day 2 - immunology of joint disease

Question 1

define rheumatoid arthritis

Answer 1

Definition: Symmetrical autoimmune polyarthritis commonly affecting the peripheral joints. It is a severe inflammatory disorder which can affect men and women of any age

Question 2

epitome of RA

Answer 2

Epidemiology:
Common disease (1-2% of population)
M:F ratio 1:3
Peak incidence: young adults and premenopausal women

Question 3

RA diagnosis

Answer 3

Diagnosis is clinical: insidious, symmetrical arthritis, with painful, swollen joints.
A new diagnostic test for anti-cyclic citrullinated protein antibodies has been shown to be specific for rheumatoid arthritis

Question 4

path of RA

Answer 4

Pathology:
Main target is the synovium: inflammation, vasculitis, oedema, villous hypertrophy, chronic inflammation, infiltration by lymphocytes and macrophages, proliferation of synovial cells and erosion of articular cartilage.

Question 5

evidence of the role of the immune system in RA?

Answer 5

Evidence for role of the immune system in the disease:
High % have particular HLA type (DR4).
Associated with the presence in the blood of high titre of rheumatoid factor, an auto- antibody (usually IgM) reactive with altered autologous immunoglobulin (also anti- ribonucleoprotein and anti-perinuclear factor).

Question 6

multi systems affected by RA

Answer 6

Multi-system disorder:
Marked by a variable course with exacerbations and remissions
• chronic inflammatory granulomatous lesions (rheumatoid nodules) at many sites,
especially subcutaneous.
• vasculitis: including skin, eyes (scleritis, keratoconjunctivitis) neuropathies.
• pulmonary disease: fibrosing alveolitis, effusions and pleuritis, Caplan’s syndrome.
• Sjogren’s syndrome.
• amyloidosis.
• haematological abnormalities: anaemia, lymphadenopathy, splenomegaly, hyperviscosity.
• local complications, e.g. tendon and nerve damage

Question 7

what is • Sjogren’s syndrome.

Answer 7

Sjögren’s syndrome or Sjögren syndrome (pronounced /ˈʃoʊɡrɨn/ or /ˈʃʌrɡrɛn/[1] in English, the latter to approximate the Swedish pronounciation) is a chronic autoimmune disease in which the body’s white blood cells destroy the exocrine glands, specifically the salivary and lacrimal glands, that produce saliva and tears, respectively.[2] The immune-mediated attack on the salivary and lacrimal glands leads to the development of xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes), which takes place in association with lymphocytic infiltration of the glands.[3] That inflammatory process eventually severely damages or destroys the glands.

Sjögren’s syndrome is usually classified by a clinician as either ‘primary’ or ‘secondary’. Primary Sjögren’s syndrome occurs by itself and secondary Sjögren’s syndrome occurs when another connective tissue disease is present

Question 8

what is amyloidosis

Answer 8

Amyloidosis is a rare disease that results from accumulation of inappropriately folded proteins. These misfolded proteins are called amyloids. When proteins that are normally soluble in water, fold to become amyloids, they become insoluble and deposit in organs or tissues, disrupting normal function.[2][3] The type of protein that is misfolded and the organ or tissue in which the misfolded proteins are deposited determines the clinical manifestations of amyloidosis.

Question 9

what is felty’s syndrome?

Answer 9

Felty’s syndrome, also called Felty syndrome,[1] is characterized by the combination of rheumatoid arthritis, splenomegaly and neutropenia. The condition is more common in those aged 50-70 years, and is more prevalent in females than males and more in Caucasians than blacks. It is a deforming but inactive disease and seropositive for RF

Felty’s syndrome:
• Destructive arthritis.
• High frequency of extra-articular manifestations especially vasculitis.
• Strong family history and HLA DR4 association.
• Lymphadenopathy and splenomegaly.
• Leucopenia, often neutropenia with increased susceptibility to infection.

Question 10

role of T cells in RA

Answer 10

Role of T cells?
• Dense infiltrate of activated mature T cells (mainly CD4+ in synovium).
• Close association with particular MHC polymorphism HLA DR4.
• Therapy directed against T cells has been shown to be effective in treatment in some
cases.
• Most animal models are T cell dependent.

Question 11

role of B cells in RA

Answer 11

Role of B cells and antibodies?
• Anti B cell therapy has proved successful.
• Some animal models are B cell dependent.

Question 12

role of cytokines in RA

Answer 12

Role of cytokines?
• Evidence from both animal models and human studies that immunoregulatory cytokines are important
• Role of tumour necrosis factor (TNF): was shown to be pivotal (but not exclusive) cytokine, acting directly in both pro- and anti-inflammatory networks, and indirectly via effect on interleukins (IL), especially IL-1 and IL-6.
• Exploited to generate biological therapeutics (e.g. anti-TNF, soluble TNF receptor) which have proved to be of therapeutic value.

Question 13

Possible components in the immunopathogenesis of rheumatoid arthritis:

Answer 13

Possible components in the immunopathogenesis of rheumatoid arthritis:
• Immune complex mediated disease.
• Dysregulation of T cells and/or macrophages in the synovium with persistent
production of pro-inflammatory mediators (e.g. TNF).
• Abnormal antigen presentation in synovium.
• Excess production of free radicals and matrix metalloproteases in the synovium.

Question 14

Adverse prognostic factors in rheumatoid arthritis:

Answer 14

• High titre of serum rheumatoid factor.
• Presenting feature of insidious onset, > 50 years of age, symmetrical arthritis. • Joint erosions on X ray.
• Early appearance of nodules or vasculitis.
• Persistent disease activity in the first year after diagnosis.

Question 15

current treatments for RA

Answer 15

Current treatments:
• NSAIDS / Steroids.
• DMARD: methotrextrate, ciclosporin, gold, penicillamine, azathioprine.

• Anti TNFalpha/soluble receptor/IL-1. • Anti CD20 antibodies.
Potential future treatments:
• Anti BAFF.
• Anti angiogenesis treatments? • Gene therapy?

Question 16

what is SLE

Answer 16

Systemic lupus erythematosus

Systemic disorder characterised by the presence of circulating auto-antibodies directed
against nuclear components:
• anti-DNA (ss or ds) (note different patterns of staining on nuclei of Hep2 cell line);
• anti-histone;
• anti-Ro, anti-La, anti-Sm;
• can also can have auto-antibodies against other components of the cell:
• anti-phospholipid (associated with thrombosis) – phospholipid associated proteins especially
beta 2 glycoprotein 1;
• anti-red cell (associated with haemolytic anaemia);
• rheumatoid factor;
• cell or organelle specific, e.g. mitochondria, smooth muscle cell.

Question 17

SLE epidemiology

Answer 17

Epidemiology:
• Female&raquo_space; male
• Drug - induced forms - similar disease?
• Auto-antibodies may be present, but no disease seen?
• Familial but not HLA-linked

Question 18

clinical manifestations of SLE

Answer 18

Principal clinical syndromes:
• Arthritis - low grade, no pannus, no erosions
• Erythema - butterfly rash, alopecia, photosensitivity
• Lymphadenopathy and splenomegaly
• Anaemia and leucopenia
• Myalgia
• Serositis - pleuritis, pericarditis
• Glomerulonephritis
• Pulmonary manifestations: fibrosing alveolitis
• Endocarditis (Libman - Sacks)
• Neurological manifestations - association with arteritis, thrombosis, anti-cardiolipin antibodies

Question 19

hypotheses of pathogen of SLE

Answer 19

Numerous hypotheses about pathogenesis: primary and perpetuating phases of disease are recognised:

1. Immune complex mediated disease
2. Association with primary classic complement deficiencies
3. Infectious agent: viral
4. Environmental agents: drugs, photosensitivity
5. Genetic associations
6. Defect in immunoregulation

Question 20

immunological investigations in RA and SLE

Answer 20

Rheumatoid factor:
RA = +ve in >70%; high titre
SLE = +ve in <10%
SLE = +ve, 70-80%

CRP
RA = increased
SLE = usually normal

C3 and C4 levels
RA = normal or increased
SLE = normal or decreased

Serum Ig levels
RA = normal
SLE = often increased

Question 21

what is c) Systemic sclerosis (scleroderma)

Answer 21

Systemic sclerosis (scleroderma)
• Systemic disease characterised by sclerosis of connective tissue.
• Often associated with other auto-immune diseases.
• Polyarthritis, induration of skin, Raynaud’s phenomenon.
• Involvement of blood vessels at other sites - gut wall, kidney, lung.

Question 22

what is Sjogren’s syndrome

Answer 22

Sjogren’s syndrome
• Clinical features: Dry mouth, dry eyes, and arthritis.
• Antibodies to extractable nuclear antigens (ENA): Ro and La; and Ig (Rheumatoid factor). • Destruction of salivary and lacrimal glands associated with lymphoid infiltration, germinal centre formation, sometimes progression to lymphoproliferative disorder.
• Association with other auto-immune diseases frequent.

Question 23

Include following core investigations in patients with suspected immune joint disease:

Answer 23

Acute phase reactant e.g. CRP and ESR Antibody e.g. ANA, ENA, RF Complement e.g. C3, C4
Immune complexes

Question 24

immunology of Sjogren’s Syndrome

Answer 24

• Autoimmune inflammation of the salivary and lacrimal glands causes dry eyes and mouth.
• High IgG levels lead to persistently very high ESR but normal CRP.
• ANA, anti-Ro and anti-La are the most common autoantibodies
• RF often positive but anti-CCP is not and they do not get erosive arthritis

Question 25

immunology of Systemic sclerosis (SSc)

Answer 25

Systemic Sclerosis (Scleroderma) • ANA positive in 90% of cases • Anti-dsDNA normal • Anti-centromere suggests LIMITED SSc (sometimes called CREST syndrome) • Anti-Scl70 suggests DIFFUSE SSc • In the diffuse form more widespread areas of skin are involved • Oesophageal dysmotility and dysphagia are common • Watch out for breathlessness – could be pulmonary fibrosis or pulmonary hypertension

Question 26

immunology of Seronegative inflammatory arthritis

Answer 26

* Despite the negative antibodies, we can make a diagnosis of inflammatory arthritis on the symptoms and signs. * You could confirm this by ultrasound scan of the joints showing synovitis. * Prognosis is generally better than in seropositive disease. * Inflammatory markers are lower and Hb usually normal * Less likely to respond to B cell depletion with rituximab

Question 27

immunology of Seropositive rheumatoid arthritis

Answer 27

* Not all patients with RA have positive autoantibodies * 70-80% have rheumatoid factor BUT healthy people can also have RF * In contrast fewer patients have anti-CCP but it rarely occurs in healthy people * The combination of RF +ve, anti-CCP +ve makes RA very likely * These seropositive patients have a worse outlook and need more aggressive treatment. * Inflammatory markers tend to be high and Hb may be low

Question 28

immunology of SLE

Answer 28

* Classic symptoms (especially photosensitive facial rash) * Commonest in young women (esp Afro-Caribbean) * ANA positive in 95% but not specific * High anti-dsDNA and anti-Sm are specific * High ESR and normal CRP * Low Hb, WC and/or platelets are common * Complement depletion suggests active inflammation in the tissues.

Question 29

immunology of Drug –induced autoantibodies

Answer 29

• Anti-TNF drugs do induce ANA and anti-dsDNA in a minority of patients . • Complement is not usually depleted because these antibodies are not causing tissue inflammation • In a drug reaction ESR and CRP are likely to go up together (not like SLE) • If the drug is stopped the antibodies should disappear. • In most cases patients don’t get ill. Drug-induced lupus is a condition with mild symptoms and anti-histone antibodies usually associated with other drugs (isoniazid, procainamide, minocycline) rather than anti-TNF.

Question 30

To make a diagnosis of Lupus the patient must have had at least FOUR of these 11 manifestations at any time since the onset of the disease.

Answer 30

1. Malar rash fixed red rash over the cheeks 2. Discoid rash red patches of skin associated with scaling and plugging of the hair follicles 3.  Photosensitivity rash after exposure to sunlight 4.  Mucosal ulcers small sores that occur in mucosal lining of mouth and nose 5. Serositis inflammation of the delicate tissues covering internal organs and abdominal pain 6. Arthritis -very common in lupus, pain in the joints   7. Renal disorders usually detected by routine blood and urine analysis 8. Neurological disorder seizures or psychosis 9. Haematological disorder haemolytic anaemia, leukopenia, thrombocytopenia   10. Immunologic disorder tests on LE cells, anti-DNA and anti-SM antibodies   11. Anti-Nuclear Antibody (ANA blood test) when found in the blood and the patient is not taking drugs, it is known to cause a positive test for lupus in most cases, but is not necessarily conclusive  

Question 31

Treatments for SLE:

Answer 31

Nonsteroidal anti-inflammatory drugs (NSAIDs) Antimalarials, such as hydroxychloroquine The mainstay of lupus treatment involves the use of anti-inflammatory corticosteroid hormones such as: Prednisone hydrocortisone Methylprednisolone Dexamethasone Corticosteroids can be given by mouth, in creams applied to the skin, or by injection. Immunosuppressives, such as azathioprine and cyclophosphamide, restrain the overactive immune system. In some patients, methotrexate (chemotherapy) may be used to help control the disease. Biological therapies