1B rheumatoid arthritis and other inflammatory diseases Flashcards
What is arthritis?
Disease of the joints
What are the two major divisions of arthritis?
- Osteoarthritis (degenerative)
- Arthritis with signs of inflammation
What are some clinical examination signs of joint inflammation?
- Red
- Hot/warm
- Swelling/fluid
What are the causes of joint inflammation?
1) Infection: Septic arthritis, TB
2) Crystal arthritis: Gout, Pseudogout
3) Immune-mediated (autoimmune)
Infection and crystal arthritis are secondary inflammations in response to a noxious insult.
Immune-mediated arthritis is referred to as ‘primary inflammation’.
What are the distinguishing features of the different types of arthritis?
What is septic arthritis?
An orthopaedic emergency
What are the clinical features of septic arthritis?
Acute hot, swollen joint = SEPTIC ARTHRITIS until proven otherwise
What are the key investigations for septic arthritis?
- Joint aspiration
- Send fluid for Gram stain and culture
What is the management for septic arthritis?
- Joint lavage
- IV antibiotics
What is rheumatoid arthritis?
A chronic autoimmune disease causing synovial inflammation (synovitis)
Where is the primary site of pathology of RA?
Synovium found at:
- Synovial (diarthrodial) joints
- Tenosynovium surrounding tendons
- Bursa
What does this show?
Proximal inter-phalangeal joint synovitis
What does this show?
Extensor tensoynovitis: swelling is not above either the wrist or MCP joints
The patient has incomplete extension of the little and ring fingers (cannot stick the fingers out straight)- this is consistent with extensor tendon damage by the tenosynovitis
What does this show?
Olecranon bursitis
What is the age of onset for RA?
30-50s
What are the key features of RA?
- Chronic arthritis:
- polyarthritis
- pain, swelling and early MORNING STIFFNESS in and around joints
- may lead to joint damage and destruction: ‘joint erosions’ on radiographs
- Systemic disease with extra-articular manifestations
- Auto-antibodies usually detected in blood
Describe the aetiology of RA
There is a mixture of genetic and environmental impact.
Environmental factors include:
- Smoking
- Microbiome
- Porphyromonas gingivalis
- Poor oral health
What is ACPA?
Anti-citrullinated protein antibodies (ACPA)
Smoking causes citrullination of proteins in lung epithelium. P. gingivalis can also cause citrullination.
What is the strongest genetic risk factor for RA?
HLA-DR
HLA-DRb chain amino acids 70-74 (‘shared epitope’). Smoking & shared epitope synergistically increase risk
What other genetic factors other than HLA-DR are there for RA?
- 100 other genetic loci that contribute to RA risk (polygenic), e.g. PTPN22, IL6R
- Effect of a risk allele at any given locus typically modest
- Cumulative genetic burden rather than any one variant determines risk
How is a GWAS done?
- Compare allelic frequencies at a given genetic single nucleotide polymorphism (SNP) between cases vs controls
- Repeat across the genomes for millions of SNPs
- Identify the SNPs associated with disease risk
What are the implications of HLA genetic associations?
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 joint involvement in RA
- Symmetrical
- Affects multiple joints (polyarthritis)
- Can affect 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)
Describe the difference in presentation in hands between RA and OA
What are systemic extra-articular features of RA?
- Fatigue (v common)
- Fever
- Weight loss
What are organ-specific extra-articular features of RA?
- Subcutaneous nodules
- Lung disease – nodules, interstitial lung disease (ILD)/ fibrosis, pleuritis
- Ocular inflammation e.g. episcleritis
- Vasculitis
- Neuropathies
- Felty’s syndrome – triad of splenomegaly, leukopenia and rheumatoid arthritis
- Amyloidosis
What are subcutaneous nodules?
Central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue.
Occur in ~30% patients
What are subcutaneous nodules associated with?
- Severe disease
- Extra-articular manifestations
- Rheumatoid factor
What does this show?
Rheumatoid nodules in the hands – another common location and not easily missed. Here you can see them around the PIP joint of the right index and left index, middle and ring fingers
What does this show?
Rheumatoid nodule – this is typical position (ulnar border of forearm) where you might detect nodules. If they are present it confirms the diagnosis of rheumatoid arthritis and is invariably associated with rheumatoid factor. Do not forget to examine this area carefully in patients with polyarthritis – it would be foolish to miss such an important clinical finding
Describe the histopathology of a healthy synovial membrane
1-3 cell layer that lines synovial joints
Contains:
- macrophage-like (type A synoviocyte)
- fibroblast-like (type B synoviocyte) cells
- type I collagen
What is the function of the synovial membrane?
Maintenance of synovial fluid
Describe the histopathological changes in RA
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
Describe the pathology of RA and a cellular and molecular level
- Autoreactive B cells
- Autoreactive T cells
- Cytokines
- TNF-alpha
- IL-6
- IL-1
XS pro-inflammatory vs anti-inflammatory cytokines (‘cytokine imbalance’)
What treatment is given for autoreactive B cells?
Rituximab
What treatment is given for autoreactive T cells?
Abatacept
What treatment is given for the cytokines in RA?
- anti-TNF-alpha
- anti-IL6R
What is TNF-alpha?
The cytokine tumour necrosis factor-alpha (TNFα) is the dominant pro-inflammatory cytokine in the rheumatoid synovium
How does TNF-alpha cause RA?
Its pleotropic actions are detrimental in this setting:
- Inflammatory cell recruitment, angiogenesis, lymphangiogenesis -> Pannus formation
- Matrix metalloproteases -> Cartilage loss
- Osteoclast activation -> Bone loss (erosions, osteopenia)
What bloods are investigated in RA?
- Inflammatory response
- ↑ ESR ↑ CRP
- Sometimes normocytic anaemia
- ↑PLT
- Autoantibodies
- Rheumatoid factor (RF) = antibodies that bind IgG
- Anti-CCP antibodies
Are RFs a good indicator for RA?
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
CCP antibodies most specific for rheumatoid arthritis and associated with more aggressive/erosive disease
Which antibodies precede symptom onset in RA?
- RF and ACPAs
- ACPAs predate first clinical symptoms of RA by a median of 4.5 years
What are radiographic features of RA?
- Soft tissue swelling
- Peri-articular osteopenia
- Bony erosions
- erosions only occur in established disease. Modern therapy aims to treat EARLY before erosions (permanent damage)
What US changes in RA are there?
- Synovial thickening (synovial hypertrophy)
- Increased blood flow (seen as doppler signal)
- May defect erosions not seen on plain X-Ray
What is the treatment goal of RA?
Prevent joint damage
What does management of RA require?
- Early recognition of symptoms, referral and diagnosis
- Prompt initiation of treatment: joint destruction = inflammation x time
- Aggressive pharmacological treatment to suppress inflammation
What pharmacological treatment is given for RA?
- Glucocorticoid therapy (‘steroids’) useful acutely but avoid long-term use because of side-effects.
- DMARDs’ = disease-modifying anti-rheumatic drugs
- Immunomodulatory drugs that halt or slow the disease process
Give three examples of NSAIDs and explain their relevance in RA management
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
What is ‘treat to target’?
Suppress disease activity to improve outcome
How is ‘treat to target’ achieved?
Achieved by regular objective measurement of disease activity e.g. DAS28 score
What are biological therapies?
Proteins (usually Abs) that specifically target a protein
Give two biologics for RA targeting cytokines classes and list examples for each
- Inhibition of tumour necrosis factor-alpha (anti-TNF)
- antibodies (infliximab, adalimumab, golimumab, certolizumab)
- fusion proteins (etanercept)
- Inhibition of interleukin-6 (IL-6 inhibition) signalling
- antibodies against IL-6 receptor (tocilizumab; RoActemra)(Sarilumab; Kevzara)
Give two biologics targeting lymphocyte classifications and examples of each
- B-Cell depletion
- Rituximab: Ab against B cell antigen CD20
- Blocking T cell co-stimulation
- Abatacept: fusion protein- extracellular domain of CTLA-4 linked to modified Fc portion of human immunoglobulin G1
How is rituximab given and what does it result in?
- Two IV infusions; 2 weeks apart
- Results in rapid depletion of peripheral B cells
- Usually repopulate after ~6-9 months
What are side effects of rituximab?
Infusion reactions, infection, hypogammaglobulinaemia
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 is psoriasis?
- 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
What is the dominant pathogenic pathway of psoriatic arthritis?
IL-17, IL-23
Describe the relation between skin disease severity and joint manifestations
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
Describe clinical presentations of psoriatic arthritis
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 does this radiograph show?
Asymmetrical pattern of joint involvement
Erosions of interphalangeal joints (IPJs)
MCPJs not affected (unlike RA)
What does this radiograph show?
Dactylitis (‘sausage finger’)
due to enthesitis
What is reactive arthritis?
Sterile inflammation in joints following infection elsewhere in the body
What are common infections of reactive arthritis?
- Urogenital (e.g. Chlamydia trachomatis)
- GI (e.g. salmonella, shigella, campylobacter)
Reactive arthritis may be first manifestation of HIV or hep C infection
What are some important extra-articular manifestations of reactive arthritis?
- Enthesitis (tendon inflammation)
- Skin inflammation
- Eye inflammation
How long do symptoms show for reactive arthritis?
- Symptoms follow 1-4 weeks after infection and this infection may be mild
- Reactive arthritis NOT the same as infection in joints (septic arthritis)
How do glucocorticoids work?
- 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
How are glucocorticoid steroids administered?
- Oral prednisolone
- Intramuscular (IM) methyl prednisolone
- Intravenous (IV)
- Intra-articular (IA)
What are side effects of steroids?
Many and bad!
Cushing’s syndrome
