Select Rheumatological disorders_110817.pptx

Systemic lupus erythromatosus and rheumatoid arthritis are common rheumatological disorders that must be at the finger tips of all clinicians.

1. Select Rheumatological Diseases

2. We hope to look at: Rheumatoid Arthritis - RA Systemic Lupus Erythematosus – SLE Osteoarthritis – OA Gout 2

3. Rheumatoid Arthritis - RA RA affects approximately 0.5–1% of European and North American adults Asian studies report 2.8–3.5 cases per 1000, and the disease is said to be less common in rural Africa Women:Men ratio is 3:1 The peak age of incidence for women is 50–60 years and somewhat surprisingly for men is >70 years RA presenting after the age of 60–65 is often referred to as  late-onset RA  or ‘LORA’. The likelihood that a first-degree relative of a patient will share the diagnosis is 2–10 times the population prevalence of the disease. EULAR, Carbonell et al, 2008 3

4. Risks and pathogenesis Majority of the genetic risk is conveyed by the HLA-DRB1 and PTPN22 loci 4

5. ACR/EULAR CLASSIFICATION CRITERIA for RA Use for Pts with ≥1 joint with synovitis not better explained by another disease Summed score of ≥6 c/w RA

6. Management Disease modifying antirheumatic drugs (DMARDS) are the main stay: Synthetic DMARDS include: 1. Conventional synthetic DMARDs e.g methotraxate , sulfasalazine, leflunomide 2. Targeted synthetic DMARDs modulate a particular target implicated in the generation of inflammation. Key examples include janus kinase (JAK) inhibitors Biological agents e.g. Anti- tumour necrosis factor α therapy (anti-TNF α) , Interleukin 6 receptor inhibitor ( tocilizumab), T cell costimulation blockade ( abatacept), B cell depletion (rituximab) 6

7. Systemic Lupus Erythematosus – SLE SLE is a heterogeneous disease influenced by a variety of genetic and environmental factors. Innate and adaptive immune responses contribute to the autoimmune dysfunction observed in SLE. Autoantibodies form immune complexes that drive target organ inflammation in most individuals with SLE. The global SLE incidence was estimated to be 5.14 (1.4 to 15.13) per 100,000 person-years** In women, the values were 8.82 (2.4 to 25.99) per 100 000 person-years and 0.34 million people annually, while in men, the estimates were 1.53 (0.41 to 4.46) per 100 000 person-years and 0.06 million people annually, respectively** 7 doi :  10.1093/rheumatology/kew427 ** doi :  10.1136/ard-2022-223035

8. 8 Pathogenesis : Loss of adaptive immune tolerance (blue) leads to an increase in autoreactive B cells. Signals from self-antigens, TLR ligands, BAFF/APRIL and T-cell-derived cytokines promote the formation of germinal centres and the production of autoantibodies. Innate immune defects leading to increased availability of self-antigens (pink) include increased NETosis , impaired clearance of apoptotic debris and reduced phagocytosis. Self-antigens form ICs with autoantibodies, enabling FcR γ- mediated uptake and activation of several downstream pathways. Inflammation and tissue damage (green) is caused by mediators released by recruited inflammatory cells and IC-induced complement activation. Abs: antibodies; Ags : antigens; APRIL (CD256): a proliferation-inducing ligand; B: B cell; BAFF (CD257): B-cell-activating factor; BAFF-R: B-cell-activating factor receptor; BCMA: B-cell maturation antigen; BCR: B-cell antigen receptor; FcR γ: Fc receptor- γ; fDC : follicular dendritic cell; HLA class II: human leucocyte antigen class II; mDC : myeloid dendritic cell; M Φ: macrophage; Mo: monocyte; NET: neutrophil extracellular trap; ox- mDNA : oxidized mitochondrial DNA; pDC : plasmacytoid dendritic cell; Stat1: signal transducer and activator of transcription (a transcription factor); T: T cell; TACI (CD267): transmembrane activator, calcium modulator and cyclophilin ligand interactor; T-bet: a T-box transcription factor; Tfh : T follicular helper; TLR7/9: Toll-like receptors 7 and 9. doi :  10.1093/rheumatology/kew427

9. 9 Clinical Domains and Criteria Criteria Weight           Constitutional Fever 2 Hematologic       Leukopenia 3 Thrombocytopenia 4 Autoimmune hemolysis 4 Neuropsychiatric       Delirium 2 Psychosis 3 Seizure 5 Mucocutaneous Non-scarring alopecia 2 Oral ulcers   2 Subacute cutaneous or discoid lupus   4 Acute cutaneous lupus 6 Serosal Pleural or pericardial effusion    5 Acute pericarditis 6 Musculoskeletal Joint involvement   6 Renal Proteinuria >0.5g/24h   4 Renal biopsy class II or V lupus nephritis   8 Renal biopsy class III or IV lupus nephritis 10 EULAR/ACR clinical domains and criteria for systemic lupus erythematosus Antinuclear antibodies (ANA) must be present at a titer of ≥1:80 on HPe-2 cells, or an equivalent positive test is required. The additive criteria follow a positive ANA; the presence of at least one clinical criterion and a total score of 10 is required for classification as SLE. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9662848/table/TAB4/?report=objectonly

10. 10 Immunological Domains and Criteria Criteria Weight Antiphospholipid antibodies     Anti-cardiolipin antibodies OR Anti- β2GPI antibodies OR Lupus anticoagulant 2 Complement proteins     Low C3 OR low C4 3 Low C3 AND low C4 4 SLE specific antibodies       Anti-dsDNA antibody OR Anti-smith antibody 6 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) immunological domains and criteria for systemic lupus erythematosus https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9662848/

11. 11 Antimalarials are still considered to be the cornerstone of treatment for systemic lupus erythematosus (SLE). Glucocorticosteroids are an important component of SLE treatment as they rapidly ablate the autoimmune response in organ-threatening manifestations, but the risk for damage accrual increases considerably at doese of > 5–7.5 mg/day. Belimumab, a fully humanized monoclonal antibody which inhibits B-lymphocyte stimulator, is the only targeted biologic agent licensed for the treatment of SLE to date. Adjuvant treatments and non-pharmacological interventions are fundamental in the context of a holistic approach to the treatment of patients with SLE. Among emerging therapies, anifrolumab , a fully human monoclonal antibody, has shown positive results in a phase III trial, indicating the potential of anti-interferons in the treatment of SLE. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410873/ TREATMENTS FOR SLE

12. 12 Drug Monitoring Hydroxychloroquine Baseline fundal exam of the eye, then annual screening after 5 years treatment 24 Corticosteroids Baseline and annual bone densitometry 3 Annual diabetes check 3 , 25 Periodic ophthalmology review for cataracts and glaucoma Azathioprine TMPT activity before starting treatment Full blood count at 2?"4 weeks for 2?"3 months, then every 3 months Methotrexate Full blood count and liver function test every 2?"4 weeks for 3 months, then every 2?"3 months until 6 months. Monitor every 3 months when patient is stable 7 , 26 Mycophenolate Full blood count at 2?"4 weeks, then every 3 months Cyclophosphamide Full blood count every 2 weeks for a month, then monthly Rituximab Optional: check CD19+ B cells to confirm depletion https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358053/

13. 13 https://image4.slideserve.com/9237918/pathological-changes-in-osteoarthritis-l.jpg

14. Osteoarthritis Investigations X-ray Treatments Weight loss Braces NSAIDS Steroid injections Physiotherapy – nerve stimulation for pain, exercises for muscle strength 14

15. 15 https://s3.amazonaws.com/static.wd7.us/a/aa/Gout_pathogenesis.png

16. 16 https://www.uspharmacist.com/article/pharmacologic-management-of-gout

17. 17 https://www.uspharmacist.com/article/pharmacologic-management-of-gout