Rheumatology - Connective tissue diseases

Question 1

What is SLE? In which patients is it most common?

Answer 1

SLE is the commonest, autoimmune systemic connective tissue disease. It is associated with pathogenic autoantibodies resulting in immune complex formation and complement mediated tissue damage.

The disease course is relapsing and remitting and it has a variable course and prognosis - 95% 5 year survival.

The peak incidence for SLE in women is in late middle age and is slightly later for men. In all age groups except neonates, lupus is more common in females than males.

Question 2

What are the clinical features of lupus?

Answer 2

The general features of lupus are relatively non specific and include fatigue, fever, lymphadenopathy, and weight loss. It should be noted that lymphoma is the most common malignancy that occurs in the early stages of lupus, so patients presenting with lymphadenopathy should have a biopsy to rule out malignancy. Myositis is rare, but patients do report myalgia.

SLE can mimic RA or bacterial endocarditis and may cause nephrotic syndrome.

Question 3

Which system is most commonly involved in SLE?

Answer 3

The musculoskeletal system is most commonly involved in SLE in over 90% of cases. Patients experience:

• myalgia
• arthralgia (but not inflammatory synovitis as seen in RA)
• migratory polyarthralgia with early morning stiffness
• Jaccoud’s deformity: non deforming, reducible arthropathy caused by tendonitis rather than synovitis affecting the fingers, wrists, elbow, shoulders, knees and ankle
• avascular necrosis (hip) due to prolonged steroid therapy

Question 4

What rashes are common in lupus?

Answer 4

Mucocutaneous involvement is common in lupus and occurs in about 80% of cases (this includes skin and mucuous membranes). The classic rash of lupus is the malar “butterfly” rash which bridges the nose and cheeks but spares the area between the nose and lips. This helps distinguish it from the rash of acne rosacea which is also common in older women.

Photosensitivity is also common and causes most of the rashes in lupus. These patients can only be briefly exposed, but the rash persists for a long time.

The discoid or scarring rash also appears in a photosensitive distribution and me be the only manifestation of lupus - subacute cutaneous lupus. If these patients have a positive ANA they are more likely to develop systemic disease.

Vasculitis rashes may also occur.

Question 5

Other than rashes, what are the other mucocutaneous features of SLE?

Answer 5

• Raynauds phenomenon (25-50% of cases)
• non-specific erythema
• alopecia
• oral and mucosal ulceration
• nail fold infarcts
• livedo reticularis (“fish net stockings”) predominantly on the legs

Question 6

What are Sicca symptoms?

Answer 6

Many patients with lupus and other rheumatological conditions can have dry eyes and mouth which is more typically associated with Sjogren’s disease. When they appear in SLE or other diseases they are referred to as secondary Sjogrens.

Question 7

What are the significant pulmonary features of lupus?

Answer 7

Lung involvement in present in 40-50% of cases.
Pleurisy is most common, which can occasionally occur with an effusion. It is also important to investigate patients presenting with pleuritic chest pain for a PE and infection.

Patchy consolidation and areas of collapse or diffuse reticular shadowing on X-ray is also common.

Less common are:

• “shrinking lung syndrome”
• lupus pneumonitis, which may cause fibrosis or be haemorrhagic (rare but often fatal)
• PE in patients with antiphospholipid syndrome
• pulmonary hypertension

Question 8

What are the cardiac manifestations of lupus?

Answer 8

• mild pericarditis (may be the first presenting complaint)
• myocarditis is less common (presents as heart failure or arrhythmias)
• non-infective thrombotic endocarditis (Libman-Sacks)
• hypertension is usually associated with renal involvement
• coronary artery disease

Question 9

How does lupus affect the kidneys?

Answer 9

SLE is associated with a range of glomerulonephritides. Almost all patients will have histological abnormalities on biopsy and 50% will have clinical renal involvement.

Clinical presentation includes:

• hypertension
• haematuria
• proteinuria
• nephrotic syndrome
• AKI
• end stage renal disease

Most renal disease is asymptomatic and serum creatinine will only increase when eGFR is reduced below 50%.

Question 10

What are the indications for renal biopsy in lupus patients?

Answer 10

Proteinuria of > 0.5g/24 hour collection is the main indication for biopsy. Especially if red or white cells are present in the urine in the absence of infection or menstrual loss.

If there are red cell casts and proteinuria it is highly likely that there will be a proliferative nephropathy on biopsy. If there is proteinuria but not casts it is likely the patient will have nephrotic syndrome and a membranous nephropathy.

Question 11

What are the neurological features of lupus?

Answer 11

Neurological involvement of lupus usually arises in the context of active systemic disease. These can include:

• headache
• stroke (vasculitis or atherosclerosis)
• polyneuropathy (glove and stocking)
• mononeuropathy (single due to vasculitis affecting vasa nervorum; or multiplex)
• seizure
• tremor
• psychosis

CNS manifestations are associated with a poorer prognosis.

Question 12

What are the reproductive complications of lupus?

Answer 12

Patients who have the antiphospholipid syndrome are predisposed to recurrent miscarriages and foetal growth restriction.

Transmission of anti-Ro and anti-La antibodies (ENAs) across the placental can lead to neonatal lupus syndrome, where babies are born with a photosensitive lupus rash, or congenital heart block.

Question 13

What is anti-phospholipid syndrome?

Answer 13

Although first described as part of SLE, most patients with antiphospholipid syndrome do not meet the criteria for SLE.

APS is an autoimmune disorder characterised by:

• venous (DVT/ PE) or arterial thromboses (TIA/ CVA or MI)
• obstetric morbidity (recurrent spontaneous miscarriages usually in the second or third trimester)
• thrombocytopenia and abnormalities of the CNS, skin and heart valves

Question 14

What are the haematological findings in SLE?

Answer 14

1) Anaemia
- most patients with lupus will have a normochromic normocytic anaemia of chronic disease
- sometimes it has an iron deficiency pattern and is due to blood loss that can be precipitated by drugs (e.g. steroids, NSAIDs)
- less common but more characteristic is a haemolytic anaemia (Coombs positive, high reticulocytes, raised haptolgobins)

2) Leucopaenia
- lymphopaenia (common) - >1/7
- neutropaenia

3) Thrombocytopaenia
- moderately reduced due to anti-phospholipid antibodies
- severe reduction may be due to other antibodies causing bleeding disorders

4) Raised ESR but LOW CRP (SLE has a poor acute phase response)

Question 15

What auto-antibodies are used to diagnose lupus?

Answer 15

Antibodies to nuclear antigens (ANA) are sensitive but not specific for SLE, and ANA positive antibodies are found in all patients with active disease.

Antibodies to double stranded DNA (dsDNA) are specific for lupus or lupus overlap disorders. They are useful for identifying patients at risk of renal disease (lupus nephritis) and monitoring disease activity. Other antibodies do not fluctuate with disease activity as much as dsDNA.

Antibodies to extractable nuclear antigens (ENA) are common - e.g. anti-Sm, Ro, La, RNP

Question 16

How are complement levels affected in SLE?

Answer 16

Complement levels are low in lupus, especially low C3 and C4. CRP is normal in active disease because SLE has a poor acute phase response. High CRP can indicate another cause - e.g. infection.

The low complement levels in SLE indicate complement consumption. But interpretation of complement levels in patients with SLE is complicated because inherited complement deficiencies predispose to SLE. For example, a low C4 may reflect consumption or a deficiency of one or more of the four C4 alleles.

Question 17

How should antiphospholipid syndrome be investigated?

Answer 17

Antiphospholipid antibodies (aPL - e.g. anticardiolipin, “lupus anticoagulant”) blind to plasma proteins or charged phospholipids in cell membranes. These antibodies bind to phospholipids used in coagulation tests, paradoxically causing an anticoagulant effect in vitro with prolongation of the APTT, hence the term lupus anticoagulant.

Question 18

What are anti-histone antibodies associated with?

Answer 18

These are associated with SLE, but also drug induced SLE. Drugs associated with SLE include Procainamide, hydralazine, and the tetracyclines (especially minocycline used to treat acne).

Question 19

How should SLE be managed?

Answer 19

General measures:

• avoidance of UV light
• warm socks and gloves for Raynaud’s phenomenon
• antibiotics for intercurrent infection
• NSAIDs for joint paint (care! - peptic ulcer, interstitial nephritis, renal impairment, HTN and atherosclerosis so are contraindicated in SLE patients with renal failure)
• antimalarials (e.g. hydroxychloriquine) when skin and joint disease predominate and can be used to maintain remission. Cause lens opacities (eye checks)
• corticosteroids (oral or pulsed IV) when NSAIDs and antimalarials are insufficient
• immunosuppressants - steroid sparing agents (e.g. azothioprine, methotrexate) can be used once the disease is under control. Cyclophosphamide and mycophenolate mofetil are reserved for cases of organ or life threatening disease. Cyclosporin A can be used in patients with leucopaenia and thrombocytopaenia as they do not affect white cell counts
• patients with anti-phospholipid syndrome should be treated with anti-thrombotics

Question 20

What is the diagnostic criteria for SLE?

Answer 20

ACR criteria for SLE states that >4 of the following criteria are required, either serially or simultaneously. These can be remembered by the mnemonic A RASH POINts MD

• Arthritis
• Renal disease
• ANA
• Serositis (pleuritis, pericarditis)
• Haematological disorder
• Photosensitivity
• Oral ulcers
• Immunological disorder
• Neurological disorder
• Malar rash
• Discoid rash

Question 21

What is systemic sclerosis?

Answer 21

This is a generalised disorder of CT affecting skin (scleroderma) and internal organs.

It is characterised by fibrotic arteriosclerosis of peripheral and visceral vasculature. There is also extracellular matrix accumulation (especially collagen) in skin and viscera.

Systemic sclerosis is associated with a number of specific auto antibodies but there role in pathogenesis is unclear.

It takes 2 forms a localised variant called CREST or systemic variants.

Question 22

What immunological changes occur in scleroderma?

Answer 22

There is infiltration of the skin and other affected organs by activated CD4+ and CD8+ T cells, increased cytokine production (especially IL-1, TNF and TGF), increased expression of adhesion molecules (e.g. selectins, integrins) and polyclonal B cell activation (with associated hypergammaglobulinaemia).

Question 23

What are the skin manifestations of scleroderma?

Answer 23

• thickened, taut, waxy skin (eventually becomes atrophic)
• beaked nose, puckered mouth
• telangiectasia
• sclerodactyly (tightening of the skin of the fingers)
• flexure contractures
• Raynaud’s phenomenon (+/- digital pulp atrophy/ infarction)

Question 24

What are the gastrointestinal features of scleroderma?

Answer 24

• microstomia (small mouth with limited opening)
• oesophageal dysmotility (resulting in reflux oesophagitis)
• small bowel malabsorption
• constipation (+/- overflow)

Question 25

How does CREST present?

Answer 25

Limited cutaneous systemic sclerosis (LCSS) formerly known as CREST syndrome (Calcinosis, Reynauds, oEsophageal dysmotility, Scleroderma and Teilangiectasia). This is the diffuse form of scleroderma that typically presents in females aged 30-50 years with a long history of Raynauds.

LCSS is characterised by limited skin involvement (typically the mouth, feet and hands) and the late appearance of visceral complications often limited to pulmonary hypertension.

Question 26

How does systemic sclerosis present?

Answer 26

It is important to remember that scleroderma has both a diffuse form (CREST) and a systemic form. The systemic form is sometimes called diffuse cutaneous systemic sclerosis (DCSS). This is a more extensive form of disease often with an abrupt onset. Skin involvement is both truncal and acral; visceral involvement may involve the heart (CCF, arrhythmias), lung (fibrosis), kidneys (accelerated HTN) and GI involvement.

Question 27

What investigations are required for scleroderma?

Answer 27

• BP - monitor closely for hypertension (due to increased risk of developing renal disease and accelerated HTN)
• Renal function - best measured using eGFR
• Autoantibodies - ANA, anti-ENA (anti-Scl70), anti-centromere
• Pulmonary function tests - usually restrictive pattern with decreased diffusion capacity. If positive should do high resolution CT of the chest to work out the nature of disease
• ECG
• Radiology (CXR, CT chest, barium swallow)

NB - SSc is associated with a high ESR and CRP

Question 28

What autoantibodies are associated with systemic sclerosis?

Answer 28

ANA - 90% of patients will have positive ANA, and this occurs in both the diffuse and limited SSc

Anti-centromere - 10-20% of patients who have limited SSc (CREST) particularly those with oesophageal dysmotility and pulmonary HTN

Anti-Scl-70 (Topoisomerase) - occurs in 15-20% of patients with diffuse SSc and is associated with those that will go on to develop widespread gut disease and accelerated hypertension

Question 29

How should systemic sclerosis be managed?

Answer 29

No treatment has been proven to alter the course of the disease. Symptomatic treatment includes:

• CCBs, vasodilators, cold avoidance/ use of thermal gloves and abstinence from smoking reduce the symptoms of Raynauds phenomenon
• antacid therapy/ PPI
• Physiotherapy helps with muscle stiffness
• Prostaglandins, PDE5 inhibitors and endothelin antagonists may help reduce progression of pulmonary hypertension
• ACEi reduces risk of renal failure
• Penicillamine may be of value

Question 30

What is the most common cause of death in patients with scleroderma?

Answer 30

• renal crisis
• pulmonary HTN
• myocardial ischaemia

Question 31

What is myositis?

Answer 31

Myositis is inflammation of striated muscle and there are 4 recognised sub groups:

1) myositis
2) dermatomyositis (with skin involvement)
3) overlap syndrome (with other connective tissue diseases)
4) associated with malignancy (most common in over 50s)

Question 32

What autoantibody is associated with myositis?

Answer 32

Anti-Jo1

Question 33

What are the clinical features of myositis?

Answer 33

Myositis presents with pain, stiffness and tenderness of muscles. These then become increasingly weak, especially in the proximal muscles of the arms and legs.

As the disease progresses, there can be involvement of the face, bulbar and respiratory muscles.

About 20% of patients will develop pulmonary fibrosis (especially those with anti-Jo1 antibodies) and some develop arthralgia and RA like changes in the fingers.

Question 34

What skin changes are associated with myositis?

Answer 34

• Heliotrope rash = purple discolouration around the eyes, especially in children
• Gottron’s papules = rash over the bony joints of the hand (e.g. MCP, PIP, DIP)
• Machinists hands = dry cracked hands

Calcinosis can also occur in dermatomyositis even though it is more commonly associated with scleroderma.

Question 35

How should myositis be investigated?

Answer 35

• serum CK levels: usually markedly raised and a marker of response to treatment; alanine transaminase levels are also raised
• EMG: confirms myopathy and excludes denervation
• Muscle biopsy for definitive diagnosis
• MRI: to identify a suitable site for biopsy if the myositis is patchy (best modality to visualise muscle inflammation)
• Autoantibody profile: 1/3 of all patients do not have any detectable auto-antibodies
• Positive ANA and anti-ENA antibodies are common but do not reliably distinguish from other connective tissue disorders
• Anti-Jo-1 is specific and can help to identify sub groups of patients with anti-synthetase syndrome (fever, myositis, interstitial lung disease, Raynauds)
• Anti-RNP is associated with mixed connective tissue disease

NB - patients over 50 should be investigated for malignancy which is strongly associated with myositis in this age group

Question 36

How is myositis managed?

Answer 36

Corticosteroids are the mainstay of treatment for myositis and can be given orally or by IV pulses. Steroids can cause muscle weakness so should not be used for prolonged periods of time.

Immunosuppressants can be used in patients who require increased steroid use or relapse. Methotrexate or azothioprine are first choice and cyclophosphamide can be added if there is lung involvement. Cyclosporin A is used if patients are refractory.

IVIg can also be used in refractory cases.

Question 37

What is Sjogren’s syndrome?

Answer 37

This is a slowly progressive inflammatory disease affecting primarily the exocrine glands. There are many overlaps with SLE. There are lymphocytic infiltrates into the exocrine glands and it is characterised by anti-Ro and anti-La antibodies.

It is best distinguished from lupus by mucosal swelling and dryness early on in the disease.

Question 38

What is the Schirmer tear test? How is Sjogren’s investigated?

Answer 38

This is the test for dryness of the eyes, where reduced production of tear fluid can be demonstrated in the clinic.

Other investigations include:

• Slit lamp experiment with Rose Bengal staining confirms dryness and corneal damage
• Salivary flow rates and scintigraphy
• Raised ESR but normal CRP
• Biopsy of minor salivary glands shows focal T cell infiltrates
• Anti-Ro and anti-La antibodies

Question 39

What are the extra-glandular features of Sjogren’s disease?

Answer 39

• arthralgia
• Raynaud’s
• interstitial lung disease
• interstitial nephritis
• purpura

Sjogrens syndrome is also associated with an increased risk of B cell lymphoma. Babies born to mothers with Sjogrens syndrome who have anti-Ro antibodies are at risk of congenital heart block.