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Systemic Lupus Erythematosus,Connective Tissue Disease and

Vasculitis

Stuart H Ralston

ARC Professor of RheumatologyUniversity of Edinburgh

Systemic Lupus Erythematosus,Connective Tissue Disease and

Vasculitis

Stuart H Ralston

ARC Professor of RheumatologyUniversity of Edinburgh



Diseases to be discussedDiseases to be discussed

Connective Tissue Diseases• SLE

• Antiphospholipid Syndrome

• Sjogren’s Syndrome (SS)• Polymyositis

• Dermatomyositis

• Systemic Sclerosis (SSC)• Mixed connective tissue disease

Vasculitis• Polymyalgia rheumatica

• Temporal arteritis

• ANCA associated vasculitis

– MPA– GPA

– Churg Strauss Syndrome

• Polyarteritis nodosa

• Takayasu’s arteritis• Behchet’s syndrome



Connective Tissue Diseases and

Vasculitis are rare

Connective Tissue Diseases and

Vasculitis are rare



Relationships between SLE, CTD and

vasculitis

Relationships between SLE, CTD and

vasculitis

SSC

SLE

Myositis

Sjögren

RA

GPA

MPA

PMR

GCA

PAN Behçet’s Takayasu’s

Strong HLA association

Many risk alleles shared

Antinuclear antibodies

Several distinct diseases

Anti-neutrophil cytoplasmic antibodies

APS

A N C A

+ v e

CSS



Epidemiology of Systemic Lupus

Erythematosus and CTD

Epidemiology of Systemic Lupus

Erythematosus and CTD

• Females more commonly affected

– SLE 10:1– Scleroderma 4:1

• Peak age at onset 20-40 years

• Significant morbidity and increased mortality– Cardiovascular disease

– Pulmonary hypertension

– Renal failure

• Considerable clinical overlap between disorders– Mixed connective tissue disease



Autoantibodies are a hallmark of SLE

and connective tissue disease

Autoantibodies are a hallmark of SLE

and connective tissue disease• Different antibodies associated with

different clinical features– ANA – SLE (100%) and other CTD (>40%)

– Anti dsDNA - specific to SLE (100%)

– Anti Sm – specific to SLE (20%)

– Anti Ro / La – SLE, Sjogren’s (60-80%)– Anti-centromere – CREST (60%)

– Anti Jo-1 – Myositis, ILD (20%)

– Anti Scl -70 – SSc (20%)– Anti-phospholipid antibodies – SLE &

thrombosis

• Anti-nuclear antibodies are not thought to

be pathogenic

• Different antibodies associated with

different clinical features– ANA – SLE (100%) and other CTD (>40%)

– Anti dsDNA - specific to SLE (100%)

– Anti Sm – specific to SLE (20%)

– Anti Ro / La – SLE, Sjogren’s (60-80%)– Anti-centromere – CREST (60%)

– Anti Jo-1 – Myositis, ILD (20%)

– Anti Scl -70 – SSc (20%)– Anti-phospholipid antibodies – SLE &

thrombosis

• Anti-nuclear antibodies are not thought to

be pathogenic

Homogeneous

Speckled

Nucleolar

ANA staining



Pathogenesis of Systemic Lupus

Erythematosus

Pathogenesis of Systemic Lupus

Erythematosus• Incompletely understood

• Autoimmune disorder– Abnormal B-cells increased immunoglobulin production

– Interferon signalling pathway upregulated

– Defective apoptosis?

– Immune complex vasculitis

• Genetic component– HLA strongest association

– Complement gene mutations– Other genes

• Environmental trigger?

• Incompletely understood

• Autoimmune disorder– Abnormal B-cells increased immunoglobulin production

– Interferon signalling pathway upregulated

– Defective apoptosis?

– Immune complex vasculitis

• Genetic component– HLA strongest association

– Complement gene mutations– Other genes

• Environmental trigger?



Systemic Lupus ErythematosusSystemic Lupus Erythematosus

• Clinical features:

– Arthralgia, arthritis– Photosensitive skin rash,

– Raynaud’s, alopecia

– Seizures, psychosis

– Leukopenia, thrombocytopenia,

haemolytic anaemia, thrombosis

– Pleurisy, pericarditis, valve disease

– Glomerulonephritis– Recurrent miscarriage

• Investigations– ANA, anti dsDNA +ve

– ESR CRP


– Arthralgia, arthritis– Photosensitive skin rash,

– Raynaud’s, alopecia

– Seizures, psychosis

– Leukopenia, thrombocytopenia,

haemolytic anaemia, thrombosis

– Pleurisy, pericarditis, valve disease

– Glomerulonephritis– Recurrent miscarriage

• Investigations– ANA, anti dsDNA +ve

– ESR CRP

Butterfly (photosensitive) rash in SLE

Scarring alopecia Arthritis



ARA Criteria for diagnosis of Systemic

Lupus Erythematosus

ARA Criteria for diagnosis of Systemic

Lupus Erythematosus

1. Malar Rash

2. Discoid Rash3. Photosensitive Rash

4. Oral ulcers

5. Arthritis (non erosive)6. Serositis (pleurisy, pericarditis)

7. Renal disorder (protein, casts)

8. Neurological disorder (seizure, psychosis)

9. Haematological disorder (haemolytic anaemia,leukopaenia, thrombocytopenia)

10. Anti DNA or antiphospholipid antibodies

11. Antinuclear antibodies

SLE: 4/11 or morefeatures present serially or

simultaneously



Antiphospholipid syndromeAntiphospholipid syndrome

• Pathogenesis:

– Functional antibodies to platelet and endothelialmembranes

– Primary or secondary to SLE

• Clinical features:– Arterial and venous thrombosis

– Headaches, migraine

– Livedo reticularis

– Recurrent miscarriage• Investigations:

– Anticardiolipin antibody / Lupus anticoagulant

• Pathogenesis:

– Functional antibodies to platelet and endothelialmembranes

– Primary or secondary to SLE

• Clinical features:– Arterial and venous thrombosis

– Headaches, migraine

– Livedo reticularis

– Recurrent miscarriage• Investigations:

– Anticardiolipin antibody / Lupus anticoagulant

Livedo reticularis in APS



Management of Systemic Lupus

Erythematosus

Management of Systemic Lupus

Erythematosus

• Mild disease– NSAID, analgesics, sunblock

– HCQ, low dose steroids

• Moderate disease– Steroids plus Azathioprine or methotrexate

• Resistant or life-threatening disease– Pulse steroids and cyclohosphamide

– Pulse steroids and mycophenolate– Belimumab (inhibits B-cell differentiation)

• Antiphospholipid syndrome

– Anticoagulation

• Mild disease– NSAID, analgesics, sunblock

– HCQ, low dose steroids

• Moderate disease– Steroids plus Azathioprine or methotrexate

• Resistant or life-threatening disease– Pulse steroids and cyclohosphamide

– Pulse steroids and mycophenolate– Belimumab (inhibits B-cell differentiation)

• Antiphospholipid syndrome

– Anticoagulation



Systemic Sclerosis / SclerodermaSystemic Sclerosis / Scleroderma

• Pathogenesis:

– Genetic contribution– Immune cell activation

• Clinical features:– Severe Raynaud’s

– Skin thickening

– Oesophageal dysmotility

– Hypertension, renal failure

– Lung disease (PAH +ILD)• Investigations:

– ANA +ve speckled pattern

– Anti Scl70 (20%)

• Pathogenesis:

– Genetic contribution– Immune cell activation

• Clinical features:– Severe Raynaud’s

– Skin thickening

– Oesophageal dysmotility

– Hypertension, renal failure

– Lung disease (PAH +ILD)• Investigations:

– ANA +ve speckled pattern

– Anti Scl70 (20%)

Skin fibrosis

Telangiectasia in

CREST

Raynaud’s &

digital ulceration

Oesophagealdysmotility



Clinical spectrum of Systemic SclerosisClinical spectrum of Systemic Sclerosis

• Limited Ssc

– Better prognosis– Calcinosis

– Raynaud’s

– OEsophageal dysmotility

– Sclerodactyly

– Telangiectasia

• Diffuse Ssc– Worse prognosis

– Skin disease more extensive


– Interstitial lung disease

• Limited Ssc

– Better prognosis– Calcinosis

– Raynaud’s

– OEsophageal dysmotility

– Sclerodactyly

– Telangiectasia

• Diffuse Ssc– Worse prognosis

– Skin disease more extensive


– Interstitial lung disease

10-year survival in L-SSc and

D-SSc

10-year survival in L-SSc and

D-SSc

Nihtyanova et al. A&R 2014Nihtyanova et al. A&R 2014



Management of Systemic SclerosisManagement of Systemic Sclerosis

• Raynauds

– Nifedipine, bosentan, heated gloves• Oesophageal disease

– Proton pump inhibitors

• Hypertension– Antihypertensive drugs

• Pulmonary hypertension– Bosentan, Sildenafil

• Pulmonary fibrosis– Cyclophosphamide & steroids

• Skin disease

– No effective treatment, anti IL-6 under investigation

• Raynauds

– Nifedipine, bosentan, heated gloves• Oesophageal disease

– Proton pump inhibitors

• Hypertension– Antihypertensive drugs

• Pulmonary hypertension– Bosentan, Sildenafil

• Pulmonary fibrosis– Cyclophosphamide & steroids

• Skin disease

– No effective treatment, anti IL-6 under investigation

IL-6 expression in dermis in SSc



Sjorgen’s SyndromeSjorgen’s Syndrome

• Pathogenesis:

– Inflammation of salivary &lachrymal glands


– Dry eyes and dry mouth– Primary or secondary

• Investigations– Schirmer test

– ANA+ve, Ro La +ve

– Salivary gland biopsy

• Treatment

– Symptomatic

• Pathogenesis:

– Inflammation of salivary &lachrymal glands


– Dry eyes and dry mouth– Primary or secondary

• Investigations– Schirmer test

– ANA+ve, Ro La +ve

– Salivary gland biopsy

• Treatment

– Symptomatic

Schirmer’s test

Parotidenlargement

Salivary glandinflammation



Polymyositis & DermatomyositisPolymyositis & Dermatomyositis

• Pathogenesis

– Genetic component (HLA)– Immune activation


– Proximal muscle weakness– Muscle pain & stiffness

– Rash, Gottron’s papules

– Underlying malignancy

• Investigations:– Raised CK, ESR, CRP

– EMG / MRI

– Muscle biopsy

• Pathogenesis

– Genetic component (HLA)– Immune activation


– Proximal muscle weakness– Muscle pain & stiffness

– Rash, Gottron’s papules

– Underlying malignancy

• Investigations:– Raised CK, ESR, CRP

– EMG / MRI

– Muscle biopsy

Helitrope rashGottron’s papules

Inflammatory infiltrate on

muscle biopsy



Treatment of Polymyositis &

Dermatomyositis

Treatment of Polymyositis &

Dermatomyositis

• High dose corticosteroids

– Prednisolone 80mg/day gradually decreasing

• Immunosupressives as steroid sparing agents– Methotrexate

– Azathioprine

– Mycophenylate

• Immunoglobulin infusions in resistant cases

• Screen for and treat underlying malignancy– CT chest abdomen, pelvis

– GI investigations

• High dose corticosteroids

– Prednisolone 80mg/day gradually decreasing

• Immunosupressives as steroid sparing agents– Methotrexate

– Azathioprine

– Mycophenylate

• Immunoglobulin infusions in resistant cases

• Screen for and treat underlying malignancy– CT chest abdomen, pelvis

– GI investigations



VasculitisVasculitis

• Polymyalgia rheumatica• Temporal arteritis

• ANCA associated vasculitis

– Microscopic polyangiitis– Granulomatosis with polyangiitis

– Churg Strauss Syndrome

• Polyarteritis nodosa• Takayasu’s arteritis

• Behchet’s syndrome

Primary Vasculitis Secondary Vasculitis

• Rheumatoid arthritis• SLE

• Sjogren’s syndrome



Classification of Primary VasculitisClassification of Primary Vasculitis

Jennette et al, Arth Rheum 2013Jennette et al, Arth Rheum 2013

• Anti-neutrophil

cytoplasmic antibodies

(ANCA)• Proteinase 3 (PR3)

• Myeloperoxisase (MPO)

• Antibodies may be

pathogenic• Transfer to animals can

mimic some aspects of

disease

Anatomical classificationPathogenic classification



Polymyalgia Rheumatica and Giant cell

Arteritis

Polymyalgia Rheumatica and Giant cell

Arteritis• Pathogenesis:

– Genetic component (HLA and other genes)

– Immune activation

• Clinical features:– Overlapping syndromes

– Rare under 55 years– Shoulder & pelvic girdle pain & stiffness,

– Headache, Jaw claudication

– Visual symptoms and blindness

– Systemic upset

• Investigations– Raised ESR & CRP

– Temporal artery biopsy

• Pathogenesis:– Genetic component (HLA and other genes)

– Immune activation

• Clinical features:– Overlapping syndromes

– Rare under 55 years– Shoulder & pelvic girdle pain & stiffness,

– Headache, Jaw claudication

– Visual symptoms and blindness

– Systemic upset

• Investigations– Raised ESR & CRP

– Temporal artery biopsy Enlarged temporal artery

Giant cell arteritis



Management of Polymyalgia Rheumatica

and Giant cell Arteritis

Management of Polymyalgia Rheumatica

and Giant cell Arteritis

• Corticosteroids– Prednisolone 40-60mg daily in GCA (~0.75mg/kg)

– Prednisolone 10-20mg daily in PMR

– Symptoms improve dramatically in 2-3 days

• Gradually reduce steroid dose– Approx 5mg/week till 20mg

– Approx 2.5 mg/week till 10mg

– Approx 1mg/week till steroids withdrawn• Other treatments

– Bisphosphonates for bone protection

– Methotrexate or azathioprine as steroid sparing agents

• Corticosteroids– Prednisolone 40-60mg daily in GCA (~0.75mg/kg)

– Prednisolone 10-20mg daily in PMR

– Symptoms improve dramatically in 2-3 days

• Gradually reduce steroid dose– Approx 5mg/week till 20mg

– Approx 2.5 mg/week till 10mg

– Approx 1mg/week till steroids withdrawn• Other treatments

– Bisphosphonates for bone protection

– Methotrexate or azathioprine as steroid sparing agents



Granulomatosis with polyangiitis

(Wegener’s Granulomatosis)

Granulomatosis with polyangiitis

(Wegener’s Granulomatosis)• Pathogenesis

– Genetic predisposition (HLA-DP)– Environmental trigger

• Clinical features– Nasal and orbital destruction

– Cavitating lung lesions with

pulmonary bleeding

– Glomerulonephritis

• Investigations:– PR3-ANCA positive

– ESR & CRP raised

– Low complement

• Pathogenesis

– Genetic predisposition (HLA-DP)– Environmental trigger

• Clinical features– Nasal and orbital destruction

– Cavitating lung lesions with

pulmonary bleeding


• Investigations:– PR3-ANCA positive

– ESR & CRP raised

– Low complement Lung lesion Nasal involvement

Orbital involvement



Microscopic polyangiitis (MPA)Microscopic polyangiitis (MPA)

• Pathogenesis

– Genetic predisposition (HLA-DQ)– Environmental trigger?

• Clinical features

– Skin rash / systemic upset– Lung haemorrhage


– Neuropathy / Abdominal pain

• Investigations:– MPO-ANCA positive

– ESR, CRP raised

– Low complement

• Pathogenesis

– Genetic predisposition (HLA-DQ)– Environmental trigger?

• Clinical features

– Skin rash / systemic upset– Lung haemorrhage


– Neuropathy / Abdominal pain

• Investigations:– MPO-ANCA positive

– ESR, CRP raised

– Low complement

Neuropathy with foot drop

Vasculitic rash



Polyarteritis nodosa (PAN)Polyarteritis nodosa (PAN)

• Pathogenesis

– Unknown in most cases– Some secondary to HBV

• Clinical features– Abdominal pain

– Haematuria, and nephritis

– Arthralgia, myalgia

– Neuropathy

– Skin lesions and infarcts• Investigations:

– Angiography

– ESR, CRP raised

• Pathogenesis

– Unknown in most cases– Some secondary to HBV

• Clinical features– Abdominal pain

– Haematuria, and nephritis

– Arthralgia, myalgia

– Neuropathy

– Skin lesions and infarcts• Investigations:

– Angiography

– ESR, CRP raisedBing et al, BMJ Case Reports 2012



Churg Strauss SyndromeChurg Strauss Syndrome

• Churg-Strass Syndrome

(CSS)– Asthma, eosinophilia

– Allergic rhinitis

– Neuropathy– Arthralgia, myalgia


– Systemic symptoms

• Investigations:– ESR, CRP raised

– Eosinophils raised

– MPO-ANCA +ve (~50%)

• Churg-Strass Syndrome

(CSS)– Asthma, eosinophilia

– Allergic rhinitis

– Neuropathy– Arthralgia, myalgia


– Systemic symptoms

• Investigations:– ESR, CRP raised

– Eosinophils raised

– MPO-ANCA +ve (~50%)

Lung infiltrates

Eosinophilic

glomerulonephritis



Management of Systemic VasculitisManagement of Systemic Vasculitis

• Induce remission:– High dose steroids and cyclophosphamide

– High dose steroids and rituximab for ANCA

positive vasculitis

• Maintain remission– Low dose steroids and immunosupressives

– Treatment can sometimes be withdrawn

• Other treatments– MENSA during cyclophosphamide

– Bone protection

• Induce remission:– High dose steroids and cyclophosphamide

– High dose steroids and rituximab for ANCA

positive vasculitis

• Maintain remission– Low dose steroids and immunosupressives

– Treatment can sometimes be withdrawn

• Other treatments– MENSA during cyclophosphamide

– Bone protection



Takayasu’s VasculitisTakayasu’s Vasculitis

• Vasculitis of aorta and main branches

• Cause unknown• Clinical features

– Bruits, absent pulses

– Systemic upset– Headache, Syncope

– Hypertension

• Investigations– Angiography

– ESR, CRP – not very useful

• Management– Steroids, immunosuppressives

• Vasculitis of aorta and main branches

• Cause unknown• Clinical features

– Bruits, absent pulses

– Systemic upset– Headache, Syncope

– Hypertension

• Investigations– Angiography

– ESR, CRP – not very useful

• Management– Steroids, immunosuppressives Takahashi et al , AJNR 2002



Behcet’s SyndromeBehcet’s Syndrome

• Vasculitis of arteries and veins

– Associated HLA B51

• Clinical features– Mouth and genital ulcers

– Erythema nodosum / skin lesions– Uveitis, arthritis

– Thrombosis

• Investigations– Leukocytosis, ESR, CRP variable

– Pathergy test

• Management– Colchicine, steroids, immunosuppressives

• Vasculitis of arteries and veins

– Associated HLA B51

• Clinical features– Mouth and genital ulcers

– Erythema nodosum / skin lesions– Uveitis, arthritis

– Thrombosis

• Investigations– Leukocytosis, ESR, CRP variable

– Pathergy test

• Management– Colchicine, steroids, immunosuppressives Pathergy test

Mouth ulcers



SummarySummary

• Uncommon but important conditions

– Easily missed and consequences severe• Wide variety of clinical presentations

• Genetic component to most diseases

– HLA and other genes• Steroids and immunosuppressives mainstay of

treatment

• Significant morbidity• Long-term adverse effects of treatment– Osteoporosis

– Opportunistic infections

– Cancer

Documents

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