U11C3 Rheumatoid Arthritis Flashcards
What is rheumatoid arthritis (RA)?
- Systemic autoimmune disease that is characterised by chronic inflammation of the synovial joints.
- Affect multiple symmetrical joints
- Leads to progressive destruction of the synovial joints through loss of cartilage and bone.
- Results in loss of function and disability, reduced quality of life, increased comorbidity and often a shortened life expectancy.
Healthy vs RA joint
Healthy synovium-
- has a thin lining typically 1-2 cells thick
- consists of macrophage like synovial cells (type 1) and fibroblast synovial like cells (type 2)
- synovial sublining is loose connective tissue tissue with numerous blood and lymphatics vessels
RA synovium-
- lining layer has been come thick to around 6-8 cells, hyperplasia (increase proliferation of synovial cell) and hypertrophy (increase in synovial cell size)
What are the 5 main steps of the pathophysiology of RA?
- Infiltration of synovium by inflammatory cells and proliferation of synovial cells
- Increase in blood vessel formation
- Increased chemokine production and upregulation of adhesion molecules expression on vascular endothelium
- Cytokine production initiates matrix metalloproteinases (MMPs) release leading to degradation of matrix
- Pannus formation
What happens in infiltration of synovium ? (1)
by inflammatory cells and proliferation of synovial cells
- Occurs via trafficking of leukocytes out of blood vessels through a process called leukocyte extravasation
- A response to inflammatory signals produced within the synovial tissue - promote a change in the adhesiveness of endothelial cells lining blood vessels
- Leukocytes recruited include neutrophils, monocytes, mast cells, T-cells and B-cells
- The process consists of four sequential steps:
How is blood vessel formation increased? (2)
- Synovial hypoxia is a consequence of the hyperproliferative synovium with increased consumption of oxygen in RA (20 times) and reduced blood flow
- Response to hypoxia and the increased metabolic demands of the synovial tissue activate hypoxia-inducible factor (HIF), leading to the release of pro-angiogenic factors
- Pro-inflammatory cytokines (TNF-α and IL-1β) within RA joint are angiogenic
- Increased angiogenesis in RA
How is chemokine production increased and upregulation of adhesion molecules expression on vascular endothelium? (3)
- CXCL8 (IL-8), CXCL5 and CXCL1 are important in RA. Abundant in synovial tissue, synovial fluid and blood. Produced by macrophages
- Upon TNFα activation of vascular endothelium, E-selectin and ICAM expression upregulated, leading to increased leukocyte recruitment from the circulation into RA synovium
- CCL2 (MCP-1) potent chemoattractant for monocytes via CCR2
- CCL3 (MIP-1α) recruits monocytes, lymphocytes, basophils and eosinophils via CCR1,5
- CCL5 (RANTES) recruitment of lymphocytes and monocytes via CCR1,3 and 5
What is the result of cytokine production? (4)
What is pannus formation?
-
describes the hyperproliferative, inflammatory invasive vascularised tissue mass that is a hallmark feature of the joint in RA
- Consists of macrophage-like & fibroblast-like synovial cells in the synovial tissue and the large number of infiltrating leukocytes (CD4+ T lymphocytes, B cells, plasma cells and dendritic cells)
- Develops from the normal synovium & invades cartilage and bone
- Fibroblast-like synovial cells and activated chondrocytes produce MMPs, ADAMTS, pro-inflammatory cytokines and prostaglandins leading to cartilage degradation
- Fibroblast-like synovial cells and T-lymphocytes secrete RANKL which activates osteoclasts to destroy bone
What is the genetic factor associated with RA?
Thehuman leukocyte antigen(HLA) system or complex is a group of related proteins that are encoded by themajor histocompatibility complex(MHC)gene complexin humans
- RA is associated with the HLA-DRB1 gene. In particular, with DRB1 alleles encoding the shared epitope (SE): is a sequence of 5 amino acids common to HLA-DRB1 alleles known to confer increased risk of RA…….QKRAA, QRRAA or RRRAA
- The SE is located in the 3rd hypervariable region of the β1 domain, amino acids 70 – 74, within the peptide-binding cleft (groove) of the MHC class II molecule
- The amino acid side chains are important in the context of antigen binding and TCR interaction
- Multiple genes outside the HLA region have been associated with RA, primarily with an increased risk of developing the disease- PTPN22, PADI4, STAT4, CTLA4, IL2 and CD40 (encode proteins important for immune system function) but non-MHC risk alleles represent only 3-5% of the genetic burden of RA
Which HLA genes are associated with autoimmune diseases?
What environmental factors are associated with RA?
- Smoking
- Asbestos
- Pollutants
- Diet
- GI dysbiosis
- Peridontal disease
- Infections
What are the autoantibodies associated with RA?
Rheumatoid factor
- RF (rheumatoid factor) are IgM, IgG, IgA and IgE antibodies all with specificity for Fc region of IgG antibody
- RF in RA are characterised by their high affinity for IgG
- Produces in joint by B cells
Anti-citrullinated protein antibodies (ACPA) or anti-cyclic citrullinated peptide antibodies (anti-CCP)
- ACPA recognise modified proteins which all contain the non-standard amino acid citrulline: examples include keratin, filaggrin, fibrin/fibrinogen, histones and type II collagen
- Citrulline created by post-translational modification: peptidyl arginine deiminases (PADI) catalyse deamination of the amino acid arginine to citrulline. These enzymes cause the local citrullination of synovial proteins, such as fibrin.
How is RA diagnosed?
Blood tests-
- Full blood count
- ESR (erythrocyte sedimentation rate)
- CRP (C reactive protein)
- Urea and electrolytes
- Liver function tests
- Serum urate
- Consider Thyroid function, glucose
- Autoantibodies- anti CCP, ANA
Imaging
- X-ray- soft tissue swelling, juxta-articulatory osteopenia and erosions
- Ultrasound- synovitis, tenosynovitis ands erosions
Inflammatory vs non-inflammatory arthritis clinical presentation
What are the signs and symptoms of RA?
Sub-acute onset of:
- Pain and stiffness hands, wrists, feet +/- large joints
- 1 hour morning stiffness
- +/- Joint swelling – eg difficulties with rings
- Undue fatigue
- Difficulties with certain activities – opening jars + bottles, keys
- In some cases, more prominent systemic symptoms – eg weight loss
Specific features in history:
- Skin problems
- Scaly rash; photosensitive rash; rash on face
- Eye problems
- Grittiness; acute red eyes; red eye + blurred vision
- Dry mouth
- Alopecia
- Raynaud’s
- Preceding illnesses (eg viral illness)
- Family history
Examination findings:
- May be normal
- Anaemia
- Lymphadenopathy
- Palmar erythema
- Articulatory tenderness
- Soft tissue swelling
- Diminished grip strength
- Impaired fist formation
- Inability to extend elbows fully
What are the extra-articular features of RA?
Eyes- Dry eyes, episcleritis, scleritis, scleromalacia
Skin- Ulcers
Nervous system- Carpal tunnel syndrome, Peripheral neuropathy, Cervical myelopathy and Vasculitis – mononeuritis multiplex
Blood vessels- Premature atherosclerosis and Vasculitis
Lungs- Pulmonary fibrosis, Pulmonary nodules, Pleurisy, pleural effusions
Heart- Pericarditis, pericardial effusions
Blood- Anaemia of chronic disease, thrombocytosis
What are the risk factors of RA?
Epigenetic factors- Promoter regions on DNA can become hyper- or hypo-methylated. This leads to an increase in the transcription of genes for pro inflammatory (IL6, CD40L) and anti inflammatory (CTLA4) molecules.
Hormonal factors- Female : Male = 2-3:1. Some research has shown that the disease is more likely to be developed when a hormonal change occurs i.e. menopause or after giving birth. This could be due to the immunomodulatory role of oestrogen.
Obesity- Adipose tissue can secrete adipokines which have a proinflammatory effect, potentially causing the activation of an immune response.
Psychiatric conditions (e.g., PTSD, depression)- Dysregulation of the neuroendocrine systems caused by chronic stress can lead to inflammation. Antidepressants given to patients with depression acts as a protective factor
Other immune mediated disease- Conditions such as autoimmune thyroid diseases (Hashimoto’s and Grave’s), Type 1 diabetes, alopecia, vitiligo, IBD and maybe MS. This is thought to be due to a combination of genetic risk factors, host factors and external environmental factors (genes linked to RA have been linked to other autoimmune diseases)
Smoking- RA risk is correlational to pack-years and cessation of smoking is associated with a decreased risk. Smoking increases oxidative stress in the body due to inhalation of free radicals, and the production of ROS in the body Inflammation of the lungs activates immune response and has also been found to trigger anti-CCP antibody production. Therefore, smoking + HLADRB-1 = increased severity
Microbiota and infectious agents- Viruses, bacteria and other pathogens may contribute to RA through immune activation, epitope spreading and molecular mimicry. P. Gingivalis is a major cause of periodontitis and it has also been associated with RA (chronic inflammation of the gums)
Exposure to inhaled agents- Silica, textile dust and inorganic dust (e.g., asbestos, cement).
Low socioeconomic status- is associated with increased RA risk and worse disease outcome. (link to health inequalities – education, food insecurity and career more likely to work in manual labour as well as level of stress due to financial pressure)
Diet- Healthy diet (fruit, veg, less process foods, healthy oils and low sodium) has been linked to decreased risk of RA. Low alcohol consumption has been found as a protective factor
What are the signs and symptoms of RA?
Swan neck: Hyperextension of proximal interphalangeal joint along with the flexion of distal interphalangeal joint
Boutonnieres: Permanent flexion of the proximal interphalangeal joint and overextension of the distal interphalangeal joint
Ulnar deviation/Z-thumb: Hyperextension of the interphalangeal joint and fixed flexion and subluxation of the metacarpophalangeal joint
Rheumatoid nodules: Large necrotising granulomas at site of inflammation
What are the diagnostic tests for RA?
Bloods-
- Erythrocyte sedimentation rate- raised as it assesses inflammation in the body
- C-reactive protein- raised as it is another inflammatory marker
- Rheumatoid factor(RF)- present but not always
- Anti-CCP- present but not always
Gals- asses gait, arms, legs and spine
What is the DAS28?
What is the treatment and management for RA?
- naproxen
- esomeprazole
- prednisolone
- methotrexate
- trimethoprim
- hydroxychloroquine
- adalimumab
What are the complementary and alternative treatment options for RA?
What are the differential diagnoses?
