Rheumatology E-learning

University of Szeged

Department of Rheumatology and Immunology

Overview

„Prototype” autoimmune disease

The most common and variable systemic

autoimmune connective disease

Female:male: 10:1

Prevalence: 1:2000

Typical age at onset: 20-30 years

More prevalent among people with African

and Hispanic origin

Disease course, prognosis Course: fluctuating.

Provoking factors (e.g. sunshine, infection, drug): exacerbationor flare or relapse

After treatment: remission

Active disease causes acuta organ failure (nephritis, cerebritis, arthritis, severe skin laesions, respiratory failure etc.) and mayeven cause death. Furthermore, it leads to irreversible damage(e.g. renal failure, deforming arthritis, lung fibrosis, fingernecrosis, etc.)

The aim of patient care: 1. prevent relapses 2. detect diseaseactivity as early as possible (e.g. proteinuria, synovitis, pericardial rub, subtle cognitive decline), and treat effectively

Prognosis: 10 year survival now is higher than 90%

But: nephritis occurs in 40-50%, and end-stage renal failuredevelops still in about 10-15% of affected patients

Irreversible damage (related to both disease and drug/corticosteroid!/ accumulates, and quality of life is still poor

Joint involvement in SLE

Articular (polyarthritis / polyarthralgia)

Most common manifestation (70-80% of patients)

Symmetric, involving mostly the small joints

Fingers, wrists > shoulders > feet, knees, elbows

Joint pain, tenderness, swelling and reduced mobility

Usually there is less swelling and shorter morning

stiffness than in rheumatoid arthritis

Pain is often severe

In contrast with rheumatoid arthritis, there is no

pannus, no cartilage and bone destruction (= non-

erosive on radiograph)

But may be deforming in many cases

SLE arthritis

Deformities look like those in

RA (ulnar deviation, swan

neck, etc.)

But: they are not fixed, but

reducible, even hypermobile

due to ligamentous laxity:

Jaccoud’s arthropathy:

Skin involvements

Very common (> 50%)

Acute: photosensitive rash, butterfly

erythema, small vessel vasculitis (purpura or

urticarial)

Subacute: SCLE (subacute cutaneous LE)

Chronic: discoid LE, livedo reticularis,

panniculitis

Photosensitive rash, butterfly erythema and

SCLE are provoked by ultraviolet light

(sunshine)

SLE – butterfly erythema

Erythematous plaque over the nose and the cheeks, but the

nasolabial folds are spared

SLE – photosensitive dermatitis

SLE – photosensitive rash

Subacute

cutaneous

lupus

Predilection sites: arms, upper torso

Severe subacute cutaneous LE

provoked by sun-exposure

Note also the Jaccoud’s arthropathy

SLE – discoid laesion

Discoid lupus erythematosus

SLE – digital vasculitis

Haematological involvement

Anaemia

autoimmune, Coombs-positive haemolytic

autoimmune myelopathy (decreased

haematopoesis)

non-haemolytic (anaemia of the chronic disease)

Leukopenia, lymphopenia

Thrombocytopenia

Haemolytic anaemia in SLE

Normocytic, Coombs-positive, reticulocyte counthigh, Fe norm/high, LDH high, bilirubin high, haptoglobin low

Chronic or acute haemolytic crisis Warm antibodies – IgG – phagocytosis –

extravascular sequestration in the spleen Cold antibodies – IgM – bind between 4-15 C –

complement activation – intravascularhaemolysis

Leukopenia in SLE

WBC: < 4000/ul

Lymphocyte: <1500

Activity sign! – if WBC decreases, lupus flare may be suspected

Anti-lymphocyte antibodies, accelerated apoptosis

If a lupus patient presents with fever, otherinflammatory symptoms: leukopenia helps in thedifferentiation from infection vs lupus flare

Must be differentiated from myelosuppressive adverseeffects of immunosuppressive drug (e.g. azathioprin, methotrexate, mycophenolate mofetil)

Thrombocytopenia in SLE

May be chronic and mild-to-moderate (plateletcount > 50 G/L) – treatment may not be necessary

In other cases, it may be acute and critical (plateletas low as < 5 G/L) – immediate agressiveimmunosuppression is necessary

Anti-platelet (GP IIb/IIIa complex) antibodies

Fc-receptor-mediated phagocytosis in the spleen

Diff. dg.: Antiphospholipid syndrome

Drug adverse effect

Infection

Thrombotic thrombocytopenic purpura

Bone marrow histology from an SLE

patient with fatal pancytopenia

Megakariocyte hyperplasia

CD8-positive cytotoxic lymphocytic

infiltration

Serositis

Pleuritis, pericarditis, ascites

Pleuritis (prevalence in SLE: 30-40%)

Sharp chest pain exacerbated by inspiration,

cough

Dyspnea

Coughing

Physical exam:

○ Pleuritic rub

○ Dullness on percussion, diminished respiratory

sounds on auscultation

Pericarditis

Prevalence in SLE: 30-40%

Symptoms Dull or sharp retrosternal pain

Increasing dyspnea

Physical finding Pericardial rub (synchronous with heart sounds)

Increased heart dullness with percussion

Diminished heart sounds with auscultation

If severe: dilated jugular veins, cyanosis, dyspnea, signs of heart failure

Diagnosis: ECG, echocardiography

If severe: emergency. Achieve quick dg and diff dg with physical exam, ECG and echocardiography, and administer corticosteroid. If not, pericardium drainage with puncture or surgical fenestration is performed, but with appropriate dg it can usually be prevented

Lupus nephritis

Acute or chronic glomerulonephritis

Prevalence in SLE: 40-50%!

Key determinant of prognosis, organ damage

and quality of life in SLE

Progresses to end-stage renal disease in

about 10% of affected patients

Frequently diagnosed late – urinalysis on

every patient visit!

Lupus nephritis - symptoms

Nephritis syndrome

Proteinuria (>0,2 g/die)

Microscopic haematuria (dysmorphous red blood cells)

Leukocyturia („sterile pyuria”)

Cellular (red blood cell or white blood cell) casts

Hypertension

Renal function impairment

Nephrotic syndrome

Proteinuria > 3,5 g/die

Hypalbuminaemia

Hyperlipidaemia

Oedema

Nephroso-nephritis syndrome

Asymptomatic proteinuria or microscopic haematuria

Lupus nephritis – clinico-

pathological classification

Dysmorphous red blood cell

Red blood cells with small „ear” or „bud”

indicating that they have passed through the

glomerulus. They always indicate glomerular

disease! Simple but vital differentiation from

lower urinary tract origin.

„Mickey mouse red

blood cell

Red blood cell cast

Diffuse proliferative lupus GN

Courtesy of Prof. Éva Kemény Éva (Dept of Pathology)

Membranous lupus nephritis

(ISN/RPN class V )

Courtesy of Prof. Kemény Éva (Dept

of Pathology)

Vascular involvement is SLE

Raynaud’s phenomenon

Livedo reticularis

Arterial and venous thrombosis, pulmonary

embolism (see: Antiphospholipid syndrome -

APS),

Vasculitis

Accelerated atherosclerosis (APS)

Raynaud’s phenomenon

Transient white (one-phase), white and blue (two-

phase – the most common) or white, blue and red

(three-phase) discolouration of the fingers

Often associated with pain, numbness – this may be

the presenting complaint, rather than the

discolouration

In severe cases: ulceration, gangrene may develop

(especially in the most severe forms of Raynaud’s, i.e.

in systemic sclerosis, systemic vasculitis or

antiphospholipid syndrome

Differential diagnosis of

Raynaud’s phenomenon• Primary Raynaud’s: no underlying disease. Vasomotor

lability, vegetative dystonia, requires no specific

treatment

• Secondary Raynaud’s: there is an underlying disease

involving the circulatory system

○ Systemic connective tissue autoimmune disease (systemic

sclerosis, SLE, systemic vasculitis, antiphospholipid syndrome,

Sjögren’s syndrome – but: in rheumatoid arthritis: almost never)

○ Thoracic outlet syndrome (compression)

○ Hypothyreoidism, hyperthyreoidism

○ Smoking, atherosclerosis, diabetes mellitus

○ Hyperviscosity (paraproteinaemia, polycythaemia vera)

Raynaud’s phenomenon

Digital ischaemia

Livedo reticularis

www.dermquest.com

If transient, provoked by cold: probably normal

If fixed: severe microcirculatory abnormality – e.g. antiphospholipid

syndrome – in this case, it may herald a subsequent vascular

catastrophy, e.g stroke

Leukocytoclastic vasculitis

Leukocytic

infiltration, vessel

wall necrosis,

degradation of

granulocytes

Clinically presents

as purpura or

urticarial vasculitis

Frequent in SLE,

Sjögren’s and

small-vessel

vasculitides

(ANCA-associated

or Henoch-

Schönlein)

Purpura

Anti-phospholipid syndrome

Arterial or venous thrombosis, repeated spontaneousabortion or intrauterine death caused by autoantibodies thatpromote thrombosis (antiphospholipid antibodies)

Primary or secondary (associated with SLE, RA, infection ormalignancy)

Acute symptoms: Stroke, myocardium infarction, bowelinfarction, hypadrenia, obliterative atherosclerosis, gangraene, deep venous thrombosis, pulmonary embolism.

Chronic symptoms: Dementia, focal neurological signs, epilepsy, valvular heart disease, infertility, premature birth.

Catastrophic anti-phospholipid syndrome – simultaneousthrombosis in more than two organs

Antibodies: anti-cardiolipin, anti-beta2-GPI, lupusanticoagulant (prolonged activated partial thromboplastintime)

Must be suspected in every case with early vascular events, even if autoimmune symptoms are not present!

Pulmonary involvement

Acute:

lupus pneumonitis (e.g. lymphocytic interstitialpneumonitis - LIP, organizing pneumonia - OP)

diffuse alveolitis

diffuse pulmonary haemorrhage

Chronic

fibrosing alveolitis (non-specific interstitialpneumonitis – NSIP)

pulmonary hypertension

„shrinking lung” syndrome

Acute lupus pneumonitis

Progressive dyspnea

Coughing

Fever

Often accompanied by pleuritis – pleuritic

chest pain

Bilateral infiltrates on radiography and lung

CT

Lymphocytic interstitial pneumonitis

Diffuse pulmonary haemorrhage

Haemorrhagic alveolitis, alveolar capillaritis

Acute, severe alveolar capillary wall damage

Immune complex-deposition

Acute dyspnea, coughing, rapid anaemia, haemoptoe

Mortality: 40-80%

Iv. methylprednisolone, iv. cyclophosphamide, plasmapheresis

Bilateral alveolar patchy infiltrates

(alveolar filling)

On histology: immune-complex

deposition in the perialveolar

interstitium

Central nervous system in SLE

Anti-phospholipid-mediated

Focal, ischaemic laesions

Stroke, transverse myelitis, chronic cognitive

decline

Non-anti-phospholipid-mediated

Diffuse cerebral dysfunction („lupus-cerebritis”)

Psychosis, altered mental status, epilepsy,

headache

SLE – further organ

involvements Endocarditis, myocarditis

Fever, low-grade fever

Weight loss, chronic fatigue syndrome

Myositis

Oral ulceration

Secondary Sjögren’s syndrome

Retinal vasculitis, episcleritis

Autoimmune hepatitis

Amenorrhaea, infertility, repeated spontaneous

abortion, intrauterine death, premature birth

SLE – laboratory changes

Elevated ESR, but CRP is typically normal

Cytopenia (anaemia, leukopenia, thrombopenia)

Proteinuria, haematuria

Antinuclear antibody (ANA)

Anti-double-stranded DNA antibody (anti-dsDNA)

Extractable nuclear antibody (ENA) anti-SSA/Ro, anti-SSB/La, anti-U1RNP, anti-Sm

Anti-phospholipid antibodies (anti-cardiolipin, anti-beta2-glycoprotein 1), lupus anticoagulant …

Anti-nucleosome, anti-C1q (nephritis!)

Decreased complement-3 (C3), C4

ANA – homogenous pattern

Direct immunofluorescence: autoantibodies that bind to cell nucleus are

visualized by radiolabelled antibodies – screening method, and the exact

autoantigen-specificity is determied by ELISA

ANA – speckled pattern

ANA – nucleolar pattern

ANA – anti-centromere positivity

SLE – pathogenesis I.

Impaired apoptosis-

regulation

Complement-receptor 1

polymorphism

Immune-complex clearance ↓

Increased

apoptosis (UV

light, infection,

drugs)

INCREASED SUPPLY

OF ANTIGEN

(CHROMATIN)

SLE pathogenesis II.

Viral and self

nucleic acids

activate the type-

I interferon

system through

Toll-like

receptors

Self-perpetuating circle of immune-

complex-mediated IFN-α activation

and autoantibody production

Rönnblom L, Arthritis Rheum 2006;54:408

Key players: plasmocytoid

dendritic cells, interferon-

alpha, autoantibody-

producing B-cells and plasma

cells, Th2, Th17, and to

lesser extent, Th1 cells

Effector pathways – in analogy with Coombs-Gell

classification of allergic pathways

Activated Th0 (naive)-

lymphocytes

Th17 and Th1 effector T-

cells

B-lymphocytes → plasma cells

Activated Th2 lymphocytes

III. Immune-complex

deposition:

Nephritis

Vasculitis

II. Direct autoantibody-

mediated cell damage

Dermatitis

Cytopenia

Anti-phospholipid-symptoms

Myositis

IV. Predominantly cell-

mediated organ

manifestations

Arthritis

Serositis

Central nervous system

symptoms

Dermatitis

Sec. Sjögren’s syndrome

Management of SLE

Lifestyle patient education: Avoid sunshine – always use suncream when leaving home

Oral anticoncipient: to be avoided in anti-phospholipid positivepatients and during active disease

Aim: control of flares, and preservation of remission

During flares: corticosteroids and otherimmunosuppressants – intensity is determined by theseverity of flare (low-medium-high dose corticosteroid + methotrexate, cyclophosphamide, rituximab, intravenousimmunoglobulin, plasmapheresis, etc.)

After disease has become quiescent: tapering of corticosteroids, use of maintenance immunosuppression(hydroxychloroquine + less potent immunosuppressantse.g. azathioprin, methotrexate)

Treatment

Mild cases (mild skin or joint involvement): NSAID, topical skin treatment, hydroxy-chloroquine

Chloroquine, hydroxi-chloroquine Originally: antimicrobial agent against malaria

Proven to reduce the frequency and severity of flares(current guidelines: lifelong antimalarial to every lupuspatient!)

Vitamin D Effective immunomodulatory agent: reduces

autoimmunity, promotes antimicrobial defense

Prevents osteoporosis – mandatory if corticosteroidsare administerd

Treatment II.

Cases of intermediate severity

E.g. serositis, cytopenia, marked skin or jointinvolvement, etc., but no involvement of vitalorgans (renal, pulmonary, central nervoussystem, cardiac)

During active disease: corticosteroid (12-64 mg methylprednisolon) + azathioprin, methotrexate, cyclosporine, mycophenolate mofetil

In remission: taper off corticosteroids, maintainother immunosuppressants for 3-5 years (+ antimalarial, Vitamin D3 lifelong)

Treatment III

Severe, life-threatening organ involvements(carditis, nephritis, systemic vasculitis, cerebralmanifestations): high-dose intravenouscorticosteroid (500 mg methylprednisolone) + iv. cyclophosphamide

Or: + rituximab (anti-CD20 monoclonal antibody)

In critical situations: plasmapheresis or iv. immunoglobulin

Maintenance: mycophenolate mofetil,

tacrolimus

cyclosporine (especially membranous nephritis, thrombocytopenia, myositis)

belimumab (monoclonal antibody to the cytokineB-lymphocyte stimulator (BLyS)

Rituximab (anti-CD20) – long-lasting B-cell

depletion

B-lymphocyta stimulator (BLyS) or B-

cell activating factor (BAFF)

Cancro et al J Clin Invest 2009

Belimumab (anti-BLyS), the first approved

biologic in lupus