RHEUMATOLOGY

Contents
CONNECTIVE TISSUE DISORDERS.................................................................................................................3
Polymyositis / dermatomyositis.............................................................................................................4
Relapsing polychondritis.......................................................................................................................10
Mixed connective tissue disease..........................................................................................................13
Sjogren’s syndrome..............................................................................................................................15
Adult onset Still’s disease.....................................................................................................................21
Familial Mediterranean Fever..............................................................................................................23
IgG4 related disorders..........................................................................................................................24
Systemic Lupus Erythematosus............................................................................................................26
Systemic sclerosis.................................................................................................................................48
Safety guidelines for biologics – BSR 2018 Aug....................................................................................58
VASCULITIS...............................................................................................................................................60
Giant cell arteritis / PMR......................................................................................................................63
Takayasu arteritis..................................................................................................................................65
Polyarteritis nodosa..............................................................................................................................66
Kawasaki disease..................................................................................................................................69
Thrombangiitis obliterans.....................................................................................................................69
Granulomatosis with polyangitis..........................................................................................................70
Eosinophilic granulomatosis with polyangitis......................................................................................72
Microscopic polyangitis........................................................................................................................72
Henoch Schonlein Purpura / IgA vasculitis...........................................................................................75
Cryoglobulinemic vasculitis and cryoglobulinemic syndromes............................................................76
Behcet’s disease....................................................................................................................................79
Cogan syndrome...................................................................................................................................83
ARTHRITIS..................................................................................................................................................85
RHEUMATOID ARTHRITIS..........................................................................................................................86
SERONEGATIVE SPONDYLOARTHRITIS.....................................................................................................109
Psoriatic arthritis.................................................................................................................................117
 Enteropathic arthritis..........................................................................................................................118
Reactive arthritis.................................................................................................................................119
X RAY DIAGNOSIS....................................................................................................................................121
Crystal arthropathies..............................................................................................................................123
GOUT...................................................................................................................................................123
PSEUDOGOUT.....................................................................................................................................127
Calcium apatite deposition disorders.................................................................................................128
Calcium oxalate crystal disease..........................................................................................................128
Diffuse Idiopathic Skeletal Hyperostosis (DISH).......................................................................................130
OSTEOARTHRITIS.....................................................................................................................................132
SEPTIC ARTHRITIS....................................................................................................................................133
CONNECTIVE TISSUE DISORDERS
1. SLE – separate note
2. RA – separate note
3. SSCl
4. SjS
5. Behcets
6. PM/DM
7. MCTD
8. Overlap syndrome
9. Undifferentiated CTD
10. IgG4 RD
Polymyositis / dermatomyositis

Inflammatory proximal myopathy (PM/DM)

Epid
F:M = 3:1
40-50s

RF
Idiopathic
HLA?
Paraneoplastic, sp DM

Path

CFx
Classical
Proximal muscle weakness, LL > UL, tender in 50%
Bulbar weakness
Respiratory weakness
+/- ILD (NSIP), arthritis, RP. – these predicted by anti synthetase Abs (eg:Jo Ab)

Skin
In DM (and amyopathic DM)
Gottron papule, heliotrope rash are pathgnomonic

Gottron’s papules (if lesions are macules, then called Gottorn’s sign. Those appear more over
other joints. )

DD for Gottron’s

Psoriasis
Lichen planus
* Both are characterized by scaling, but Gottorns may
also some times scale off
SLE – over phalanx >> over joint
Bulemia nervosa (Russell Sign)

Heliotrope rash and mid facial erythema (nasolabial folds not spared)
 DD: SLE. NSL spared

Photodistributed poikiloderma
An area of hyper and hypopigmented skin, telengiectasia and epidermal atrophy
Shawl sign – behind the neck, V of the neck and upper chest
Holster sign – bilateral lateral thighs

Nailfold changes
Periungular
erythema
Dilated capillary loops (nailfold telengiectasia)
Overgrown cuticle (severity indicates activity of skin disease)

Psoriasiform scalp lesions

Calcinosis cutis – more with juvenile PM/DM, can calcify the entire body

Lung ILD (NSIP > UIP)

More with anti synthetase type

Cardiac Myocarditis

Esopahgeal – SkM dysmotility

Antisynthetase syndrome
Definition = Ab + 2 of ILD / PM / polyarthritis
Acute onset
DM/PM
Mechanics hand
RP
Non erosive arthritis
ILD more than in other PM
Anti synthetase Ab – anti Jo, OJ, EJ,PL-7, PL-12, KS, Zo, Ha (Ab against tRNA synthetase)

Clinically Amyopathic DM (CADM)

Hypomyopathic DM – asymptomatc. Myopathy noted in EMG, CPK, Bx
Amyopathic DM – no clnical and investigational Fx of myopathy
Provisional after 6m
Confirmed after 2y

MDA5 Ab associated DM
Ulcerating Gottron’s papules
Amyopathic DM
Rapidly worsening ILD
Arthritis

Investigations findings
ESR CRP high
CPK, AST, LDH, aldolase – high
EMG – myopathic pattern (1. Fibrillations at rest, 2. Polypahsic short potentials on contraction, 3. Salvos
of repetitive potentials on stimulation)
Biopsy – see below. Select a muscle that is weak but not wasted. Avoig EMGed muscle
ANA – 40-80%
RF – 50%
Anti RNA synthetase (anti Jo etc) – defines anti synthetase syndrome
Ab associated with Cancer associated DM – anti - MJ, TIF
Ab that predicts low risk for CA by high risk for ILD – (the myositis specific Ab) SRP, Mi2, synthetase,
RNP, PM-SCl

Diagnosis fo dermatomyositis

Bohan Peter Diagnostic criteria

1. Symmetrical PM with neck weakness, progressive over weeks to months

2. Bx of myopathy
3. High muscle enzymes – CPK, AST, ALT, aldolase, LDH
4. Typical EMG triad – acute denervation, fibrillation, small polyphasic MUAP
 5. DM skin features
Exclusion of other causes for myopathy

Neurology Ox Case Hx :
EMG showed acute denervation, increased spontaneous activity with fibrillations, positive sharp waves
and a myopathic picture with small polyphasic motor unit action potentials. The combination of acute
denervation and myopathic features on EMG is typical of an inflammatory myopathy (dermatomyositis,
polymyositis and inclusion body myositis).

DD
DM vs PM
Steroid myopathy
IBM – M, > 50y, distal, asymmetric (quad, finger flexors, ankle dorsiflexors), CPK NL/mildly high
Other myopathy – endocrine (thy, cushing)

DM PM IBM
Skin More None M, > 50y, distal,
Underlying CA More Less asymmetric (quad,
Path Complement mediated Tc mediated myocyte finger flexors, ankle
vasculitis injury dorsiflexors), CPK. Can
Histology Perifascicular Intrafascicular affect face
(perimyceal) and (endomyceal) L NL/mildly high
perivascular L infiltrates infiltrates
Vasculitis and infarcts Scattered single fibre
Muscle fibre groups necrosis
necrosed

IMNM (Immune mediated necrotizing myopathy. Old name : NAM – Necrotizing Autoimmune
myopathy)
Muscle necrosis w/o inflammation. Highest CPK among myopathies
SRP Ab associated : not associated with CA. responds to imm supp
HMGCR Ab associated : asso with statin use. ILD & skin in 10%. Weak link to CA. Rx IVIG
Ab negative IMNM : strong link to CA

Treatment

High dose steroids (1mg/kg); MPP if severe weakness / resp failure / dysphagia
Taper slowly over 9-12 months (half dose by 6m)
Assess response by muscle weakness (Manual Muscle Score 8). Better than CPK

Steroid sparing agents

MTX for all unless CIn
Reduces disease activity, reduces fibrosis, improves outcome
 Start early before fibrosis sets in
Avoid in ILD, liver disease, planning pregnancy, alcohol user

Alternatives – AZT (avoid in TPMT deficient)

PCP prevention - U2D recommends cotrim 1 tab daily for PCP prevention, when pt is on Glcc + other
agent. 1 tab can be used with MTX, but not 2 or more.

Physiotherapy and OT

OP prevention
Ca, vit D, stop smoking
Bisphos if
< 40y, AND OP # or on pred > 7.5/d for > 5m AND BMD Z < -3 / ??
> 40y OP # / T < -2.5 / FRAX > 10% for MOPF / FRAX > 1% for FNF

Poor response to Glcc + MTX

1. Poor compliance
2. Paraneoplastic
3. IBM (Men, > 50y, distal > prox, asymmetric)
4. Steroid myopathy – normal CPK, biopsy – type 2 fibre atrophy, improves after stopping Glcc
5. Alternative contributor – hypoK, hypoTh

When to screen for malignancy ?

Clinical evidence of a CA
Steroid resistant disease
Fishing expeditions discouraged
(dermatologists are bit more aggressive in searching for CAs. They actually think of doing CT/endoscopes
on Dx and annually upto 5y. in SL CAs have been Dxed even after 5y)

Complications

SoB
Muscle weakness
ILD
Pneumonia / PCP
Myocarditis / MI
PE
Disease monitoring –
Manual Muscle Testing – 8

Long case

Assess for
Respiratory failure – neck power, SBC
Cancer – don’t miss breast, testes
Relapsing polychondritis

Aetiology
2/3 idiopathic
1/3 associated with other
CTD
Vasculitis
MDS

Epid
Any age. Peak onset 40-60y
M=F

Path – L infiltration, proteoglycan, collagen and elastin depletion, chondocyte apoptosis, fibrosis

CFx
Phenotypes
1. MDS associated – worst prognosis
2. Laryngotracheobronchial variant – recurrent RTIs
3. Other cartilages, benign

Red ear sparing the ear lobe Cauliflower ear after chronic damage saddle nose

Ear
Tinnitus, vertigo, deafness (conductive : destruction / SND : vasculitis)

Nose
Nasal stiffness, crusting, epistaxis, hypogeusia
Saddle nose after chronic damage

Eye
Episcleritis, scleritis, keratitis, uveitis, orbital pseudotumor / proptosis, Salmon patch lesion in
conjunctive (also in lymphoma, leukemia, sarcoidosis, MM, amyloid – a patch of lymphocyte infiltration)
Large airway disease

Chronic cough, Dyspnoea, OSA, Stridor, Thick resp secretions, Tenderness over larynx / trachea
Recurrent RTIs
PFT : variable upper airway obstruction in tracheomalacia

Joints
Mono / oligo / poly
Small / large
Asym / sym
Non erosive, inflammatory type
Non inflammatory synovial fluid
Histology – chronic synovitis

Cardiac – AR, MR

Renal – RPGN, TIN, MsPGN

Probably represents associated disease / misclassified ANCA vasculitis

CNS
MnM, CNS vasculitis

Ix
High WBC, plt, ESR, CRP
Immune markers of associated CTDs
CXR, CT chest, PFT
2d echo
UFR, RFT

DD
GPA – lung, renal
Lymphoma

Dx
McAdam criteria
3 or more of
1. Auricular chondritis
2. Inner ear disease
3. Eye – conjunctivitis, episcleritis, scleritis, keratitis, uveitis
4. Nasal bridge chondritis
5. Airway chondritis
6. Non erosive seronegative inflammatory arthritis

Modified (Damiani) criteria

 Positive McAdam
  Histology of chondritis
 Steroid / dapsone responsive chondritis
NHx
Relapsing
Slow progressive
Low grade static (benign)
Rapid progressive and fatal

Rx

Mild disease (isolated peripheral chondritis of nose, auricle, joints)

NSAID 10d trial
Pred 30-60 mg/d or dapsone 50-100 mg/d

Mild to moderate organ involvement

Pred 1 mg/kg/d
If not controlled in 1m, add MTX / AZT / LEF
After sustained remission for 3m, start tapering

Severe / Life threatening organ disease (CNS, renal, laryngotracheal, necrotizing scleritis)
Pred 60 mg/d + CPM 2mg/kg (titrated to keep neutrophil count ~ 1500)
Add on MTX / AZT / LEF
Mixed connective tissue disease

ARDSM – acrosclerosis, raynauds, dactylitis, synovitis, myositis

*** in SLE 40% have nti U1 RNP. Go by clinical profile

NHx

Fatigue, A, Myalgia RP  SLE, RA, PM features evolve over years

Speckled ANA, U1RNP, dactylitis : highly suspicious of MCTD

U1RNP is associated with

Early RP
Early PHT
Erosive arthritis, RF +ve, anti CCP +ve

Can evolve in to a different AI syndrome over time

Typical Fx
Raynaud phenomenon and swollen hands or puffy fingers
A high titer speckled pattern antinuclear antibody (ANA) (usually ≥1280)
The absence of severe renal and central nervous system (CNS) disease
More severe arthritis, which is sometimes deforming
The development of pulmonary arterial hypertension (PAH), which differentiates MCTD from both SLE
and scleroderma
Autoantibodies whose fine specificity is anti-U1 ribonucleoprotein (RNP), especially antibodies to the 70
kD protein
Although myositis is a feature, clinical weakness is not prominent (do not present with proximal
myopathy), but CPKs are very high in 1000 +.
Prognosis better than other CTDs
Can overlap with SLE, RA (MCTD-SLE overlap etc)

CoDs
1. PAH
2. ILD
3. Myocarditis
4. Renovascular HTN and ICH

Mgt
Steroids for SLE like complications ( aseptic meningitis, myositis, pleurisy, pericarditis, and myocarditis
etc) - . myositis, skin symptoms respond well to steroids, if not, consider alternative Dx. (RRH
But nephrotic syndrome, Raynaud phenomenon, deforming arthropathy, acrosclerosis, and peripheral
neuropathies are usually steroid resistant
Ritux for Rx resistant ITP, AIHA
IVIG for resistant skin and myositis
PHT – similar to PHT gen Mgt. steroids / Cyclophosphamide may help

OCP / HRT does not cause flares

Sjogren’s syndrome

Definition
 Autoimmune
 Lymphocytic infiltration of exocrine galnds
 Dry eyes, dry mouth
 Extraglandular features

Epidemiology
F:M=9:1

Classification
Primary
Secondary – to established SLE, SSCl, RA, PM/DM, PBC

Pathology
Autoimmune
Lymphocytic infiltration at exocrine glands - T cells predominant (CD4+) in mild disease. B cells in
severe disease. B cell hyperactivity – (oligomonoclonal IgM kappa band in 25%)

Extragladnular involvement
Epithelitis – TIN, PBC
Cryoglobulinaemia related IC deposition – GN, vasculitis
Lymphocyte proliferation – LIP, lymphoma

Presentation
Classical
Mid aged female with
Dry eyes – gritty, daily, > 3m
Dry mouth –dry, need water for swallowing solids, wake up night to drink water, > 3m,
swollen partoids, dental caries, wearing dentures
Dyspareunia
+/- background CTD

Extra glandular manifestations

Skin
1. Xerosis – dry skin – itchy
2. Vasculitis – small vessel – purpura / medium vessel : PAN like picture. Latter is often with
Cryoglobs (U2D. usu cryo is small vessel vasculitis). Predicts lymphoma and death due to disease

3. Raynauds
 4. Annular erythema – raised ring (DD: Sweet Xd)/ polycyclic with scaling edge (DD: Subacute
Lupus) / urticarial like. All are non scarring, photosensitive, face and neck
5. Other – EN, LR, LP, vitiligo, cutaneous amyloidosis, granuloma annulare

MSK
1. Arthralgia – small and large. +ve RF / CCP predicts progression to RA
2. Mild myopathy

Lungs
1. Large airway disease – mucus deficiency, lack of saliva to protect from gastric acid
2. ILD – NSIP commonest. LIP strong association. Other UIP, COP

Cardiac – rare. Pericarditis, myocarditis, blocks (rarer than in neonates. No strong association with Abs)

GIT
1. Celiac
2. AIH, PBC
3. Pancreatic exocrine failure is surpurisingly uncommon. AI sclerosing pancreatitis probably occurs
with IgG4 – RD than with SjS

Renal
1. TIN
2. RTA
3. GN (MmPGN with cryo)

Genitourinary
1. VV dryness, dyspareunia
2. Interstitial cystitis

Neurology
PNS
1. Painful sensory neuropathy
2. Ataxic neuronopathy with ganglionitis – ataxia and autonomic dysfunction (Adie, tachy,
orthostatic hypotension)
3. Axonal SM PN
4. Pure sensory trigeminal neuropathy (spares V1 / corneal reflex intact. Lesion in gasserian
ganglion)

CNS
Multifocal recurrent events with long gaps in between
1. Stroke like events, cereblellar motor sensory effects, fits
2. Encephalopathy – dementia
3. Myelitis
4. ON, chorea
5. Aseptic meningitis

Hematological
Diagnosis
ACR/EULAR 2016

Exclusions
1. HCV
2. HIV
3. Sarcoid
4. IgG4RD
5. GVHD
6. H&N radiation
7. Amyloid

SICCA criteria 2012

AECG criteria 2002

Need 4/6 including III or IV

Approach
Objective evidence of
Dry eyes Schirmer test
Rose Bengal staining

Dry mouth Saxon test

Sialometry (not while on anticholinergics)
MRI evidence of salivary gland abnormalities (salt pepper or honey comb look)

Evidence of AI etiology
 Anti Ro / Anti La (can become positive with negative ANA). One or both are +ve in 60-80% of SjS.
 Established CTD – SLE, SSCl, PM-DM, RA
 Anti centromere Ab
 ANA > 1:320 AND positive RF

Lip biopsy if in doubt

Rule out mimickers HHH GIRLS

HIV – Diffuse CD8 lymphocytosis syndrome. Rare due to HAART. Parotid swelling sicca, lymphocytic
interstitial pneumonitis
HCV (males, older, hepatitis CRyo picture)
HTLV-1
Chronic GVHD
IgG4 (eosinophilia, high IgG4, pancreatitis, PSC, retroperitoneal fibrosis, inflammatory pseudotumors in
lungs breasts liver)
Radiation to head neck
Leukemia (B/L), Lymphoma (uni> bilateral)
Sarcoid – CXR, Ca

Look for secondary cause – SLE, SSCl, RA, PM

Investigate for complications

ABG, K, urine pH, acid loading, SE, UFR

Schirmer’s test
Standard kit filter paper over lower eyelid at lateral and mid 1/3 junction. Keep eyes gently closed.
Without topical anesnthesia to assess reflex tearing. < 5mm in 5min is positive for SjS

Ocular surface staining

to detect damaged tissue
rose Bengal – painful. Purple colour of devitalized tissue
alternative – fluorescein for cornea and lissamine
for conjunctiva
degree of staining is scored by standard criteria. Cut offs are
defined to say +ve or -ve

Saxon test chew a sponge and see the weight gain

DD
Dry eyes syndrome
SjS
Vit A Defi (xerostomia)
Age related dryness
Benign epithelial sialadenitis and dacroadentitis –precursor of LMALT, histo similar otSjS and
lymphoma. Ab negative
Anticholinergic drugs

Miculicz Xd (parotid and lacrimal enlargement)

SjS
IgG4 disorders
Lymphoma
Sarcoidosis (also shares arthritis and TIN. Bx can differentiate). HeerfordtXd, amyloidosis
Infections (Mumps, EBV, CMV, Coxsackie, HIV)
WG rarely causes BL parotid swelling
E&M – DM, cirrhosis, Chr pancreatitis, acro, hypogonadism
Predictors of lymphoma / GN

1. Persistent parotid swelling

2. Purpura, leucopenia
3. Low C4
4. Cryoglobulinaemia

Do UFR and lip biopsy to catch lymphoma!!

Rx

Tears
Avoid direutics, antiHTN, anticholinergics, antidepressants, windy or smoking areas, soft contat lenses,
corneal transplant, systemic pilorcarpine
Regular water, nystatin / clotrimazole for candida

Arthritis – HCQ, MTX, pred

Raynauds – nifedipine
RTA – HCO3
Vasculitis
Lymphoma – CHOP

MRI parotids - SjS

Adult onset Still’s disease

Yamaguchi critieria

5, at least 2 of majors

Major (FARL)
1. Fever > 102.2F for > 1week
2. Arthralgia / arthritis > 2wk
3. Rash – non pruruitic, mac pap, salmon pink, trunk / limbs, with fevers
4. Leucocytosis WBC > 12, N > 80%

Minor
1. Sorethroat
2. LN
3. Liver / spleen enlarged
4. High AST, ALT, LDH
5. RF and ANA (< 1:100) negative

Exclude
Infection, malignancy, other rheumatic disease

Note: ferritin, ESR, CRP are not there in criteria

Classical presentation
Fever, arthralgia, rash, pleurisy, LN

Ix
Joint XR - Periarticular osteopenia, erosions, narrow jt space

DD
Infection
Viral syndrome (parvo B19, hepatitis, HIV) – lacks quotidian fever and rash
Bacterial – IE (positive culture, band forms in blood picture are unusual in AOSD)

Rheumatic
RA – no fever, rash, LN. positive RF/ anti CCP
SLE – alopecia, skin lupus, RP, GN – not seen in AOSD
DM/PM – high CPK uncommon in AOSD
PAN – vasculitis, renal not usual in AOSD
Ferritin > 3000 not seen with other rheumat diseases than AOSD.

Neoplasms
 Lymphoma – LN Bx of AOSD may show paracortical immunoblastic hyperplasia, which is also
seen in lymphoma. Demonstration of bengin polyclonal B cell hyperplasia in IHC excluded
lymphoma
Angioimmunoblastic T cell lymphoma
Multicentric Castleman

DRESS – 2-6 wk after exposure

Eosinophilia, lymphocytosis (ASOD - neutrophilia)
Skin Bx

Schnitzler Xd
Fever, arthralgia, LN
Chronic urticaria, IgM kappa monoclonal gammopathy, bone pain, skeletal hyperostosis

Sweet Xd
Abrupt painful, edematous, and erythematous papules, plaques, or nodules on the skin
Fever, neutrophilia
History and Bx to differentiate

Kikuchi

HLH

Complications
MAS

Rx
Mild
NSAID (ibuprofen 800mg tds / naproxen 500mg bd)  if fail in 2 weeks  pred 0.5-1 mg/kg/d

Moderate
Pred 0.5-1 mg/kg/day  poor response at 2m (cant come below 10mg/d) :
Articular predominant : MTX  3-6m  infliximab
Non articular : anakinra (IL1 decoy)  tocilizumab (IL6 R blocker)  canakinumab (IL1beta
decoy)

Life threatening
MPP + anakinra
Familial Mediterranean Fever

Familial Mediterranean Fever (FMF, also known as recurrent polyserositis) is an autosomal recessive
disorder which typically presents by the second decade. It is more common in people of Turkish,
Armenian and Arabic descent

Features - attacks typically last 1-3 days

1. pyrexia
2. abdominal pain (due to peritonitis)
3. pleurisy
4. pericarditis
5. arthritis / synovitis
6. erysipeloid rash on lower limbs
7. rapid response to colchicines

DD
SLE – wont respond to colchicines
AIP – will have a positive urine PBG
Tel Hashomer criteria for the diagnosis of familial Mediterranean fever

Major:
● recurrent febrile episodes accompanied by peritonitis, synovitis, or pleuritis
● amyloidosis of amyloid A type without predisposing disease
● favourable response to colchicine.
Minor:
● recurrent febrile episodes
● erysipelas-like erythema
● FMF in a first-degree relative.

◆ Definitive diagnosis — two major or one major and two minor.

◆ Probable diagnosis–one major and one minor

Management
colchicine may help
Steroids are useless
Follow up with UFR – p’uria in amyloidosis
IgG4 related disorders

Spectrum of disorders characterized by

1. IgG4 +ve lymphoplasmacytic infiltration
2. Tumor like swellings in organs
3. Storiform fibrosis

Responds well to steroids

Epid
Mid – old men

CFx

Lymphadenopathy in most. May be the only feature

LoA & LoW ++ with Multiorgan disease

Organ diseases
1. Autoimmune pancreatitis – focal mass, Obs J
2. Salivary gland disease
a. Kruttner Xd – isolated sumbandibular gland disease
b. Miculicz Xd – affects all 3 of lacrimal, parotid and submandibular
3. Retroperitoneal fibrosis (periaortitis) – can cause obstructive nephropathy
4. Other organ disease
a. Reidel thyroiditis, fibrosing variant of Hashimoto thyroiditis
b. Sclerosing cholangitis
c. TIN, MGN, parenchymal nodules (mimicking RCCA)
d. Hypophysitis
e. Orbital pseudotumor
f. Lung – solitary nodule, bronchovascular plane fibrosis, alveolar – interstitial fibrosis,
ground glass
g. Constrictive pericarditis - rare

Dx

Histology
IgG4+ Lymphoplasmacytic infiltration + fibroblasts + eosinophils
Fibrosis
Thrombophlebitis (not in LN)
High serum IgG4, IgE

DDx
Gen LN
Diff from TB, Castlemann, sarcoid, lymphoma by lack of B symptoms, modest lymph node enlargement,
striking response to steroids
Fx on LN Bx
* no fibrosis and phlebitis. Often has Eosinophil infiltrates
* IgG4 +ve plasma cells in a LN biopsy is not Dxtic because these plasma cells occur in other CTDs / AIDs
as well
5 patterns
Castlemann Xd like
Follicular hyperplasia
Interfollicular expansion
Progressive transformation of germinal centre like
Nodal inflammatory pseudotumor

IgG4 related pancreatitis

DDx: Mimcs pancreatic cancer. Latter too can have high plasma IgG4 (but usu not > 2 x ULN)
CT – diffusely enlarged pancreas (sausage shaped) and halo around the origin are unique to IgG4R-AIP

IgG4 related sclerosing cholangitis

DDx: Mimics PSC / cholangiocarcinoma
Less obst jaundice, less regional LN, less pancreatomegaly, less CA19-9 and more interstitial fibrosis,
higher IgG4 level in plasma in IgG4RSC than in PSC/chaolangioCA
* no mention of cirrhosis as a manifestation of IgG4RD

IgG4 sialadenitis
DDx SjS
Milder sicca symptoms, associated allergic rhinitis, asthma, TIN, negative RF, ANA, and Sp. Anti ro and La
favours IgG4RD
Differentiated from histology (IgG4 positive lymphoplasmactic infiltration, thrombophlebitis etc) and
plasma IgG4 and IgE

Orbital pseudotumor
DDx – TB, WG, lymphoma, Graves, mets

Lung fibrosis + LN
DDx sarcoidosis

Skin Fx are non specific, and not like SSCl

NHx
Chronic disease
Remitting and relapsing
Risk of malignancy not certain

Rx
Good response to steroids
Some may need steroid sparing agents
 Systemic Lupus Erythematosus

Definition
AID with multisystem involvement
Typically – skin, hemat, renal, cerebral

Epidemiology
M:F=9:1
Young adults

Pathogenesis

Tissue
Defective apoptotic clearance
injury Load of debris (prot, nuclear material)
May be inherited !
complements

Ab – Ag complex

Defects in apoptotic debris clearance

B and T cell activation  including Plasma cells
autoreactive clones
Plasmacytoid IgG forms ICs which mediates tissue injury by
- IFN ( activate lymphoctyes, myeloids,
dendritic cells
cause inflammation)
with Fc R - Complement &
- FC alfa-gamma mediated pathways
Vicious cycle is sustained by maintaining B cell B cells
survival

IFN alfa
BAFF / BLyS
Leucocytes
activated

Tissue
injury
SLICC 2012 criteria / Clinical features
Auto antibodies in SLE

Most specific for SLE – dsDNA, Smith, anti ribosomal P

Rim pattern not seen when human cells are used as the medium (HEp-2). This method is more sensitive
than using rat cell medium where rim pattern may be seen
Typical ANA IF patterns
SLE – homogenous- ds DNA / speckled (Smith, ribosomal P)
dcSSCl – Speckled, SCl-70 (topoisomerase)
lcSSCl – centromere
MCTD – speckled - U1RNP
Anti Ro – associated with neonatal lupus and congenital heart block
Anti histone Ab
50% of SLE
Almost all with drug lupus.

IF pattern Ag Disease Predictions

Rim dsDNA SLE
Homogenous dsDNA SLE, RA
histone SLE drug/Iry
Speckled Smith SLE
Ro, La SjS Ro – neonatal CHB/lupus, Rowell
Jo, Mi-2 PM/DM
 SCl-70 dcSSCl SCl 70 – ILD
U1 RNP MCTD U1RNP – PHTN, RP, arthritis
U3 RNP SSCl? U3RNP – PHTN
RNA polymerase 3 SSCl RNA poly-3 – renal crisis
Ribosomal P SLE Ribosomal P – CNS, lupus hepatitis
Centromere Anti centromere lcSSCl PHTN
Nucleolar Anti nucleolar SLE, SSCl
PM-SCl SSCl PM-SCl – LcSSCl, myositis, calcinosis
RNP - ribonucleoprotein

Prognosis

Commonest CoD – ASCVD

x 7 increase in CAD
x 8 increase in stroke
x 17 increase in CV death
compared ot normal population

60% develop LN, 17% progress to ESRD

Flare
Symptoms /signs – lethargy, fatigue, arthralgia, worsening rash alopecia
Renal, CNS, vascular involvement predicts flares
Investigations – high dsDNA, BLyS
Low C3

Targets for therapy

IFNs
IFN three groups – I, II, III
IFN I – 14 subtypes – alfa, gamma etc
Too diverse to overcome by Ab to IFN
IFN R blockade is under trials - anifrolumab

BAFF/BLyS
BLyS released from leucocytes, binds to BAFF receptors in B cells
Maintains B cell survival, thus protecting autoreactive B cells against apoptosis

Belimumab – IgG1 lamba mAb neutralizing BLyS. Only FDA approved biologic for SLE
Atacicept – prevents BLyS and APRIL activating their receptors (BAFF-R, BCMA, TACI)
* ~ 50% of SLEs have high IFNalfa and BLyS, and its them in whom anti BLyS works best. HCQ
also decreased BLyS levels in this cohort

Inhibition of B cell activation by blocking intracellular second messenger systems

Eg: Bruton Janus Kinase under trial
Janus Kinase inhibitor Tofacitinib worked well for RA

Disease monitoring
ESR, dsDNA, nucleosome Ab – parallels disease activity
Hypoalb and alouria are markers of Lupus nephritis

SLEDAI and BILAG (British Isles Lupus Activity Group) are the most commonly used tools, but designed
for research than for clinical use.
SLE responder index (SRI) / SRI-50 – determines 50% improvement of disease

Simplified classification of SLE severity (BSR 2017)

Management
Only 4 drugs are FDA approved
Aspirin / NSAIDs
HCQ
Prednisolone
 Belimumab
Sunscreen
Stop smoking
?? vaccination
Mild SLE

Dose Benefits Monitoring

GC Topical for skin Symptoms relief GC toxicity // dose
IA / IM for arthritis For induction, 0.5 mg/kg/d is often good Dose increase by 1mg
Oral SC for enough (Prof PG) increases organ damage
remission induction by 2.8%
(20/d x 14d)
Maintenance <
7.5mg/d
HCQ < 6.5 mg/kg/d Beneficial for skin, MSK, renal, serositis, For retiopathy
Imm sup, fever, fatigue, CNS CQ > HCQ > Mepacrine
reduce Reduces flares, maintains remission, Sp when used :
prolif, inhib prevents thrombosis, improves > 6.5mg/kg/d
thrombosis, pregnancy outcomes, reduces neonatal > 7y
photo- CHB KD / LD
protective, Improves lipids, Glc, CVDr and mortality Screen annually.
Reversible in the initial
stages
neuromyotoxicity,
cardiomyopathy
NSAID Short course of arthralgia, myalgia, Avoid in LN
fever, serositis Higher risk of hepatitis,
Try to minimize use aseptic meningitis, TIN,
allergy in SLE
MTX < 25mg/wk Joint and skin Sy Avoid in pregnancy,
Steroid sparing effect renal failure
Sunscreen High SPF (sun Prevent skin flares (and some organ
protection factor flares too!!!)
30-50)

Moderate SLE
GC (pred 0.5mg/kg/d) / MPP
MTX, AZA, MMF, CSP, tac
Belimumab, rituximab

AZA
2-2.5 mg/kg/d
Reduce flares, GC sparing
No reduction in CVDs
Can use in renal disease. Not excerted renally
No increase in subfertility, teratogenecity, cancer

MMF
GC sparing
Reduce flares
Cytopenias +, teratogenic

CSP / TAC

No cytopenias
Preg / BF safe

LEF
weak evidence
Use only when no other drug can be used!

Rituximab
For refractory moderate SLE
Avoid pregnancy for 6m
2 RCTs failed to meet endpoints (EXPLORER for non renal SLE and LUNAR for LN). RITUXILUP on the way
Reasonable evidence from cohort studies
Risks of ling term use – hypogammaglobulinemia, infections, PML

Belimumab
For refractory moderate SLE
BLISS 52 and 76
Improves skin, MSK and overall disease activity

Severe disease - Organ or life threatening

MPP / pred 1mg/kg/day

MMF or CPM
Rituximab / belimumab
IVIG, PLEX for TTP, CAPS, severe cytopenias, rapidly deteriorating confusional state
Steroids
Prednisolone 9 mg/d = 25 mg/d (low dose = high dose)
MPP pulsing much less SE and oral regimens
Prednisolone
> 6mg/d – increase risk of organ injury by 50%
10 - 19 mg/d – increase CVDr x 2.4
> 20 mg/d = increase CVDe x 5

CYCP
EUROLUPUS regimen – low dose frequent CPP (500mg 2 weekly 3 m) is as effective as high dose les
frequent regimen (1g 4 weekly 6 months)

CY-A oral CycA is as effective as IV CPP for induction (CYCLOFA… trial 2014)

Rituximab
EXPLORER & LUNAR trials – no benefit (drawback – Pt were on high steroids)
RITUXILUP – 2 doses of rituximab and MMF daily is good enough to stop Glcc altogether

New:
Belimumab (BLISS 52 & 76)

ORGAN SPECIIFC MANAGEMENT

CUTANEOUS LUPUS
Most do not meet the SLE criteria, but still benefit from SLE-Skin therapy
Topical alone for mild disease
Systemic for
1. Multifocal
2. Severe
3. High scarring risk

SLE specific skin lesions

Chronic
Discoid - localized (above the neck), generalized (above and below neck) hypertrophic
(verrucous)
Panniculitis (Lupus profundus)
Tumid
Chillblains
Mucosal lupus

Sub acute
Plaques - Psoriasiform/ Polycyclic / annular

Acute
1. Macular- Malar erythema, photodistribution erythema
2. MP
3. Bullous SLE
4. TEN SLE

Mgt
General measures
 Stop smoking
 PPIs statins – trigger subacute lupus
 Avoid heat and sun
 Sunscreen
o Need SPF > 70 sunscreens (for cancer prevention 30 s enough. But lupus skin is more
sensitive)
o With UVA blocker

Topical therapy
Steroids
Tacrolimus – non steroid T cell inhibitors – no skin thinning
IL steroids

Systemic therapy
Antimalarials
HCQ – takes months to work
If not effective, add quinine. Takes 1-2 mo to act
If combination is not effective, switch to CQ

Other ImmSupps
conventional
MTX
MMF
AZT – safe in preg, but less effective
Thalidomide – for severest cases. Risk of DVT (new - lenalidomide)

Biologics
Belimumab – some benefit trial level
Rituximab – some benefit in acute lupus, but may trigger subacute lupus! Clear benefit
in bullous lupus where glcc and dapsone often doesn’t work
Anifrolumab -under trial. IFN receptor blockern
Ustekinumab – under trial - . IL-23, 12 blockers

Rowell syndrome –

Need all major and 1 minor

LUPUS NEPHRITIS
Definition

In a pt with SLE, LN is diagnosed if;

Persistent Proteinuria >0.5 g/24h OR

UFR protein more than 3+
Spot UPCR > 0.5

OR

Cellular casts OR
Active urinary sediment (> 5 RBC/hpf, > 5 WBC / hpf or RBC or WBC cast )

OR

Lupus nephritis on Bx

Indications renal biopsy in SLE

1. Rising creatinine without an explanation
2. Proteinuria > 1g / 24h OR in spot UPCR
3. Proteinuria > 0.5g/24h AND RBC > 5/hpf
4. Proteinuria > 0.5g/24h AND cellular casts

Importance of renal Bx
Confirm diagnosis
Stage LN
Activity and chronicity index
Tubular, vascular and interstitial status

Treatment

Name EM – IC deposition LM – cellularity Rx

I Minimal mesangial Mesangial (minimal) No proliferation No Rx
II Mesangioprolif Mesangial Mesangial prolif No Rx
III Focal proliferative Subendothelial Prolif in < 50% glomeruli Aggressive
IV Diffuse Subendothelial Prolif in > 50% of glomeruli Aggressive
proliferative
V Membranous Subepithelial Membrane thickening Aggressive if
concurrent III/IV
VI Advanced > 90% of glomeruli sclerosed RRT
sclerosing
Higher chronicity index predicts poor Rx response

General measures
1. HCQ: All with LN need HCQ (reduces flares, renal damage, clotting events)
2. ACEi: All with proteinuria > 0.5g/24h need ACEI / ARB (reduces proteinuriaby 30%, slows
progression of renal impairment)
3. BP < 130/80
4. Statins if LDL > 100

Immunotherapy - Class III / IV Glcc + CPP / MMF (CPP = MMF)

Drug Induction Maintenance

Glcc Pulse MPP (500-1000mg daily x 3 ~ 5mg/d Expert opinion
(common to days)
both followed by oral Glcc (0.5 – 1
regimens) mg/kg/d) for 1m and taper
MMF (MMF 2-3 g / day x 6 months* lower dose ALMS trial.
regimen) for 3 years *3g if: crescents / proteinuria /
rising Cr
CPP (CPP IV CPP 500 mg 2 weekly for 6 AZT or MMF Euro-lupus Nephritis Trial (ELNT)
regimen) doses OR AZT not for induction (less
IV CPP 500-1000mg monthly for 6 efficacious)
months

Evidence
 NIH studies established CPP based regimens are superior to Glcc alone. NIH protocol included high
dose CPP IV monthly for 6 months and 2 quarterly pulses. Dose was titrated to WBC nadir.
 ELNT (n=90) showed that low dose CPP 500mg/dose 2 weekly for 6 doses is equal in efficacy (in
achieving renal remission). Equal efficacy and safety was confirmed at 10 yr follow up of ELNT.
 ACCESS trial among ethincally diverse North Americans (with blacks and hispanics) designed to
assess abatecept Vs Eurolupus showed abatecept is inferior. This study also had comparable renal
remission (24hUPE < 0.5g and NL CrCL at 6m) rates (20-25%) to Europeans in ELNT and ALMS
(Aspreva Lupus Management Study)
* MMF – mycophenolic acid, is an inhibitor of inosine 5 monophosphate dehydrogenase and deplete
guanosines in T and B cells. Pass med says, it is equal in efficacy to CPP but causes less infections and is
therefore preferred over CPP for Rx of LN

Local data on euro-lupus regimen

2017 BMC Res Notes Nalaka Herath et al: sample comparable to ELNT. Retrospective observational.
Response rate 75% (ELNT 71%)
Relapse rate 36% (ELNT 27%)

Assessing response to therapy

Monitor BP, 24uPE / UPCR, UFR, C3, C4, anti-dsDNA Ab
Reduction of proteinuria by 25% at 2 months
Reduction of proteinuria to < 1g/d at 6 months
Reduction of C3 C4 at 2 months
Predicts better prognosis
Ideally, resolution should be defined by histological assessment. Proteinuria may settle despite having
on going histological disease, thus ending up in ESKD. Similarly, even if proteinuria persists, if the
histology has cleared, immunosuppressants are not needed!

CPP can induce permanent infertility in both men and women.

MMF is therefore preferred if family in incomplete.
MMF is teratogenic. Stop 6 weeks before attempting pregnancy

LN with crescents
Induction with IV CPP and IV MPP (followed by 1mg/kg/d of prednisolone) probably better than MMF
induction
In summary
Induce Eurolupus / NIH OR MMF + GC x 6m
Success maintenance : with MMF / AZT
Failure
 Re induction with the other regimen
 success  maintain with MMF / AZT
 failure  ritux / CNI + GC

When to re biopsy?
1. In complete remission, before stopping treatment, to confirm histological remission
2. In a flare after complete remission, if the first biopsy was class II or V (if the first was III/IV, it is likely
to be the same; but with II/V it is likely to have switched)

Partial or no response or deterioration while on therapy occurs with the same histology so biopsy is
unlikely to be of use

Neurolupus
Central nervous system
> 5 % Stroke
Seizures
1-5% headache, depression, cognitive dysfunction,
Cranial nerve palsies (III, IV, VI, VIII > > V, VII), optic neuritis
Acute confusional state
Myelopathy (TM, thrombosis, NMO)

Peripheral
MnM
PN
GBS
MG
Plexopathy
Myopathy

Central nervous lupus pathogenesis and classification

aPL mediated ischaemia stroke, cognitive impairment
anti neural Ab inflammation fits, psychosis
DD for acute confusional state / fits
CNS lupus
CNS infection
CVST
TTP
CAPS
Steroid psychosis (actually mood > psychosis, in SLE, psychosis > mood)

Demyelinating disorders of spine need aggressive Rx to prevent long term disability

Start MPP empirically after excluding or covering for infections

Rx
Trend towards lower steroids dosing
MPP 500 mg/d  0.5-0.75 mg/d maintenance pred
AZT or MMF as steroids sparing and for maintenance
For severe cases
CPM
PLEX – refractory LN / CNS / hemat or TTP, CAPS etc
IVIG – refractory heamt, TTP, CAPS

G
Drug induced lupus (DIL)
Skin and arthralgia
Serositis
Renal and cerebral involvement is unusal

Drugs:
Procainamide
Hydralazine
Diltiazem
Phenytoin
Isoniazid
Minocycline
SSZ

ANA +ve in all (100% - usu its anti histone Ab).

Antihsitone Ab in 90%
Anti Ro and anti Sm in 5%
dsDNA always negative (except with minocycline and biologics – infliximab etc)
Major organs not affected (except SSZ – renal lupus)
Complements normal in DIL (except in biologic induced lupus)

SLE in pregnancy
Tend to flare unlike most other AI disorders

Contraception in SLE
Problems
COC – increase DVT
CIn in – APLS, moderate to severe active SLE, HTN, smoking, obesity, past DVT
Can use cautiously if in remission with none of above CIn
COCP does not increase disease flares

Options
Barriers – high failure rate (18% annual preg rate among proper users!)
Cu IUCD – very effective. Increase uterine bleeding
POP and depots (???can be considered for those who are APLS negative and has stable or inactive SLE)
Depo provera – 3m
Progesterone subdermal implants- 3y (Jadelle - 3-5y)
Mirena IU system – 5y. Mirena – does not increase DVT. Decrease uterine bleeding. Useful for those on
anticoagulants
Fertility in SLE
Patients with SLE are not infertile, but may have low fertility :
Low due to
Disease activity
Amenorrhea due to flares
GFR < 60
 Drugs – CPM
APLS – does this reduce ability to conceive or risk of MC / IUD etc ??
* in contrast, RA does reduce fertility

Preserving fertility
GnRH analogues while on CPM stops ovulation and reduces follicles exposed to CPM

Assisting fertility
OI + IVF safe in inactive or stable disease (consider risk of ovarian hyperstimulation and DVT)
Anticoag / aspirin for those with APLS improves fertility

Problems to anticipate
Maternal:
1. SLE flare
2. APLS : DVT, CAPS
3. Pre eclampsia
Fetal / newborn :
1. MC, IUGR, preterm birth, IUD
2. Neonatal lupus – NLE, CHB, hepatic and hematological lupus
3. Drug teratogenicity

Risk of death in SLE during pregnancy

Higher than non-SLE pregnancies
Lesser than non-pregnant SLEs!

Pre-pregnancy screening
1. Rule out contra indications for pregnancy
2. Identify other risk factors for adverse pregnancy outcomes
a. Anti Ro anti La
b. aPL (BSR recommends screening for aPL with LA, aCL Ab and anti GP II Ab for all newly Dxed
SLE and SLE planning for pregnancy even if they have not had thrombotic events)
3. Modify medication – start / consider aspirin, LMWH, HCQ, FA, Ca, nife / labe / mdopa / hydral /
doxazosin. stop ACEI, statin, warfarin, DMARDS except CASH (CSP/TAC, AZT, SSZ, HCQ)
DAMRDS TO STOP : MTX (6.6%), CPM (27%) and MMF (27%) [stop due to teratogenecity, rates in
brackets, normal population terato rate is 3%]. LEF terato rate is 4.8%, Europeans do not
recommend to stop LEF
4. Plan F/U – rheumat, nephro, O&G ++ liaision in a specialized centre
5. Keep in remission for 6m (2014 review suggests, 4m is enough)

Contra indications for pregnancy in SLE

Within 6m
Severe flare (Disease activity – Sy, Si, ESR, dsDNA titre, C3 C4, SLEDAI)
Renal flare (UFR)
Stroke

During previous pregnancy

 Pre eclampsia or HELLP despite therapy with aspirin and heparin

Significant organ involvement (Cr, 2D echo, CXR/PFT sos)

CKD : Cr > 2.8 mg/dL / eGFR < 30
CCF : EF < 40%
ILD : FVC < 1L or < 50% of predicted best
PHT: syst PAP > 50 mmHg

APLS Mgt

Persistent aPL positivity

With thrombotic events without thrombotic events

With preg complications without preg complications

Fetal loss+ preterms only

ASA & [Link] ASA from planning ASA from T2 none (except peripartum DVT Px)
PP: warfarin [Link] from confirm

ASA – aspirin 75
Impact of isolated Positive aPL on pregnancy are not known. No therapeutic recommnedations exist.

Ro – La Mgt – see CHB

Pre-pregnancy medication modification

- Stop ACEi, statins, MMF
- Should be at least 3m off MTX (2y off lefra) prior to conception
- Switch to AZT
- Can continue HCQ. If needed, CSP, AZT, Tacrolimus, steroids are ok in pregnancy. Can give aspirin
and PCM. NSAIDs should be stopped after 32wk (persistant PDA0)
- Keep steroids at the lowest possible dose (maternal DM, HPT, fetal IUGR, cleft palate / lip, may be
neurocognitive impairment)
- Biologic DMARDS
o Infliximab : safe till late T2
o Adalimimuab, etanercept : safet till T3
o Certolizumab : safe throughout
- Post portum
o Only CPM is CIn
 o MTX levels in BM are low. Take the pill and feed after a 4h gap. Same for other DMARDs
as well
o Biologics can be started 1-2 wk after an uncomplicated delivery
- BP control – methyldopa, labetalol, nifedipine, hydralazine
- Give aspirin to all with SLE going in to pregnancy, starting from 12 weeks, to prevent pre eclampsia
- Supplements
o Folic acid 0.4mg/d, increase to 5mg/d if was on MTX within last 3m, has DM, obesity or
Hx of NTDs
o Caclium 1g/day for all – reduces pre eclampsia and PTD
- Optimum body weight – improve fertility, reduce DVT

Indications for aspirin

1. Aspirin 75mg n from T2 to all mothers with SLE irrespective of aPL status (reduces pre eclampsia,
IUGR, IUD, maternal death by 10%)
2. LN
3. APLS – with DVT (from planning stage) / fetal loss (from planning stage) / PTD (from T2)
4. Risk of / presence of placental insufficiency

Indications for LMWH

For obstetric benefits
1. APLS with history of fetal loss – from the time of confirmation of preg. prophylactic dose

For maternal DVT prevention

1. APLS with history of DVT – therapeutic dose from the time of confirmation of pregnancy
2. Proteinuria > 1-2 g/day – prophylactic dose

HCQ during pregnancy prevents

Flares
Organ damage
DVT
Bone mass loss
Mortality long term
Reduce fetal brady and neonatal lupus in Ro/La positive mothers

Monitoring during pregnancy

Risk if flares increased due to high estrogen state and shift of immunity from Th1 to Th2

Mother for
- disease flare (Sy Si, BP, dsDNA titre, C3 C4 – fall by > 25% from baseline, UFR – up to doubling of pre-
pregnancy proteinuria is expected with pregnancy and ACEi withdrawal, FBC). C3 and C4
increase during normal pregnancy. Low C3,C4 or even normal range C3 C4 with a > 25% decline
from baseline should suggest a flare
Often mild – skin and joint
Sts major – commonest are renal and hemat
- PIH
- DVT

Fetus for placental insufficiency (IUGR, oligohydramnios, Umbilical vein Doppler) and CHB (FHR, fetal
echo)

Problems in interpretation of clinical features and investigations

Pregnancy itself can cause
Malar and palmar erythema, edema, hair loss, fatigue
High ESR (dilutional anemia and high fibrinogenaemia)
Proteinuria
High complements (masking low complements of SLE flare)
Thrombocytopenia, anemia

Options for managing SLE during pregnancy

Maintenance – CSP / TAC, AZT, steroids (try to avoid or give the lowest dose. Try to keep < 7.5mg/day),
HCQ
For flares – MPP, IVIG, PLEX

In case of doubt, IVIG is the safest immunomodulator to treat disease flare without increasing risk of
sepsis

SLE/LN flare Pre eclampsia

Timing Any > 20weeks
P/W Edema, hypertension, renal impairment Headache, visual symptoms,
Other SLE symptoms flare RUQ pain, clonus
UFR Proteinuria and active sediment Proteinuria and bland sediment
FBC NL except in concomitant hemat flare. Low Plt Low plt. H’lysis.
if APLS, TTP, ITP
VEGF and NL Low
Placental GF level
Uric acid Normal High
AST ALT Normal High
dsDNA, C3, C4 High dsDNA, C3 C4 fall by > 25% Normal
After delivery No improvement Improves

Management of labour

Mode of delivery
LSCS for obstetric indications – increase risk of bleeding, DVT, problems for future pregnancies

Medication adjustments
IV HC 50-100mg tds on entering labour. Double the oral pred for 2-3 days post partum
LMWH
Discontinue at onset of labour
Stop 12h before (if prophy dose) / 24h ebfore (if therapeutic dose) before induced labour

Post-partum care of the mother

Step up pred for 2-3 days
Continue LMWH for 6 weeks. Can convert to warfarin after 5-7 days of delivery upon maternal
preference
Encourage mobility and breast feeding
Assess for disease flare – risk may be increased

Neonatal outcomes
Effects of IUGR etc

Neonatal lupus
1. Neonatal lupus erythematosus – SCLE rash on forehead. Resolves w/o scarring by 6m (with
clearance of maternal Ab)
2. Complete heart block – permanent. Needs PPM. Increase neonatal mortality
3. Hematologic hepatic neonatal lupus - transient
All predicted by anti Ro and La Abs. IgG type is actively transported across placenta between 16-30
weeks

CHB
 Affects 2% of Ro positive pregnancies
 Mothers with SLE, SjS, MCTD (and may be UCTD) are at risk
 USS heart at 18-20 weeks. Consider repeating at 26-28 wk. US recommends regular screening
between 16 – 28 weeks
 Record FHR 1-2 weekly at ANC. Urgently refer if FHR is < 110
 FHR < 55 predicts fetal hydrops and IUD – extremely poor prognosis for the fetus
 Can try dexamethasone or betamethasone – crosses placenta. Prednisolone does not (catabolized
by placental ?hydroxylase enzyme). EBM for benefit of Glcc is not convincing
 Increase the risk of CHB in subsequent pregnancies by 18%
 HCQ 400mg/d (5.5 – 6 mg/kg/d, no dose change from non pregnant values) reduce development of
CHB and recurrence in mothers with Ro positivity
DD for
Difficulty in standing up from sitting position
1. Prox myopathy
2. Hip AVN
3. Path #

Proximal muscle weakness in SLE

1. Polymyositis
2. Steroid myopathy
3. Osteomalacia
4. Diabetic plexopathy (Amyotrophy)
5. Hypothyroidism
6. Statin

Fits
1. Cerebral lupus
2. CVST
3. Stroke / ? CAPS
4. Infection
5. TTP
6. Uremia
7. HTN encephalopathy

AKI
1. LN
2. TTP / CAPS
3. Sepsis
4. Malignant HTN

Cytopenias
1. Hemat lupus
2. Drugs
3. BM infections
4. HLH

HRT – can be used for menopausal symptoms. Balance the risk of DVT in those with APLS
Systemic sclerosis

Definition
Autoimmune disease causing vasculopathy and fibrosis

Classification
Scleroderma (thickened skin)
Localized
Linear scleroderma – dermatomal sclerosis, childhood
Morphea (localized / generalized) – spares face and hands

Systemic
LcSSCl

DcSSCl
RP with scleroderma, ILD,
SCl sine scleroderma
SSCl like organ and Ab profile

LcSSCl dcSSCl
% 70% 30%
Skin Face, below EJ, KJ Trunk, prox limbs
RP RP precedes scleroderma by years RP with scleroderma
RS PAH ILD
Renal crisis Less more
In CREST In all
Ab Centromere Scl 70 /(topoisomerase 1)
Prognosis Better. 5y survival 90% Worse. 5y survival 70%

Epidemiology
M:F=1:4

Pathology
Autoimmunity

Vasculopathy
RP, nailfold capillary abnormlaities, PAH, renal disease, GAVE,
Clinical features
Skin
Nails
Dilated loops – early disease
Dropouts – active disease
Tortuous loops – advanced disease

Raynauds phenomenon
Primary (raynauds disease) OR secondary (R phenomenon)
On cold exposure / stress:
White (ischemia)  blue (cyanosis)  on rewarming remains blue for 15-20 min and then turns red
(reperfusion)
Ischemic symptoms: tingling / pain / ulceration

Secondary causes
1. SLE, RA Features favouring
2. Leukaemia secondary Raynauds
3. Type 1 cryoglobulinaemia,cold agglutinins 1. Onset after 40y
4. OCP, ergots 2. Female sex
5. Cervical rib 3. Unilateral
6. Operating vibrating tools 4. Affects thumb
5. Digital ulceration
Treatment 6. Features of SLE / RA
AVOID – cold, stress, BB, smoking, OCP (warmers, gloves) 7. Auto Ab
1st line – CCBs (nife 30-180mg/d, amlod 5-20m/d) 8. Rashes
2nd line – add sildenafil if not possible topical GTN 9. Rarely chilblains (painful
3rd line – losartan, prazosin, fluoxetine itchy swellings on hands
Ulceration – aspirin, IV prostacyclin (iloprost) infusion, bosentan feet etc)
Acute ischemia with new thrombosis – anticaog / T’lysis, IV prostacyclin
Acute ischemia with ulceration - add sympathectomy (chemical – local
lidocaine) / surgical (cervical / local digital)
Pictures of sclerodactyly, RP, speckled leucoderma, calcinosis cutis, GAVE, esophageal dysmotility
bariums, ILD HRCT,
Calcinosis cutis
Diagnosis
2013 ACR / EULAR criteria

Suspect SSCl
Alternative etiologies unlikely
Exclude those without digital skin sclerosis
Scoring
Skin thickening of fingers, extending proximal to MCP 9 OR
Thickening only distal to MCP 4 OR
Puffy finger 2

Finger tip pitting scars 3 OR

Finger tip ulcers 2

Telengiectasia 2
Abnormal nailfold capiilaries 2
PHT & / or ILD 2
RP 3
Ab (centromere / Scl 70 / RNA polymerase III) 3

 9 ir more suggests SSCl

 Sn Sp 90-95%
  10% of MCTDs becomes positive for SSCl with this

Auto antibody profile

ANA – speckled pattern
U3 RNP – PAH
RNA polymerase III – renal crisis
PM SCl - myositis
DD

Overall clinical profile

 MCTD
 Overlap syndrome

for skin changes S M S D E P N G – scleredema, Myxedema, scleremyxedema, Diab, Eos,

POEMS, NSF, GVHD

Sclerederma
Thickening of upper trunk skin, upper back and behind shoulders, face. Spares fingers. Spares
esophagus. Affects tongue (spared in scleroderma). Visceral disease and other skin lesions (RP,
calcinosis, speckled leucoderma) are rare / not seen
3 types
Type 1 post infectious. Commonly streptococcus. Resolves in 3-6m. Rx - penicillin
Type 2 with haemat neoplasms (usu paraproteinaemia). Treat the cause. IVIG
Type 3 with diabetes. Improving glycemic control will not improve the skin
When occurs in T1DM – called sclerederma of Buschke

Biopsy – collagen excess < mucopolysaccharide accumulation between collagens, stained in Alcian stain.
No fibroblasts (as in scleromyxedema or NSF). No infl infiltration as in scleroderma (which will also have
abundant collagen but no mucopolysaccharides)
Scleromyxedema (papular mucinosis)
IgG lambda
AL amyloid / MM associated

Eosinophilic fasciitis
Often after a vigourous exercise, some have +ve borrelia serology
Erythema, swelling, induration, groove sign
Forearms and claves, sparing hands and feet
High E, ESR, CRP, polyclonal hypergammaglob
Dx – deep skin biopsy upto muscle level
MRI can help
Rx – pred (1-1.5 mg/kg/d)  MTX, other, biologics

Diabetic cheiroarthropathy
Chronic T1DM
No RP, Calcinosis, ulceration, Abs

Myxedema

POEMS
Hyperpigmentation, hypopigmented patches, sclerodactyly

NSF
 2.5-5% risk if eGFR is < 30
 Appearance similar to eosinophilic fasciitis, but affects palms and soles too
 Usu 2-4 weeks after the Gd exposure
 CFx
o Initial feature may be erythematosus swelling, resembling cellulitis. Indurates and form
plaques with woody / cobblestone / peau d orange texture. Can extend deep even to muscle
level. Skin fibrosis cause contractures
o Starts from feet, ankles, legs, hands, wrists. Extends proximally. Trunk less commonly
affected, head and face spared. But yellow plaques in sclera are characteristic. Some get
sclerodactlyly
o Some have visceral fibrosis as well. – restrictive lung disease with low DLCO ( what happens
to KCO?), pleural, pericardial and dural fibrosis, fibrotic cardiomyopathy
 Dx – skin punch biopsy – fibroblasts, fiborosis
 Px
o Avoid Gd in GFR < 30, in AKI or CKD
o If essential, HD within hours after the procedure and repeat once in 24h
 Rx
o physioRx and splints to prevent contractures
o KT (restoration of GFR halts progression)
 SSCl Scleromyxedema NSF E fasciitis
Distribution Face and limbs Face and limbs Spares face Spares hands and feet
Associated RP + - No RP -
ESR High High High ? high
Special Ix ANA / SCl-70 IgG Lambda band None High E

Chronic GVHD

Treatment

Pulmonary disease in SSCl

1. ILD
2. PHTN – PAH, type III PHTN, CETPH, pulmonary capillary hemagiomatosis, PVOD
3. Other

ILD
NSIP > UIP
Fibrotic > cellular NSIP. Temporally homogenous. No fibroblast foci
50% of DCSSCl, 25% LcSSCl
Onset often coincides with skin disease onset
Presence predicts poor prognosis

Dx
HRCT
PFT – restrictive – FVC and/or TLC < 80% predicted, reduced DLCO (<80% predicted), small flow volume
loop.
Lung biopsy if atypical Fx present (fever, asymmetric CXR Fx, nodules, rapid onset and progression)

Rx
1st line – MMF
2nd line – CPP : IV preferred over oral
Alrternative – AZT
For refractory disease – rituximab.
Lung transplant (+ heart if PHT+)
Treatment in early disease (where inflammation is active) is more likely to be of benefit

Scleroderma Lung Study (SLS)

SLS-I
Oral CPM 2mg/kg/d or less (for 12m) was superior to plcebo in Rx of SSCl ILD, at 24m

SLS-II
MC-RCT USA
N = 146
MMF 1.5g bd x 24m Vs CPM 2mg/kg/d x 12m (placebo for next 12m)
MMF was not superior in efficacy (FVC improvement)
MMF was safer (less cytopenias, drug witdrawals, overall and lung related mortality)

SLS – III
Phase II trial
MMF 1.5g bd Vs MMF + prifenidone
Target N 150
Underway

PHTN
10-15% of SSCl
Causes
PAH – commonest cause. More in LcSSCl
PH-ILD
CTEPH –
PVOD / PCH – may be 2 ends of a spectrum. Imaging shows pulmonary edema. Normal LA pressures.
(U2D: normal PCWP). Pul edema worsens with vasodilators. Typically higher PA systolic pressures than
in PAH (> 45mmHg)
PHTN screening: Ex SoB, presyncope, syncope, angina (RV strain), loud P2, TTE estimated PA
pressure > 35mmHg,
NT proBNP high
Confirmation: RHC – PAP > 25 mmHg with PCWP < 15 mmHg
Features to suggest PAH
1. LcSSCl
2. Non advanced ILD on HRCT
3. SpO2 > 88% at rest and exertion
4. Annual DLCO reduction > 20%
5. FVC / DLCO < 1.6
In pulmonary veno occlusive disease (PVOD) and PCH causing PHT, vasodilators will cause pulmonary
edema, so important to rule out.

Other lung involvements

Pl effusion – L exudative
Pleuritis, HF, PE, cancerpneumonia, pericarditis with tamponade, SLE overlap

pneumothorax, Brochiectasis, resp muscle weakness, bronchiolitis, lung CA

Renal disease
Commonest cause for proteinuria in SSCl is penicillamine. Disappears after withdrawal
Causes of renal disease in SSCl
1. Drugs – NSAIDs, penicillamine, diuretics, CSP
2. Disease – renal ischaemia, GN rare
3. Hypovolemia / pre renal – PHT / HF / diarrhea
4. HTN

Scleroderma renal crisis

10-20% of DCSScl. Much rarer in LCSScl
If it is going to occur, it will invariably come within the first 5y from disease onset

1. Acute severe hypertension – lesser the degree of BP elevation, worse the outcome
2. Progressive renal failure
3. UFR – normal / mild proteinuria with few cells or casts

RF
diffuse SSCl
Steroids
Anti RNA polymerase III Ab
Black race (Sharma Q 198)
Cold weather (Sharma Q 198)
Path
Obliterative vasculopathy of arcuate and interlobular arteries

Clinical predictors of renal crisis

1. dcSSCl
2. < 5y
3. RNA polymerase I and III Ab
4. Tendon friction rubs
5. Pericardial effusion
6. Unexplained anemia / thrombocytopenia

CFx
HTN (NL BP in 10% - poor prognosis)
Renal failure
MAHA. Thrombocytopenia is less than in TTP / HUS
Proteinuria+, hematuria not usual

DD
other MAHAs
1. TTP/HUS
2. Catasptrophic APLS
3. Malignant hypertension
4. Transplant rejection

Rx
Captopril (best studied ACEI). Rapid onset and short duration of action allows dose titration
Reduce BP ~ 20mmHg / day, to reach baseline BP in 72h
If not enough – try amlodipine
Better to avoid beta blokcers – theoretical risk of Raynauds
Rapid reduction of BP with IV labetalol / nitroprusside worsens renal function
HD
KT – do less well than other CKD pts, but is better than SSCl on chronic HD
50% develop ESKD

Skin disease

Monitor modified Rodnan scale (same evaluator)

Dexamethasone pulses …
Safety guidelines for biologics – BSR 2018 Aug

Pre treatment screening

1. FBC, RFT, LFT for all
2. TB screen for all –
a. Mantoux / IGRA
i. IGRA less affected by pre existing immunodeficiency
ii. Neither useful in past TB cases
b. CXR – do for all.
c. Sp AFB – to rule out active TB
3. Viral hepatitis screen for all
a. HBsAg, HBsAb, HBcAb
b. HCV Ab
4. Lipid profile before tocilizumab

Pre treatment optimization

1. TB
a. Latent TB -
 i. H 6m / HR 3m
ii. Can start biologics after completing 1m of Rx
b. Active TB
i. full therapy
ii. can start biologics after 3m
c. etanercept has the least TB reactivating potential out of TNF blockers

2. hepatitis - positive hep B screen / HCV screen

a. DNA load / RNA load
b. Start anti hepB therapy
c. Can give biologics cautiously
d. Extra caution with HCV

3. Rule out active infection

4. Vaccination –
a. Hep B if at risk
b. VZV – if Ab negative / no PHx of disease / vaccination
c. Annual influenza and pneumococcal – less efficacious. Still, do give.

Co-morbidities
CCF – no longer a CIn. Anti TNF may even improve EF and reduce re MI
HIV – can give biologics as long as CD4 > 200 and viral load is undetectable
Pregnancy ?
Cancer
No definite evidence of increased risk
Take measures to prevent non melanoma skin cancer
In past cancer pts, prefer rituximab

Monitoring
FBC, RFT, LFT
3-6 montly
Monthly if also on a cDMARD
Monthly fot tocilizumab.
Lipid profile – 3 monthly for tocilizumab

VZV exposure  give PEP if not Ab+

PML – avoid rechallenge
Demyelination – avoid rechallege
Lupus  swtich to non TNF Rx

Avoid live att vaccines. If needed, give a 2-4wk off Rx period

Stop peri-op
-3-6m  + 2wk for ritux
-4wk  + 2wk for toci
Concerns of ASCVD
bDMARDS increase LDLC. Will they increase ASCVD ?
TNFai and MTX increase HDL

VASCULITIS

Vasculitis clinical syndrome

1. Constitutional symptoms
2. Palpable purpura*, GN, Pulmonary infiltrates, Mononeuritis multiplex
3. Unexplained ischemic events / pulse deficits (bruits, absent pulses)

Palpable purpura is a feature of small vessel vasculitis.

Medium vessel vasculitis (PAN) classically causes nodules, ulcers, reteform purpura and livedo racemosa
Bx: infl infiltrate in /around vessel + fibrinoid necrosis (fibrin deposition in the wall / lumen).
Large vessel vasculitis – lymphohistiocytic infiltration in media. Small /medium vasculitis- adventitia

Vasculitis DD
Vasculitis mimics Causing secondary vasculitis
CTDs SLE, SSCl SLE, SSCl, RA, SjS, PM, Behcets
Hemat APLS, TTP -
Infections IE, Syphilis, histoplasmosis, gonococcemia, IE, HCV (Cryo), HBV (PAN), EBV, HIV
 Lyme, Whipple, RMSF, ??leprosy (L/M/S), histoplasmosis, TB (pANCA + in
25%),
Neoplasms Myxoma, lymphoma, carcinomatosis HCL (causes PAN), lymphoma, leukemia
AIDs Sarcoid, amyloid, IgG4RD, Goodpasture UC, PBC, sarcoidosis (L/M/S Vessel)
Drugs Cocaine, amphetamine, ergots Hydralazine, PTU
Penicillin, allopurinol, sulfonamides,
phenytoin, thiazide, gold

Investigate with:
1. ESR, CRP
2. ANA, ANCA, C3 & C4 (low in SLE, cryo), cryoglobulins, RF
3. HBV, HCV, HIV, SABE screens
4. Organ screen
5. Vascular imaging / biopsy

ANCA
cANCA – all are PR3 (proteinase 3): GPA (> 90%), MPA (40%)
pANCA – MPO / non specific.
MPO: CSS (60%), MPA (50-75%), idiopathic crescentic GN, PSC (70%), GPA (25%)
Non specific : SLE, MCTD, UC, RTA(?), CFA, AIH

- MPO and PR3 are cytosolic proteins

- Neutrophils activated by TNFa and IL-1 translocate cytoplasmic MPO and PR3 to cell membrane.
- ANCA Abs bind to cell membrane bound target Ags and stimulate Neutrophils to
 Attack endothelial cells
 Release IL-1 ans IL-8
- However, pathogenic role of ANCA Ab are doubted due to :
 Presence of active disease with negative ANCA
 No correlation between disease activity and ANCA titre
 Presence of ANCA Ab despite disease remission
(ref HPIM)

Chappel Hill Consensus Criteria classification

LARGE VESSEL
1. Giant cell arteritis
2. Takayasu arteritis

MEDIUM VESSEL
1. PAN
2. Kawasaki

SMALL (TO MEDIUM) VESSEL

1. ANCA associated pauci immune
 a. PR3 – GPA, MPA
b. MPO – EGPA
2. Immune complex mediated
a. Anti GBM
b. IgAV (HSP)
c. Cryoglobulinemic
d. Hypocomplementemic urticarial vasculitis (anti C1q vasculitis)

VARIABLE VESSEL
1. Behcet’s
2. Cogan’s

SINGLE ORGAN
1. PACNS
2. Cutaneous small vessel vasculitis
3. Isolated aortitis

VASCULITIS WITH SYSTEMIC DISEASE

SLE, RA, SSCl, relaspsingpolychondritis, SABE

VASCULITIS WITH IDENTIFIED ETIOLOGY

HBV-PAN, HCV-Cryo, paraneoplastic, hydralazine-ANCA

New classification system under study: DCVAS study – Diagnosis and Classification of Vasculitis, a
multi centre observational study in 32 countries conducted by Oxford. Data collection completed in Dec
2017.
Susac – vascuopathy. BRAO, SND, subacute encephalopathy. Corpous callosum lesion in MRI

Primary Secondary
Large GCA TB, syphilis, sarcoid
Pulseless TAK
Medium PAN HBV – PAN
Renal, coronary Kawasaki HCL – PAN like
ischemia Sarcoid
SjS – PAN like
RA vasculitis ulcer Bx = PAN like
?? cocaine
Tobacco – thrombangiitis obliterans
(intima infl in arteries and veins. Med-
small)
Small AAV – GPA, EGPA, MPA 2ry AAV: hydralazine, PTU, levamisole
Rash, GN, DAD, IC mediated : GBM, cryo, IgAV (HSP), (cut cocaine),
MnM HUV (C1q) IC : SLE, SjS, RA, PM/DM, SABE, HCV-cryo.
sarcoid
Variable vessel Behcet Sarcoid
 Cogan HIV
Single organ PACNS, cutaneous SVV, isolated renal, TBM  endarteritis
isolated aortitis

Management principles of vasculitis

1. Rule out mimics
2. Rule out secondary cause if found treat it
3. Identify extent of organ injury
4. Immunosuppression
a. Steroids
b. Cyclophosphamide if steroids not enough or needed in high doses
c. Alternatives – AZT, MMF, ritux, TPEX
5. Monitor for disease remission & relapses and for drug toxicities

Drugs causing vasculitis

Often limited to skin – palpable purpura, urticaria, hemorrhagic blisters, ulcers

Rarely GN and DAH, sp with ANCA +ve types

Drugs
Allopurinol, thiazide, sulfonamides, phenytoin, penicillin, gold
MPO ANCA – hydralazine, PTU

Rx
Stop the drug
Glcc, CPM for organ disease. Rapid taper

Cocaine associated vasculitis

1. Mid line destructive destructive lesion – ischemic damage to nasal septum and palate
2. Levamisole related ANCA associated vasculitis (purpura, ENT, agranulocytosis)

Giant cell arteritis / PMR

Granulomatous vasculitis of larger arteries
Features
 > 50 years
 New onset (e.g. < 1 month) headache (found in 85%) – temple region
 tender, palpable, non pulsatile temporal artery
 Jaw claudication (65%)
 visual disturbances secondary to anterior ischemic optic neuropathy
o blindness
o Charles Bonnet Xd: visual hallucinations with visual loss. Ischemic injury to optic pathway
o Diplopia – BS / nerve ischemia
o Cortical blindness
 features of PMR: aching, morning stiffness in proximal limb muscles (not weakness)
 Lethargy, depression, low-grade fever, anorexia, night sweats
 Rare : BS ischemia, cortical blindness, renal/coronary/aortic (AA, AD) / mesenteric involvement.
Cranial MnM

Investigations
 ESR > 50 mm/hr (note ESR < 30 in 10% of patients). CRP may also be elevated
 Temporal artery biopsy: skip lesions may be present. CD4+ L, macrophages, giant cells, breached
IEA. Biopsy falsely negative in 9-44%. No benefit in repeating the Bx. USS guided Bx is an option.
BSR recommends biopsy to be at least 1 cm long, ideally 2cm or more. Bx should be done before or
within 7d of steroid therapy
 note creatine kinase and EMG normal. Will have high ALP (may be bile duct ischemia), high Plt, low
albumin.

Dx : 3 of the 5 in bold above (BSR 2010 criteria)

Temporal artery biopsy

Giant cells within a granuloma

Treatment
 high-dose prednisolone - there should be a dramatic response within 48h, if not R/v diagnosis
 urgent ophthalmology review. Patients with visual symptoms should be seen the same-day by an
ophthalmologist. Visual damage is often irreversible
 transient visual loss indicates impending blindness and should be treated with IV MPP 1g/d x 3d
 if already blind, give oral full dose

uncomplicated GCA pred 0.75 – 1 mg/kg

complicated GCA jaw or tongue claudication pred 1 mg/kg
transient visual losses MPP – pred
bisphos & PPI for all
GIACTA trial
Tocilizumab weekly + Glcc x 26 wk Vs
Give high dose pred for 1 month or till symptoms CRP improves
Tocilizumab EOW + Glcc x 26 wk Vs
Taper slowly. May add MTX for steroid sparing
Placebo + Glcc x 26 wk Vs
For relapse
Placebo + Glcc x 52 wk
Headache only reverse the last step down
Claud back to 1mg/kg
Both toci groups achieved
Visual MPP
Better rates of sustained
remission at 52 wks (~ 55% Vs 16%)
Follow up Ix
Less glcc need
ESR CRP FBS
Better safety outcomes
2 yearly CXR, 2DEcho – for aortic root aneurysms

For PMR, small Glcc dose is adequate (20mg/d or less). 40-50% of GCA develop PMR. 15% of PMRs
develop GCA. These transitions are not ffected by Glcc

PMR

Elderly, HLA DR4

Joint stiffness, LoW, LoA. No vasculitis (unless with GCA)
No arthritis / synovitis? – large joint synovitis (my note).can be unilateral in onset. But become bilateral
within weeks

Dx criteria
1. age > 50y
2. ESR > 40
3. symptms > 1/12
4. 2 or more of SJ, HJ, neck affected, worse mane & morning stiffness > 30min
5. Rapid response to prednisolone < 20mg/d

Ix
High ESR > 40 in 90%, high CRP > 22 in 90%
AST ALT mildly high
Very high ALP suggests GCA
XR – non erosive
TA Bx
 If ESR remains high despite symptomatic improvement
Not affected by low dose Glcc

DD fo PMR
1. Hypothyroidism – slow relaxing AJ
2. Fibromyalgia – widespread pain, no stiffness, normal ESR, CRP
3. Proximal myoapthy - Polymyositis – very high CPK, muscle weakness, statin, osteomalacia
4. Polymyalgic onset RA – poorly respond to Glcc, elevated anti CCP Ab (polymyalgic picture comes
before development of synovitis)
5. Late onset RA – RF, anti CCP Ab, synovitis
6. LEMS – LL weakness at onset
7. GCA / vasculitis

Rx - Low dose prednisolone

Takayasu arteritis

Inflammation of aorta and its amin branches causing steonosis

Subclavian, carotid, renal, iliac

Aetiology
Unknown
? linked to TB

Epid
Japanese women

Presentation
Constitutional symptoms
Claudication
Hypertension
Bruits

Dx
CT angiogram of aorta and branches
MR angiogram
Rule out syphilis and TB

Rx
Life long steroids
Manage HTN etc
Polyarteritis nodosa
Definition Necrotizing inflammation of
Medium artery necrotizing vasculitis medium-sized or small arteries
ANCA negative without glomerulonephritis or
vasculitis in arterioles, capillaries,
Epidemiology
or venules
M : F = 1.5 : 1
Peak in 50s - CHCC

Aetiology
Most – idiopathic
Some secondary PAN – HBV >> HCV, hairy cell leukaemia
2ry PAN is clinically identical to idiopathic PAN. Starts within 4m of onset of HBV infection

Pathogenesis
IC deposition
Intimal proliferation, thrombosis, aneurysm formation

CFx
Classical presentation

 Middle aged male

 Constitutional symptoms
 Abdominal pain
 HTN, Renal failure
Skin
Purpura, LR, vesiculobullous eruptions, SC nodules – typically along lateral surfaces of feet where
medium vessels bifurcate.
Erythema nodosum like lesions – a panniculitis (inflammation in SC fat, due to vasculitis)
Digital gangrene

EN PAN panniculitis
Site Shins >> forearms, thighs LL
Pain + +
Ulceration No Yes
Histo L infiltrate in septae. Meischer’s radial N infiltration in septae. L in chronic phase.
granulomas Medium artery vasculitis

Take a surgical biopsy to capture SC fat and medium size vessels. PuchBx is inadequate.

Renal
HTN
Minimal UFR activity
Small hematomas, Focal ischemia

Neurology
MnM / PN (S, M, SM)
Ocular TIA – commonest CNS Fx
Stroke, SAH, psychosis, myelopathy, cord hematoma

GIT
Mesenteric vasculitis, mesenteric angina
Rare : Ischemic necrosis and perforation, malabsorption, ischemic pancreatitis

Cardiac :IHD, ischemic / HTN CMpathy

Other: Orchitis, ION, splenic infarct

Ix
RFT, UFR, LFT
HBV, HCV
FBC, B pic – hairy cells
ESR, CRP high
HIV, ANA, ANCAs, C3 C4, SPEP – negative
Cryoglobs may be +ve rarely in HBV / HCV associated
PAN
Biopsy

Light micrograph of a small muscular renal artery in polyarteritis nodosa. Diffuse inflammation of
the adventitia, PMNL infiltrates, thickening of the inner layers by loose connective tissue
(arrows). The lumen (L) is significantly narrowed. fibrinoid necrosis of tunica media. Old and new
lesions within the same specimen. Spares arterioles, capillaries and venules. Involvement of a
vessel this large would be unusual in microscopic polyarteritis or granulomatosis with polyangiitis
(Wegener's).

Renal arteriogram in large-vessel polyarteritisnodosa

showing characteristic microaneurysms (small
arrows) and abrupt cutoffs of small arteries (large
arrows)

PAN 2ry to HBV is essentially associated with active hep B

during PAN presentation, with positive HBV DNA and
HBsAg +. If those are negative, it is likely that the patient
has idiopathic PAN (even if the pt had a PHx of HBV)

DD (CHINA)
1. Other vasculitides – ANCA,cryo, HSP
2. CTDs – SLE
3. SABE, atrial myxoma
4. HIV
5. Amphtamine vasculitis

ACR classification criteria for PAN

In a patient with vasculitis, 3 or more of

1. Otherwise unexplained weight loss greater than 4 kg

2. New-onset diastolic blood pressure greater than 90 mmHg
3. Elevated levels of serum blood urea nitrogen (>40 mg/dL or 14.3 mmol/L) or creatinine
(>1.5 mg/dL or 132 micromol/L)
4. Testicular pain or tenderness
5. Livedo reticularis
6. Myalgias (excluding that of the shoulder and hip girdle), weakness of muscles, tenderness of leg
muscles, or polyneuropathy
7. Mononeuropathy or polyneuropathy
8. Evidence of hepatitis B virus infection via serum antibody or antigen serology
9. Characteristic arteriographic abnormalities not resulting from noninflammatory disease
processes
10. A biopsy of small- or medium-sized artery containing polymorphonuclear cells

Treatment - Glcc, CPM, Glcc sparing (AZT, MTX, MMF), IVIG for
neuropathy, PLEX, rituximab sp for refractory cases
PAN without HBV/HCV
Mild disease
Prednisolone 1mg/kg/d x 1m tail off.
Add AZT or MTX or MMF if not tolerating Glcc or cannot come below 10mg/d

Mod to severe disease (renal, GI, neuro, cardiac)

Glcc + CPM induction and Glcc + AZT/MTX/MMF maintenance
For life threatening disease Glcc as MPP 1g/d x 3d --> oral pred 1mg/kg/d
CPM can be oral or IV (600mg/m2 2 weekly three doses and monthly 4 – 10 months)
Case reports of - rituximab

PAN with HBV / HCV

Treat virus alone
If severe vasculitis, can add Glcc cautiously

Treatment of HTN
ACEI or ARBs. If Cr rise by 30% or more, switch to CCBs

Kawasaki disease
Criteria
High fever > 5d with 4/more of
1. BL conjunctival injection
2. Strawberry tongue
3. Palm and sole erythema, edema, scaling in convalescence
4. Polymorphus rash
5. Cervical LN > 1.5 cm
Do echo to find coronary artery aneurysms
Rx – high dose aspirin + IVIG +/- steroids

Thrombangiitis obliterans
 Young (< 45y) male (3:1) smokers
 Hypersensitivity response to tobacco
 Inflammation of tunica intima of med-small As and Vs
 Pw – claudication, critical limb ischemia, absent distal pulses, Raynauds phenomenon
 Dx – exclude other thromboembolism, arteriography
 Rx – stop smoking, amputation

Small vessel vasculitis – skin, neuro, renal, lung

Palpable pupura
Bx a fresh lesion (24-48h) since they evolve fast. DIF helps to
Differentiate IG mediated Vs pauci immune vasculitis
Dx IgA vasculitis / HSP
Aetiological Dx: IgM in cryo type 2/3; IgA; complements in hypocomp urticarial vasculitis
For DIF, specimen should be sent in Michelle solution or N saline, not in formalin.

Granulomatosis with polyangitis

Older adult
M=F

Criteria
 Lack consensus
 A/W DCVAS
 In general:
 o Upper airway disease
o Lung parenchymal disease
o Renal / glomerular disease
o Granuloma in histology / ANCA serology

Presentation

ENT
GPA (90%) > MPA (30%)
Crusting, ulceration, granulomatous soft tissue masses (pseudotumors), SND/CD/mixed

Lung (same in GPA and MPA)

Consolidation / infiltration / nodule / cavity – persistent > 1m
Migratory over time
Airway stenosis (larynx / trachea / bronchi)

Renal
GN – H’uria, subnephrotic p’uria, RPGN
* nephrotic range p’uria suggests
Secondary FSGS after long standing disease
Alternative co-existing glomerular disease (MGN etc)

Skin
Leucocytoclastic vasculitis
Urticaria, LR, palpapable purpura, EN, PG, ulcer, nodule, Sweet

Eye
C/E/S, retinal vasculitis, pseudotumor

Other
Neuro : MnM, cranial pseudotumors, SND

Diagnosis
Needs a biopsy to show granuloma
If not, ANCA helps tentative diagnosis

Other Ix
Esr, crp – HIGH
UFR, dysmorphic RC, RFT
CXR, CT-chest, BAL (to look for alveolar hemorrhage)

Biopsy
Necrotizing segmental GN
Skin and renal are the most helpful
Skin – leucocytoclastic vasculitis with negative IHC for Ab / complements
Renal – pauci immune glomerulonephritis. Granulomas are seen only rarely
Focal GN: > 50% of glomeruli are normal
 Crescentic : > 50% of gloms have crescents
Sclerotic : > 50% gloms are globally sclerosed (>80% of glomerulus is sclerosed)
Mixed : < 50% gloms NL, < 50% have cresecents, < 50% are sclerosed

* renal limited vasculitis: identical histology to above, no extra intestinal Fx, so late presentation and so
will have more slcerosis

Lung and sinus biopsies are not very helpful

Differential Diagnosis
 EGPA – eosinophilia, asthma
 PAN – renal infarcts, microaneurysms, RAS. No GN, negative ANCA
 Goodpasture – 40% have ANCA (MPO > PR3)
 Bacterial infections
 Levamisole contaminated cocaine can produce vasculitis with both PR3 and MPO ANCA

IgAN, MGN, SLE-LN, PIGN, Goodpasture can co exist with ANCA vasculitis

Treatment
Induction
No organ / life threatening disease
Steroids + MTX / ritux

Organ / life threatening disease (AKI, sev alveolar h’rrhage, motor neuropathy, CNS vasculitis, orbital
pseudotumor, GI bleeding, myocarditis)
Steroids + CPM / ritux
Add PLEX if:
Sev alv hemorrhage
Concomitant anti GBM Ab +ve
Cr > 4 mg/dL

Maintenance
AZT, MTX (avoid in preg), ritux (avoid in hep B, PR3 ANCA : ? no Evidence)

For relapses
Reinduce
Maintenance same drug if relapsed after stopping Rx. Different drug if relapsed while on therapy

Eosinophilic granulomatosis with polyangitis

4/6:
Asthma
Migratory chest infil
Peripheral neuropathy
Systemic vaculitis (cardiac/renal/hepat)
E > 10%
Extravasc Eosinophils

Microscopic polyangitis

Non immune complex mediated ANCA associated small vessel vasculitis

Casuing GN and pulmonary capillaritis
Without granuloma formation (differentiates from GPA)

Epid
Late 50s
M>F

Path
Non IC mediated small vessel vasculitis with capillaritis
CFx
GN
DAH  hemoptysis
Skin vasculitis
GI vascultitis
No upper airway involvement or pulmonary nodules

Ix
High ESR< W, PLt
Low Hb
MPO ANCA in 75%

DD
Goodpasture
GPA

Dx
Clinical + ANCA + Biopsy

Rx
Glcc, CPM, ritux – similar to GPA
 WG (GPA) CSS MPA
Granuloma Yes Yes No
Criteria
Epid / RF Mean 40y Mean 48y Mean 57 y
M:F = 1:1 M:F = 1.2:1 M>F
Key Fx URT, lung nodules, renal Asthma, eosinophilia, GN. Lung – DAH
neuropathy, vasculitis
Classical P/w ENT, renopulmonary Wosening asthma Cx, PN. Renopulmonary
CVS 10% pericarditis, coronary Cardiac-
vasculitis, CMpathy Small vessel (A’ole, cap,
DVT venule) granulomatous
vasc.
RS 95%:Sinusitis, septal perf, Asthma, rhinitis, nasal Capilaritis – DAH
subglottic stenosis, polyps. Sinusitis No URT disease
90%: nodules, bronchial scar, No lung nodules
bronchiectasis, DAH, pul edema
(renal)
Renal 80%: FSGS  RPGN Mild 80% - RPGN
Skin 50%: rash 50% purura, SC nodules Vasculitic rash
Eye 50%:C/S/ES/U/ retrobulbar SOL
GIT Vasculitis
CNS MnM, CN palsy, CNS lesions MnM 70% MnM
Haemat Anemia (schistocytes, Burr cells), Eosinophilia High plt, WBC, Low Hb
hi PMNL, NO eosinophilia
Infl markers Hi ESR, hi complements ESR, fibrinogen, alfa2 High ESR,
antiglobulin high
ANA 10-20%
Specific Ab 90% cANCA (PR3) high Sp pANCA (MPO) pANCA 75%(MPO)
IgA (50% K&C)
10% pANCA
RF in few
X ray / CT Waxing & waning lung nodules Miratory chest infil DAH
70%. 50% cavitate.
Airspace opac – DAH/pul edema
Retic shadows
Diagnosis lung Bx + Clinical+ANCA Clinical, ANCA Needs biopsy
necrotizing granulomatous
vasculitis
Disease Not // to ANCA titre (? can
activity monitor activity K&C9;587 and
Sharma Q 141 says it //s disease)
Prognosis Fatal if unRx Fatal in unRx 75% 5 yr survival
With CPM – 75% complete 25% 5yr survival
remission, 80% 5y survival
CoD CKD / AKI (RPGN) Cardiac DAH, cardiac, renal, GI
Glcc Induc: Enough for many Same as WG
ImmMod Glcc + CPM / Daily oral CPM as add on
Biologics Glcc + ritux
Other TPEX for RPGN & sp if pul hmrg
Maint:
MTX / AZT /MMF
KT: yes if good remission
achieved

RAVE trial : ritux 375 mg/m2 weekly x 4 doses + daily oral CPM 2mg/kg 6m Vs glcc + CPM for ANCA
vasculitis
Ritux regimen was non inferior in inducing remission, and probably superior for recurrent cases.
Superior in GPA (PR3), non inferior in MPO (MPA)

MAINRITSAN trial – ritux 500mg at 0, 0.4, 6, 12, 18 months Vs AZT for maintenance (after Glcc CPP
induction) in ANCA vasculitis – ritux was superior

In general, for maintenance of renal disease in

ANCA - AZT
SLE - MMF

Henoch Schonlein Purpura / IgA vasculitis

Small vessel vasculitis causing

Purpura – buttocks and LLs without low plt or coagulopathy
GN – mic h’uria, HTN, mild renal impairment
GI vasculitis – Abd colics, blood and mucus diarrhea
Arthralgia / arthritis

Epid
Children > adults
M>F

Ppt by
URTI
Drugs
Food
Insect bites
Immunizations

CFx
Abdominal pain, BM diarrhea
Purpuric rash
GN
Arthritis arthralgia
Orchitis

Dx
Skin Bx – leucocytoclastic vasculitis with IgA and C3 deposition
Renal Bx – often not needed

Ix
High W, plt
UFR – active sediment
C3, C4 – normal
IgA levels - increased

Rx
Analgesics
PCM
NSAIDS (avoid if GN+ or GI bleeding +)
Who needs steroids?
1. Intractable pain (jts, GI, orchitis)
2. Arthritis limiting mobility
3. Renal impairment or proteinuria > 1g/d (do biopsy in these two groups to see the extent of
crescents which determines prognosis)
Prednisolone 1 mg/kg/d and taper with clinical response over 6-8 weeks
Steroids improve – GI symptoms, tissue edema, arthritis
Steroids do not
Improve renal disease / skin disease (U2D: helps skin) / duration of illness / relapse risk
RPGN – benefit from TPLEX + cytotoxics (case reports)

Relapse rate 10-40%

ESKD 1-5%, mostly in adults

IgA associated diseases

HSP
IgAN
IBD (CrD specially)
Alcoholic liver disease
?celiac disease

Cryoglobulinemic vasculitis and cryoglobulinemic syndromes

Cryoprecipitation Protein precipitation in cold temperature

Cryoglobulin serum (& plasma) proteins that precipitate in cold temperature (Ig and
Complements)
Cryofibrinogen plasma proteins that precipitate in cold temperature (fibrinogen, fibrin,
fibronectin, FDP)

Cryoglobulin syndrome
Clinical syndrome associated with cryoglobulins
Hyperviscocity syndrome (with MM or WM. Type I)
Vasculitis syndrome – Meltzer triad of pupura, arthralgia, myalgia (with HCV (type II), other
CTDs, infections or malignancies – type III)

Brouet’s classification based on type of Ig

Type I monoclonal IgM MM, WM

Type II polyclonal Igs with a monoclonal IgM that has RF activity HCV, HIV

Type III polyclonal Igs with no monoclonal Igs AIDs

Normal people also have CGs. But when their production is excessive and clearance by macrophages is
overwhelmed, it causes disease

CFx

Type I CG hyerviscosity and thrombosis – SKIN KIDNEY MARROW

Skin effects - Raynauds, digital ischemia, gangrene, Livedo
Blurring, headache, dizziness, nausea, ataxia, stroke, confusion, coma

Type II, III SKIN, KIDNEY, NEURO

Meltzer triad (purpura, arthralgia, myalgia), constitutional symptoms.

Skin purpura. RP, LR, acrocyanosis less than in type I. predilection to LL, may be gravitational
effect
Nail fold capillary telengeictasia (on capillaroscopy)

MSK arthralgia myalgia in RA distribution >> arthritis, myositis

Neuro PN / MnM, often mild

RS small airway disease and impaired gas exchange. ILD rare

Renal MmPGN (II, III), thrombotic disease (I). puria huria>nephrotic, nephrtic, AKI

Biopsy
Leucocytoclastic vasculitis
Eosinophilic material (not eosinophils) in vessel lumen, extending to intima, causing vessel wall
inflammation
IgM, IgG, C3 staining on IF
Type I CG – non inflammatory thrombosis

Renal Bx
MmPGN
MsPGN, vasculitis, intraglomerular hyaline thrombi

Cryoglobulin levels
40% of normal have CGs, but undetectable by standard assays and negative in cryocrit
Type I CG – very high CG levels
Type II, III – high CG

* Very high CG can cause a falsely high WBC and Plt in automated machines

Complements
C4 (& C1q, C2) – low
C3 – normal / low

High ESR, CRP

Serologies: RF +. Anti CCP +ve in 7%. ANA in SLE-cryo. Anti LKM in HCV

Cryoglobulin test
Blood sample maintained at 37C until serum is separated. So, collection in to warmed tube without
anticoagulants (alter precipitations), centrifuged at 37C and serum separated at 37C. then cooled to 4C
and left or 5-7d for CG to precipitate.

Cryocrit - % volume of CG ppt from total serum volume

~0% normal
> 0.5 % positive
Type I ~ 50%
Type II 2-7%
Type III 1-3%

IG typing –monoclonal band is often IgM HC and kappa LC in cryo II

Prognosis– determined by the underlying disease. CG positivity doesn’t seem to impact it.
Type II are at risk of B cell NHL. Risk is greatly amplified if etiology is HCV

Treatment
Type I
 Treat the cause
Plasmapheresis for severe hyperviscosity

Type II/III
Treat the cause
Treat vasculitis

Behcet’s disease

Behcet’s
Definition Orogenital ulcers and uveitis
Criteria Rec (>3 per yr) oral ulcers (aphthous or herpetiform) & 2 of
1. Rec genital ulcers
2. Eye lesions
3. Skin lesions
4. Pathergy +ve see below : ICBD 2014: EGO PaNVaS
Classification -
Epid / RF M > F, Turks, Japs, Irans. 20-40y
More severe in M
HLA HLA B51 (turk, Jap, Iran)
? DR2, DR7
Key path Only vasculitis that affects both A & V of all sizes
Key Fx Orogenital ulcers, uveitis, vascular, CNS
Classical P/w Painful Oral ulcers (~100%) (canker sores)
Genital ulcers (60-80%) – painful. uniquely scarring
Atypical P/w DVT, hmpotysis
CVS DVT (thrombophlebitis, LL, IVC, SVC, PV, CVST), vasculitis arterial thrombosis
* atherosclerosis is NOT accelerated
RS Extremely rare
Hughes – Stovin Syndrome: Pul A thrombosis and aneurysm + peripheral
venous thrombophlebitis.
Pul A aneurysms p/w hemoptysis, misDx as PE, anticoag worsens!
Renal Extremely rare. Amyloidosis may occur ~ 8y from onset. Other : GN (IgA,
Crescentic), TIN
Skin EN (septal panniculitis), pseudofolliculitis, papulopustular lesions
Aphthous or herpetiform oral ulcers
Pathergy phenomenon (> 2mm papule / pustule that appears 48 hours after a
5mm deep skin prick by a 20-gauge needle – prick at 45 degree angle and keep
for 90s or inject 0.1% saline) (if clinical lesion is not apparent, can do a Bx to
show neutrophil infiltration)
MSK (sym, 40% Mono or oligo arthritis. Non erosive, non deforming, asymmetric, large jt
destruction) (DD: SpA, ReA, sarcoid, IBD)
Eye Uveitis (A/P), retinal vasculitis, Optic neuritis – all need systemic Rx
50% blinds (If unRx)
GIT Abdominal pain, colitis, diarrhea. Can mimic IBD (colitis / ileitis with oral ulcers!)
CNS 20%. Multifocal lesions (diff from MS: more CS tract affected, subcortical but
nor predilection to periventricular regions)
Aseptic meningitis, CVST, raised ICP
Haemat - (1-5% can have secondary APLS  a reason for anticoagulation)
Infl markers High
ANA -
Specific Ab None
X ray / CT -
Prognosis Worse in males
CoD Perforate colonic ulcers can kill!
NSAIDs
Glcc Topical for aphthous ulcers
Systemic for uveitis and CNS
ImmMod Colchicine for EN (if pt gets diarrhea, that means colchicine is working),
arthralgia
Thalidomide for resistant ulcers
Other for uveitis and CNS
Biologics Anti TNF for severe uveitis, CNS, GI Behcets
Other
All common manifestations are self limiting except uveitis
Oral ulcer in Behcets. Painful. Necrotic centre. Well defined margin. Erythematous surrounding. Similar
to aphthous in appearance and histology, but multiple. Heels spontaneously in 1-3 weeks. Major ulcers
(> 1cm) leave a scar. Oral ulcers are the first to come and last to disappear in the disease course.

Genital ulcers in Behcets – painful, commonly scarring (very unique for behcets), uncommonly recurring.

Retinal vasculitis with hemorrhages (L). advanced retinal ischemia with OA (R)

International Criteria for Behcet’s Disease (ICBD 2014)

EGO PaNVaS

DD for recurrent oral ulcers SINBDHP

 1. SLE, reactive arthritis
2. IBD, Celiac
3. Neutropenia
4. Behcet’s
5. Dermat – SJS, Lichen planus, Pemphigus
6. HSV, HIV
7. Periodic fever syndromes

Important DDs

for Oral ulcers + genital / diarrhea / DVT / red eye / arthritis

IBD (sp Crohn’s disease) – DVT is unusual in these pts. GI biopsy shows no granulomata in Behcets

For neuro Behcet’s

MS / NMO
CNS vasculitis
APLS

DVT + hemoptysis
PE
Hughes Stovin (DVT + pul A aneurysm with de nono thrombosis and bleeding)

Associated conditions
APLS – needs anticaog
MAGIC syndrome
Mucosal And Genital ulcers with Inflamed Cartilage Xd
Fulfills criteria for Behcets and relapsing polychondritis
Rx – colchicine  steroids

Mgt (colchicine for orogenital & arthritis. Pred, AZT for organs)

Oral ulcers topical triamcinolone cream (0.1%) tds (after meals), sucralfate cream tds.
Lignocaine 2% before meals dental procedures etc. IL triamcinolone injections
Genital ulcers topical triamcinolone
Colchicine to prevent recurrent oro-genital ulcers. If those fail, try oral prednisolone, AZT

Arthritis – colchicine, pred AZT

Eye –
anterior uveitis alone – topical steroids and midriatic (cyclopentolate, scopolamine)
Posterior chamber involvement: pred + AZT. If not enough -
Severe eye disease (deterioration of vision by 2 or more levels in a 10 level VA assessment / retinal
vasculitis / macular disease) – add cyclosporine or infliximab
Large vessel vasculitis – pred + cyclophosphamide
DVT – pred + AZT + warfarin

Neuro Behcet – pred + AZT

Colchicine
MoA
Acts by inhibiting (immune - inflammatory) cell mitosis by inhibiting tubulin polymerization which is
needed to form microtubules for mitosis.
Also accumulates in and inhibits neutrophil chemotaxis and superoxide formation.

Uses
gout, OA, recurrent pericarditis, FMF

SE
Diarrhea, vomiting, abd pain
SM polyneuropathy
Myopathy

Interactions
Statin /fibrate – myopathy
Ciclosporin – nephrotoxicity – myopathy and AKI
Macrolides – increase colchicine toxicity

DVT in Behcets is managed with steroids. It’s a result of vasculitis rather than thrombophilic states.
Nevertheless if warfarin is required must exclude pulmonary artery aneurysm. (CTPA. At least ask for Hx
of hemoptysis)
Cogan syndrome

Autoimmune
Young adults (15-30y)

Interstitial keratitis + vestibular and ocular dysfunction (inner ear disease) +/- systemic vasculitis

IK – painful red eye with reduced vision. Also uveitis, retinitis

VOD – episodic vertigo (Meniere like), progressive hearing

impairment (BL high freq SND)

Vasculitis
Large (aortitis, AR, aneurysms) or medium-small
LoA, LoW, fatigue
LN, HSM
Pulmonary infiltrates, pericarditis
Arthritis, urticarial
DD
Sarcoid
PAN
GPA
RA
Rx Pred +/- other

BL high freq SND in Cogan (also in Alports!) UL low freq SND in Meniere (BL in 30%. Advancing
disease: low + high freq SND  all freq SND)
 ARTHRITIS

Joint pain

Articular Extra articular

 Deep diffuse  Superficial, focal
 Reduce active & passive  Limited active, normal passive
 Crepitus, effusion, deformity  No joint signs

Duration Tendinitis, bursitis, myalgia

Acute arthritis < 6 wk Chronic arthritis > 6 wk

I-CIDP Inflammatory Non-inflammatory

– EMS, relieve with activity,
Infection – SA, TB, Ng, viral constitutional symptoms, soft
Crystal – G, PsG, CaAp, chol? tissue swelling, high ESR, CRP OA
Infl – acute RA, acute sarcoid, Charcot
pSpA, IBD, Poncet
Degen – acute OA
Paraneoplastic
 Symmetric
1. RA
2. SLE
3. Sarcoid
4. PsA – RA type / DIP type
5. Other – SSCl, HH (2,3),
PBC (2,3), ReA, IBD, Cryo
Paraneoplastic – acute, BL WJ, AJ, no response to rheumatic Rx,
responds to CA Rx. Precedes CA by 3-20m
Sarcoid – acute : mono-oligo. Chronic – symmetrical RA type
IBD – mono/oligo acute. Chronic – Small Js, SI.

RHEUMATOID ARTHRITIS

Epidemiology / RF
F:M = 3:1
HLA DR4 – predicts poor prognosis too
Smoking – activates innate IR
Sex hormones incidence equal in post menopausal women and men
OCP probably delays onset, no other significant impact
Global incidence falling (KC)

pathogenesis

abnormal synovial cells

macrophage like synoviocytes – produce chemokines. Acitavate synovial B cells and others.
Fibroblast like synoviocytes – circulate between joints

Synovial B cells – produce IgM and IgA Ab against Fc of IgG. Autoaggregate and activate macrophages
High affinity antiboides are not a feature of RA unlike in other autoimmune disorders

T cells – lesser role played by CD4 T cells. (anti CD4 drugs didn’t work). TH17 cells play a role. (IL17)

Anti CPA production is triggered by filaggrin, type II collagen, vimentin

Chemokines  JAK/STAT activation  IL-6 expression

Pathology
Inflamed and hyperplastic synovium (pannus)
Boggy swelling
Interfere with cartilage blood flow, produce cartilage damaging cytokine  cartilage thins out
Bone exposed to cytokines  juxtaarticular osteopenia
Bone damaged by synovium along the the attachement of synovial margins causing marginal
erosion  joint deformities
MRI detects this damaging synovium in the first 3-6m of illness, before erosions appear in XR
Early Rx with anti TNFa and low dose steroids will slow down or reverse erosions.

Clinical presentation

Presentation DD
Chronic persistent - Symmetrical small joint arthritis of insidious onset. PsA
Remitting and relapsing course SLE
Remitting – remits after several years with minimal residual damage Acute nodal OA
Transient – resolves in < 12m with no joint damage. seronegative Post viral arthritis
PMR
AL amyloidosis (small
jt arthritis, CTS,
nodules)
Palindromic rheumatism SA
Acute monoarhritis, resolves in 48-72h. Gout
50% - get chronic RA predicted by RF/ACPA SpA
Some – remain in palindromism Trauma
Some - remit

ACR/EULAR 2010 diagnostic criteria

For a patient presenting with definite synovitis of at least one joint with no other explanation:

JOINTS*
1 large 0
2-10 large 1
1-3 small 2
4-10 small 3
> 10 (with 1 small)** 5
SEROLOGY
RF / Anti CCP neg 0
Weakly (x1-3 ULN) 2
Strongly + (> x3 ULN) 3

INFLAMMATORY MARKERS
ESR / CRP high 1

DURATION
> 6 wk 1

Typical erosive X ray – confirms RA, no need of criteria

If not, > 6 from above score, RA highly likely

* Large Jt – SJ, EJ, HJ, KJ, AJ

Small Jt – MCP, PIP, WJ, 2-5 MTP
Joints not considered : 1st MTP jt, CMC jt DIPs
** for this category, at least 1 jt should be a small jt. Others can be large jts or other small jts (TMJ, ACJ,
SCJ etc)

Old 1987 ACR criteria: 4 or more of

1. Symmetrical
2. 3 or more
3. Small joints of hand
4. Morning stiffness > 1h
5. Rheumatoid nodule
6. RF
7. X ray
First four, each should be for > 6 weeks
Draw backs – had to wait for 6 weeks, large joint presentations missed, nodules not common, no
assessment of infl markers

CFX
Joint involvements
Hand and wrist
1. Ulnar deviation and palmar subluxation at MCP– minimal functional impairment once pt adapts
2. Boutenniere and swan neck and Z thumb deformities at PIP
3. Dorsal subluxation of ulnar styloid  risk of tendon rupture and 4 and 5 finger drop. Need
urgent Sx. Piano key sign

SJ
Initially mimics rotator cuff tendinosis with a painful arc
Pain at night
Later – rotator cuff tears and global stiffening – (like frozen shoulder I think)
EJ – fixed flexion deformity

Foot
1. MTP swelling and pain
2. Broad feet
3. Hammer toe
4. Ulcers, callus
5. Loss of arches, valgus position ankle

KJ
Effusion – aspirate and inject steroids
Popliteal cyst
Varus / valgus deformity
Secondary OA

HJ Less common than KJ. Later disease – protrusion acetabulae

c- spine
upper c spine synovitis, ligament tears and instability – atlanto
axial subluxation (this is the only spinal column involvement in
RA)
disease best detected by MRI
C spine XR lateral view in neck extension and flexion will show C
spine instability when fully flexed, a gap of > 3mm between
dens and anterior arch of the atlas indicates anterior
displacement of the atlas.
Do open mouth and AP, lateral views first to exclude odontoid #
or severe subluxation. If those are negative only, proceed with
lateral X ray in flexion

Other joints
TMJ, acromioclavicular jt, sternoclavicular, criocaetynoid

Non articular Complications

Skin Rheumatoid nodules. Can ulcerate / get infected. Susbside with disease remission
 PG

RS (can present before joint involvement – passmed RS q7). more in men

Pleural effusion – low sugar, low pH
Lung fibrosis – UIP > NSIP
MTX alveolitis
Lung nodules
Caplan Xd
Infections (with drugs - TB)
OAD – bronchiectasis --- Bronchiolitis obiterans
PHTN, vascutilitis
Crycoaretynoid arthritis
Thoracic cage restriction due to arthritis

MSK
Deformities
Ruptured tendons, joints (Bakers cyst)
Chord compression
OA
Pseudogout
Septic arthritis-staph aureus. BC often positive. ABtc and drain

Vasculitis
Nail fold infarcts, vasculitis rash, MnM, bowel ischaemia
More in smokers with advanced seropositive deformed burnt out inactive disease

CVS CVD (increased by NSAID and Glcc. Some protection by DMARDs - DPPM), raynauds
Pancarditis – often asymptomatic and insignificant
DVT – may co exist with ruptured baker’s cyst!
RA is an independent risk factor for ASCVD, equivalent to DM

CNS
MnM / PN – due to vasculitis
CTS, TTS
Cord compression

Eye
Sicca
Scleritis, episcleritis (painful – U2D, painful - DPPM)– painful red eye. In severesero+ disease
Scleromalacia perforans
Corneal melting, painful, blurring, red eye – perforate commonly. Need high dose ssteroids

Renal amyloidosis (nephrotic and CKD) – serum amyloid A protein (SAP) deposition
Drug toxicities – NSAID (TIN, MCD, AKI due to low GFR), Au, penicillamine (MGN)

Hemat
Felty – splenomegaly and neutropenia (more in HLA DR4). > 10y of disease, often active. 1/3 are
burnt out disease with deformed hands.
 LN
Anemia – ACD, IDA (gut bleeding - NSAIDs), hypersplenism, MTX, associated pernicious/hypoth,
AIHA
Thrombocytosis in active disease. Thrombocytopenia (pancytopenia) in Felty
Lymphoma – with long term immunosuppressants
Large Granulocytic Lymphoma – LGL (early active disease)

Leg ulcers
Rheumatoid vasculitis – PAN like Bx
Arterial insufficiency
Venous insufficiency
Diabetic ulcer

Felty syndrome
50-70y, F>M
Deforming chronic (many eyars) seropositive but inactive RA with HLA –DR4, nodules and extra articular
Fx
Mechanism of neutropenia :
Splenic pooling
Anti G-CSF Ab
Anti neutrophil Ab (Peter Server, Galvani)
Cytotoxic L causing maturation arrest of myeloids (BM: hyperplasia or normal myeloids)
Increased N margination
LN, LoW, (mimic lymphoma), splenomegaly, nodules, pigmentation, vasculitis and ulcers
NCNCA, low neut, low plt, impaired T and B cell immunity, abn LFT
RF always positive. Some have ANA.

Mgt
DMARDs (MTX  Ritux  Pred 40mg/d), G-CSF if N < 1000. TNFa do not work
Splenectomy – if recurrent infections. Benefits – improve N count, reduce infection rate, may improve
vasculitis and ulcerations. Neutropenia may recur, but at a lesser degree.

Felty LGL
Phase of RA Advanced disease Early disease
Type of RA Seropositive, severe, deforming, burnt Seropositive
out, DR +ve, extra articular +, nodules+
Presentation Neutropenia Neutropenia, lymphocytosis, LGLs in BP / BM
* in Asians PRCA > neutropenia
Signs LN, HSM, deformed joints, SjS, LN, HSM, minimal complications of RA
vasculitis, UIP, nodules
Rx MTX . CSP MTX / CSP / CPM  chemo (chlorambucil).
Consider splenectomy for rec infections No place for splenectomy

Serology
RF - +ve in 70%. Doesn’t parallel disease activity. Predicts severe disease, extra aticular disease better
than anti-CCPAb does (vasculitis, ILD, skin nodules, Felty’s), predicts good response to ritux and poor
disease prognosis.

ACPA (anti citrullinated peptide Ab. Commonest in use is anti CCP Ab)– high Sp (90%), less Sn (70%).
Appears months-yrs before clinical disease. Predicts severe disease and poor prognosis
Small fraction of pt are ACPA –ve but RF +ve. Therefore doing both increases (Sn and Sp)
ACPA in SLE / SjS predicts erosive arthritis
False positive in TB

ANA - +ve in 30% at low titres

With effective Rx both RF and ACPA will fall (RF more markedly and more frequently than ACPA) (U2D),
but are not good enough to monitor disease activity.

XR regular narrowing of jt space. Soft tissue swelling, marginal erosions, juxta articular osteopenia
Doppler US very Sn method to detect persistent synovitis
MRI detects changes early. Method of choice for KJ, C spine

Joint fluid high WC (> 50 000), low glucose (but > 25% fo RBS), moderate protein (30-50g/L)
Pleural fluid exudate, low pH, low Glc

Rheumatoid vasculitis
Medium > small
Skin ulcers, MnM / PN, heart (pericarditis), eyes (scleritis)
Small  purpura
Rx – steroids + CPM

Detecting a flare
Worsening jt symptoms
Skin nodules, ulceration
Thrombocytosis
High ESR , CRP

Defining Remission:
1. Moring stiffness < 15 min
2. No fatigue / joint pain / joint tenderness / soft tissue swelling
3. ESR Nl (men < 20, women < 30)

Assessing disease activity

All disease activity tools look at 28 joints. 10 MCPs, 10 PIPs, 2 each of WJ EJ SJ KJ
Original DAS included 44 joints

DAS 28 SDAI CDAI

Calculation SJC, TJC, ESR, PGA (1- SJC+TJC+PGA+EGA+CRP SJC+TJC+PGA+EGA
100) GAs 1-10 GAs 1-10
Remission < 2.6 < 3.3 < 2.8
Mild 2.6-3.2 33.-11 2.8-10
Moderate 3.2-5.1 11-26 10-22
High >5.1 >26 22-76
Response to treatment fall by 6.5
Positives Good correlation Include CRP Purely clinical, no need
Used in guidelines for Arrhythmatic of Ix
treatment decision cumulation. No special No need of special
making calculation calculations

Negatives Needs a calculator Excludes AJ, HJ, foot CRP not looked at!
AJ, HJ, foot not included Needs CRP
Physicians assessment ? over reliance on CRP
not included

In DAS28 CRP, CRP replaces ESR. Cut offs are the same.

Management

1. Analgesics
 2. Physiotherapy
3. DMARDs - Start early. commonest 1st line MTX
4. Steroid
a. short course for induction of remission in case of 1 st presentations or relapses
b. Intra articular / intra muscular steroid injections
c. SC for disease refractory to DMARDs + Biologics
5. Biologics – In: when DAS remains > 5.1 twice, one month apart despite optimum Rx with 2
DMARDS including MTX
6. Cardiovascular risk reduction and osteoporosis Px / Rx

Treatment approach

Once diagnosed, irrespective of disease activity level, start on DMARD monotherapy. MTX preferred.
If poor response;
- DMARD combination
- Biologics (anti TNF preferred first)
- DMARD + biologic combination
If poor response to TNFi monotherapy add 1 or 2 DMARDs
Can try, sequential biologics
If refractory to DMARD + biologics, add a short course (< 3m) of steroids at the lowest possible dose

DMARDs – takes 2-3m to show clinical benefit. So R/v 3 monthly, and if no response in 6m,
act!

Conventional synthetic DMARDs – MTX, SSZ, LEF, HCQ

MoA Dose SE Monitor

MTX DNA 5-25 mg/wk Hepatotoxic, FBC, LFT, Cr
(OoA 1-2m) synthesis marrow toxic, 2-4weekly x 3m
inhibitor acute pneumonitis 8-12 weekly x 3m
(DHFR inhib) teratorgenic (stop x 12 wkly thereafter
3m)
Leflunamide Blocks T cell 10 – 20 mg/d Hepatotoxic Same as MTX (ACR
(OoA 1m) division Marrow toxic 2015)
HTN, DPLD
Teratogenic (stop for
2y in F, < 1y in M)
SSZ Unknown 2-4 g/d Hepatotoxic Same as MTX
Marrow toxic
Rash, oligospermia,
Heinz body anemia,
megalblastic anemia,
orange urine
HCQ Unknown 200 – 400 mg/d Diarhoea, corneal Eyes yearly
deposits, retinopathy,
neuromyotoxicity
D Unknown 250 – 750 mg/day Proteinuria, low plt FBC, UFR 1-2 wekly
penicillamine Lupus like, MG like  4-6 weekly
Reversible loss of taste
Gold Unknown IM 50 mg/m Proteinuria, low plt FBC, UFR with each
injection
Ciclosporin Blocks T cell 150 – 300 mg/d Renal imp, HTN FBC, LFT,RFT, BP 2-4
activation weekly

Adding folic acid to MTX reduces SE as well as efficacy! (K&C)

MTX max dose for west – 25 mg/wk, china 20 mg/wk, japan 16mg/wk!
csDMARDS are equal in efficacy, but all trials were old, and done with lower MTX doses
adding csDMARDs were not superior to switching csDMARDs
HCQ – no benefit on joints. Improves lipids and glucose!

Biologics

Anti TNFs
1st line is anti TNFs
Except infliximab, all others can be used as monotherapy. Infliximab should be combined with MTX to
prevent formation of neutralizing Abs
Biologics are never combined. Try 1, if it fails, stop it and try a different biologic.

Pregnancy.
All biologics are category B, except rituximab which is cat C
Try to minimize use in T1
If given, newborn should not receive BCG for at least 6m

TB
All increase risk of TB (primary / reactivation). Less with etanercept and golimumab.
Do mantoux – if positive (indicate latent disease) exclude active disease by CXR and cultures (If active
disease +, need complete Rx of TB before starting biologics). If no active disease, give INAH for 6m
before starting biologics. After completing at least 1m of INAH can start biologics.

Hepatitis B and C – need caution with ati TNFs. Monitor AST, ALT. advanced liver disease and renal
failure are CIn for biologics.

Heart failure – avoid anti TNFs – not any more.

Lymphoma
RA pts on anti TNFs are at a slightly high risk of lymphoma (but no other CAs). Few may become ANA
+ve with reversible lupus like syndrome, leucocytoclastic vasculitis and ILD.
Avoid in past lymphoma or demyelinating disorders. Use ritux for them.
Drug induced lupus with biologics
Biologics cause lupus – skin, joints, serositis
Positive ANA, dsDNA, histone, Sm and low C3 C4
Resolves after discontinuation

Group Drugs MoA Route SE

Anti TNF-alfa Etanercept Decoy receptor Infliximab – IV Infections
for TNF alfa (0,2,6, then 8 TB reactivation
Infliximab, Anti TNF weekly?) Basal cell CA of skin
adalimumab receptor Ab Others – SC Etanercept,
Golimumab adalimumab –
certolizumab Demyelination and
reversible lupus
Anti B cell Rituximab Binds to CD20 IV, 1g rpt in 2 Infections
reduce B cell weeks. 2nd line TB reactivation
number Premed HC,
piriton, PCM
Anti T cell Abatacept Inhibit T cell co- SC
stimulation 2nd line
Anti IL-6 Tocilizumab AB against IL-6 For TNF failure Hypercholesterolaemia
receptor For MTX Leucopenia
intolerance
Anti IL-1 Anakinra Decoy receptor Not Inferior effiacy
for IL-1 recommended
JAK inhibitors Tofacitinib – RA, Oral Phase II / III
PsA
Upadacitinib –
RA (SELECT)
Baricitinib (1 & 2)
– SLE
Filgotinib (PsA,
SpA)

CVD risk reduction

Assess risk at least every 5 y
Consider for PsA and AS as well
Use HDLC and LDLC. Use SCORE tool. RA needs multiplication of risk score by 1.5 (if not already included
in the risk tool)
Statins, BP control, glycemic control, lifestyle, stop smoking.
Monitoring response / activity assessment

EBM
Baricitinib superior to adalimumab – an RCT in 2015, abstract

In general, bDMARDs are all equal in efficacy. Using bDAMRDs in combination with a csDMARDs gives
better efficacy than bDMARDs alone. However, if csDMARDs are contraindicated, use tocilizumab or
tofacitinib. Because those 2 are superior to MTX in efficacy when used as monotherapy

Tofacitinib – ORAL Solo (monoRx Vs placebo), ORAL Step (with MTX Vs MTX mono)
Greater ACR 20 or 50 or 70 response and disability (HAQ-DI)
SE - diarrhea, URTI, HTN, headache, hepatitis, TB
Late analysis – effects sustained at 4yrs

Local research
Low dose ritux (500mg) + MTX is equal in effectiveness (> 60% response rate) and safey to leflunamide +
MTX
RCT, N = 40, FU 24 weeks
Ref : H Wijesinghe et al BMC MSKD, 2017

Pregnancy
Can give SSZ, HCQ. Stop MTX 3 months prior to conception
Steroids safe after 14 wk. before, that, crosses placenta and causes cleft palate and PIH.

ACR 2016 guidelines

Phase I csDMARD – improve in 3m, target in 6m
Phase II bDMARD / tsDMARD for high risk. 2nd DMARD for low risk. bDMARD if 2nd csDMARD fails
Phase III alternative bDMARD / tsDAMRD

csDMARDS – conventional synthetic DMARDs – MTX, LEF, SSZ

bDMARDs – biological [Link] derived from an organic source – current day – by
biotechnology
bsDMARDs – biosimilar (structurally almost equal to the reference biologic. Minor changes in clinically
inactive regions acceptable)
interchangable product – biosimilars shown in trials to have same efficacy and safety outcomes to the
reference biologic. Allows dispensor to issue the IDP without prescribers permission
tsDMARDs – targetted synthetic DMARDs – JAK inhibitor

nomenclature
mab – monoclonal Ab
zomib – proteasome inhibitor
nib – small moelcule inhibitor
for mabs
xi – chimeic - mixed human and mice (Rotuximab)
u- fully human (evolocumab, secukinumab – IL17Ai)
o – mouse
z – humanized ~95% human (mepolizumab, , idaracizumab – dabi reversal)

Glcc short course

Oral pred 30mg/d
IV Mehtyl pred 250m stat
IM methyl pred 120mg stat
Required for bridging of csDMARDS as they take time to act. Not needed for bDAMRDS / tsDMARDs as
they act fast
Tail off and stop by 3m. not beyond 6m. do not use low dose (< 7.5mg/d) long term

In the UK (NICE) bDMARDS considered when :

2 cDMARDs fail causing DAS28 > 5.1 at least twice, at least 1m apart

Prognosis
With Rx 25% recover completely ! (K&C)
Poor prognosis:-
1. Insidious onset
2. Number of swollen joints
3. Level of disability at onset
4. High ESR, CRP, ACPA, RF titres
5. NCNC anemia
6. Erosive changes in imaging
7. Poor socioeconomy
8. Smoking
Predictors of progressive disease in early RA
1. Age
2. Female
3. Symmetrical small joint involvement
4. Morning stiffness > 30min
5. > 4 swollen joints
6. CRP > 20
7. RF / ACPA +ve

What treatment offers CVD risk reducing benefit in RA?

Statins
Anti TNFs
Causes of

Neutropenia
Felty, LGL
MTX
AZT
Gold

Anemia
ACD
Drug induced GI bleeding – NSAIDs, steroids
AIHA
Drug induced megaloblastic anemia – MTX
Associated autoimmune disease – hypothyroidism, pernicious
Splenomegaly
Felty
LGL
Amyloid
lymphoma

Renal disease
MGN, MmPGN, MsPGN, TIN, amyloid
Drugs – NSAIDs (TIN, MCD, papilloary necrosis)
Au, penicillamine – MGN

Dyspnea
Lung
Pneumonia – CAP, TB, PCP
ILD of RA (UIP)
MTX – ILD (HP)
Pleural effusion
PHT

Anemia

Cardiac
IHD/HF
Pericarditis
Cardiac amyloid
Eosinophilic myocarditis

Renal failure
NSAIDs
Amyloid – AA, drug induced (penicillamine, gold, NSAID)

Unrelated

Approach
CXR, HRCT
 UIP
 anti CCP
 high = RA – ILD – Rx RA with DMARDs
 normal = consider IPF – and consider pirfenidone
 HP = MTX – stop MTX, switch to AZT etc

When giving MTX for RA-ILD patients, closely monitor DLCO. If it falls below 70% better to stop MTX and
switch to another agent

Pregnancy
Often remit
In pregnancy. PCM safe. NSAIDs safe, but avoid in T3 (oligohydramnios)
Pregnancy – CASH : ciclosporin, AZT, SSZ, HCQ can be used. Glucocorticoids increase PIH and cleft
palates if used in T1. Better to wait till this limit is passed.
Breast feeding – none can be used (? Except penicillamine and gold)
Leflunamide and MTX should be stopped at least 3 months before trying to conceive

Joint fluid analysis

non inflammatory
OA
Trauma
Neuropathic arthropathy
RhF, SLE, chronic sarcoid, scleroderma

Inflammatory
RA
SpA
crystal
 RhF, SLE, chronic sarcoid, scleroderma

Septic
Bacterial / other infections

Pseudo-spetic (WC > 100 000.mm3)

RA
Gout
Leukemia infiltration
Intra articular injections

Hemorrhagic
Hemophilia
Scurvy
Bleedin disorder
Trauma

Eosinophic joint fluid allergt, parasite, Lyme

Rhuematoid hands Short case

Consent

Look around walking aids, splints

Look at the pt – cushingoid, psoriasis, dyspneic, pain

Hand examination

Look
Palmar
skin – CTD scar, nodules, finger tip vasculitic infarcts,
Muscle – wasting
Tendons – triggering

dorsum
skin – Gottron’s, sclerodactyly
Nails – pitting (DD Psoriasis), nail fold infarcts (vasculitis)
Muscles – wasting
Joints – spindling, deformities (B, SN, ZT, MCP palmar sub & Ulnar deviation)

Feel
Dorsum
Warmth over PIP, MCP, WJ
Swelling – each PIP, MCP, WJ
Styloid – piano key sign (ruptured ulnar collateral lig – mobilized styloid)
 Sclerodactyly –
Palmar
Triggering

Move
Fist (hand jt mobility)
Pincer grip / Buttoning unbuttoning
PAD, DAB, thumb abduction, radial sensory loss
Prayer, reverse prayer, (WJ mobility)
Pronate – supinate (eating movement)
X across chest (Rh nodule, olecranon bursa, tophi, psoriasism, thin skin purpura of Cushing)
hands on occiput (SJ intergrity, proximal muscles – steroids / PM-DM overlap)
Earlobe – gouty tophi, Hairline – psoriasis, SSCl

Systemic examination
Eyes – red, vision, pallor
Mouth – ulcers (drug neutropenia, SLE), pigmentation (addison)
Neck – C spine movements, LN
Chest – ILD, effusion, PHT, BP
Abdomen – spleen (Felty / LGL), HSM (amyloid)
Legs – HJ, KJ, AJ, feet, edema (nephrotic)

Presentation

This female patient has deforming symmetrical small jt arthritis, characterized by ZT, B. SN deformities,
subluxations, most likely due to rheumatoid arthritis. She has 10 tender and swollen joints suggesting
active synovitis. She has complicatiosn of the disease like anemia and drug effects like

I examined the hands of this female

On inspection –
Rheumatoid type Jt deformities – B, SN, PS and UD of MCP, DS-US
Muscle wasting
Skin – nodules, scars
Nail changes / sclerodactyly / Gottron’s

On palpation
Warmth, swelling,
styloid

Movements
Neurological

Functional status
Therefore my conclusion is
this patient has rheumatoid arthritis
causing …… deformities, small muscle wasting
with/out Fx of active disease as evidenced by warm tender swelling of …..
causing functional

I would like to further evaluate for

Involvement of other joints
Systemic complications – ILD, PHT, splenomegaly, edema
Adverse effects of drugs – striae, proximal myopathy
Evidence of overlapping other CTDs and AIDs

Plan of management is to
Confirm Dx (r/v records, serologies, X rays )
Assess acitivity – ESR, CRP, Tools
Ix for complications – FBC, LFT, UFR, RFT, CXR
Review current therapy and modify accordingly.
Methotrexate pharmacology

MoA
Inhibits DHFR (that converts DHF to THF, the active form) thus inhibiting cellular metabolism
including nucleic acid synthesis
MTX is a pro-drug that is activated by polyglutamation within cells. This reaction is slow and
takes 27 weeks to reach a steady state, explaining the reason for weekly dosing and duration
required to manifest results.
Anti inflammatory effects may be mediated by increased extra cellular adenosine level when Rx
with MTX

PK
A : unaffected by food. Higher the dose, lesser the bioavailability.
D:
M : acitavated intracellularly. excreted unchanged
E : renal. GFR dependent

Evidence for benefit

Reduces pain, tenderness, swelling, ESR
Halts disease progression
Improves functional status
Cannot reverse joint erosions. May retard progression.
Inferior to biologics
Reduces cardiovascular mortality
Worsens subcutaneous nodules in RA !
Dosing
Tablet strength2.5mg
Starting dose 7.5 mg a week (starting at a higher dose increases stomatitis, GI upset, fatigue)
Titration – 2.5 mg a week every 1-2 week
Maximum dose – 30 mg/week

Dosing considerations
Avoid in eGFR < 30
Low dose in eGFR 30-60 (keep 7.5 -10mg)

Split dosing (12 hourly 3 doses)

May increase bioavailability – not proven in trials
May reduce adverse effects – not proven in trials
Tried when weekly dose exceeds 15mg
Spreading doses over 2-4 days a week increases toxicity

Folic acid 1mg daily (or folinic acid 2.5mg once a week) reduces hemat SE, other SE and serum
homocysteine levels without losing therapeutic effect (upto folic acid 5mg/d or folinic acid 7
mg/wk). keep a gap of 24h between MTX and FA doses.
NICE: FA 5mg wed or FA 1mg everyday except sunday

Duration
Life long unless serious side effect develops
Stopping will cause a flare within 3-6 weeks

Adverse effects

Uncommon severe

Hepatotoxity
R/F – alcohol, viral hepatitis, cumulative dose
Monitor LFT 4-8 weekly. If elevated, reduce MTX dose and repeat LFT in 1-2 weeks. If > 6/12
LFTs per year are abnormal (AST > x3, Alb < 34) do liver biopsy
Associated with liver folate depletion. Mechanism uncertain. FA helps to prevent.
Px
1. Screen and Rx viral hepatitis before MTX !
2. FA
3. Avoid acohol
4. Monitor AST and albumin
5. Caution in NASH
NICE (passmed): if ALT > x2 ULN, stop MTX

Pulmonary toxicity

Idiosyncratic, within first year of Rx, FA independent

MTX pneumonitis ILD of RA Opportunistic infection – PCP,

crypto, histo, asperg
Subacute Chronic Acute – subacute
Fever cough SoB Cough SoB Fever cough SoB
Eosiniphilia is characteristic UIP > NSIP > other BAL culture
(seen in 50%)
HRCT Often HP, sts OP or NSIP
Improves after stopping the Anti CCP -ve : IPF – try pirf
drug. Pred only if severe. Anti CCP +ve : RA-UIP – give
Cannot rechallenge. DMARDs
Approach – stop MTX, look for infections and LVF. Note that HRCT is HP pattern but has
eosinphilia in MTX lung injury

Infections
Uncommon
CRs of PCP and other
Increased risk if on combination Rx
Interfere with T cell function

Myelosuppression
Macrocytic anemia
Pancytopenia not common
Isolated leuco / thrombo / erythrocytopenia!
R/F: - renal impairment, daily dosing
Px monitor FBC monthly x 3m, 2 monthly x 6m and 3 monthly thereafter
Rx: folinic acid

Hodgkin lymphoma

Nephrotoxicity
With high dose
Crystal nephropathy and tubular injury
Renal failure reduces MTX excretion and worsens systemic toxicities. Minimized by giving glucarpidase
an enzyme that cleaves MTX and facilitates renal excretion

Minor side effects

 1. Gastrointestinal problems such as nausea, stomach upset, and loose stools. Helped by
PPI / H2RB prior to MTX dose (evening or morning before MTX)
2. Stomatitis or soreness of the mouth. Reduced by FA – if develops, stop MTX and cnsult
specialist (passmed)
3. Macular punctate rash that usually occurs on the extremities and spares the trunk
4. Central nervous system problems including headache, fatigue, or impaired ability to
concentrate (related to raised adenosine)
5. Alopecia
6. Fever, but infection should be excluded
7. Hematologic abnormalities, particularly macrocytosis

Folic acid
 1 mg/day upto 5mg/day including the day of MTX (few studies showed significant reduction
in MTX efficacy). Passmed: Folic 5mg a week
 Reduces
o Hepatitis – MTX depletes liver FA, how this causes hepatitis is unclear
o GI effects
o Stomatitis
 If not enough, switch to
o Folinic acid 2.5 – 5mg per week, 12h away from MTX dose

Avoid concomitant cotrimoxazole : severe marrow suppression by folate depletion

Management of MTX toxicity

IV folinic acid 2mg/kg 6 hourly until toxicity is resolved

Folinic is the active form of folic acid/. Available IV PO and IM (PO and IM given for MTX
overdose, to prevent toxic effects, 15mg 6 hourly until MTX levels are below toxic levels or for 3
days) (folinic acid is also used in methanol poisoning, trimethoprim overdose, or
pyremethamine overdose)

Azathioprine
Purine mimick antimetabolite
Prodrug. Converted to active 6MP in RBCs (?. In U2D)

A: good GI
D: 30% protein bound
M: activated to 6MP
E: 45% excreted unchanged in urine. Rest converted to 6MP
Biological t ½ : 24h
 TIMP is the active form (and
causes marrow toxicity)
Allopurinol inhibits XO. TPMT
deficiency directs 6MP towards
TIMP.

MoA: reduce T and B cell

proliferation and therefore Ig
and IL-2 porduction

SEs
1. Marrow suppression – predicted by low levels of thiopurine methyl transferase
- If N < 1000 or L < 600 or W < 4000 or plt < 150, reduce the dose by 50%. If no
improvement, stop AZT forever.
2. Opportunistic infections – PCP, so if coRx with glcc
3. Non melanoma skin cancer (SqCCA) (commonest CA wirh AZT), NHL, Kaposi, ut Cx, vulval.
Sp in post KT pts, not so much in rheumat

Relatively safe in pregnancy. No fertility issues reported

Cyclophosphamide

Hemorrhagic cystitis
Px: hydration, frequent micturion, Mesna (IV. 20% of CPM dose per each dose, in 3 doses -
15min, 4h and 8h of starting CPM)
Dx: cystoscopy

Subfertility
Sperm / oocyte banking
GnRH analogs with CPP inhibits oogenenssi during treatment period and protect them from
toxicity. ()

Teratogenicity
Both men and women are at risk
Infections
Some prescribe prophylactic cotrim

Cancer
Leukemia
Skin cancer

SERONEGATIVE SPONDYLOARTHRITIS

Inflammatory backache / joint disease + enthesitis + negative RF, ACPA, ANA + HLA B27 associated

Inflammatory backache
Backache for > 3m with 4 of these 5
1. < 40 y
2. Insidious onset
3. Night pain (note: morning stiffness is not a Fx!s)
4. Improves with exercise
5. Does not relieve by rest

Types of SpA (old approach)

1. AS
2. PsA
3. Reactive arthritis
4. Enteropathic arthritis
5. Juvenile SpA
6. Idiopathic SpA
7. Axial spondyloarthritis (diagnosed when MRI = SI + 1 of below OR MRI –ve + HLA B27 +ve + 2 of
below:
– infl backache / responds to NSAIDs / FHx / Hx of IBD / arthritis / enthesitis / uveitis /
dactylitis / psoariasis)

Traditional classification is getting less emphasis. Dx is AxSpA and pSpA with or without Ps or IBD.
 SpA

Axial SpA (AxSpA) peripheral SpA (pSpA)

AS (plain XR SIitis+) non radiographic axSpA

Although nrAxSpA do not meet modified New York criteria for AS, they do equally benefit from therapy
as for AS (AKA rAxSpA)

Features in common to seronegative spondyloarthritdies

Genetic link : HLA B27 / FHx of SpA

5 MSK Fx: IBP, Alternating buttock pain, asym oligoarthritis, Enthesitis,
Dactylitis
Extra articular Fx – Uveitis, AR, apical fibrosis, AV blocks,
psoriasis, IBD (therefore EN), urethritis (ReA)
Ix Fx :ESR / CRP (elevated in 50%), Negative RF / ant CCP
Rx Fx: Good response to NSAIDs

Diagnostic criteria
Diagnosis of SpA

ESSG (European Spondyloarthropathy Study Group)

Inflammatory spinal pain or synovitis and 1 of

Sacroilitis SpA
Enthesitis 1. Inflammatory back pain
Alternating buttock pain 2. Clinical sacroiliitis
IBD 3. Enthesitis
FHx of SpA 4. Genetics – HLA B27 / FHx of SpA

Amor criteria Uveitis, dactylitis, peri arthritis, IBD,

Inflammatory back pain NSAIDs response
Unilateral buttock pain
Alternating buttock pain
Enthesitis
Dactylitis
Anterior uveitis
Peripheral arthritis
HLA B27 or FHx of SpA
Good response to NSAIDs
Score 1 each for first 2, 2 each for rest.

Ankylosing spondylitis
Diagnosis of AS Inflammatory back pain
Radiographic sacroiliitis
Reduced lumbar spine mobility
Reduced chest expansion
Modified New York Criteria

 Low back pain with inflammatory characteristics

 Limitation of lumbar spine motion in sagittal and frontal planes
 Decreased chest expansion
 Bilateral sacroiliitis grade 2 or higher
 Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical
criteria

Rome Criteria
 Low back pain and stiffness for >3 months that is not relieved by rest
 Pain and stiffness in the thoracic region
 Limited motion in the lumbar spine
 Limited chest expansion
 History of uveitis
Diagnosis of ankylosing spondylitis when any clinical criteria present with bilateral sacroiliitis grade 2
or higher

HLA B27
90% of AS
70% of PsA
50% of IBD-SpA
Predict SIitis, uveitis, dactylitis

Ankylosing spondylitis
A seronegative SpA, characterized by asymmetric SIitis, and progressive ankylosis of spine.
Associated with B27, uveitis, enthesitis

Epidemiology
M : F = 3 : 1 (D), 5:1 (K&C)
Young age

Pathology
Enthesitis + synovitis (extension of enthesitis to the synovium)
Neovascularization of the enthesis
Ossification of the enthesis forming syndesmophytes and when advanced causes ankylosis

Pathogenesis
Genetic risk

Environtmental triggers at skin / MM  IL-23  T cell  IL 17 and TNFa  inflammation

 IL 22  ossification

Classical presentation
Inflammatory Low backache (worse in the morning with stiffness and relieved by activity)
Alternating buttock pain, disturbing sleep
Retention fo L-lordosis in forward flexion is an early Fx
Schoebers
Kyphosis

MSK Fx
Sacroiliitis
Spinal facet joint syndesmophytes, ankylosis
Atlantoaxial subluxation
Peripheral arthritis:
40%
F>M
Inflammatory asymmetric large joint mono/oligo arthritis
Enthesitis - Achilles tendinitis, plantar fasciitis

Extra articular manifestations of AS (10 A’s)

1. anterior uveitis
2. (atlantoaxial subluxation)
3. apical fibrosis
4. aortitis
5. aortic regurgitation
6. AV block
7. Amyloidosis
8. IgA nephropathy
9. Arachnoiditis  cauda equina
10. Achilles tendonitis and associations with plantar fasciitis and inflammatory bowel disease

NHx
Joint ankylosis
Starts from SI, ascneds

Ix
 ESR / CRP – high in 50%
 XR pelvis AP – SIJ erosions, joint space changes, sclerosis, ankylosis
 Radiographic sacroiliac (SI) changes are graded as follows:
Grade 0 – Normal
Grade 1 – Suspicious
Grade 2 – Minimal sacroiliitis
Grade 3 – Moderate sacroiliitis
Grade 4 – Ankylosis
Fx : Sym SI. Wide –Narrow-ank. Subchond erosion Periosteitis.
 Spinal X ray
1. Squaring of vertebrql body, Romanus lesions, Shiny corner sign
2. Fine sym marginal syndesmophytes.
3. Facet joint fusion.
4. Bamboo spine, Dagger sign, Trolley track sign.
 5. Osteoporosis.
6. AA jt sublux.
7. Anderson lesion (Sp-disciitis)
 MRI T1 with Gd and T2 with STIR (or T1 and T2 with fat suppression) sequence of SIJs oblique-
coronal view – subchondral bone marrow edema
 HLA B27 – positive in 95% of AS. 8% of population is HLA B27 positive. Of all with B27, 6% gets AS.
Thus, B27s confers a relative risk of 80 for AS. (PACES Bilal)

ASAS modified Berlin algorhythm. SnSp 75-80%. Guide only.

Treatment of AS
More than the exact type of SpA, management is aimed at treating the key domains affected
Axial arthritis, Peripherla arthritis, enthesitis / dactyltis, skin, eye

1. NSAIDs – offers symptom relief. Retards radiological progression. Rapid symptom relief in 48h is
a diagnostic clue.
 2. Consider SAARDs (Slow Acting Anti Rheumatic Drugs) – SSZ, MTX, LEF, pamidronate,
thalidomide. Weak evidence. Reserved for anti TNF contra indicated or refusing pts. For them,
SAARDs are preferred over non TNF biologics (ACR/SAA/SARTN 2015). Offer SSZ for peripheral
arthritis (EULAR 2017)
3. TNFa inhibitors
ACR/SAA/SARTN 2015
a. No reponse / intolerance of 2 NSAIDs over 1month or
b. Partial response to 2 NSAIDs over 2 months
No preferred anti TNF
For IBD, TNFa Ri preferred over etanercept
For recurrent iritis, infliximab and adalimumab preferred over etanercept

BSR/BHPR 2016:
Offer anti TNF for active disease (BASDAI > 4 and VAS for spinal pain > 4 at two points 4 weeks
apart) despite standard therapy (2 NSAIDs at least 2 weeks each). Transient flares of AS lasts 2-3
weeks. If scores are high for 4 weeks, warrant treatment.
Assess response at 3m, 6m and then every 6m. adequate response is a reduction of BASDAI and
VAS by 2 or more, from baseline.
Infliximab
Golimumab
Adalimumab

ASAS/EULAR 2016
Active disease defined as BASDAI > 4 or ASDAS > 2.1
If one anti TNF fails, consider another TNFi or IL17i (secukinumab)
Phase I 2 NSAIDs 4 weeks
Phase II bDMARDs 6m trial
Phase III alternative bDMARDs
Improvement is defined as fall of BASDAI by 2/more or ASDAS by 1.1/more

Summary of all fits to phased approach

4. Glucocorticoids
a. Systemic – avoid except in {peripheral jt flare} / pregnancy / IBD flare
b. Local – for monoarthritis, single SIitis, iritis, enthesitis
c. Avoid injections to / around Achilles, patellar and quadriceps ligaments
5. Physiotherapy – to preserve joint ROM and breathing exercise retard disease progression
6. Stop smoking
7. Surgery
Total hip arthroplasty for severe hip pain or disability
Corrective spinal osteotomy – avoid (ACR/SAA/SARTN 2015). Consider in specialized centres
(EULAR 2017)

New therapies
Anti IL17A : Ixekizumab – superior to placebo in biologic naïve NSAID failing rSpA. (COAST-V)
JAK1 inhibitor : Filgotinib – phase 2 trial (TORTUGA) – effective and safe
Screening

DEXA for OP – may be altered by syndesmophytes, but no evidence for any recommendation, therefore
still recommended to do DEXA (spine and hips)
Cardiac screening not indicated (ECG< 2D echo)

Disease activity indices

ASDAS (Ankylosing Spondylitis Disease Activity Score)
Back pain
Peripheral joint pain / swelling
Morning stiffness duration
Patient’s global assessment
CRP / ESR
Inactive < 1.3
Moderate 1.3 – 2.1
High 2.1 – 3.5
Very high > 3.5
Drop by
> 1.1 clinically important improvement
> 2.0 major improvement

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

Fatigue
Neck back hip pain
Other joint pain and swelling
Discomfort
Morning stiffness duration
Out f 5

Therapeutic problems
SpA in CKD / PCKD – NSAIDs CIn in renal impairment

SpA with IHD

SpA increase ASCVD risk
NSAIDs are CIn after acute ASCVD / acute HF
NSAIDs decrease antiplatelet effects of aspirin
SpA limits physical activity
SpA limits Ex ECG

Place of MTX in SpA

Not the first line for axial / peripheral disease
If SSZ is not effective / tolerated, can try
Infliximab efficacy wanes over time due to autoAb formation. In RA, combining MTX is beneficial to
prevent this. Whether it applies to SpA as well is not known.

SpA and fertility

Probably no direct link
SSZ – reversible oligospermia
MTX – teratogenic, stop before 3m for both male and females
Leflunamdie – teratogenic, stop for 2y in women & ?3y in men. If not, offer cholestyramine washout
monitoring blood leflunamide levels (not available in SL)

SpA and TB
TB can cause sacroilitis – unilateral.
Anti TNFa may cause reactivation. Watchout for fever after 3-4 inflixi doses
For those who had treatment compelted TB, can give TNFai after excluding active TB
For those who haven’t had TB, screen for latent TB (mantoux / IGRA)
If negative, can give TNFai
If positive, rule out active disease, start INAH, and after completing INAH for 2m, can give TNFai
If INAH causes hepatitis, use an alternative regimen
Golimumab, etanercept, IL-17i and IL-23i probably carries lower risk of TB reactivation

Short case
Axial skeleton – stand, walk, lean, bend, breath
spine mobility (neck, lumbar AP and lat all restricted)
Flesche test (lean on to a wall. Gap between occiput and wall. 0 in normal)
Modified Schober’s test
Sacroilitis
Chest expansion (< 1.9cm is restricted?. PACES: < 2.5cm)

Systemic
Sit
 Hair line for psoriasis
 Eye: Ant uveitis – red eye, loss of vision
 Hands and ULs: Dactylitis, small jt arthritis, psoriatic nails, behind elbow psoriasis, EJ, SJ
 Chest : Apical fibrosis, AR (cardiac apex, murmur), AV block
Lie down

 Cardiac apex
 Abdomen : Amyloidosis – Hepatosplenomegaly, Umbilicus – psoariasis rash
 LL: Knee joints, psoariatic rash
Leg – EN,
Ankle edema – amyloid / AR-HF
Achilles – Enthesitis, plantar fasciitis
Psoriatic arthritis

Epidemiology
Affect 10-20% of Ps patients. In 70% arthritis comes after skin. In 20% it comes before skin
M=F

Articular disease Patterns

1. Symmetrical polyarthritis (30-40%). F>M. RA like, less extensive, more benign. ‘sometimes
indistinguishable from RA. Often RF and anti CCP are negative. Positive in ~ 5-10%’
2. Asym oligoarth. (20-30%). KJ, AJ, sausage digits
3. DIP arth. 10%. Classic. M>F
4. Ps SpA – less severe than AS. 50% are B27 +
5. arth. Mutilans. 5%. Fingers toes.
a. Severe osteolysis  flail joints  total bone resorption  telescoping
b. Joint subluxation
c. Joint ankiylsosis

Extraarticular extra cutaneous Fx

Uveitis – only in HLA B27+ Ps SpA.
Conjunctivitis

X ray features
1. DIP or PIP, MCP
2. Jt space narrowing
3. Eccentric erosions
4. osteosclerosis
5. tuft resorption
6. pencil in cup
Dx criteria for research – CASPAR criteria
Skin, nail, dactyltis, juxta articular new bone formation, negative RF

Rx
NSAIDs for mild cases – may worsen skin
DMARDS – MTX is DoC/ also SSZ, LEF, CycA. avoid HCQ – causes exfoliation
BIOLOGICS
Anti TNFs
Ustekinumab – emerging (IL 12/23 R block)
OTHER - Acitretin, PUVA

New therapies for PsA

Filgotinib (JAK1 inhibitor) – EQUATOR – phase 2; good efficacy and safety

Psoriatic SpA
NSAIDs worsen skin disease. But only with some NSAIDs, and with person to person variation. If
skin relapses, switch to a different NSAIDs.
Steroid withdrawal can flare the skin. Tail off very slowly
HCQ worsens skin, avoid in Ps SpA
If peripheral arthritis is present, use MTX

Enteropathic arthritis

Epidemiology
UC 10% , CD 20%
Peri // IBD
SI (16%) AS (6%) doesn’t // IBD

CFx
SpA: Symmetrical SIitis and/or SpA that clinically and radiologically mimics AS
Peripheral arthritis
Type 1: remitting and relapsing Mono/oligoarthritis, sp of KJs. // disease flares, may precede IBD
Type II: chornic polyarthritis, sp of MCPs, with intermittent worsening, not // IBD wont preced
IBD

** unexplained IDA in a SpA may be the first clue to IBD

Dx
IBD
SpA on imaging
HLA B27

Diarrhea and arthritis

1. IBD and
a. SpA / pSpA
b. Septic arthritis
c. Steroid induced osteonecrosis (pain >> swelling)
2. Infections
a. TB, Brucella, Whipple (KL, AJ > SIJ)
3. Infectious diarrhea and ReA
4. Behcet, SLE
5. OA  NSAIDs  microscopic colitis

Rx
Rx of IBD resolves arthritis

IBD and NSAIDs

Conflicting evidence
NSAIDs probably ppt flare, increase disease activity (loss of beneficial immunomodulatory effects of PG)
Less with COX2i

Reactive arthritis

1-4 weeks after dyssentry (Yersinia, Salmonella, Shigella, Campylobacter, Clostridium difficile) or

urethritis / STI (Sexually Acquired Reactive Arhritis – SARA- Chlamydia trachomatis, , and Chlamydia
pneumoniae)
Arthritis after other bacterial and viral infections are conventionally called post-infectious arthritis.

Classical presentation
NSU + reactive arthritis + conjunctivitis (reiters traid)

Commonest presentation
Acute LL asymmetrical oligoarthritis
MTP >> Calc > AJ > KJ

Other articular features

Achilles tendinitis, plantar fasciitis
SIitis in 15-20%
Dactylitis
Joint fluid - WC rich. Reiter cells (vacuolated macrophages with ingested neutrophils)
Extra articular features
Fever, LoW,
Skin - Keratoderma blenorrhagica ( (waxy yellow/brown papules on palms and soles) ), Circinate balanitis
((painless vesicles on the coronal margin of the prepuce ), Nail dystrophy (= to Ps), Painless mouth ulcer, EN
(rare-emed)
conjunctivitis (seen in 50%)
Uveitis – 30% of chronic cases. Rare on presentation
rare serositis
CNS - MEitis, seizures, peripheral neuropathy

Dx
SpA / OlioA: Xrays, Jt fluid aspiration (Reiters cells)
Urethritis evidence - HVS - chlam
Dyssentry evidence – SFR, culture (will detect salmonella, shigella)
2 glass test

NHx
1st attack self ltd.
25% - Relapsing disease (recurrent infection causing recurrence of ReA)
10% - Rec chronic arthritis > 60% (often HLA B27 +ve. Relapse even without recurring infection)

Rx
Rx NGU – DC / Azithro
Rx arhtitis – NSAIDs  DMARDs for severe / rec disease. Local GLcc

Ankylosing spondylitis Enteropathic Psoriatic arthritis Reactive arthritis

arthritis
Epid M : F = 3 : 1 (D), 5:1 (K&C) M=F M:F 15:1
Typical p/w DIP arthritis NSU, reactive arthritis,
RA like is conjunctivitis (reiters traid)
commonest Often p/w arthritis alone –
Oligoarth is 2nd acute LL oligoarthritis
commonest Fever, LoW, rare serositis
MSK SIitis, SpA SIitis, SpA RA like Oligo / mono arthritis
Peripheral oligoarthritis Oligoarthritis oligoA Enthesitis
Enthesitis Enthesitis DIP arthritis SIitis in 15-20%
SpA
Arthritis mutilans
Skin - EN Ps rash. KB, CB, nails, painless
Aphthous ulcer Nail changes mouth ulcers, EN
Eye A. Uveitis Iritis, Conjunctivitis
conjunctivitis Uveitis
X ray Sym SI. Asym SIitis
sym smooth marginal syndesmophytes Asym coarse non marginal syndesmopytes
NSAIDs Often enough For mild cases 1st line
(can worsen skin)
LocalGlcc Local Glcc for monoarthritis, uveitis. Systemic for uveitis
DMARDs MTX, SSZ only for Rx of IBD remits MTX – DoC. For rec dis, severe
peripheral Arthritis arthritis AVOID HCQ keratoderm, severe sympt
Anti TNF Yes For IBD In Yes ?
Other Rx No place for ritux Ustekinumab Doxy / azithro for NSU
X RAY DIAGNOSIS
OA
1. Variable narrowing of joint space
2. Osteophytes
3. Bone cysts
4. Subchondral sclerosis (rare erosive variant –
subcondral erosions)

Inflammatory arthritis
1. Bone erosions (marginal, subchondral)
2. Regular narrowing of joint space
3. Soft tissue swelling

RA SpA (PsA)
Distribution MCP, PIP DIP (or PIP, MCP)
Penia / itis Osteopenia > perioseitis Periosteitis > osteopenia
Erosions Marginal (attachment site of synovium) Eccentric (?intra articular, extra chondral)

RA
Juxta articular osteopaenia
No periosteitis (bone prolif)
Affects prox joints of the hand / foot

SpA
Periosteitis +
Min Juxta articular osteopaenia (in late adv disease)
Distal joints of hand / foot

SLE
Normal jt space
No erosions
Osteopaenia +
Soft tissue swelling
Non erosive deforming arthritis – Jaccouds
Gout
Early – Nl
Late – punched out erosions with sclerosed margins and overhanging edges

Haemochromatosis
Classically 2nd and 3rd MCP jt. Hook osteophytes, sp on dominant hand

NSAID pharmacology

CVD
Increase MI, stroke, HF
NS-NSAIDs and COX2i
In those with and without preexisting disease
Therefore NSAIDs are CIn in acute ASCVD.
Least risks options : celecoxib = naproxen , ibuprofen
Reduction of efficacy of aspirin
By competing to bind with COX in platelet but without inhibiting its action.
All NS NSAIDS
Much less with celecoxib.

GI bleeding
Risk in decreasing order
KINDAPTIM
Ketoprofen > Indomethacin > Naproxen > Dicolfenac > Aspirin > Piroxicam > Tenoxicam > Ibuprofen >
Meloxicam

Enteric coated aspirin offers no significant benefit, probably because GI toxicity is mediated by
systemically by absorbed aspirin

COX2i cause less PUDs but benefit is lost if combined with low dose aspirin and then warrants prophlaxis
with misoprostol / lanzaprazole 15-30mg/d / esomoprozole 20-40mg/d

Steroid choice
Mostly based on prescribers experience

Oral MPP vs oral pred

MPP causes less fluid retention but is much more costlier
Crystal arthropathies
MSU acute gout, chronic tophaceous gout.
CPPD pseudogout, chondrocalcinosis
Basic CaPO4 calcific periarthritis, calcinosis

Cholesterol chronic RA, post Glcc injection

CaC2O4 acute arthritis in HD pts

GOUT
Inflammatory arthritis secondary to mono sodium urate crystal deposition
Commonest inflammatory arthritis world wide
M:F = 5:1
Only a minority of hyperuricaemicpt develop gout, so urate lowering therapy is not recommended in
asymptomatic hyperuricemicpts

RF
Diminished renal excretion of urate – 90% of cases (body’s urate eliminiation – 2/3 kidney, 1/3 - gut)
Renal failure
Alcohol
Drugs – HCT, frusemide, CSP, Pyrazinamide
Pb toxicity (saturnine gout)
Lactic acidosis
Ineherited high reabsorption

Overproduction
MPD / LPD
Psoriasis
Inherited – LeschNyhan syndrome (XLR, mental retardation, self mutilation, choreoathetosis), glycogen
storage disease

High intake – beer, red meat, high fructose diet

Other- metablicXd

Pathogenesis
An autoinflammatory disease – NRP3 receptors detect urate crystals – IL-1beta  IL-8  attract PMNL
 ingests urate crystals and get activated.

CFx
50% - 1st MTP
Axial and proximal limb large joints are rarely affected
Very acute onset. Peak within 2-6h, waking the pt early morning
Very severe pain, swelling and red skin
Marked swelling
Fever, malaise, confusion
Self limiting in 5-14d with complete resolution, with pruritus and desquamation over the jt
Usu 1 jt only. Occasionaly, few other joints get affected sequesntially. Very rarely they are affected
simultaneously.

Chronic gout
Persistent pain and joint damage
Tophi – on extensor surface of fingers, wrist, EJ, Achilles. Can ulcerate, and discharge white material. Can
induce local inflammation with or without infection and secrete pus!

Dx
Serum uric acid – often normal during an acute attack
Joint fluid –
Negitvely birefringent needle shaped urate crystals under polarized light

Imaging - characteristic punched out marginal erosions with sclerotic margins and overhanging edges in
chronic arthropahty
DDx
Septic arthritis
Infective cellulitis
Reactive arthritis
Monoarticular RA
Rx
Acute attack
- High dose NSAIDs (naproxen 750mg stat – 500mg bd/tds; diclofenac 100mg stat, 50mg tds/qds;
indomethacin 75mg stat, 50mg tds/qds for 24-48h, then continue at a lower dose for 1week)

- Colchicine 1mg stat and 0.5mg bd-tds preferred in renal disease / PUD where NSAIDs cannot be given
Can cause severe diarrhea and colics (colchicine inhibits microtubule aggregation and therefore cell
division)

- Joint aspiration +/- local steroid injection (only if infection is conclusively excluded)

- Short course of oral pred 15mg/d / IM steroids. Sp if NSAIDS and colchicines are not possible

Prevention of recurrence
Indications for treatment
1. Recurrent arthritis (>1 per year)
2. Joint damaging disease
3. Renal impairment
4. Very high uric acid levels
5. Tophi
 6. Nephrolithiasis
Start ~ 2-4 weeks after resolution of a flare.
Anticipate another flare with initiation of urate lowering therapy. Therefore continue NSAID / colchicine
for the first few months. (- 2-4wk to +4wk with allopurinol – KC, 6m with febuxostat - DPPM)
Target uric acid level - < 360 micmol/L (< 6mg/dL) (BSR), < 300micmol/L (EULAR)

Allopurinol 1st line. xanthine oxidase inhibitor

Worsens inflammation if given without NSAID
Less safe in renal disease (max dose 100mg/d). SE- GI, rash, SJS, marrow suppression
100mg/d (50m/d in eldey / old). Increase monthly. Upto a maximum of 900mg/d.
Aim is to keep uric acid level < 300 mcg/L

Febuxostat non purine analog xanthine oxidase inhibitor

Safer in renal disease, since metabolism is hepatic
More potent than allopurinol, so more risk of flare ups as well. Continue NSAID /
colchicine for the first 6m
May increase CVD, so not 1st line

Pegloticase a conjugated uricase.

IV 2 weekly. Tophi regress. Flares become less frequent.
Highly effective when other agents fail
Development of antiboides make them ineffective

Rasburicase

Probenecid, sulfinpyrzone
Uricosuric. Inhibits uric acid reabsorption
Not for urate stone formers. Avoid in renal disease
Effect antagonized by salicylates, so avoid those.
SE – serious heptatoxicity, banned in Europe

Other measures
- Lose weight
- Stop HCT, convert to ACEI / losartan / CCB (both have urate lowering effects) / bumetanide (non
uricosuric diuretic)
- Limit high animal protein diet (liver kidney seafood mackerel), high fructose diet (carbonated
drinks – ‘non-diet’). Reduce urate levels by 15%
- Anakinra – specific anti IL-1beta Ab. Role in resistant disease may be justifiable.
- Lesinurad – urate transporter. Reduces urate levels. No reduction in flares. Expensive,
nephrotoxic.

Complications
KD –
Uric acid nephropathy –
acute tubular obstruction
reversible AKI
tumor lysis, rhabdomyolysis
 Rx – IV fluids (keep UOP > 100ml/h), frusemide, NaHCO3 (urine pH > 7 dissolves urate
crystals), allopurinol
urate nephropathy
tubular crytals induce giant cell infl reaction  chronic TIN  irreversible CKD
ONLY IN THOSE WITH CHRONIC GOUTY ARTHRITIS
Stones – with or without arthritis
Joint – destruction, deformity
Tophi – almost always in CKD / chronic diuretic use (CCP MCQ class)
 128

PSEUDOGOUT
Calcium pyrophosphate dehydrate deposits in hyaline cartilage
Older adults

RF for chondrocalcinosis
4 Endocrine – acro, hypoth, hyperPTH, hypoMg
5 Genetic – HH, WD, hypophosphatasia, alkaptonuria, familial
2 Degenerative – OA, old age

CFx
Asymptomatic in many! – choncrocalcinosis incidentally detected on XR

Acute inflammatory arthritis (pseudogout)

Fever, ill, confused
Acute severe monoarthritis
1. Commonest – KJ by far. Menisci and hyaline cartilage
2. WJ (triangular fibrocartilage), SJ, AKJ, EJ
3. Pubic symphysis
Triggered by intercurrent illness, trauma, surgery

Chronic inflammatory arthropathy

superimposed on OA background with intermittent acute episodes
Chronic arthritis (same jts as above) with morning stiffness, inactivity gelling
Most affected joints have OA and varying degrees of synovitis
No tenosynovitis and extraarticular manifestations of RA
Can be severely destructive and deforming, mimicking neuropathic joints

Ix
Joint fluid – CPPD crystal – rhomboidal crystals with weakly positive birefringence under polarized light.
Joint fluid can look purulent.
XR – calcified cartilages – their absence does not exclude pseudogout
Exclude SA
Ix for a 2ry cause if
Present < 25y age
Polyarticular disease

Rx
Joint aspiration
NSAID, colchicine
IA steroids
Chronic arthropathy – as for OA
 129

Calcium apatite deposition disorders

Ca phosphate carbonate crystals

Deposit in three circumstances
1. Dystrophic calcification – Calcification of damaged tissues. Normal serum Ca / P
2. Metastatic calcification – in hypercalcemic states (? And in hyperphosphatemic states)
3. Articular deposition
a. Periarticular structures – tendons, bursa, ligaments
b. Intra articular – in blood vessels of synovium

Pathogenesis of articular calcium apatite deposition disorders

 Reason for apatite deposition is not clear

 Not all with calcium depositions develop disease
 May cause tendonitis, bursitis etc. often self limiting
 Intra articular depositions in some patients cause abnormal synovial cell activation that release PGE,
cytokines, collagenases that damage joint structure causing a destructive arthropathy
o Typical site – SJs of elderly : Milwaukees shoulder
o Other sites – HJ, KJ, erosive OA of hands
 30-50% of OA pts have apatite crystals in joint fluid. Flares may be related episodic apatite arthritis

(worsening pain in an OA  SA, pseudogout, ca apatite, flare)

Dx of apatite arthritis
1. XR – calcifications
2. Joint fluid – W < 2000 per micL, lymphocytic
3. Definitive – demonstration of apatite crystals – by EM!

Rx
NSAIDs short course

Calcium oxalate crystal disease

Primary oxalosis – CaC2O4 deposits in

Secondary oxalosis –
In ESKD
Ca2C2)4 deposits in viscera, cartilage, bones, vessels
Worsened by vitamin C supplements (vit C metabolized to oxalate, not removed by HD!!)

Path
Cartilage deposits of CaC2O4
Intermittently shed to synovial fluid  activate synovial cells  inflammation jt destruction
 130

CFx
Acute monoarthritis – cannot differentiate from gout / pseudogout / apatite arthritis

Dx
XR – chondrocalcinosis
Jt fluid - W < 2000 /micL (N or L)
Polarized light – bipyramidal, strong birefringent (often variable shape and variable birefringence)

Rx
NSAIDs, colchicines, IA steroids, aggressive HD – not great results
Liver transplant for primary oxalosis

Cholesterol crystal disease

After IA glcc injection
 131

Diffuse Idiopathic Skeletal Hyperostosis (DISH)

(ankylosing hyperostosis, Forestier disease, and Forestier-Rotes-Querol disease)

Definition
Idiopathic
Non inflammatory
Calcification and ossification of spinal ligaments and entheses

Epidemiology
> 40y
M>F

Aetiology / risk factors

Mechanical stress - Ossification more on the right side in thorax (aortic pulse effect?). May be heavy
manual work
Vitamin A excess – postulated
Metabolic syndrome – exposure to IGF-1 etc

Pathology
Abnormal osteoblast activity at entheses

Presentation
Asymptomatic (incidentally detected on XR)
Neck / back pain / limb pain
Morning stiffness in 80%
Restricted, sp lateral, mobility of thoracic spine
Does NOT cause radilculopathy / sciatica / canal stenosis / neruogenic claudication
Extra axial
SJ, EJ, KJ pain due to enthesopathy

Anterior ligament hyperostosis of the C spine can cause pressure effects

Dysphagia, hoarseness, stridor, aspiration pneumonia, sleep apnea, atlantoaxial subluxation or
pseudoarthrosis, and thoracic outlet syndrome

Posterior longitudinal ligament hyperostosis causes pressure effects  cervical myelopathy

Spine X ray
Thoracic > cervical and lumbar
Thoracic –ossification of ALL. R > L. preserved disc and facet joints. Flowing calcification (arrow. Like
dissolved candle wax)

C and L spines-
Symmetrical ossification of ALL
 132

Radiolucent areas anterior to L3 and L4 (arrows) represent the space between the vertebral body and
the ossified anterior longitudinal ligament.

Dx
Clinical and radiological

Rx
Physiotherapy
PCM  NSAIDs
 133

OSTEOARTHRITIS
2ry osteoarthritis
Any chronic arthritis
Recurrent hemarthrosis
HH
Acromegaly
Recurrent trauma

Types
Mono-oligo OA – KJ, HJ
Generalized OA
Nodal OA – DIP, PIP, 1st CMC, 1st MTP, cervical and lumbar
Erosive OA

When to image / Ix further

< 45y without risk factors / trauma etc
Night pain / rest pain
Rapidly worsening pain
Unusual site

CFx
Pain, swelling, effusion
Gelling – stiffness < 15 min
Worse with activity / evening

Dx – weight bearing X ray

Irregular narrowing of jt space
Osteophytes
Subchondral sclerosis
Bone cysts
Rare – subchondral erosions

Management
1st step
Weight loss
Quadriceps strengethening

Pharmacological
1st line : PCM, topical NSAIDs (useful for hands and KJ only)
 134

2nd line : oral NSAIDs / COX2i (avoid if on aspirin), capsaicin topical (inhibit TRPV1 receptor in
nociceptive fibres, suppress substance P. commonest SE : burning sensation, resolves over time),
duloxetine, opioids, IA steroids (effect lasts 4 weeks)

Non pharm
Supports, braces, TENS, shock absorbing sole shoes

Joint replacement surgery

Acute worsening of OA
1. Septic arthritis – diseased joint is vulnerable
2. OA flare
3. Crystal – cal pyrophosphate (Pseudogout), calcium apatite
4. Trauma – meniscal tear etc?

SEPTIC ARTHRITIS
Staph aureus – adhesion molecule to syovium (MSCRAMM – microbial Surface Component
Recognizing Adhesive Matrix Molecules)
Special bugs
STI – Ng
TB
HH - siderophilics (Yersinia, Vibrio vulnificus)
SCA - Salmonella (staph in Sickle cell trait)
IVDA - Pseudomonas

Dx
JFA – W > 50 000, Neut, culture
Kocher’s criteria – fever, inability to weight bear, high ESR, high WBC

Rx
IV Abtcs
Needle aspiration to decompress. Arthrotomy and wash out / arthroscopy allows better
debridement and adhesiolysis
Mobilization
Immobilize in functional position for initial 5 days
Passive range of motion exercise start gradually
Avoid weight bearing till clinical synovitis resolves

Abtc choice
MSSA – fluclox 2g 6h
MRSA – vanc 15mg/kg od-bd, linez 600mg bd po/IV
G neg – cetriax 2g od / cefotax 2g tds
Pseudo – ceftaz + genta / Aztreonam + genta
 135

IV 14d, PO 14d

PO choices for MRSA – clinda, doxy, cotrim, linezolid