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Year 2 - BRS > 8.5 - Rheumatoid and other inflammatory arthritis > Flashcards

8.5 - Rheumatoid and other inflammatory arthritis Flashcards

1
Q

What is arthritis?

A

Disease of the joints

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2
Q

What are the two major divisions of arthritis?

A
  • osteoarthritis (degenerative arthritis)
  • inflammatory arthritis (arthritis with signs of inflammation)
    • red, hot/warm, swelling/fluid
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3
Q

In osteoarthritis, what does lack of joint space indicate?

A

Loss of articular cartilage leading to bone in contact with bone

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4
Q

What are some causes of joint inflammation (and what type of inflammation are they)? (3)

A
  1. infection - septic arthritis, tuberculosis
  2. crystal arthritis - gout, pseudogout
  3. immune-mediated (autoimmune) - rheumatoid arthritis, psoriatic arthritis, reactive arthritis, SLE
  • 1+2 = secondary inflammation in response to a noxious insult
  • 3 = primary inflammation
  • 2+3 = sterile inflammation (1 is non-sterile inflammation)
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5
Q

Compare inflammation in degenerative (osteoarthritis) vs immune-mediated vs crystal arthritis vs septic arthritis.

A
  • OA: none/little
  • IM: yes - autoimmune
  • CA: yes - secondary to crystals
  • SA: yes - secondary to infection
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6
Q

Compare speed of onset in degenerative (osteoarthritis) vs immune-mediated vs crystal arthritis vs septic arthritis.

A
  • OA: slow
  • IM: sub-acute
  • CA: rapid
  • SA: rapid
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7
Q

Compare synovial fluid analysis in degenerative (osteoarthritis) vs immune-mediated vs crystal arthritis vs septic arthritis.

A
  • OA: no inflammatory cells, sterile
  • IM: inflammatory cells, sterile
  • CA: inflammatory cells, sterile, crystals
  • SA: inflammatory cells, bacteria (not sterile)
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8
Q

Compare CRP in degenerative (osteoarthritis) vs immune-mediated vs crystal arthritis vs septic arthritis.

A
  • OA: normal
  • IM: high
  • CA: high/very high
  • SA: very high
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9
Q

Compare WCC in degenerative (osteoarthritis) vs immune-mediated vs crystal arthritis vs septic arthritis.

A
  • OA: normal
  • IM: usually normal
  • CA: usually normal
  • SA: high
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10
Q

What causes septic arthritis?

A

Bacterial infection of a joint (usually caused by spread from the blood)

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11
Q

Why is septic arthritis a medical emergency?

A

If untreated, it can rapidly destroy a joint

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12
Q

When do we consider septic arthritis?

A

Acute hot, red, swollen joint = SEPTIC ARTHRITIS until proven otherwise

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13
Q

How is septic arthritis presented clinically? (1a recap)

A
  • acute red, hot, painful, swollen joint
  • usually only one joint affected (monoarthritis) - gonococcal septic arthritis is an exception which often affects multiple joints (polyarthritis) and is less likely to cause joint destruction
  • typically fever + patient often systemically unwell
  • consider septic arthritis in any patient with an acute painful, red, hot, swelling of a joint, especially if there is a fever
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14
Q

What is the key investigation for diagnosis of septic arthritis?

A

Joint aspiration - send fluid for gram stain and culture (urgent)

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15
Q

How is septic arthritis managed?

A

Joint washout (lavage) & IV antibiotics

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16
Q

What organisms commonly cause septic arthritis - 1a recap? (3)

A
  • Staphylococcus aureus
  • Streptococcus
  • Gonococcus
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17
Q

What is rheumatoid arthritis?

A

Chronic autoimmune disease characterised by pain, stiffness and symmetrical synovitis (inflammation of the synovial membrane) of synovial joints

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18
Q

What is the primary site of pathology of rheumatoid arthritis?

A

Synovium

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19
Q

What is synovitis?

A

Inflammation of the synovial membrane

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20
Q

Where is the synovium found (and therefore where is the primary site of pathology of rheumatoid arthritis)? (3)

A
  • synovial joints - e.g. proximal inter-phalangeal (PIP) joint synovitis
  • tenosynovium surrounding tendons - e.g. extensor tenosynovitis - patient cannot fully extend little and ring fingers
  • bursa - fluid filled sacs that provide lubrication for easy movement e.g. olecranon bursitis
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21
Q

Describe the epidemiology of rheumatoid arthritis.

A
  • common: prevalence 1%
  • sex bias F:M 2:1
  • age of onset usually 30-50s
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22
Q

What are the key features of rheumatoid arthritis?

A
  • chronic arthritis:
    • polyarthritis
    • symmetrical
    • pain, swelling and early morning stiffness in and around joints (around 30 min) - vs in OA<30min + better with movement
    • may lead to joint damage and destruction - ‘joint erosions’ on radiographs
  • systemic disease with extra-articular manifestations
  • autoantibodies usually detected in blood (e.g. rheumatoid factor)
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23
Q

Is rheumatoid arthritis genetic or environmental?

A

A mixture of both

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24
Q

How can we use twin studies to estimate the contributions of genetics vs environment?

A
  • look at concordance of a trait in monozygotic vs dizygotic twins
    • look at pairs of twins - ask if one twin has the disease, how often does the other?
  • if the concordance rate for MZ > DZ twins, this indicates a genetic component
  • if the disease was purely genetic, the concordance rate would be 100% for MZ twins
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25
Q

What have twin studies shown about the genetic basis of rheumatoid arthritis?

A
  • MZ ~15% concordance
  • DZ ~4% concordance
  • i.e. a mixture of genes and environment (as not 100%), but genes involved
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26
Q

What environmental factors can contribute to rheumatoid arthritis? (4)

A
  • smoking (can cause citrullination of proteins in lung epithelium –> ACPA)
  • microbiome
  • Porphyromonas gingivalis (can cause citrullination of proteins in lung epithelium –> ACPA)
  • poor oral health
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27
Q

What is the strongest genetic risk factor for rheumatoid arthritis?

A

HLA-DR4

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28
Q

In rheumatoid arthritis, what is the shared epitope?

A
  • HLA-DRbeta chain amino acids 70-74 (= ‘shared epitope’)
  • smoking and shared epitope synergistically increase risk
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29
Q

What have genome-wide association studies shown about rheumatoid arthritis?

A
  • 100 other genetic loci (other than HLA-DR) contribute to RA risk (polygenic) e.g. PTPN22, IL6R
  • effect of a risk allele at any given locus typically modest (small effect)
  • cumulative genetic burden rather than any one variant determines risk
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30
Q

What is HLA class 1?

A
  • HLA A, B and C
  • HLA class 1 expressed on all cells
  • cells present peptide in association with HLA class 1 to CD8 (killer) T cells
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31
Q

What is HLA class 2?

A
  • HLA D
  • HLA class 2 only expressed on professional antigen presenting cells including dendritic cells, macrophages, B cells
  • APCs present peptide in association with HLA class 2 to CD4 (helper) T cells
  • CD4 T cells provide ‘help’ to B cells (–> antibodies)
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32
Q

What are the implications of HLA genetic associations in rheumatoid arthritis and ankylosing spondylitis?

A
  • HLA class 1 association (e.g. HLA-B27 in AS) implicates CD8 T cells in pathogenesis
  • HLA class 2 association (e.g. HLA-DR4 in RA) implicates CD4 T cells and B cells
  • this fits with autoantibodies (made by B cells) in RA but not in AS
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33
Q

What is the pattern of joint involvement in rheumatoid arthritis?

A
  • symmetrical
  • affects multiple joints - polyarthritis
  • can affect both small and large joints, but nearly always small joints involved - particularly hands and feet
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34
Q

What are the commonest affected joints in rheumatoid arthritis? (6)

A
  • MCP
  • PIP
  • wrists
  • knees
  • ankles
  • MTP
35
Q

Compare joint stiffness/pain and activity in rheumatoid vs osteoarthritis.

A
  • RA - prolonged morning and inactivity stiffness
  • OA - pain worse with activity
36
Q

Compare joint involvement in rheumatoid vs osteoarthritis.

A
  • RA - PIPs, MCPs, wrist
    • DIPs spared vs OA
    • symmetrical
  • OA - DIPs, PIPs, thumb CMC
    • MCPs spared vs RA
    • asymmetrical
37
Q

What are the extra-articular features of rheumatoid arthritis? (3 + 7)

A

Systemic inflammation:

  • fatigue
  • fever
  • weight loss

Organ-specific:

  • subcutaneous nodules
  • lung disease - nodules, ILD/pulmonary fibrosis, pleuritis
  • ocular inflammation e.g. episcleritis
  • vasculitis
  • neuropathies
  • Felty’s syndrome (triad of splenomegaly, leukopenia and RA)
  • amyloidosis
38
Q

What are subcutaneous nodules in rheumatoid arthritis?

A
  • characterised by central area of fibrinoid necrosis surrounded by histiocytes (macrophages) and peripheral layer of connective tissue
  • occur in 30% of patients
  • associated with: severe disease, extra-articular manifestations, rheumatoid factor
  • common locations: just distal to elbow and on fingers
39
Q

What does a healthy synovial membrane consist of?

A
  • 1-3 cell deep lining containing:
    • macrophage-like phagocytic cells (type A synoviocyte)
    • fibroblast-like cells that produce hyaluronic acid (type B synoviocyte)
    • type I collagen
40
Q

What is the synovium like in rheumatoid arthritis?

A

Synovium becomes a proliferated mass of tissue (pannus) due to:

  • neovascularisation
  • lymphangiogenesis
  • inflammatory cells: activated B and T cells, plasma cells, mast cells, activated macrophages
41
Q

What is the issue with cytokines in rheumatoid arthritis?

A

Excess of pro-inflammatory vs anti-inflammatory cytokines (cytokine imbalance)

42
Q

What are the cellular and molecular players involved in the pathogenesis of rheumatoid arthritis? (3)

A
  • autoreactive B cells
  • autoreactive T cells
  • cytokines:
    • TNF-alpha
    • IL-6
    • (IL-1)
43
Q

What can we use to target autoreactive B cells in treatment for rheumatoid arthritis?

44
Q

What can we use to target autoreactive T cells in treatment for rheumatoid arthritis?

45
Q

What can we use to target cytokines (mainly TNF-alpha) in treatment for rheumatoid arthritis?

A

Anti-TNFalpha, anti-IL6R

46
Q

What is the dominant pro-inflammatory cytokine in rheumatoid arthritis?

A

Tumour necrosis factor-alpha (TNF-a) in the rheumatoid synovium

47
Q

What are the pleotropic actions of TNF-alpha in the pathogenesis of rheumatoid arthritis? (3)

A
  • inflammatory cell recruitment, angiogenesis, lymphangiogenesis –> pannus formation
  • matrix metalloproteinases –> cartilage loss
  • osteoclast activation –> bone loss (erosions, osteopenia)
48
Q

What might you see in the bloods of someone with rheumatoid arthritis?

A
  • inflammatory response
  • raised ESR and CRP
  • sometimes normocytic anaemia and raised PLT
49
Q

What autoantibodies might you see in the bloods of someone with rheumatoid arthritis? (2)

A
  • rheumatoid factor (RF) = antibodies that bind to IgG
    • RF can be positive in other autoimmune and infective conditions, and in individuals without disease
    • therefore RF +ve in the absence of clinical features does not necessarily indicate RA
  • anti-CCP antibodies - most specific for RA, associated with more aggressive/erosive disease
50
Q

What have studies from stored samples from blood donors who later developed rheumatoid arthritis show about autoantibodies? (2)

A
  • RF and ACPAs precede symptom onset
  • ACPAs predate first clinical symptoms of RA by a median of 4.5 years
51
Q

Describe the development of rheumatoid arthritis in terms of genetic predisposition.

A

Genetic predisposition (asymptomatic) –> preclinical autoimmunity (asymptomatic) –> tissue inflammation and injury (symptoms)

52
Q

What are the radiographic (X-ray) features of rheumatoid arthritis? (3)

A
  • soft tissue swelling
  • peri-articular osteopenia (less white around joints)
  • bony erosions (only occur in established disease, aim to prevent)
53
Q

When do erosions occur in rheumatoid arthritis?

A

Erosions only occur in established disease - the aim of modern therapy is to treat EARLY before erosions (permanent damage) has occurred

54
Q

What is a limitation of using X-rays for rheumatoid arthritis?

A

Information from X-rays is limited to bony structures

55
Q

What is a better imaging modality than X-rays for rheumatoid arthritis?

A

Ultrasound is a much better test for detecting synovitis - (US, usually of hands and wrists, can be performed alongside clinical assessment in a dedicated early arthritis clinic)

56
Q

What ultrasound changes are seen in rheumatoid arthritis? (3)

A
  • synovial hypertrophy (thickening)
  • increased blood flow (seen as doppler signal - corresponds to neovascularisation)
  • may detect smaller erosions not seen on plain X-ray
57
Q

Why is MRI not used commonly for imaging rheumatoid arthritis?

A

Can also be used but is expensive and time-consuming

58
Q

What is the treatment goal for rheumatoid arthritis?

A

Prevent joint damage (irreversible)

59
Q

What does preventing joint damage in rheumatoid arthritis management require? (4)

A
  • early recognition of symptoms, referral and diagnosis
  • prompt initiation of treatment: joint destruction = inflammation x time
  • aggressive pharmacological treatment to suppress inflammation
  • MDT input where needed e.g. physiotherapy, occupational therapy, surgery
60
Q

What are pharmacological treatment options for rheumatoid arthritis? (3)

A
  • glucocorticoid therapy (steroids) - useful acutely but avoid long-term use due to side-effects
  • (NSAIDs e.g. ibuprofen - symptom relief but increasingly less important)
  • DMARDs (disease-modifying anti-rheumatic drugs) - immunomodulatory drugs that halt/slow the disease process (usually immunosuppressive)
61
Q

What is the first line treatment regime for RA?

A
  • combination DMARD therapy: usually methotrexate + hydroxychloroquine and/or sulfasalazine
  • PLUS IM or short course of oral steroids
62
Q

What is the second line treatment regime for RA, if disease is still active after combination DMARD therapy + oral steroids?

A

Biological therapies (usually therapeutic monoclonal antibodies) targeting specific molecules e.g. anti-TNF-alpha blockade

63
Q

Why are NSAIDs no longer used to treat RA?

A
  • e.g. ibuprofen, naproxen, diclofenac
  • historically used but increasingly less relevant
  • can provide partial symptom relief but do not prevent disease progression
  • unfavourable long-term side-effect profile
64
Q

How does steroids/glucocorticoid therapy work for treating RA?

A
  • glucocorticoids bind the glucocorticoid receptor (GR)
  • GR resides in cytoplasm
  • on binding to glucocorticoids, steroid-GR complex translocates to nucleus and binds DNA response elements, affecting transcription
65
Q

What are some methods of steroid administration? (4)

A
  • oral prednisolone
  • intramuscular (IM) methyl prednisolone
  • intravenous (IV)
  • intra-articular (IA)
66
Q

What are the side effects of steroids? (1 + 10)

A

Cushing’s syndrome

  • mood disturbance - mania, depression, anxiety
  • cataracts
  • sleep apnoea (weight gain)
  • increased BP, CVD risk
  • T2DM
  • weight gain, central obesity
  • osteoporosis
  • skin thinning
  • myopathy
  • increased infection risk
67
Q

What is the concept of ‘treat to target’ in RA?

A

Suppress disease activity to improve outcome

68
Q

How is ‘treat to target’ for RA achieved clinically?

Suppress disease activity to improve outcome

A
  • regular objective measurement of disease activity e.g. DAS28 score
  • DAS28 score = composite of no. of tender joints, no. of swollen joints, patient visual analogue score (VAS), ESR (or CRP)
  • if DAS28 not suppressed, escalate treatment
69
Q

What are biological therapies?

A

Proteins (usually antibodies) that specifically target a protein

70
Q

What are some biologics targeting cytokines in RA? (2)

A
  1. inhibition of TNF-alpha (anti-TNF)
    - antibodies: infliximab, adalimumab, golimumab, certolizumab
    - fusion proteins: etanercept
  2. inhibition of IL-6 signalling
    - antibodies against IL-6 receptor:
    - tocilizumab (RoActemra)
    - sarilumab (Kevzara)
71
Q

What are some biologics targeting lymphocytes in RA? (2)

A

1. B cell depletion
- rituximab - antibody against the B cell antigen CD20
- given as two IV infusions, two weeks apart
- results in rapid depletion of peripheral B cells
- usually repopulate after 6-9 months
- side effects: infusion reactions, infection, hypogammaglobulinaemia
2. blocking T cell co-stimulation
- abatacept - fusion protein - extracellular domain of CTLA-4 linked to modified Fc portion of human immunoglobulin G1
- T cells require two signals to activate:
- i) MHC + peptide on APC binding to TCR on T cell
- ii) CD80/CD86 on APC binding to CD28 on T cell
- abatacept blocks signal ii)

72
Q

What is seronegative autoimmune arthritis?

A
  • family of conditions with overlapping clinical features and pathogenesis
  • unlike RA, RF and CCP antibodies are not present in blood (‘seronegative’)
  • but they are still immune-mediated
73
Q

What conditions are part of seronegative autoimmune arthritis? (4)

A
  • psoriatic arthritis
  • reactive arthritis
  • ankylosing spondylitis - inflammation of spine (spondylitis) and sacro-iliac joints (sacro-iliitis)
  • IBD-associated (Crohn’s disease / ulcerative colitis)
74
Q

What is the general pattern of joint involvement in seronegative autoimmune arthritis? (4)

A
  • subacute/chronic
  • mono or oligo, large joint (but psoriatic arthritis can be small joint and poly)
  • may involve spine
  • asymmetrical
75
Q

What is psoriatic arthritis?

A
  • psoriasis is an immune-mediated disease affecting the skin
  • scaly red plaques on extensor surfaces (e.g. elbows and knees)
  • 10% of psoriasis patients also have joint inflammation
  • unlike RA, rheumatoid factors are not present (seronegative)
76
Q

What is the dominant pathogenic pathway in psoriatic arthritis?

A

IL-17/IL-23

77
Q

In psoriatic arthritis, what is the link between skin disease and joint manifestations?

A
  • skin disease severity is not correlated to joint manifestations
  • examine skin carefully for small areas of psoriasis (NB scalp, umbilicus)
  • sometimes nail changes may be only manifestation e.g. nail pitting, onycholysis
78
Q

How does psoriatic arthritis present clinically?

A
  • varied clinical presentations
  • classically asymmetrical arthritis affecting IPJs (MCPs not affected unlike RA)
  • enthesitis (inflammation of tendon insertions) –> can cause dactylitis (sausage finger)

But can also manifest as:

  • spinal and sacroiliac joint inflammation
  • oligoarthritis of large joints
  • arthritis mutilans
  • symmetrical involvement of small joints (rheumatoid pattern)
79
Q

What is reactive arthritis?

A

Sterile inflammation in joints following infection elsewhere in the body

80
Q

What are some common infections that can cause reactive arthritis? (2)

A
  • urogenital (e.g. Chlamydia trachomatis)
  • GI (e.g. Salmonella, Shigella, Campylobacter infections)
81
Q

What are the important extra-articular manifestations of reactive arthritis? (3)

A
  • enthesitis (tendon inflammation)
  • skin inflammation
  • eye inflammation
82
Q

What may reactive arthritis be the first manifestation of?

A

May be the first manifestation of HIV or hepatitis C infection

83
Q

Who does reactive arthritis affect commonly?

A
  • young adults with genetic predisposition (e.g. HLA-B27) and environmental trigger (e.g. Salmonella infection)
  • symptoms follow 1-4 weeks after infection and this infection may be mild
84
Q

What are the differences between reactive arthritis and septic arthritis? (Synovial fluid culture, antibiotic therapy, joint lavage)

A
  • reactive arthritis not the same as septic arthritis where there is active infection in joint - with reactive arthritis it is sterile = infection has cleared
  • synovial fluid culture: +ve for SA, sterile for RA
  • antibiotic therapy: yes for SA, no for RA
  • joint lavage: yes (for large joints) for SA, no for RA

Year 2 - BRS (84 decks)

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