Rheumatoid Arthritis

1. Genetics
   1. 1st degree relatives of a patient with RA will share diagnosis of RA 2-10 times greater cf the general population ! Uncertainty remains about the extent to which genetics play a role ! allelic variation in the HLA-DRB1 gene, which encodes the MHC II β-chain molecule. ! Non-MHC loci may also contribute E.g. tyrosine phosphate non-receptor 22 (regulates T & B cell function appears to be associated exclusively with anti-CCP positive disease).
2. Environment
   1. Smoking
      1. Most reproducible risk factor, it confers an increased risk of 1.5 – 3.5 greater than non-smokers. ! Risk remains high up to 15 years after smoking cessation. ! Cessation isn’t generally associated with reduced disease activity. ! Smoking is almost exclusively related to Rheumatoid factor (RF) and anti-citrullinated protein antibody (anti-CCP) positive disease
   2. EBV
      1. IgG antibodies against EBV antigens are higher in patients with RA 26/07/17 than the general population. ! EBV DNA has also been found in synovial fluid and synovial cells of RA patients. ! Unable to establish a causal link

1. CD4+ helper T cell activation appear to be involved in co-ordinating the chronic inflammatory response.
   1. Stimulate macrophages and fibroblast-like synoviocytes to release inflammatory mediators and proteases ! Help B cell to produce autoantibodies ! Differentiate into Th1 and Th17 cells which secrete pro- inflammatory mediators ! Directly and indirectly increase osteoclast activity
2. B cells and Autoantigens
   1. Autoantigens – Serum RF and anti-CCP antibodies are present in 75-80% of patients with RA ! RF have not been identified as pathogenic, nor does higher levels always mean higher disease activity. But RF positive patients tend to have a more aggressive disease. ! Anti-CCP antibodies maybe present long before they develop symptoms of RA, and those with positive antibodies have a poorer prognosis ! Other autoantigens identified with possible links to RA include: ! including type II collagen, human cartilage gp-39, aggrecan, calpastatin, BiP (immunoglobulin binding protein), and glucose-6-phosphate isomerase

1. The pathologic hallmarks of RA are synovial inflammation and proliferation, focal bone erosions, and thinning of articular cartilage.
2. Chronic inflammation leads to: ! synovial lining hyperplasia and the formation of pannus ! the pannus contains fibroblast-like synoviocytes and granulation- reactive fibro-vascular tissue that invades the underlying cartilage and bone ! the area under the pannus is heavily infiltrated with inflammatory cells, including T and B lymphocytes, macrophages, mast cells, and mononuclear cells that differentiate into multinucleated osteoclasts ! structural damage to the mineralized cartilage and subchondral bone (osteoclast mediated). ! periarticular osteopenia and thinning of the bony trabeculae ! bone marrow lesions ! generalized osteoporosis
3. The end results of chronic inflammation for joint structure are variable. ! Loss of cartilage may result in a loss of the joint space. ! The formation of chronic granulation or scar tissue can lead to loss of joint motion or bony fusion (called ankylosis). ! Laxity of tendon structures can result in a loss of support to the affected joint, leading to instability or subluxation. ! Tendon contractures also may occur, leading to chronic deformity.

1. Effects of RA on hands:
   1. Ulnar deviation, carpal tunnel syndrome, subcutaneous rheumatoid nodules, flexion contractures (boutonniere deformity - flexion of PIP joint, and hyperextension of DIP joint) and swan neck deformity (hyperextension of PIP joint and flexion of DIP joint)
2. Early diease is usually insidous and can be episodic or acute and may develop over weeks to months - Prodromal symptoms include; fatigue, weakness, low grade fever, loss of appetite, myalgia, joiint stiffness/pain and stiffness and myalgie may precede develop of joint swelling (heat, functional loss)
3. Late disease features include: loss of joint motion, joint weakness and deformity, atrophy of muscle, occurs espically in the hand

1. Although joint involvement in RA is the 1˚ feature in RA, its important recognise that, as a systemi disease, other organ systems are often involved. Rheumatoid nodules - occur in 20% of patients, 1˚ located on the extensor surface of elbow, forearm, hand and fingers

   Annotations:

   • erferg
   1. Vasculitis - invasion of blood vessel walls by inflammatory cells resulting in an obliteration of the vessel, producing infarction of tissue distal to the area of involvement - finger/nail beds, lower limbs ulcers often a consequence, nerves and organs
   2. Pulmonary - pleural effusion, pulmonary fibrosis and nodules
   3. Cardiac: pericarditis, mitral valve disease ( obstruction (stenosis) , leakage (regurgitiation) and bulging backward during valve closure (prolapse)), conduction defects
   4. Skin: palmr erythema, cutaneous vasculitis
   5. Eye complications: Sjogrens syndromes (dry gritty eyes with slight redness but normal vision) and scleritis (sevre pain and occasionally reduces vision
   6. Neurological complications: Entrapment of peripheral nerves - carpal tunnel, ulnar, peripheral neuropathy (assoicated with the disease, compression of nerve roots) and compression of cervical region of the spinal cord
   7. Complication of RA: Feltys syndrome, depression, loss of independent liiving, increased risk of infections, complications of medical and surgical treatment

1. Symptoms duration of longer than 6 weeks, early morning stiffness for longer than 1 hour, arthritis in three or more regions, bilateral compression tenderness of the metatarsophalangeal joints, symmetry of the areas affecte, rheumatoid factor posivity, anti0cyclic citrullinated peptide (anti-CCP) antibody positivty, bony erosions evident on Xrays of the hands or feet (uncommon in early disease) and family hisotry of imflam anthritis

1. Drug treatment

   Annotations:

   • Goals of treatment:  - relief of symptoms - preservation of function - prevention of structural damage and deformity - Prevention or reduction of co-morbidities  - Maintenance of patients normal life style 
   • Simple Analgesia: - paracetamol, dextroprppxyphene and codeine are used for simple pain relief, strong narcotic analgesics should be avoided NSAIDs: - use for symptomatic relief of RA but do not alter the course of disease
   1. Corticosteroids

      Annotations:

      • Intra-articular corticosteroids can help to settle a flare Bolus IV or IM corticosteroids can be used as adjunct to slower acting second line drugs Daily oral corticosteroids may be during the initial treatment of RA if the disease is moderate/severe. Regular dosing is controversial 
      1. Actions of inflam cells include
         1. Decreased egress of neutrophils from bleed vessels and reduced actiavtion of neutrophils, macrophages and mast cells 2˚ to decreased transcription of the genes for cell adhesion factors and cytokines
         2. Decreased overall activation of T-helper (Th) cells, reduced clonal proliferation of T cells, and a 'switch' form the Th1 to the Th2 immune response
         3. Decreased fibroblasts function, less production of collagen and glycosaminoglycans, and, under some circumstances, reduced healing and repair
      2. Actions on the mediators of inflam and immune responses include
         1. decreased production of prostanoids through reduced expression of cyclo-oxygenase-2. decreased generation of many cytokines, including IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF- alpha, cell adhesion factors and granulocyte-macrophage coloby-stimulating factor. These are largelt 2˚ to inhibition of gene transcription
         2. Reduction in the [] of complement components in plasma
2. Physical therapy
3. Complementary therapy

1. DAS28 is a composite outcome measure that asses
   1. How many joints in the hands, wrists, elbows, shoulders, and knees are swollen and/or tender? The erythrocye sedimentation rate (ESR) or C reactive protein (CRP) in the blood to mesausre the degree of inflammation. The patients Visual analgoue score (a simple scale) to assess how they are feelng on that day from 0 (very good_ to 10 (very bad)
   2. The results are combined to produce the DAS28 score, which correlates with the extent of disease activity: <2.6: disease remission, 2.6-3.2: low disease activity, 3.2-5.1: moderate disease activity and >5.1: high disease activity

Annotations:

• Presence of rheumatoid factor Presence of anti-CCP antibodies Raised erythrocyte sedimentation rate (ESR) Raised C reactive protein concentration (CRP) AnaemiaThrombocytosisRaised ferritin concentration as acute phase proteinRaised serum globulin concentrationsRaised serum alkaline phosphatase activityAntinuclear antibodies may be present in some patients    

1. Rheumatoid factors are anti-immunoglobulins and anti-IgG and anti-IgM especially is an immunological hallmark of rheumatoid arthritis. It is found in sera of 75-80% of patients with RA however as a diagnostic toll it lacks specificty: RF can be found in 1-5% of heealthy population, RF can be found in other connective tissue disease such as Sjogren syndrome and systemic lupus erthematosus. The other patients are persistently seronegative despite otherwise typical disease
2. Indicators of acute phase responses are a raised ESR and the presence of a acute phase proteins such as CRP are commonly found in patients with RA - reflects general acute inflammation, may give indication of effectiveness of drug treatment, disease is likely to progress if a rasied ESR (or presence of C reactive protein) persists and progression can still occur if they dont persists
3. Anemia of chronic disease is often present in inflam conditions and is resistant to normalisation w/ iron supplement (differential diagnosis is important. If other causes of anaemia are ruled out this introduces a therapeutic problem - iron deficiency (blood loss caused by NSAIDs), suppression of bone marrow function - caused by sulphasalzine, penicillamin, gold & cytotoxic drugs, folate deficinecy - caused by methotrexate, sulphasalazine and haemolysis (caused by sulphasalazine and dapsone)
4. Thrombocytosis - platelets often counts rise and fall in direct correlation with disease activity (can also be from toxicity of immunosuppressive therapy and associated with felty's syndrome. Leukopenia - is associated with Feltys syndrome (can also be from toxicity of methotrexate, gold, sulfasalazine, penicillamine and immunosuppressive drugs and leukocytosis often a result of corticosteroid treatment
5. LFTs maybe give abnormal results - transaminases and ALP may be moderaltey elevated when the disease is active. Radiography - hands are normal at presentation or may show swelling of the soft tissue, loss of joint space or periarticular osteoporosis and erosions typical of RA develop within 3 years of the start of the disease in over 90% of patients