8.5 - Rheumatoid and other inflammatory arthritis Flashcards
1
Q
What is arthritis?
A
Disease of the joints
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
3
Q
In osteoarthritis, what does lack of joint space indicate?
A
Loss of articular cartilage leading to bone in contact with bone
4
Q
What are some causes of joint inflammation (and what type of inflammation are they)? (3)
A
- infection - septic arthritis, tuberculosis
- crystal arthritis - gout, pseudogout
- 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)
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
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
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)
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
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
10
Q
What causes septic arthritis?
A
Bacterial infection of a joint (usually caused by spread from the blood)
11
Q
Why is septic arthritis a medical emergency?
A
If untreated, it can rapidly destroy a joint
12
Q
When do we consider septic arthritis?
A
Acute hot, red, swollen joint = SEPTIC ARTHRITIS until proven otherwise
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
14
Q
What is the key investigation for diagnosis of septic arthritis?
A
Joint aspiration - send fluid for gram stain and culture (urgent)
15
Q
How is septic arthritis managed?
A
Joint washout (lavage) & IV antibiotics
16
Q
What organisms commonly cause septic arthritis - 1a recap? (3)
A
- Staphylococcus aureus
- Streptococcus
- Gonococcus
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
18
Q
What is the primary site of pathology of rheumatoid arthritis?
A
Synovium
19
Q
What is synovitis?
A
Inflammation of the synovial membrane
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
21
Q
Describe the epidemiology of rheumatoid arthritis.
A
- common: prevalence 1%
- sex bias F:M 2:1
- age of onset usually 30-50s
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)
23
Q
Is rheumatoid arthritis genetic or environmental?
A
A mixture of both
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
25
What have twin studies shown about the genetic basis of rheumatoid arthritis?
- MZ ~15% concordance
- DZ ~4% concordance
- i.e. a mixture of genes and environment (as not 100%), but genes involved
26
What environmental factors can contribute to rheumatoid arthritis? (4)
- 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
27
What is the strongest genetic risk factor for rheumatoid arthritis?
HLA-DR4
28
In rheumatoid arthritis, what is the shared epitope?
- HLA-DRbeta chain amino acids 70-74 (= 'shared epitope')
- smoking and shared epitope synergistically increase risk
29
What have genome-wide association studies shown about rheumatoid arthritis?
- 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
30
What is HLA class 1?
- 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
31
What is HLA class 2?
- 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)
32
What are the implications of HLA genetic associations in rheumatoid arthritis and ankylosing spondylitis?
- 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
33
What is the pattern of joint involvement in rheumatoid arthritis?
- symmetrical
- affects multiple joints - polyarthritis
- can affect both small and large joints, but nearly always small joints involved - particularly hands and feet
34
What are the commonest affected joints in rheumatoid arthritis? (6)
- MCP
- PIP
- wrists
- knees
- ankles
- MTP
35
Compare joint stiffness/pain and activity in rheumatoid vs osteoarthritis.
- RA - prolonged morning and inactivity stiffness
- OA - pain worse with activity
36
Compare joint involvement in rheumatoid vs osteoarthritis.
- RA - PIPs, MCPs, wrist
- DIPs spared vs OA
- symmetrical
- OA - DIPs, PIPs, thumb CMC
- MCPs spared vs RA
- asymmetrical
37
What are the extra-articular features of rheumatoid arthritis? (3 + 7)
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
What are subcutaneous nodules in rheumatoid arthritis?
- 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
What does a healthy synovial membrane consist of?
- 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
What is the synovium like in rheumatoid arthritis?
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
What is the issue with cytokines in rheumatoid arthritis?
Excess of pro-inflammatory vs anti-inflammatory cytokines (cytokine imbalance)
42
What are the cellular and molecular players involved in the pathogenesis of rheumatoid arthritis? (3)
- autoreactive B cells
- autoreactive T cells
- cytokines:
- TNF-alpha
- IL-6
- (IL-1)
43
What can we use to target autoreactive B cells in treatment for rheumatoid arthritis?
Rituximab
44
What can we use to target autoreactive T cells in treatment for rheumatoid arthritis?
Abatacept
45
What can we use to target cytokines (mainly TNF-alpha) in treatment for rheumatoid arthritis?
Anti-TNFalpha, anti-IL6R
46
What is the dominant pro-inflammatory cytokine in rheumatoid arthritis?
Tumour necrosis factor-alpha (TNF-a) in the rheumatoid synovium
47
What are the pleotropic actions of TNF-alpha in the pathogenesis of rheumatoid arthritis? (3)
- inflammatory cell recruitment, angiogenesis, lymphangiogenesis --> pannus formation
- matrix metalloproteinases --> cartilage loss
- osteoclast activation --> bone loss (erosions, osteopenia)
48
What might you see in the bloods of someone with rheumatoid arthritis?
- inflammatory response
- raised ESR and CRP
- sometimes normocytic anaemia and raised PLT
49
What autoantibodies might you see in the bloods of someone with rheumatoid arthritis? (2)
- 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
What have studies from stored samples from blood donors who later developed rheumatoid arthritis show about autoantibodies? (2)
- RF and ACPAs precede symptom onset
- ACPAs predate first clinical symptoms of RA by a median of 4.5 years
51
Describe the development of rheumatoid arthritis in terms of genetic predisposition.
Genetic predisposition (asymptomatic) --> preclinical autoimmunity (asymptomatic) --> tissue inflammation and injury (symptoms)
52
What are the radiographic (X-ray) features of rheumatoid arthritis? (3)
- soft tissue swelling
- peri-articular osteopenia (less white around joints)
- bony erosions (only occur in established disease, aim to prevent)
53
When do erosions occur in rheumatoid arthritis?
Erosions only occur in established disease - the aim of modern therapy is to treat EARLY before erosions (permanent damage) has occurred
54
What is a limitation of using X-rays for rheumatoid arthritis?
Information from X-rays is limited to bony structures
55
What is a better imaging modality than X-rays for rheumatoid arthritis?
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
What ultrasound changes are seen in rheumatoid arthritis? (3)
- synovial hypertrophy (thickening)
- increased blood flow (seen as doppler signal - corresponds to neovascularisation)
- may detect smaller erosions not seen on plain X-ray
57
Why is MRI not used commonly for imaging rheumatoid arthritis?
Can also be used but is expensive and time-consuming
58
What is the treatment goal for rheumatoid arthritis?
Prevent joint damage (irreversible)
59
What does preventing joint damage in rheumatoid arthritis management require? (4)
- 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
What are pharmacological treatment options for rheumatoid arthritis? (3)
- 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
What is the first line treatment regime for RA?
- combination DMARD therapy: usually methotrexate + hydroxychloroquine and/or sulfasalazine
- PLUS IM or short course of oral steroids
62
What is the second line treatment regime for RA, if disease is still active after combination DMARD therapy + oral steroids?
Biological therapies (usually therapeutic monoclonal antibodies) targeting specific molecules e.g. anti-TNF-alpha blockade
63
Why are NSAIDs no longer used to treat RA?
- 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
How does steroids/glucocorticoid therapy work for treating RA?
- 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
What are some methods of steroid administration? (4)
- oral prednisolone
- intramuscular (IM) methyl prednisolone
- intravenous (IV)
- intra-articular (IA)
66
What are the side effects of steroids? (1 + 10)
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
What is the concept of 'treat to target' in RA?
Suppress disease activity to improve outcome
68
How is 'treat to target' for RA achieved clinically?
| Suppress disease activity to improve outcome
- 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
What are biological therapies?
Proteins (usually antibodies) that specifically target a protein
70
What are some biologics targeting cytokines in RA? (2)
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
What are some biologics targeting lymphocytes in RA? (2)
**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
What is seronegative autoimmune arthritis?
- 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
What conditions are part of seronegative autoimmune arthritis? (4)
- psoriatic arthritis
- reactive arthritis
- ankylosing spondylitis - inflammation of spine (spondylitis) and sacro-iliac joints (sacro-iliitis)
- IBD-associated (Crohn's disease / ulcerative colitis)
74
What is the general pattern of joint involvement in seronegative autoimmune arthritis? (4)
- subacute/chronic
- mono or oligo, large joint (but psoriatic arthritis can be small joint and poly)
- may involve spine
- asymmetrical
75
What is psoriatic arthritis?
- 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
What is the dominant pathogenic pathway in psoriatic arthritis?
IL-17/IL-23
77
In psoriatic arthritis, what is the link between skin disease and joint manifestations?
- 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
How does psoriatic arthritis present clinically?
- 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
What is reactive arthritis?
Sterile inflammation in joints following infection elsewhere in the body
80
What are some common infections that can cause reactive arthritis? (2)
- urogenital (e.g. Chlamydia trachomatis)
- GI (e.g. Salmonella, Shigella, Campylobacter infections)
81
What are the important extra-articular manifestations of reactive arthritis? (3)
- enthesitis (tendon inflammation)
- skin inflammation
- eye inflammation
82
What may reactive arthritis be the first manifestation of?
May be the first manifestation of HIV or hepatitis C infection
83
Who does reactive arthritis affect commonly?
- 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
What are the differences between reactive arthritis and septic arthritis? (Synovial fluid culture, antibiotic therapy, joint lavage)
- 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
