🩻MSK🩻 - Inflammatory & Rheumatoid Arthritis Flashcards
What are the 2 types of arthritis?
Osteoarthritis (degenerative arthritis)
Inflammatory arthritis
What are the signs of joint inflammation?
Red
Hot/warm
Swelling/fluid
What are the causes of joint inflammation?
Infection - septic arthritis, TB
Crystal arthritis - gout, pseudogout
Autoimmune
Which causes of joint inflammation fall into which category of inflammation?
Infection + crystal arthritis - secondary inflammation
Immune-mediated (autoimmune) - primary
Which causes of joint inflammation are sterile and which are not?
Crystal + autoimmune - sterile
Infection - non-sterile
How is degenerative arthritis immediately distinguishable from inflammatory conditions upon investigation?
No inflammation (red, hot, swollen joint)
Slow speed of onset
Synovial fluid analysis - sterile, no inflammatory cells
Normal CRP
Normal WCC
What would you see in a synovial fluid analysis of the inflammatory causes of arthritis?
Autoimmune - inflammatory cells, sterile
Crystal - inflammatory cells, sterile, crystals
Septic - Inflammatory cells, bacteria
What are the expected CRP levels for the inflammatory arthritises?
Autoimmune - raised
Crystal - raised or significantly raised
Septic - significantly raised
Which is the only arthritis that causes an increased WCC?
Septic
(autoimmune and crystal arthritis can, but it is unusual)
What arthritis is an orthopaedic emergency?
Septic arthritis
What presentation (i.e. collection of symptoms) must always be treated as an emergency in arthritis?
Acute hot, swollen joint (i.e. anything suggestive of septic arthritis)
Treated as septic arthritis until proven otherwise
What investigation should be performed in the case of an acute red, hot, swollen joint?
Joint aspiration
Send fluid for gram stain and culture
What is the management for septic arthritis?
Joint washout (lavage) and IV Abx
What are the types of autoimmune arthritis?
What are the key history and examination points for arthritis?
Speed of onset/duration?
Worse or better with movement?
Prolonged morning/inactivity stiffness?
No of joints?
Size of joints?
Spinal involvement?
Pattern/symmetry?
Signs of inflammation (red, warm, swollen)
What is rheumatoid arthritis?
Chronic autoimmune disease
Primary site of pathology is the synovium - “synovitis” = inflammation of the synovial membrane
Where on the body does RA often manifest?
Outline RA in a clinical setting, including the epidemiology and key features
Common, Sex bias F:M 2:1
Age of onset usually 30-50s
Chronic, polyarthritis
Pain, swelling, early morning stiffness
May lead to joint damage and destruction - ‘joint erosions’ on radiographs
Systemic disease with extra-articular manifestations
Auto-antibodies usually detected in blood
What is the aetiology of RA?
Concordance in monozygotic vs dizygotic twines = 15%vs4% - mix of genes and environment
Female
What are some environmental factors for RA?
Smoking
Microbiome
Porphyromonas gingivalis
Poor oral health
How does smoking lead to RA?
RA and anti-citrullinated protein antibodies (ACPA)
Smoking -> citrullination of proteins in lung epithelium
P. gingivalis can also cause citrullination
(all the info we’re given on it lol)
What is the strongest genetic risk factor for RA?
HLA-DR
Explain the significance of HLA in RA
HLA,B,C (HLA1) expressed on all cells - present peptide to CD8 cells
HLA D (HLA2) expressed on APCs - present peptides to CD4 T cells
HLA class 2 association (HLA-DR4 in RA) implicates CD4 T cells and B cells - RA involves autoantibodies
Compare the implications of HLA mutations in ankylosing spondylitis vs RA
HLA class 1 association (eg HLA-B27 in Ankylosing spondylitis) implicates CD8 T cells in pathogenesis
HLA class 2 association (HLA-DR4 in RA) implicates CD4 T cells and B cells
This fits with autoantibodies (made by B cells) in RA but not in Ank Spond
Describe the pattern of join involvement in RA
Symmetrical
Polyarthritis
Affects both small and large joints, but nearly always small joints involved - particularly hands and feet
What are the most commonly affected joints in RA?
Metacarpophalangeal joints (MCP)
Proximal interphalangeal joints (PIP)
Wrists
Knees
Ankles
Metatarsophalangeal joints (MTP)
Compare hands affected by RA and OA
RA - prolonged morning and inactivity stiffness
OA - pain worse with activity
What are the systemic extra-articular features of RA?
Fatigue (very common)
Fever
Weight loss
What are some of the organ specific extra-articular features of RA?
Subcutaneous nodules
Lung disease - nodules, ILD/fibrosis, pleuritis
Ocular inflammation (e.g. episcleritis)
Vasculitis
Neuropathies
Felty’s syndrome – triad of splenomegaly, leukopenia and rheumatoid arthritis
Amyloidosis
What are the subcutaneous nodules in RA?
Central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue
~30% of patients
What are subcutaneous nodules associated with in RA?
Severe disease
Extra-articular manifestations
Rheumatoid factor
Where are the most common locations for subcutaneous nodules in RA?
Hands (e.g. PIP joints)
Ulnar border of the forearm
What occurs to the synovium in RA?
Synovium becomes a proliferated mass of tissue - pannus
Neovascularisation
Lymphangiogenesis
Infiltration of inflammatory cells
Which inflammatory cells will you find in RA?
activated B and T cells
plasma cells
mast cells
activated macrophages
Outline a healthy synovial membrane?
1-3 cell layer that lines synovial joints
Contains:
macrophage-like (type A synoviocyte)
fibroblast-like (type B synoviocyte) cells - secrete type I collagen
Functions: maintenance of synovial fluid
What are the cellular and molecular “players” involved in RA?
Autoreactive B cells
Autoreactive T cells
Cytokines - TNF-alpha, IL-6, (IL-1)
Excess of pro-inflammatory vs. anti-inflammatory cytokines (‘cytokine imbalance’)
What is the treatment for autoreactive B cells in RA?
Rituximab
What is the treatment for autoreactive T cells in RA?
Abatacept
What is the treatment for excess pro-inflammatory cytokines in RA?
anti-TNFalpha, anti-IL6R
What is the dominant pro-inflammatory cytokine in the synovium in RA?
Tumour necrosis factor-alpha (TNFα)
How does TNFα contribute to pannus formation?
Inflammatory cell recruitment
Angiogenesis
Lymphangiogenesis
How does TNFα cause joint space narrowing?
Activates chondrocytes - release matrix metalloproteases
Leads to cartilage loss - joint space narrowing
How does TNFα lead to bone less and osteopenia?
TNFα activates osteoclasts
Summarise the chain of effects of TNFα that leads to arthritis?
What are the investigations for RA?
Inflammatory response - ↑ ESR ↑ CRP
(sometimes normocytic anaemia - ACD)
Rheumatoid factor - antibodies that bind IgG
Anti-CCP antibodies
What should be noted about an isolated case of a raised RF?
RF can be positive in other autoimmune and infective conditions, and in individuals without disease.
Therefore, RF positive in the absence of clinical features does not necessarily indicate rheumatoid arthritis
Outline Anti-CCP antibodies
Most specific for rheumatoid arthritis and associated with more aggressive/erosive disease
What is the relationship between the presence of autoantibodies and presentation of symptoms?
Presence of specific autoantibodies precedes the onset of symptoms - “a storm brewing”
What would be seen in an X-ray of someone with RA?
X-rays
Radiographic features of RA:
Soft tissue swelling
Peri-articular osteopenia
Bony erosions
What is a limitation of using X-rays for RA?
Information from X-rays is limited to bony structures
Bony erosions occur only in established disease. The aim of modern therapy is to treat EARLY before erosions (permanent damage) has occurred
What image modality could be used instead of X-rays in early RA?
Ultrasound - (or MRI but is expensive and time consuming)
What would be seen in an US of someone with early RA?
Synovitis
Synovial thickening (synovial hypertrophy)
Increased blood flow (seen as doppler signal)
May detect erosions not seen on plain X-ray
What is the treatment goal of RA?
Prevent joint damage
What does the treatment goal for RA require?
Early recognition of symptoms, referral and diagnosis
Prompt initiation of treatment - joint destruction = inflammation x time
Aggressive pharmacological treatment to suppress inflammation
Multidisciplinary input where needed e.g. physiotherapy, occupational therapy, surgery
What is can be used for acute management of RA?
Glucocorticoid therapy (steroids)
Why are glucocorticoids not suitable for long term management of RA?
Adverse side effects
Many and bad
Cushing’s syndrome, CVD, Infection, Obesity/weight gain, Mania, depression, anxiety, myopathy, sleep apnoea, diabetes
Don’t need to know the list, just know its some bad shit
Outline the mechanism of glucocorticoid action
Glucocorticoids bind the glucocorticoid receptor (GR)
GR resides in cytoplasm
On binding by glucocorticoids, steroid-GR complex translocates to the nucleus and binds DNA response elements, affecting transcription
What are the methods of glucocorticoid administration?
Oral prednisolone
Intramuscular (IM) methyl prednisolone
Intravenous (IV)
Intra-articular (IA)
What is used for long-term pharmacological treatment of RA?
DMARDs - disease-modifying anti-rheumatic drugs
Immunomodulatory drugs that halt or slow the disease process
Outline the first line pharmacological therapy for a presentation of RA?
Outline second line pharmacological therapy for a presentation of RA and when you would use it
If disease still active after first line treatment
Outline the role of NSAIDs in RA management
Historically used but increasingly less relevant
Can provide partial symptom relief but do not prevent disease progression
Unfavourable long-term side-effect profile
What is the “treat to target” concept for RA treatment?
Suppress disease activity to improve outcome
How is disease activity measure?
DAS28 = composite of
no. of tender joints,
no. of swollen joints,
patient visual analogue score (VAS),
ESR (or CRP)
If DAS28 not suppressed -> escalate treatment
What are biological therapies?
Biological therapies are proteins (usually antibodies) that specifically target a protein
What are the main biological therapy target cytokines in RA?
tumour necrosis factor-alpha
IL-6
What are the cellular targets of RA biological therapy?
B cell depletion
Blocking T cell co-stimulation
How is B cell depletion achieved?
Rituximab – antibody against the B cell antigen, CD20
Given as two iv infusions, 2 weeks apart
Results in rapid depletion of peripheral B cells
How is T-cell co-stimulation blocked?
Abatacept - fusion protein - extracellular domain of CTLA-4 linked to modified Fc portion of human immunoglobulin G1
T cells require 2 signals to activate:
MHC + peptide on APC binding to TCR on T cell
CD80/CD86 on APC binding to CD28 on T cell
Abatacept blocks signal 2
What is seronegative inflammatory arthritis?
Family of conditions with overlapping clinical features and pathogenesis
Unlike rheumatoid arthritis, RF and CCP antibodies not present in blood (“seronegative”) BUT they are immune-mediated
What are the common seronegative inflammatory arthritises?
Psoriatic arthritis
Reactive arthritis
Ankylosing spondylitis
IBD-associated arthritis (not tested in exam)
What is psoriatic arthritis?
Psoriasis is an immune-mediated disease affecting the skin
Scaly red plaques on extensor surfaces (eg elbows and knees)
~10% of psoriasis patients also have joint inflammation
Rheumatoid factors not present (seronegative)
What is the immune involvement in psoriatic arthritis?
Dominant pathogenic pathway is interleukin-17/interleukin-23 (IL17-IL23)
What is the link between skin disease and joint manifestations in psoriatic arthritis?
Skin disease severity not correlated to joint manifestations
Examine skin carefully for small areas of psoriasis (NB scalp, umbilicus)
Sometimes nail changes may be only manifestation
How does psoriatic arthritis present in clinic?
Varied clinical presentations:
-Classically asymmetrical arthritis affecting IPJs
-Enthesitis (inflammation of tendon insertions)
But also can manifest as:
-Spinal and sacroiliac joint inflammation
-Oligoarthritis of large joints
-Arthritis mutilans
-Symmetrical involvement of small joints (rheumatoid pattern)
What is reactive arthritis?
Sterile inflammation in joints following infection elsewhere in the body
Which infections commonly cause reactive arthritis?
urogenital (e.g. Chlamydia trachomatis)
gastrointestinal (e.g. Salmonella, Shigella, Campylobacter infections)
Reactive arthritis may be first manifestation of HIV or hepatitis C infection
What are some important extra-articular manifestations of reactive arthritis?
Enthesitis (tendon inflammation)
Skin inflammation
Eye inflammation
What causes reactive arthritis to arise?
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
What is important to note about reactive arthritis?
Reactive arthritis NOT the same as infection in joints (septic arthritis)
What are the key differences between septic and reactive arthritis?
*Abx not indicated for joints in reactive arthritis, but may be used to treat underlying infection (e.g. if its an STI)
26 year old man
Back pain for 1 year.
Very stiff in the morning. Loosens up with exercise.
Has been taking paracetamol
Also pain in buttock region
Pain varies from R to L, sometimes both.
Bilateral Achilles tendonitis on and off
1) What other questions would you ask?
Ask “red flag” back pain symptoms
Look for evidence of extra-articular disease e.g. iritis/anterior uveitis (painful red eye, possibly blurring of vision), psoriasis etc…
26 year old man
Back pain for 1 year.
Very stiff in the morning. Loosens up with exercise.
Has been taking paracetamol
Also pain in buttock region
Pain varies from R to L, sometimes both.
Bilateral Achilles tendonitis on and off
2) What clinical signs would you look for on examination?
Look, feel, move. In particular assess for a) loss of normal lumbar lordosis of the spine b) reduced movements (e.g. restricted lumbar spine flexion – ask patient to touch toes)
Lower limb neuro exam
Systemic exam for signs of extra-articular disease eg psoriasis, uveitis….
(In back pain, important to consider non-spinal causes/referred pain eg abdominal aortic aneurysm (AAA) so exam abdomen, but the history here is not in keeping with AAA)
26 year old man
Back pain for 1 year.
Very stiff in the morning. Loosens up with exercise.
Has been taking paracetamol
Also pain in buttock region
Pain varies from R to L, sometimes both.
Bilateral Achilles tendonitis on and off
3) What are the differential diagnoses? State the one you think is most likely
History highly suggestive of inflammatory spondyloarthritis: prolonged morning stiffness suggests inflammation, with characteristic buttock pain of sacro-iliitis
Achilles symptoms - enthesis
Absence of psoriasis or IBD symptoms/signs - ankylosing spondylitis very likely
Possible but unlikely “in the real world” where patients don’t give perfect histories is a prolapsed disc
26 year old man
Back pain for 1 year.
Very stiff in the morning. Loosens up with exercise.
Has been taking paracetamol
Also pain in buttock region
Pain varies from R to L, sometimes both.
Bilateral Achilles tendonitis on and off
What investigations would you do? What might you expect them to show?
1) Bloods and 2) Imaging.
FBC, U&E, LFT - important before prescribing drugs
ESR, CRP will be helpful in determining the presence of inflammation
HLA-B27 - genetic marker of Ank Spond (not in all cases)
Imaging is most likely to secure the diagnosis
X-ray of sacro-iliac joints + lumbar spine not unreasonable - in this case likely straight to MRI spine+SIJs
26 year old man
Back pain for 1 year.
Very stiff in the morning. Loosens up with exercise.
Has been taking paracetamol
Also pain in buttock region
Pain varies from R to L, sometimes both.
Bilateral Achilles tendonitis on and off
5) For your most likely differential diagnosis, outline the likely management plan
First line - NSAIDs
NSAIDs fail - anti-TNF-alpha therapy would be second-line
Physiotherapy also important to maintain spinal range of movement
A 60 year old woman who has recently moved to the UK from abroad attends her GP surgery complaining of long-standing joint pains.
Pain affects multiple joints, but especially hands, wrists, and feet
She says she received medication for this but can’t tell you any further details of the drugs
1) Describe the abnormalities in the photo
Chronic deformity of fingers. Hyperflexion of index finger DIPJ, hyperextension of PIPJ
“Swan neck deformity”. There may be a small nodule over the thumb MCPJ
A 60 year old woman who has recently moved to the UK from abroad attends her GP surgery complaining of long-standing joint pains.
Pain affects multiple joints, but especially hands, wrists, and feet
She says she received medication for this but can’t tell you any further details of the drugs
2) What is the diagnosis?
Swan neck deformity = a sign of chronic rheumatoid arthritis (can also occur in lupus, but less commonly)
A 60 year old woman who has recently moved to the UK from abroad attends her GP surgery complaining of long-standing joint pains.
Pain affects multiple joints, but especially hands, wrists, and feet
She says she received medication for this but can’t tell you any further details of the drugs
3) What tests would you do?
Bloods and imaging
Bloods: FBC, U&E, LFT, ESR, CRP
RF, CCP. (+/- ANA if any symptoms to suggest lupus or autoimmune connective tissue disease)
Imaging: x-ray hands (looking for erosions and periarticular osteopenia)
If still unsure - ultrasound helpful in detecting active synovitis
A 60 year old woman who has recently moved to the UK from abroad attends her GP surgery complaining of long-standing joint pains.
Pain affects multiple joints, but especially hands, wrists, and feet
She says she received medication for this but can’t tell you any further details of the drugs
4) What treatments do think she might have had?
Likely inadequate treatment given the deformities
Maybe she was diagnosed before biologics became available or they weren’t available or affordable in her country?
1) Can you summarise the pattern of joint involvement?
Asymmetrical, large joint oligoarthritis
2) What do you think the synovial fluid analysis will show?
Inflammatory cells but sterile
(This is not septic arthritis – afebrile, normal WCC, CRP up but not very high. Septic joint usually presents as a monoarthritis)
3) What will the rheumatoid factor test result be?
Negative – this is a classic reactive arthritis history (“seronegative arthritis” family)
4) Likely diagnosis?
Reactive arthritis
1) Describe the x-ray image
X-ray of the knee (actually the right knee – but not easy to tell that here as fibula not clearly visualise
Severe joint space narrowing medially (femur and tibia are in “bone on bone” contact)
Subchondral sclerosis (increased whiteness, indicating bony changes NB subchondral = “beneath the cartilage”)
Osteophyte at the tibia medial edge of the joint (bone spur)
2) What is the diagnosis?
Osteoarthritis
3) Describe the main pathological process in this condition?
Cartilage loss
