Week 5 - inflammatory arthritis Flashcards
Which genes are associated with a higher risk of rheumatoid arthritis? (LO1)
- HLA DRB1
- HLA DRB4
List some environmental risk factors associated with rheumatoid arthritis. (LO1)
- Smoking.
- Pollution.
- Infection.
- Obesity.
- Immunisation.
- Blood transfusion.
- Previous termination of pregnancy.
- Ages 40-60.
- Females to males, 2:1.
List some protective factors against developing rheumatoid arthritis. (LO1)
- Vitamin C.
- Vitamin E.
Describe the basic epidemiology of rheumatoid arthritis. (LO1)
- Overall prevalence worldwide: 0.8-1%.
- Females more at risk than males.
- Both genders more at risk as they age.
- Link found between Pakistanis developing rheumatoid arthritis after moving to a western environment (England).
Explain the link between ethnicity and the risk of developing rheumatoid arthritis. (LO1)
- Pima Indians - 5-6%.
- Europeans, South Americans - 0.5-1%.
- Africans, Asians - <0.4%.
Describe the pathophysiology of rheumatoid arthritis. (LO1)
- An environmental factor may initiate primary inflammation in a genetically susceptible individual.
- This can occur in various tissues and trigger the immune response to citrullinated proteins.
- The resulting anti-citrullinated protein/peptide antibodies (ACPAs) are distributed through the circulation and may form immune complexes with citrullinated proteins produced in an inflamed synovium, boosting the inflammatory process.
- This will be associated with the infiltration and activation of neutrophils, macrophages and lymphocytes, cell death, extracellular DNA trap formation, activation and release of peptidylarginine deiminases (PADs), de novo citrullination and disversification of the ACPA response.
What is meant by citrullination? (LO1)
- Citrullination of synovial cells in the joint is the conversion of the amino acid arginine in a protein into the amino acid citrulline.
- Increased rheumatoid factor shows loss of tolerance to citrulline.
How is the synovium linked to the pathogenesis of rheumatoid arthritis? (LO1)
- An inflamed synovium is central to the pathogenesis.
- The synovium shows increased angiogenesis, cellular hyperplasia, influx of inflammatory cells, changes in the expression of cell surface adhesion molecules, and many cytokines.
- The synovial lining becomes hyperplastic, with infiltration of the sublining with mononuclear cells including T cells, B cells, macrophages, and plasma cells.
- This formation of locally invasive synovial tissue is characteristic and it is involved in causing erosions seen in rheumatoid arthritis.
Explain how cytokines are involved in the pathogenesis of rheumatoid arthritis. (LO1)
- Cytokines affect all phases of the inflammatory process.
- TNF, IL-1 and IL-6 seem to be the most abundant in the joint.
- Both TNF and interleukins promote proliferation, metalloproteinase expressions, adhesion molecule expression, and further secretion of other cytokines.
- The proliferation of new blood vessels provides for the hypertrophic synovium.
- This inflammatory setting, when not treated, leads to the eventual destruction of the joint.
Describe the presentation of rheumatoid arthritis. (LO1)
- PC of bilaterial, symmetrical pain and swelling of the small joints of the hands and feet lasting >6 weeks.
- Morning stiffness over 1 hour.
- Articular or extra-articular.
- Visible deformity seen in smaller joints of the hands, feet and cervical spine.
- Main joints affected: PIP, MCP, MTP, base of the thumb and big toe.
- Boutonniere deformity - PIP flexion with DIP hyperextension.
- Swan-neck deformity - PIP hyperextension, DIP hyperflexion.
- Hallux valgus or hammer-toe in the feet - can see rheumatoid nodules in both.
- Extra-articular manifestations: nodules on the skin, a pleural effusion (lungs), pericarditis (heart), tenosynovitis (muscles) or keratoconjunctivitis sicca (eyes).
Describe a complication of rheumatoid arthritis. (LO1)
- Ulnar deviation due to inflammation of the MCP joints, causes the fingers to dislocate.
- As the tendons pull on the dislocated joints, the fingers tend to drift towards the ulnar side.
How can rheumatoid arthritis presentations vary in terms of onset? (LO1)
- Additive - will start in one joint and spread but will continue in that initial joint.
- Insidious in 70% of patients - slow onset, rather than acute.
- Palindromic - will come and go, and flare up.
- Polymyalgic - can look polymyalgic rheumatica.
Describe the investigations for rheumatoid arthritis. (LO1)
- Take a history.
- Inspect the joints for the common presentations.
- Perform full examination on the affected areas.
- Blood test - raised ESR and CRP, raised RF, raised anti-CCP, anaemia of chronic disease, neutrophilia.
- X-ray.
- DAS-28 score.
Explain why anti-CCP is preferred to diagnose rheumatoid arthritis rather than rheumatoid factor (RF). (LO1)
- RF is more sensitive but less specific.
- anti-CCP is less sensitive but more specific.
- Anti-CCP is used more than RF because RF is found in other other diseases such as endocarditis, hepatitis, TB, bronchitis, cirrhosis, malignancy, ageing, and many more.
- Positive anti-CCP can be seen in 40% of seronegative patients but it’s a good predictor of erosive disease.
- Anti-CCP can be positive when RF is negative.
- Anti-CCP plays more of a pathogenic role in RA.
- Anti-CCP is positive in about 70% of patients with RA.
- RF is positive in about 60-70% of patients with RA. It is not required for diagnosis but is helpful if present.
Explain why we use x-rays to investigate rheumatoid arthritis, especially when deformities are visible without. (LO1)
- Shows deviation of digits and subluxation of the MCP or MTP joints.
- RA can also lead to erosions within the bones of the joint as the synovium has become inflamed.
- Erosions are seen in around 40-73% of patients within the first year of RA.
Describe what is meant by DAS-28. (LO1)
- A scoring system designed to diagnose rheumatoid arthritis.
- 28 joints are assessed on the patient and they are given a score based on multiple factors.
List the factors used for the DAS-28 scoring system. (LO1)
- Tenderness of joints.
- Swelling of joints.
- ESR from bloods and general health assessment (ask the patient how active they think their disease is on a scale of 1-10).
- The feet and ankle are missed from this exam as it was designed to be quick and easy.
Describe the management of rheumatoid arthritis. (LO1)
- NSAIDs - OTC, Naproxen, intermittent steroids (in that order).
- DMARDs - within 3 weeks of presentation to prevent damage to joints and soft tissues.
- 1st line DMARDS (non-biologics) - methotrexate, leflunomide, hydroxychloroquine, sulfasalazine.
- If one of these is not effective, another can be prescribed - up to 3 non-biologics can be given.
- If DAS-28 > 5.1 and 2 DMARDs are not effective, biologic DMARDs should be considered.
- Biologic DMARDS include TNF-alpha inhibitors (infliximab, adalumimab), T-cell blockers (abatacept), B-cell depletion (rituximab), IL-6 inhibitors (toclizumab), JAK inhibitors (tofacitinib).
Describe the prognosis of rheumatoid arthritis. (LO1)
- If treated early and aggressively, good prognosis - achieving good disease control.
- If there’s a delay in treatment initiation or if it remains untreated, patient may be disabled within 10 years.
- Untreated RA is also associated with premature mortality, most commonly from coronary artery disease.
- Flares are common even in patients well-controlled with DMARDs. Temporary oral corticosteroids are usually adequate.
- For patients in remission, or low disease activity who are taking biological DMARDs, discontinuing of the drugs could lead to increased risk of losing remission.
Describe the basic epidemiology of lyme disease. (LO2)
- Bacterial infection caused by Borrelia burgdorferi and spread by vectors such as Ixodes scapularis (black-legged tick).
- Most common vector-borne disease in the US and Europe. One of the most common notifiable disease in the US.
- Most common in temperate regions of the Northern hemisphere.
- Majority of cases usually occur in spring and early summer as that’s when outdoor activity increases due to good weather.
- Men and women are at equal risk and all ages can be affected.
- Age groups with highest risk: 10-19 years and 50-59 years.
Describe the presentation of lyme disease. (LO2)
- Erythema migrans - expanding red, ring-like rash at the site of the bite. 50-90% of lyme disease patients have it.
- Musculoskeletal: arthralgia/arthritis - monoarticular/oligoarticular, most common in knee joints.
- Neurological: cranial nerve palsy, encephalitis.
- Cardiovascular - carditis with atrioventricular blockage.
List the clinical investigations for lyme disease. (LO2)
- Erythema migrans rash - enough to make a diagnosis and begin treatment.
- Myalgia.
- Fatigue.
- Fever.
- Headache.
Describe the investigations for lyme disease in the absence of an erythema migrans rash. (LO2)
- Enzyme-linked immunosorbent assay (ELISA) test - positive result for Lyme disease.
- Confirmatory immunoblot test - positive result for Lyme disease.
ELISA test are used to confirm the presence of antibodies relating to a specific infectious disease.
Describe the management of lyme disease. (LO2)
- Post-exposure prophylaxis - single dose of doxycycline within 72 hours of tick removal if the tick has been attached for about 36 hours.
- For erythema migrans - doxycycline for 10 days or amoxicillin, cefuroxime or phenoxymethylpenicillin for 14 days.
- For lyme arthritis - oral antibiotics (doxycycline, amoxicillin, cefuroxime, phenoxymethylopenicillin) for 28 days and NSAIDs for symptom relief.
Describe the prognosis of lyme disease. (LO2)
- Lyme disease is usually curable with a complete course of the appropriate antibiotics.
List some causes of chronic inflammation. (LO3)
- Persistent infection - most common.
- Infection with viruses, mycobacteria, parasites and fungi.
- Autoimmune disease - e.g. allergic reactions + asthma.
- Foreign material - e.g. thorn in hand.
- Carcinoma.
List the cells involved in chronic inflammation. (LO3)
- Macrophages are the main cell - there are two subtypes: M1 and M2.
- Lymphocytes are also involved: T-cells and B-cells.
List the subtypes of macrophages and explain their function. Which cytokines are they activated by? (LO3)
- M1 - pro-inflammatory - activated by bacteria or IFN-γ from T-cells.
- M2 - anti-inflammatory - activated by IL-4 or IL-13 from T-cells.
Describe the types of lymphocytes involved in chronic inflammation and explain their function. (LO3)
- B-cells - activated by T helper cells.
- T-cells - CD4+ helper T cells have 2 main subtypes: Th1 and Th2.
- TH1: secrete IFN-γ.
- TH2: important in allergies.
What is meant by granulomatous inflammation and what is it caused by? (LO3)
- The formation of granulomas: a collection of activated macrophages/epithelioid histiocytes.
- Caused by:
- Foreign material.
- Sarcoidosis.
- Crohn’s disease.
- Cat scratch disease.
How do granulomas form? (LO3)
- Macrophages process and present an antigen to CD4+ T helper cells.
- They then secrete IL-12, causing CD4+ T helper cells to differentiate into Th1.
- Th1 secrete IFN-γ which converts macrophages into epithelioid histiocytes and giant cells.
N.B. levels of IFN-γ are helpful in indicating TB.
List the three stages of healing. (LO3)
- Coagulation phase.
- Inflammatory phase.
- Proliferative/granulation tissue phase.
List the three subtypes of tissues based on their regenerative capacity. (LO3)
- Labile - stem cells present, e.g. skin.
- Stable - can regenerate when needed, e.g. liver.
- Permanent - lack of regenerative potential, e.g. myocardial tissue.
Describe the coagulation phase of wound healing. (LO3)
- Started by Hageman factors coming into contact with collagen.
- This starts thrombosis (blood clotting) caused by the coagulation cascade.
Describe the inflammatory phase of wound healing. (LO3)
- Neutrophils, macrophages and platelets arrive.
- Neutrophils and macrophages clear out the wound.
- Platelets degranulate.
Describe the proliferative phase of wound healing. (LO3)
- Degranulation of platelets releases growth factors causing new cells to enter the wound.
- Proliferation of new capillaries and fibroblasts.
List the two types of scar with excess scar tissue and explain the difference. (LO3)
- Hypertrophic scar - excess production of scar tissue localised to the wound.
- Keloid scar - excess production of scar tissue out of proportion to the wound size - caused by excess type 3 collagen and more common in black people.
List the factors that can cause delayed wound healing. (LO3)
- Infection - causes more PAMPs.
- Ischaemia - reduces blood supply and healing needs blood supply.
- Foreign bodies - increase infection.
- Diabetes - can impair growth factors and cause narrowing of blood vessels - also makes blood more sugary which favours pathogens.
- Malnutrition - reduces essential elements needed: copper and vitamin C for collagen cross-linking and zinc which is a co-factor for collagenase (replaces type 3 with type 1).
What is meant by immune tolerance? (LO4)
- A concept which explains why we do not make antibodies against “self” antigens.
What is meant by immunological self? (LO4)
The identity of cells which have “self” antigens. These antigens are recognised by T cells and the immune system does not create antibodies against these antigens.
N.B. We can still make antigens against other’s antigens, e.g. tissue rejection.
Describe acquired immunity. (LO4)
- Gene rearrangement in T and B cells is essential in acquired immunity and these are random.
- Rearrangements must be acquired after encountering foreign antigens and pathogenic antigens.
- B cells cannot make antibodies without T cell help. B cells must also present antigens to T cells to survive.
- Memory (T and B) cells can respond quickly to secondary infections.
- Plasma cells secrete antibodies.
- Th1 cells aid the effector function of antibodies.
- Th2 cells aid B cell differentiation and antibody production, e.g. after a vaccine.
Briefly describe antigen presentation. (LO4)
- The pathogen is phagocytosed by an antigen presenting cell, e.g. macrophage/dendritic cell.
- The pathogen is placed in a lysozyme where it is digested by proteolysis.
- The antigen is loaded onto an MHC so it can be presented to T cells.
What is the difference between MHC and HLA? (LO4)
Trick question:
- HLA and MHC are the same thing.
- HLA - human leucocyte antigen - humans.
- MHC - major histocompatibility complex - mice.
Describe the function of MHC/HLA proteins. (LO4)
They present pathogenic peptides to immune cells - usually T cells.
What are the two types of HLA/MHC proteins and where are they found? (LO4)
- MHC class I - most cells except neurons.
- MHC class II - antigen presenting cells.
Why do we get tissue rejection even though all humans have MHC/HLA proteins? (LO4)
- The proteins which form the MHC/HLA vary between individuals.
- This is why rejection can occur if a donor and recipient aren’t matched.
- The genes for MHC/HLA is >3 million base pairs on chromosome 6 and to prevent an immune response, the MHC/HLA protein must be IDENTICAL to the “self” protein.
List some diseases associated with mutations of HLA genes. (LO4)
Broadly, these are called autoimmune conditions. Mutations of the HLA gene leads to misidentification of the “self” antigen, leading to autoimmune disease.
HLA I mutations:
- HLA B27 - Ankylosing spondylitis + other seronegative arthropathies.
HLA II mutations:
- HLA-DR3 - Rheumatoid arthritis.
- HLA-DR3/DQ2/DQ8 - Type 1 Diabetes Mellitus.
Briefly describe T cells loading with “self” peptides. (LO4)
- Our cells are constantly carrying out protein homeostasis which is the breakdown of proteins to maintain intracellular protein levels.
- Proteins broken down in the proteosome are called “self” peptides. These self-peptides are loaded onto MHC/HLA and presented to T cells receptors (TCRs) as “self”.
- An immune response can be triggered by both the wrong antigen and the wrong MHC (organ donation).
Briefly describe the recognition of MHC. (LO4)
Peptide complexes by the T cell receptor triggers signal transductions which lead to gene expression. This promotes synthesis of cytokines and cell adhesion molecules, leading to an immune response.
B cells require T cells in order to survive and produce antibodies. How do these cells find each other? (LO4)
- Within secondary lymphoid organs, e.g. lymph nodes.
- The lymphatic system receives B and T cells from primary lymphoid organs where they are produced.
- B and T cells are stored in lymph nodes and are constantly coming across antigens until an immune response is triggered.
Briefly describe the process from innate immunity until antigen presentation. (LO4)
- Pathogens express PAMPs which are recognised by toll-like receptors (TLRs).
- This triggers phagocytosis and degradation of the PAMPs in the lysosome.
- A peptide is formed, bound to MHC and presented.
- The APCs change expression of cell adhesion molecules to move into the lymph vessels where they seek out T cells.
- APC presents MHC II loaded peptide, if it is not recognised as “self”, the T cells start to divide.
- T cell division is why lymph nodes swell during infection.
What are PAMPs and which receptors correspond to them? (LO4)
Pathogen-associated molecular patterns are recognised by toll-like receptors (TLRs).
Types of pathogen-associated molecular patterns:
- Flagella - recognised by toll-like receptor 5 (TLR5).
- Lipopolysaccharides - recognised by toll-like receptor 4 (TLR4).
- Cell walls - recognised by toll-like receptor 2 (TLR2).
Why are dendritic cells better antigen presenting cells (APCs) than others? (LO4)
They have a larger surface area and therefore, a higher yield of MHC II bound peptides.
Why do the lymph nodes swell during infection? (LO4)
This is due to T cell division after recognition of the antigen as non-self in the lymph nodes.
Where do T cells mature? (LO4)
Thymus.
Where do B cells mature? (LO4)
Bone marrow.
Name the two parts of the selection process for T cells. (LO4)
Positive selection.
Negative selection.
Describe the selection process for T cells. (LO4)
POSITIVE SELECTION:
- If the immature T cells cannot bind to MHC “self” at all, they die.
- If the immature T cells bind weakly/moderately to MHC “self” peptide, they survive.
- These cells mature and are found in the lymphatic system.
NEGATIVE SELECTION:
- If the immature T cells bind strongly to MHC “self” peptide, they die.
- If the immature T cells bind weakly/moderately to MHC “self” peptide, they survive.
What is meant by central tolerance? (LO4)
The elimination of self-reactive T cells in the thymus.
Describe the positive selection process for T cells. (LO4)
- If the immature T cells cannot bind to MHC “self” at all, they die.
- If the immature T cells bind weakly/moderately to MHC “self” peptide, they survive.
- These cells mature and are found in the lymphatic system.
Describe the negative selection process for T cells. (LO4)
- If the immature T cells bind strongly to MHC “self” peptide, they die.
- If the immature T cells bind weakly/moderately to MHC “self” peptide, they survive.
Why do T cells not attack “self” antigens? (LO4)
- T cells are produced from precursor cells.
- The precursor cells have not undergone gene rearrangement. They do not express T cell receptors and cannot bind antigens.
- Mature T cells leaving the thymus have undergone gene rearrangement but most of these cannot bind strongly to “self” antigens.
- Self-reactive T cells are suppressed and destroyed. The mature T cells must pass checks to ensure they do not react to “self”. Failure of this test leads to their destruction.
- B cells rely on T cells so if the T cells are not self-reactive, B cells are normal.
How do diseases associated with HLA gene mutations arise? (LO4)
The mutations allow some self-reactive T cells to escape the thymus and stimulate B cells to produce self-reactive antibodies.
List the drugs used for the treatment of pain in rheumatoid arthritis. (LO5)
NSAIDs:
- Improves joint pain and stiffness.
- No effect on disease activity or progression.
- If one doesn’t work, try another.
Corticosteroids.
- Improves pain and swelling.
- Low dose of prednisolone used before DMARDs become effective.
- Intra-articular via intramuscular administration.
- IV route for general flare up.
Which category of drugs are used for the prevention of damage in rheumatoid arthritis? (LO5)
Disease modifying antirheumatic drugs (DMARDs).
List the key features of DMARDs. (LO5)
- Suppress disease activity.
- Slow the process of joint erosion.
- Some suppress the immune system.
- Others inhibit cell replication.
- Slow-acting and take weeks to produce a clinical effect.
- If one DMARD doesn’t work, you can try another or add one.
- Most DMARDS are not understood.
List the most common DMARDs. (LO5)
- Azathioprine.
- Cyclophosphamide.
- Ciclosporin.
- Gold.
- Hydroxychloroquine.
- Leflunomide.
- Methotrexate.
- D-penicillamine.
- Sulfasalazine.
List the side effects of the most common DMARDs. (LO5)
Azathioprine: - GI disturbance. - Bone marrow suppression. Cyclophosphamide: - Bone marrow suppression. - Increased risk of malignancy. - Infertility. Ciclosporin: - Renal impairment. - Hypertension. - Bone marrow suppression. Gold: - Rash. - Proteinuria. - Bone marrow suppression. Hydroxychloroquine: - Retinal damage. Leflunomide: - Hypertension. - GI disturbance. - Bone marrow suppression. Methotrexate: - GI disturbance. - Oral ulcers. - Raised liver enzymes. - Pneumonitis. - Bone marrow suppression. D-penicillamine: - Rash. - Proteinuria. - Bone marrow suppression. Sulphasalazine: - GI disturbance. - Raised liver enzymes. - Bone marrow suppression.
List the side effects of azathioprine. (LO5)
Azathioprine is a DMARD.
- GI disturbance.
- Bone marrow suppression.
List the side effects of cyclophosphamide. (LO5)
Cyclophosphamide is a DMARD.
- Bone marrow suppresion.
- Increased risk of malignancy.
- Infertility.
List the side effects of ciclosporin. (LO5)
Ciclosporin is a DMARD.
- Renal impairment.
- Hypertension.
- Bone marrow suppression.
List the side effects of gold as a DMARD. (LO5)
- Rash.
- Proteinuria.
- Bone marrow suppression.
List the side effects of hydroxychloroquine. (LO5)
Hydroxychloroquine is a DMARD.
- Retinal damage.
List the side effects of leflunomide. (LO5)
Leflunomide is a DMARD.
- Hypertension.
- GI disturbance.
- Bone marrow suppression.
List the side effects of methotrexate. (LO5)
Methotrexate is a DMARD.
- GI disturbance.
- Oral ulcers.
- Raised liver enzymes.
- Pneumonitis.
- Bone marrow suppression.
List the side effects of D-penicillamine. (LO5)
D-penicillamine is a DMARD.
- Rash.
- Proteinuria.
- Bone marrow suppression.
List the side effects of sulphasalazine. (LO5)
Sulphasalazine is a DMARD.
- GI disturbance.
- Raised liver enzymes.
- Bone marrow suppression.
Describe the monitoring required of patients on methotrexate. (LO5)
- Full blood count, liver function test and renal function test every 4-8 weeks.
Describe what is meant by therapy using biologics for rheumatoid arthritis. (LO5)
- DMARDs are non-biologics.
- Biologics target inflammatory mediators of rheumatoid arthritis.
- They’re widely used.
- They either target TNF-α or other cytokines at different stages.
List some agents inhibiting TNF-α in rheumatoid arthritis. (LO5)
- Etanerpt - soluble TNF-α receptor.
- Infliximab - monoclonal antibody against TNF-α.
- Adalimumab - monoclonal antibody against TNF-α.
List some drugs that manipulate other cytokines in rheumatoid arthritis. (LO5)
- Rituximab - monoclonal antibody against B-cells, used when TNF-α treatment has failed.
- Abatacept is a T-cell co-stimulation modulator.
List some inflammatory markers. (LO6)
- Erythrocyte sedimentation rate (ESR).
- C-reactive protein (CRP).
- Fibrinogen and fibrinogen-derived peptides.
Others:
- Urea and electrolytes.
- Liver function tests.
- Plasma viscosity.
List some inflammatory markers found in a full blood count. (LO6)
- Normocytic anaemia.
- Microcytic anaemia.
- Haemolytic anaemia.
- Macrocytic anaemia.
- Reactive thrombocytosis.
- WBC count.
Describe how normocytic anaemia can be used as an inflammatory marker. (LO6)
- May show chronic inflammation or traumatic blood loss.
- Normocytic just means low blood cell count but the cells are of normal shape and size.
- This is not due to the other type of anaemia.
Describe how microcytic anaemia can be used as an inflammatory marker. (LO6)
- Smaller red blood cells can be seen.
- NSAIDs and chronic GI blood loss can contribute to this.
