Week 2 - D - Connective Tissue Diseases - Systemic lupus erythematous, Sjorgen's, Systemic Sclerosis, M.C.T.D, A.P.S

Question 1

Systemic Lupus Erythematosis (SLE) is a chronic autoimmune disease, the presentation and disease course of which can be highly variable. Which organs are mainly involved in systemic lupus erythematous?

Answer 1

Systemic lupus erythematous is a multisystemic autoimmune disease

It mainly involves the

• skin,
• joints,
• kidneys,
• blood cells,
• and nervous system

but can affect almost any organ system.

Question 2

What is the a longstanding proposed mechanism for the development of autoantbodies in SLE? How does this lead to persistence of antigen and immune complex production?

Answer 2

A longstanding proposed mechanism for the development of autoantibodies in SLE is that there is a defect in apoptosis that causes increases cell death and a disturbance in immune tolerance

* The defective clearance of the apoptotic cell debris allows for the persistence of antigen and immune complex production

Question 3

Many clinical manifestations of SLE are mediated by circulating immune complexes that form with antigens in various tissues What are common locations for where the antibody-antigen complexes are deposited in SLE? What type of hypersensitivity is SLE?

Answer 3

Immune complexes are formed in the blood vessels

The immune complex deposition is common in the basement membrane of the skin and kidneys

SLE is a type 3 hypersensitivty

Question 4

How do the immune complexes deposited on the basement membrane in lupus cause damage?

Answer 4

Immune complexes when deposited on the basement membrane of different organs causes activation of complement and other inflammatory cells such as neutrophils

The enzymes released from the neutrophils lead to endothelial damage of the basement membrane

Question 5

What serous membrane can become inflamed in lupus? What is inflammation of a serous membrane known as?

Answer 5

The lung pleura and pericardium can become inflamed in lupus - serositis

Lung pleural inflammation leads to pleural effusion

Pericardial inflammation leads to pericarditis

Question 6

Which sex is lupus more common in? Which race is lupus more common in? When is the typical onset of lupus?

Answer 6

* Lupus is more common in women than in men - more than 90% of cases in women

* Lupus is more prevalent in black persons in the UK and US however the disease is rarely reported in blacks in Africa, suggesting that there may be an environmental trigger, as well as a genetic basis, for disease in these populations.

* Typical age of onset of lupus is in a persons 20s to 30s

Classic patient - Afro-Carribean woman of child bearing age

Question 7

Presentation can be very variable and a wide range of systems may be involved

* What are the constitutional features of lupus?

* What are the muco-cutaneous features of lupus?

* What are the musculoskeletal features of lupus?

Answer 7

Constitutional symptoms - fever, fatigue, weight loss

Muco-cutaneous features - malar rash, scarring alopecia, Raynaud’s disease, photosensitivity, discoid lupus

Musculoskeletal features - arthalgia (joint pain), myalgia (muscle pain), inflammatory arthritis

Question 8

What are the respiratory features of lupus?

What are the cardiac features of lupus?

What are the renal features?

Answer 8

Resp features - pleurisy, pleural effusion, pneumonitis, PE, pulmonary hypertension

Cardiac - pericarditis, pericardial effusion, pulmonary hypertension, non-infective endocarditis

Renal features - presence of proteinuria or red cell casts

Question 9

How much protein is found in urinalysis as part of the clinical criteria of diagnosis for lupus? What type of glomerulonephritis is caused by lupus

Answer 9

Proteinuria >500mg (0.5g) in urinalysis

Lupus typically causes a membranous glomerulonephritis

Question 10

Which antibody is present in about 95% of all SLE patients however is not specific for lupus? Which antibody is highly specific for lupus and is usually tested for if lupus test positive for the antibody in question above? How sensitive is this antiboyd? Name a third antibody that can be tested for in lupus?

Answer 10

Anti-nuclear antibody (ANA) is found in about 95% of all SLE patients however is not specific

Anti-double standred DNA (anti dsDNA) antibody is highly specific but only about 60% sensitive

Anti-Sm (anti-Smith) antibodies are very specific for lupus but have a low sensitivity

Question 11

Once diagnosis of lupus is confirmed, what is important to screen for?

Answer 11

Once diagnosis of lupus is made you must confirm organ involvement

Question 12

How do complement levels vary in lupus and why?

Answer 12

As before mentioned, the deposition of the immune complexes in the basement membrane of organs activated complement and neutrophils

Complement levels are therefore low in lupus denoting that they are being used up

Question 13

There are various classification criteria that exist to help diagnose SLE - image shows one used in MSK coretext What are the three best ways to monitor the disease activity in SLE?

Answer 13

* Monitoring anti-dsDNA levels - vary positively with disease

* Monitoring complement C3 and C4 levels - vary negatively with disease denoting consumption of complement (C3d and C4d - the degradation products increase)

* Monitoring ESR levels - vary positively with disease

Question 14

What is found with CRP levels in SLE?

Answer 14

CRP levels are usually normal in lupus - think of SLE whenever someone ha a multisystem disorder but CRP normal

Question 15

The management of SLE depends on its manifestations. If a patient only complains of joint pains, skin symptoms and serositis, eg a mild flare up - what is the preferred treatment option? What is given for maintenance after flare up has been treated?

Answer 15

If a patient only complains of skin manifestations, joint pains and serositis eg a mild flare up - prescribe NSAIDs, topical steroids and hydroxychloroquine

NSAIDs and hydroxychloroqiuine usually given for maintenance therapy once flare ups have been treated

Question 16

What do moderate/severe flare ups of lupus require as treatment (means there is organ involvement)?

Answer 16

Urgent IV high dose steroids and cyclophophamide may be used If unresponsive, biological agents may be required

Question 17

In cases of drug induced systemic lupus erythematous, what is the management? What antibodies are found here?

Answer 17

Drug induced systemic lupus erythematous - once recognized the drug, discontinue should help the symptoms to resolve and the addition of NSAIDs will quicken the healing process

Autoantibodies found - anti-histone antibodies

Question 18

Sjorgen’s syndrome is an autoimmune condition characterized by what? What does this typically cause?

Answer 18

Sjorgens, syndrome is an autoimmune condition characterised by lymphocytic infiltrates in exocrine glands

This typically causes dryness of the eyes and mouth (sicca symptoms)

Question 19

What swelling can Sjorgen’s also present with? Other glands are also affected by Sjorgen’s syndrome causing symptoms such as what?

Answer 19

Sjorgen’s syndrome can often present with massive parotid swelling

Oher glands affected can lead to

• * Vaginal dryness
• * Dry cough
• * Dysparenuia
• * Dysphagia

Also is associated with joint problems

Question 20

Sjorgen’s syndrome can be a primary condition or can occur secondary to other conditions such as what? What serious condition is there an increased risk of in patients diagnosed with Sjorgen’s syndrome?

Answer 20

Sjogrens syndrome can be a primary condition or can occur secondary to other autoimmune conditions like RA and SLE.

There is an increased risk of lymphoma in patients diagnosed with Sjorgens’ syndrome

Question 21

What is the diagnoses of Sjorgen’s syndrome based on?

Answer 21

The diagnosis of Sjorgens syndrome is based on

* Ocular dryness - confirmed by Schirmer test

* Positive antibodies

* Typical features on a lip gland biopsy - shows focal lymphocytic aggregation

Question 22

How is Schirmer’s test carried out?

Answer 22

Schirmer’s test

Doctor place a piece of filter paper inside the lower eyelid of both eyes and the person closes their eyes.

After 5 minutes the doctor removes the filter paper and assesses how far the tears have travelled on the paper.

<5mm in 5 minutes is a positive test

Question 23

What antibodies are tested for in Sjorgen’s syndrome? (give both names of the antibodies)

Answer 23

Anti Ro (aka anti-SSA) and/or

Anti-La (Anti-SSB) antibodies are associated with Sjorgen’s syndrome

Question 24

What is the usual treatment of Sjorgen’s syndrome? - to treat the dry eyes and dry mouth

Answer 24

Artificial tear drops and dental care are given for the treatment of sicca symptoms

Question 25

What is given if the eye drops or dental care fail to treat the sicca symptoms of Sjorgen’s?

Answer 25

Dry eyes

* 1st line - artificial tears

* 2nd line - ciclosporin eye drops

* 3rd line - cholinergic agenet eg pilocarpine

Dry mouth

* 1st line - dental care

* 2nd line - cholinergic agent eg pilocarpine

Question 26

Sjorgen’s syndrome can cause arthralgia and fatigue. What is sometimes given for treatment of the arthralgia?

Answer 26

NSAIDs and hydroxycloroquine

Question 27

What is this disease? Commonly presents with raynaud’s disease, hardening of the skin What cause the hardening of the skin?

Answer 27

Systemic sclerosis (SSc) is a systemic connective tissue disease.

Characteristics include vasomotor disturbances (Raynaud’s) and hardening of the skin

Excessive collagen deposition is what causes the hardening of the skin

Question 28

Generally, renal and lung changes are responsible for death in patients with systemic sclerosis. What percentage of patients with systemic sclerosis have pulmonary hypertension? What percentage of deaths in systemic sclerosis does pulmonary hypertension account for?

Answer 28

30% of patients with systemic sclerosis have pulmonary hypertension

12% of deaths in systemic sclerosis are caused by pulmonary hypertension

Question 29

What are the features of limited systemic sclerosis? (formerly known as CREST)

Answer 29

Limited Systemic Sclerosis

Calcinosis - subcutaneous deposits of calcium may be seen in digits

Raynaud’s phenomemon

Eosophgeal dysmotility

Sclerodactyly - localised thickening and tightening of the skin of fingers

Telangiectasia - usually on the face- dilated capillaries

& pulmonary hypertension

Question 30

Limited: skin involved tends to be confined to face, hands and forearms and feet. Organ involvement tends to occur later

* Which antibodies are associated with limited systemic sclerosis? How does diffuse systemic clerosis tend to present? * What antibodies are associated with diffuse systemic sclerosis?

Answer 30

Anti-centromere antibodies are associated with limitied systemic sclerosis (CREST and pulmonary hypeertension)

Diffuse systemic sclerosis - skin changes develop rapdily and can involve whole body, organ invovlement is early

Anti-Scl-70 is associated with diffuse systemic sclerosis

Question 31

There is no one overall treatment for SSc. Management tends to be tailored to the specific issues

What can be given to treat Raynaud’s disease (1st, 2nd and 3rd line?

Answer 31

1st line - lifestyle measures - wear gloves, stop smoking

2nd line - calcium channel blocker (nifedipine) or sidenafil (phosphodisterase-5-inhibitor) - they increase blood flow to the finers

3rd line - ilioprost - dilates arteries

Question 32

What can be given to treat any renal involvement in systemic sclerosis? What can be given to treat the oesophageal dysmotility?

Answer 32

Renal involvement - give ACEi

GI involvment - for acid reflux due to oesophageal dysmotility give proton pump inhibitors

Question 33

What pulmonary artery pressure is normal and what is classified as pulmonary hypertension? How is pulmonary hypertension measured? What can be given to treat this?

Answer 33

Normal mean pulmonary arterial pressure (mPAP) is 12-20mmHg.

Pulmonary hypertension is defined as a mPAP >25mmHg or >30mmHg during exercise

A Swan-Ganz pulmonary artery catheterization is the passing of a thin tube (catheter) into the right side of the heart and the arteries leading to the lung - used to measure pulmonary arterial pressure

Question 34

What are some of the pulmonary vasodilators used for the treatment of pulmonary hypertension?

Answer 34

* Phosphodiesterase-5 inhibitors - sildenafil

* Endothelin receptor antagonist - bosentan

* Prostacylin agonist - iloprost

Question 35

What is given in systemic sclerosis to treat patients with progressive lung involvmeent? ie interstitial lung disease

Answer 35

Immunosupression usually with cyclophosphamide is given for diffuse systemic sclerosis

Question 36

Mixed connective tissue disease is a defined condition which features symptoms also seen in other connective tissue diseases (CTDs). What are different features of mixed connective tissue disease? Which antibody is common in MCTDs?

Answer 36

• Raynauds phenomenon
• Arthralgia/arthritis
• Myositis
• Sclerodactyly
• Pulmonary hypertension
• Interstitial lung disease (ILD)

MCTDs associated with anti-RNP antibodies

Question 37

What is carried out regularly in patients who present with MCTDs?

Answer 37

Because of the risk of pulmonary hypertension, regular echocardiograms (annually) are suggested.

Screening for ILD with pulmonary function tests should also take place.

Question 38

What is the disorder that manifests clinically as recurrent venous or arterial thrombosis and / or foetal loss? when does the foetal loss tend to occur? It can often occur as a primary disease but can be associated with other CTDs. Which one is the main association?

Answer 38

Anti-phospholipid syndrome manifests clincally as recurrent venous or arterial thrombosis and / or foetal loss

The foetal loss tends to occur late - typically second or third trimester but can occur at any time

It can occur as a primary disease but is often associated with systemic lupus erythematous

Question 39

APS may contribute to an increased frequency of stroke or MI, especially in younger individuals. What are the anti-phosopholipid antibodies that are looked for in anti-phospholipid syndrome? What are the features that these can cause? (clue menomic- CLOT)

Answer 39

• APS antibodies
• Lupus anticoagulant
• Anti-cardioplin antibodies
• Anti-beta-2 glycoprotein antibodies

Antibodies cause

• C oagulation defects (arterial and venous)
• L ivedo reticularis - pink /blue mottling of the skin
• O bestetric (recurrent miscarriage - 2nd or 3rd trimester)
• T hrombocytopenia Also migraines may be present

Question 40

What is the lifelong treatment of anti-phospholipid syndrome? What is used during pregnancy? Do patients who are found to have positive antibodies but have never an episode of thrombosis in APS require anti-coagulation?

Answer 40

The mainstay of treatment is anti-coagulation for those with an episode of thrombosis.

In patients with recurrent pregnancy loss, low molecular weight heparin is used during pregnancy (warfarin is teratogenic).

Patients who are found to have positive antibodies but who have never had had an episode of thrombosis do not require anti-coagulation.