granulomatous inflammation of vessels with hypereosinophilia and
resembling pneumonia
150% ANCA positive) eosinophilic tissue infiltration, sometimes associated With p-ANCA or c-ANCA
• Systemic vasculitis
· other manifestations include coronary arterhis, myocarditis and neuropathy
Microscopic polyangiitis -pauci'lmmune necrotizing vasculitis, affecting kidneys Inecrotizing
170% ANCA positive, usually p-ANCA) glomerulonephritis), lungs (capillaritis and alveolar hemorrhage), skin
Medium-sized vessel
Polyarteritis nodosa -any age [average 40-50'sl, unknown etiology in most cases
·segmental non-granulomatous necrotizing inflammation
Kawasaki's lsee Pediatrics, P941 -Tlymphocyte response and granuloma formation
Large vessel -Tlymphocyte response and granuloma fomnation
Giant celi arteritis (temporal arteritis) -over 50 years of age, more common in women, inflammation predominantly of the aorta and
those arteries originating from it
Takayasu's arteritis · "pulseless disease; increased ESR, fever, night sweats, chronic inflammation, most often
the aorta and its branches, usually young adults of Asian descent, F>M
------
Other Vasculitides
Buerger's disease · also known as thromboangiitis obliterans, inflammation secondary to pathological clotting,
affects small and medium-sized vessels of distal extremities, most important etiologic factor is
cigarette smokmg, mnst common in Asian males, may lead to distal claudication and gangrene
Behcets disease -pathology: leukoclastic vasculitis, multisystem disorder presenting with ocular involvement,
recurrent oral and genital ulceration, venous thrombosis, skin and jOint involvement
Vasculitis mimicry ·cholesterol emboli, atrial myxoma
Predominantly Cutaneous Vasculitis

SMALL VESSEL NON-ANCA ASSOCIATED VASCULITIS
• subdivided into
• drug-induced vasculitis
• serum sickness reaction
• vasculitis associated with other underlying primary diseases
Dr.JKR
RH16 Rheumatology Seropositive Rheumatic Diseases: Vasculitides Toronto Notes 2008

• 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
o
Wegener's Granulomatosis
SMALL VESSEL ANCA-ASSOCIATED VASCULITIS
.... ',
9'\-------------,
Definition
• granulomatous inflammation of vessels that may affect the upper airways (rhinitis,
sinusitis), lungs (pulmonary nodules, infiltrates), and kidneys (glomerulonephritis,
Classic Features: renal failure)
• necrotizing granulomatous vasculitis • highly associated with cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA)
of lower and upper respiratory tract • incidence 5 per 100,000; more common in Northern latitudes
• focal segmental glomerulonephritis
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
• transformation from inflammatory prodrome (serous otitis media and sinusitis) to
full-blown vasculitic syndrome
Signs and Symptoms

• systemic
• malaise, fever, weakness, weight loss
• ENT
• sinusitis or rhinitis, nasoseptal perforation, saddle nose deformity, extension
into the orbit with proptosis, hearing loss
• pulmonary
• cough, hemoptysis, tracheobronchial erosion, pneumonitis, lung nodules,
infiltrations, cavitary lesions
• renal
• segmental necrotizing glomerulonephritis (vasculitis rarely seen)
• other
• joint, skin, eye complaints, vasculitic neuropathy
Investigations
• other tests include
• specific: ANCA (c-ANCA > p-ANCA)
• renal or lung biopsy
• general: anemia, leukocytosis, elevated ESR
• possible decline in c-ANCA and ESR used to monitor response to treatment in some
patients
Treatment
• prednisone 1 mg/kg for 6-12 months ± cyclophosphamide 2 mg/kglday PO for
3-6 months followed by high dose methotrexate (20-25 mg porsc weekly)
• consider biologic agents (infliximab, rituximab, IVIg) and plasmapheresis in systemic
disease resistant to corticosteroids plus cyclophosphamide
Dr.JKR
Toronto Notes 2008 Seropositive Rheumatic Diseases: Vasculitides/Seropositive Rheumatic Diseases: Investigations Rheumatology RH17
Polyarteritis Nodosa (PAN) .e...-. ~ _ [.

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 - - - - - - - - - - - ,
• focal panmural necrotizing inflammatory lesions in small and medium-sized arteries
• thrombosis, aneurysm or dilatation at lesion site may occur There is an association between
• healed lesions show proliferation of fibrous tissue and endothelial cells that may lead hepatitis Bsurface antigen
to luminal occlusion (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 '" ~ ~
,.l-----------,
• elevated Cr or BUN
• hepatitis B positive Consider PAN in a non-diabetic
• arteriographic abnormality (commonly aneurysms) patient with mononeuritis multiplex.
• biopsy of artery showing presence of granulocytes or macronuclear leukocytes
in the artery wall
Treatment
• prednisone 1 mglkglday ± cyclophosphamide 2 mglkglday PO
• :!: anti-viral therapy to enhance clearance of HBV
Giant Cell Arteritis (Temporal Arteritis)

LARGE VESSEL VASCULITIS
Signs and Symptoms
• temporal headaches ± scalp tenderness due to inflammation of involved portion of the Medical Emergency
temporal or occipital arteries Untreated, GCA can lead to per-
• sudden, painless loss of vision and/or diplopia due to narrowing of the ophthalmic or
manent blindness in 20-25%!
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 GCA CRITERIA
biopsy within 14 days of starting steroids, angiography Age >50, new headache, temporal artery
tenderness or decreased pulse, ESR over
Treatment 50, and abnormal artery biopsy. Presence
• if suspect GCA, immediately start high dose prednisone 1 mglkg in divided doses of 3or more criteria yields sensitivity of
tapering prednisone as symptoms resolve; highly effective in treatment and in 94%, specificity of 91%.
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 Differential Diagnosis of Elevated
• ESR (erythrocyte sedimentation rate) increases with the increase of acute phase ESR
reactants, and chronically, with increase in gamma globulins Rheumatoid arthritis, PMR, GCA, hypoal-
• C3, C4 often decrease in active SLE buminemia, anemia, muhiple myeloma,
• urinalysis to detect disease complications (proteinuria, active sediment) bacterial infections, malignancy. ESR
• serology: autoantibodies (Table 14, RH18) (and CRPI is insensitive for PM/DM, AS,
• synovial fluid analysis (Table 19, RH24) PSS, SLE, viral infections.
• radiology (plain film, CT, MRI, ultrasound, bone densitometry, angiography,
bone scan)
Dr.JKR
RH18 Rheumatology Seropositive Rheumatic Diseases: Vasculitides/Seronegative Rheumatic Diseases Toronto Notes 2008
Table 14. Autoantibodies and Their Prevalence in Rheumatic Diseases

Autoantibody Disease Normal Comments
RF RA80% <5% Autoantibodies IIgM >IgG >IgAI directed against Fe
Sjogren's 50% domain of IgG
SLE 20% 10-10% over age 65
Present in most seropositive diseases
Levels correlate with disease severity in RA
Non-specific; may be present in IE, tuberculosis, hep Cinfections,
silicosis, sarcoidosis
ANA SLE 98% <5% Antibodies against nuclear components

MCTD95% other CTDs IDNA, RNA, histones, centromere)
Sjogren's 70-90% 1:40 dilution found in 5-30% of the normal population
CREST 80% Sensitive but not specific for SLE
4 patterns:
11 Rim pattern in SLE
21 Homogenous (diffuse) pattern in SLE, RA, drug-induced lupus
31 Speckled pattern in SLE, PSS, RA, MCTD, Sjogren's, scleroderma
4) Nucleolar pattern in scleroderma
Anti-dsDNA SLE 50-70% 0% Specific for SLE

Levels correlate with disease activity
Anti-Sm SLE <30% 0% Specific but not sensitive for SLE
Anti-Ro ISSAI Sjogren's 40-95% 05% Subacute cutaneous SLE and mothers of babies with neonatal
lupus SLE 25%
Anti-La (SSBI Sjogren's 40% 0% Usually occurs with anti-Ro

SLE 10%
Antiphosphollpid APS <5% By definition present in APS

antibodies (LAC, ACLAI SLE 31-40% Only small subset of SLE patients develop clinical syndrome of APS
If positive will get afalse positive VDRL test
Anti-histone Drug-induced SLE >90% 0%

Idiopathic SLE >50% 0%
Antl-RNP MCTD 0% By definition present in MCTD; present in many other CTD
Anti-centromere CREST> 80% 0% Specific for CREST variant of PSS

Anti-topoisomerase I PSS 26-76% 0%
(formerly ScI-701
c-ANCA Active Wegener's >90% 0% Specific and sensitive
p-ANCA Wegener's 10%, 0% Nonspecific and poor sensitivity Ifound in ulcerative colitis,
other vasculitis polyarteritis nodosa, microscopic polyangiitis, Churg-Strauss, rapidly
progressive glomerulonephritisl
Anti-Mi-1 Dermatomyositis 15-10% Specific but not sensitive
Antibodies against SLE Perform direct Coomb's test

RBCs, WBCs, or Test hemoglobin, reticulocyte,
platelets leukocyte and platelet count, antiplatelet Abs
Sero_negative Rheumatic Diseases

Table 15. A Comparison of the Spondyloarthropathies
Feature AS PsA ReA IBD
M:F 5:1 1:1 8:1 1:1
Age onset 20's 35-45 20's any
Peripheral arthritis 25% 96% 90% Common
Distribution Axial, LE Any LE LE
Sacroiliitis 100% 40% 80% 20%
Dactylitis Uncommon 35% Common Uncommon
Enthesitis Common Common Common Less Common
Skin lesions Rare 100% Common Occasional
Nil specific Psoriasis Keratoderma Pyoderma, Erythema
Nodosum
Uveitis 30% Occasional 20% Rare
Urethritis Rare Occasional Common Rare
Aortic Regurgitation Occasional Rare Occasional Occasional
HLA-B27 90% 40% 80% 30%
Dr.JKR
Toronto Notes 2008 Seronegative Rheumatic Diseases Rheumatology RH19
Ankylosing Spondylitis (AS)

---"-------~--~
Definition
• inflammatory arthritis involving the sacroiliac joints and vertebrae
• prototype of the spondyloarthropathies

• 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 • SI

• spondylitis
• axial • hip
• mid and lower back stiffness, pain at rest, persistent buttock pain, painful • shoulder
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 Figure 10. Common sites of
• spinal restriction: lumbar, thoracic, cervical spine in flexion, extension involvement of AS
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
• extra-articular manifestations of Ankylosing Spondylitis
• ophthalmic: acute anterior uveitis (25-30% patients) (6 As):
• cardiac: aortitis, aortic regurgitation, pericarditis, conduction disturbances, heart Atlanto-axial subluxation
failure (rare) Anterior uveitis
• renal: amyloidosis and IgA nephropathy Apical lung fibrosis
• respiratory: apical fibrosis (rare) Aortic incompetence
• neurologic: cauda equina syndrome (rare) 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 Consider AS in the differential for
causes of aortic regurgitation.
Table 16. Types of Back Pain
Parameter Mechanical Inflammatory
Past History ± ++
Family History +
Onset Acute Insidious
Age (years) 15-90 <40
Sleep Disturbance ± ++
Morning Stiffness <30 minutes >1 hour
Involvement of Other Systems +
Exercise Worse Better
Rest Better Worse
Radiation of Pain Anatomic (L5-S1) Diffuse (thoracic, buttock)
Sensory Symptoms +
Motor Symptoms +
Treatment
• conservative/non-pharmacologic
• heat
• prevent fusion in poor posture and disability by: exercise (e.g. swimming),
postural and deep breathing exercises, outpatient PT, smoking cessation
Dr.JKR
RH20 Rheumatology Seronegative Rheumatic Diseases Toronto Notes 2008
• medical
• NSAIDs: do not alter natural history
• DMARDs for peripheral arthritis (sulfasalazine, methotrexate)
• Biologics for axial involvement
• manage extra-articular manifestations
• surgical
• hip replacement, vertebral osteotomy for marked deformity
I.
Prognosis
• spontaneous remissions and relapses are common and can occur at any age
• function may be excellent despite spinal deformity
• favorable prognosis if female and age of onset >40
• early onst:'t with hip disease may lead to severe disability; may require arthroplasty
o
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 - - - - - - - - - - - ,
Etiology
• onset following an infectious episode either involving the CI or CD tract
• Cl: Shigella, Salmonella, Campylobaeter, Yersinia species
The triad of arthritis, conjunctivitis, • CD: Chlamydia (isolated in 16-44% of ReA cases), Mycoplasma species
and urethritis is 99% specific (but • acute pattern of clinical course
51% sensitive) for ReA. • 1-4 weeks post-infection
• lasts weeks to years with 1/3 chronic
• often recurring
",' ,
•. l - - - - - - - - - - - ,
• spinal involvement persists
Epidemiology
Look for genetic predisposition • in HLA-B27 patients, axial> peripheral involvement
(HLA-B271 and infection. • 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
• 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

• 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 Check "hidden" areas for psoriatic
• nail involvement includes pitting, transverse or longitudinal ridging, lesions (ears, hair line, umbilicus,
discolouration, subungual hyperkeratosis, onycholysis, and oil drops anal c1ett, nailsl.
• musculoskeletal
• 5 general pattems
• asymmetric oligoarthritis (most common -70%)
• arthritis of DIP joints with nail changes
• destructive (mutilans) arthritis (5%)
• symmetric polyarthritis (similar to RA)
• sacroiliitis and spondylitis (usually older, male patients)
• ophthalmic
• conjunctivitis, iritis (uveitis)
• cardiac and respiratory (late findings)
• aortic insufficiency
• apical lung fibrosis
• neurologic
• cauda equina syndrome
• radiologic
• floating syndesmophytes
• pencil and cup arpearance at IP joints
• osteolysis, periostitis
Treatment
• treat skin disease (e.g. steroid cream, salicylic .md/or retinoic acid, tar, UV light)
• first-line is NSAlDs; if they fail to reduce synovitis and pain then use intra-articular steroids
• persistent or severe disease with erosive arthritis --> DMARDs, biologic therapies
• spinal disease -+ biologic therapies
Inflammatory Bowel Disease (lBD) -------~~-~
(see Gastroenterology. G20)

• manifestations of ulcerative colitis and Crahn's disease include peripheral arthritis
'" ,,
,'\-------------,
(large joint, asymmetrical), spondylitis, and hypertrophic osteoarthropathy
Both ankylosing spondylitis and
• arthralgia, myalgia, osteoporosis and aseptic necrosis of bone 2° to steroid treatment of
IBD-arthritis feature symmetric
bowel inflammation
sacroiliitis.
• 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
RH22 Rheumatology Crystal-Induced Arthropathies 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
Hyperuricemia
• primary or genetic
• mostly due to idiopathic renal underexcretion (90%)
• also idiopathic overproduction or abnormal enzyme production/function
• 1st MTP "0
• ankle
u • secondary
• knee • dietary excess
• underexcretion (>90%) - renal failure, drugs, systemic conditions
• overproduction «10%) - increased nucleic acid turnover states
Figure 11. Common sites of
• majority of people with hyperuricemia do not have gout, and normal or low uric acid
involvement in gout
levels do not rule out gout
(asymmetric joint involvement)
• common precipitants: EtOH, dit'lary excess, dehydration (e.g. thiazide and loop
'- ~ ,
.:r-----------,
diuretics), trauma, illness, surgery
• other associated conditions: hypertension, obesity, diabetes, starvation
An acute gout attack may mimic Epidemiology

cellulitis. However, joint mobility • most common in males >45 years old
is preserved in cellulitis. • extremely ran:' in premenopausal female
Signs and Symptoms

• recurrent episodes of acute arthritis
• acute gouty arthritis
• painful, usually involving lower extremities (e.g. first MTP joint = "podagra")
• joint mobility may be limited
• attack will subside on its own within several days to weeks and mayor may
not recur
• tophi
• urate deposits in cartilage, tendons, bursae, soft tissues, and synovial membranes
• common sites: first MTP, ear helix, olecranon bursae, tendon insertions
(common in Achilles tendon)
• kidney
• gouty nephropathy
• uric acid calculi
"" Investigations
Precipitants of Gout • joint aspirate: >90% of joint aspirates show crystals of monosodium urate (see Table 19,
RH24) (negatively birefringent)
Drugs are FACT: • differential diagnosis includes pseudogout, trauma, sepsis, OA
Furosemide
Aspirin/Alcohol Treatment
Cytotoxic drugs
Thiazide diuretics Alacute gout
• NSAIDs: high dose, then taper as symptoms improve
Foods are SALTS: • corticosteroids: intra-articular, oral or intra-muscular (if renal or Gl disease and/or
Shellfish if NSAIDs contraindicated or tail)
Anchovies • colchicine within first 24 hours but effectiveness limited by narrow therapeutic range
Liver and Kidney • allopurinol can worsen an acute attack (therefore do not start during acute flare)
Turkey
Sardines 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)
• 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 • knee
• polyarticular wrist
Signs and Symptoms • hand (MCP)
• affects knees, wrist, MCP joints, hips, shoulders, elbows, ankles, big toe • foot (1st MTP)
• may present as chronic arthritis with acute exacerbations
• 5% will mimic rheumatoid arthritis (symmetrical polyarticular pattern with morning Figure 12. Common sites of
stiffness and constitutional symptoms) involvement in CPPD
• may be triggered by dehydration, acute illness, surgery, trauma
• 50% of the patients will develop degenerative joint changes
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
"" ',
.1-----------,
• x-rays show chondrocalcinosis: punctate radiodensities in fibrocartilaginous structures
(e.g. knee menisci) or linear radiodensities in hyaline articular cartilage Differential Diagnosis of Acute
• chondrocalcinosis seen in 75% of pseudogout Monoarthritis
• differential diagnosis includes gout, trauma, sepsis, RA • septic arthritis
(see Infectious Diseases, 1022)
Treatment • gout
• joint aspiration, rest, and protection • pseudogout
• l\SAIDs - also used for maintenance therapy • trauma
• prophylactic colchicine PO (controversial) • hemarthrosis
• intra-articular steroids to relieve intlarnmation • osteonecrosis
• osteoarthritis
Table 18. Gout vs. Pseudogout ·tumour
• systemic inflammatory disease
Parameter Gout Pseudogout
• polyarthritis presenting with
Gender M>F M.F
monoarticular symptoms
Age Middle-aged males Older
Post-menopausal females
Onset of disease Acute Acute/insidious
Crystal type Negative birefringence, Positive birefringence,
needle-shaped rhomboid-shaped
Distribution Fi rst MTp, foot Knee, wrist, polyarticular
Radiology "Holes in bones" Chondrocalcinosis
OA (knee, wrist, 2nd and 3rd MCP)
Treatment Indomethacin, colchicine, allopurinol NSAIDs
Synovial Fluid Analysis

• synovial fluid is an ultrafiltrate of plasma plus hyaluronate; it lubricates joint surfaces
and nourishes articular cartilage
Three Most 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
RH24 Rheumatology Crystal-Induced Arthropathies/Septic ArthritisINon-Articular Rheumatism Toronto Notes 2008
Table 19. Synovial Fluid Analysis

Parameter Normal Non-Inflammatory Inflammatory Infectious Hemorrhagic
Colour Clear Clear Opaque Opaque Sanguinous
Viscosity High Idue to High Low Low Variable

hyaluronate)
WBClmm' <200 <2,000 >2,000 >50,000 Variable
%PMN <25% <25% >25% >50% Variable
Examples Trauma Seropositives Septic arthritis Trauma

Osteoarthritis Seronegatives Hemophilia
Neuropathy Crystal arthropathies CPPD
Hypertrophic·
arthropathy
Non-Articular Rheumatism
• disorders that plimarily affect soft tissues or periarticular structures
• includes bursitis, tendinitis, tenosynovitis, fibromyalgia (fibrositis) and polymyalgia
rheumatica
[ Polymyalgia Rheumatica (PMR) _ _- ' ' - - .J
Definition
• characterized by profound pain and stiffness of the proximal extremities (girdle area)
• closely related to giant cell arteritis (15% of patients with PMR develop GCA)
.... ',
.}------------, Diagnosis
PMR Criterie
• age >50 years
1. Age over 50
• more than two affected muscle groups
2. Bilateral aching/morning • at least a one month duration
stiffness>1 month • increased ESR
3. ESR over 40 mm/hr • rapid and lasting response to corticosteroids
4. Prompt response to low-dose • must rule out infection, RA, SLE, PAN, polymyositis, malignancy, and giant cell
corticosteroids arteritis
Epidemiology
• incidence 50 per 100,000 per year in those over age 50
• age of onset typically >50, F:M = 2:1
Signs and Symptoms

• constitutional symptoms prominent (fever, weight loss, malaise)
• morning stiffness of symmetrical proximal muscles (neck, hip and shoulder girdles,
thighs)
• physical examination reveals tender muscles but no weakness or atrophy
• laboratory investigations often reveal anemia, elevated ESR, CRP and platelets;
normal CK
Treatment
• goal of therapy: symptom relief
• start with steroid dose of 15-20 mg PO daily
• taper slowly over 2-year period monitoring ESR and symptoms closely
• treat relapses aggressively (50% relapse rate)
Dr.JKR
Toronto Notes 2008 Non-Articular Rheumatism Rheumatology RH25
Fibromyalgia
-"""-------------------------'
Definition
• chronic, widespread pain with characteristic tender points
Diagnosis
• history of widespread pain for at least 3 months in four quadrants of body
• pain in 11 of 18 tender points with approximate force of 4 kg by digital palpation
• must rule out numerous other causes (e.g. polymyositis, polymyalgia rheumatica,
thyroid disorders, sleep apnea), although presence of second clinical disorder does not
exclude the diagnosis of fibromyalgia
Epidemiology
• F:M=3:1
• primarily ages 25 to 45, some adolescents
• prevalence of 2-5% in general population, higher in rheumatology patients
• overlaps with chronic fatigue syndrome and myofascial pain syndrome
• strong association with psychiatric illness
Investigations
• laboratory investigations typically normal unless underlying illness present
• workup includes: TSH, ESR, laboratory sleep assessment
Signs and Symptoms

• widespread aching, stiffness and reproducible tender points (see Figure 13)
• fatigue
• sleep disturbance: non-restorative sleep, difficulty falling asleep, and frequent
wakening
• symptoms aggravated by physical activity, poor sleep, emotional stress
• patient feels that joints are diffusely swollen although joint examination is normal
• neurologic symptoms of hyperalgesia, paresthesias
• associated with irritable bowel or bladder syndrome, migraines, tension headaches,
obesity, depression, and anxiety
Treatment
• conservative
• education - disease is benign, non-deforming and does not progress
• exercise program (walking, aquatic exercises)
• support back and neck: neck support while sleeping, abdominal muscle
strengthening exercises
• stress reduction; psychiatric treatment when necessary
• biofeedback, meditation, acupuncture, physiotherapy may be helpful
• medical
• low dose tricyclic antidepressant (e.g. amitriptyline)
• for sleep restoration
• select those with lower anticholinergic side effects
• NSAIDs if pain interferes with sleep
"-:.~
Paired tender points
"- " "') occiput Occiput: at suboccipital muscle insertion
! . trapezius
supraspinatus
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, upper outer quadrants
gluteal Greater trochanter: posterior to trochanteric prominence
Knee, at medial fat pad
Figure 13.Tender Point Sites
Dr.JKR
RH26 Rheumatology Summary of Arthritic Diseases/Clinical Approach to Arthritis Toronto Notes 2008
Summary of Arthritic Diseases

Table 20. Classification of Arthritis and Characteristic Features
Classification Characteristic Features
Degenerative
Osteoarthritis (OA) Insidious onset
Older age (>50 years old)
Negative serology
Seropositive rheumatic diseases

1. Connective Tissue Disease Positive serology
Rheumatoid Arthritis (RA) Constitutional symptoms
Systemic lupus erythematosus (SLE) Skin nodules, ulcers, rash
Antiphospholipid antibody syndrome (APS) Raynaud's phenomenon
Scleroderma/progressive systemic sclerosis (PSS) Vascular involvement
Polymyositis (PMY)ldermatomyositis (OMY) Renal involvement
Mixed connective tissue disease (MCTO) Neurological involvement
Sjogren's syndrome Sicca syndrome
2. Vasculitides see Table 15

Polyarteritis nodosa (PAN) Medium vessel disease
Microscopic polyangiitis Small vessel disease, ANCA associated
Wegener's granulomatosis Small vessel disease, ANCA associated
Predominantly cutaneous vasculitis Small vessel disease, non-ANCA associated
Giant cell arteritis (GCA) Large vessel disease
Seronegative rheumatic diseases Axial skeleton involvement

Ankylosing spondylitis (AS) Anterior uveitis, conjunctivitis, urethritis
Reactive arthritis Enthesitis, sacroiliitis, dactylitis, urethritis
Psoriatic arthritis Psoriasis, keratoderma, E. nodosum
Inflammatory bowel disease (lBO) Family history and HLA-B27 association
Crystal-induced Remitting, recurring pattern

Gout (monosodium urate) Mono or oligoarthritis
Pseudogout (calcium pyrophosphate dihydrate) Tophi
Hydroxyapatite deposition disease Renal involvement
Septic/infectious Acute monoarthritis or migratory polyarthritis

Constitutional symptoms
Non-Articular
Localized (bursitis, capsulitis, tendinitis, myositis) Periarticular structures affected
Generalized (fibromyalgia, polymyalgia rheumatica) Trigger points
Clinical Approach to Arthritis
Approach to Making a Decision

I I
I Articular
_J I
Non-Articular
I
Inflammatory Degenerative Localized Generalized
I II I
I I I I
Seropositive Bursitis
Seronegative
Crystal
Prim<lry
Secondary II Tendinitis
Capsulitis
Fibromyalgia
PMR
Septic
II
Figure 14. Clinical Evaluation of Arthritis: Approach to Making a Diagnosis
With permission of Dr,Arthur A.M.Bookman
Dr.JKR
Toronto Notes 2008 Common Medications Rheumatology RH27
Common Medications
Table 21. Common Medications for Osteoarthritis
Class Generic Drug Name Trade Name Dosing Indications Contraindications Adverse Effects
acetaminophen Tylenol™ 500 mg tid 1st line Hepatotoxicity
Overdose>10 g
Potentiates Warfarin
NSAIDs ECASA 325-975 mg qid 2nd line GI bleed Nausea, tinnitus, vertigo, rash,
ibuprofen AdviiTMMotrin™ 200-600 mg tid Renal impairment dyspepsia, GI bleed, PUD,
diclofenac Volta~enTM 25-50 mg tid Allergy to ASA, NSAIDs hepatitis, renal failure, HTN,
diclofenac/misoprostol Arth rate C™ 50-200 mg tid Pregnancy IT3) nephrotic syndrome
naproxen Naprosyn™, Aleve™ 125-500 mg bid
meloxicam MoblCOX™ 7.5-15 mg 00
COX-2 celecoxib Celebrex'M 200 mg 00 High risk for Renal impairment Delayed ulcer healing
Inhibitors GI bleed: age>65 Sulfa allergy (celecoxib) Renal/hepatic impairment
hx of GI bleed, PUD Cardiovascular disease Rash
D1!ler treatments Comments
Combination analgesics Enhanced short term effect compared to acetaminophen alone
(acetaminophen + codeine) More adverse effects: sedation, constipation, nausea, GI upset
Intra-articular corticosteroid injection Short-term (weeks··months) decrease in pain and improvement in function
Do not inject >3-4 times/year in the same joint
Intra-articular hyaluronan q6months Modest decrease in pH in

Used for mild-mode. ate OA
Precaution With chicken/egg allergy
Topical NSAIDs 1.5% vvt/wt topical diclofenac (Pennsaid)

May use for patients who fail acetaminophen treatment and who wish to avoid systemic therapy
Capsaicin cream Moderate decrease in pain
Glucosamine sulfate/chondroitin Limited clinical studies

No regulation by Health Canada
Table 22. DMARDs Used in the Treatment of Rheumatoid Arthritis

Genetic Drug Name Trade Name Dosing Contraindications Adverse Effects
COMMONLY USED
hydroxychloroqulne Plaquenil'M 400-600 mg 00 initially Retinal disease, G6PD deficiency GI symptoms, macular damage, neuromyopathy, skin rash
$ 200-400 mg 00 maintenance
sulfasalazine Salazopyrim™ 1000 mg bid Sulfa/ASA allergy, kidney disease, GI symptoms, headache, leukopenia, rash
$ Azulfidine™ (US) G6PD deficiency
methotrexate Rheumatrex'M qweekly Bone marrow suppression, Urticaria, GI symptoms, tubular necrosis,
$ FolexiMexate'M 7.5-25 mg PO/IM/SC liver disease, significant lung disease, myelosuppression, cirrhosis, pneumonitis, oral ulcers
immunodeficiency, pregnancy, EtOH abuse
gold !injectable) Solganal'M weekly or monthly injections lBO, kidney/liver disease Rash, mouth soreness/ulcers, proteinuria,
$ Myocrysine'M marrow suppression
NOT COMMONLY USED
cyclosporine Kidney/liver disease, Bleeding, hypertension, decreased renal
$$ infection, hypertension function, hair growth, tremors
gold (oral! lBO, kidney/liver disease Diarrhea, rash, stomatitis

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

$ loss, vomtting, diarrhea
cyclophosphamide Kidney/liver disease Cardiotoxicity, GI symptoms, hemorrhagic cystitis,

$ nephrotoxictty, bone marrow suppression, sterility
penicillamine Penicillin allergy Rash, loss of taste/appetite, GI symptoms,

$ hematologic/kidney disease nephritic syndrome
NEWER DMARDs (Biologicals) MECHANISM OF ACTION
leflunomide Arava™ 10-20 mg PO 00 Inhibits pyrimidine synthesis and has antiproliferative activity
$$$
etanercept Enbrer M 25 mg biweekly FUSion protem ofTNF receptor and Fc portion of IgG
$$$ or 50 mg weekly Decreases number of active joints by 50% from baseline after 6 months
SC mjectlons
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, Causes B cell depletion, binds to CD20

$$$ 2weeks apart
Dr.JKR
RH28 Rheumatology Summary Key Questions Toronto Notes 2008
Summary Key Questions

QUestions Answers
1. List 6signs of osteoarthritis on Joint line tenderness, bony enlargement at affected
physical examination. 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 il morning stiffness>1hr

outlined by the American College of Rheumatology. iiI arthritis of >3 joints
How'many of these criteria are required for the iiil arthritis of hand joints
diagnosis of RA? 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 60-80%

are rheumatoid factor positive?
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. il malar rash

How many of these criteria are required iil discoid rash
for the diagnosis of SLE? 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 ANA 198% sensitivel

for the diagnosis of SLE?
8. List five major pharmacologic agents Hydralazine, isoniazid, procainamide, chlorpromazine and methyldopa
that are associated with drug-induced lupus.
9. Listthe three commonest Thromboembolic events, recurrent spontaneous abortions,

manifestations of APS. thrombocytopenia
10. What are the features of scleroderma Malignant arterial hypertension (> 150/90 mmHgl.1'Cr, oliguria,
renal crisis and what percentage of patients and microangiopathic hemolytic anemia, 10-15% of scleroderma
with scleroderma are at risk of patients are at risk of developing scleroderma renal crisis.
developing renal crisis?
11. List the 5diagnostic criteria for il progressive symmetric proximal muscle weakness
polymyositis/dermatomyositis. iil elevated muscle enzymes (CK, aldolase, LoH, AST, All)
iii) EMG changes
ivl muscle biopsy
vi typical rash of dermatomyositis (required for the
diagnosis of oMI
Definite PM/OM if fulfill 4criteria; probable if fulfill 3criteria;

possible if fulfill 2criteria
12. List the features of the classic Dry eyes, dry mouth, and inflammatory arthritis.
triad of Sjiigren's disease.
13. What type of malignancy are Non-Hodgkin's lymphoma.

patients with Sjogren's at greatest risk
of developing?
Dr.JKR
Toronto ;'\Totes 2008 Summary Key Questions Rheumatology RH29
Questions Answers
14. List the diagnostic crrteria for i) nasal or oral inflammation, ulcers, epistaxis
Wegener's granulomatosis. iil abnormal CXR findings including nodules, cavitations
How may of these criteria are required iii) urinary sedimentlprotein, RBC castsl
for the diagnosis of Wegener's granulomatosis? ivl biopsy of involved tissue: lung tissue shows granulomas;
renal tissue shows necrotizing segmental granulomatosis
To diagnose Wegener's aminimum of 2of the above criteria

are required.
15. List the diagnostic criteria for >3 out of 10 required:

polyarteritis nodosa. How many of the il weight loss >4 kg
criteria are required for the diagnosis of PAN? 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 il age >50 yrs

of Giant Cell Arteritis. iii temporal artery tenderness or decreased pulse
iii) ESR >50
ivl abnormal artery on biopsy
17. List the differential diagnosis of an RA, PMR, GCA, hypoalbuminemia, anemia, multiple myeloma,
elevated ESR. bacterial mfecllOns, malignancy.
18. What are the common joints involved SI, hip, shoulder
in ankylosing spondylitis?
19. What percentage of patients with 95% of patients with AS are HlA-B27 positive. 9% of the general
ankylosing spondylitis are HlA-B27 positive? population is HlA-B27 positive.
What is the prevalence of HlA-B27
in the general population?
20. What GI and GU infections precede GI infec~ons - Shigella, Salmonella, Campy/obacter, Yersinia;
the development of Reactive Arthritis? GU infections - Chlamydia, Mycoplasma species.
21. List the 5general MSK patterns of il asymmetric oligoarthritis

psoriatic arthritis. ii) arthrrtis of DIP joints wrth nail changes
iii) destructive Imutilansl arthrrtis
iv) symmetric polyarthritis
v) sacroilirtis and spondylitis
22. What are the common sites of 1st MTP, ankle, knee. The pattern of joint involvement is
involvement in gout and what is the asymmetrical.
pattern of joint involvement?
23. What are the common preciprtants Alcohol, dietary excess, dehydration, thiazide and loop
of gout attacks? diure~cs, trauma, illness, and surgery
24. List 3risk factors for the Old age, advanced OA, and neuropathic joints
development of pseudogout.
25. What are the common srtes of Knee, polyartlcularwrisl. MCP, 1st MTP
involvement in pseudogout?
26. What is the differential diagnosis Septic arthritis, gout, pseudogoul. trauma, hemarthrosis,
of acute monoarthritis? osteonecrosis, osteoarthritis, tumor, systemic inflammatory
disease, polyarthrrtis presenting with monoarticular symptoms
27. What are the tender point sites Occiput, trapezius, supraspinatus, low cervical, second rib, lateral
in fibromyalgia? epicondyle, gluteal, greater trochanter, medial fat pad of knee.
28. What are the features for the diagnosis Age >50, bilateral aching/morning stiffness for 1month, ESR
of polymalgia rheumatica? >411, prompt response to low-dose corticosteroids.
Dr.JKR
RH30 Rheumatology References Toronto Notes 2008
References
ACR Subcommittee on Rheumatoid Arthritis Guidelines, 2002. Guidelines for the Management of Rheumatoid Arthritis: 2002 Update,
Arthritis & Rheumatism 46121:328·346.
ACR, Guidelines for Referral and Management of Systemic Lupus Erythematosus in Adults· 9199,
ACR. Guidelines for the Medical Management of Osteoarthritis of the Hip - 11/95.
ACR. Guidelines for the Medical Management of Osteoarthritis of the Knee - 11195.
Bathon JM, Martin RW, Fleischmann RM, et al. 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

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Rheumatology

Justine Cohen, Amanda Mayo and Julia Warden, chapter editors

Basic Anatomy Review 2 Summary of Arthritic Disease 26

Basics of Immunology 2 Clinical Approach to Arthritis 26

Differential Diagnoses of Common ..... 3 Summary Key Questions 28

Seropositive Rheumatic Diseases:

Seropositive Rheumatic Diseases:

Seropositive Rheumatic Diseases:

Seronegative Rheumatic Diseases . ... .18

Toronto Notes 2008 Rheumatology RHI

Basic Anatomy Review

Normal Joint Degenerative Joint Infiammatory Joint

©Frances Yeunq 200S; revised by Desmond Ballance 2006

Figure 1. Structure of normal, degenerative and inflammatory joint

Immune Mechanisms of Disease

Immunogenetics and Disease

Table 1. Classes of Major Histocompatibility Complexes (MHCs)

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

II HLA-Dp, -DO, -DR Antigen presenting cells Recognized by CD4+ (helper)

III Complement In plasma Chemotaxis, opsonization,

Table 2. HLA-Associated Rheumatic Disease

827 Ankylosing spondylitis In AS, relative risk = 70-90

DR4, DR1 Rheumatoid arthritis 93% of patients

DR3 Sjogren's syndrome DR3 associated with many non-rheumatic conditions

Differential Diagnoses of Common

Table 3. Differential Diagnosis of Joint Pain

Patterns of Joint Involvement

Table 5. Seropositive vs. Seronegative Rheumatic Diseases

.... ,,.l------------, 3. Arthritis of hand joints

Etiology and Pathophysiology

B- and T-cell ~putrophil Promotes Proliferation

Figure 5. Proposed Pathogenesis of RA

Signs and Symptoms

Classification of Global Functional Status in RA

Complications of Chronic Synovitis

Extra-Articular Features (EAF)

Extra-Articular Features Figure 6. Joint deformities

ea.n- rlT..-Str8lIgies i1 EJIt1 A) Education, occupational therapy, physiotherapy, vocational coun-

Etiology and Pathophysiology

Signs and Symptoms

[ Antiphospholipid Antibody Syndrome (APS)

Signs and Symptoms

premature birth at <34 wks gestational age

SclerodermalProgressive Systemic ·Sclerosis (PSS}

Etiology and Pathophysiology

Figure 9. Forms of Scleroderma

Signs and Symptoms

Table 10. Clinical Manifestations of Scleroderma

Dermatologic Initial phase characterized by painless non·pitting edema

Gastrointestinal (N90%) GI tract becomes arigid tube leading to decreased motility

Renal Mild proteinuria, creatinine elevation and/or hypertension are common

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

Cardiac Left ventricular dysfunction, pericarditis, pericardial effusion, arrhythmias

Endocrine Hypothyroidism common

Idiopathic Inflammatory Myopathy

POLYMYOSITIS (PM)IDERMATOMYOSITIS (OM)

Etiology and Pathophysiology

Signs and Symptoms

• early symptom is difficulty lifting head off pillow

• Inclusion Body Myositis

Etiology and Pathophysiology

Signs and Symptoms